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Alphapharm Pty Ltd v H Lundbeck A/S (includes corrigendum dated 27 June 2008) [2008] FCA 559 (24 April 2008)

Last Updated: 12 June 2009

FEDERAL COURT OF AUSTRALIA

Alphapharm Pty Ltd v H Lundbeck A/S [2008] FCA 559


CORRIGENDUM


ALPHAPHARM PTY LTD (ACN 002 359 739) v
H LUNDBECK A/S AND LUNDBECK AUSTRALIA PTY LTD (ACN 070 094 290)
NSD 1120 OF 2005


LUNDBECK AUSTRALIA PTY LTD (ACN 070 094 290) v
SECRETARY OF THE DEPARTMENT OF HEALTH & AGEING OF THE COMMONWEALTH OF AUSTRALIA AND ALPHAPHARM PTY LTD
NSD 1870 OF 2005


ARROW PHARMACEUTICALS PTY LTD (ACN 003 144 170) v
H LUNDBECK A/S
NSD 954 OF 2006


H LUNDBECK A/S v COMMISSIONER OF PATENTS AND
ALPHAPHARM PTY LTD
NSD 1078 OF 2006


LINDGREN J
24 APRIL 2008 (CORRIGENDUM 27 JUNE 2008)
SYDNEY


IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
NSD 1120 OF 2005
BETWEEN:
ALPHAPHARM PTY LTD (ACN 002 359 739)
Applicant/Cross-respondent
AND:
H LUNDBECK A/S
Respondent/First Cross-claimant

LUNDBECK AUSTRALIA PTY LTD (ACN 070 094 290)
Second Cross-claimant

IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
NSD 1870 OF 2005
BETWEEN:
LUNDBECK AUSTRALIA PTY LTD (ACN 070 094 290)
Applicant
AND:
SECRETARY OF THE DEPARTMENT OF HEALTH AND AGEING OF THE COMMONWEALTH OF AUSTRALIA
First Respondent

ALPHAPHARM PTY LTD (ACN 002 359 739)
Second Respondent

IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
NSD 954 OF 2006
BETWEEN:
ARROW PHARMACEUTICALS PTY LTD
(ACN 003 144 170)
Applicant
AND:
H LUNDBECK A/S
Respondent

IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
NSD 1078 OF 2006

ON APPEAL FROM THE COMMISSIONER OF PATENTS
BETWEEN:
H LUNDBECK A/S
Applicant

JUDGE:
LINDGREN J
DATE OF ORDER:
27 JUNE 2008
WHERE MADE:
SYDNEY

CORRIGENDUM


  1. In the first sentence of para 761 of the Reasons for Judgment delete “General Relevance” and insert “Factual Basis”.
I certify that the preceding paragraph is a true copy of the Corrigendum to the Reasons for Judgment of the Honourable Justice Lindgren.

Associate:


Dated: 27 June 2008


FEDERAL COURT OF AUSTRALIA

Alphapharm Pty Ltd v H Lundbeck A/S [2008] FCA 559


PATENTS – validity – patent for (+)-enantiomer of the racemate, citalopram, and for method of obtaining that enantiomer – patentee also held previous patent for the racemate – both the racemate and the enantiomer, drugs for the treatment of depression – (+)-citalopram claimed to be therapeutically more effective than citalopram – challenge to validity of claim for (+)-citalopram – construction of claim – whether for (+)-enantiomer as an independently existing molecule or whether also for (+)-enantiomer when part of racemate – whether claim for (+)-enantiomer anticipated by patent for citalopram – whether (+)-enantiomer as an independent molecule was obvious – Australian test for obviousness – application of that test to product claims for the (+)-enantiomer, and to method claim for the method of obtaining it – lack of utility – product claim for a dosage that, inter alia, was less than and more than a useful dosage range.
Held: (1) upon its proper construction, product claimed was the independently existing enantiomer; (2) the invention of the independently existing enantiomer was not anticipated by the patent for the racemate; (3) the Australian “matter of routine” test for obviousness, when applied to the invention of the product, equated to the question whether those skilled in the art, as a matter of routine, would have had the goal of obtaining separate enantiomers in the expectation that one would be a desirable drug for the treatment of depression; (4) one of the product claims relating to dosage failed test of utility; (5) on the evidence, neither the (+)-enantiomer nor the method for obtaining it was obvious at the priority date.


PATENTS – extension of term – patent for (+)-enantiomer of the racemate, citalopram, and for method of obtaining that enantiomer – patentee also held previous patent for the racemate – both the racemate and the enantiomer, drugs for the treatment of depression – (+)-citalopram claimed to be therapeutically more effective than citalopram – both Cipramil (goods based on racemic citalopram) and Lexapro (goods based on (+)-citalopram) entered in Australian Register of Therapeutic Goods (ARTG) – application for extension of term of patent for (+)-citalopram – Commissioner of Patents initially granted extension sought – subsequently, following hearing before her delegate, decided to reduce term of extension on ground that “first regulatory approval date” was date when goods Cipramil based on racemate had been entered in ARTG – appeal by patentee – opponent pharmaceutical company contending that no extension at all should have been granted because application for extension had been made outside six month period following date of first inclusion in ARTG of goods containing the (+)-enantiomer, namely, Cipramil, of which the active pharmaceutical substance was the racemate – questions of proper construction of Patents Act 1990 (Cth) ss 70, 71, 77 – whether goods based on racemate “contain” individual enantiomer – meaning of “first regulatory approval date” in s 70(5) of Act.
Held: (1) Cipramil contained pharmaceutical substance (+)-citalopram; (2) application for extension of term of patent had not been made within six months of first inclusion in ARTG of Cipramil; (3) in circumstances, Commissioner had lacked power to grant any extension to term of patent; (4) Register of Patents to be rectified by removal of particulars of extension.


PATENTS – infringement – patent for (+)-enantiomer of the racemate, citalopram, and for method of obtaining that enantiomer – generic company applying to Therapeutic Goods Administration (TGA) for registration of generic drug based on (+)-enantiomer of citalopram – whether doctrine of “mechanical equivalents” or “non-essential integers” applicable to method of obtaining pharmaceutical compound – generic pharmaceutical company producing generic drug only for purpose of applying for regulatory approval – s 78(2) of Patents Act 1990 (Cth).
Held: (1) doctrine of mechanical equivalents applied so that certain different steps in method did not prevent generic company’s method from infringing method the subject of patent; (2) no infringement by reason of s 78(2).


PATENTS – Therapeutic Goods Act 1989 (Cth) (TG Act), s 25A – protected information – patentee held earlier patent for racemate (citalopram) and under later patent for one of its enantiomers ((+)-citalopram) – registration in Australian Register of Therapeutic Goods (ARTG) of therapeutic goods (Cipramil) of which racemate was active component – later registration in ARTG of therapeutic goods (Lexapro) of which (+)-citalopram was active component – generic company applying for registration in ARTG of goods of which (+)-citalopram was active component – question whether information that patentee had supplied to Therapeutic Goods Administration (TGA) in connection with its application to register Lexapro could be used by TGA in connection with generic company’s application to register generic drug – s 25A of TG Act had effect that certain information about other therapeutic goods not to be used in evaluation of therapeutic goods for registration in ARTG – whether information supplied by patentee on its application for registration of Lexapro was such “protected information” in respect of generic company’s application to register generic drug – question whether Cipramil was goods “containing” (+)-citalopram for purposes of s 25A(2)(c) of TG Act.
Held: (1) Cipramil contained (+)-citalopram; (2) information given by patentee in relation to registration of Lexapro was therefore not protected information and could be used by TGA in evaluation of generic company’s application to register generic drug.


EVIDENCE – expert opinion evidence – professor of psychiatry citing carrying out of clinical studies and their results for purpose of showing that patented enantiomer had far greater therapeutic effects than those of previously patented racemate – clinical studies carried out after priority date – whether surprisingly favourable results relevant – whether citation of clinical studies and their results admissible – whether order should be made under s 136 of Evidence Act 1995 (Cth) limiting use to be made of psychiatrist’s evidence.
Held: (1) carrying out of clinical studies after priority date of patent and the results of those studies irrelevant to state of common general knowledge as at priority date, and therefore not probative on issue of obviousness; (2) citation of clinical studies and their results not rendered inadmissible for failure to prove them otherwise than by psychiatrist’s hearsay evidence; (3) s 60 of Evidence Act 1995 (Cth) applied to the clinical studies and their results, cited by psychiatrist; (4) no order made under s 136 of that Act.


Patents Act 1990 (Cth) ss 13(3), 18, 40, 70, 71, 77, 78, 119A
Therapeutic Goods Act 1989 (Cth) ss 25A, 26B
Evidence Act 1995 (Cth) ss 59, 60, 136
Patents Regulations 1991 (Cth) reg 10.7
Therapeutic Goods Regulations 1990 (Cth) Sch 9


Acme Bedstead Co Ltd v Newlands Bros Ltd [1937] HCA 63; (1937) 58 CLR 689 cited
Advanced Building Systems Pty Ltd v Ramset Fasteners (Aust) Pty Ltd [1998] HCA 19; (1998) 194 CLR 171 cited
Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59; (2002) 212 CLR 411 applied
Angiotech Pharmaceuticals v Conor [2007] EWCA Civ 5; [2007] RPC 20 cited
Atlantis Corporation Pty Ltd v Schindler (1997) 39 IPR 29 distinguished
Beecham Group Ltd v Bristol Laboratories Ltd (1977) 1B IPR 665 referred to
Boehringer Ingelheim International GmbH v Commissioner of Patents [2001] FCA 647; (2001) 112 FCR 595 discussed
Borowski v Quayle [1966] VR 382 cited
Bristol-Myers Squibb Co v FH Faulding & Co Ltd [2000] FCA 316; (2000) 97 FCR 524 cited
Burroughs Corporation (Perkins’s Application) [1974] RPC 147 cited
Cadbury Schweppes Pty Ltd v Darrell Lee Chocolate Shops Pty Ltd [2006] FCA 363; (2006) 228 ALR 719 cited
CCOM Pty Ltd v Jiejing Pty Ltd [1994] FCA 1168; (1994) 51 FCR 260 cited
Clorox Australia Pty Ltd v International Consolidated Business Pty Ltd (2006) 68 IPR 254 cited
Décor Corporation Pty Ltd v Dart Industries Inc (1988) 13 IPR 385 cited
EI Dupont De Nemours & Co v Imperial Chemicals Industries plc [2002] FCA 230; (2002) 54 IPR 304 cited
F Hoffman-La Roche & Co AG v Commissioner of Patents ([1971] HCA 3; 1971) 123 CLR 529 cited
F Hoffmann-La Roche AG v Chiron Corporation (2000) 47 IPR 516 cited
Flexible Steel Lacing Co v Beltreco Ltd [2000] FCA 890; (2000) 49 IPR 331 cited
Flour Oxidising Co Ltd v Carr & Co Ltd (1908) 25 RPC 428 cited
General Tire & Rubber Co v Firestone Tyre & Rubber Co Limited [1972] RPC 457 cited
Generics (UK) Ltd v H Lundbeck A/S [2007] EWHC 1040; [2007] RPC 32 referred to
Glaxo Group Ltd’s Patent [2004] EWHC 477; [2004] RPC 43 cited
H Lundbeck A/S v Generics (UK) Ltd [2008] EWCA 311 referred to
Harrington-Smith v State of Western Australia (No 2) [2003] FCA 893; (2003) 130 FCR 424 referred to
HG v The Queen [1999] HCA 2; (1999) 197 CLR 414 cited
Hill v Evans (1862) 1A IPR 1 cited
Imperial Chemical Industries Pty Ltd v Commissioner of Patents [2004] FCA 1658; (2005) 213 ALR 399 cited
In re Adamson (1960) 275 F 2d 952 not followed
In re O’Farrell [1988] USCAFED 411; (1988) 853 F 2d 894 at 903) cited
Jango v Northern Territory (No 4) (2004) 214 ALR 608 cited
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58; (2004) 217 CLR 274 cited
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) [2007] HCA 21; (2007) 235 ALR 202 referred to
Lubrizol Corporation Inc v Imperial Chemical Industries plc [2000] FCA 1464; (2000) 50 IPR 526 cited
Makita (Australia) Pty Ltd v Sprowles (2001) 52 NSWLR 705 referred to
Merck & Co Inc v Arrow Pharmaceuticals Ltd [2003] FCA 1344; (2003) 59 IPR 226 discussed


Merck Frosst Canada Inc v Canada (Minister of National Health and Welfare) (2000) 8 CPR (4th) 48 referred to
Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19; (1977) 137 CLR 228 cited
Minnesota Mining and Manufacturing Co v Beiersdorf (Australia) Ltd [1980] HCA 9; (1980) 144 CLR 253 applied
Minnesota Mining and Manufacturing Co v Tyco Electronics Pty Ltd [2002] FCAFC 315; (2002) 56 IPR 248 cited
National Research Development Corporation v Commissioner of Patents [1959] HCA 67; (1959) 102 CLR 252 cited
Neolab Ltd and others v H Lundbeck AS 3 Ni 9/05 (EU) cited
Neowarra v Western Australia (No 1) [2003] FCA 1399; (2003) 134 FCR 208 cited
Nesbit Evans Group Australia Pty Ltd v Impro Ltd (1997) 39 IPR 56 cited
Nicaro Holdings Pty Ltd v Marlin Engineering Co (1990) 91 ALR 513 cited
NutraSweet Australia Pty Ltd v Ajinomoto Co Inc [2005] FCA 1524; (2005) 67 IPR 381 cited
Olin Corporation v Super Cartridge Co Pty Ltd [1977] HCA 23; (1977) 180 CLR 236 cited
Olin Mathieson Chemical Corporation v Biorex Laboratories Limited [1970] RPC 157 cited
Ortho-McNeil Pharmaceutical Inc v Mylan Laboratories Inc 348 F Supp 2d 713 approved
Pfizer Canada Inc v Apotex Inc (1998) 78 CPR (3d) 3 referred to
Pfizer Overseas Pharmaceuticals v Ely Lilly & Co [2005] FCAFC 224; (2005) 225 ALR 416 cited
Pharmacia Corporation v Merck & Co Inc [2002] RPC 775 cited
Pharmacia Italia SpA v Mayne Pharma Pty Ltd (2006) 69 IPR 1 discussed
PhotoCure ASA v Queen’s University at Kingston [2005] FCA 344; (2005) 216 ALR 41 cited
Prejay Holdings Ltd v Commissioner of Patents [2003] FCAFC 77; (2003) 57 IPR 424 discussed
Ranbaxy Australia Pty Ltd v Warner-Lambert Company LLC (No 2) [2006] FCA 1787; (2006) 71 IPR 46 referred to
Re Application of Eli Lilly & Co [1982] 1 NSWLR 526 referred to
Rehm Pty Ltd v Websters Security Systems (International) Pty Ltd (1988) 11 IPR 289 cited
Richardson-Vicks Inc’s Patent [1995] RPC 568 cited
Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980; (2000) 177 ALR 231 cited
Saccharin Corporation Ltd v Anglo-Continental Chemical Works Ltd (1900) 17 RPC 307 referred to
Sachtler GmbH & Co KG v RE Miller Pty Ltd [2005] FCA 788; (2005) 65 IPR 605 cited
Seyfang v G D Searle & Co [1973] QB 148 cited
Société Des Usines Chimiques Rhône-Poulenc v Commissioner of Patents [1958] HCA 27; (1958) 100 CLR 5 cited
Sydneywide Distributors Pty Ltd v Red Bull Australia Pty Ltd [2002] FCAFC 157; (2002) 55 IPR 354 cited
Wellcome Foundation Ltd v V.R. Laboratories (Aust) Pty Ltd [1981] HCA 12; (1981) 148 CLR 262 cited
Wm Wrigley Jr Company v Cadbury Schweppes Pty Ltd (2006) 66 IPR 298 followed


Blanco White TA, Patents for Inventions and the Protection of Industrial Design (5th ed, Stephens, London, 1983)
Bodkin C, Patent Law in Australia (Thomson Lawbook Co, 2008)
Chadbourn JH (ed), Wigmore on Evidence (Little, Brown & Co, Boston, 1979)


ALPHAPHARM PTY LTD (ACN 002 359 739) v
H LUNDBECK A/S AND LUNDBECK AUSTRALIA PTY LTD (ACN 070 094 290)
NSD 1120 OF 2005


LUNDBECK AUSTRALIA PTY LTD (ACN 070 094 290) v
SECRETARY OF THE DEPARTMENT OF HEALTH & AGEING OF THE COMMONWEALTH OF AUSTRALIA AND ALPHAPHARM PTY LTD
NSD 1870 OF 2005


ARROW PHARMACEUTICALS PTY LTD (ACN 003 144 170) v
H LUNDBECK A/S
NSD 954 OF 2006


H LUNDBECK A/S v COMMISSIONER OF PATENTS AND
ALPHAPHARM PTY LTD
NSD 1078 OF 2006


LINDGREN J
24 APRIL 2008
SYDNEY

IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
NSD 1120 OF 2005

BETWEEN:
ALPHAPHARM PTY LTD (ACN 002 359 739)
Applicant/Cross-respondent
AND:
H LUNDBECK A/S
Respondent/First Cross-claimant

LUNDBECK AUSTRALIA PTY LTD (ACN 070 094 290)
Second Cross-claimant
JUDGE:
LINDGREN J
DATE OF ORDER:
24 APRIL 2008
WHERE MADE:
SYDNEY

THE COURT ORDERS THAT:


  1. The proceeding be stood over to Friday 9 May 2008 at 9:30am for the making of orders, including orders as to costs.
  2. The parties attempt to agree on the orders to be made.
  3. If the parties agree on the orders to be made, they supply a copy of those orders to the Associate to Lindgren J by Monday 5 May 2008.
  4. If the parties fail to agree on the orders to be made, they serve (with a copy to the Associate to Lindgren J), by Monday 5 May 2008, the forms of the orders they respectively propose and submissions in support.

Note: Settlement and entry of orders is dealt with in Order 36 of the Federal Court Rules.

IN THE FEDERAL COURT OF AUSTRALIA
NSD 1870 OF 2005
NEW SOUTH WALES DISTRICT REGISTRY

BETWEEN:
LUNDBECK AUSTRALIA PTY LTD (ACN 070 094 290)
Applicant
AND:
SECRETARY OF THE DEPARTMENT OF HEALTH AND AGEING OF THE COMMONWEALTH OF AUSTRALIA
First Respondent

ALPHAPHARM PTY LTD (ACN 002 359 739)
Second Respondent
JUDGE:
LINDGREN J
DATE OF ORDER:
24 APRIL 2008
WHERE MADE:
SYDNEY

THE COURT ORDERS THAT:


  1. The proceeding be stood over to Friday 9 May 2008 at 9:30am for the making of orders, including orders as to costs.
  2. The parties attempt to agree on the orders to be made.
  3. If the parties agree on the orders to be made, they supply a copy of those orders to the Associate to Lindgren J by Monday 5 May 2008.
  4. If the parties fail to agree on the orders to be made, they serve (with a copy to the Associate to Lindgren J), by Monday 5 May 2008, the forms of the orders they respectively propose and submissions in support.

Note: Settlement and entry of orders is dealt with in Order 36 of the Federal Court Rules.


IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
NSD 954 OF 2006

BETWEEN:
ARROW PHARMACEUTICALS PTY LTD
(ACN 003 144 170)
Applicant
AND:
H LUNDBECK A/S
Respondent
JUDGE:
LINDGREN J
DATE OF ORDER:
24 APRIL 2008
WHERE MADE:
SYDNEY

THE COURT ORDERS THAT:


  1. The proceeding be stood over to Friday 9 May 2008 at 9:30am for the making of orders, including orders as to costs.
  2. The parties attempt to agree on the orders to be made.
  3. If the parties agree on the orders to be made, they supply a copy of those orders to the Associate to Lindgren J by Monday 5 May 2008.
  4. If the parties fail to agree on the orders to be made, they serve (with a copy to the Associate to Lindgren J), by Monday 5 May 2008, the forms of the orders they respectively propose and submissions in support.

Note: Settlement and entry of orders is dealt with in Order 36 of the Federal Court Rules.


IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
NSD 1078 OF 2006
BETWEEN:
H LUNDBECK A/S
Applicant
AND:
COMMISSIONER OF PATENTS
First Respondent

ALPHAPHARM PTY LTD (ACN 002 359 739)
Second Respondent
DATE OF ORDER:
24 APRIL 2008
WHERE MADE:
SYDNEY

THE COURT ORDERS THAT:


  1. The proceeding be stood over to Friday 9 May 2008 at 9:30am for the making of orders, including orders as to costs.
  2. The parties attempt to agree on the orders to be made.
  3. If the parties agree on the orders to be made, they supply a copy of those orders to the Associate to Lindgren J by Monday 5 May 2008.
  4. If the parties fail to agree on the orders to be made, they serve (with a copy to the Associate to Lindgren J), by Monday 5 May 2008, the forms of the orders they respectively propose and submissions in support.

Note: Settlement and entry of orders is dealt with in Order 36 of the Federal Court Rules.


IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
NSD 1120 OF 2005
BETWEEN:
ALPHAPHARM PTY LTD (ACN 002 359 739)
Applicant/Cross-respondent
AND:
H LUNDBECK A/S
Respondent/First Cross-claimant

LUNDBECK AUSTRALIA PTY LTD (ACN 070 094 290)
Second Cross-claimant

IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
NSD 1870 OF 2005
BETWEEN:
LUNDBECK AUSTRALIA PTY LTD (ACN 070 094 290)
Applicant
AND:
SECRETARY OF THE DEPARTMENT OF HEALTH AND AGEING OF THE COMMONWEALTH OF AUSTRALIA
First Respondent

ALPHAPHARM PTY LTD (ACN 002 359 739)
Second Respondent

IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
NSD 954 OF 2006
BETWEEN:
ARROW PHARMACEUTICALS PTY LTD
(ACN 003 144 170)
Applicant
AND:
H LUNDBECK A/S
Respondent

IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
NSD 1078 OF 2006

ON APPEAL FROM THE COMMISSIONER OF PATENTS
BETWEEN:
H LUNDBECK A/S
Applicant
AND:
COMMISSIONER OF PATENTS
First Respondent

ALPHAPHARM PTY LTD (ACN 002 359 739)
Second Respondent

JUDGE:
LINDGREN J
DATE:
24 APRIL 2008
PLACE:
SYDNEY

REASONS FOR JUDGMENT


TABLE OF CONTENTS

Section
Para No.
A
INTRODUCTION AND BACKGROUND
[1] – [78]
B
THE PATENT
[79] – [113]
C
CONSTRUCTION OF THE PATENT
[114] – [153]
D
NOVELTY
[154] – [174]
E
OBVIOUSNESS
[175] – [426]
F
MANNER OF MANUFACTURE – s 18(1)(a) OF THE ACT
[427] – [441]
G
LACK OF DEFINITION – s 40(2)(b) OF THE ACT
[442] – [447]
H
LACK OF FAIR BASING – s 40(3) OF THE ACT
[448] – [460]
I
LACK OF CLARITY – s 40(3) OF THE ACT
[461] – [465]
J
INUTILITY – s 18(1)(c) OF THE ACT
[466] – [474]
K
THE LUNDBECK APPEAL (EXTENSION OF TERM)
PROCEEDING – ALPHAPHARM’S AND ARROW’S CLAIMS
FOR RECTIFICATION UNDER s 192 OF THE ACT
[475] – [544]
L
THE TGA (PROTECTED INFORMATION) PROCEEDING
[545] – [633]
M
INFRINGEMENT BY ALPHAPHARM
[634] – [697]
N
ADMISSIBILITY OF CERTAIN EVIDENCE
[698] – [783]
O
CONCLUSION
[784] – [785]

SECTION A – INTRODUCTION AND BACKGROUND

General

  1. These four proceedings, which were heard together, relate to Australian patent No 623144 (the Patent or the Australian Escitalopram Patent) held by H Lundbeck A/S (Lundbeck), a Danish pharmaceutical company.
  2. Lundbeck applied for the Patent on 13 June 1989. The application was a Convention application and was said in the application to be based on application No 8814057 for a patent made in the United Kingdom on 14 June 1988 (the UK Escitalopram Patent – see [79] below). The title of the invention in the Patent is: “(+)-Enantiomer of citalopram and process for the preparation thereof”.
  3. Citalopram is a molecule patented by Lundbeck which is used for the treatment of depression. Citalopram is a chiral molecule, a racemic mixture (or racemate) comprising in equal measure two enantiomers. Enantiomers are non-superimposable mirror images of each other. They are designated “(+)” or “(–)” based on a particular physical property referred to below, and “R” or “S” based on their three-dimensional structure. The correlation between the (+) or (–) and the R or S designations can only be determined, however, through experimentation.
  4. In the case of citalopram, experimentation subsequent to the priority date has shown that the (+)-enantiomer is in fact the S-enantiomer. It is commonly referred to as “S-citalopram”, and has the International Nonproprietary Name “escitalopram”.
  5. The Patent discloses processes for obtaining escitalopram, and data showing that (+)-citalopram is therapeutically more active than citalopram itself, and more than 100 fold more active than (-)-citalopram.
  6. The 20 year term of the Patent was due to expire on 13 June 2009. The term has, however, been extended as discussed at [28] ff below.
  7. Citalopram is an invention claimed in Australian patent No 509,445 (the Australian Citalopram Patent) dated 5 January 1977, the term of which was sixteen years commencing on that date. The Australian Citalopram Patent was, in turn, said in the application to be based on the application No 1486/76 for a patent filed in Great Britain on 14 January 1976 (the UK Citalopram Patent). The title of the invention in the Australian Citalopram Patent is “phthalanes”, a class of compounds that includes citalopram.
  8. In various ways, the proceedings before the Court raise issues concerning the relationship between citalopram and escitalopram. Broadly, the issues can be separated into those that relate to patentability (raised in the proceedings brought by Alphapharm Pty Ltd (Alphapharm) and Arrow Pharmaceuticals Pty Ltd (Arrow) for revocation of the Patent), infringement (a cross-claim in Alphapharm’s revocation proceeding) and regulatory aspects (all four proceedings).

Proceeding NSD 1120 of 2005 (the Revocation Proceeding)

Alphapharm’s claim for revocation

  1. The Patent comprises six claims. In proceeding NSD 1120 of 2005 (“the Revocation Proceeding”), Alphapharm seeks a declaration that all six claims are invalid, and an order pursuant to s 138(3) of the Patents Act 1990 (Cth) (the Act) revoking them all, or, in the alternative, an order pursuant to s 192 of the Act that the Register be rectified to remove an extension of the term of the Patent from the Register of Patents (the Register).
  2. The six claims are as follows:
1. (+)-1-(3-dimethylaminopropyl)-1-(4’-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile and non-toxic acid addition salts thereof.

2. The pamoic acid salt of (+)-1-(3-dimethylaminopropyl)-1-(4’-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile.

3. A pharmaceutical composition in unit dosage form comprising as an active ingredient, a compound as defined in claim 1, together with a pharmaceutically accepta[ble] carrier or excipient.

4. A pharmaceutical composition in unit dosage form comprising, as an active ingredient, the compound of claim 2, together with a pharmaceutically acceptable carrier or excipient.

5. A pharmaceutical composition in unit dosage form, according to claim 3 or 4, wherein the active ingredient is present in an amount from 0.1 to 100 milligram per unit dose, together with a pharmaceutically acceptable carrier or excipient.

6. A method for the preparation of the compound of claim 1, which comprises:
(a) reacting a compound of the formula

2008_55900.jpg

with an enantiomerically pure acid derivative as an acid chloride, anhydride or labile ester, subsequently separating the resolved intermediate enantiomer for (+)-citalopram having the formula
2008_55901.jpg
wherein R is a labile ester group; by HPLC or fractional crystallization, and then treating said intermediate enantiomer with strong base: or
(b) reacting a compound of formula II with the enantiomer of an optically active acid affording the pure enantiomer salt of the compound of formula II for (+)-citalopram, and subsequently performing ringclosure via a labile ester by reacting the pure enantiomer of formula II as a base with an activated acid with simultaneous addition of a base and, if desired, transferring the (+)-citalopram obtained to a pharmaceutically acceptable salt thereof.

Claims 1–5 are product claims. Claim 6 is a method claim.

  1. According to Alphapharm’s further amended particulars of invalidity filed in Court on the hearing:
  2. At the hearing, senior counsel for Alphapharm indicated that Alphapharm was content to proceed on the basis of a priority date of 14 June 1988. I proceed on the basis of that priority date of 14 June 1988.
  3. I will discuss the case that Alphapharm seeks to make in respect of these grounds of invalidity in due course.

Alphapharm’s alternative claim for rectification of the Register

  1. Alphapharm’s alternative claim for rectification of the Register concerns the interaction between the Act and the Therapeutic Goods Act 1989 (Cth) (the TG Act). Under the TG Act, a pharmaceutical substance may not be marketed in Australia unless it is, or is contained within, a therapeutic good that is registered on the Australian Register of Therapeutic Goods (ARTG).
  2. Alphapharm’s application for rectification of the Register raises the same issues as are raised in the Lundbeck Appeal (Extension of Term) Proceeding (discussed at [45] ff below).
  3. An appropriate starting point for an understanding of Alphapharm’s alternative claim for rectification of the Register is the Act’s provisions relating to the extension of the terms of patents in Pt 3 of Ch 6 of the Act.
  4. Section 67 of the Act provides that the term of a standard patent is 20 years from the date of the patent. Section 65 provides, relevantly, that the date of a patent is the date of filing of the complete specification, being 13 June 1989 in the present case.
  5. Part 3 (ss 70–79A) of the Act is headed “EXTENSION OF TERM OF STANDARD PATENTS RELATING TO PHARMACEUTICAL SUBSTANCES”. Section 70 of the Act provides, relevantly, as follows:
(1) The patentee of a standard patent may apply to the Commissioner for an extension of the term of the patent if the requirements set out in subsections (2), (3) and (4) are satisfied.
(2) Either or both of the following conditions must be satisfied:
(a) one or more pharmaceutical substances per se must in substance be disclosed in the complete specification of the patent and in substance fall within the scope of the claim or claims of that specification;
(b) ...
(3) Both of the following conditions must be satisfied in relation to at least one of those pharmaceutical substances:
(a) goods containing, or consisting of, the substance must be included in the Australian Register of Therapeutic Goods;
(b) the period beginning on the date of the patent and ending on the first regulatory approval date for the substance must be at least 5 years.
(4) ...
(5) For the purposes of this section, the first regulatory approval date, in relation to a pharmaceutical substance, is:
(a) if no pre-TGA marketing approval was given in relation to the substance [none was given in the present case] — the date of commencement of the first inclusion in the Australian Register of Therapeutic Goods of goods that contain, or consist of, the substance; or
(b) ...
(6) ...

  1. Section 71(2) of the Act provides a time limit for applications for an extension of the term of a standard patent. It provides:
An application for an extension of the term of a standard patent must be made during the term of the patent and within 6 months after the latest of the following dates:
(a) the date the patent was granted;
(b) the date of commencement of the first inclusion in the Australian Register of Therapeutic Goods of goods that contain, or consist of, any of the pharmaceutical substances referred to in subsection 70(3);
(c) the date of commencement of this section.

  1. Sections 74–76 of the Act provide:
74(1) If a patentee of a standard patent makes an application for an extension of the term of the patent, the Commissioner must accept the application if the Commissioner is satisfied that the requirements of sections 70 and 71 are satisfied in relation to the application.
(2) If the Commissioner accepts the application, the Commissioner must:
(a) notify the applicant in writing of the acceptance; and
(b) publish a notice of the acceptance in the Official Journal.
(3) The Commissioner must refuse to accept the application if the Commissioner is not satisfied that the requirements of sections 70 and 71 are satisfied in relation to the application.
(4) If the Commissioner refuses to accept the application, the Commissioner must:
(a) notify the applicant in writing of the reasons for the refusal; and
(b) publish a notice of the refusal in the Official Journal.

75(1) The Minister or any other person may, in accordance with the regulations, oppose the grant of an extension of the term of a standard patent on the ground that one or more of the requirements of sections 70 and 71 are not satisfied in relation to the application for the extension. The Minister or other person may not oppose the grant of the extension on any other ground.
(2) If the grant of an extension of the term of a standard patent is opposed, the Commissioner must decide the case in accordance with the regulations.
(3) The Commissioner must give the applicant and the opponent a reasonable opportunity to be heard before deciding a case.
(4) The applicant, and any opponent, may appeal to the Federal Court against a decision of the Commissioner under this section.

76(1) The Commissioner must grant an extension of the term of a standard patent if:
(a) there is no opposition to the grant; or
(b) in spite of opposition, the Commissioner’s decision, or the decision on appeal, is that the extension should be granted.
(2) If the Commissioner grants an extension, the Commissioner must notify the applicant in writing of the grant and publish a notice of the grant in the Official Journal.
  1. Finally, s 77 provides for the calculation of the term of an extension as follows:
(1) If the Commissioner grants an extension of the term of a standard patent, the term of the extension is equal to:
(a) the period beginning on the date of the patent and ending on the earliest first regulatory approval date (as defined by section 70) in relation to any of the pharmaceutical substances referred to in subsection 70(2);
reduced (but not below zero) by:
(b) 5 years.
(2) However, the term of the extension cannot be longer than 5 years.

  1. Underlying these provisions are certain assumptions. One is that it may be unreasonable to expect a patentee to derive a sufficient return from a pharmaceutical patent within 20 years because of the necessity, under the TG Act, of first having the relevant goods listed on the ARTG, and of the time that it may take to obtain that listing. Another assumption, however, is that the patentee should not be permitted to “sit on its hands” once the patent has been issued and once the relevant goods have been listed on the ARTG.
  2. Two timing aspects of the provisions are noteworthy. Section 71(2) relevantly requires an application for an extension to be made within six months after the date of the “first inclusion” in the ARTG of “goods that contain, or consist of, any of the pharmaceutical substances referred to in subsection 70(3)”. This provision reflects a view that, ordinarily, ARTG registration should mark the beginning of exploitation. If there is some difficulty in the patentee’s exploiting its patent promptly following ARTG registration, it is expected to bring this to light and to apply for an extension without delay.
  3. The second timing aspect is found in ss 70(3)(b) and 77. These provisions reflect a policy that extensions are intended for circumstances in which the patentee has not been in a position to exploit the invention adequately. Thus, if the period beginning on the date of the patent and ending on the first regulatory approval date does not exceed five years, the period of the extension is zero, because, after all, the patentee will still have had the benefit of at least 15 years’ exploitation of the patent. On the other hand, if the first regulatory approval date occurs say 15 years into the term of the patent, the period remaining available for exploitation of the patent is only some five years, and the period of the extension for which s 77 provides would be some ten years if s 77(1) stood alone. However, subs (2) reduces this period to five years because it provides for a maximum extension of five years in all cases.
  4. Since 3 January 1998, Lundbeck Australia Pty Ltd (Lundbeck Australia), a subsidiary of Lundbeck, has marketed an anti-depressant medicine in Australia under the trade mark “CIPRAMIL” (Cipramil). Cipramil was included in the ARTG on 9 December 1997, as citalopram hydrobromide, an acid addition salt of citalopram.
  5. Since 1 October 2003, Lundbeck Australia has marketed an anti-depressant medicine in Australia under the trade mark “LEXAPRO” (Lexapro). Lexapro was included in the ARTG on 16 September 2003 as escitalopram oxalate. It will be recalled that the (+)-enantiomer of citalopram, which experimentation shows is S-citalopram or escitalopram, is the subject of the Patent.
  6. I turn now to the extension of the term of the Patent.
  7. Lundbeck applied for the extension on 22 December 2003. The Commissioner of Patents (Commissioner) granted the extension on 27 May 2004. The extension granted was from and including 14 June 2009 to 13 June 2014. Particulars of the extension granted were entered on the Register.
  8. The date of Lundbeck’s filing of its application for the extension, 22 December 2003, was well within six months of the inclusion of Lexapro in the ARTG on 16 September 2003. However, Alphapharm’s contention is that the relevant first inclusion in the ARTG was the inclusion of Cipramil in the ARTG on 9 December 1997. If Alphapharm is correct, Lundbeck had only until 9 June 1998 to apply for an extension and the application it made on 22 December 2003 was well out of time, and it was not open to the Commissioner to grant an extension. (I note that Alphapharm’s amended statement of claim uses the date 20 November 1997. However, the trial seemed to have proceeded on the basis that the 9 December 1997 date is correct.) The question raised is whether, for the purpose of the statutory provisions mentioned, the pharmaceutical substance, the (+)-enantiomer of citalopram, was “contained in” the pharmaceutical good, Cipramil. This question is related to other issues in the case, such as the issue of novelty (was the (+)-enantiomer the subject of the Patent not novel by reason of the earlier Australian Citalopram Patent?) and the issues in the TGA (Protected Information) Proceeding discussed at [36] ff below.
  9. Alphapharm pleads in para 7 of its amended statement of claim that Cipramil “contains” a substance which is a mixture of the (+)-enantiomer of citalopram and the (–)-enantiomer of citalopram. In its further amended defence, Lundbeck replies that S-citalopram and R-citalopram are the appropriate descriptors of (+)-citalopram and (-)-citalopram when in a racemic mixture, but otherwise it denies the allegations in the paragraph. Thus, Lundbeck denies that Cipramil “contains” (+)-citalopram.
  10. The period from the date of the Patent (13 June 1989) to 9 December 1997, when Cipramil was included in the ARTG, is 8 years, 5 months and 26 days. The period from the date of the Patent (13 June 1989) to 16 September 2003, when Lexapro was included in the ARTG, is 14 years, 3 months and 3 days. Accordingly, whichever of the competing contentions as to the “first regulatory approval date” is correct, Lundbeck’s application for the extension of term satisfied s 70(3)(b) of the Act, because each of the periods was a period of “at least five years”.
  11. If the correct first regulatory approval date is 9 December 1997, s 77(1) makes the term of the extension 8 years, 5 months and 26 days minus five years, which is 3 years, 5 months and 26 days. This period, added on to the original 20 year term of the Patent expiring on 13 June 2009, would extend the term of the Patent to 9 December 2012. The Commissioner contends that the Register should reflect this period if Alphapharm’s contention as to the first regulatory approval date is correct (see the Lundbeck Appeal (Extension of Term) Proceeding discussed at [45] ff below).
  12. If, on the other hand, the correct first regulatory approval date is 16 September 2003, s 77(1) would make the term of the extension 14 years, 3 months and 3 days minus 5 years, which is 9 years, 3 months and 3 days. But s 77(2) provides that the term of an extension cannot be longer than five years, and so the term of the extension would be reduced to five years. This extension of five years, added on to the 20 year term of the Patent expiring on 13 June 2009, would extend that term to 13 June 2014. This was the extension, particulars of which the Commissioner entered in the Register, that Lundbeck supports (again see the Lundbeck Appeal (Extension of Term) Proceeding discussed at [45] ff below).

Lundbeck’s cross-claim against Alphapharm for infringement

  1. In the Revocation Proceeding, Lundbeck and the exclusive licensee of the Patent in Australia, Lundbeck Australia (together, the Lundbecks) cross-claim against Alphapharm for infringement of the Patent. A claim was made that certain particulars of the alleged infringement were confidential, but any difficulty on the hearing in this respect was overcome by the co-operation and common sense of the parties (which was a characteristic of the hearing throughout). The alleged infringement is of product claims 1, 3, and 5 and of method claim 6(b). The Lundbecks allege that Alphapharm has used, whether for the purpose of obtaining regulatory approval to market a pharmaceutical substance in Australia or in other countries or otherwise, manufactured, imported, sold or otherwise disposed of, or offered to import, sell (whether in Australia or elsewhere) or otherwise dispose of, or kept for the purpose of sale, use or other disposition:

(i) (+)-citalopram or a salt thereof as claimed in claim 1 of the Patent; or
(ii) a pharmaceutical composition as claimed in claim 3 or claim 5 of the Patent;

or has done any of those acts in respect of a product resulting from the use of the method claimed in claim 6(b) of the Patent, or authorised, procured or induced a person to do any of the acts mentioned above.

  1. In particular, the Lundbecks rely on Alphapharm’s threat to manufacture and sell goods containing (+)-citalopram in Australia if Alphapharm obtains the necessary regulatory approvals and listings. The Lundbecks also rely on steps already taken by Alphapharm in connection with its application to the Therapeutic Goods Administration (TGA) to that end.

Proceeding NSD 1870 of 2005 (the TGA (Protected Information) Proceeding)

  1. In proceeding NSD 1870 of 2005 (the TGA (Protected Information) Proceeding), Lundbeck Australia seeks a declaration that the information it provided to the Secretary of the Department of Health and Ageing of the Commonwealth of Australia (the Secretary) in respect of its applications for the registration of various therapeutic goods on the ARTG containing the active substance escitalopram oxalate, is “protected information” within the meaning of s 25A(2) of TG Act. Section 25A provides:
(1) When evaluating therapeutic goods for registration, the Secretary must not use information about other therapeutic goods that is protected information.

(2) Information is protected information if:
(a) the information was given to the Secretary in relation to an application to register therapeutic goods (the new goods):
(i) not being therapeutic devices; and
(ii) consisting of, or containing, an active component; and
(b) the information is about the active component and is not available to the public; and
(c) when the application to register the new goods was lodged:
(i) no other therapeutic goods consisting of, or containing, that active component were included in the Register; and
(ii) no such therapeutic goods had been included in the Register at any time before then; and
(d) the new goods became registered on or after the commencement of this subsection; and
(e) 5 years have not passed since the day the new goods became registered; and
(f) the person in relation to whom the new goods are registered has not given the Secretary permission in writing for the Secretary to use the information.

(3) For the purposes of subsection (2), an active component, in relation to therapeutic goods, is a substance that is, or one of the substances that together are, primarily responsible for the biological or other effect identifying the goods as therapeutic goods.

(4) The use of protected information contrary to subsection (1) does not render the Commonwealth, the Secretary or a delegate of the Secretary liable to a person in respect of loss, damage or injury of any kind suffered by the person as a result of, or arising out of, the use of that information.

  1. In its statement of claim, Lundbeck Australia “particularises” the information it alleges it gave to the Secretary in relation to the registration of Lexapro, which it contends is “protected information” within s 25A of the TG Act (the Information), as follows:
The Information included information in each of the following categories:
(a) Chemical, Pharmaceutical and biological information;
(b) Pharmaco-toxicological information; and
(c) Clinical information.

  1. Lundbeck Australia seeks, inter alia, prohibition or an injunction prohibiting the Secretary, an officer of the Commonwealth (see s 39B(1) of the Judiciary Act 1903 (Cth)), from using the Information or permitting it to be used when evaluating any application by a person other than Lundbeck Australia, notably Alphapharm, for the registration of therapeutic goods pursuant to s 25(1) of the TG Act, for so long as the Information remains protected information within the meaning of s 25A(2).
  2. In pleading that the Secretary threatens and intends to use the Information in evaluating other therapeutic goods for inclusion in the ARTG, Lundbeck Australia is referring to the fact that in the Revocation Proceeding, Alphapharm alleges that if marketing approval is granted, it wishes to manufacture and sell in Australia goods containing (+)-citalopram, and that goods cannot be marketed in Australia unless they are first registered on the ARTG. Lundbeck Australia complains that it will suffer loss and damage if the Information is not treated by the Secretary as protected, and is used by the Secretary in the evaluation of the therapeutic goods of Alphapharm for registration on the ARTG. In support, it also refers to the fact that by s 25A(4) of the TG Act, Lundbeck Australia is precluded from recovering any of that loss or damage from the Secretary.
  3. In the course of the proceeding, I ordered that Alphapharm be added as second respondent. The Secretary and Alphapharm have filed defences. In substance, they put in issue Lundbeck Australia’s allegation that the Information constitutes “protected information” within s 25A(2). The defences are not identical. One defence raised by both the Secretary and Alphapharm is that the Information was not protected information as defined in s 25A(2) of the TG Act because para (c) of that subsection was not satisfied because, when the application to register Lexapro was lodged, other therapeutic goods containing the same active component that the Information was about (escitalopram), were already included in the ARTG. Of course, the other therapeutic goods to which the Secretary and Alphapharm are referring are Cipramil (citalopram hydrobromide), an acid addition salt of the racemate citalopram.

Proceeding NSD 954 of 2006 (the Arrow Proceeding)

  1. In proceeding NSD 954 of 2006 (“the Arrow Proceeding”), Arrow Pharmaceuticals Pty Ltd (“Arrow”), like Alphapharm, seeks a declaration that claims 1 to 6 of the Patent are invalid, an order that they be revoked and that the Register be rectified pursuant to s 192 of the Act by removing the particulars of the Patent from the Register. In the alternative, Arrow seeks an order that the Register be rectified by removing all record of the extension of the Patent and of the period of the extension, and recording, instead, that the term of the Patent will expire on 13 June 2009, or in the alternative, 9 December 2012.
  2. Arrow also complains that claims 2 to 5 of the Patent are not entitled to a priority date earlier than 13 June 1989, being the date of the filing of the application on which the Patent was granted. It asserts that those claims are not fairly based on the alleged priority document, namely, the UK Escitalopram Patent. (However, like Alphapharm, Arrow was content to proceed on the basis of a priority date of 14 June 1988 - see [12] above.) Arrow asserts that the alleged invention, so far as claimed in claims 1 to 6 of the Patent, is not a patentable invention because it is:

Arrow also asserts that the complete specification does not comply with s 40(3) of the Act in that claims 1 to 5 are not clear and succinct and claims 3 to 6 are not fairly based on the matter described in the specification. Accordingly, Arrow seeks revocation of the Patent under s 138(3) of the Act and removal of the particulars of the Patent from the Register.

  1. In relation to the alternative application for rectification of the Register, like Alphapharm, Arrow alleges that the first regulatory approval date was 9 December 1997, because that was the date when Cipramil was first included in the ARTG, and Cipramil contains citalopram which is a racemic mixture of (+)-citalopram and (-)-citalopram. Accordingly, like Alphapharm, Arrow complains that it was a misrepresentation for Lundbeck to represent to the Commissioner, as it did when it applied for and obtained the extension, that 16 September 2003 was the relevant first regulatory approval date.
  2. Given the overlap of Arrow Proceeding with the Revocation Proceeding, I find it convenient in these reasons, generally speaking, to refer only to Alphapharm when addressing various issues. However, it should be understood that my reasoning applies equally to Arrow’s submissions on the same issues.

Proceeding NSD 1078 of 2006 (the Lundbeck Appeal (Extension of Term) Proceeding)

  1. I turn last to proceeding NSD 1078 of 2006 (the Lundbeck Appeal (Extension of Term) Proceeding). This proceeding is an appeal by Lundbeck from part of a decision of the Commissioner, by her delegate, Dr SD Barker, issued on 19 May 2006. That decision was a decision to direct that the entry in the Register in respect of the Patent be amended by alteration of the expiry of the extension on the ground that the extended term was not calculated from the “first regulatory approval date” referred to in s 77 of the Act, with the consequence that reg 10.7(7) of the Patents Regulations 1991 (Cth) (the Regulations) required the Commissioner to amend the Register by bringing forward the expiry of the Patent.
  2. (In H Lundbeck A/S v Commissioner of Patents [2006] FCA 163, I held that reg 10.7(7) was intra vires s 228 of the Act. Bennett J followed me in Pfizer Corporation v Commissioner of Patents (No 2) (2006) 69 IPR 525, and on appeal from her Honour, the Full Court agreed with us: see Pfizer Corporation v Commissioner of Patents [2006] FCAFC 190; (2006) 155 FCR 578. An application by Pfizer Corporation for special leave to appeal to the High Court was refused: see [2007] HCA Trans 93.)
  3. As noted earlier, on 27 May 2004 the Commissioner granted the extension. No opposition was entered to the grant of it in the time provided by the Regulations. However, Alphapharm later wrote to the Commissioner asserting that the Commissioner had been misled by Lundbeck as to the true first regulatory approval date. On 13 July 2005, the Acting Deputy Commissioner of Patents copied Lundbeck into correspondence stating that the Commissioner considered that she was obliged to amend the entry in the Register of the expiry of the term of the Patent from 13 June 2014 to 9 December 2012 under reg 10.7(7) of the Regulations. This was on the footing that the correct first regulatory approval date was 9 December 1997, the date of the registration of Cipramil in the ARTG.
  4. The Commissioner’s letter requested Lundbeck either to provide reasons why the Commissioner should not make the amendment or to accede to the amendment. Lundbeck did not accede to the amendment and there was a hearing before Dr Barker at which Lundbeck and Alphapharm made submissions. This led to the decision of 19 May 2006 from which Lundbeck now appeals, as it is entitled to do under s 154 of the Act and reg 10.7(9) of the Regulations.
  5. Regulations 10.7(7), (8) and (9) provide:
(7) If:
(a) an extension of the term of a standard patent for a pharmaceutical substance has been granted under section 76 of the Act; and
(b) the Commissioner becomes aware that the first regulatory approval date in relation to the pharmaceutical substance is earlier than:
(i) the date of commencement of the first inclusion in the Australian Register of Therapeutic Goods that was supplied, under subregulation 6.9(2), with the application for the extension of the term; or
(ii) the date of the first approval that was supplied, under subregulation 6.10(2), with the application for the extension of the term;
the Commissioner must amend the relevant entry in the Register to insert the correct extension of the term of the patent.

(8) If the Commissioner proposes to amend an entry in the Register under subregulation (7), the Commissioner must:
(a) give notice to that effect to the patentee; and
(b) act in accordance with regulations 22.22 to 22.24 as if those regulations applied to a decision to amend an entry.

(9) An appeal lies to the Federal Court against a decision of the Commissioner to amend the Register under subregulation (7).

  1. Regulations 22.22 to 22.24, referred to in para (8)(b), provide for the giving of notice and of an opportunity to be heard, before the Commissioner exercises a discretionary power adversely to a person.
  2. Dr Barker decided that the decision of Wilcox J in Merck & Co Inc v Arrow Pharmaceuticals Ltd [2003] FCA 1344; (2003) 59 IPR 226 (Merck) governed the issue before him. As Dr Barker understood the position, Merck produced the result that it did not matter that escitalopram was a new chemical entity having properties different from those of the racemate, citalopram, or that the registration of citalopram under its brand name Cipramil on the ARTG did not give the right to market escitalopram except as part of the racemate. All that mattered was that Cipramil did in fact “contain” escitalopram, or put another way, that escitalopram was present (to some extent) in Cipramil, and that Cipramil was included in the ARTG. It was also immaterial, according to Dr Barker, that escitalopram was not responsible for all of the activity of Cipramil.
  3. Dr Barker concluded that since citalopram hydrobromide, marketed under the brand name Cipramil and containing escitalopram, was first registered on the ARTG on 9 December 1997, the Commissioner was required by reg 10.7(7) to amend the relevant entry in the Register to reflect the correct extension of the term of the Patent as expiring on 9 December 2012 (see [32] above).
  4. Lundbeck complains that the Dr Barker erred in finding that the first regulatory approval date was the date on which Cipramil was registered on the ARTG, and that Dr Barker ought to have found that it was the date on which Lexapro was so registered (see [33] above).

Which legislative régime applies?

  1. The Revocation Proceeding (including the cross-claim for infringement) falls to be decided under the Act. However, the application for the Patent was filed on 13 June 1989 under the Patents Act 1952 (Cth) (the 1952 Act). The application for the Patent was advertised and accepted on 7 May 1992. That was well after the commencement of the Act (being the first day after the end of the period of 6 months beginning on 30 October 1990). The Patent was therefore granted under the Act on an application lodged under the 1952 Act. In these circumstances, s 234(2) of the Act is applicable. That subsection and s 234(5) of the Act relevantly provide:
(2) Where, before the commencing day:
(a) a patent application had been lodged under the 1952 Act; and
(b) a complete specification...had been lodged under that Act in respect of the application; and
(c) the application had not been withdrawn or finally dealt with;
then, subject to this Chapter and the regulations, this Act applies on and after that day:
(d) in relation to the application as if it were a complete application made under this Act; ...

(5) Objection cannot be taken to:
(a) an application mentioned in subsection (2); or
(b) a patent granted on such an application;
and such a patent is not invalid, so far as the invention is claimed in any claim, on any ground that would not have been available against the application or patent, as the case may be, under the 1952 Act.

  1. The effect of these provisions is that the Patent can be revoked under the Act only on a ground of invalidity that would have been available under the 1952 Act. In any case where a relevant ground of invalidity under the 1952 Act is narrower than the corresponding ground under the Act, the patentee has the benefit of the narrower ground and is not to be worse off than if the 1952 Act had continued to operate: NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd [1993] FCA 404; (1993) 44 FCR 239 at 250 ff per Lockhart J, with whom Northrop J agreed and with whom Burchett J agreed on this point; ICI Chemicals & Polymers Ltd v Lubrizol Corporation Inc (2000) 106 FCR 214 (Lubrizol) at [22]–[24]; Aktiebolaget Hässle v Alphapharm Pty Ltd [2000] FCA 1303; (2000) 51 IPR 375 at [8]–[10].

Professors Banwell and Davies

  1. Lundbeck and Alphapharm led evidence from a number of experts, not all of whom were cross-examined. Two of the experts, Professor Martin Banwell called by Alphapharm, and Professor Stephen G Davies called by Lundbeck, conferred and produced a joint report (the Joint Report) in which they responded to six issues that had been formulated by the legal representatives of Alphapharm and Lundbeck. In response to each issue, they stated matters on which they were agreed, and, where they disagreed, their respective positions. The legal representatives of Alphapharm and Lundbeck played no part in the Professors’ conference or in their formulation of their responses to the six questions.
  2. The Joint Report of Professors Banwell and Davies was admitted in part as Exhibit A9 and, as to the remainder, as Exhibit A10.
  3. Professors Banwell and Davies were sworn in in immediate succession, and in addition to being cross-examined in the conventional manner, they had the opportunity, in a “concurrent evidence” session, to elaborate on their positions and to respond to questions asked by me, as well as to questions asked by each other.
  4. Both Professors Banwell and Davies are highly qualified in the area of organic chemistry. I discuss their qualifications and experience further at Section E [207] ff.

General chemical background

  1. In order to understand the issues in these proceedings, it is necessary to have some understanding of organic chemistry. The following outline is based on the affidavit evidence of Professors Banwell and Davies and on the text, Morrison and Boyd, Organic Chemistry, published by Allyn and Bacon (Morrison and Boyd), to which they referred. At the priority date of 14 June 1988, the 5th edition of this text, published in 1987, was a standard text for students and organic chemists. It would be tedious for every phrase or sentence that I quote to be placed within quotation marks and for distinctions to be made between quotation and paraphrase. I acknowledge, however, my quotation from, and otherwise my reliance on, paras 16 to 56 of Professor Banwell’s affidavit sworn 11 August 2006, Annexure 1 to Professor Davies’s affidavit sworn 4 April 2007, and Chapters 1 and 4 of Morrison and Boyd.

Atoms and molecules

  1. Organic chemistry is a specialised branch of chemistry dedicated to the study of molecules that contain carbon atoms. Atoms are the building blocks of all matter. They are composed of three types of particles: protons, which carry a positive (+1) charge; neutrons, which carry no charge; and electrons, which carry a negative (–1) charge. Protons and neutrons are held together by very strong forces and constitute the “nucleus” of an atom. Electrons orbit the nucleus at different levels.
  2. The chemical elements, such as carbon, hydrogen and oxygen, are particular types of atoms. Each element has a unique number of protons, which, if the element is uncharged, is equal to its number of electrons. Some elements have a more stable number of electrons than other elements. Stability is achieved by filling orbitals known as electron shells. The first electron shell requires two electrons. The second and third each require eight electrons. The greatest stability is reached when the outermost electron shell for the particular element is full. Elements interact with each other in order to achieve a stable number of electrons either by gaining, losing or sharing electrons.
  3. Molecules are combinations of atoms. They are described by molecular formulae which utilise chemical symbols for each element followed by numeric subscripts for the number of atoms of that element in the molecule. For example, a molecule of water is shown as H2O to signify that the molecule comprises two atoms of hydrogen (H) and one of oxygen (O). Citalopram comprises the elements hydrogen, oxygen, carbon (C), fluorine (F) and nitrogen (N). In complicated molecules, groups of atoms with a specific function are called functional groups. An example in this case is the hydroxyl group (OH).
  4. Atoms are held together in molecules by electron sharing, in a process called covalent bonding. A covalent bond refers to the sharing of two electrons between two atoms, so that both electrons fall within the outer shell of each atom. Most elements need to share a certain number of electrons to be stable. For example, in order to achieve stability, hydrogen, which has one electron and needs to fill the first electron shell (which has a capacity of two electrons), forms one covalent bond; carbon, which has six electrons and needs to fill both the first electron shell and the second electron shell (which has a capacity of eight electrons), forms four covalent bonds; and chlorine (Cl), which has seventeen electrons and needs to fill the first, second and third electron shells, forms one covalent bond. When an atom of hydrogen reacts with an atom of chlorine, they share one electron with each other to make a covalent bond. Once this happens, both atoms have a stable number of electrons and a molecule of hydrogen chloride is the result. Pictorially, a hydrogen chloride molecule (HCl) is represented by a line joining the two atoms to indicate a covalent bond (H–Cl).
  5. Stereochemistry is the study of the three-dimensional structure of molecules. A molecular formula generally conveys little about how the constituent atoms are physically arranged with respect to each other. Structural formulae have been developed to convey two-dimensional (2D) and, where appropriate, three-dimensional (3D) arrangements of atoms within a given molecule.
  6. Diagram I below shows several ways of representing the molecule methane. Within that diagram, Drawing 1 is the molecular formula. Drawing 2 is a 2D structural formula that shows the connectivity of the atoms, but not their orientation in space. Drawing 3 is a projection drawing showing the 3D spatial arrangement of the atoms. The solid wedge indicates that the hydrogen atom at the lower right is coming directly out of the plane of the paper, whereas the broken or hashed wedge shows that the hydrogen atom to the right lies behind the plane of the paper. Straight lines show bonds in the plane of the paper.

Diagram I – Various formulaic representations of methane

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Isomers and enantiomers

  1. Molecules with the same molecular formulae but different connections or different spatial arrangements between atoms are called isomers. Structural isomers differ in the way in which the atoms are connected together. In the case of stereoisomers, the atoms are connected in the same way, but the atoms are arranged differently in space. Stereoisomers behave similarly in many chemical reactions. However, in some chemical reactions they behave quite differently. This is particularly the case when stereoisomers interact with molecules within living organisms, such as enzymes within the human central nervous system.
  2. There are two types of stereoisomers: enantiomers and diastereomers. Enantiomers are non-superimposable mirror images of each other, much like a person’s left hand and right hand. Diastereomers are not mirror images of each other and have different physical and chemical properties. Objects that have a non-superimposable mirror image, such as human hands, are chiral. A chiral molecule can exist in two isomeric forms, each of which is the mirror image of the other, that it to say, is not superimposable on the other. An achiral molecule lacks that feature: its isomeric forms are superimposable on one another. In organic chemistry, a molecule that contains a carbon atom bonded to four different atoms or functional groups is chiral. For example, the molecule bromochlorofluoromethane is chiral because it has bromine (Br), chlorine, fluorine and hydrogen atoms attached to the central carbon atom. In Diagram II below, Drawing 4 shows the 2D structure of bromochlorofluoromethane and Drawings 5 and 6 show the 3D structures of the two enantiomers.

Diagram II – 2D structure (4) and two enantiomers (5 and 6)
of bromochlorofluoromethane

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4
5
Mirror
6
  1. It is common ground that in 1988, an ordinary skilled but non-inventive chemist, being given a 2D structural formula with a single chiral centre (such as Drawing 4) would recognise the presence of two enantiomers (Drawings 5 and 6). The 2D structural formula would represent either a single enantiomer or, if the molecule was part of a mixture, the two enantiomers in either equal or unequal parts. It is also common ground that if that chemist was also given some background to the origin of the molecule or mixture, the chemist would be able to determine which of those situations applied. This is because of what was known about how enantiomers are produced.
  2. Generally speaking, chiral molecules exist in nature only as one enantiomer. However, when chiral molecules are synthesised in a laboratory, there is a 50% probability that either enantiomer will be produced, so the two enantiomers are produced in equal parts. The resultant mixture is known as a racemate or racemic mixture. It may be a solid, liquid or gas. To obtain an unequal mixture of the enantiomers, or a single enantiomer, some specific step must be taken in the synthesis (enantio-selective synthesis).

Labelling enantiomers as (+) or (-) and as R or S

  1. . There are two conventions for describing enantiomers. The first depends on the physical property of the rotation of plane-polarised light (optical activity). Enantiomers rotate plane-polarised light in opposite directions. Enantiomers are designated (+) (dextrorotatory) or (-) (levorotatory) on the basis of whether, in solution, they rotate plane-polarised light clockwise (to the right) or anti-clockwise (to the left), respectively. Because enantiomers rotate plane-polarised light in opposite directions to equal extents, a racemate has no net rotation of plane-polarised light. It is optically inactive.
  2. The second way of describing enantiomers is an abstract theoretical description (as distinct from requiring physical testing) and provides an absolute configuration. Enantiomers are designated R or S on the basis of the direction of rotation when the molecule is abstractly positioned according to certain standard rules (the Cahn Ingold Prelog (CIP) rules). The rules are based on the atomic number (number of protons) of each atom or functional group connected to the chiral centre. First, each atom or functional group is labelled 1 to 4, with 1 indicating the highest atomic number and 4 indicating the lowest atomic number. Second, the molecule is visualised so that the atom or group labelled 1 (and so having the lowest atomic number) is directed into the page. Third, a curved arrow is drawn from the 1 position to the 2 position and then to the 3 position, and from the 3 position to the 4 position. If the arrow points clockwise, the configuration is designated R (Latin: rectus, right); if it points anticlockwise, the configuration is designated S (Latin: sinister, left). Diagram III below shows the two enantiomers of bromochlorofluoromethane, reoriented so that the atom with the lowest atomic number (H) is facing away from the page. The enantiomers are designated R and S based on the descending priority of the other three elements.

Diagram III – 3D structure and R and S designations of two enantiomers (7 and 8)
of bromochlorofluoromethane


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7
8
  1. It is common ground that in 1988, an ordinary skilled but non-inventive chemist, being given a 2D structural formula with a single chiral centre, could, by applying the CIP rules, have drawn the absolute configuration of each of the two enantiomers, R and S.

Application to citalopram

  1. The following is the 2D structural formula of citalopram:

Diagram IV – 2D structural formula of citalopram
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This formula uses a convention for organic molecules where carbon and hydrogen molecules are not identified by symbols. For example, each of the lines surrounding the N (nitrogen) on the right side of the structure represents a bond to a carbon atom, which is itself bonded to two or three hydrogen atoms. The hydrogen atoms never appear in such formulae. Because each carbon atom must have four covalent bonds, bonds to hydrogen atoms are inferred if a junction has less than four bonds emanating from it. The hexagon ‘rings’ contain carbon atoms at each junction. Double bonds between carbon atoms are indicated by double lines and single bonds by single lines. The carbon atoms at each junction are also bonded either to another carbon atom (indicated by a bond ending in a junction), a fluorine atom (indicated by – F) or a hydrogen (not represented by symbol).

  1. It is not in dispute that, based on the principles referred to above, including the CIP rules, a chemist could, at the priority date, identify from the formula in Diagram IV:

Furthermore, a chemist could, at the priority date, depict the R and S enantiomers of citalopram, but not which of them would be the (+)-enantiomer and (-)-enantiomer. There is no fixed relationship between the R and S dichotomy and the (+) and (-) dichotomy. It is only as a result of testing with plane-polarised light that one can know which of the R and S enantiomers is the (+)-enantiomer and which is the (-)-enantiomer.

Major Depressive Disorder and selective serotonin reuptake inhibitors

  1. Depression, and in particular, Major Depressive Disorder (MDD) is a common psychiatric disorder. Its basis is thought to be a disruption of normal neural transmission. Serotonin (5-HT) is a neurotransmitter which allows messages to be transmitted between nerves. By the priority date of the Patent, it was understood that neurotransmission by, relevantly, serotonin was comparatively deficient in MDD sufferers. It was thought that if the reuptake of 5-HT by nerve cells could be inhibited, there would be more free 5-HT in the synapses between the nerve cells, and that this additional 5-HT would improve neurotransmission and therefore give relief from MDD.
  2. Citalopram and escitalopram is a selective serotonin reuptake inhibitor (SSRIs). The term “selective” implies the avoidance of undesirable side effects. Citalopram and escitalopram are compounds that selectively block only the uptake of 5-HT. In 1988, there were no SSRIs on the market, although some had been launched previously and withdrawn due to toxicity, while others were being developed. Fluoxetine (sold under the brand name “Prozac”), paroxetine (sold under the brand name “Seroxat”), and citalopram were early SSRIs. Fluoxetine and citalopram were racemates and paroxetine was a single enantiomer. Citalopram was considered to be the most selective of these SSRIs.
  3. Since 1988, other SSRIs have been introduced, including escitalopram.

SECTION B – THE PATENT

The various earlier patents

  1. I find it convenient to list here the various patents which were referred to in the evidence. They fall into three groups:

The Citalopram Patents

  1. The UK Citalopram Patent based on Convention application No 1486/76, filed in Great Britain on 14 January 1976.
  2. The Australian Citalopram Patent, being Australian patent No 509,445 dated 5 January 1977, for an invention entitled “phthalanes” of a given general chemical formula, and based on the Convention application for the UK Citalopram Patent.
  3. The US Citalopram Patent, being United States patent No 4,136,193 dated 23 January 1979, for the same invention and based on the application for the UK Citalopram Patent.

The Diol Patents

  1. The UK Diol Patent, being application No 8419963, filed the United Kingdom on 6 August 1984.
  2. The Australian Diol Patent, being Australian patent No 574819 dated 2 August 1985 for a “novel intermediate and method for its preparation” and based on the application for the UK Diol Patent.
  3. The US Diol Patent, being United States patent No 4,650,884 dated 17 March 1987 for the same invention and based on the application for the UK Diol Patent (the US Diol Patent).

The Escitalopram Patents

  1. The UK Escitalopram Patent, being patent application No 8814057 filed in Great Britain on 1 June 1989 with a priority date of 14 June 1988.
  2. The EU Escitalopram Patent, being European patent No 0 347 066, based on the application for the UK Escitalopram Patent being for “New enantiomers and their isolation”. (The validity of the EU Escitalopram Patent has been the subject of three decisions:
  1. The Australian Escitalopram Patent, being Australian patent No 623144 dated 9 June 1989 (application filed on 13 June 1989), based on the application for the UK Escitalopram Patent, being for “(+) Enantiomer of Citalopram and process for the preparation thereof” – the Patent.
  2. The US Escitalopram Patent, being United States patent No 4,943,590 dated 24 July 1990, based on the application for the UK Escitalopram Patent, being for “pharmaceutically useful (+)-1-(3-dimethylaminopropyl)-1-(4’-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile and non-toxic acid addition salts thereof”.
  3. The US Re-issued Escitalopram Patent, being United States patent No 34,712 dated 30 August 1994 (a re-issue of the US Escitalopram Patent) based on the application for the UK Escitalopram Patent and being for “pharmaceutically useful (+)-1-(3-dimethylaminopropyl)-1-(4’-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile and non-toxic acid addition salts thereof”. (The validity of this US Re-issued Escitalopram Patent was the subject of a decision of the United States District Court for the District of Delaware given on 13 July 2006 in Forest Laboratories Inc v Ivax Pharmaceuticals Inc 438 F Supp 2d 479 (2006) and of the decision on appeal from that decision, given on 5 September 2007 by the United States Court of Appeals for the Federal Circuit in Forest Laboratories Inc v Ivax Pharmaceuticals Inc 501 F 3d 1263 (2007).)

The complete specification of the Patent

  1. I will now summarise the content of the complete specification of the Patent.
  2. I set out the claims of the Patent at [10] above. The specification states that “the present invention relates to the two novel enantiomers of the antidepressant drug 1-(3-dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3,-dihydroisobenzofuran-5-carbonitrile (citalopram) of the following formula I:

2008_55907.jpg


and to the use of these enantiomers as antidepressant compounds as well as the possible use as geriatrics [sic – their possible use with geriatrics] or in the cure of obesity or alcoholism”.

  1. The specification states that the invention includes pharmaceutically acceptable salts of the enantiomers of compound I (being a compound of the formula I set out above), and gives examples of such pharmaceutically acceptable organic salts and inorganic salts.
  2. The specification states that the invention is also concerned with the method to resolve the racemate of I into the individual isomers. In this context, “the individual isomers” means the individual enantiomers.
  3. According to the specification, citalopram, the racemate, was disclosed in the US Citalopram Patent. The US Citalopram Patent is the US equivalent of the Australian Citalopram Patent, on which Alphapharm relies as an anticipation of the Patent. Both the US Citalopram Patent and the Australian Citalopram Patent were based on the UK Citalopram Patent (see [79] above).
  4. The specification states that citalopram has proved to be an efficient antidepressant compound in man, and has been shown pharmacologically to be a very selective inhibitor of 5-HT reuptake.
  5. The specification states that previous attempts to crystallise diastereomeric salts of citalopram enantiomers have failed. This calls for some explanation.
  6. A conventional approach to the resolution of a racemate is to attempt to react it with a chiral organic acid (resolving agent) prepared as a single enantiomer. The theory is that the two enantiomers of the racemate will form two different diastereomeric salts with the single enantiomer of the acid. Diastereomers were discussed at [68] above. Diastereomers can have different physical and chemical properties. One of the properties which may differ between the diastereomeric salts is the propensity to crystallise, and it is possible by means of this difference to isolate one of the diastereomeric salts. As Dr Bøgesø of Lundbeck explained in his affidavit: “....if suitable conditions can be found to exploit [the propensity to crystallise], it is possible to crystallize out of solution only one of the diastereomeric salts...the isolated salt may then be recrystallized and then transformed into the free base which again may be transformed to a salt and crystallized, thereby isolating a single pure enantiomer of the originally racemic material”. This technique is called fractional crystallisation.
  7. There are two prerequisites for success in using fractional crystallisation. First, it is necessary that crystals be obtained, and this is not assured. Second, it is necessary that the diastereomers have different degrees of solubility for preferential crystallisation of one enantiomer to occur. As will be noted below, Dr Bøgesø gave evidence that his attempts to separate the enantiomers of citalopram in this way had been unsuccessful, principally because he could not obtain crystallisation, and on the one occasion when he did obtain it (with (+)-camphorsulfonic acid), separation was not obtained.
  8. The specification states, however, that “[s]urprisingly, it has now proven possible to resolve the intermediate 4-(4-dimethylamino)-1-(4’-fluorophenyl)-1-(hydroxy-1-butyl)-3-hydroxymethyl) benzonitrile, II, into its enantiomers and finally in a stereoselective way to convert these enantiomers to the corresponding citalopram enantiomers.” The process just described (and described in more detail below) was referred to as “Reaction Scheme II” before me.
  9. Formula II, referred to above, is as follows:
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This formula II is of the intermediate diol of citalopram. Reaction Scheme II thus consists of a resolution of this diol into its own enantiomers and then, in a stereoselective way, a conversion of those enantiomers to the enantiomers of citalopram.

  1. The intermediate racemic diol (II) was disclosed in, for example, the US Diol Patent. The US Diol Patent is the equivalent of the Australian Diol Patent, and both the US and the Australian Diol Patents were based on the UK Diol Patent (see [79] above).
  2. A “Reaction Scheme I” (described in more detail below) is also referred to in the specification. Reaction Scheme I reads: “Likewise, monoesters of II formed by optically active carboxylic acids could be separated into the corresponding diastereomers and subsequently converted directly into citalopram enantiomers in a stereoselective ringclosure reaction”. The “optically active carboxylic acid” that featured in the case was “Mosher’s Reagent” or “Mosher’s acid chloride”.
  3. The “intermediate” or “precursor” diol was the essence of both Reaction Schemes I and II. The reference to “stereoselective” in both Reaction Schemes signifies the importance of stereoselectivity in the step from the enantiomer of the diol (in Reaction Scheme II) or monoesters of the diol (in Reaction Scheme I) to the enantiomer of citalopram. The ringclosure reaction had to be, in general terms, one that enabled optical activity to be retained, and racemisation (or “re-racemisation”) to be avoided.
  4. According to the specification it was shown, surprisingly, that almost the entire 5-HT uptake inhibition resided in the (+)-enantiomer of citalopram.
  5. Reaction Scheme I is depicted in the specification as follows (I have taken the liberty of indicating with square brackets and arrows on the diagram certain features of the reaction):

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  1. The racemic diol (which is compound II – see [90] above) is depicted at the top of the diagram. It includes at the top left a benzonitrile ring. Attached to the right of this ring is hydroxyl methyl (CH2OH), which is a primary alcohol (the carbon in the alcohol being bonded to one other carbon). Below that is a further alcohol comprised of the hydroxyl group (OH) and the carbon (C), which is a tertiary alcohol (the carbon being bonded to three other carbons). The bottom ring is a flourophenyl ring.
  2. The difficulty has resided in the point at which ring closure is to occur. The challenge is to maintain stereoselectivity, that is to say, to avoid racemisation.
  3. The first step is to react compound II (the diol) with an enantiomerically pure acid derivative in either its (+) or (-) form. The agent shown in Reaction Scheme I is in fact Mosher’s acid chloride.
  4. The diastereoisomers are subsequently separated by means of high pressure liquid chromatography (HPLC). (I discuss HPLC in more detail at Section E [302] ff. For now, it suffices to say that HPLC, like fractional crystallisation referred to above, is a method that can be used to obtain the individual enantiomers from a racemate.)
  5. What one gets following separation by HPLC is a pure diastereometric form of Mosher’s ester. The “H”, which can be seen in the primary alcohol group (CH2OH) does not appear in the Mosher’s ester, and the chloride (Cl) which appears in the Mosher’s acid chloride also does not appear in the Mosher’s ester. The hydrochloric acid (HCl) that leaves is referred to as the “liberated HCl”.
  6. Finally, the purified diastereoisomers referred to in the preceding paragraph are each treated with a strong base in an inert organic solvent, such as toluene, to yield the separated positive (+) or negative (-) enantiomers of citalopram (as the case may be). The (+)-enantiomer and (–)-enantiomer of citalopram ultimately obtained appear at the foot of the diagram. In each case the letter O (oxygen) indicates the point at which ring closure takes place.
  7. The ring closure is preferably performed at a relatively low temperature, minus 20oC to room temperature. If the reaction between the Mosher’s ester and the strong base takes place at too warm a temperature, ring closure becomes fast and spontaneous, and a racemate, rather than the pure enantiomers, can form.
  8. The problem with Reaction Scheme I was that Mosher’s acid chloride was very expensive. Once those concerned worked out what was happening with the Mosher’s acid chloride, they progressed to Reaction Scheme II, to which I now turn.
  9. Reaction Scheme II is depicted in the specification as follows (again, I have taken the liberty of indicating with square brackets and arrows on the diagram certain features of the reaction):

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One commences with either the (+)-enantiomer or the (–)-enantiomer of the diol. The (+)-enantiomer or the (–)-enantiomer has already been obtained by the beginning of the diagram. They have been obtained by reacting the racemic diol with an optically active acid (examples given in the specification include the respective enantiomers of tartaric acid and di-(p-toloyl)tartaric acid).

  1. The first step shown in the diagram is the addition of an acid chloride (in this case methanesulfonyl) to the enantiomer of the diol, and, simultaneously, a base (in this case triethylamine) in an inert organic solvent at 0oC.
  2. The final product, depicted at the foot of the diagram, is the pure enantiomer (either the (-) or (+) enantiomer) of citalopram. If the starting product was the (+)-enantiomer of the diol, the end product is (–)-citalopram. If with the starting product was the (–)-enantiomer, the end product is (+)-citalopram.
  3. The point at which ring closure takes place is indicated in the formula at the foot of the diagram by O (oxygen).
  4. The square brackets in the diagram indicate that the product within them is an intermediate product. It is a labile ester and is not stable. It is formed during the course of the reaction. The process from the addition of the acid chloride to the pure form of the enantiomer of citalopram being a continuous one.
  5. The specification gives examples of the implementation of Reaction Scheme I (Example 1 at p 6) and Reaction Scheme II (Example 2 at pp 7-8). Example 3 is not relevant.
  6. At pp 9-12 of the specification is an account of the inhibition of 3H-serotonin uptake in rat brain synaptosomes, including a table of the pharmacological test results. I need not set them out or discuss them in detail. As a 5-HT re-uptake inhibitor, (+)-citalopram is shown to be a little more effective than citalopram itself and more than 100 times more effective than (-)-citalopram.
  7. At p 12 of the specification there is discussion of dosage forms, and at pp 12-13, a discussion of the preparation of tablets, and of a solution for injection.
  8. The Patent ends with the claims at pp 16-17 which were set out at [10] above. As will be recalled, claims 1 to 5 are product claims. Claim 6 is a claim of the two methods of obtaining (+)-citalopram, which have referred to earlier as Reaction Scheme I (Claim 6(a)) and Reaction Scheme II (Claim 6(b)).
  9. As previously noted, Lundbeck’s cross claim of infringement rests on claim 6(b) – Reaction Scheme II.

SECTION C – CONSTRUCTION OF THE PATENT

General

  1. Claims 1, 3, 5 and 6 are the subject of Alphapharm’s invalidity attack. Alphapharm has no interest in the pamoic acid salts of claims 2 and 4. It may be, however, that those two claims stand or fall with claim 1. It is common ground that if Alphapharm’s construction argument should succeed, claims 1, 3 and 5 would be invalid.
  2. Alphapharm’s attack based on lack of novelty is closely related to the question of the proper construction of the Patent.
  3. I will discuss below the extensive submissions that were addressed to the construction issue, but I will state at once my conclusion. The symbol (+)- in claim 1 (and in claim 2) indicates the particular enantiomer that is distinguished by the feature of rotating plane-polarised light to the right (under standard conditions – see Section G below). The property of rotating plane-polarised light to the right (clockwise) or to the left (anticlockwise) which distinguishes one enantiomer from the other and each from the racemate, is able to be detected only when that enantiomer is present other than as a part of the racemate. This is because when in a racemic mixture, the polarisation of light by each enantiomer is “cancelled out” by the other enantiomer, and there is thus no net polarisation of light. The skilled addressee in 1988 would have understood claim 1 to refer specifically to (+)-citalopram.
  4. In the absence of a context permitting otherwise, the skilled addressee would not have understood the claim to the invention of (+)-citalopram to refer to that compound merely as part of the unresolved racemate. Rather, the skilled addressee would have understood the claim to the invention of (+)-citalopram to refer to that compound as something that had an existence independent of that of the racemate.
  5. The only context that I take into account in arriving at this conclusion is that it was part of common general knowledge:
  6. It is not that the (+)-citalopram compound does not exist when it is part of the racemate. The skilled addressee would understand that it exists whether a part of the racemate or apart from it, and that the purpose of the (+) symbol is only to distinguish it from the (–)-enantiomer and from its being merely part of the racemate or of some other mixture. The (+) or (–) symbol, devoid of any context suggesting otherwise, implies distinctness from the racemate.
  7. Analogies are usually imperfect and are often only alternative ways of posing the problem to be solved. Nonetheless, the following two analogies are, I think, illuminating.
  8. First, take a reference to “blue” or to “yellow”. It is understood to signify something different from “green”. Yet green is said to consist of blue and yellow.
  9. Again, take a reference to a “black stick figure in a black square frame”. That description is not met by the same square entirely black. Yet when the black stick figure is one of a sufficient number of (say 1,000) different black stick figures all drawn within the same frame, the resulting solid black square can be said to contain the initial black stick figure, although we can no longer see it.
  10. So, the unqualified reference to the (+)-enantiomer of citalopram in claim 1 refers to something different from that enantiomer as an indistinguishable part of the unresolved racemate.
  11. My construction, independently arrived at, accords with that of District Judge Keeley in Ortho-McNeil Pharmaceutical Inc v Mylan Laboratories Inc 348 F Supp 2d 713. Her Honour had to construe a claim of “An S(–)-pyridobenzoxazine compound represented by [a certain formula]”. Her Honour said (at 726):
Thus, while it is certainly necessary to distinguish a new invention over the prior art, there is no indication that an inventor must use a plain-English purity limitation, as Mylan contends. Instead, an inventor may use anything that a person skilled in the relevant art would understand to limit the claim. In this case, the term “S(–)” clearly and plainly limits the claim language to the levorotatory enantiomer. Those skilled in the art clearly understand the term “S(–)” to affirmatively denote only the levorotatory enantiomer of a racemic compound, and not the racemic compound itself.

Later (at 729-730) Keeley J said that those skilled in the art would have understood the claim to cover “levofloxacin with a purity that was highly, but less than 100%, optically pure”. Her Honour’s observations apply mutatis mutandis to the present case.

  1. While my construction would leave unanswered the question how much “impurity” would prevent a compound from meeting the formula in claim 1 (see below), it does establish that when the compound is present only as 50% of a racemate, it does not meet the description in claim 1.
  2. The construction outlined above is also supported by the body of the specification and a certain convention in the way in which chemists understand references to compounds, both discussed below, but does not depend on those two additional considerations. I rely on them as alternative bases for my construction if I am wrong in thinking that claim 1 is unambiguous.

Rules of construction

  1. The parties’ written submissions referred to numerous authorities on the construction of patents, and, in particular, on the construction of patent claims. I need not refer to more than the following:

Professors Banwell and Davies on the meaning that the Patent claims would convey to the hypothetical skilled chemist at the priority date

  1. Issue 5 in the Joint Report related to the construction of claim 1. Paragraphs (a) and (b) posed the following questions to Professors Banwell and Davies:
(a) Does the reference in Claim 1 to (+)-1-(3-dimethylaminopropyl)-1-(4’-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile denote any level of purity?
(b) If so, what level of purity does it denote and why?

  1. The reference to “purity” is a reference to the purity of the positive enantiomer compound. The questions predicate the issue whether the reference in claim 1 to the (+)-enantiomer includes a reference to that enantiomer in the racemic mixture. Professors Banwell and Davies agreed that (+)-1-(3-dimethylaminopropyl)-1-(4’-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile denotes a specific single enantiomeric form of the compound and not the racemate. Professor Banwell stated that “purity is irrelevant as it is a claim in a patent”. Professor Davies, on the other hand, stated that with no other information, the reference in claim 1 denotes material of at least 95% enantiomeric purity (see below).
  2. In their Joint Report, Professors Banwell and Davies addressed question 5(c) which was as follows:
Is there a convention among chemists that when the absolute purity of a “pure” compound is not specified, it is understood to mean “at least 95% pure”? If so, where in the standard literature (as at 1988) can that convention be found?

They gave a common answer as follows:

In the open literature and particularly when dealing with experimental matters the claims to single compounds where no purity is given, or where they are described as “pure” (eg enantiomerically or chemically pure) are by convention understood to indicate at least 95% pure. This convention is not specifically stated in the literature but was in 1988 and indeed [is] today the standard benchmark arising from the limits of the techniques used to establish purity. This convention is generally practised throughout the chemical literature including in the publications of both MGB [Professor Banwell] and SGD [Professor Davies]. [my emphasis]

The question was posed in relation to “pure” compounds. I understand the question and the Professors’ common answer to extend to compounds, such as that in claim 1, “where no purity is given”, that is, where no explicit reference to purity is made. A possible alternative interpretation is that question and answer refer only to the situation where the compound is described as “pure” but no numerical specification as to the level of purity is given. In that case, the question and answer would not be relevant to claim 1. I reject this alternative. The Professors had claim 1 before them and must be taken to have expressed their agreement (above) and disagreement (see below) by reference to it. In any event, the Joint Report was overtaken to some extent by the oral evidence referred to below.

  1. Asked, whether claim 1 of the Patent referred to at least 95% enantiomerically pure S-citalopram (question 5(d) of their Joint Report), the two Professors disagreed. Professor Banwell answered “No”, again explaining that purity is irrelevant because the claim is a claim in a patent. Professor Davies answered “Yes”, adding that a chemist will automatically apply the convention wherever a compound’s name occurs.
  2. The disagreement between the two Professors was elaborated upon in their affidavits. Professor Davies stated:
Claim 1 of the Patent would be understood to mean the individual, ie enantiomerically pure (+) enantiomer of citalopram. By enantiomerically pure I mean at least 95% pure. I say at least 95% because the established convention among medicinal chemists is that when the absolute purity of a “pure” compound is not specified, it is understood to mean “at least 95% pure”. This is because the standard method for measuring purity (including optical purity) (NMR) can only reliably detect impurities if they are present at a level of 5% or greater. I believe that any medicinal chemist reading the claim would have this understanding of this claim, both now and in 1988.

In response, Professor Banwell stated:

Claim 1 of the Patent claims (+)-1-(3-dimethylamionoproply)-1-(4’-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile as well as non-toxic acid addition salts of that enantiomer. In my view, Claim 1 refers to the single (+) enantiomer in the form of the free base or the salt. In this context purity is not a relevant concept. You either have the (+) enantiomer, or you do not have the (+) enantiomer.

  1. Lundbeck submits that Professor Banwell’s assertion that purity is irrelevant because we are concerned here with a claim in a patent is the expression of a legal opinion of which Professor Banwell is not entitled to give evidence.
  2. Professor Banwell would be entitled to give evidence, if his experience qualified him to do so, that the formulae of chemical compounds are in fact understood differently by chemists according to whether they appear in patents or in other documents, but that was not his evidence. I think that Professor Banwell meant that while he agreed that formulae of single compounds in the open literature (such as journal articles) are understood as importing the concept of 95% purity, he reserved his position as to patents, no doubt because his experience did not enable him to say whether chemists would apply the 95% purity convention to their reading of patents. Professor Davies said that he had “no knowledge or experience” of a convention according to which chemists read patents differently from the open literature, and Professor Banwell gave no evidence of the existence of such a convention.
  3. While it is not necessary for me to resolve this difference in view of my conclusion expressed at [116], [125] above, I see no reason why an exception is to be made in the case of patents. If chemists understand a formula for a single compound when it appears in the open literature to have a certain meaning, why would they not read the same formula in a patent in the same way, at least in the absence of an indication to the contrary in the specification? Since there is no evidence that they would not, I infer that they would.
  4. Senior counsel for Alphapharm suggested that in his affidavit (see [132] above), Professor Davies was saying that the 95% purity criterion applies only when some such qualifier as “pure” or “individual” appears. Senior counsel for Alphapharm submitted that Professor Davies departed from that more limited proposition to the more general one that an unqualified reference to the formula of a single compound imports the 95% purity qualification.
  5. Professor Davies was cross-examined at some length on this matter. He agreed with senior counsel for Alphapharm that if, in the open literature, there was an express reference to the “pure” or “individual” enantiomer, the skilled reader would take the reference to be a 95+% pure enantiomer. Senior counsel for Alphapharm drew Professor Davies’s attention to the fact that claim 1 did not say “individual” or “pure”. Professor Davies’s response was two-fold. First, he pointed out that the specification elsewhere used the words “pure” and “individual” in the present context. In fact it does, as appears in some of the extracts referred to at [141] below. Second, Professor Davies stated that in any event, even without any express reference to “individual” or “pure”, a 95+% level of purity is understood. He said:
... if you go to a catalogue, a chemical catalogue, and you buy a compound +x, you would expect that to be more than 95% pure unless something else was stated. So when you’re stating a single – a compound with a descriptor like “+” in this case, then you expect it to be that enantiomer of 95% or above.

and

... if I buy a compound from a chemical catalogue that says “compound X”, I would expect it to be 95% or more in purity. Otherwise that would tell me in the description. If it is “(+)-citalopram” in a chemical catalogue, I would expect it to be 95% or more.

Professor Davies also stated:

... if I go to a chemical catalogue and buy something, I expect it to be 95% or more pure. Otherwise, the person selling it to me would make it clear to me that it was not so pure.

  1. In my opinion, the effect of Professor Davies’s testimony, which I accept, is that chemists at the priority date and now would understand the bare formula of claim 1 to require a compound that was at least 95%  pure (+)-citalopram.
  2. There was in evidence a commercial catalogue of chemicals available for purchase, and Alphapharm pointed to specifications of purity levels in it, nearly all of them being higher than 95%. Alphapharm’s suggestion seems to be that Professor Davies’s evidence related to a hypothetical situation because a level of purity is always specified. However, this one catalogue does not establish Alphapharm’s proposition. If anything, I think the catalogue supports Professor Davies’s evidence, because it at least suggests that chemists expect a very high level of purity, far higher than 50%.
  3. I accept Professor Davies’s evidence that in the absence of the specification of a level of purity, the convention of “at least 95%” applies. I also accept that the convention is applicable to the formula stated in claim 1.

The body of the specification

  1. Lundbeck refers to numerous references in the specification, outside the claims themselves, as supporting the view that claim 1 is to the isolated (+)-enantiomer:
(a) the title: “(+)-Enantiomer of Citalopram and process for the preparation thereof”, that is not both enantiomers as part of a racemate;

(b) page 1, lines 1-5 – “the two novel enantiomers ... and to the use of these enantiomers as antidepressant compound”, that is, not the use of the enantiomers as part of the racemate;

(c) page 2, lines 12-13 – “the invention is also concerned with a method to resolve the racemate ... into the individual enantiomers”;

(d) page 2, line 14 – the acknowledgement of the racemate in the prior art;

(e) page 3, lines 4-6 the discovery that almost the entire 5-HT uptake inhibition resided “in the (+) citalopram enantiomer” – this is something which is only measurable at the macroscopic level and on the isolated enantiomer;

(f) page 3, lines 9-10 – the production of the enantiomer from the enantiomerically pure diol – “with fully [sic] conservation of stereoconfiguration”;
(g) The description of the method at page 3, line 20-21 – “yielding the pure citalopram enantiomers”;

(h) Page 4 – Reaction scheme I starting with racemic diol and ending separately with the (+) and (-) enantiomers. The skilled person knows this is a scheme which is carried out with macroscopic preparations of these molecules – not single molecules;

(i) page 5, lines 1-9 – description of steps b) and c) [which forms example 2] which provides “stereoselective ringclosure of the pure enantiomers”;

(j) page 6, line 1-29 – Example 1 resolution by method a) – the isolation of 0.6g of the (+) enantiomer with an optical purity of 99.6% and the
(-) enantiomer with 99.9% optical purity;

(k) page 7-8 – Example 2 resolution by methods b) and c) – the isolation of 8gm of (+) citalopram and, the isolation of 10gm of (-) citalopram;

(l) page 8, line 13 – by comparison in Example 3 of racemic, that is (±)-citalopram;

(m)the administration of quantities of the separated enantiomers to mice and in the rat brain assay at pages 9 – 10;

(n) the results reported in Table 1 on page 11 for “(+)-citalopram, (-)-citalopram and (±)-citalopram. These are of the isolated enantiomers in contrast to the racemic composition;

(o) page 12, line 21 – tablets containing 5 milligrams of (+)-citalopram;

(p) page 13, line 1 – tablets containing 50 milligrams of (+)-citalopram;

(q) page 13, line 12 – syrup containing 10 milligrams of (+)-citalopram;

(r) page 13, line 21 – solution for injection containing 50 milligrams of (+)-citalopram;

(s) page 13, line 25 – solution for injection containing 10 milligrams of (+)-citalopram;

(t) page 14, line 5 – combinations of (+)-citalopram with other active ingredients;

(u) page 14, line 8 – “As previously stated, when isolating the enantiomers of citalopram ....”;

(v) page 14, line 29- an adequate quantity of (+)-citalopram (for symptom alleviation);

(w) claim 6 in which the corresponding method claim is to the method for the production of a compound in claim 1, which comprises converting the diol enantiomer in a stereoselective way to the (+) enantiomer which is isolated as such.

  1. Senior counsel for Alphapharm makes the point that the use of “individual”, “pure”, “separated” and “isolated” or derivatives of those terms is a two-edged sword: Why were they omitted from claim 1 if not to suggest that what was claimed was not to be limited by such qualifiers? Notwithstanding the force of this submission, I think that if claim 1 is ambiguous (as indicated earlier, I do not think it is), the specification as a whole teaches that claim 1 refers to the independently existing (+)-enantiomer, and not to merely the (+)-enantiomer when a part of unresolved (±)-citalopram.

Other submissions

  1. Alphapharm submits that it is no more permissible to read in the word “pure” than it was to read the qualifier “drainage” into the claims in the patent specification in Atlantis Corporation Pty Ltd v Schindler (1997) 39 IPR 29 (Atlantis). The invention in that case was entitled in the complete specification “Drainage Cell” and was stated to relate to “the provision of adequate drainage by artificial means” and to have particular application in the area of landscape gardening”. However, the claims simply described a rigid cell structure.
  2. A Full Court of this Court held that the claims were unambiguous and were simply in respect of the rigid structure without any limitation by reference to the purpose of “drainage”.
  3. In my view, the facts in Atlantis are distinguishable. There was no question in Atlantis of whether the object was claimed an object in its own right. Quite apart from:

I would have understood an unqualified reference to (+)-citalopram, whether in the open literature or in a patent, to refer to that compound when other than merely part of the unresolved racemate.

  1. Alphapharm draws attention to the fact that both Professors Banwell and Davies said that from the formula for the racemic mixture (citalopram) they could deduce the formulae for the (+)-enantiomer and the (-)-enantiomer. I do not think this fact to be persuasive as to how claim 1 is properly to be construed.
  2. Alphapharm draws attention to the Patent’s title as it existed prior to amendment and to the terms of overseas Escitalopram Patents.
  3. Prior to amendment, the title of the Patent was “New enantiomers and their isolation” (it will be recalled that the amended title is “(+) enantiomer of citalopram and process for the preparation thereof”). Section 116 of the Act provides that “[t]he Commissioner or a court may, in interpreting a complete specification as amended, refer to the specification without amendment”. Alphapharm does not refer to aspects of the pre-amendment complete specification other than the title, or to evidence of the circumstances surrounding the amendment. I do not find claim 1 to be so uncertain or ambiguous in its meaning that I gain assistance from the pre-amendment title.
  4. Alphapharm points out that claim 1 of the US Escitalopram Patent and claim 1 of the Re-issued US Escitalopram Patent (see [79]) were as follows:
1. A compound selected from substantially pure (+)-1-(3-Dimethylaminopropyl)-1-(4’-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile and non-toxic acid addition salts thereof. [my emphasis]

  1. It is noteworthy, however, that there was no reference to purity in the relevant claims in the EU Escitalopram Patent (see [79]) , yet the German Federal Patents Court was able to say (Neolab Ltd & Ors v H Lundbeck AS 3 Ni 9/05 (EU), 27 August 2007 at pp 29-30):
... it follows from a comparison with the formulation of patent claim 7, which is directed to the (-)-enantiomer of the 4-[4-dimethylamino)-1-(4’-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl) benzonitrile and thus of the enantiomerically pure diol intermediate and the monoester thereof, that the formulation of patent claims 1 and 2 of the patent in dispute exclusively means the (+)-enantiomer of the 1-(3-dimethylaminopropyl)-1-(4’-fluorophenyl)-1,3-diyhydroisobenzofuran-5-carbonitrile in purified form together with its salts, and not for instance a mixture with a numerically undefined, but considerable amount of the (-)-enantiomer.

  1. I do not derive particular assistance from the form of the claims in the US Escitalopram Patent or the US Reissued Escitalopram Patent or from the observations made by the German Federal Patent Court.
  2. Alphapharm submits that if any degree of purity is to be implied, it should be the 99.6% optical purity or the 99.9% optical purity that are referred to in example 1 in the specification. However, those measures of optical purity are addressed to something different and do not indicate that persons skilled in the art would understand claim 1 to be referring to a compound of either of those degrees of purity.

Conclusion on construction

  1. In summary, the reference in claim 1 to (+)-1-(3-dimethylaminopropyl)-1-(4’-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile is a specific reference to the enantiomer of citalopram that rotates plane-polarised light to the right, and, there being no context suggesting a different possibility, is not apt to refer to the (+)-enantiomer merely as present in the racemate.

SECTION D – NOVELTY

  1. Senior counsel for Alphapharm indicated that Alphapharm was content to proceed on the basis of a priority date of 14 June 1988. I do likewise.
  2. In their respective openings, senior counsel for Alphapharm and counsel for Arrow abandoned the attack on claim 6(b) on the ground of lack of novelty. That ground remains relevant only to the product claims.
  3. The definition of “prior art base” now includes documents publicly available outside the patent area (see subpara 18(1)(b)(i) of the Act and the definition of “prior art base” in Schedule 1 of the Act), whereas that notion in the 1952 Act was limited by reference to being novel in Australia (para 100(1)(g) of the 1952 Act). It follows (see [55] above) that Alphapharm must prove that the invention was “not novel in Australia”, that it to say, not novel by reference to disclosures in Australia.

The test of novelty and the question of enabling disclosure

  1. It is common ground that the basic test for lack of novelty in Australia is the “reverse infringement test”, which was enunciated by Aickin J in the following well-known passage in Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19; (1977) 137 CLR 228 at 235:
The basic test for anticipation or want of novelty is the same as that for infringement and generally one can properly ask oneself whether the alleged anticipation would, if the patent were valid, constitute an infringement ...

This rule is stated in Blanco White TA, Patents for Inventions and the Protection of Industrial Design (5th ed, Stephens, London, 1983) at [4-102] as follows:

The test for lack of novelty is essentially the same as the test for infringement; that is to say, a prior use will invalidate a claim if it was such that it would infringe that claim if carried out after the grant of the patent concerned; while a prior disclosure will invalidate if it contains a clear description of, or clear instructions to do or make, something that would infringe if carried out after grant.

  1. Lundbeck submits that there are two elements of the reverse infringement test: first, that the alleged anticipation must disclose all of the essential features of the particular claim it is said to anticipate; and, second, that the alleged anticipation must have enabled the addressee to carry out the invention. Alphapharm submits: “The submissions of Lundbeck misapplied the doctrine of enabling disclosure, even assuming it applies in Australia”. Alphapharm submits, however, that the applicability of the doctrine need not be decided because there is no dispute that the Australian Citalopram Patent “enabled” the racemate, that is, the positive enantiomer, but only with the negative enantiomer in equal proportions. Clearly, the issue of the proper construction of claim 1 discussed above directly arises.
  2. Both parties rely on the following passage from the English Court of Appeal’s judgment in General Tire & Rubber Co v Firestone Tyre & Rubber Co Limited [1972] RPC 457 at 485-486:
If the prior inventor’s publication contains a clear description of, or clear instructions to do or make, something that would infringe the patentee’s claim if carried out after the grant of the patentee’s patent, the patentee’s claim will have been shown to lack the necessary novelty, that is to say, it will have been anticipated. The prior inventor, however, and the patentee may have approached the same device from different starting points and may for this reason, or it may be for other reasons, have so described their devices that it cannot be immediately discerned from a reading of the language which they have respectively used that they have discovered in truth the same device; but if carrying out the directions contained in the prior inventor’s publication will inevitably result in something being made or done which, if the patentee’s patent were valid, would constitute an infringement of the patentee’s claim, this circumstance demonstrates that the patentee’s claim has in fact been anticipated.
If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee’s claim, but would be at least as likely to be carried out in a way which would not do so, the patentee’s claim will not have been anticipated, although it may fail on the ground of obviousness. To anticipate the patentee’s claim the prior publication must contain clear and unmistakeable directions to do what the patentee claims to have invented: Flour Oxidising Co Ltd v Carr & Co Ltd (1908) 25 RPC 428 at 457, line 34, approved in BTH Co Ltd v Metropolitan Vickers Electrical Co Ltd (1928) 45 RPC 1 at 24, line 1. A signpost, however clear, upon the road to the patentee’s invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee. [my emphasis]

This passage has been followed in Lubrizol at [61] and in numerous other cases.

  1. In my opinion, it is clear that the earlier disclosure must be “enabling”: see for example, Hill v Evans at 8 (“the antecedent statement must be such that a person of ordinary knowledge of the subject would at once perceive, understand and be able practically to apply the discovery without the necessity of making further experiments and gaining further information before the invention can be made useful”); Flour Oxidising Co Ltd v Carr & Co Ltd (1908) 25 RPC 428 at 457 per Parker J (“clear and unmistakable directions so to use [the earlier apparatus]”); Acme Bedstead Co Ltd v Newlands Bros Ltd [1937] HCA 63; (1937) 58 CLR 689 at 707 per Dixon J; Olin Corporation v Super Cartridge Co Pty Ltd [1977] HCA 23; (1977) 180 CLR 236 at 260-262 per Stephen and Mason JJ; Nicaro Holdings Pty Ltd v Marlin Engineering Co (1990) 91 ALR 513 at 531-532 per Gummow J (the supposed anticipation must not require of the skilled but non-inventive addressee “the exercise of any inventive ingenuity and the taking of any inventive step”); Bristol-Myers Squibb Co v FH Faulding & Co Ltd [2000] FCA 316; (2000) 97 FCR 524 at [67] per Black CJ and Lehane J (“must give a direction or make a recommendation or suggestion which will result, if the skilled reader follows it, in the claimed invention”); Imperial Chemical Industries Pty Ltd v Commissioner of Patents [2004] FCA 1658; (2005) 213 ALR 399 at [61] ff per Crennan J; Pfizer v Eli Lilly at [313]-[324] per French and Lindgren JJ.
  2. What does “enabling disclosure” mean in the context of a product claim? It means that the earlier disclosure must point unmistakeably to the (+)-enantiomer of citalopram, as distinct from the racemate, as a drug desirable to obtain.

The alleged documentary anticipations

  1. Initially Alphapharm and Arrow relied on European Patent No. 149 077 and US Patent No. 4,602,035 as denying novelty to method claim 6(b), but, as mentioned above, ultimately they did not press that argument.
  2. The challenge to the product claims is based on two prior art documents:
    1. A publication of Dr Donald F Smith, “The Stereoselectivity of Serotonin Uptake in Brain Tissue and Blood Platelets: The Topography of the Serotonin Uptake Area”, Neuroscience and Biobehavioural Reviews, vol 10 pp 37-46 (1986), which was said to have become publicly available in Australia on or about 8 October 1986;
    2. Publication of Australian Citalopram Patent in Australia on or about 13 July 1978.

(1) The Smith article

  1. The Smith article states that it has two aims: to give a concise account on available information on effects of stereoisomers on 5-HT uptake; and to use the information to derive a topographical map of the hypothetical 5-HT uptake area.
  2. The paper reviews studies of numerous stereoisomers, and gives structural drawings of the compounds cited in it. In relation to citalopram, the paper states (at 45):
It is also of interest to mention citalopram, which is a racemic drug with potent inhibitory effect on 5-HT uptake ... Although effects of the individual enantiomers of citalopram have never been studied, the model predicts that the (R)-enantiomer (XXX) is far more potent than the (S)-enantiomer as 5-HT uptake inhibitor ... Thus, the present model can be tested by determining whether these predictions are correct.

The reference to “XXX” is a reference to a structural drawing of the R-enantiomer of citalopram that appeared earlier in the paper.

  1. The Smith article suggests that the R-enantiomer rather than the S-enantiomer can be expected to be the more potent of the two. Dr Smith’s prediction was wrong and points away from the invention. It is common ground that in the case of citalopram, the R-enantiomer is the (–)-enantiomer, and it is the S-enantiomer that is the (+)-enantiomer. The Patent relates to the (+)-enantiomer.
  2. An article that teaches away from an invented product cannot be said to have pointed the skilled but non-inventive addressee to that product: cf Pfizer v Eli Lilly at [314], [323].
  3. The addressee would have to conduct further experiments, conduct research and gain further information to hit upon the present invention. The Smith article would be a distraction.

(2) The Australian Citalopram Patent

  1. The question whether the inventions claimed in the product claims were anticipated by the Australian Citalopram Patent depends on my construction of those claims outlined at Section C above.
  2. Alphapharm puts its case on novelty in relation to the Australian Citalopram Patent in two ways. First, it says that a person who follows the teaching of that patent will make the racemic mixture, and that that mixture contains the (+)-enantiomer which is the subject of the Patent. Second, it submits that the citalopram formula itself discloses the (+)-enantiomer of citalopram, because those skilled in the art recognise instantly (and would have recognised in 1988) that the citalopram molecule has a chiral centre, that is, a carbon atom with four bonds each connecting to a different atom or group, which means that it will exist in two enantiomeric forms which are mirror images of each other. I will deal with these two submissions in turn.
  3. The Australian Citalopram Patent did not refer to “enantiomers”. It did not expressly or by implication otherwise disclose the individual enantiomers. It disclosed the racemate and enabled the obtaining of it. Whether this anticipated the present invention turns on my construction of the Patent – see Section C above. The skilled but non-inventive addressee reading the Australian Citalopram Patent would have understood that (±)-citalopram consisted of the (+)-enantiomer of citalopram and the (-)-enantiomer, each as to 50%, and would have been able to identify the formulae for the S and R enantiomers, but would not have known, in the absence of experimentation, which was (+) and which was (-). These facts would not, however, point specifically to the independent existence of the enantiomers which is, according to my construction of the Patent specification, of the essence of claim 1. If I had construed claim 1 as referring to (+)-citalopram when present in the unresolved racemate, the Australian Citalopram Patent would have been an anticipation. But because of my construction outlined at Section C above, a person taught by the Australian Citalopram Patent, although taught to desire to obtain the racemate, would not be taught to desire to obtain the specific (+)-enantiomer in its own right.
  4. Similarly, the Australian Citalopram Patent’s citalopram formula did not disclose the independently existing (+)-enantiomer.
  5. I note that if In re Adamson (1960) 275 F2d 952 is authority for the proposition that a patent for a racemate necessarily anticipates a claimed invention of either of its enantiomers, I respectfully disagree.

Conclusion on novelty

  1. Alphapharm’s attack on the Patent on the ground that the invention lacked novelty fails.

SECTION E – OBVIOUSNESS

Relevant law

  1. Obviousness is perhaps the most critical aspect of the Revocation Proceeding (and the Arrow Proceeding). This appears to be the first time an Australian patent relating to a single enantiomer has been challenged on the ground of obviousness (the obviousness ground was abandoned in Ranbaxy Australia Pty Ltd v Warner-Lambert Company LLC (No 2) [2006] FCA 1787; (2006) 71 IPR 46 (Ranbaxy) as noted by Young J at [15]).
  2. The history of the emergence of obviousness or lack of inventive step as a distinct ground of invalidity has been recently traced by the High Court in Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) [2007] HCA 21; (2007) 235 ALR 202 (Lockwood v Doric (No 2)) at [38]–[49], and by a Full Court of this Court in Ajinomoto Co Inc v NutraSweet Australia Pty Ltd [2008] FCAFC 34 at [63]–[91]. I need not discuss that history.
  3. As noted at [55] above, the Patent can be revoked under the Act only on a ground of invalidity that would have been available under the 1952 Act. Obviousness was treated differently under the 1952 Act from the way in which it is treated under the Act. Section 100(1) of the 1952 Act provided:
A standard patent may be revoked, either wholly or in so far as it relates to any claim of the complete specification ... on one or more of the following grounds, but on no other ground:...
(e) that the invention, so far as claimed in any claim of the complete specification ... was obvious and did not involve an inventive step having regard to what was known or used in Australia on or before the priority date of that claim;...
  1. The question of what was obvious is assessed from the perspective of the hypothetical non-inventive skilled addressee or team in the field of the invention, taking into account “what was known or used” (referred to as “common general knowledge”): Minnesota Mining and Manufacturing Co v Beiersdorf (Australia) Ltd [1980] HCA 9; (1980) 144 CLR 253 (Minnesota v Beiersdorf). This position is now effectively codified in ss 7(2) and 18(1)(b) of the Act, provided s 7(3) is put to one side.
  2. In Minnesota v Beiersdorf at 292-295 and in Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59; (2002) 212 CLR 411 (Astra) at [57] it was held in relation to s 100(1)(e) of the 1952 Act that publications are not to be taken into account unless their content was part of common general knowledge at the priority date. Accordingly, the issue is not whether it was obvious to conduct a literature search of a particular kind with a view to acquiring information, but whether the information that would have been obtained from the search had already entered the body of common general knowledge: Minnesota v Beiersdorf at 295; Astra at [45]. No question arises in this case regarding the results of a routine literature search.
  3. The High Court also held in Astra (at [50]–[53]) that obviousness was to be determined by asking whether a hypothetical non-inventive skilled addressee, equipped with the common general knowledge as at the priority date, would have taken steps towards the invention “as a matter of routine” in the expectation that they might well produce the invention or some other useful result (endorsing statements in Wellcome Foundation Ltd v V.R. Laboratories (Aust) Pty Ltd [1981] HCA 12; (1981) 148 CLR 262 (Wellcome) at 286 and Olin Mathieson Chemical Corporation v Biorex Laboratories Limited [1970] RPC 157 (Olin) at 187-188). The High Court has therefore insisted on the two elements: (1) being led as a matter of routine to the desired result; and (2) having a reasonable expectation of achieving that result.
  4. In so holding, the High Court rejected a less demanding “worth a try” or “obvious to try” test. Astra therefore stands for the rejection of a line of United Kingdom authority to the effect that “all of the courses of action which present themselves without the exercise of invention are obvious”: Pharmacia Corporation v Merck & Co Inc [2002] RPC 775 at 818 (see Astra at [54] per Gleeson CJ, Gaudron, Gummow and Hayne JJ). Their Honours explained that “[t]he tracing of a course of action which was complex and detailed, as well as laborious, with a good deal of trial and error, with dead ends and the retracing of steps [a description taken from the judgment of the trial Judge] [was] not the taking of routine steps to which the hypothetical formulator [would be] taken as a matter of course” (at [58]; also per Callinan J at [185]).
  5. I am aware of the observations made by the English Court of Appeal in relation to the High Court’s judgment in Astra in Angiotech Pharmaceuticals v Conor [2007] EWCA Civ 5; [2007] RPC 20 at [39]–[45] which were quoted by Kitchin J in Generics v Lundbeck at [73]. Those observations are of no relevance to my task.
  6. Astra also stands as authority for the following propositions:
  7. In Gambro Pty Ltd v Fresenius Medical Care South East Asia Pty Ltd (2004) 61 IPR 442 (Gambro), Allsop J pointed out (at [353]) that it is wrong to divide up the inventive process into conception and practical implementation: it is the whole that must be considered and it suffices that there is only one inventive step involved (see also National Research Development Corporation v Commissioner of Patents [1959] HCA 67; (1959) 102 CLR 252 at 262).
  8. Evidence of the patentee’s own lack of success in earlier attempts is probative of the inventive nature of a successful solution to a problem (Wellcome at 287); the question of what weight is to be given to that evidence will depend on all the circumstances including the patentee’s qualifications and experience in the field of the invention. Inventions that reveal an “unfelt want or need” are as likely or sometimes more likely to involve an inventive step as those that fulfil a “long-felt want” (Wellcome at 287; Astra at [38]).

Obviousness in relation to the product claims and the method claim

  1. Obviousness means different things in relation to the product claims (claims 1–5) and the method claim (claim 6). Alphapharm criticises Lundbeck for failing to make that distinction.
  2. In the case of the method claim, the question of obviousness assumes as the starting point the goal of obtaining the (+)-enantiomer. In relation to the product claims, on the other hand, the question is whether that goal was itself an obvious one to pursue. Common general knowledge of methods available to resolve racemates may, however, be relevant to the obviousness of the product claims. It is relevant to the question whether it was obvious to want to obtain (+)-citalopram to ask whether it was part of common general knowledge that there were or were not available straightforward, inexpensive methods of doing so that were expected to succeed.
  3. Thus, while I agree with Alphapharm that the criterion of inventive step is conceptually different in the contexts of the product and method claims, the obviousness or non-obviousness of the method claimed is potentially of relevance to that of the product claims.
  4. In terms, the question “was the (+)-enantiomer of citalopram obvious?” conveys little meaning without an assumed background. Part of that background is that the question is being asked in connection with a contention that the (+)-enantiomer, being one of two enantiomers of a patented racemate, was not itself a patentable invention at the priority date. The obviousness question to be asked in relation to the product claims is whether it was obvious to the hypothetical skilled non-inventive addressee or team to “want to have” the (+)-enantiomer of citalopram as a drug for the treatment of depression. Was the aim of obtaining (+)-citalopram an “obvious goal” or “obvious desideratum”?
  5. Senior counsel for Alphapharm embraced the “obvious desideratum” terminology. However, he appeared to equate it with “mere conception”. But merely to conceive of obtaining something is a measure far less demanding than that of “obvious to want to have” or “obvious to desire to obtain”, which lies at the heart of “obvious goal” or “obvious desideratum”. It was part of the common general knowledge that racemates consisted of (+) and (–) enantiomers in equal quantities and that the resolution of some racemates into their enantiomers had occurred. Therefore, the obtaining of the separate (+) and (–) enantiomers of citalopram was conceivable. The obviousness of the invention of (+)–citalopram requires more than this.
  6. It is not required, however, in order for Alphapharm to establish obviousness in relation to the product claims, that it establish that it was obvious to want to have the (+)-enantiomer specifically. To obtain the (+)-enantiomer is also to obtain the (–)-enantiomer. At the priority date it was not known where the therapeutic benefits of citalopram lay – whether they lay in both enantiomers (and if so in what proportions) or only in one. Accordingly, when I speak of a desire to obtain the (+)-enantiomer, I mean a desire to obtain the (+) and (–) enantiomers.
  7. In the case of a particular product, secondary evidence such as evidence that there was or was not a long felt need for, and therefore motivation to obtain, the product, that the product has been attended by commercial success, and that there has been copying by others, such as competitors, may assume importance: see Lockwood v Doric (No 2) at [115] - [116].

The field of the invention

  1. For the purpose of determining obviousness, it is necessary to identify the field of the invention in order to identify the relevant skilled but non-inventive addressee or team, and the common general knowledge possessed at the priority date. The field of the invention is the “art” to which the invention claimed relates: Gambro at [349] and authorities there cited.
  2. Alphapharm describes the field of the invention as “the development of a potential new form of a drug, by a hypothetical entity in Australia, employing or consulting with a team of experts as discussed [later in its submissions]”.
  3. Lundbeck, on the other hand, submits that the field is: “(+)-citalopram and its salts, compositions of (+)-citalopram and its salts, and methods of making (+)-citalopram”. This description is, generally speaking, merely a summary description of the products and method the subject of the Patent, and is not, in my view, a description of the field of an invention.
  4. I would describe the field of the invention as the field in Australia of the development and operation of SSRIs for the treatment of depression.

The relevant addressee

  1. While evidence of the efforts of the inventor and of the efforts (or absence of them) of the patentee’s opponent and others is admissible as relevant to the issue of obviousness (see, for example, Wellcome at 287), the question is an objective one requiring the creation of a hypothetical person, skilled but non-inventive in the art, or a hypothetical team of such persons. The concept of common general knowledge at the priority date must be proved by evidence, and the assumption made that the hypothetical person or team was possessed of that common general knowledge.
  2. The steps that must be taken in order to resolve the present issue must be taken at a level of abstraction. It would perhaps be surprising if the inventor or any particular expert witness called by a party challenging the validity of the patent conformed, as at the priority date, precisely and in all respects to the notional person skilled in the art and possessed as at that date the common general knowledge, no more and no less, than that established by the evidence. The need to exercise some caution in relation to acceptance of the evidence of the inventor was recently emphasised by Jacob LJ in his Lordship’s dissenting judgment in Nichia Corporation v Argos Ltd [2007] Bus LR 1753 (CA).
  3. It is common ground that the relevant addressee would be a team that included or consisted of medicinal chemists. Medicinal chemists identify, design and synthesise drugs for therapeutic use. Some of their skills overlap with those of synthetic chemists and formulation chemists. The medicinal chemists would have tertiary qualifications up to a PhD in chemistry or significant practical experience. It is agreed that they would have been likely to consult with pharmacologists and psychiatrists, although it is not agreed whether or not pharmacologists and psychiatrists would also be members of the hypothetical team.
  4. The relevant addressee may be different for the different claims of the Patent. The Patent deals with a molecule and its salts (claims 1 and 2), pharmaceutically acceptable compositions of the molecule and its salts (claims 3, 4 and 5), and a method for producing the molecule (claim 6). Claims 1, 2 and 6 are clearly within the province of medicinal chemistry. The background knowledge and experience of pharmacologists and psychiatrists is also potentially indirectly relevant to those claims. Since claims 3, 4 and 5 relate to post-synthesis stages of drug development, pharmacologists and psychiatrists are more likely to be members of the team, or at least consultants to it, in respect of these claims. Chemists with skills in the formulation of pharmaceutically acceptable dosage form will also be involved.
  5. In their submissions, the parties did not distinguish between the various claims of the Patent for the purpose of identifying the hypothetical addressee or team.
  6. In my opinion, the relevant addressee for all claims is a team of experienced medicinal chemists, either possessing skills in formulation, or having access to advice from formulation chemists, and having access to advice from both pharmacologists and psychiatrists.
  7. In its submissions, Lundbeck proffered the following more detailed and perhaps narrower description based on Professor Davies’s affidavit:
116. ...the skilled addressee, in this case, will compromise a medicinal chemist (experienced in the design, synthesis and modification of chemical compounds for biological evaluation and in determining structure activity relationships for optimisation of desired biological activity) with a PhD in chemistry and a few years experience working in a laboratory of a pharmaceutical company, a person with a Bachelor’s Degree and three to four years of similar experience, or a technician with ten to fifteen years of experience.

117. The skilled addressee is likely to:
(a) be guided by a psychiatrist/clinician able to identify areas of unmet need and to conduct clinical trials; and
(b) consult pharmacologists particularly with respect to the conduct of in vitro biological assays and in vivo animal studies.

118. The psychiatrist/clinician and pharmacologists are not involved, however, in the development of the invention per se and do not form part of the addressee “team”.

I do not see this description, although it is more detailed, as being significantly different from that which I gave in the preceding paragraph, at least provided the word “experienced” is understood to include those undertaking medicinal chemistry in universities and research institutes.

  1. For convenience, in the following discussion I may refer to the relevant addressee as a medicinal chemist. However, in fact he or she would be a member of a team as described above, and would not be working in isolation.
  2. Lundbeck asserts that none of Alphapharm’s witnesses fit the description of the skilled but non-inventive addressee. It submits that, as a result, Alphapharm has led no evidence as to what was common general knowledge in Australia at the priority date. Lundbeck attacks, in particular, the evidence of Professor Banwell who, at the priority date, was an academic chemist involved in synthesis of chemical compounds, and had never resolved a racemate into its enantiomers where that route of resolution had not previously been published. As will appear, I do not accept that Professor Banwell’s evidence was entitled to no weight on this ground, although because of his comparative lack of relevant practical experience, I did not find his evidence as cogent as that of Professor Davies.
  3. No single witness conformed entirely to the hypothetical skilled but non-inventive addressee as at the priority date. In summary, the expert witnesses were as follows:
Alphapharm witnesses:
Professor Banwell
See below – based in Australia
Dr Rowe
Formulation chemist with experience in drug development and testing – based in Australia
Professor Day
Pharmacologist, toxicologist and rheumatologist with experience in the development and conduct of clinical studies of numerous pharmaceutical drugs – based in Australia
Professor Mitchell
Academic and clinical psychiatrist; former member of the Australian Drug Evaluation Committee (ADEC) and as such responsible for assessing and advising the TGA on psychotropic medications and associated clinical trial material – based in Australia
Lundbeck witnesses:
Professor Davies
See below – based in the UK
Dr Robertson
Medicinal chemist currently in industry (initially a synthetic chemist) - based in the UK at the priority date; now based in Australia.
Professor Montgomery
Psychiatrist; former member of the Committee on Safety of Medicines UK and as such involved in assessing antidepressants for regulatory approval; also Chairman of Lundbeck’s Global Advisory Board of Experts and as such recommended to Lundbeck that studies suggested worthwhile to investigate (+)-citalopram.

(Dr Bøgesø and Mr Gundertofte of Lundbeck gave evidence of the facts relating to the development of (+)-citalopram within Lundbeck, not expert opinion evidence (see [243] ff below).)

  1. Two Professors of Chemistry were called, one by Alphapharm, the other by Lundbeck. In the following paragraphs, I give an account of their qualifications and experience.
  2. Professor Banwell is Professor (Level E2) of the Research School of Chemistry, Australian National University – a position he has held since 2005. Since graduating from the University of Wellington in the 1970s and taking his PhD degree in 1979 from that University, he has held a number of teaching and research positions in Australia and overseas. He was appointed Professor in the Research School of Chemistry, Australian National University, in 1999.
  3. Professor Banwell is a Fellow of the Royal Australian Chemical Institute and a Fellow of the Australian Academy of Science. He is associated with the Organic Chemistry Division of the Royal Australian Chemical Institute, an organisation that covers many aspects of medicinal chemistry. He is a member of the Australian Research Council’s College of Experts acting within the field of chemistry. He acted as a chemistry consultant for the former CSIRO Division of Molecular Science (Fine Chemicals Program) from 1995 to 2004. Currently he is a synthetic and medicinal chemistry consultant for Biota Holdings Pty Ltd, Cryptopharma Pty Ltd, and Progen Industries Pty Ltd. He states: “the roles which I have held have involved activities in both organic and medicinal chemistry”.
  4. Professor Banwell has authored and co-authored approximately 200 publications and has been named as an inventor or co-inventor on six PCT-level patents.
  5. Professor Davies is Chairman of Chemistry at the University of Oxford and is the Waynflete Professor of Chemistry of that University.
  6. Professor Davies also graduated in the 1970s, taking his PhD degree in 1975 from the University of Oxford. In 1980, he received a DSc degree from the University of Paris.
  7. After completing his DSc degree, Professor Davies returned to Oxford as an academic. At that time he began acting as a consultant to several pharmaceutical companies on their research into, and development of, pharmaceutical compounds. Those consultancies gave him a detailed knowledge of much of the companies’ ongoing research in the 1980s. In addition, companies funded studentships with him, which meant that he had frequent visits and interactions with the companies’ scientists.
  8. Professor Davies’s particular expertise was in stereochemistry. While he was consulted on the preparation of racemic diastereomers, he was not consulted on the preparation of single enantiomer compounds during the 1980s to any real extent. In his experience, there was little interest in industry at that time in the resolution of racemates. Professor Davies states that molecules that were first made as racemates tended to proceed as racemates through development, whereas molecules that were first made as individual enantiomers (those based on naturally occurring homochiral molecules) proceeded through development as single enantiomers.
  9. Professor Davies was the founder (in 1989), and is still Editor in Chief of Tetrahedron Asymmetry, which he describes as a leading journal that reports advances in knowledge of all aspects of stereochemistry in organic, inorganic, organometallic, physical and bioorganic chemistry. As Editor in Chief, Professor Davies has read nearly every submission to that Journal over the last 17 years – some 600 to 700 papers a year.
  10. Over the period from 1974 to 2006, Professor Davies has authored or co-authored some 408 learned articles. Over the period 1984 to 1998, he received nine awards in recognition of his work. From 1986 to date, he has been a member of 13 chemistry related committees as well as editor or member of the editorial board of some seven learned journals.
  11. In 1992, along with others, Professor Davies founded Oxford Asymmetry Ltd, which became a division of Oxford Asymmetry International plc. In his affidavit, Professor Davies states that the mission of Oxford Asymmetry Ltd was “to provide pharmaceutical companies with homochiral compounds of interest on any desired scale, from small amounts as a first preparation for biological evaluation, to commercial quantities”. Oxford Assymetry Ltd was engaged in the preparation of compounds with high enantiomeric purities and specialised in three principle methods for achieving this: using single enantiomer “chiral pool” starting materials; asymmetric synthesis; and chiral separations by various methods (resolutions). Professor Davies states that Oxford Asymmetry Ltd was one of the first companies in the world to specialise in producing synthetic homochiral compounds. He further states that, when his company was established, there was scepticism about the need for its services and he was told many times that the industry did not need to resolve racemic compounds on a regular basis. Nonetheless, according to Professor Davies, the industry changed dramatically in the 1990s and the company’s workforce grew from three employees to 250 employees by the time the company was sold in 2000.
  12. Professor Davies agreed that the hypothetical team would include not only medicinal chemists experienced in the area who were working in industry, but also those working in a university or research institute who were frequently consulted by industry. There was evidence of the sharing of knowledge of chemists from industry and from academia at conferences. Professor Davies engaged in these activities. So did Professor Banwell, though not to the same extent. This is not to detract in any way from the qualifications, experience and eminence of Professor Banwell. It is only to say that his contact with the pharmaceutical industry has not been as frequent or sustained as has that of Professor Davies. As indicated above, Professor Davies had close and frequent contact with the industry at an earlier time than did Professor Banwell. Until his consultancies as a medicinal chemist with three pharmaceutical companies in recent times, Professor Banwell was exclusively in academia. On any question as to the interests, concerns and practices within the pharmaceutical industry in 1988, I regard Professor Davies as the more qualified.
  13. I have come to the conclusion that it is not possible to exclude in its entirety the evidence of any of the expert witnesses on the basis that the witness was not qualified to give evidence relevant to the issue of the knowledge, understandings and expectations of the hypothetical skilled but non-inventive addressee as at the priority date. However, this is far from saying that each of the expert witnesses’ testimony was entitled to equal weight on all matters about which they testified.

The relevant priority date

  1. As noted earlier, there is no dispute that the relevant priority date is 14 June 1988.

Common general knowledge

  1. In Minnesota v Beiersdorf, Aickin J described the notion of common general knowledge (at 292):
The notion of common general knowledge itself involves the use of that which is known or used by those in the relevant trade. It forms the background knowledge and experience which is available to all in the trade in considering the making of new products, or the making of improvements in old, and it must be treated as being used by an individual as a general body of knowledge.

As noted earlier, it was held in Astra that information recorded in a document, even a document widely circulated within the art, is not part of general common knowledge merely because the skilled addressee could be expected to locate it. The question is whether it is “generally accepted without question” or “generally regarded as a good basis for further action” by the bulk of those in the art: Minnesota Mining and Manufacturing Co v Tyco Electronics Pty Ltd [2002] FCAFC 315; (2002) 56 IPR 248 at [100], quoting Blanco White TA, Patents for Inventions and the Protection of Industrial Design (5th ed, Stephens, London, 1983) at [4-207].

  1. Both sides agree that the common general knowledge included knowledge of:

The chemistry of chiral molecules

  1. The evidence of witnesses on both sides established that the common general knowledge of a medicinal chemist at the priority date of 14 June 1988 included the information set out under the heading “General Chemical Background” (see [60]–[75] above). It included knowledge that:

(a) a molecule with a single chiral centre is composed of two enantiomers;
(b) generally speaking, when a chiral molecule is synthesised, the two enantiomers are produced in equal proportions, thus creating a racemate;
(c) the absolute configurations of the two enantiomers are designated R and S and can be drawn using knowledge of the structural formula of the chiral molecule;
(d) enantiomers differ in the physical property of the rotation of plane-polarised light to the right (or clockwise) (+), or to the left (or anticlockwise) (–), but experimentation is required to designate which of the R and S enantiomers of a particular chiral molecule is (+) and which is (–);
(e) in the case of some racemates, the (+) and (–) enantiomers have different pharmacological activity;
(f) the pharmacological activity of a racemate could lie in one enantiomer exclusively, both enantiomers equally, or in both enantiomers in unequal proportions; and
(g) there was no way of knowing which of the possibilities in (f) applied if a molecule only existed as a racemate.

  1. There was some dispute over whether the common general knowledge in relation to (e) included knowledge that one enantiomer may in fact have antagonistic effect, with the result that the therapeutically active enantiomer, once it was isolated, would have greater beneficial effect than the racemate. Professor Day said that this was part of common general knowledge in 1988, but Professor Montgomery disagreed. The preponderance of the evidence is that the general understanding was that at the most, all of the therapeutic benefits of the racemate could reside in one enantiomer, and that the other enantiomer was mere “ballast”. While some skilled addressees may have known of the possibility of antagonistic effect from the other enantiomer, I am not persuaded that this knowledge was part of common general knowledge in 1988.

The content of the Australian Citalopram Patent and further chemical background forming part of common general knowledge

  1. The Australian Citalopram Patent was published at the priority date of the Patent, although citalopram was not yet commercially available, either in Australia or overseas. Dr Bøgesø said that by as early as 1980 “citalopram was in development, and it was known within Lundbeck, the scientific community and the industry generally, to be extremely selective in its activity”. A letter dated 12 June 1988 from Dr Donald F Smith to Dr John Hyttel of Lundbeck stated that “...certainly citalopram is patented by Lundbeck. The whole world knows about that compound...” [my emphasis].
  2. All that matters is that it is common ground that the relevant addressee would have the Australian Citalopram Patent as the starting point. That addressee would know the structural formula of citalopram and would know that it was an effective anti-depressant drug.
  3. It is agreed that given the structural formula of citalopram, the skilled addressee would have recognised immediately that it was a chiral molecule. The synthesis taught by the Australian Citalopram Patent would produce a racemate composed in equal proportions of a (+)-enantiomer and a (–)-enantiomer. It is agreed that it was not known whether the pharmacological activity of the citalopram racemate lay in one enantiomer exclusively, in both enantiomers equally, or in both enantiomers in unequal proportions. Other possibilities are to be found in the expert evidence. Professor Day referred to seven possibilities in his affidavit and he expanded these to nine in the witness box (see [391] below). It is common ground that it was impossible to discern from the Australian Citalopram Patent or otherwise the precise effect that the individual enantiomers had: it was necessary to separate and test them.
  4. The common general knowledge at the priority date also included knowledge that:
  5. The chemistry background outlined in the paragraphs that follow formed part of the common general knowledge in 1988, and is relevant to the evidence relating to the issues to be discussed below. The outline builds on the discussion of General Chemical Background at [60]–[75] above, on the evidence of Professors Banwell and Davies, and on Morrison and Boyd.
  6. Carbon readily forms rings involving a number of carbon atoms connected together. Citalopram contains two six-carbon rings and one ring that contains four carbon atoms and an oxygen atom (the component known as dihydroisobenzofuran). The formation of the dihydroisobenzofuran ring was one of the key issues in the evidence relating to the method claim. The method for making (+)-citalopram involves creating this ring in a stereoselective way, that is, in a way that does not produce a racemate. The method uses a precursor called a diol. A diol is a molecule that contains two hydroxyl (OH) groups. These two groups are also known as alcohols. The method requires those hydroxyl groups to be brought together and one oxygen atom to stay, while its partnering hydrogen atom and the other hydroxyl group are “cleaved off” as a water molecule.
  7. Lone pairs (the extra electrons in an atom’s outer shell that are not involved in bonding) are important for interactions between molecules because they can be used to form new covalent bonds. In these proceedings, lone pairs were referred to as the “sticky handles” of a molecule.
  8. A molecule that has lone pairs or sticky handles is called a nucleophile. The lone pairs are attracted to the nuclei (in particular, the protons) of atoms in other molecules. The molecule citalopram is a nucleophile. In citalopram, atoms of oxygen (with its two lone pairs) and nitrogen (with its one lone pair) can function as sticky handles.
  9. Nucleophiles often form bonds with electrophiles. Electrophiles are deficient in electrons and carry a positive charge or partial positive charge. This may be because there is a large difference in the number of protons associated with two covalently bonded atoms (for example, in hydrogen chloride, hydrogen has one proton and chlorine has 17 protons) – a phenomenon known as electronegativity.
  10. An important type of reaction of nucleophiles is the nucleophilic substitution reaction. This occurs when a nucleophile bonds with an electrophile and “kicks off” a group in the process. An atom with a lone pair (from the nucleophile) “attacks” the positively charged atom of the electrophile, substituting itself for the leaving group (the most electronegative atom attached to that positive atom). The leaving group acquires the lone pair. For our purposes, it is relevant to consider only electrophiles that contain carbon as the positively charged atom (due to it being bonded to a more electronegative atom or group of atoms).
  11. There are two main mechanisms by which nucleophilic substitution can occur. These are distinguished by the descriptors SN1 (unimolecular nucleophilic substitution) and SN2 (bimolecular nucleophilic substitution). In substance, the distinction depends on whether the substitution occurs in one step or two steps. Confusingly, the SN1 reaction involves two steps: it is called “1” because the important rate-determining step involves only one molecule (the electrophile). The SN2 reaction involves one step: it is called “2” because the important rate-determining step involves both the nucleophile and the electrophile simultaneously.
  12. The first step of the SN1 reaction involves loss of the leaving group from the electrophile to give a positively charged intermediate molecule. Loss of an electron pair from a central carbon atom means that it has only three electron pairs around it. The most favourable structure for a molecule containing a carbon atom and three adjoining atoms is trigonal planar (flat). In the second step of the SN1 reaction, the nucleophile attacks the intermediate flat molecule. Being flat, there is an equal probability that the nucleophile will attach to one side or the other of the intermediate. Therefore, if a single enantiomer of the electrophile is used, the SN1 process always results in a racemate. Professor Davies said that a first year undergraduate would put aside the SN1 reaction for this reason.
  13. In the case of the single step of the SN2 reaction, bond-making and bond-breaking occur simultaneously. The nucleophile attacks the carbon atom at the same time as the leaving group leaves. Importantly, the nucleophile must attack the central carbon atom at or close to 180° from the leaving group. There is no flat intermediate. Therefore the electrophile maintains its original stereochemistry. If the electrophile is a single enantiomer, the SN2 process will result in a single enantiomer. It was agreed that it would be necessary to proceed via an SN2 reaction in order to resolve the diol precursor (a single enantiomer) stereospecifically.
  14. The rate of the SN1 reactions depends on the rate of formation of the intermediate. For SN2 reactions, the rate depends principally on molecular shape and orientation, because the attacking nucleophile and the leaving group need to line up correctly (at 180° or close to it) in order for a fruitful reaction to result. The position can be illustrated by a pen and its cap. It is only the 180° alignment that immediately allows the pen to enter its cap, although with some small difficulty and delay an angle close to 180° will also permit it to do so. If the angle of attack in an SN2 reaction is not 180° but is close to it, the process will be slower. If the angle is not sufficiently close to 180°, the pathway will not work at all.
  15. Ring formation or closure involves bringing together chains of atoms. The ease of ring closure depends on the molecular shape of those chains. As described in the General Chemical Background at [60]–[75] above, the most favourable molecular shape involves maximum separation between electron pairs. In the case of a chain of carbon atoms, the most favourable shape involves the hydrogen atoms and adjacent carbon atoms being configured in what is known as a staggered conformation. If the electron pairs are near to each other, there is an eclipsed conformation, which is highly disfavoured due to bond-bond repulsion. The following diagram illustrates the staggered and eclipsed formations:

2008_55911.jpg


  1. In a saturated system (one that contains no carbon-carbon double bonds and is said to be “saturated” with hydrogen atoms), rotation around bonds is unrestricted, so the two ends of the chain can be brought close together in such a way that a staggered conformation is maintained. Further, an SN2 reaction is readily achievable, since the nucleophile can achieve a trajectory of close to 180° without introducing strain or significant eclipsing interactions.
  2. In an unsaturated system (one that contains a carbon-carbon double bond and therefore less hydrogen atoms), the two ends of the chain cannot approach so easily due to the rigid shape (trigonal planar) around the double bond. In order to obtain ring closure, it is more likely that one of the connecting atoms will have to eclipse the rest of the molecule, which is disfavoured. Further, because of the geometrical constraint of the double bond, a nucleophile in an SN2 reaction can not approach from 180°: the angle of attack is, at best, 140°.
  3. In the case of citalopram the ring is unsaturated because it contains a carbon-carbon double bond. Professor Davies said that an unsaturated system would not readily close to a ring incorporating oxygen since it would involve significant eclipsing interactions, and a trajectory close to 180° is not readily achievable. He said that ring closure would be unexpected. Either the reaction would not take place, or it would be so slow that other reactions, such as polymerisation, would compete. Professor Banwell, on the other hand, said that by analogy with a fully saturated system, an unsaturated system would also achieve ring closure. Both experts agreed that trying the SN2 ring closure on the racemic diol would have shown whether the ring formation was feasible, but would not have informed on the overall stereochemical outcome of the process.

What happened at Lundbeck before the priority date

  1. Two witnesses called by Lundbeck were closely involved in research towards the making of (+)-citalopram: Dr Klaus Peter Bøgesø and Mr Klaus Gundertofte. The Patent named Dr Bøgesø and a third employee of Lundbeck, Dr Jens Perregaard, as the inventors, and Lundbeck as the assignee of the invention. Dr Bøgesø and Mr Gundertofte gave evidence of the course of events that led to the obtaining of (+)-citalopram. Lundbeck did not call Dr Perregaard although it appears that he was available.
  2. The evidence of Dr Bøgesø and Mr Gundertofte is relevant to the issue of obviousness as it relates to both the product claims and the method claim. They were experienced medicinal chemists who desired to obtain the enantiomers of citalopram. I consider their testimony to be important on the issue of obviousness.

Dr Bøgesø

  1. Dr Bøgesø commenced work with Lundbeck in 1971 as a research medicinal chemist. Since then, he has published around 50 scientific papers in peer reviewed journals on medicinal chemistry, drug discovery, pharmacology and biology. He is the named inventor on some 26 patents including the Patent and the Australian Citalopram Patent. He is currently the Vice President for Lundbeck Research Denmark at Lundbeck.
  2. Dr Bøgesø has been involved in drug development of a number of different compounds targeting diseases of the central nervous system. It was in 1972 that he was one of the inventors of citalopram, and beginning in 1980, he led attempts by the medicinal chemistry group within Lundbeck to resolve it into its enantiomers. This was, however, only a part-time or intermittent activity concerning one of several research projects in which he was involved. He said he viewed it as an academic and personal project, rather than a commercial one, while acknowledging that it would provide pharmacological information of interest to Lundbeck.
  3. The “project” of preparing the individual enantiomers extended from 1980 to 1988 and was one of the most difficult pieces of research that Dr Bøgesø had ever been involved in.
  4. When he joined Lundbeck in 1971, he was assigned to make new chemical compounds as part of a number of projects to produce pharmaceuticals which were believed to be effective in treating disorders, such as depression. One such project involved compounds which personnel at Lundbeck thought might be effective as SSRIs. As part of that project, he and other members of his team synthesised approximately 60 new chemical entities, including citalopram, which was first made in August 1972. Of citalopram, Dr Bøgesø stated:
When tested citalopram proved to be a highly selective SSRI and went on eventually to become a hugely successful anti-depressant treatment worldwide. I (with my colleague A.S. Toft) am a co-inventor of citalopram. Citalopram was not in fact approved for sale on prescription until 1989, some seventeen years after first preparation.

  1. From the first making of citalopram in 1972 and its resolution in 1988, the Medicinal Chemistry Department at Lundbeck searched for effective compounds against diseases of the central nervous system, including more effective anti-depressants. Over all, between 1965 and about 1988, there were 3945 new compounds synthesised, more than 60 of which were further developed in one way or another. Of these, 15 went to the clinical phase and by 1988, three of those were on the market and another four were in the late stages of development.
  2. Dr Bøgesø’s Department’s research was directed to identifying one or more lead compounds with some activity of interest in each project, after which the objective was to make new derivatives of that lead compound. Dr Bøgesø states:
The new compounds in the SSRI project and some compounds in other projects were optically active. As a general matter we did not prepare resolved enantiomers of such compounds. The principal reason for this was that resolutions were time consuming, difficult and sometimes impossible to achieve. The approach in Lundbeck and, I believe, in most companies, was to make and test as many new derivatives as possible, thereby elucidating structural/activity relationships.

In some instances in the 1970s and 1980s, Lundbeck did attempt resolutions, but only when there was a very good reason to do so, as in the case of the family of molecules called within Lundbeck the “indanes”, comprising four different stereoisomers.

  1. Dr Bøgesø states that by 1980, citalopram was in development, and that it was known within Lundbeck, within the scientific community and within the industry generally, that citalopram was extremely selective in its activity. Dr Bøgesø states:
Because of this high selectivity, there was no interest within the industry that I was aware of, in investigating the separate enantiomers in order to look for new antidepressant medicines. However, as a co-inventor, I was interested in this from an academic and personal point of view, and it would have been useful for Lundbeck to have some data about the enantiomers. As I have indicated above, during my work on the indane project, I had gained experience with resolution techniques. Also, the indanes had two phenyl rings and an amine group which bore some resemblance to citalopram, so I decided to try a number of the same techniques that had been successful in the indane project, on citalopram.

Lundbeck sought to emphasise that Dr Bøgesø was interested in resolving citalopram “from an academic and personal point of view”.

  1. Dr Bøgesø states that the “classical method for attempting to resolve racemic amines was (and still is) to use fractional crystallisation (described at [87] above). This technique requires that crystalline salts be formed.
  2. Dr Bøgesø states that a problem he had already faced in the 1970s was that citalopram had proved to be an extremely difficult molecule from which to make crystalline salts. The only salts he and his team had managed to produce in crystalline form were the oxalate and hydrobromide salts. However, neither oxalic acid nor hydrobromic acid is chiral, so they would not permit resolution into enantiomers. Dr Bøgesø states: “This low propensity to form any crystalline salts was a major problem in my attempts to resolve citalopram”.
  3. Dr Bøgesø attempted to resolve citalopram using various resolving agents. They were the (+) and (–) forms of five acids, of which he found that only the (+)-enantiomer of camphorsulfonic acid produced crystals with citalopram. However, he was unable to find conditions in which those crystals selectively precipitated as a single diastereomeric salt of citalopram.
  4. Dr Bøgesø used a range of techniques in order to try to promote crystallisation, although he did not record them all. He recounts his various attempts to resolve citalopram commencing in about June 1980. Exhibited to his affidavit are such records as he kept of his work.
  5. In December 1983, Dr Bøgesø attended a course on “Strategies for Optical Resolution” held in Stockholm, Sweden. The course was conducted by a leading expert on the resolution of racemates into their enantiomers, Professor A Collet. The course brought to Dr Bøgesø’s attention a new resolving agent, bis naphthyl phosphoric acid, which had been invented as a resolving agent by Professor Collet. Dr Bøgesø synthesised some of that acid, but had no success in using it to resolve citalopram.
  6. Dr Bøgesø also continually reviewed the literature for successful resolutions that he might adapt to try with citalopram.
  7. By about 1984, it was clear to Dr Bøgesø that direct resolution of citalopram was extremely difficult and that he would have to consider other routes. He had not previously attempted to resolve citalopram by asymmetric synthesis using a precursor because it is not possible to “resolve” an intermediate if there is no chiral carbon present in the molecule. Dr Bøgesø explained that the chiral centre in the preparation of citalopram is introduced only very late in the synthetic process, at the stage where the dicarbinol base of citalopram (the diol) is produced. This, he explained, was the penultimate step in Lundbeck’s production of citalopram.
  8. Dr Bøgesø and his colleagues considered but rejected the technique of resolving the diol. Their main reason was that they did not believe it would work because the next step, conversion to the final citalopram molecule, would involve chemistry on the chiral carbon which they thought would result in full or partial racemisation of the enantiomer. Dr Bøgesø explained:
The strong acid used in the final step of the production process to convert the diol into citalopram (the ring closure step) would lead to formation of an intermediate carbonium ion [also known as a carbocation] on the central carbon, which has only three bonds, and is therefore a flat molecule. The remaining hydroxyl group would then attach to the central carbon, to close the furan ring, but could approach from either side. This would therefore result in racemisation, and we would be no further forward.

  1. Dr Bøgesø referred to further potential problems with the diol option. First, the process Lundbeck was employing in the production of citalopram did not involve the isolation of the diol – the diol “was merely a transient intermediate in the production process, and it was not easily isolated in pure form”.
  2. Secondly, very few acids formed a crystalline salt with citalopram, and the experience at Lundbeck was that the diol behaved very similarly to citalopram so far as salt formation on the amine group was concerned. There was therefore no reason to believe that the diol would be any more likely to crystallise as diastereomeric salts than citalopram itself was, or that even if it did crystallise, it would selectively crystallise only one of the two enantiomers.
  3. Dr Bøgesø stated that the structure of the diol, with two hydroxy (OH) groups, potentially offered a further method of resolving the racemate, namely the creation of an ester on one of the hydroxy groups using an optically pure chiral acid chloride (to produce two diastereomeric esters), followed by resolution by conventional HPLC (or perhaps, fractional crystallisation). However, a third potential problem was that it might not be possible to create a mono-ester of the diol on only one of the hydroxy groups – both groups on the diol were, in principle, susceptible to formation of an ester. If esterfication of both hydroxy groups occurred, the result would be a mixture of compounds.
  4. A fourth potential problem with the diol-ester strategy was the stability of any ester that formed (assuming it was possible to create a mono-ester). Any ester used had to be stable enough to enable separation of the diastereomers by chromatography or crystallisation, yet labile enough to be removed under conditions that would not induce racemisation.
  5. Even if these various problems were overcome, there would remain an ester from which it would be necessary to cleave the acid moiety off, without affecting any other part of the molecule. According to Dr Bøgesø, this could have posed its own problems.
  6. These various concerns were all factors which contributed to the view held by Dr Bøgesø and his colleagues that the diol route would be more problematic than attempting to resolve citalopram itself. Moreover, the diol route would not eliminate the major problem of racemisation upon the ring closure.
  7. In late 1983, Dr Bøgesø and his team embarked upon alternative ways to resolve citalopram.
  8. The first alternative was to attempt to produce derivatives of citalopram, resolve those derivatives and then convert them back into the single enantiomers of citalopram. The first derivative selected was desmethyl citalopram. Another was the N-benzyl derivative. However, Dr Bøgesø was unable to produce any crystals of the citalopram derivatives.
  9. In the mid 1980s, Dr Bøgesø discussed with his co-workers and technicians the possibility of using other potential resolving agents. Indeed, on a lighter note, he recalls offering a bottle of whiskey if they managed to produce a crystalline form of citalopram with a resolving agent – he did not have to pay out on his offer.
  10. A further separation method of which Dr Bøgesø was generally aware, but of which he learned more from Professor A Collet at the “Strategies for Optical Resolution” course in Stockholm, was separation by means of HPLC (discussed in more detail at [302] ff below) . Dr Bøgesø explains HPLC in general, and chiral HPLC in particular. Chiral HPLC is used to separate chiral compounds into their individual enantiomers. In the 1980s, chiral HPLC was an emerging technology. Dr Bøgesø had read a few reports in the literature relating to the use of chiral HPLC to separate molecules, although they were all smaller than citalopram (up to roughly half its size). He was not aware of any compounds the size of citalopram having being separated by the use of this technique. Nonetheless, Dr Bøgesø suggested to his colleague, Klaus Gundertofte, a chemist who had been hired by Lundbeck in 1982 partly due to his experience with HPLC, that he explore the possibility. Mr Gundertofte attempted to do so but was not successful (see [287] ff below).
  11. Sometime between August 1985 and September 1986, Dr Bøgesø prepared a note of his experimental attempts to resolve citalopram. He concluded in that note that:
It is very unlikely that citalopram or N-derivatives can be resolved via salts with optically active acids.

Under the heading “Other possibilities” in the note, Dr Bøgesø set out his thinking on possible future strategies for resolving citalopram as follows:

(1) resolution of a derivative with the salt forming group close to the chiral centre, eg:

2008_55912.jpg

Followed by chemical conversion to citalopram.

(2) separation on chiral phase HPLC, eg on cellulose acetate or dextrin column.

Dr Bøgesø states that by the time he prepared that note, he had formed the view that some sort of asymmetric synthesis of the enantiomers of citalopram would have to be considered in more detail, rather than direct resolution of the citalopram molecule itself.

  1. According to the annual report for 1987 of Lundbeck’s Medicinal Chemistry Department, in the Spring of 1987 “the chemists were instructed by the citalopram project group to attempt once again to resolve citalopram” because Lundbeck often received “enquiries with regard to the pharmacology of the enantiomers”. According to the report, separation tests were conducted using HPLC with an optically active carrier both at the Danish Pharmaceutical University and on Lundbeck’s own equipment, but without success.
  2. Dr Bøgesø explained the steps that were taken between about August/September 1986 and late 1987/early 1988 that led to success. A “breakthrough” occurred in late 1987. Dr Bøgesø states:
At this stage of the project, towards the end of 1987, and some 7 years after starting, we decided to look again at the diol. I discussed the problem with Jens Perregaard. Our concerns remained that there was a low likelihood of success of resolving the diol, and we had no strategy to deal with the problem of racemisation. Nevertheless, we decided to try both the ester and salt strategies. I cannot recall how many reagents Jens Perregaard used in his attempts to make an ester with the diol, however, he was eventually successful using 2-methoxy-2-(trifluoromethyl)-phenylacetic acid chloride. I had never before used this reagent as it is a “shift reagent” for use in NMR analyses (ie an analytical tool), and I cannot recall why Jens Perregaard chose this particular reagent on this occasion.

Dr Bøgesø further states:

By utilising the basic ring-closure reaction that Jens Perregaard had first observed when trying to make the citalopram ester, we had inadvertently circumvented the problem of racemisation on ring closure. It turned out that this was a new method to convert the diol to the final citalopram molecule, while retaining the stereochemistry of the molecule.

  1. Further work was done on the diol route with a view to producing larger quantities of the enantiomers. In his affidavit, Dr Bøgesø states:
97. Using the basic ring closure mechanism we had developed starting from the observation by Jens Perregaard of the spontaneous ringclosure of an ester, we were able to convert this enantiomerically pure (–)diol, via an ester, to the pure (+)enantiomer of citalopram. The reaction was able to be performed at considerably larger scale than the original HPLC separation method.

98. This reaction is described in reaction scheme II in the escitalopram patent.

  1. Predictably, the annual report for 1988 of Lundbeck’s Medicinal Chemistry Department heralded the success. The relevant part of the report began:
As indicated in the Annual Report for 1987, the intensified attempts to resolve Citalopram were on the way to success, which indeed also happened immediately after the turn of the year. The method was based on a derivation of the “dicarbinol base” that is an intermediate in the production. Optically active α-methoxy-α-trifluormethyl phenyl acetic acid chloride may, under mild reaction conditions, selectively ‘over-esterize’ the primary alcohol group in the dicarbinol base. By means of preparative HPLC fractioning, performed several times, a complete separation was achieved in the two diastereomer esters. Through treatment with a strong base (tert. BuOK) it was ring-closed stereoselectively to citalopram.

Mr Gundertofte

  1. I turn now to the evidence of Klaus Gundertofte. Mr Gundertofte is a principal scientist in the Department of Computational Chemistry at Lundbeck. His thesis for his Masters degree (1981) concerned the use of specific reagents to synthesise heterocyclic compounds, and included the use of thin layer chromatography, liquid chromatography and both analytical and preparative HPLC.
  2. Mr Gundertofte explains that HPLC is a chemistry based tool for quantifying, analysing and preparing chemical compounds. I discuss HPLC in more detail at [302] ff below.
  3. In his Masters work, Mr Gundertofte used both analytical and preparative HPLC. Mr Gundertofte first used analytical HPLC in about 1977. He first used preparative HPLC, which was then a relatively new technique, when his university first obtained preparative HPLC equipment in about 1978. Upon completion of his Masters thesis in 1981, he was very experienced in the use of HPLC.
  4. Mr Gundertofte commenced work with Lundbeck in January 1982 as a medicinal chemist, and has been continuously employed by Lundbeck since then.
  5. For his first four or five years with the company, Mr Gundertofte devoted between 30% and 50%  of his time to working with HPLC in connection with various projects in the Medicinal Chemistry Department.
  6. Over the years, Mr Gundertofte has given presentations and seminars, both within Lundbeck and externally, on the use of preparative HPLC in medicinal chemistry. Following one such presentation at the Danish Technical University, he was asked to prepare a paper. He did so and the paper was published in the journal Dansk Kemi (Danish Chemistry): “Preparative HPLC – a valuable tool in pharmaceutico-chemical research” Dansk Kemi (1985) pp 49-53. The paper discussed the theoretical and practical considerations involved in using HPLC for preparative purposes in medicinal chemistry. The paper was published in February 1985, and Mr Gundertofte agreed that it would have been prepared in 1984.
  7. In or around 1987, Mr Gundertofte’s colleague, Henrik Pedersen, began taking over responsibility for the preparative HPLC activity at Lundbeck. Mr Gundertofte ceased working with HPLC at around that time, although his technicians still undertook HPLC work for him until about 1988.
  8. On 1 March 1989, Mr Gundertofte was promoted to the position of Head of Computational Chemistry at Lundbeck.
  9. When Mr Gundertofte began working at Lundbeck in 1982, one of his first tasks was to set up a preparative HPLC laboratory. While Lundbeck regularly used analytical HPLC in 1982 to test the purity of compounds or reaction mixtures, it did not have any preparative HPLC equipment. Mr Gundertofte’s responsibility included the selection, purchase and commissioning of such equipment. He sourced equipment throughout his first year at Lundbeck.
  10. Once the HPLC laboratory was established, Mr Gundertofte and his technicians were its primary users. Over the time of his involvement with the laboratory, he and they separated many hundreds of reaction mixtures at the request of other medicinal chemists at Lundbeck.
  11. In working with HPLC, one can manipulate a number of parameters in an attempt to improve the outcome of an experiment. The parameters include the choice of solvents, temperature, pressure, flow rate, pH and the stationary phase used. Over time, Mr Gundertofte was able to reduce the trial and error involved in determining these parameters, and became able to determine in a systematic rather than random way what adjustments to make to the parameters. He referred to his experience in his Dansk Kemi paper.
  12. While at Lundbeck, through his regular reading of journals, Mr Gundertofte became aware of the availability of chiral materials for use in HPLC mainly for the purpose of analysing chiral compounds. He explains that on standard (non-chiral) HPLC columns, enantiomers cannot be separated. The use of chiral HPLC columns, on the other hand, allows separation of racemic compounds.
  13. Chiral HPLC was a new area in the early 1980s and was not one that Mr Gundertofte or the other medicinal chemists he knew at Lundbeck and elsewhere, knew very much about. Soon after he joined Lundbeck, he learned that his colleagues in the Medicinal Chemistry Department had been trying, unsuccessfully, to separate citalopram into its enantiomers using classical fractional crystallisation techniques. At Departmental meetings attended by the research scientists in the Medicinal Chemistry Department, the associated difficulties were often discussed. At one meeting Mr Gundertofte raised the possibility of using chiral HPLC. Dr Bøgesø, who was then the senior research chemist in the group, asked him to go ahead and try that technique.
  14. On 17 November 1983, Mr Gundertofte attended a course in Stockholm entitled “Determination of Optical Isomers” conducted by the Swedish Pharmaceutical Association. The course concerned the use of analytical chiral HPLC techniques. The focus of the course was the use of chiral HPLC on an analytical scale in order to determine enantiomeric purity. The course did not specifically address either the separation of chiral compounds into separate enantiomers or the use of chiral HPLC on a preparative scale.
  15. Mr Gundertofte and some of his colleagues reviewed the literature for any references to the use of chiral HPLC for the separation of compounds with similar structural elements to citalopram, but did not find any. They therefore decided to try to resolve citalopram on any chiral column that was available. All of the columns tried were analytical columns, rather than preparative columns.
  16. The first chiral HPLC column Mr Gundertofte used was the DNBPG (“Pirkle”) HPLC column. Professor William Pirkle of the University of Illinois developed the chiral stationary phase used in this kind of column. From Mr Gundertofte’s review of the literature, it was the only chiral HPLC column that Mr Gundertofte knew to be commercially available. Some 40 separate runs were conducted on the column using different combinations of solvents, temperature, pressure and pH values, but without success.
  17. The second column Mr Gundertofte tried was the “Immobilised protein HPLC column”. The manufacturer was Pharmacia in Sweden. This column was a prototype that was not commercially available, but Mr Gundertofte was able to access it through Lundbeck’s collaboration with the manufacturer. Again some 40 experiments were conducted but without success.
  18. The third column Mr Gundertofte tried was the “Triacetate cellulose HPLC column”. Again, this column was not commercially available. Mr Gundertofte obtained the chiral stationary phase material from Merck at Darmstadt, and “packed it” himself. Again, he unsuccessfully ran some 40 experiments.
  19. After the focus of Mr Gundertofte’s work changed in 1987, his technicians and other colleagues unsuccessfully made a further attempt to separate citalopram into its enantiomers by using a “beta cyclodextrin chiral HPLC column”.
  20. Finally, in about 1987 Mr Gundertofte sought help from Associate Professor Hansen of the Royal Danish School of Pharmacy (now called the Danish University of Pharmaceutical Sciences), Copenhagen. Professor Hansen was an expert in separation by chiral HPLC, and his university had a microcrystalline cellulose triacetate chiral HPLC column, to which Lundbeck did not have access as it was not commercially available. However, Professor Hansen was not able to resolve the compound on that column.
  21. Mr Gundertofte states that the choices of the chiral HPLC columns and column packing materials that he made were based solely on the columns and materials available. He said that he and his colleagues kept a close eye on the relevant literature at the time and that they used every type of chiral HPLC column that they could get their hands on.
  22. Mr Gundertofte ceased trying to separate citalopram into its enantiomers using chiral HPLC when he heard that his colleague, Jens Perregaard, had succeeded in doing so by chemical means using an intermediate diol. By that time, Mr Gundertofte had had more than ten years’ experience in using HPLC techniques, including several years of experience in using chiral HPLC.

Lundbeck’s evidence as to the superior clinical properties of escitalopram

  1. A significant amount of Lundbeck’s evidence and submissions on obviousness related to the alleged superior clinical properties of escitalopram. In essence, Lundbeck submits that the addressee of ordinary skill would have predicted, at best, that escitalopram might be up to twice as effective as citalopram (convey the same benefit for half the dose), and would not have predicted, as it says proved to be the fact, that one enantiomer would or might be many times more effective than the racemate because the other enantiomer was antagonistically active. Lundbeck’s key expert witness on the question of what the post-priority date clinical studies showed was Professor Montgomery.
  2. Alphapharm led evidence from Professor Day and Professor Mitchell, and senior counsel for Alphapharm cross-examined Professor Montgomery, in each case with a view to showing that the post-priority date clinical studies on which Professor Montgomery relied did not necessarily show the clinical superiority of escitalopram, at least to the extent claimed. Alphapharm’s basic submission, however, was that Professor Montgomery’s evidence of that kind was irrelevant to obviousness.
  3. I agree with Alphapharm for the reasons I give at Section N [741] ff below. Therefore expert evidence led by Alphapharm directed to countering that of Professor Montgomery as to what post-priority date studies proved, is likewise irrelevant.

The Method Claim

Three possible methods of obtaining the enantiomers of a racemate

  1. Three possible methods of obtaining the separate enantiomers of a racemate were discussed in the evidence. I will first outline their general nature.

Fractional crystallisation

  1. The “classical method” of resolution of racemic amines was in 1988 (and still is) fractional crystallisation, a technique that was described by Dr Bøgesø in para 24 of his affidavit (see [87] above).

High performance liquid chromatography (HPLC)

  1. HPLC is a chemistry-based tool for quantifying, analysing, preparing and separating molecules. In the present context, it is, like fractional crystallisation, a technique for directly resolving a racemate itself into its enantiomers.
  2. HPLC is an enhanced version of liquid chromatography. In liquid chromatography, material such as silica (the stationary phase) is packed in a glass tube or column, and a solvent containing the product of interest (the mobile phase) is allowed to flow through the column according to gravity. Rather than relying on gravity, in HPLC pressure is applied to push the solvent through the column.
  3. The time taken for individual molecules within the mobile phase to move through the column depends on the interactions between them and the material in the stationary phase. Retention of any one molecule in that phase depends on its own specific chemical or physical properties.
  4. HPLC is either analytical, if the aim is merely to ascertain what molecules are present in a given mixture, or preparative, if the aim is to isolate a certain quantity of an end product.
  5. In working with HPLC, one can manipulate the number of parameters in an attempt to improve the outcome of an experiment. The parameters include the solvent to be used, temperature, pressure, flow rate, pH, and the stationary phase to be used.
  6. Enantiomers cannot be separated on standard HPLC columns, because their physical and chemical properties are identical (apart from their property of rotating plane-polarised light in opposite directions). The use of chiral HPLC columns, on the other hand, where the stationary phase comprises a chiral material, allows the resolution of racemates based upon the different three-dimensional interactions of the respective enantiomers with the chiral stationary phase.

Stereoselective synthesis

  1. Professor Robertson described stereoselective synthesis (also called asymmetric synthesis) in his affidavit, under the heading “Stereoselective synthesis”, as follows:
...a medicinal chemist could ... have turned to a variety of asymmetric synthetic techniques in order to obtain a single enantiomer of a desired compound. One option was to devise an entirely new synthetic route using single enantiomers of a chiral starting material and proceeding in a fashion designed to avoid destroying the chiral centre. Another option was to take a precursor chiral molecule in a known synthetic route, resolve that precursor into its component enantiomers and then perform the remaining synthetic steps on only one of the separated enantiomers of the precursor in a fashion designed not to upset the configuration of the chiral centre.

  1. There was at times a degree of terminological confusion between the witnesses as to the use of the term “stereoselective synthesis” or its equivalents. At least this can be said: the technique was contrasted with the resolution of citalopram into its enantiomers by fractional crystallisation or chiral HPLC. The terminological confusion appears to have arisen because the expression, according to the description given by Professor Robertson in the preceding paragraph, may include a reference to an initial step of resolving a precursor into its enantiomers, before the “remaining synthetic steps” are performed.
  2. There are two important points to note about stereoselective synthesis for present purposes. First, an appropriate starting molecule must be chosen. That molecule, if racemic, must be capable of being resolved into single enantiomers. Second, it must be possible to perform synthetic steps to move from these enantiomers to the enantiomers of citalopram whilst retaining stereoselectivity, that is to say, avoiding re-racemisation.
  3. The starting molecule of most relevance to this case was the “precursor diol” (also referred to as the “intermediate diol”). The precursor diol was the penultimate step in the making of citalopram. The process comprising resolution of the precursor diol into its individual enantiomers, and then movement from those enantiomers to the individual enantiomers of citalopram (via stereoselective ringclosure) is Reaction Scheme II disclosed in claim 6(b) of the Patent. This process was referred to as the “diol route” or “precursor diol route”.

The issues

  1. Senior counsel for Alphapharm submitted that claim 6 must fail if the diol route of claim 6(b) was obvious (whether or not claim 6(a) was also obvious). He explained that Alphapharm was therefore focussing on claim 6(b).
  2. The most contentious issue was whether the hypothetical team would have been led as a matter of routine with an expectation of success to try to obtain the individual enantiomers of citalopram by stereoselective synthesis of the precursor diol. This involves a number of questions: Was stereoselective synthesis a technique that was part of the common general knowledge in 1988? If so, would the ordinary skilled chemist have come up with the precursor diol as candidate starting material? If so, would the ordinary skilled chemist have, as a matter of routine with an expectation of success, tried to obtain the individual enantiomers of citalopram by means of the diol route?
  3. Another issue that arose was whether the hypothetical team would have been led as a matter of routine with an expectation of success to try to obtain the individual enantiomers of citalopram by use of chiral HPLC. It appeared to be common ground that if chiral HPLC had been an obvious and straightforward method of resolving citalopram itself, claim 6 of the Patent would not have involved an inventive step. This second issue also involves a number of questions: Was HPLC part of the common general knowledge in 1988? If so, would the ordinary skilled chemist have, as a matter of routine with an expectation of success, tried to obtain the individual enantiomers by means of chiral HPLC?

The evidence of Professors Banwell and Davies

  1. At the outset, I think it is necessary to state that while Professors Davies and Banwell were both eminent Professors in the field of Organic Chemistry, I prefer generally the evidence of Professor Davies to that of Professor Banwell. Professor Davies was, I think, was in a better position to take into account, and he did better take into account, the position of the non-inventive skilled addressee in 1988 before the priority date.
  2. Professor Banwell was able to suggest courses of action that might be worthwhile to try, but he did not to point to instances of their success. A valid criticism that Lundbeck levels at Professor Banwell’s testimony is that often when challenged, his response was that he thought that somewhere in the literature there was some support for pursuing a particular line that he was advocating. For example, in relation to catalytic enantio-selective synthesis (one method suggested by him for obtaining the individual enantiomers of citalopram), Professor Banwell was asked which syntheses he had in mind, and he replied “essentially nucleophilic additions of two ketones in the presence of chiral entities, for example”. But when Professor Davies said he knew of no such processes that had succeeded in making a diaryl tertiary alcohol, Professor Banwell could only respond: “I think there are some examples, and there’s enough literature out there to encourage one to pursue that possibility”. Professor Banwell had not himself assayed the task. In cross-examination he said that he was not able “off the top of my head” to identify anywhere in the literature the manufacture of a tertiary alcohol where the ketone–starting material was sandwiched between two aromatic rings. When further pressed, he said that he had not scrutinised the literature to check whether a tertiary alcohol had ever been manufactured in those circumstances. He also agreed that he had not plotted out each step of the enantio-selective synthesis that was depicted by his retrospective analysis.
  3. Another aspect of Professor Banwell’s testimony on the present issue that I sometimes found unsatisfactory was his frequent references to what a medicinal chemist would “consider”. It was not clear that he was saying, or that his experience qualified him to say, what a medicinal chemist would actually have done as a matter of routine, which, in the present case, is the critical issue. It does not satisfy the Australian test of obviousness to be able to suggest courses of action that might be “worth a try” or “obvious to try”.
  4. In order to give persuasive opinion evidence on that issue, an expert would have to possess a good grasp of the position “on the ground” in 1988, including knowledge of the risk/cost balance as it was perceived by those in the field. It appeared to me that often Professor Banwell was rationalising retrospectively from present day theoretical positions.
  5. Professor Davies, on the other hand, was able to test suggested courses of action by reference to experience in the real world, and the real world of 1988 in particular. In my assessment, Professor Davies demonstrated a greater appreciation of the need to concentrate attention on the position that existed in 1988, and of the need to avoid the contamination of hindsight.

The Joint Report

  1. A convenient starting point for consideration of the obviousness of the method claim is the Joint Report. Professors Banwell and Davies were asked in relation to the obtaining of individual enantiomers from racemates in general, what methods or techniques were generally available and to what extent they were used as at 14 June 1988. They agreed:
  2. Asked whether the first technique chosen would be chiral HPLC in the case where the racemic mixture was an oil, the Professors disagreed. Professor Banwell said “Yes”, while Professor Davies said “No”.
  3. Professor Banwell explained that the use of chiral HPLC avoids any chemical steps including ones such as salt formation, which, in the case of citalopram, would risk causing racemisation. He said that even though only small amounts of the enantiomers might be expected, if these were crystalline the quantity could be amplified by using them as seeds for fractional crystallisation of the racemate.
  4. For his part, Professor Davies said that which method, if any, would work was not predictable. Chiral HPLC would not give useful amounts of single enantiomers, and amplification of very small amounts was not a reasonable expectation. Professor Davies thought that where applicable, diastereomeric salt formation was a reasonable technique to try first since the salt was likely to be a solid that might be amenable to fractional crystallisation. If racemisation was a problem on the conversion of the salt back to the free base, it would certainly also be a problem under the conditions in the stomach.
  5. Asked specifically about the various ways of obtaining the enantiomers of citalopram as at 14 June 1988, Professors Banwell and Davies were agreed that the approaches would include trying to resolve citalopram itself by an appropriate method. If this proved impossible, resolution of “one of several possible suitable precursors” would be attempted. They were agreed that a “suitable precursor” would be one giving a reasonable expectation of subsequent conversion to citalopram without racemisation.
  6. Professor Banwell thought the diol precursor the “obvious choice” as it had “two extra handles [a reference to the “sticky handles” – see [231] above] in addition to the amine that should make its resolution easier and subsequent conversion to citalopram by an SN2 pathway should be easy”.
  7. Professor Davies, on the other hand, considered the diol precursor to not be the obvious choice because conversion to citalopram without racemisation would not be expected. He emphasised that resolution methods are not predictable and that only one “handle” is needed to make diastereoisomers, so that the presence of more than one handle is irrelevant. In any event, Professor Davies considered that the diol precursor effectively had only one extra handle since the tertiary alcohol was chemically unsuitable for forming diastereomers.
  8. The final question in the Joint Report relating to the method claim concerned ring formation (ring closure). Asked what mechanism and stereochemistry of ring formation was understood at 14 June 1988, Professors Banwell and Davies agreed that:

In relation to ring closure of an unsaturated system Professors Banwell and Davies disagreed. The relevance of this is that the diol route involves ring closure in an unsaturated system.

  1. For his part, Professor Banwell thought that chemists would assume, by analogy with a fully saturated system readily closing to a saturated five membered tetrahydrofuran ring, that closure of an unsaturated system to a dihydrofuran (that is, the dihydroisobenzofuran of citalopram) would also be easy.
  2. Professor Davies, on the other hand, considered that chemists would not expect closure of an unsaturated system to a dihydrofuran to be easy, since it would involve significant eclipsing interactions and a trajectory close to 180° would not be readily achievable. Such interactions would be expected to prevent ring closure or to slow it down to such an extent that other reactions such as polymerisation would compete. Professor Davies referred to statements in the scientific literature to the effect that such ring closures are “difficult” and “slow”.
  3. Both Professors agreed that trying the SN2 ring closure on the racemic precursor diol would have shown whether the ring formation was feasible but would not have informed on the overall stereochemical outcome of the process.
  4. Professor Banwell conceded that it was necessary to make a correction to a statement made in one of his affidavits. He had there stated that a paper by Bigler et al (AJ Bigler, KP Bøgesø, A Toft and V Hansen, “Qualitative structure-activity relationship in a series of selective 5-HT uptake inhibitors”, European Journal of Medicinal Chemistry – Chimica Therapeutica (1977) vol 12 (3), pp 289-295) described the diol precursor to citalopram, but in the Joint Report he acknowledged that it did not do so and therefore did not teach that the enantiomers of the diol precursor were capable of existence or that they had already been prepared.

The obviousness of the diol route

Methods for obtaining enantiomers as debated by Professors Banwell and Davies, in particular the use of the precursor diol

  1. Extensive debate took place between the witnesses as to the hierarchy of approaches that they would have used in order to obtain the individual enantiomers of citalopram. For example, there was debate over whether ordinary chemists would have first considered resolution of the racemate directly (by, for example, fractional crystallisation or chiral HPLC) or whether they would have first considered using stereoselective synthesis.
  2. It will be recalled that Dr Bøgesø first attempted to resolve citalopram directly, but being unsuccessful, considered alternative routes. Dr Bøgesø considered attempting to obtain the individual enantiomers of citalopram using the precursor diol. He stated that he thought of that course “before 1984, 1983, 1982”. I recounted earlier (at [259] ff) the reasons why he did not pursue it at that time. Instead he considered using HPLC and derivatives of citalopram, and did so.
  3. Professor Davies said that resolution of citalopram itself would have been an obvious starting point. He said:
... resolution of citalopram itself would have been an obvious thing to start with. It has a handle on it, to use Professor Banwell’s terminology “handle”, where you have an amine that could form diastereomeric salts. I think that would have been an obvious place to start. There’s no need to do any further chemistry to get the citalopram enantiomers, other than release it from an amine ammonium salt, which is a very simple operation that, in my view, has little or no risk of causing racemisation. If you’ve managed to resolve them, you could easily find ways to release the citalopram molecules. So I start with that.

  1. Professor Davies accepted, however, that if resolution of citalopram failed, the addressee would turn to stereoselective synthesis. It would then be a matter of choosing an appropriate starting material. However, Professor Davies stated that, when considering stereoselective synthesis, the precursor of first choice would not have been the diol. Professor Davies identified the various precursors that a skilled addressee in 1988 would have preferred to the diol and gave the reasoning processes that they would have engaged in. He concluded:
The diol precursor ... proposed by Professor Banwell in this process, I think to somebody of ordinary skill in the art in 1988 would have not been an obvious precursor that they would think would do an SN2 process to come back.

  1. For his part, Professor Banwell identified, under the heading “Practical Methods for Obtaining Individual Enantiomers”, the following hierarchy of steps in order of preference:
(A) Enantioselective Synthesis
(i) the chiron approach,
(ii) catalytic enantioselective synthesis.

(B) Resolution
(i) chiral chromatography,
(ii) direct fractional crystallisation,
(iii) derivatisation using stoichiometric amounts of a chiral reagent then separation of the resulting diastereoisomers,
(iv) kinetic resolution of enantiomers [essentially a variation on (iii) above],
(v) enzymatic resolution of enantiomers.

(C) Resolution of a Precursor then Conversion into Target Compound
The same techniques as used in (B) apply here but the added requirement is that the resolved precursor can then be converted into the target compound without racemisation.

Minimising the total number [of] chemical manipulations in obtaining the target enantiomer(s) would be a significant consideration in selecting from amongst the methods available.

  1. In cross examination, however, Professor Banwell accepted that the “skilled and unimaginative chemist in 1988 would almost certainly have looked first at resolving citalopram before considering a precursor”. This would suggest that, like Professor Davies, Professor Banwell would have considered resolution of a precursor followed by conversion into the target compound only after attempts to resolve citalopram directly had failed.
  2. Unlike Professor Davies, Professor Banwell considered that the precursor diol was “an obvious” precursor to choose. In his affidavit, Professor Banwell said that Alphapharm’s solicitors, Mallesons Stephen Jaques (Mallesons), provided him with a structural formula of an unidentified compound (in fact it was citalopram, although he was not told so) and that the first approach he articulated to obtain its enantiomers was to consider using the precursor diol molecule. Indeed, he drew the precursor diol molecule on a whiteboard in Mallesons’ office, and that was prior to his seeing Formula II of the Patent specification.
  3. It should be noted that Professor Banwell’s evidence in relation to the question posed to him by Mallesons in their office was not entirely clear. He said that after some discussion, he was asked whether there would be “a logical precursor to [the] molecule” and “whether there was a suitable precursor that might be available that might be amenable to resolution”. This suggests that he was being asked to address himself specifically to precursors. Elsewhere, however, he suggested that the question put to him was simply how to obtain pure enantiomers of the molecule. Once he identified the diol in answer to the question posed to him (whatever it may have been), he was not given the opportunity to elaborate on it or to consider or suggest alternatives.
  4. Professor Banwell was cross-examined on a draft of his affidavit. He amended a draft that described the diol precursor molecule as “the first approach ... to consider” (in the context of discussing identification of suitable precursors), so that it was to read “a possible first approach ... to consider”. He agreed that when considering precursors, “other first approaches” were also possible: he was not prepared to commit himself to the precursor diol as “the” first approach that would have been taken.
  5. I accept that the hypothetical addressee or team would first have tried as a matter of routine fractional crystallisation of the racemate. The evidence is that this would not have succeeded, and so they would have considered trying to obtain the enantiomers by other means. This was the evidence of Professor Davies. Professor Banwell seemed to support that approach at one stage, although ultimately I think he did not. I accept that the ordinary skilled team would have embarked on a research project. Such a project would have incorporated a number of strategies for resolving citalopram, including the use of a suitable precursor.
  6. It was not disputed by Professor Davies that, if resolution of citalopram itself did not succeed (it did not), the ordinary skilled chemist in 1988 would have thought about or considered resolution of the diol and obtaining the individual enantiomers of citalopram from the individual enantiomers of the diol. The more important question for present purposes is whether, having considered use of the precursor diol (whether after failing in their attempts to resolve citalopram directly or to obtain the enantiomers through other methods), the ordinary skilled addressee or team would have chosen the precursor diol as appropriate starting material and would have tried, as a matter of routine and with expectation of success, to obtain the individual enantiomers of citalopram by means of the diol route.
  7. Professor Davies’s evidence is that they would have rejected use of the precursor diol because both its resolution and the ring closure stage would have posed difficulties.

Resolution of the precursor diol

  1. Professor Banwell said that prior to 14 June 1988, a PhD chemistry student would have readily recognised that a precursor diol was ideal for resolution by a range of techniques (he specified “chiral HPLC, covalent-diastereomer resolution, kinetic resolution or even straightforward fractional crystallisation separation techniques”). He added that such a student would then search to see if the precursor molecule had already been made and, if so, prepare or perhaps purchase some as a starting point for resolution. If the material had not been reported in the literature, he accepted that a method for its preparation and resolution would need to be devised. Professor Banwell conceded that in June 1988 it was not known that the enantiomers of the diol precursor of citalopram were capable of existence or that they had already been prepared.
  2. Professor Banwell thought that the extra “handles” of the precursor diol would allow for ease of resolution of the diol. He suggested that the “added functionality within the diol precursor ... allows for hydrogen bonding possibilities that might assist with crystallisation”. However, when asked for any evidence he had that the making of “lots of hydrogen bonds” would make crystallisation easier, he could only reply “I think there’s evidence out there that that is the case”.
  3. Unlike Professor Banwell, Professor Davies did not accept that having more than one “handle” was an advantage.

The ring closure step

  1. Once the diol’s individual enantiomers were obtained, it would have been necessary to achieve stereoselective ring closure in order to obtain the individual enantiomers of citalopram.
  2. Professors Banwell and Davies were agreed that an SN1 reaction would be followed by racemisation, complete or partial. Therefore, it was only if an SN2 reaction took place that stereoselective ring closure would occur.
  3. Professor Davies rejected the view that in 1988 it could have been predicted with any confidence that the precursor diol route would have led to successful ring closure without racemisation. He considered that the ring closure of the diol intermediate without racemisation was very surprising.
  4. Analysis of the stereochemistry (the spatial arrangement of the atoms in a molecule) was one of the ways of predicting whether a stereoselective SN2 reaction would occur. Professor Davies stated that the ordinary skilled chemist would not be able to tell that the ring closure in the precursor diol would undergo an SN2 reaction pathway without undertaking experimental work. Professor Banwell, on the other hand, was of the view that an analysis of the stereochemistry of the precursor diol would have suggested that ring closure would occur by way of an SN2 reaction.
  5. Professor Davies explained in detail why a chemist of ordinary skill in 1988 would not have predicted that an SN2 reaction would be successful in leading to the obtaining of the individual enantiomers, both in his affidavits and in oral evidence. He said that analysis of the stereochemistry (that is, the spatial arrangement of the atoms) of the precursor diol would lead to a conclusion that it was unlikely that an SN2 reaction would be successful, so that a chemist of ordinary skill would not have pursued the diol route.
  6. Professor Davies gave reasons why an SN2 proposal would give rise to “very bad eclipsing interactions”, which, it will be recalled, are the disfavoured conformation. He said that the conformation would not achieve anything approaching the 180° angle (cf the pen and pen cap analogy mentioned at [238] above) required for an SN2 reaction. “Baldwin’s Rules” (which took their name from Professor Sir Jack E Baldwin, Professor Davies’s predecessor as Waynflete Professor of Chemistry at Oxford University) were used to predict the favouring or disfavouring of a ring closure, and were accepted to form part of common general knowledge at the priority date. Professor Davies was at pains to emphasise that those rules could not be relied on as predicting an SN2 reaction. The reason, he explained, is that according to those rules, in order for the SN2 reaction to occur, the terminal atoms must be able to achieve the required trajectories of 180° or near to that. There was some debate about the extent of deviation from the ideal 180° angle that could occur so that an SN2 reaction might still proceed. While the favourable configuration can occur in a saturated system, the precursor diol is an unsaturated system.
  7. The debate between Professors Banwell and Davies over the present issue led to their agreeing to disagree. Professor Banwell said:
... I think Professor Davies’s cap-and-pen analogy is a very good one for teaching undergraduates about SN2 reactions, but the reality, in my view, is that the cap of the pen has a much wider mouth and the diameter of the pen is narrower and, in that sense, there’s quite a lot of play in terms of the precise trajectory that the pen can adopt, the thin pen can adopt, in entering the wide cap, would be my response to that.

  1. Professor Banwell pointed out that Professor Davies had been using a simplified model that did not incorporate the substituents, and that this led Professor Davies to an analysis that was not valid. Professor Banwell stated that the introduction of substituents changes things dramatically, as would have been predicted by “anyone working in the area of ring closure or in any synthesis area”. He said that the introduction of substituents, and the subsequent analysis of such a system, “would have encouraged one to pursue the SN2 process”. Professor Banwell did not consider that standard stereoelectronic considerations suggested that the reaction was highly disfavoured.
  2. In his analysis of such a system undergoing an SN2 reaction, Professor Banwell called in aid an “MM2” analysis of the ring closure step. He had made his MM2 calculations on his laptop computer in Sydney on the Sunday afternoon before he testified, and produced them at the hearing. Professor Davies was confronted with them for the first time in the witness box. He gave his initial response to them then and elaborated on that initial response after he had had the opportunity to consider them further overnight. Professor Davies said that an MM2 calculation was not something done in 1988 by “people of ordinary skill” or “chemists who were making decisions”. Rather, Professor Davies said that it was done only by “specialist departments in companies, if they had them”.
  3. Ultimately, Professor Banwell accepted that the computer program he had used to undertake his MM2 calculations, called “Chem 3D”, had not been created by 1988. He agreed that in 1988, the required calculations could have been performed only by the use of a digital VAX mainframe computer. He agreed that the average medicinal chemist would not have had direct access to such a computer, and would have needed to collaborate with others in order to have the calculations performed.
  4. While Professor Banwell insisted that collaborations took place in 1988, it is difficult to avoid the impression that his approach was contaminated by the “benefit of hindsight”. It does not follow that because a calculation could be done comparatively easily by Professor Banwell on a laptop computer in a hotel room in 2007, it would have occurred to the hypothetical skilled but non-inventive chemist in 1988 to have the calculations performed through a collaboration. I do not accept that it would have been a matter of routine in 1988 for medicinal chemists to have performed Professor Banwell’s MM2 calculation.
  5. In any event, the most Professor Banwell was able to say was that MM2 analysis and calculations would have “perhaps encouraged” confidence that the SN2 reaction would occur.
  6. The areas of disagreement between Professors Banwell and Davies were explored extensively both in their session of concurrent testimony and in cross-examination. I need not discuss that evidence in any further detail.
  7. I am not persuaded that a chemist of ordinary skill in 1988 would have predicted that an SN2 reaction would occur. The precursor diol comprises an unsaturated ring, and in these circumstances pathways alternative to ring closure would be predicted to be favoured.

Conclusion on obviousness of the diol route

  1. In my opinion, on the evidence, the non-inventive skilled addressee in 1988 would not, as a matter of routine and with the expectation of success, have been led to try the precursor diol route of claim 6(b) in order to obtain the enantiomers of citalopram. It was not obvious that closure of the ring by an SN2 reaction would have been favoured. In this respect, the skilled addressee would have taken into account the fact that the system he or she was dealing with was unsaturated, not saturated. On the basis of the evidence of Professor Davies, I accept that successful ring closure and avoidance of racemisation would not have been expected as a matter of course and would have been, as it was in fact, a (more than) pleasant surprise.
  2. It will be recalled that Dr Bøgesø and his colleagues considered but rejected the procedure of resolving the diol, precisely because they feared that ring closure would not be achieved and that racemisation would occur. Dr Bøgesø also referred to other reasons why he and his colleagues did not initially pursue the diol route (see [259] ff above). I accept his evidence. It supports the expert opinion evidence of Professor Davies as to what the ordinary skilled addressee would be likely to have thought and done in 1988

HPLC

  1. On the evidence, at the priority date the existence of the HPLC technique was part of common general knowledge.
  2. Alphapharm relies on Professor Davies’s agreement in the Joint Report that, as at 14 June 1988, analytical-type chiral HPLC was one method available for trying to obtain single enantiomers. This common ground does not advance matters far. The determinative question is, once again, whether actual use of chiral HPLC to obtain the individual enantiomers of citalopram was a matter of routine.
  3. I will address the evidence of each of the relevant witnesses in turn.
  4. Professor Day’s research team had used HPLC to separate the enantiomers of ibuprofen. He had written about the use of HPLC with an optically active stationary phase (“Liquid Chromatographic Determination and Plasma Concentration Profile of Optical Isomers of Ibuprofen in Humans” [1984] J Pharm Sci vol 73 no 11, 1524-1544).
  5. In cross-examination, Professor Day confirmed that his team had acquired the enantiomers of ibuprofen from a commercial source, and that they administered both the racemate and the enantiomers to humans. After administering the racemate, they measured the individual enantiomers, which involved separation (so that they could be told apart). The work of separation was performed by Professor Day’s team. They used an achiral analytical column (not a chiral HPLC column). Professor Day explained that it was not “a production line as part of the development of a product” but was “simply measuring and quantitating the amounts of these enantiomers following giving the racemate”. He said that his team “derivatised the enantiomers with an optically active reagent and ... used a column to separate the individual enantiomers”
  6. I do not find Professor Day’s evidence persuasive on the precise issue of whether HPLC would be likely to have been used as a matter of routine to separate the enantiomers of citalopram or those of a precursor of citalopram. Although an impressive witness, Professor Day:
  7. Professor Robertson also knew about HPLC. He said that the methods available in 1988 for resolving a racemate included chiral thin layer chromatography and chiral HPLC. He said, however, that both were evolving sciences and that the equipment available was limited, and in some cases in the developmental stage.
  8. As noted earlier, Mr Gundertofte was familiar with the chiral HPLC technique and used it at Lundbeck in the early 1980s. He gave an external presentations concerning HPLC, before publishing his article in Dansk Kemi in 1985. As previously recounted, his attempts to resolve citalopram by the use of chiral HPLC were unsuccessful.
  9. Professor Banwell was aware of the seminal contributions to HPLC techniques, prior to the priority date, of Professor W H Pirkle of the University of Illinois at Champaign-Urbana. Professor Pirkle introduced the first commercially available HPLC chiral stationary columns in the early 1980s. Professor Banwell said he recalled reading review articles in and around 1986 in the Journal of Chromatography, in which the use of chiral HPLC and the availability of chiral columns were discussed.
  10. However, when Dr Donald F Smith of Aarhus University Denmark wrote to Professor Pirkle in 1985 seeking to spend time working with him in order “to learn the methods related to [Professor Pirkle’s] chiral HPLC column in order to determine stereoisomers of psychotropic drugs”, Professor Pirkle replied in the following rather pessimistic terms:
I am afraid that most of your compounds don’t look very likely to resolve on our present columns. Tertiary amines pose a problem for us and many of your compounds fall into this category. Moreover, if your aim is preparative resolution, then be aware that we do not have as many varieties of preparative columns as we have analytical columns.
...

We have a reasonable idea as to how our columns separate enantiomers. Most of your compounds do not have the proper combination of functional groups to allow them to be separated on our columns. We can try, of course, but expect limited success.

The exchange between Dr Smith and Professor Pirkle is telling for what it implies: at least in 1985 chiral HPLC as a means of resolving enantiomers was a new area of research, and preparative HPLC, in particular, was a scarce resource, even for Professor Pirkle.

  1. In the concurrent testimony session, Professor Banwell adhered to the view he had expressed in the Joint Report that chiral HPLC was preferable to other techniques of obtaining the individual enantiomers, including fractional crystallisation, because it avoided the necessity of doing any chemistry, including salt formation.
  2. Professor Banwell acknowledged, however, certain difficulties associated with HPLC. They included, but were not limited to, the following:
  3. Another difficulty was acknowledged in the Joint Report. It will be recalled that it was agreed in that report that analytical type chiral HPLC, if successful, would yield only very miniscule amounts of the resolved enantiomers. In the concurrent testimony session, Professor Davies illustrated this difficulty:
Let’s say, for example, you want to make 100mg. That is a tenth of a gram of material, so it is a small amount of material. You take 5 micrograms of the racemic material. Then, if it is a perfect separation and you can collect absolutely everything of your separate enantiomers, you are only going to get 2.5 micrograms per run, and that is 0.0025mg every time you do it. So to collect 100mg, you have to do 40,000 runs. A typical time to do a run is about half an hour, and, on that basis, in order to get 100mg, it is going to take you more than two and a quarter years, assuming that you run the column 24 hours a day, seven days a week for that entire time ...
So that is just to make 100mg. If you were prepared to take less, 10mg would still take you 83 days, and 1mg is going to take you 8.3 days, but at 24 hours a day for seven days a week.
If you want to go on and do something else with these materials – for instance, make crystalline derivatives of compounds that have never been made before – then I would suggest you need 100mg. That would be the type of amount you are looking for. This is a completely impractical technique to go for that. Even at 10mg, 83 days sitting there doing nothing all that time is not a practical way to produce any material through this type of technique.

Professor Banwell suggested amplifying these amounts by using them as “seeds” for fractional crystallisation of the racemate (see [322] above), but I was not persuaded by this suggestion in the light of the exchanges between Professors Davies and Banwell concerning it.

  1. From the evidence, it appears that the medicinal chemist would have known of analytical chiral HPLC, and would have known of the Pirkle columns that had become commercially available. He or she would have known, however, that even analytical chiral HPLC was the subject of continuing research and did not promise success in respect of any particular racemate.
  2. The hypothetical addressee or team would certainly not, in light of the difficulties of using HPLC, as a “matter of routine”, have thought of preparative chiral HPLC as a means of resolving citalopram into its enantiomers. It was therefore not a technique that prevented the method of claim 6 from involving an inventive step.

Conclusion on obviousness in relation to the invention claimed in the method claim

  1. For the above reasons, the attack on the method of claim 6 on the ground of obviousness fails. I am not satisfied that the hypothetical addressee or team would, as a matter of routine, have either (a) resorted to the precursor diol, or (b) used the technique of chiral HPLC to resolve either citalopram itself or any racemic precursor of it.
  2. While the evidence that was before Kitchin J in Generics v Lundbeck was clearly different from that which was before me, I assume that the evidence of the course of experimentation that was followed at Lundbeck was similar. In any event, his Lordship’s summary (at [154]) accords with my findings on the evidence in the present case:
Assuming the skilled person decided to embark upon the task of trying to obtain the individual enantiomers there was no real dispute between the parties that he would initially choose to attempt to resolve the final molecules. Only if this failed might he then consider alternative methods such as using enantiomerically pure precursors. But here his anxiety would be that subsequent reaction steps might result in the production of an enantiomerically impure final product. As I shall explain, scientists at Lundbeck attempted to resolve citalopram by classical resolution techniques using diastereoisomers, by using new resolving agents, by attempting to resolve derivatives and by using techniques of asymmetric synthesis, all over the period 1980 to 1988. In addition, they attempted to resolve citalopram using analytical chiral HPLC from 1983 to 1987. None of these techniques were successful. The claimants accepted that citalopram is not easily resolved by making diastereoisomers. However, they submitted the skilled addressee would not regard failure in relation to this molecule as the end of road. I accept that this was so. But the work Lundbeck undertook illustrates that the road to which the claimants referred was long and uncertain.

The Product Claims

  1. The word “routine” that has become a common feature in formulations of the obviousness test in Australia (see [180] above) is more comfortably applicable to discussions of methods than products. However, the “matter of routine” test can be applied to product claims. The question to be asked is whether it would have been a matter of routine for those skilled in the art to adopt the goal of obtaining the enantiomers of citalopram for use of one of them as a drug for the treatment of depression.
  2. In Astra, the High Court described (at [53]) the reformulation of the “Cripps question” by Graham J in Olin at 187-188. Their Honours stated that that approach should be accepted. Adapting that test to the circumstances of the present product claims, I would state the test as follows:
Would the hypothetical addressee or team as at 14 June 1988, equipped with the Australian Citalopram Patent and possessed of the common general knowledge within the field at that time, adopt as a matter of routine the aim of obtaining the (+)-enantiomer of citalopram in the expectation that it might well produce a useful alternative to, or a better drug than, citalopram?

While I think that the hypothetical addressee or team in 1988 would have recognised the possibility of an advantage in obtaining the enantiomers because of the possibility of the therapeutic benefits of the racemate being found to reside in one of them, I do not think that the goal of obtaining the enantiomers would have been adopted as a matter of routine, as is required for the Australian test of obviousness to be satisfied.

The Joint Report

  1. Again, a convenient starting point is the Joint Report.
  2. Professors Banwell and Davies were asked: “What were the motivations (chemically and academically, but excluding regulatory) for obtaining the enantiomers of a known racemate?”
  3. The two Professors agreed that academic curiosity could provide such a motivation, “provided some purpose, such as proving a hypothesis, would be served by so doing” . They also agreed that “[n]othing [was] guaranteed in synthesis, including the ability to obtain single enantiomers of a racemate”.
  4. The Joint Report recorded, however, a point of disagreement. Professor Davies said that citalopram would be expected to racemise under the acid conditions (pH3, 37oC) of the stomach, and therefore there would be no real motivation to obtain the single enantiomers of citalopram. Professor Banwell agreed that “some leakage of the enantiomer stereochemistry towards the racemate” might be expected in the stomach, but considered that “the conditions described (884 Patent) for the acid catalysed ring closure of the diol precursor to citalopram (70% sulphuric acid, 80oC, 3 hours) suggest complete racemisation [was] unlikely”. (The reference to the “884 Patent” was a reference to the US Diol Patent.)

Relevance of the non-obviousness of the method of claim 6

  1. The discussion that follows assumes, as concluded above, that there was not to hand an obvious method of obtaining the enantiomers of citalopram. It was a “tricky” task, as Morrison and Boyd wrote, to obtain the enantiomers of a racemate. Research, time and cost promised to be involved, as Dr Bøgesø and Mr Gundertofte found. There was not at hand a straightforward, inexpensive method that would immediately give results.
  2. This background tells, thought not conclusively, against the suggestion that the ordinary skilled but non-inventive chemist would have seen as obviously desirable the obtaining of the enantiomers of citalopram.

General motivation to obtain enantiomers of racemic mixtures

  1. Alphapharm suggested that the following formed part of the common general knowledge at June 1988 and provided a motivation for obtaining enantiomers of racemic mixtures:
  2. For its part, Lundbeck asserts that by reason of the lack of expertise and cost associated with obtaining individual enantiomers, there was little interest within the pharmaceutical industry of obtaining the individual enantiomers. Furthermore, Lundbeck contends that in the specific case of citalopram, a highly selective SSRI drug with no evidence of toxicity, there was no specific motivation to obtain individual enantiomers.
  3. I will consider each of Alphapharm’s suggested grounds of motivation in turn, before considering the general (lack of) interest in the pharmaceutical industry and the specific case of citalopram.

The therapeutic effects as between the enantiomers

  1. Professor Day expressed the opinion that prior to June 1988 there were nine possible ways in which enantiomers might act therapeutically. Professor Day’s nine possibilities were:
    1. both enantiomers may have nearly identical efficacy and toxicity;
    2. both enantiomers may have the same pharmacological effects but one may be more potent than the other;
    3. one enantiomer may possess virtually all of the pharmacological activity while the other is essentially inactive (“ballast”);
    4. one enantiomer may possess virtually all of the pharmacological activity while the other is essentially inactive, but that other may be toxic;
    5. both enantiomers may be pharmacologically active, but have qualitatively different therapeutic effects, for example both are agonists at different receptors, antagonists at different receptors, or agonists and antagonists at the same receptor;
    6. both enantiomers may be pharmacologically active but in a counter-active manner, for example one enantiomer might be binding to the receptor and the other might be binding to a different allosteric site, which affects the binding of the first receptor, potentially affecting the potency of the other enantiomer;
    7. the racemate may be superior to the single enantiomer;
    8. one enantiomer may be inactive but is converted into an active form in the body; and
    9. the disposition of the drug in the body may be stereoselective because when the drug is metabolised in the body, the enzymes themselves might be stereoselective.
  2. I also note the work of Professor E J Ariens of the Institute of Pharmacology and Toxicology, and Department of Clinical Pharmacy, University of Nijmegen, The Netherlands. Professor Ariens was writing in 1983 and 1984, urging that more attention be given to isolating enantiomers so that the supposedly inactive one might be discarded. His point was that one was not necessarily inactive and might in fact be contributing to side effects. In the summary at the start of his article “Stereochemistry, a Basis for Sophisticated Nonsense in Pharmacokinetics and Clinical Pharmacology “Eur J Clin Pharmacology (1984) vol 26, pp 663-668, Professor Ariens stated: “The therapeutically non-active isomer in a racemate should be regarded as an impurity (50% or more)”.
  3. Professor Day emphasised that even once the effects of the individual enantiomers were determined, the decision whether to abandon a drug entirely (assuming it was not suitable in its racemic form) or to try to develop the single enantiomer was a complex matter for decision.
  4. While I accept that it was part of the common general knowledge that one enantiomer might possess all of the pharmacological activity of the racemate, as previously noted I am not persuaded that it was part of common general knowledge that obtaining the enantiomers might offer more than the same therapeutic effects for half the dosage.
  5. In any event, even if Professor Day’s nine possibilities formed part of common general knowledge, they do not suggest that it was part of that common general knowledge that obtaining an individual enantiomer was an “obviously desirable result” as Alphapharm must establish.

Toxicity – in particular, thalidomide

  1. Alphapharm relied on evidence touching the pharmaceutical drug, thalidomide, as showing that there was an interest in resolving racemates into their enantiomers and a desire on the part of pharmaceutical companies to do so.
  2. Professor Banwell stated in his affidavit that he recalled lecturing to undergraduate students prior to 14 June 1988, using the thalidomide case to exemplify the significant impact that chirality can have on the biological action of an organic molecule containing a single centre of chirality. He explained that thalidomide was a pharmaceutical drug, administered as a racemate, that had been prescribed for treating morning sickness in pregnant women. In the early 1960s the drug was reported to cause birth defects in babies, and as a result of the disaster stricter drug testing was introduced.
  3. Professor Banwell explained that it was later discovered that one enantiomer of the drug was safe while the other caused teratogenic effects (that is to say, damaged the embryo). As a consequence, Professor Banwell explained, the isolation of single enantiomers became an increasingly significant research focus around the world, and the possibility that different enantiomers might behave differently in the human body became an issue of major concern to drug developers.
  4. Professor Day said that thalidomide was used during the period from 1957 to 1961 and it was later discovered that one of its stereoisomers was safe while the other had the teratogenic effects.
  5. In his Dansk Kemi article published in February 1985, Mr Gundertofte stated that all teratogenicity was found in (S)-thalidomide.
  6. Professor Davies accepted that in a general sense, awareness of the thalidomide problem gave rise to an awareness of the significance of enantiomers that led to debate as to the need for regulation, although he said that resolution of thalidomide into its enantiomers would not have made any difference because it “still couldn’t have been administered to humans because it racemises and you [would] have still seen the teratogenic effects”.
  7. I accept that the thalidomide disaster stimulated interest on the part of pharmaceutical companies and regulators in the resolution of racemates and in the roles that the respective enantiomers had had in the adverse effects caused by that drug. However, I do not infer that in 1988 they felt impelled towards resolution of racemic drugs, or, in the case of the regulators, towards insisting upon resolution of them.

Regulatory motivation

  1. There was very little evidence before the Court touching on the issue of regulatory intervention. At the priority date there was no regulatory requirement that a racemate be resolved into its enantiomers. In a Guideline published in February 1987, Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances, the US Food and Drug Administration (FDA) stated that drug manufacturers would “ideally” undertake to obtain the various individual potential stereoisomers. However, manufacturers were not required to follow the guideline.
  2. Professor Day gave evidence that “the effect [of the Guideline] would be that [a pharmaceutical company] would [resolve the enantiomers of a racemate] unless [it was] a little bit lax in attending to [its] duty”. He noted that, given the length of time taken to register a drug, it “would be a risky business not to take close note” of the suggestion, even though it was not mandatory to do so.
  3. Professor Banwell said that in 1988 he had heard that there was debate going on around the world as to whether regulators should require companies to produce the individual enantiomers. He said he “sensed [it] was impacting on companies [he] was collaborating with”. It is difficult to know what to make of this evidence. First, it is at a level of generality. Second, it is not as though Professor Banwell was a consultant to any pharmaceutical company in or before 1988. From 1982 to 1986 he was a Lecturer in Chemistry at the University of Auckland in New Zealand, and in 1986 accepted appointment as Lecturer in Organic Chemistry at the University of Melbourne down to 1989 when he became a Senior Lecturer in Organic Chemistry at that University – a post he held from 1989 to 1992. I have referred earlier to the limitations on Professor Banwell’s experience in relation to the actualities of the pharmaceutical industry. No doubt he would have conversed with the chemists of any pharmaceutical company with which his university team collaborated, but this is a rather weak foundation for evidence of the present aspect of common general knowledge.
  4. Professor Davies was at pains to distinguish between the position in 1988 and that which developed in the early 1990s, after the first FDA regulations in relation to testing enantiomers came into force. He conceded that there were, by 1988, a few individuals who were suggesting that racemic drugs should be sold only as enantiomers, but he said that that was then a relatively recent and minority view. Rather, while it had been known for some years previously that the two enantiomers of a particular biologically active racemic compound could exhibit different levels of activity, this was not a concern as long as the racemate had been shown to be safe and efficacious in clinical trials in humans.
  5. There is a question whether the content of the US FDA Guideline had become part of common general knowledge by 14 June 1988. Even if it had, I am not satisfied that it would, by then, have provided a motivation of any significance for the resolution of a racemic drug such as citalopram, that appeared to be both very effective and non-toxic.

Commercial reasons

  1. Alphapharm submits that there were commercial and “patent driven” reasons, as distinct from scientific or medical reasons, for obtaining the individual enantiomers. In this context, Alphapharm described the strategy as “chiral switching”. Alphapharm referred to:
  2. I do not think, however, it is proved that commercial and patent-related considerations gave rise in 1988 to a motivation among skilled non-inventive chemists to resolve racemates in general or citalopram in particular. Moreover, the relevance to obviousness of some of the considerations relied on by Alphapharm was not made clear.
  3. This is not to say that Lundbeck was unaware of any potential commercial and patent-related benefits associated with resolving racemates. In the annual report for 1988 of its Medicinal Chemistry Department, which reported success in obtaining the individual enantiomer by the use of the precursor diol, the statement was made: “Furthermore, our opportunities for extending the “lifetime” of citalopram were increased”.

General lack of interest in the pharmaceutical industry

  1. On the present question, Professor Davies’s evidence of his attempt in the early 1990s to interest the pharmaceutical industry in the preparation of enantiomers is significant. Paragraphs 19-23 of Professor Davies’s affidavit sworn 21 December 2006 were as follows:
19. My particular expertise was in all aspects of the control of stereochemistry. However, while I was consulted on (amongst other things) the preparation of racemic diastereomers, I was not consulted on the preparation of single enantiomer compounds during the 1980s to any real extent. In my experience there was little interest in industry at this time in the resolution of racemates. Molecules that were first made as racemates, tended to proceed as racemates through development, whereas molecules that were first made as individual enantiomers (those based on naturally occurring homochiral molecules) proceeded through development as the single enantiomer. The reason for this attitude was that the additional expense and difficulty of resolution of racemic materials meant this exercise was not worthwhile, as evidenced by the fact that in the 1980s the industry was selling many more synthetic pharmaceutical compounds as unresolved racemates rather than single enantiomers.

20. This attitude began to change in the early 1990s, primarily because the US Food and Drug Administration (FDA) (and sometime later, the European regulatory authorities) were becoming interested in racemic drugs from a regulatory point of view, and it was apparent that regulatory guidelines and requirements concerning such drugs were likely to be introduced. In the early 1990s it was recognised in the industry that those requirements were likely to include the obligation to provide some data relating to the individual enantiomers of a racemic drug.

21. As a result, I perceived that there would be an increasing need in the pharmaceutical industry for a centre of excellence in the area of the preparation of enantiomers. Along with others, I therefore founded Oxford Asymmetry Ltd in 1992, which became a division of Oxford Asymmetry International plc. The mission of Oxford Asymmetry Ltd was to provide pharmaceutical companies with homochiral compounds of interest on any desired scale, from small amounts as a first preparation for biological evaluation, to commercial quantities. The company was engaged in the preparation of compounds with high enantiomeric purities. We were specialists in three principle methods for achieving this: using single enantiomer “chiral pool” starting materials, asymmetric synthesis; and chiral separations by various methods (resolutions).

22. Oxford Asymmetry Ltd was one of the first companies in the world to specialise in producing synthetic homochiral compounds. Around the time my company was started, I recall talking to many of my clients in the pharmaceutical industry about my company and its capabilities. I recollect that the majority of my clients were very sceptical about the need for such a service, and I was told on many occasions that the industry simply did not need to resolve racemic compounds on a regular basis. Nevertheless, that the industry changed quite dramatically in the 1990s is demonstrated by the fact that the company grew from 3 employees to 250 employees by the time it was sold in 2000.

23. Even though it is no longer our core business, my present company, Vastox, is, even today, retained to assist pharmaceutical companies in preparing compounds with high enantiomeric purities.

  1. Professor Davies also described the resolution of racemates in the 1980s as “a black art”, and he said that while the literature prior to 1988 did record some successful resolutions, failure was common. He points out that the literature, understandably, did not record such failures.
  2. Professor Davies addressed this question specifically. He said:
26. .... as a result of my frequent contact with chemists in pharmaceutical companies conducting research to find a better drug, my experience in 1988 was that such chemists preferred to search by chemically modifying lead compounds (or other compounds), for example, by adding or deleting substituents, changing existing substituents and moving substituents around the molecule, in search of the right combination to increase activity and reduce toxicity. In this way, their aim was to improve the activity of the compound by orders of magnitude. It is perfectly possible to have a two dimensional non-chiral (or achiral) molecule which is active on the same arrangement of sites as a three dimensional, chiral molecule, assuming one can position the relevant functional groups in the right place. In my experience, chemists at that time preferred to find such an achiral derivatised molecule, rather than trying to resolve a racemate.

27. If a company did contemplate resolution, there were very few experts in the 1980’s in resolution techniques that it could turn to (although there might have been individuals with some experience within some companies’ chemistry departments). Expertise in this art at that time was generally passed by informal exchange of information and experience within pharmaceutical companies.
  1. I accept Professor Davies’s testimony. Clearly, he was not saying that there had been no attempts to obtain enantiomers before the priority date: Lundbeck itself had been trying to do just that for some seven or eight years in the case of citalopram.
  2. In cross-examination, Professor Day agreed with a view expressed in a 1992 FDA document to the effect that whether enantiomers should be developed had been, at least up to that time, largely an academic question because commercial separation of enantiomers from racemates was so difficult and expensive.
  3. While accepting that there is no way of predicting the ease or success of resolution, Professor Banwell stated that “there are methods for resolution available at modest cost that would be worth trying”. Professor Banwell’s evidence went only so far as saying that the relevant addressee would explore the possibility of resolution, with an expectation that the two enantiomers might have differing behaviours in biological systems. He did not go so far as to say that the skilled addressee would be led directly to desire to obtain the enantiomers in the expectation that one would or might well be more effective than the racemate.

Specific motivation to resolve citalopram

  1. It was not disputed that citalopram was known to be a safe and effective antidepressant drug.
  2. Professor Montgomery said that citalopram itself was highly selective. Lundbeck submits that this shows that there was no reason to embark on a costly and lengthy project to produce the enantiomers. Professor Davies said that citalopram worked with no adverse side effects, and so there was no motivation to resolve it.
  3. Professor Robertson stated in his affidavit:
97. ... the medicinal chemist would have weighed up the usefulness of the desired result, if it were obtainable. In the case of citalopram, I have been given copies of and have read the following paper: Hyttel J “Neurochemical Characterisation of a New Portent and Selective Serotonin Uptake Inhibitor: Lu 10-171”, Psychopharmacology 51, 225-233 (1977). [Dr Hyttel was employed by Lundbeck]

98. From this review paper, I understand that citalopram as a racemate was undergoing clinical trials, including trials assessing it against other SSRIs. Citalopram was performing well in these studies (Hyttel 1977). Importantly, citalopram had very high selectivity as a serotonin reuptake inhibitor, by comparison to its activity at other amine uptake proteins (transporters). Furthermore, citalopram had a good safety and tolerability profile.

99. As mentioned above, different enantiomers of a molecule may have 100. comparable or quite different activities. Sometimes one enantiomer is responsible for the therapeutic activity and the other is responsible for the reported side effects. However, with citalopram, there were no particularly troublesome reported side effects. Furthermore, the paper demonstrates that all of the SSRIs reported on have activity which is comparable with one another. None of them seems therapeutically to be considerably better than any of the others.

100. If there appears to be no toxicity or other undesirable activity with a molecule, separating the enantiomers may have provided no useful benefit. A possible scenario therefore is that the individual enantiomers would have very similar activity. The other alternative was that one enantiomer had all or most of the desired therapeutic activity and the other enantiomer was essentially inactive. In such a case, resolution of the enantiomers might provide scope for administering only half the dose of a single enantiomer than is required of the racemic mixture for a given therapeutic effect. At the time, whilst there were a number of authors who were advocating for the removalof “ballast”, the most outspoken of whom was Ariens, ...

101. Although it was perhaps not unheard of for one enantiomer to act as an antagonist and the other enantiomer to act as an agonist at a specific receptor, it was very unusual. The usual result would be to discover that one enantiomer was a bit less active than the other or had improved selectivity for the target protein. From the work that I have done with pharmacologists, I believe that a pharmacologist would be more familiar with two different enantiomers exhibiting different binding strength at the same site on the receptor ...

102. Weighing all of this up, I would have rated the inclination for a pharmaceutical company to expend any considerable resources continuing to try to resolve citalopram in 1988 as low. Beyond trying fractional crystallisation of diastereoisomeric salts and perhaps some chiral HPLC, as I have described above, I believe that a medicinal chemist would have directed that the available resources be directed towards projects with a greater prospect of a useful outcome.

103. This is precisely what occurred in the project in which I was involved, as described above, concerning the synthesis of prostaglandins and Pl3 kinase inhibitors. When we could not readily resolve a racemate, even one that looked promising, the decision was made to move forwards with the racemate rather than to continue to try to resolve it into its component enantiomers.

This evidence given by Professor Robertson accords with that of Professor Davies: the course more likely to be followed would be to develop the racemate rather than to seek to obtain its enantiomers.

  1. As the evidence of Dr Bøgesø and Mr Gundertofte shows, Lundbeck devoted some resources to the venture. However, the project appears to have been pursued as a part-time and intermittent activity by Dr Bøgesø, and later by Mr Gundertofte. I do not accept that their motivation was just “an academic and personal point of view”, to use Dr Bøgesø’s words, but nor do I accept that they or Lundbeck felt pressingly motivated.
  2. I am not satisfied that there was any significant felt need or desire to obtain the enantiomers of citalopram, which was known already to be a drug that was very selective in its activity.

The prospect of racemisation in the stomach

  1. I referred at [385] above to the disagreement between Professors Banwell and Davies as to whether (+)- or (–)-citalopram would be expected to racemise under the acid conditions of the stomach, and whether, depending on the answer, there was or was not any real motivation to obtain its enantiomers.
  2. Professor Davies’s argument seems to be that in 1988, it would have been part of common general knowledge that separating out the enantiomers would be futile because the individual enantiomer, when administered to humans, would have been expected to re-racemise in the stomach. Any benefit of administering an individual enantiomer, as opposed to racemic citalopram, would have been lost.
  3. Professor Davies’s concern was apparently not shared by the Lundbeck scientists, who pursued resolution over a period of some seven to eight years.
  4. I do not think that the present issue is in any way determinative. However, on this issue, I prefer the evidence of Professor Banwell. He thought that some leakage of the enantiomer stereochemistry towards the racemate might be expected in the stomach, but that complete racemisation was unlikely.

Conclusion on obviousness in relation to the invention claimed in the product claims

  1. For the reasons given above, it was not obvious, that is to say, a matter of routine to want to have the separate enantiomers of citalopram: obtaining the enantiomers of citalopram was not an obvious goal to adopt.

SECTION F – MANNER OF MANUFACTURE – S 18(1)(A) OF THE ACT

Introduction

  1. Section 138(3) of the Act provides that the Court may revoke a patent, either wholly or so far as it relates to a claim, on, relevantly, the ground “that the invention is not a patentable invention” (para (b)). The notion of a “patentable invention” is defined in s 18. One essential criterion is that the invention “is a manner of manufacture within the meaning of s 6 of the Statute of Monopolies” (para (a) of s 18(1)).
  2. The expression “invention” is defined in Schedule 1 of the Act to mean:
any manner of new manufacture the subject of letters patent and grant of privilege within section 6 of the Statute of Monopolies, and includes an alleged invention.
  1. It has been held that the concluding words “and includes an alleged invention” qualify only the word “new”: NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd [1995] HCA 15; (1995) 183 CLR 655 (Philips v Mirabella) at 662. Accordingly, provided “newness” is alleged, the expression “manner of new manufacture” can be regarded as synonymous with “manner of manufacture,” that is to say, the words “and includes an alleged invention” enable newness as an objective fact to be eliminated from consideration.
  2. In determining whether what is claimed fits the description of a “manner of manufacture”, one must confine one’s attention to the face of the specification: Philips v Mirabella at 663-664; Advanced Building Systems Pty Ltd v Ramset Fasteners (Aust) Pty Ltd [1998] HCA 19; (1998) 194 CLR 171 (Ramset) at [38]; CCOM Pty Ltd v Jiejing Pty Ltd [1994] FCA 1168; (1994) 51 FCR 260 (CCOM v Jiejing) at 291). The notion of a manner of manufacture does not incorporate considerations of novelty or inventiveness which are dealt with independently and comprehensively in s 18(1)(b), s 7, and the definitions of “prior art base” and “prior art information” in Sch 1: see Ramset at [30]-[34] (dealing with s 100 of the 1952 Act).
  3. Alphapharm submits that in relation to the new manner of manufacture criterion, the case is one of a “mere desideratum” (the expression “a mere method or mere idea or mere desideratum” was used in Burroughs Corporation (Perkins’s Application) [1974] RPC 147). Senior counsel for Alphapharm frankly conceded that, in a sense, Alphapharm’s submission in this respect rose no higher than its case on obviousness. Indeed, he conceded that it was more confined than that case because the character of a manner of manufacture must appear on the face of the specification, and common general knowledge cannot be taken into account as it can in the context of obviousness.
  4. In Philips v Mirabella, the High Court held that s 18(1)(a) refers to “a process which is a proper subject matter of letters patent according to traditional principle” (at 667). That “traditional principle” has been described as “the body of case law that has accumulated governing what kinds of things can be the subject of valid patents”: Bodkin C, Patent Law in Australia (Thomson Lawbook Co, 2008) at [2040].
  5. I must ask myself, therefore, whether the Patent specification, lays claim to an invention falling within or outside “traditional principle”.
  6. In para 4 of its further amended particulars of invalidity, Alphapharm gives the following particulars of its contention that the alleged invention as claimed in each claim is not a patentable invention because it is not a manner of manufacture within the meaning of s 6 of the Statute of Monopolies:
(i) The invention claimed in the Patent is a mere discovery of the components of Citalopram that were disclosed in the Citalopram Patent;

(ii) There is no invention disclosed on the face of the specification;

(iii) The specification discloses no barrier crossed or advantage achieved over the disclosure of the Citalopram Patent;

(iv) Insofar as the Respondent contends that the alleged invention as claimed in claims 1-5 of the Patent is a selection of the invention claimed in the Citalopram Patent, that selection discloses no substantial advantage over the invention claimed in the Citalopram Patent;

(v) The alleged invention as claimed in claims 1-5 of the Patent consisted merely of a known substance the known properties of which made it suitable for use. The known substance was Citalopram. The known use of Citalopram was as a 5-HT reuptake inhibitor. Its known properties were:
(a) that Citalopram contains an asymmetric carbon;
(b) that Citalopram is a racemic compound;
(c) that Citalopram is comprised of two enantiomers, namely, (+)- Citalopram and (-)-Citalopram;
(d) that (+)-Citalopram and (-)-Citalopram have different pharmacological activity;
(e) that pharmaceutically acceptable salts of (+)-Citalopram could be formed; or

(vi) The alleged invention as claimed in claim 6(b) was a mere new use of known processes. The known processes were:
(a) the use of enantiomers of optically active acids to afford pure diastereomeric salts;
(b) performing stereoselective ring closure using a labile ester (such as methanesulfonyl chloride) with the simultaneous addition of a base (such as triethylamine) in an inert organic solvent (such as dichloromethane).

Lundbeck did not advance a “selection” case, and so particular (iv) may be put to one side. Most of the particulars relate to the product claims: only particular (vi) relates expressly to the method claim.

  1. Alphapharm relies on the fact that the Patent specification refers to the US Citalopram Patent and the US Diol Patent and so imports their contents. In substance, Alphapharm submits that in the light of the importation of the content of the US Citalopram Patent in particular, the Patent specification does not claim a manner of manufacture but claims as a desideratum the (+)-enantiomer that was indirectly disclosed in the various Citalopram Patents.
  2. The enantiomer (+)-citalopram is, however, a new compound with properties previously unknown. The Patent specification does not acknowledge, expressly or by implication, that the (+)-enantiomer is a compound with known properties. On the contrary, it claims that the (+)-enantiomer is an independently existing molecule that has unexpected and surprising properties that could not have been predicted from the properties that citalopram was known to have.
  3. It is useful, I suggest, again to consider the analogies given at Section C [121]-[123]. The imperfection of the analogies is demonstrated in the context of manner of manufacture, because the colours blue and yellow (and the black stick figure) already exist and their properties are already known. While a method for extracting blue or yellow from green (or the black stick figure from the solid black square) might be valid as a method claim, a product claim to the colour blue or the colour yellow (or the black stick figure) would fail the manner of manufacture test because it would be a claim to something that already had an independent existence and the properties of which were already known.
  4. The enantiomer (+)-citalopram is different. It had never been an independently existing molecule and, apart from the fact that, by reason of its definition, it rotated plane-polarised light to the right, its properties were unknown.
  5. For the above reasons, the product claims are claims of a manner of new manufacture.
  6. Claim 6, the method claim, does not fall outside the notion of a “manner of new manufacture” either and I do not understand Alphapharm to have addressed independent submissions to the contrary, notwithstanding particular (vi).
  7. The Patent should not be revoked on the ground that the invention claimed is not a patentable invention.

SECTION G – LACK OF DEFINITION – S 40(2)(B) OF THE ACT

  1. A ground on which the Court is empowered to revoke a patent is that the specification does not comply with s 40(2): see s 138(3) of the Act. Section 40(2) provides that a complete specification must, inter alia, describe the invention fully, including the best method known to the applicant of performing the invention (para (a)) and, where it relates to an application for a standard patent, end with a claim or claims defining the invention (para (b)).
  2. Alphapharm pressed two grounds of attack in relation to its contention that the specification did not comply with these requirements, both of which were dependent on the construction that the Court gave to claim 1:
    1. If I should find, as a matter of construction, that claim 1 and dependent claims are not for (+)-citalopram in its absolute configuration as S-citalopram, the claims in the specification do not define the alleged invention because (+)-citalopram could be either the S-citalopram enantiomer or the R-citalopram enantiomer, depending on the conditions (including the solvent used) to determine the direction in which the enantiomer rotates plane polarised light.
    2. If I should find that claim 1 and dependent claims are not for (+)-citalopram on a molecular level, the claims do not define the alleged invention because they could include any mixture of enantiomers in the absolute configurations of S-citalopram and R-citalopram in any proportion ranging from 51% to 100%.
  3. In the case of citalopram, the (+)-enantiomer is now known to be the S-enantiomer, that is to say, it is the S-enantiomer that causes plane-polarised light to rotate to the right (clockwise).
  4. Professor Davies said that the determination of rotation and of the extent of it is “measured at the sodium D-line” in a “standard solvent under standard conditions”, and that there is a convention according to which a reference to the (+)-enantiomer assumes that form of measurement under those conditions. He said that in the literature, there can be found a very small percentage of specific rotations that are not quoted according to those criteria, and that there is normally a particular reason for a departure from them (such as, “because the compound solution is coloured and absorbs at the sodium D-line”). He thought that perhaps in 2% of cases, the measurement was not made at the sodium D-line and said that in those cases it is always specified at which different wavelength they were measured. In the present case, the specification identified the solvent as methanol. In answer to the question whether, under different conditions, the same enantiomer might rotate light differently, Professor Davies said that there are “very rare” examples in which the enantiomer rotates light differently according to the solvent used. There is no suggestion in the evidence that citalopram is such a “very rare” case.
  5. In my opinion, there is no substance in Alphapharm’s first ground of attack. When the specification refers to the (+)-enantiomer of citalopram, it is referring to the enantiomer of citalopram that rotates plane-polarised light to the right when measured at the sodium D-line when methanol is the solvent used and standard conditions apply. In these circumstances, and in the light of what we now know, the reference to the (+)-enantiomer was in fact unmistakably a reference to the enantiomer that is the S-enantiomer, even though the claim did not and could not say so. This view is not displaced by the evidence of Professor Davies to which I referred to the general effect that in the case of some racemic mixtures (not citalopram) and perhaps in a non-standard solvent and measured against a wavelength other than the sodium D-line, the S-enantiomer may rotate plane-polarised light to the left.
  6. There is no substance either in the second ground of attack because I have held that the claims are specifically in respect of the (+)-enantiomer as an independent molecule, not to it merely as part of an unresolved racemate.

SECTION H – LACK OF FAIR BASING – S 40(3) OF THE ACT

  1. Section 40(3) of the Act requires that the claims be “fairly based on the matter described in the specification.” A comparison between the claims and the rest of the specification is called for.
  2. What is required is that there be a real and reasonably clear disclosure in the body of the specification, taken as a whole, of the invention that is claimed in the claims so that those who may wish to exploit the invention as claimed after the patent has expired will be enabled to do so: see, for example, Société Des Usines Chimiques Rhône-Poulenc v Commissioner of Patents [1958] HCA 27; (1958) 100 CLR 5 at 11 per Fullagar J; F Hoffman-La Roche & Co AG v Commissioner of Patents [1971] HCA 3; (1971) 123 CLR 529 at 539; CCOM v Jiejing at 281-282; Rehm Pty Ltd v Websters Security Systems (International) Pty Ltd (1988) 11 IPR 289 at 304; Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58; (2004) 217 CLR 274 (Lockwood v Doric) at [69].
  3. In Lockwood v Doric, it was held in relation to the fair basing requirement of s 40(3) that:
  4. Alphapharm contends that each of claims 3, 4, 5 and 6 of the Patent is not fairly based on matter described in the specification in so far as it claims, or is referable to, a pharmaceutical composition or a method of preparing one, where the pharmaceutical composition is other than for:
  5. This contention is referable to the statement at page 1 of the specification that the invention relates to the two novel enantiomers of the anti-depressant drug [citalopram] “and to the use of these enantiomers as anti-depressant compounds as well as to the possible use as geriatrics or in the cure of obesity or alcoholism”.
  6. Alphapharm also apparently founds its fair basis attack on a passage at page 14, lines 26-29 of the specification, that states:
The invention also comprises a method for the alleviation, palliation, mitigation or inhibition of the manifestations of certain physiological-psychological abnormalies [sic – abnormalities] of animals, especially depressions by administering to a living animal body, including human beings, an adequate quantity of (+)-citalopram ...
  1. The claims were set out at [10] above. It is convenient to repeat here claims 3, 4 and 5 (which, it will be recalled, are product claims) as follows:
3. A pharmaceutical composition in unit dosage form comprising as an active ingredient, a compound as defined in claim 1, together with a pharmaceutically acceptable carrier or excipient.

4. A pharmaceutical composition in unit dosage form comprising, as an active ingredient, the compound of claim 2, together with a pharmaceutically acceptable carrier or excipient.

5. A pharmaceutical composition in unit dosage form, according to claim 3 or 4, wherein the active ingredient is present in an amount from 0.1 to 100 milligram per unit dose, together with a pharmaceutically acceptable carrier or excipient.

  1. Claims 3 and 4 claim (+)-citalopram and the pamoic acid salt of (+)-citalopram, respectively, in unit dosage form. The invention of this is disclosed at various points in the body of the specification, including:
  2. None of those disclosures are limited by reference to the treatment of depression, geriatrics, obesity or alcoholism.
  3. Claim 5 claims (+)-citalopram and its pamoic acid salt in unit dosage form in a dose range from 0.1 to 100 mg. Disclosure of this occurs in the body of the specification, including at:
  4. Again, none of these disclosures are limited by reference to the treatment of depression, geriatrics, obesity or alcoholism.
  5. I do not think that the fact that it is stated on p 1 of the specification that the invention “relates to the two novel enantiomers of the anti-depressant drug [citalopram] and to the use of these enantiomers as anti-depressant compounds as well as the possible use as geriatrics or in the cure of obesity or alcoholism” signifies that the disclosure made in the text to follow is limited by reference to the four possible uses mentioned. Similarly, I do not think that the passage at page 14, lines 26-29 quoted above confines the disclosure. On a fair overall view of the specification, the disclosure is of the products claimed in claims 1-5 and the method of claim 6 for the preparation of the compound of claim 1.
  6. In my view the claims are fairly based on the disclosure made in the body of the specification.

SECTION I – LACK OF CLARITY – S 40(3) OF THE ACT

  1. Section 40(3) of the Act requires that the claim or claims be “clear and succinct”.
  2. Alphapharm submits that claims 1 to 5 lack clarity in two respects:
    1. They do not identify the conditions in which the (+)-citalopram of claim 1 will rotate a plane of polarised light to the right, and although there is a convention about wavelength, there is no convention about the solvent to be used, and examples 1 and 2 in the Patent specification make it clear that the solvent needs to be specified;
    2. The claims fail to identify the level of purity required.
  3. In relation to the first of these grounds, I accept Professor Davies’s testimony that there is a standard set of solvents and standard conditions and standard concentration (see [445] above). I find that there is no lack of clarity in the description of the product of claim 1.
  4. In relation to the second ground of attack, I have earlier accepted that the convention of 95% purity is applicable to the construction of claim 1 so that readers of claim 1 and its dependent claims 2 to 5 would understand that a (+)-enantiomer at least 95% pure was being referred to.
  5. The attack based on lack of clarity fails.

SECTION J – INUTILITY – S 18(1)(C) OF THE ACT

  1. Section 18(1)(c) of the Act provides that in order to be a patentable invention for the purposes of a standard patent, the invention, so far as claimed in any claim, must be “useful”.
  2. Alphapharm’s further amended particulars of invalidity contain two particulars of inutility:
(a) In so far as the alleged invention claimed in claim 5 includes a unit dose containing other than a therapeutically effective amount of (+)-Citalopram, the alleged invention is not useful;

(b) Insofar as the invention claimed in claim 1 (and dependent claims) is not limited to the (+)-citalopram enantiomer, that rotates a plane of polarized light to the right in the conditions set out in Examples 1 and 2 of the Patent the claim is not useful and does not meet the promise of the invention because it includes the (R)-citalopram enantiomer of citalopram which is not responsible for 5-HT uptake inhibition; see Patent, page 3 lines 4-5. [emphasis in original]

The reference to the Patent, page 3, lines 4-5 is a reference to the following sentence:

Furthermore, it was shown to our surprise that the entire 5-HT uptake inhibition resided in the (+)-citalopram enantiomer.
  1. There is a principle that all that is within the scope of a claim must be useful if the claim is not to fail for inutility, or, to express the matter differently, a claim is bad if it covers means that will not produce the desired result even if a skilful person would know which means to avoid: Wm Wrigley Jr Company v Cadbury Schweppes Pty Ltd (2006) 66 IPR 298 at [138] and authorities there cited.
  2. Alphapharm relies on the testimony of Professor Montgomery who was asked what the highest therapeutically useful unit dose of escitalopram was. He said that it was 20 mg of escitalopram, but that in treating obsessive compulsive disorder (OCD) clinicians normally use above that level, and that unit dosages of 30 mg and 40 mg are often used in the treatment of resistant OCD.
  3. Professor Montgomery was also asked what would be the minimum useful dose. He said that 5 mg was found to be effective in the treatment of social anxiety disorder in a very large study, but that that amount was found to be ineffective in the treatment of generalised anxiety disorder. He said that there is a general notion that one should use lower doses in the case of the elderly, and that the 5 mg dose is used for the treatment of them.
  4. Alphapharm submits that this evidence demonstrates that the claimed range of 0.1 to 100 mg per unit dose includes quantities below the useful minimum of 5 mg and above the useful maximum of 40 mg. Accordingly, so Alphapharm’s submission goes, claim 5 lacks utility because it claims quantities outside the “useful” range.
  5. I agree. Claim 5 cannot be saved by implying any minimum or maximum of the kind of which Professor Montgomery gave evidence. To do so would be inconsistent with the claim as framed and would amount to an amendment of it.
  6. In relation to claim 1, I have concluded earlier that that claim is limited to (+)-citalopram in its absolute configuration as S-citalopram. Accordingly as Alphapharm accepts, this takes away the basis of its second ground of attack for inutility.
  7. In my view, claim 5 fails for inutility and the Patent should be revoked so far as it relates to claim 5 on the ground that the invention, so far as claimed in claim 5, is not a patentable invention because it is not useful within the meaning of s 18(1)(c) of the Act.

SECTION K – THE LUNDBECK APPEAL (EXTENSION OF TERM) PROCEEDING – ALPHAPHARM’S AND ARROW’S CLAIMS FOR RECTIFICATION UNDER S 192 OF THE ACT

Introduction

  1. I referred to the provisions of the Act relating to the extension of the terms of patents (ss 67, 68, 70, 71, 74–76 and 77) at [16] – [21], outlined the circumstances of the extension of the term of the Patent at [27] – [33], and discussed the Lundbeck Appeal (Extension of Term) Proceeding at [45] – [53]. I will not repeat what I have said in those passages.
  2. It will be recalled that Cipramil (citalopram hydrobromide) was included in the ARTG on 9 December 1997, and that Lexapro (escitalopram oxalate) was included in the ARTG on 16 September 2003.
  3. As foreshadowed at [15] above, the same issues arise in relation to Alphapharm’s and Arrow’s applications under s 192 of the Act for rectification of the Register to remove particulars of the extension of the term, as arise in relation to the Lundbeck Appeal (Extension of Term) Proceeding.
  4. Alphapharm has pending an application before the TGA for the purpose of enabling it to market a therapeutic good containing escitalopram oxalate. Therefore, Lundbeck concedes that Alphapharm is a “person aggrieved” within the meaning of s 192 of the Act and so has standing under that section to apply for rectification of the Register.
  5. The position of Arrow is different. The particulars to para 15 of Arrow’s statement of claim state that Arrow wishes to market a product in Australia containing (+)-citalopram. Affidavit evidence served by Arrow on the day prior to the commencement of the trial did not take matters much further. That evidence was to the effect that Arrow intends to market and sell in Australia a generic pharmaceutical product containing (+)-citalopram upon the expiry or earlier revocation of the Patent.
  6. Lundbeck does not concede that such an intention gives Arrow standing as a “person aggrieved” for the purposes of s 192. However, Lundbeck accepts that in the light of the fact that Alphapharm and Arrow have joined cause in relation to the granting of the extension and the entry of particulars in the Register, “the issue is somewhat moot”.
  7. Alphapharm and Arrow submit that Cipramil is “goods that contain, or consist of, the [pharmaceutical] substance” within the meaning of s 70(5) of the Act, that is to say, that Cipramil is goods that contain or consist of (+)-citalopram or S-citalopram or escitalopram (they do not distinguish between the three) which, they say, is the pharmaceutical substance per se that was disclosed in the complete specification of the Patent and fell within its claims.
  8. Much of the argument at the heart of the present Section K and of the following Section L is semantic. The (+)-enantiomer of citalopram is a pharmaceutical substance of which Lexapro consists or which it contains. That enantiomer provides the therapeutic use of Lexapro (see the definitions of “pharmaceutical substance” and “therapeutic use” set out at [486] below). Lundbeck submits, however, that it is incorrect to say that the racemate citalopram, and therefore Cipramil, contains (+)-citalopram.
  9. Lundbeck’s submissions in support of this position can be regarded as (1) its “one or more pharmaceutical substance per se” submission, and (2) its “contain” submission.

(1) Lundbeck’s “pharmaceutical substance per se” submission

General

  1. I set out the relevant sections in Pt 3 of Ch 6 of the Act at [17] – [21] above.
  2. Lundbeck submits that the references to “the substance” or “the pharmaceutical substances” in s 70(3), in the definition of “first regulatory approval date” in s 70(5), in s 71(2)(b) and in s 77(1)(a), all hark back to the expression “one or more pharmaceutical substances per se” in s 70(2)(a). In general terms, the submission is that the expression “one or more pharmaceutical substances per se” in s 70(2)(a) is a reference, in the circumstances of the present case, to nothing other than the separate enantiomer (+)-citalopram. It follows, according to the submission, that the registration of Cipramil did not amount to an inclusion in the ARTG of goods that contained or consisted of the pharmaceutical substance per se, (+)-citalopram. Cipramil, so Lundbeck contends, contains a different pharmaceutical substance per se, being the racemate citalopram.
  3. The expression “pharmaceutical substance” is defined in Schedule 1 to the Act to mean, relevantly:
a substance (including a mixture or compound of substances) for therapeutic use whose application (or one of whose applications) involves:
(a) a chemical interaction, or physio-chemical interaction with a human physiological system; ...

The expression “therapeutic use” is defined in Schedule 1 to mean, relevantly:

(a) preventing, diagnosing, curing or alleviating a disease, ailment, defect or injury in persons; ...

Clearly, both citalopram and (+)-citalopram are pharmaceutical substances.

  1. Lundbeck emphasises that s 70(2)(a) requires that the pharmaceutical substance per se be disclosed in the complete specification of the patent and be in substance within the scope of the claim or claims of that patent. It is the enantiomer (+)-citalopram that meets those requirements in the case of the Patent.
  2. Lundbeck’s contention is that once it is accepted that s 70(2)(a) refers to the (+)-enantiomer only, it must be accepted that Cipramil did not contain that pharmaceutical substance.

The authorities

  1. Lundbeck refers to three authorities as being relevant to the construction of the expression “pharmaceutical substance per se”: Boehringer Ingelheim International GmbH v Commissioner of Patents [2001] FCA 647; (2001) 112 FCR 595 (Boehringer); Prejay Holdings Ltd v Commissioner of Patents [2003] FCAFC 77; (2003) 57 IPR 424 (Prejay); and Pharmacia Italia SpA v Mayne Pharma Pty Ltd (2006) 69 IPR 1 (Pharmacia).
  2. Boehringer is not entirely on point. The patent claims were for a container comprising an aerosol or spray composition for nasal administration. The composition comprised as its active ingredient a certain pharmaceutical substance. The primary Judge, Heerey J, held that s 70(2)(a) was not satisfied because the pharmaceutical substance itself (per se) was not disclosed in the complete specification and did not fall within the scope of a claim of the patent specification (Boehringer Ingelheim International v Commissioner of Patents (2001) AIPC 91-670). His Honour examined the legislative history behind ss 70–79 and concluded that patents for new and inventive processes or new and inventive modes of treatment of old or known products are not the subject of s 70: it is only patents for new and inventive products that are. Accordingly, the expression per se showed that an extension of term is to be available only where the claim is for a pharmaceutical substance as such, not a substance forming part of a method or process.
  3. The Full Court in Boehringer agreed (at [37]). Their Honours noted (at [39]) that the Second Reading Speech relating to the Intellectual Property Laws Amendment Bill 1997 (Cth), which inserted the relevant sections into the Act, spoke of “development of a new drug” and of the research and testing required before a “product” could enter the market. Their Honours also noted (at [40]) that the Explanatory Memorandum relating to that Bill spoke of the expression “pharmaceutical substance per se” as being usually restricted to “new and inventive substances”. They considered that the expression “fall within the scope of the claim or claims of that specification” in s 70(2)(a) means “[b]e included amongst the things claimed ” (at [42]).
  4. The decision in Boehringer does not govern the present case because claims 1 to 5 are indisputably product claims, and the pharmaceutical substance per se in question is indisputably the (+)-enantiomer of citalopram.
  5. In my view, Lundbeck seeks to draw more from the expression “per se” than was necessary in Boehringer. In Boehringer, the Court was concerned only to distinguish between a pharmaceutical substance that is the subject of a product claim (which they held to be within s 70(2)(a)) and a substance that forms part of a method or process claim (which they held not to be within s 70(2)(a)). The Court was not concerned, as I am, with a competition between two arguable “first regulatory approval dates” and with the question whether the substance the subject of a product claim in a later patent was contained in goods previously included in the ARTG.
  6. In Prejay a Full Court of this Court followed Boehringer. All of the claims were method claims, not product claims. The Commissioner’s delegate refused an application for an extension. The Full Court agreed with the delegate that a substance that is mentioned in the context of a method claim does not meet the requirement of s 70(2)(a) that the substance per se fall within the scope of a claim (at [23] – [24] per Wilcox and Cooper JJ, [28] per Allsop J).
  7. In Pharmacia, Weinberg J accepted the distinction drawn in Boehringer, but held (at [99]) that claim 1 of the patent before him did state “a claim to a new and inventive substance, and not to a novel process or method”. Weinberg J was also not concerned with rival first regulatory approval dates or with the associated questions that are before me.
  8. For its part, Alphapharm relies on Merck & Co Inc v Arrow Pharmaceuticals Ltd (2003) 59 IPR 226 (Merck). A patentee, Merck & Co Inc (Merck), appealed against the Commissioner’s delegate’s refusal of an extension. The appeal was undefended, the respondent having withdrawn from the proceeding. Wilcox J allowed the appeal.
  9. Sankyo Company Pty Ltd (Sankyo) had held a patent that claimed a compound of a particular formula, commonly referred to as Lovastatin. Lovastatin was entered on the ARTG. It was used for the control of cholesterol levels. Sankyo’s patent expired on 19 February 2000, and no extension was sought in respect of it.
  10. Merck applied for a patent on 3 June 1980 with priority dates in 1979 and 1980. The patent was granted on the basis of the exclusion of certain claims which related to Lovastatin.
  11. Immediately after the expiration of Sankyo’s patent, Merck applied to the TGA for listing on the ARTG of a product called “Mevacor”. Listing occurred some four weeks later. After the listing, Merck applied for an extension of the term of its patent.
  12. Before the delegate, Merck argued for the extension on two bases: first, that the relevant pharmaceutical substance was Lovastatin, and, second, that it was lovastatin beta-hydroxy acid (LHA). In relation to the former ground, Merck faced the difficulty that the claims relating to Lovastatin had been excluded from the claims of the patent as granted. The delegate therefore held that Lovastatin was not a pharmaceutical substance per se that was disclosed in the complete specification of Merck’s patent and fell within the scope of any claim of that specification.
  13. In relation to Merck’s alternative argument concerning LHA, the delegate accepted that LHA was a pharmaceutical substance per se disclosed in the complete specification of Merck’s patent and that LHA fell within the claims of that specification, and so satisfied s 70(2)(a) of the Act. The question that then arose was whether Lovastatin consisted of or contained LHA.
  14. The delegate concluded that Lovastatin did contain LHA, but only as an impurity, and that this did not satisfy s 70(3)(a).
  15. On appeal, Wilcox J disagreed, saying (at [25]) that Merck’s LHA argument was “irrefutable”, and that, if only on that ground, the delegate’s decision must be reversed.
  16. His Honour stated (at [26]) that LHA was a pharmaceutical substance per se disclosed in the complete specification of the patent and falling within its claims, and that the undisputed evidence was that Mevacor contained LHA.
  17. Wilcox J considered that it was irrelevant whether or not LHA itself was included in the ARTG: that for s 70(3)(a) purposes it was enough that it was contained in some other good (Mevacor) that was included in the ARTG (at [27]). His Honour thought that it did not matter that LHA was present in Mevacor only in minute quantities (at [28]).
  18. Having regard to his conclusions supporting Merck’s LHA argument, his Honour did not need to address its argument concerning Lovastatin, although he expressed the view that it seemed to him that the delegate had been right to reject that argument.
  19. In Merck, as in the other cases referred to above, the question before the Court did not concern a competition between two arguable first regulatory approval dates. However, Wilcox J’s construction of “containing” in s 70(3) must be applicable to the word “contain” in s 70(5). If I were to follow Wilcox J, I would hold that Cipramil “contained” (+)-citalopram.

Consideration of Lundbeck’s “pharmaceutical substance per se” submission

  1. The Latin expression “per se” means “by or in itself; intrinsically. Opposed to PER ACCIDENS [defined relevantly to mean “By virtue of some non-essential circumstance; contingently, indirectly”]”: Oxford Dictionary of Foreign Words and Phrases (OUP, 1997). It is not every disclosure of every substance falling within the definition of “pharmaceutical substance” to which s 70(2)(a) refers. A non-essential or incidental disclosure of a pharmaceutical substance will not satisfy s 70(2)(a). The pharmaceutical substance must be of the essence of a disclosure made in the specification. This construction is consistent with the requirement that it fall within the scope of the claim or claims.
  2. The racemate, citalopram, is the pharmaceutical substance per se disclosed in the specification of the Australian Citalopram Patent, whereas the (+)-enantiomer of that racemate is the pharmaceutical substance per se disclosed in the specification of the Patent, in each case for the purpose of s 70(2)(a). Moreover, the inclusion in the ARTG of Cipramil on 9 December 1997 clearly signified the inclusion in the ARTG of goods that consisted of or contained the pharmaceutical substance citalopram, and the inclusion of Lexapro in the ARTG on 16 September 2003 clearly signified the inclusion in the ARTG of goods that consisted of or contained the pharmaceutical substance (+)-citalopram, in each case for the purpose of s 70(3)(a). The precise question before the Court, however, is whether Cipramil was goods that contained the pharmaceutical substance (+)-citalopram for the latter purpose.
  3. The “substance” or “pharmaceutical substances” referred to in ss 70(3)(a), 70(5), 71(2)(b) and 77(1)(a) refer to the “one or more pharmaceutical substances” referred to in s 70(2)(a), but I do not think that the expression “per se” carries over into those provisions, otherwise the Parliament would have used it again in them. Parliament did in fact use it again in s 78(2)(a) – again in respect of the disclosure in the complete specification of a patent. The disclosure in the complete specification of which s 70(2)(a) speaks is different from the notions of “inclusion”, “containing” and “consisting of” that are referable to the ARTG which are addressed in the later provisions. The omission of “per se” from those later provisions suggests that it is to suffice that the goods that are included in the ARTG “contain” only non-essentially or incidentally the pharmaceutical substance that is required to be disclosed per se in the complete specification. In my view, the per se qualification has done its work once the pharmaceutical substance disclosed in the complete specification has been identified. Thereafter, the question is the simple one whether the goods included in the ARTG contain or consist of that pharmaceutical substance, unencumbered by any per se notion.
  4. However, Lundbeck further submits that the definition of “pharmaceutical substance” (with the associated definition of “therapeutic use”) in Schedule 1 (see [486] above) itself and without more signifies that Cipramil does not contain (+)-citalopram.
  5. I do not accept this submission either. Both (+)-citalopram and racemic citalopram are for a therapeutic use which is of the same kind in each case. Indeed, the therapeutic benefit of citalopram comes from the presence in it of (+)-citalopram. It would not be right to say that Cipramil does not contain (+)-citalopram merely because the therapeutic effect of the racemate is less effective because of the additional presence in it of (–)-citalopram.

(2) Lundbeck’s “contain” submission

  1. There is overlap between Lundbeck’s “pharmaceutical substance per se” submission and its “contain” submission. In its “contain” submission, Lundbeck seeks to emphasise the different properties of citalopram and (+)-citalopram for the purpose of showing the “inappropriateness” of regarding the former as containing the latter. I will first summarise, in turn, the various aspects of Lundbeck’s “contain” submission.

It is not appropriate to say that citalopram “contains” (+)-citalopram because they are both new chemical entities (the New Chemical Entities Submission)

  1. The earlier (9 December 1997) registration was of CIPRAMIL Citalopram hydrobromide. The later registration (16 September 2003) was of LEXAPRO escitalopram (as oxalate).
  2. Lundbeck points to the fact that escitalopram oxalate (Lexapro) was approved as a “new chemical entity” by the TGA. The evidence shows that the TGA adopted the guidelines “Investigation of Chiral Active Substances” used in the European Union (the legislative basis is Directive 75/318/EEC as amended). Section 5.3 of those guidelines deals with the “Development of a new single enantiomer from an approved racemate”. The first two paragraphs of section 5.3 are as follows:
In principle this concerns the development of a new active substance requiring a complete new application. The decision to develop an enantiomer should be explained.

It would be counterproductive in this case not to use data on the corresponding racemate as far as is applicable to the enantiomer. It is thereby assumed that the applicant has the contents of the full dossier on the corresponding racemate at his disposal. Suitable “bridging” studies should be carried out to link the complete racemate data to the incomplete data on the selected enantiomer. The use of racemate results should be explained. The extent of bridging studies should be defined on a case-by-case basis...

  1. In the present case, the TGA required of Lundbeck that additional pre-clinical and clinical studies be conducted.
  2. The Australian Drug Evaluation Committee (ADEC) resolved at its 229th meeting on 21 August 2003 (Commonwealth of Australia Gazette, No GN 35, 3 September 2003) to advise that there should be approved for registration, inter alia, the following medicine:
Escitalopram oxalate – Lexapro
Tablets, 5, 10, 15 and 20mg
Lundbeck Australia Pty Ltd
New Chemical Entity: For the treatment of major depression.

  1. Professor Day had been a member of ADEC and participated in its role of advising the TGA about applications for the listing of prescription medicines on the ARTG from 1992 to 1997. Professor Day had a wealth of other experience in the fields of Pharmacology, Clinical Pharmacology, Toxicology, Rheumatology and Therapeutics. At the time of making his affidavit, he was Professor of Clinical Pharmacology in the School of Physiology & Pharmacology and the St Vincent’s Clinical School at the University of New South Wales, a position he had held since 1989. He was also Director of the Department of Clinical Pharmacology and Toxicology at St Vincent’s and Director of St Vincent’s Clinical Trials Centre, positions he had held since 1989 and 1993 respectively.
  2. Professor Day stated that in the context of the discussion of listings on the ARTG, he treated “medicine” as meaning the same thing as “pharmaceutical substance” and “chemical entity” as meaning the same thing as the active component of a pharmaceutical substance. He said that a new chemical entity medicine must be a different chemical entity medicine from one that is already registered on the ARTG and that separate registrations for two chemical entity medicines indicates the TGA had taken the view that they are not the same thing.
  3. It follows, according to Lundbeck’s submission, that s 70 of the Act does not deny Lundbeck an extension of term, because that which has been registered on the ARTG as a new chemical entity cannot be “contained” in something that was already registered on the ARTG.

It is not appropriate to say that citalopram “contains” (+)-citalopram because it is not appropriate to say that a racemic mixture contains the (+)-enantiomer (the Rotation of Plane-Polarised Light Submission)

  1. The symbol (+) signifies, by definition, that the enantiomer rotates plane-polarised light to the right (clockwise), whereas the symbol (–) signifies, by definition, that the enantiomer rotates plane-polarised light to the left (anti-clockwise). Lundbeck submits, therefore, that it is not appropriate to identify a racemate by reference to the rotation of polarised light: both enantiomers being present in equal proportions, there is no net rotation of plane-polarised light. Therefore, so the submission goes, it is inappropriate to characterise the enantiomers when in racemic form as (+) or (–) or to say that the racemate citalopram contains (+)-citalopram.
  2. Elaborating on this submission, Lundbeck contends that the appropriate descriptors of the enantiomers of citalopram when in a racemic mixture are S-citalopram and R-citalopram. Lundbeck accepts that the racemic mixture citalopram contains the molecule S-citalopram (escitalopram), and that when separated from the racemate that enantiomer rotates plane-polarised light to the right, and is therefore then appropriately called (+)-citalopram.
  3. So it is that Lundbeck can contend that:
    1. Citalopram (and therefore Cipramil) consists of, or contains in equal parts, S-citalopram (escitalopram) and R-citalopram;
    2. S-citalopram (escitalopram) is (+)-citalopram, and R-citalopram is (–)-citalopram;

yet it does not follow that

  1. Citalopram (and therefore Cipramil) consists of, or contains in equal parts, (+)-citalopram and (–)-citalopram.
  2. In cross-examination, Professor Davies was careful not to assent to the proposition that the (+)-citalopram was present in the racemate, preferring to state that molecules of the S configuration were present in the racemate.

It is not appropriate to say that citalopram “contains” (+)-citalopram because it is not appropriate to say that a racemic mixture contains the (+)-enantiomer in an isolated form (having a purity greater than 95% ) (the Purity Submission)

  1. I have previously held that the expression “(+)-citalopram” in the Patent specification refers specifically and distinctively to the single enantiomer, not merely to that enantiomer in the unresolved racemate (see Section C). Lundbeck submits that it would be inconsistent with this view to hold that citalopram contains (+)-citalopram because, in the racemate, it does not exist in the isolated and pure form, but rather at 50%  purity.

It is not appropriate to say that citalopram “contains” (+)-citalopram because they are different pharmaceutical substances with different physical, chemical, pharmacological and clinical properties and effects (the Different Pharmacological Properties and Effects Submission)

  1. In its submissions, Lundbeck discusses separately the physical and chemical properties, the pharmacological properties, and the clinical effects of, respectively, citalopram and escitalopram.
  2. One of Lundbeck’s submissions highlights the semantic nature of much of the argument. Lundbeck submits:
...the physical composition of citalopram and escitalopram is different. One contains equal amounts of each enantiomer and the other contains only a single enantiomer.

Depending on the meaning of “enantiomer” here, this statement comes close to a concession by Lundbeck that citalopram contains, to the extent of 50%, the (+)-enantiomer. No doubt, however, Lundbeck was referring to the “S-enantiomer”.

  1. In relation to the physical and chemical properties of citalopram and escitalopram, Lundbeck points out that the solubility and melting point of the two are different as, of course, is the capacity to rotate plane-polarised light. Lundbeck also points out that the evidence is that the single enantiomer can react with other chiral compounds at a rate different to the rate at which the racemate reacts with them.
  2. All that this shows, however, in my opinion, is that the racemate is not one and the same thing as the enantiomer. The statute’s use of the alternatives “contain, or consist of” also takes account of this fact.
  3. In relation to pharmacological properties, Lundbeck refers to the different physio-chemical interactions with the receptor manifested in different pharmacodynamics and pharmacokinetics. Again, I do not think that these differences resolve the present question.
  4. Professor Montgomery, Emeritus Professor of Psychiatry at the Imperial College School of Medicine, University of London, said that it was correct to say that the racemate and the S-enantiomer had “the same active ingredient” only if it was assumed that the other enantiomer, the R-enantiomer was inactive. Professor Montgomery said that he initially made that assumption and for that reason expected that the efficacy of the active enantiomer would be the same as that of the racemate at half the dose. He was surprised that the data from early studies showed that the enantiomer had a different level of efficacy, demonstrating that the R-enantiomer was also active. Lundbeck submits that it is not to the point that the serotonin reuptake inhibitory activity resides in the S-enantiomer: the point is that the R-enantiomer is also active, even though counteractive.
  5. In relation to “clinical effects”, Lundbeck concedes that the evidence that citalopram and escitalopram have different clinical effects has been disputed. It submits, however, that the uncontested difference between the physical properties and the pharmacology properties in vitro and in animals is sufficient to establish that they are different substances.

Consideration of Lundbeck’s “contains” submission

  1. For its part, Alphapharm emphasises the distinction between the requirements of s 70(2)(a) on the one hand and ss 70(3)(a) and 71(2)(b) on the other hand. That distinction, which I accepted above in the course of dealing with Lundbeck’s “pharmaceutical substance per se submission, is between the conditions in s 70(2)(a) that must be satisfied in respect of the disclosure made in a patent for which an extension is sought, on the one hand, and the requirements of ss 70(3)(a) and 71(2)(b) concerning goods included in the ARTG, on the other hand. It is ss 70(3)(a) and 71(2)(b), not s 70(2)(a), that determine whether the 9 December 1997 ARTG registration for Cipramil was a registration of goods containing or consisting of the pharmaceutical substance disclosed in the Patent. The question is simply whether Cipramil contains the (+)-enantiomer of citalopram that was disclosed in the Patent.
  2. The word “contain” is an ordinary English word and its meaning is plain. In its conjunction with the alternative “consist of”, “contain” means, according to the New Shorter Oxford English Dictionary, “include as a part ... of its substance or content” or “have inside itself”.
  3. In s 70(5)(a) it is “goods” that are to contain or are to consist of the pharmaceutical substance in question. In this context, “contain” signifies a physical relationship that is something less than “consist of”. If goods A consist of B and C, they may be seen to contain B and to contain C, but not to consist of either alone. B and C will also be goods, although they need not be recognised as continuing to have a separate existence. For example, there is no difficulty in saying that a cake “contains” milk and eggs although they are no longer recognised as having a separate existence in the cake.
  4. In relation to the New Chemical Entities Submission, I do not think that the TGA’s guideline, the resolution of ADEC or the evidence given by Professor Day bear upon the question of the proper construction of the statutory provisions. While (+)-citalopram can be accepted to be a new chemical entity as against the racemate, this does not answer the statutory question whether the latter (or, more precisely, Cipramil) “contains” the former.
  5. In response to Lundbeck’s reliance on the TGA’s guideline and the resolution of ADEC in support of its New Chemical Entities Submission, Alphapharm might just as irrelevantly call in aid statements made by Lundbeck to the TGA in connection with its application to register Lexapro. Alphapharm referred to the fact that Lundbeck had no difficulty in frequently referring to escitalopram as the enantiomer of the racemate citalopram to which the therapeutic activity of citalopram was attributed. In an article “Escitalopram versus citalopram: the surprising role of the R-enantiomer” Psychopharmacology (2004) 174, pp163-176, the authors, Dr Connie Sánchez, Dr Bøgesø and other employees of Lundbeck, began their abstract with the statement:
Rationale: Citalopram is a racemate consisting of a 1:1 mixture of the R(–)- and S(+)-enantiomers. Non clinical studies show that the serotonin reuptake inhibitory activity of citalopram is attributable to the S-enantiomer, escitalopram. A series of recent non-clinical and clinical studies comparing escitalopram and citalopram to placebo found that equivalent doses of these two drugs, ie containing the same amount of the S-enantiomer, showed better effect of escitalopram. These results suggested that the R-citalopram in citalopram inhibits the effect of the S-enantiomer.

The references in this passage are not, however, to the (+) and (-) enantiomers.


  1. The Rotation of Plane Polarised Light Submission does not show that the racemate does not contain the (+)-enantiomer. The expression (+)-citalopram refers to a physical thing, a molecule. That molecule’s property of rotating plane-polarised light to the right is no more than a means of identifying it and distinguishing it from (–)-citalopram and from (±)-citalopram, at a time when it was not known which of the S and R enantiomers was the (+)-enantiomer. The identifying and distinguishing feature of rotating plane-polarised light to the right has no other significance in the Patent or in the case otherwise. It is now known that in the case of citalopram, the (+)-enantiomer is the S-enantiomer. I do not see any difference between asking if Cipramil contains the (+)-enantiomer and asking if it contains the S-enantiomer.
  2. Citalopram contains the molecule that is identified as (+)-citalopram. It is so identified because, when isolated, it rotates plane-polarised light to the right. It is beside the point that it is only once it is isolated that it can be seen to demonstrate the reason underlying its name.
  3. The only reason why (+)-citalopram can not be seen to rotate plane-polarised light to the right when it is in the racemate, is that (–)-citalopram is also present, in an equal amount, with its property of rotating plane-polarised light to the left to precisely the same extent. The two equal but opposite propensities cancel each other out.
  4. Nor do I find the Purity Submission persuasive. The 50% of the racemate that is either enantiomer is 95%  pure. The word “contains” is an alternative to “consists of”. While it would be wrong to say that the racemate consists of either enantiomer to the extent of 95%  purity, it contains each of the two 95%  pure enantiomers to the extent of 50%  of its composition.
  5. This view is not inconsistent with my construction of claim 1, which I held to refer specifically and distinctly to the pure (+)-enantiomer, and not to that enantiomer when merely a part of the racemate. The word “contain” in ss 70(3)(a) and 71(2)(b) gives a context and raises a question not present in the Patent specification: was the pharmaceutical substance (+)-citalopram that was disclosed in the Patent contained in something larger, racemic citalopram, or, more precisely, in the goods Cipramil?
  6. Nor do I accept the Different Pharmacological Properties and Effects Submission. I have referred above to the physical relationship of inclusion which I think the word “contains” refers to in the present context. The language does not, in my view, invite or permit anything other than an inquiry into the question whether, as a matter of physical relationship, the goods Cipramil contain the molecule that, from its isolated state, derives the name “(+)-citalopram”.

Conclusion

  1. For the above reasons, Lundbeck’s appeal should be dismissed and the Register should be rectified by the omission from it of any reference to an extension of the term of the Patent.

SECTION L – THE TGA (PROTECTED INFORMATION) PROCEEDING

Introduction

  1. I outlined the nature of the TGA proceeding at [36] – [40] and will not repeat what I said there.
  2. Lundbeck Australia seeks:
  3. The following matters may be noted at the outset.
  4. First, the above formulation of the relief claimed refers to either all or some unidentified part of the information that Lundbeck provided to the Secretary “in respect of applications for the registration of therapeutic goods” of the kind described (the reference to “applications” in the plural will be noted). This is far too wide. Section 25A(2) defines “protected information” in a far more limited way.
  5. In its statement of claim, Lundbeck Australia purported to give “particulars” of the information. However, it did so only in terms of the three broad classifications set out at [37] above. Lundbeck Australia has led evidence of documents it provided to the Secretary, but documents are not information. A document may contain information that satisfies the criteria of “protected information” set out in s 25A(2) and other information that fails to do so. It does not follow from the inclusion in a document of the former, that the Secretary is prohibited by s 25A(1) from using the latter.
  6. Second, para (b) within s 25A(2) requires, firstly, that the information be “about the active component”. On the basis that Lexapro is the “new goods” referred to in s 25A(2)(a), the active component is escitalopram. Accordingly, it is necessary to identify information that is “about” escitalopram. Not all information that Lundbeck Australia gave to the Secretary in relation to its application to register Lexapro was about escitalopram.
  7. Third, again according to para (b) of s 25A(2), the information must be “not available to the public”. The Court would need to be satisfied that the information to be referred to in its order was not already available to the public, and would have to include in the order a condition that the order cease to operate in relation to any remaining information upon its becoming available to the public. The order that Lundbeck Australia proposes incorporates a qualification of the latter kind. However, it does not identify and exclude certain information that is shown to be already available to the public.
  8. Fourth, there is the question whether the criterion contained in para (c) of s 25A(2) is satisfied. When escitalopram oxalate (under the name Lexapro) was included in the ARTG on 16 September 2003 (less than five years ago – see para (e) of s 25A(2)), citalopram hydrobromide was already included in the ARTG under the name Cipramil (having been registered on 9 December 1997). The issue here is whether Cipramil was goods “consisting of, or containing”, for the purposes of para (c) of s 25A(2), escitalopram, the active component of Lexapro.
  9. The affinity between this fourth question and the questions raised in the Lundbeck Appeal (Extension of Term) Proceeding (Section K above) is clear.
  10. Fifth, Lundbeck Australia has referred to the need for confidential information that it gave to the Secretary not to be disclosed to Alphapharm. An example is information relating to patients. However, s 25A and the relief sought by Lundbeck Australia relate only to the use to be made by the Secretary when evaluating therapeutic goods for registration. A holding that the Secretary may use information given to her by Lundbeck Australia for that purpose does not mean that the Secretary is at liberty to disclose that information to Alphapharm. I am not concerned for present purposes to identify limitations on the use that it would be proper for the Secretary to make of information given to her that is not “protected information” within s 25A.

Background facts

  1. It is unlawful to market therapeutic goods in Australia unless they are registered on the ARTG.
  2. Lundbeck Australia has made three applications to the Secretary for registration of therapeutic goods that are relevant to the present case:
    1. Cipramil: As noted above, this was citalopram hydrobromide, which was registered on the ARTG as Cipramil on 9 December 1997.
    2. Cipralex: The application for registration of Cipralex was unsuccessful, and Cipralex was never registered in the ARTG.
    3. Lexapro: As noted above, this was escitalopram oxalate, which was registered on the ARTG as Lexapro on 16 September 2003.

Sections 25A(2)(d) and (e) require that the “new goods” must have become registered. Accordingly, information that Lundbeck Australia provided to the Secretary in relation to its application to register Cipralex is not within the definition of “protected information”, and the application to register Cipralex can be put to one side. The same information may be within the definition by reason of its having been also supplied in relation to the later application to register Lexapro.

  1. According to the covering letter on the Cipralex application, and according to the evidence of Gitte Dyhr, Divisional Director of Regulatory Affairs at Lundbeck, that application was a “bridging application” in the sense of an application intended “to bridge” from the data filed in respect of an earlier drug (in this case, Cipramil) to the additional data filed to support the application for registration of another drug (in this case, Cipralex).
  2. The Cipralex application was rejected by the TGA, and Lundbeck was required to file, and did file, additional data. This led to the registration of Lexapro.
  3. On 15 June 2005, Alphapharm applied for registration on the ARTG of its generic product containing escitalopram as the active component. It is not disputed that “[Alphapharm’s] generic escitalopram product is bioequivalent to Lundbeck’s escitalopram product” or that Alphapharm’s application was “an abbreviated application that does not include the vast amount of data, including clinical study and patient data, and expert reports, that a complete application for registration of a new drug substance would include”.
  4. In substance, Alphapharm invited the TGA, when evaluating its application, to rely on the data that had been filed by Lundbeck Australia, including clinical studies, patient data and expert reports, in support of Lundbeck Australia’s application to register Lexapro.
  5. The Secretary took the view that this information was not protected information within the meaning of s 25A(2) of the TG Act. The Secretary agreed, however, not to deal with this information further in connection with Alphapharm’s application without prior notice to Lundbeck Australia.
  6. In its statement of claim Lundbeck Australia alleges that it will suffer loss and damage if the information in question is not treated as “protected information” within s 25A, and is used to evaluate Alphapharm’s therapeutic goods.

Issues

  1. The question whether information provided by Lundbeck Australia to the TGA in support of its application for the registration of Lexapro is protected information for the purposes of s 25A(1), raises four issues:
    1. Is Cipramil (citalopram hydrobromide) another therapeutic good “consisting of, or containing” (+)-citalopram within the meaning of s 25A(2)(c)(i)?
    2. What is the “information” that Lundbeck Australia contends is protected?
    3. Is that information “about” the enantiomer (+)-citalopram for the purposes of s 25A(2)(b)?
    4. Is that information “available to the public” within the meaning of s 25A(2)(b)?

Evidence

  1. Lundbeck relied on affidavit evidence of Ms Dyhr, who was cross-examined.
  2. Ms Dyhr graduated from the Royal Danish School of Pharmacy with a Master of Science in Pharmacy in 1982. After working with ICI-Pharma, now Astra Zeneca, Ms Dyhr became, in 1987, Regulatory Affairs Associate at Lundbeck. In that position, she was responsible for planning and coordinating regulatory activities worldwide for pharmaceutical products manufactured by Lundbeck. In 1991, Ms Dyhr was made Head of Department of Regulatory Affairs, assuming responsibility for all operational activities for regulatory affairs, including those related to development projects and marketed products.
  3. In 1996, Ms Dyhr became Lundbeck’s Divisional Director of Regulatory Affairs and in that capacity became responsible, worldwide, for activities related to development projects and marketed products.
  4. One of Ms Dyhr’s responsibilities in this role is to direct the preparation and filing by Lundbeck subsidiaries of applications to regulatory authorities worldwide for marketing authorisations.
  5. Ms Dyhr states that she was asked “whether the information about escitalopram contained in the documents in Lundbeck’s applications is available to the public”. She states that in order to answer this question, she reviewed Lundbeck’s applications (to the TGA). Ms Dyhr states that the information is contained in documents falling within one or other of the following four categories:
    1. Study reports;
    2. Journal articles;
    3. Experts’ reports; and
    4. Summaries of the application or parts thereof.

I will deal with Ms Dyhr’s affidavit testimony in relation to each of the four categories, and some further matters, in turn.

Study reports

  1. The study reports are reports on studies of the effects of drugs on animals and humans. They include such information as the qualifying criteria for patients participating in a clinical study, the dosing régimes adopted, and the statistical plan to be adopted in analysing the resulting data. Sometimes Lundbeck contracts with an external principal investigator to carry out clinical studies. In such cases, Lundbeck follows a standard procedure designed to ensure confidentiality of the results.
  2. Mr Dyhr concludes in relation to the study reports:
The study reports, in the form in which they are included in Lundbeck’s applications for regulatory approval, are never made public. However, certain information from study reports is sometimes made available to the public, as described in further detail below.

Journal articles

  1. The research conducted in relation to escitalopram as reported in the study reports often generates scientific papers written by Lundbeck’s staff or by the investigators concerned, for presentation at scientific conferences or publication in journals. Such journal articles are often included in Lundbeck’s applications for regulatory approval in addition to the underlying clinical study reports and data.
  2. A scientific paper or journal article will contain a summary of part of one or more studies together with a discussion and conclusion in a form suitable for inclusion in a scientific journal.
  3. Accordingly, so Ms Dyhr states, to the extent that information contained in a study report is reproduced in a scientific journal article, it will have become publicly available. Ms Dyhr points out, however, that scientific papers and journal articles are usually between four and ten pages in length, whereas a corresponding study report will typically run to hundreds of pages, since it includes far more detail, including all of the underlying data, which is not appropriate for inclusion in a paper or article.

Expert reports

  1. The expert reports are very detailed reports prepared by independent experts who have reviewed the underlying raw data, summarised it and expressed their opinion on the conclusions that can reasonably be drawn. Ms Dyhr states that in relation to Lundbeck’s application to register escitalopram, there were two expert reports, one of which dealt with pharmacology and toxicology (originally dated January 2001 and revised in November 2001), and the other of which dealt with the clinical studies (and included a number of addenda).
  2. Because some data from the studies conducted in relation to escitalopram have been published in scientific journals, the expert reports contain some information that has been made available to the public. However, in addition, the expert is given access to all of the underlying data, including the unpublished data. Often the expert will request that further statistical analyses be conducted of the data. For this reason, expert reports usually contain information about the product which will not have been made available to the public.
  3. The expert reports themselves are not published, except to the regulatory authorities. To the best of Ms Dyhr’s knowledge and belief, no regulatory authority to which Lundbeck has submitted an expert report in relation to escitalopram has a practice of making such reports publicly available. I accept that the TGA would not make expert reports publicly available and would treat them as confidential. Ms Dyhr points out that the opinion of the expert, as expressed in his or her report, never becomes available to the public.
  4. The two expert reports in respect of escitalopram are in evidence as exhibits.

Summaries of the application or parts thereof

  1. These summaries are narratives summarising the results of particular studies and stating the conclusions which Lundbeck draws from them. Ms Dyhr states that preparation of such summaries is mandatory for the purpose of seeking regulatory approval in Australia and elsewhere. She acknowledges, however, that the summaries do contain some information about escitalopram which has been made available to the public, because some of the data to which the summaries refer have been published in scientific journals or otherwise become available to the public.

Ways in which information about escitalopram has become available to the public

  1. Under the heading “Ways in which information about escitalopram has become available to the public” in her affidavit, Ms Dyhr refers to the practice in some countries for the relevant regulatory authority itself to prepare and publish a summary of certain aspects of applications for registration. She gives as an example the FDA in the United States of America, which prepares drug approval reviews. In relation to escitalopram, the FDA has published certain reviews of the regulatory dossier filed in the USA. These reviews are available to the public, including the public in Australia, via the internet. Exhibited to Ms Dyhr’s affidavit is an example of a review from the FDA’s website.
  2. Barry John Spencer, who is employed by Alphapharm as a “Senior Patent Officer”, has put into evidence as Exhibit BJS-1 a CD-Rom containing copies of documents that he downloaded from the FDA website. The documents relate to the FDA Drug Approval Process for Lexapro. It is clear that the documents are publicly available in Australia. There are 18 documents comprising 683 pages.
  3. Ms Dyhr states that other countries such as Sweden and France adopt a similar process of reviewing the dossiers, although the reviews produced by authorities other than the FDA are brief (about four to six pages in length), and no country has published any information that is not also included in the reviews published by the FDA.
  4. Mr Dyhr states that the European Medicines Agency (EMA) which provides a centralised process for seeking regulatory approval in European Union countries, also produces a summary (briefer than that produced by the FDA) in relation to applications filed using the centralised procedure of the EMA. However, in respect of escitalopram Lundbeck did not use that procedure. Rather, it made applications directly in each country in which it wished to market escitalopram. Accordingly, the EMA has never produced such a summary relating to escitalopram.
  5. Ms Dyhr states that except as disclosed in the summaries described above, to the best of her knowledge, the various regulatory authorities to which Lundbeck has submitted information corresponding to that provided to the TGA have treated the information as confidential and have not made it publicly available.
  6. Ms Dyhr states that Lundbeck itself has recently adopted a practice of publishing on a website in summary form “the results of all studies conducted in relation to its products”. Mr Dyhr states that this Lundbeck website includes four to six page summaries of each of the complete studies conducted by or on behalf of Lundbeck in relation to escitalopram, and she exhibits to her affidavit an example.

Information about escitalopram that has never become publicly available

  1. Finally, in paras 46–55 of her affidavit, Ms Dyhr addresses “Information about escitalopram which has never become publicly available”. She summarises this information as being:

In relation to the latter, Ms Dyhr describes in general terms the nature and documentation of the raw data, and exemplifies this by reference to a particular clinical study report that is an exhibit. Ms Dyhr exhibits to her affidavit four scientific papers and five scientific posters (which are a subset of one of the papers) based on the data generated by that clinical study. She contrasts the limited disclosure made in the scientific papers with the comprehensive disclosure made in the clinical study itself.

  1. In Exhibit GD-7 to her affidavit, Ms Dyhr lists the documents supporting Lundbeck’s applications to the TGA which, she says, record the raw data in respect of each relevant study. She states that this is the information about escitalopram that has never become available to the public in any form.

The parties’ submissions on the four issues

(1) Is Cipramil (citalopram hydrobromide) another therapeutic good “consisting of, or containing” (+)-citalopram within the meaning of s 25A(2)(c)(i)?

  1. Lundbeck Australia does not dispute that (+)-citalopram is an active component of Lexapro. Alphapharm and the Secretary submit, however, that according to the plain meaning of s 25A, it is also an active component, indeed on one view, the active component of Cipramil, and that Cipramil consists of or contains (+)-citalopram. Lundbeck Australia does not admit that escitalopram oxalate in tablet form, which was the subject of its Lexapro application, consists of or contains (+)-citalopram as an active component.
  2. Lundbeck Australia relies heavily on the background to the relevant statutory provisions and on the arguments it made as to why Cipramil does not “contain” (+)-citalopram for the purposes of the definition of “first regulatory approval date” in s 70(5) of the Act (see Section  K above).
  3. Section 25A of the TG Act was inserted with effect from 17 April 1998 by the Therapeutic Goods Legislation Amendment Act 1998. In the Second Reading Speech on the Therapeutic Goods Legislation Amendment Bill 1997, the Parliamentary Secretary to the Minister for Health and Family Services said (Parlt of Aust, HR, Hansard, 3 December 1997, p 11933):
The changes to the therapeutic goods legislation include measures designed to improve the operating environment for the Australian pharmaceutical industry, as well as to ensure the availability of new drugs, while enhancing Australia’s commitment to its international obligations under the WTO Agreement on Trade Related Aspects of Intellectual Property Rights. This will be achieved through the introduction of a new data protection scheme for new chemical entities, referred to as ‘active components’ in the amending legislation.

At present, confidential information submitted to the Therapeutic Goods Administration in connection with applications to register products in the Australian Register of Therapeutic Goods is protected against disclosure, unless release is in the public interest, and also against use by the TGA for its own commercial benefit. Under the new ‘data protection’ scheme to be introduced by this bill, this data will now have five years of ‘data protection’. During this time, any other company seeking to register a generic copy of the registered product containing, or consisting of, the active component will be required to seek the agreement of the originator company before the TGA can directly or indirectly access or reference the originator company’s data relating to the same active component.

Applicants seeking to register generic products containing protected active components may still do so. However, they must develop and lodge their own full data package, instead of lodging an abbreviated package that demonstrates bioequivalence with a new active component. Most products that have a new active component will attract separate protection under a patent during their first five years on the market, but the ‘data protection’ regime will provide a safety net for those products which may fall outside the norm.
  1. The relevant article of the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) is Art 39 which reads:
1. In the course of ensuring effective protection against unfair competition as provided in Article 10bis of the Paris Convention (1967), Members shall protect ... data submitted to governments or governmental agencies in accordance with paragraph 3.
2. ...
3. Members, when requiring, as a condition of approving the marketing of pharmaceutical or of agricultural chemical products which utilize new chemical entities, the submission of undisclosed test or other data, the origination of which involves a considerable effort, shall protect such data against unfair commercial use. In addition, Members shall protect such data against disclosure, except where necessary to protect the public, or unless steps are taken to ensure that the data are protected against unfair commercial use.

Lundbeck Australia draws attention to the definition of “new chemical entity” in Schedule 9 to the Therapeutic Goods Regulations 1990 (Cth) (TG Regulations):

(a) a chemical, biological or radiopharmaceutical substance that has not previously been included in the Register, or

(b) an isomer, mixture of isomers, complex of, derivative of or salt of, a registered chemical substance that, having previously been included in the Register, differs from the registered substance in having different safety or efficacy properties; or

(c) ...

Lundbeck Australia points out, and the contrary was not suggested, that in the TG Regulations, the significance of something’s being a new chemical entity is that an application to register it will ordinarily attract higher fees because of the much larger volume of material that has to be considered by the TGA than in the case of a “generic product”.

  1. Lundbeck Australia also refers to Chapter 17 of the Australia/United States Free Trade Agreement dealing with intellectual property rights, in particular, Art 17.10 which is, relevantly, as follows:
Article 17.10: Measures Related To Certain Regulated Products.

1. (a) If a Party requires, as a condition of approving the marketing of a new pharmaceutical product, the submission of undisclosed test or other data concerning safety or efficacy of the product, the Party shall not permit third persons, without the consent of the person who provided the information, to market the same or a similar product on the basis of that information, or the marketing approval granted to the person who submitted such information, for at least five years from the date of marketing approval by the Party.
(b) ...
(c) ...
(d) For the purposes of this Article, a new product is one that does not contain a chemical entity that has been previously approved for marketing by the Party.
(e) ...

2. With respect to pharmaceutical products, if a Party requires the submission of ... new clinical information (other than information related to bio equivalency) ... which is essential to the approval of a pharmaceutical product, the Party shall not permit third persons not having the consent of the person providing the information to market the same or a similar pharmaceutical product on the basis of the marketing approval granted to a person submitting the information for a period of at least three years from the date of the marketing approval by the Party ...17-[26].

Footnote 17-[26] reads:

17-[26] As an alternative to this paragraph, where a Party, on the date of entry into force of this Agreement, has in place a system for protecting information submitted in connection with the approval of a pharmaceutical product that utilizes a previously approved chemical component from unfair commercial use, the Party may retain that system, notwithstanding the obligations of this paragraph.
  1. Lundbeck Australia refers to a publication of the Department of Foreign Affairs and Trade entitled “Plain English Guide to the Agreement” which provides a commentary on each article of the Australia/United States Free Trade Agreement, but I do not find it necessary to refer to that material.
  2. Lundbeck Australia also refers to ss 15AA and 15AB of the Acts Interpretation Act 1901 (Cth) (the AI Act). Section 15AA provides that in the interpretation of a provision of an Act, a construction that would promote its underlying purpose or object is to be preferred to a construction that would not do so. Section 15AB of the AI Act provides, relevantly, that extraneous material that is capable of assisting in the ascertainment of the meaning of a provision may be considered:
(b) to determine the meaning of the provision when:
(i) the provision is ambiguous or obscure; or
(ii) the ordinary meaning conveyed by the text of the provision taking into account its context in the Act and the purpose or object underlying the Act leads to a result that is manifestly absurd or is unreasonable.

  1. Lundbeck Australia submits that the expression “active component” as used in s 25A(2)(c)(i) and defined in s 25A(3) of the TG Act, is ambiguous or obscure, and that the interpretation of that expression supported by Alphapharm would lead to a result that is “manifestly absurd” or “unreasonable”. In support, Lundbeck Australia suggests that despite having required Lundbeck Australia to submit a “full regulatory application” in support of its application to register Lexapro, the TGA would not treat the information submitted in the same way as it would treat information contained in a full regulatory application submitted in support of applications to register other therapeutic goods.
  2. Lundbeck Australia summarises its submissions in relation to the interpretation of s 25A as follows:
Lundbeck therefore submits that the phrase “active component” should be interpreted synonymously with the phrase “new chemical entity”, consistently with the way these two phrases have been used both in the legislative background to s25A of the TG Act and in the TG Regulations, in accordance with Australia’s international obligations under TRIPS and the Australia/United States FTA, and in accordance with the AI Act, which can be summarised as follows:

a. “...This will be achieved through the introduction of a new data protection scheme for new chemical entities, referred to as “active components” in the amending legislation”. Second reading speech for the introduction of s25A into the TG Act;

b. “...Members, when requiring, as a condition of approving the marketing of pharmaceutical or of agricultural chemical products which utilize new chemical entities, the submission of undisclosed test or other data, the origination of which involves a considerable effort, shall protect such data against unfair commercial use”. Article 39(3) of TRIPS;

c. “...(a) a chemical, biological or radiopharmaceutical substance that has not previously been included in the Register; or (b) an isomer, mixture of isomers, complex of, derivative of or salt of, a registered chemical substance that, having previously been included in the Register, differs from the registered substance in having different safety or efficacy properties”: definition of new chemical entity contained in Schedule 9 of the Therapeutic Goods Regulations; and

d. “1. (a) If a party requires, as a condition of approving the marketing of a new pharmaceutical product, .... (d) For the purposes of this Article, a new product is one that does not contain a chemical entity that has been previously approved for marketing by the Party”. Article 17.10 of the Australia/United States Free Trade Agreement.

In the present case, the TGA rejected an application to register therapeutic goods containing escitalopram by Lundbeck which sought to bridge to data previously submitted regarding citalopram. Instead, it insisted on the preparation and submission of additional pharmacology and clinical studies.

Ultimately, when the Australian Drug Evaluation Committee (ADEC) recommended Lexapro for inclusion on the ARTG, it did so as a new chemical entity. [emphasis in original]

(2) What is the “information” that Lundbeck Australia contends is protected?

  1. The purported particularisation in the statement of claim of the information that Lundbeck Australia claims is “protected information” within s 25A cannot be accepted as a serious attempt to identify information at all.
  2. There have been progressive attempts by Lundbeck Australia to narrow its description of the information that it contends is protected information.
  3. Ms Dyhr was taken to the tables of contents of Parts III and IV of Lundbeck’s application to the TGA for the registration of escitalopram oxalate. Those tables of contents comprised 55 pages and 10 pages respectively, each page being part of a list of studies. Ms Dyhr agreed that the studies identified in italics within the lists were studies that came from the application for registration of Citalopram (citalopram hydrobromide). Lundbeck Australia accepted that the information that was contained in the studies, the titles of which were in italics in the two tables of contents, is not “protected information” because five years had passed since the day Cipramil was included in the ARTG (9 December 1997) - see s 25A(2)(e) of the Act.
  4. Lundbeck Australia has attached to its closing submissions the following lists which are relevant to the question whether Lundbeck Australia has adequately identified the information in respect of which it seeks relief:

Annexure B: “Summaries of study results as listed on Lundbeck and Forest websites [the reference to “Forest” is a reference to Lundbeck’s licensee in the USA]”

Annexure C: “List of publications concerning escitalopram”

Annexure D: “Table of material inadvertently included in GD-7 and made publicly available in FDA reviews”

  1. Lundbeck Australia concedes that it could not reasonably contend that the information contained in these documents is protected information within s 25A. It will be noted that Annexure D represents a retreat from the position as represented in Exhibit GD-7.
  2. In its closing written submissions, Lundbeck Australia reformulated the relief it seeks as follows:
a. When evaluating therapeutic goods for registration on the Australian Register of Therapeutic Goods, the First Respondent be restrained until 15 September 2008 from using the following information about escitalopram which was given to the First Respondent by the Applicant in relation to Parts I C, II C, III and IV of its applications to register therapeutic goods:
i. individual patient or animal data taken in clinical or animal studies assessing the pharmacology, toxicology or efficacy of escitalopram and summaries thereof;
ii. analyses of such data contained in the study reports included in those parts of its applications;
iii. expert opinions about the pharmacology, toxicology or efficacy of escitalopram;
save to the extent that any such data, analyses or opinions has become publicly available whether prior or subsequent to the date of these orders.

b. Without limiting the above, the following information is publicly available:
i. the information contained in Exhibit BJS-1 to the Affidavit of Barry John Spencer sworn 21 December 2006 in this proceeding;
ii. the information contained in any of the documents identified in Annexures B, C & D to these submissions.

The significance of the date 15 September 2008 is that it marks the expiry of the five-year period during which Lexapro will have been registered on the ARTG (see s 25A(2)(e) of the TG Act). The significance of Exhibit BJS-1 appears at [580] above. Annexures B, C and D were discussed at [599] above.

  1. The Secretary accepts that Lundbeck Australia is entitled to some form of relief if it is shown that some or all of the information it gave to her in relation to its application to register escitalopram oxalate (Lexapro) is “protected information” and “if an appropriate form of relief can be framed”. She submits, however, that Lundbeck Australia has not identified “protected information” within s 25A with sufficient particularity to enable a meaningful order to be made.

(3) Is the information “about” the enantiomer (+)-citalopram for the purposes of s 25A(2)(b)?

  1. Questions 3 and 4 have been indirectly referred to in the course of my discussion of Question 2.
  2. Lundbeck Australia would not be entitled to relief in respect of information that was not “about” escitalopram.
  3. In oral submissions, Lundbeck Australia submitted that it should not be accepted that s 25A called for a line by line analysis. Lundbeck Australia invited me to accept that “the data package should be treated as a whole” .
  4. The Secretary submits that Exhibit GD-7 does not assist in identifying protected information as it lists only documents that are said to contain protected information. The Secretary contends that Lundbeck does not, and indeed could not, assert that all of the information contained in those documents is “about” escitalopram. For example, the study reports necessarily contain information on other comparable drugs which is not “about” escitalopram. One example is a cardiovascular study by M Maginn, “The effect of S-citalopram (...), citalopram (...), sertraline (...), fluoxetine (...), paroxetine (...), femoxetine (...), on ECG and Hemodyamics in the isolated Perfused guinea-pig heart”. This was a report of “Non-Clinical Safety Research” conducted by Lundbeck. Another example is information contained in study reports describing patients’ circumstances and the results in the cases of those taking placebo. A further example is information about packaging and manufacturing and about the applicant, Lundbeck Australia, itself.
  5. Similarly, Alphapharm submits that the unexpressed assumption underlying Ms Dyhr’s evidence appears to be that because a study relates to escitalopram or citalopram, and has been included in an application to the TGA, the whole of the documentation of the study is “about” the active component. A particular example emphasised by Alphapharm is a study report of Forest Laboratories, Inc concerning the study “MD-01”. Alphapharm submits that, for example, page 15 of that study (“List of Patient Narratives”) could not be said, by any stretch of the information, to be “about” escitalopram.

(4) Is the information “available to the public” within the meaning of s 25A(2)(b)?

  1. The evidence has exposed Lundbeck’s initial claim as an ambit claim that was far too wide. As indicated above, Lundbeck has progressively narrowed its description of the information in respect of which it seeks relief because of evidence that documents to which its claim referred were in fact already available to the pubic.
  2. I referred earlier to much of the evidence of public availability.
  3. Clearly, once a document is available to the public, all the information contained in it is also available to the public. However, the converse does not apply. It does not follow from the fact that a particular document is not available to the public that the information in it is not available to the public. There are three possibilities: the whole of the information in the document may be contained in another document that is available to the public; some of the information in the first document may be contained in another document that is available to the public; or some or all of the information contained in the first document may be available to the public otherwise than through another document.
  4. As noted earlier, any injunctive relief to be granted in aid of s 25A would have to be subject to a condition that once the information to which the relief referred subsequently became available to the public, it then ceased to fall within the scope of the injunction.

Consideration

  1. I turn first to the “active component” question.
  2. It is not in dispute that:
  3. Lundbeck Australia relies on the submissions on which Lundbeck relied in support of its submission that the pharmaceutical substance per se that is disclosed in the complete specification of the Patent and that falls within its claims is not a pharmaceutical substance that citalopram, the subject of the Australian Citalopram Patent, contains or consists of. Those submissions were the New Chemical Entities submission, the Rotation of Plane-Polarised Light Submission, the Purity Submission, and the Different Pharmacological Properties and Effects Submission. I adopt what I have said in Section K above in relation to those submissions and also make the following comments concerning them.
  4. In relation to the New Chemical Entities submission, I note that the term “new chemical entity” is not used in s 25A or elsewhere in the TG Act. Moreover, the fact that Professor Day or others regard citalopram and escitalopram each as a “new chemical entity” is not relevant to the mixed question of law and fact that I must decide, namely, whether the former “consists of or contains” the latter within the meaning of the statute.
  5. In relation to the Rotation of Plane-Polarised Light submission, I think that the reference to (+)-citalopram is also a reference to the molecule S-citalopram. That molecule exists, whether in the racemate or separated from it. The identity of the molecule does not change according to whether it forms part of the racemate or not. Its identity does not change just because in the racemic mixture its property of rotating plane-polarised light clockwise can not be observed because it is neutralised by the equally strong property of the molecule R-citalopram of rotating plane-polarised light anti-clockwise.
  6. In relation to the Purity Submission, I need not add to what I said in Section K.
  7. In relation to the Different Pharmacological Properties and Effects Submission, the Secretary emphasises that whatever the merits of that submission in relation to s 70 and associated sections of the Act, it misses the point in relation to the definition of “protected information” in s 25A(2) of the TG Act, because the comparable concept used in s25A(2) is “active” component. Escitalopram is the active component of Lexapro and an active component that Cipramil at least contains.
  8. Section 25A(3) clearly contemplates that therapeutic goods may contain more than one active component. In the case of Lexapro, the only active component is escitalopram. In the case of Cipramil, there are probably two active components: S-citalopram and R-citalopram, S-citalopram being the therapeutically beneficial one. The word “containing” in s 25A(2)(c)(i) must be read in the light of the definition of “active component” in s 25A(3). It is not required that escitalopram be the active component of Cipramil in order for s 25A(2)(c)(i) to be enlivened. It satisfies that provision if escitalopram is contained as one of two or more active components in Cipramil.
  9. I do not think that s 25A(2)(c)(i) is ambiguous or obscure or that the ordinary meaning conveyed by it which I have indicated above leads to a result that is manifestly absurd or unreasonable within s 15AB of the AI Act. Therefore, I do not derive assistance from the numerous extraneous materials to which I have referred above.
  10. Such matters as the conduct of officers of the TGA and of Alphapharm, the evidence given by Professor Day and the references to “new chemical entity” that were introduced into the TG Regulations (by the Therapeutic Goods Amendment Regulations 2002 (SI No 2/2002)) after s 25A was introduced into the TG Act, are all irrelevant to the question of the proper construction of the TG Act.
  11. In my opinion, Cipramil contains as an active component escitalopram, the active component of Lexapro, for the purposes of s 25A of the TG Act.
  12. In view of the conclusion I have reached on Question 1, Lundbeck Australia’s application should be dismissed and it is not necessary that I consider Questions 2, 3 and 4. However, as they were fully argued, I will address them, albeit together.
  13. Alphapharm cites authorities in which it has been held that an injunction against use of confidential information must identify the confidential information with sufficient particularity: O’Brien v Komesaroff (1982) 150 CLR 310 at 324-8; Moorgate Tobacco Co Ltd v Philip Morris Ltd (No 2) (1984) 156 CLR 414 at 438-439; Corrs Pavey Whiting & Byrne v Collector of Customs (Vic) (1987) 14 FCR 434 at 443; American Cyanamid Co v Alcoa of Australia Ltd (1993) 27 IPR 16 at 20-21.
  14. Those cases, unlike the present one, were concerned with identifying information that had the requisite character of confidentiality by reason of the application of general law principles. We are concerned here to identify particular information that was given by Lundbeck Australia to the Secretary that satisfies the criteria specified in s 25A(2). I readily agree that the information must nonetheless be identified with precision and not merely in global terms, if it is to be the subject of an order of the Court. However, the process of identifying the information is rather different from the process of identifying information that is confidential in accordance with general law principles.
  15. Whether particular information falls within s 25A is an objective question that entails no element of administrative discretion on the Secretary’s part.
  16. Lundbeck Australia submits that under s 25A, the onus rests on the Secretary to satisfy herself that certain information lies outside the definition of “protected information”. It is true that if Lundbeck Australia had not launched the present proceeding, s 25A would have obliged the Secretary not to use protected information for the purpose mentioned in the section. The section would therefore have obliged the Secretary to decide, at peril of a successful proceeding for an injunction against her if she should err, which information fell within the definition. In that situation, the language of “onus” is not appropriate.
  17. Once Lundbeck Australia seeks declaratory and injunctive relief, however, it bears the onus of identifying information that falls within the definition. It is not an appropriate exercise of discretion for the Court to enjoin conduct simply in the general terms of the statutory obligation, leaving the Secretary to determine, at peril of committing a contempt of court, whether particular conduct falls within the injunction. Moreover, “entitlement” to an injunction is established only if Lundbeck Australia proves non-compliance by the Secretary, actual or threatened, with the statute, and this requires Lundbeck Australia to establish that the Secretary has used or is threatening to use, particular information that falls within the definition. Lundbeck Australia must identify all of the information that satisfies all of the (cumulative) criteria of the definition of “protected information”: the definition does not contain excisions, exclusions or exceptions, the onus of proving the operation of which may have rested on the Secretary.
  18. In my opinion, as a matter of identification of the information that the Secretary is to be ordered not to use, the formulation proposed by Lundbeck Australia in its closing written submissions (at [601] above) is adequate. It provides for the inevitable exception based on information becoming available after the date of the orders. Lundbeck Australia has attempted in Annexures B, C and D to its submissions (referred to in the proposed orders) to capture all information about escitalopram that is publicly available. In case anything has been omitted, any other information that has become publicly available is also to be excepted from the scope of the proposed order. I do not think this introduces objectionable vagueness or uncertainty.
  19. The next question is whether I am satisfied that all of the information described in paras (a)(i), (ii) and (iii) is “about” escitalopram. I am so satisfied.
  20. There may be scope for considerable argument concerning the word “about”. However, subparas (i), (ii) and (iii) within para (a) of the orders proposed by Lundbeck Australia are all tied to escitalopram, which is mentioned expressly in subparas (i) and (iii) and is referred to by implication in subpara (ii).
  21. The parties asked that I not make orders in any of the proceedings before the Court but that I publish my reasons and allow them the opportunity to agree upon the form of orders to be made. In the present proceeding, this course would have allowed the Secretary the opportunity of identifying any particular difficulty that she would encounter in complying with an order of the kind proposed. However, because I have answered Question 1 above unfavourably to Lundbeck Australia, she will not need to do so.

Conclusion

  1. Subject to any submissions that the parties may make, for the reasons given above, Lundbeck Australia’s application should be dismissed with costs.

SECTION M – INFRINGEMENT BY ALPHAPHARM

Pleadings and Particulars

  1. I referred to the cross-claim for infringement in the Revocation Proceeding at [34]-[35] above, and will not repeat what I said there. There is no issue concerning Lundbeck’s title to the Patent or Lundbeck Australia’s being the exclusive licensee of the Patent or being entitled to sue for infringement of it.
  2. In this Section M, I will refer to Lundbeck and Lundbeck Australia as “the Lundbecks” and, generally speaking, will not distinguish between them.
  3. The Lundbecks’ cross-claim is for infringement of Claims 1, 3, 5 and 6. The Lundbecks seek permanent injunctions, an order for delivery up for destruction, damages or, at the Lundbecks’ option, an account of profits, and associated relief.
  4. As particulars of infringement, the Lundbecks allege that:
  5. In the letter dated 21 September 2005 to Corrs, Mallesons stated that Alphapharm had given the TGA a certificate pursuant to s 26B(1)(a) of the TG Act in the standard form approved by the Secretary, and that for purposes in connection with having goods containing escitalopram oxalate (Escitalopram Oxalate Goods) included in the ARTG and/or obtaining similar regulatory approval under the laws of foreign countries, Alphapharm had manufactured such goods at its manufacturing plant at Carole Park, Queensland (particulars of the quantities, dosages, dates of manufacture and countries were set out in a schedule to the letter). The letter further stated:
(3) Subject to obtaining the requisite regulatory approvals and listings, it is Alphapharm’s desire to engage in the following activities (none of which have commenced) in relation to Escitalopram Oxalate Goods for the Australian market:

(i) manufacture at Carole Park;
(ii) offer for sale;
(iii) sell;
(iv) otherwise dispose of;
(v) use; and
(vi) keep for the purpose of doing any of those things.

Alphapharm does not presently intend importing Escitalopram Oxalate Goods into Australia or exporting Escitalopram Oxalate Goods (other than perhaps for regulatory purposes) from Australia.

(4) Alphapharm has not manufactured and does not intend manufacturing the active pharmaceutical ingredient escitalopram oxalate (“API”) used in its Escitalopram Oxalate Goods. Alphapharm has imported and intends in the future importing API...in the form of tablets for the Australian market. ...

(5) The intermediate used by Alphapharm’s API supplier in the process of manufacturing the API is (+/-)-4-bromo-alpha¹-(4-fluorophenol)-alpha¹-[3-(dimethylamino)propyl]-1,2-benzene dimethanol hydrobromide [not] 4-(4-dimethylamino)-1-(4’-flourophenyl)-1-(hydroxyl-1-butyl)-3-(hydroxymethyl)benzonitrile as claimed in claim 6 of the Patent...

  1. On 12 May 2006, the Lundbecks gave Alphapharm a notice to admit facts to which Alphapharm replied by a notice disputing facts dated 26 May 2006, admitting certain facts and disputing others. I will discuss the evidentiary position further below.
  2. In a later letter dated 14 July 2006, Mallesons advised Corrs that they were instructed, for clarification, to inform Corrs that Alphapharm had performed the following acts:
  3. Section 26B of the TG Act referred to above requires that in certain circumstances an applicant to the TGA for registration or listing of therapeutic goods must provide to the TGA (s 26B(1)(a)):
A certificate to the effect that the applicant, acting in good faith, believes on reasonable grounds that it is not marketing and does not propose to market, the therapeutic goods in a manner, or in circumstances, that would infringe a valid claim of a patent that has been granted in relation to the therapeutic goods; ...
  1. In its defence to the cross-claim for infringement, Alphapharm maintains that the Patent is invalid, and in addition to various denials and non-admissions, relies on s 78(2) of the Act, in so far as it may be held that the Patent is valid and the extension of term of the Patent is valid (both of which propositions are denied). Section 78(2) provided, relevantly, as follows:
If the Commissioner grants an extension of the term of a standard patent, the exclusive rights of the patentee after the grant of the extension are not infringed by a person exploiting:
(a) a pharmaceutical substance per se that is in substance disclosed in the complete specification of the patent and in substance falls within the scope of the claim or claims of that specification; or
...;

solely for purposes in connection with:

(c) having goods included in the Australian Register of Therapeutic Goods, where the goods are intended for therapeutic use; or
(d) obtaining similar regulatory approval under a law of a foreign country or of a part of a foreign country.

  1. I note that s 78(2) was repealed on 25 October 2006 by the Intellectual Property Laws Amendment Act 2006 (Cth). That amending Act also inserted s 119A into the Act. Item 4 of Schedule 7 of the amending Act provides that s 119A applies “in relation to the exploitation, at or after the time [s 119A] commences, of inventions claimed in patents in force at or after that time”. The Explanatory Memorandum for the Bill for the amending Act stated that s 78(2) continued to apply in relation to any exploitation of patents that occurred prior to the commencement of s 119A. It would therefore seem that s 119A is the provision on which Alphapharm would have to rely in respect of any exploitation on or after 25 October 2006. Section 119A is wider than s 78(2). According to the Explanatory Memorandum, the purpose of the amendment was to “allow springboarding as an exception to patent infringement on any pharmaceutical patent at any time for purposes solely in connection with gaining regulatory approval of a pharmaceutical product in Australia or another territory”. Importantly, s 119A applies where no extension of the term of the patent has been granted. If Alphapharm is successful in raising a s 78(2) defence, it could also rely on s 119A in respect of its conduct on or after 25 October 2006. Neither party referred to the repeal of s 78(2) or its replacement by s 119A.
  2. As noted at [28] above, on 27 May 2004 the Commissioner granted an extension. Alphapharm pleads that both before and since 27 May 2004 it has manufactured goods containing (+)-citalopram only for purposes in connection with having those goods included in the ARTG and/or for obtaining similar regulatory approval under the laws of foreign countries.

The Lundbecks’ submissions

The claim of infringement of the product claims (claims 1, 3 and 5)

  1. Claims 1, 3 and 5 were set out at [10] above. The Lundbecks point out that no evidence has been led in relation to infringement of claims 1, 3 and 5, apart from the admissions made by Alphapharm contained in Mallesons’ letters of 21 September 2005 and 14 July 2006 referred to earlier. The Lundbecks also rely on Alphapharm’s Notice Disputing Facts dated 26 May 2006.
  2. The Lundbecks submit that by reason of Mallesons’ letters and Alphapharm’s Notice Disputing Facts, Alphapharm admits that:

The Lundbecks submit that it follows from these admissions that Alphapharm has infringed each of claims 1, 3 and 5.

  1. In relation to Alphapharm’s defence based on s 78(2) of the Act, the Lundbecks submit that this defence is an affirmative one that is not supported by any evidence led by Alphapharm and that the defence must therefore fail. In any event, according to the Lundbecks’ submission, the defence is not raised by Alphapharm, and could not be raised by it, in relation to the period prior to 27 May 2004.

The claim of infringement of the method claim (claim 6(b))

  1. Claim 6(b) was set out at [10] above, but it is convenient to repeat it here:
6. A method for the preparation of the compound of claim 1, which comprises:
(a) ...; or
(b) reacting a compound of formula II with the enantiomer of an optically active acid affording the pure enantiomer salt of the compound of formula II for (+)-citalopram, and subsequently performing ringclosure via a labile ester by reacting the pure enantiomer of formula II as a base with an activated acid with simultaneous addition of a base, and, if desired, transferring the (+)-citalopram obtained to a pharmaceutically acceptable salt thereof.

The compound of formula II is the cyano-diol.

  1. The Lundbecks address Alphapharm’s submission that the method followed by its supplier, A (for confidentiality reasons, I will substitute the letter “A” for references to the Lundbecks’ overseas supplier), involved the use of a bromo-diol rather than the cyano-diol. In the Joint Report, the following appears under the heading “Infringement of Claim 6(b)”:
Comparison of the [A] and LUNDBECK processes (as portrayed in the Petersen affidavit [an affidavit of Hans Petersen sworn 13 December 2006 – see below]).

Overall

Agreement: Apart from the replacement of the cyano-substituent for a bromo-substituent the [A] process is the same as the LUNDBECK process. The two involve the same sequence of bond forming reactions except for the delayed introduction of the cyano group in the case of the [A] process.

Step 1: Resolution

Agreement:
The fact that the cyano-diol can be resolved by diastereomeric salt formation does not allow the prediction that the bromo-diol will also be resolvable in the same way. The experiment has to be tried to find out.
The mesomeric electron-donating ability of a bromo-substituent might make the bromo-diol more sensitive to acid than the cyano-diol.

...

(iii) Step 2: Dehydration/Cyclisation

Agreement
In terms of the SN2 cyclisation process there will be no material differences between the cyano-diol and the bromo-diol.

The nature of the diols allows the tertiary C-O bond to align perpendicular to the plane of the bromo/cyano substituted arene ring, a conformation where any differences in substituent effects can manifest themselves. In the cyclised products the tertiary C-O bond is forced to lie in a closer to coplanar arrangement with the bromo/cyano-substituted arene ring thus reducing any substituent effects.

Disagreement:
MGB: The bromo-phthalan will be more sensitive, albeit with a diminished sensitivity compared to its bromo-diol precursor, to acid than the cyano-phthalan (citalopram).
SGD: There will be essentially no material differences between the cyano-phthalan and the bromo-phthalan in terms of acid sensitivity.

Step 3: Exchange of bromo for cyano

This step is not required in the Lundbeck process.

Step 4: Precipitation of the active pharmaceutical ingredient.

Agreement:
This step is identical in the [A] and Lundbeck processes.

  1. Exhibit R9 was the following table, submitted by the Lundbecks, comparing the steps involved in the A process with the integers of Claim 6(b) (the references to ECT-1 to ECT-VIII are references to various steps in the A process as described in the A documents which formed Exhibit HP-1 to Mr Peterson’s affidavit of 13 December 2006):
[A] process step
Integer of claim 6
ECT-I & ECT-II
These steps take place in order to form the diol precursor and before the steps contemplated by claim 6(b)

A method for the preparation of the compound of claim 1, which comprises...(b)
ECT-III
[A] uses a bromo-diol rather than the cyano-diol
Reacting a compound of formula II [i.e., the cyano-diol]
ECT-III states that the diol is “treated with (+)-di-toluoyltartaric acid, which is a single enantiomer of an optically active acid
with the enantiomer of an optically active acid
ECT-III - “to get resolved (-)-amine
salt” etc is a reference to the enantiomer salt of the diol present together with (+)- hemi-di-p-toluoyltartaric acid

ECT-IV refers to neutralising (the acid) to get the (-)-amine extracted into toluene i.e., pure)
Affording the pure enantiomer salt of the compound of formula II for (+)-citalopram
ECT-V [includes] the ringclosure step
And subsequently performing ringclosure
The labile ester is the product of the reaction of the resolved diol with methanesulfonyl chloride (see below)
via a labile ester
i.e., the product of step ECT-IV
by reacting the pure enantiomer of formula II as a base
Methanesulfonyl chloride
With an activate acid
Triethylamine
With simultaneous addition of a base
ECT-VI describes reaction with oxalic acid to get the oxalate salt, which is pharmaceutically acceptable
ECT-VII describes the cyanation process which exchanges the CN in place of the Br

ECT-VIII describes reaction with oxalic acid to get the oxalate salt, which is pharmaceutically acceptable
And, if desired, transferring the (+)- citalopram obtained to a pharmaceutically acceptable salt thereof
  1. Two points to be noted from the above table are, first, that it is an integer of Claim 6(b) that it is the cyano-diol that is reacted with the enantiomer referred to, whereas the A process uses the bromo-diol; and, second, that step ECT-VII describes the cyanation process which exchanges the cyano group for the bromo.

Alphapharm’s submissions

Alphapharm’s response to the claim of infringement of the product claims (claims 1, 3 and 5)

  1. Alphapharm acknowledges that since at least August 2002 it has manufactured and marketed in Australia goods which contain (+)-citalopram, namely, its generic citalopram product which is a racemic mixture in equal parts of (+)-citalopram and (-)-citalopram. However, understandably the Lundbecks do not submit that Alphapharm has infringed the Patent by manufacturing and marketing its generic citalopram product.
  2. Alphapharm relies on s 78(2) of the Act noted at [642] above. It submits that paras (c) and (d) of s 78(2) are satisfied.

Alphapharm’s response to the claim of infringement of the method claim (claim 6(b))

  1. Alphapharm submits that on its proper construction, claim 6(b) excludes the possibility of substituting the CN (cyano) with any substituent, including Br (bromo), because the formulae in claim 6(a) demonstrate that “R” is used when substitution is intended to be covered. The formulae are set out in [10] above. It will be noted that formula II refers to CH2OH, whereas formula II' gives CH2OR, the R being a labile ester group.
  2. Alphapharm submits that the cyano-substituent on the diol is an essential integer in the various steps of claim 6(b). Claim 6(b) refers to formula II (and not to formula II’), and the specification at page 2, lines 21-28 refers to “benzonitrile” which, Professor Davies agreed, means “cyano-”. Similarly, the consistory clause at page 3, line 11 introduces the method claim with the words:
according to the invention, II is reacted with ...

and formula II at the top of page 3 is identical to formula II in claim 6.

  1. Alphapharm relies on other references in the Patent specification to formula II and to “nitrile”.
  2. Alphapharm submits that “the wording of the claims makes it clear that the relevant area has been deliberately left outside the claim”, citing Sachtler at [53].
  3. Alphapharm submits that the cross-examination of Professor Banwell established that the steps of the A process were different from the integers of Claim 6(b).
  4. Another defence raised by Alphapharm concerns the definition of “exploit” in Schedule 1 to the Act. Section 13(1) of the Act provides that, subject to the Act, a patent gives the patentee the exclusive rights, during the term of the patent, to exploit the invention and to authorise another person to do so. Section 13(3) provides that a patent “has effect throughout the patent area”. The definition of “exploit” in the Dictionary in Schedule 1 is as follows:
exploit, in relation to an invention includes:
(a) where the invention is a product – make, hire, sell or otherwise dispose of the product, offer to make, sell, hire or otherwise dispose of it, use or import it, or keep it for the purpose of doing any of those things; or
(b) where the invention is a method or process – use the method or process or do any act mentioned in paragraph (a) in respect of a product resulting from such use.

Alphapharm submits that para (b) of the definition requires that the use of the method or process be in the “patent area”. The “patent area” is defined in the Dictionary in Schedule 1 and may, for convenience, be thought of as being “Australia”.

Consideration of the claim of infringement of the product claims (claims 1, 3 and 5)

  1. It seems clear that the result of Alphapharm’s admissions is that it has infringed claims 1, 3 and 5 of the Patent, subject to its defence under s 78(2) (see [695]-[696] below).

Consideration of the claim of infringement of the method claim (claim 6(b))

Authorities

  1. The authorities relating to infringement were recently reviewed by Bennett J in Sachtler at [43]-[67]. Her Honour cautioned against the purported application of the “pith and marrow” or “substance of the invention” approach, untrammelled by the form of the claims (at [55]).
  2. It is necessary for the Court to construe claim 6(b) in the light of the common general knowledge as at the priority date. How would the non-inventive person skilled in the art at that time, possessed of that common general knowledge, have understood the words of the claim?
  3. There is little case law in Australia in relation to “mechanical equivalents” and “non-essential integers” in the context of chemical formulae. In Saccharin Corporation Ltd v Anglo-Continental Chemical Works Ltd (1900) 17 RPC 307 at 319, Buckley J held that a method claim was infringed notwithstanding that changes had been made, because the same result was achieved.
  4. In Beecham Group Ltd v Bristol Laboratories Ltd (1977) 1B IPR 665 (Beecham), the plaintiff alleged infringement of patents for a pharmaceutical compound by the importation, offering for sale and sale in the United Kingdom of the antibiotic, Hetacillin. The plaintiff held four patents relating to a new class of semi-synthetic penicillins and to methods for their manufacture. One such penicillin was Ampicillin, a valuable antibiotic. The clinical effectiveness of Hetacillin was due entirely to Ampicillin, of which it was an acetone derivative. In the presence of water, as and when administered as an antibiotic, Hetacillin would revert into Ampicillin by a reversible chemical reaction.
  5. The Lundbecks rely on a passage from the speech of Lord Diplock, the whole of the paragraph being as follows (p 710):
I have already expressed my opinion that the pith and marrow doctrine is applicable to claims for new products as well as to new processes; and I agree with the Court of Appeal that the relationship of hetacillin to ampicillin provides a clear case for its application. It was argued that what is claimed in the patents as an essential feature of the class of products to which ampicillin belongs is the presence of an amino group in the alpha position, and that this feature is absent in hetacillin. This is literally true at the time of importation and sale but it ceases to be true as soon as hetacillin is put to use for the only purpose for which it is intended. The substitution for the postulated amino group of the variant incorporated in hetacillin is evanescent and reversible and for all practical purposes of use can be regarded as the equivalent of the amino group in ampicillin. In the apt phrase used by the Court of Appeal, it is the reproduction of the substance ampicillin, albeit temporarily masked.

His Lordship was addressing a product claim. In the imported hetacillin, there was a substituent for the amino group in the alpha position, but the substitution of the variant was “evanescent and reversible” and could be regarded as the equivalent of the amino group in the alpha position in the patented drug ampicillin.

  1. The Lundbecks draw an analogy with the bromo-diol’s performance of the function of the cyano-diol.
  2. In Re Application of Eli Lilly & Co [1982] 1 NSWLR 526, it was argued by the Commissioner in an application under s 90 of the Patents Act 1952 (Cth) for an extension of term, that the patentee had not properly exploited the invention. The patent was in respect of a pharmaceutical invention called monensic acid and a new process for producing that product. The patentee had exploited and used commercially only monensin sodium, a salt of monensic acid. The Commissioner argued that the salt was a product chemically distinct from the acid.
  3. Wootten J was of the view (at 532) that a proper and convenient way to test the matter was to ask whether the sale of monensin sodium in Australia by another person would be an infringement of the patent. After referring to Beecham, his Honour held (at 534) that “the mere conversion of monensic acid to monensin sodium with the retention of substantially the same molecular structure and the same therapeutic effects, and involving only the use of a simple and well understood process, would fall within the ‘pith and marrow’ doctrine”.
  4. In the Canadian case Pfizer Canada Inc v Apotex Inc (1998) 78 CPR (3d) 3, the court stated that the doctrine of equivalents applies to compositions where there is equivalence between chemical ingredients. That approach was followed in the Canadian case Merck Frosst Canada Inc v Canada (Minister of National Health and Welfare) (2000) 8 CPR (4th) 48. In the later case, the court stated, quoting from the earlier one, that “basically, there is equivalence when the substituting ingredient or device ‘performs substantially the same function in substantially the same way to obtain the same result’”. Accordingly, the court accepted expert evidence that the chemical properties and activities of the substituted ingredient were similar to those of the ingredient that it replaced. That evidence showed that both compounds were electron withdrawing groups and would therefore allow a particular reaction to occur, resulting in the same products. Importantly, the court accepted expert evidence that “a person reasonably skilled in the art would have known of the inter-changeability of that ingredient not contained in the patent with the one that was”. Accordingly, the court found infringement proved.

The evidence

  1. In cross-examination, Professor Banwell was taken to the A documents in which, as appears at [650] above, the steps taken were identified as ECT-I through to ECT-VIII. He agreed that ECT-I and ECT-II are steps that take place in order to form the diol precursor, and prior to the first step identified in claim 6(b). Steps ECT-III to ECT-VIII correspond with the integers in claim 6(b) with only one qualification: Step ECT-III uses a bromo-diol, whereas claim 6(b) uses the cyano-diol. It follows that step ECT-VII, which describes the cyanation process that exchanges the CN for the Br, is not an integer of claim 6(b).
  2. In re-examination, Professor Banwell said that the (+)-enantiomer of citalopram in the freebase form is obtained at the A step ECT-VII (the second last box in the left column in the table set out at [650] above), that is, when the cyanation process exchanging the CN for the Br occurs.
  3. The remaining evidence on the present issue is found in an affidavit of Hans Petersen of 13 December 2006, Exhibit MGB-8 to Professor Banwell’s affidavit of 6 March 2007 entitled “Response to Petersen Affidavit”, and an affidavit of Professor Davies sworn 30 March 2007 addressing both Mr Petersen’s affidavit and Professor Banwell’s response to it.
  4. Mr Petersen is a Senior Specialist in the Process Research department of Lundbeck. He was instructed to compare the “[A] Process Description” with the process claim found in claim 6 of the Patent. At para 13 of his affidavit, Mr Petersen set out, including in diagrammatic form, each step of the A process and the corresponding step of the example of the Lundbeck process described as “resolution by methods (b) and (c)” on p 7 of the Patent specification. Mr Petersen divides both processes into four corresponding steps. In relation to step 3 (“Exchange from Bromo to Cyano”), he states that the exchange of the bromo group (Br) for a cyano group (CN) to create escitalopram is required only in the A process, since in the Lundbeck process the required cyano group is already in place before Step 1.
  5. Mr Petersen makes the following overall comments on his comparison of the two processes:
19. The only difference between the two processes described above is that, in the Lundbeck Process, the cyano group required in the final escitalopram compound is already present in Step 1 whereas, in the [A] Process, a bromo group is present and is exchanged for the cyano group at the end of the process, after ring closure.

20. The cyanation step used in the [A] process is well known for the racemic analogue and has been for many years. In the patent (US 4,136,193) in which the racemate of citalopram was first disclosed, this process of exchanging a bromo group for a cyano group using copper cyanide in DMF was described. In fact, the same patent describes that this cyanation process can be undertaken at various points in the synthetic path to citalopram. One other variation, described in WO 01/49762 A1 is the preparation of 5-cyano-phthalide from the corresponding bromo compound.

  1. Mr Petersen also states in his affidavit:
23. I would expect the resolution of either the racemic bromo-diol (as in the [A] Process) or the racemic cyano-diol (as in the Lundbeck Process) to proceed in a very similar manner. This is due to the high degree of similarity between the two diols which include the following factors.
(a) There is no difference in the overall skeleton of the two molecules. The only difference is in the two substituents, 5-Br or 5-CN, both of which are at the same position.
(b) The substituents (5-Br or 5-CN) are para to the stereogenic centre and on the opposite side of the molecule from the amino group (ending in NMe2) which is the location on the molecule at which salt formation takes place and this distance and orientation reduces the prospect that or degree to which salt formation is influenced by the 5-Br/5-CN substituent.
(c) For the purpose of the resolution step, in each diol, there is the same distance between the hydroxyl group, the chiral centre and the amino group. Accordingly, the resolution step is not significantly influenced by the 5-Br/5-CN substituents.
(d) Both the 5-Br and 5-CN groups are electronegative substituents. This means that they both attract electrons. This heightens the overall similarity between the two molecules because these substituents have the same way of donating or withdrawing electrons to or from the phenyl ring to which they are bound. A CN group is often referred to as a “psuedohalogen” due to its electron withdrawing effects.
(e) Accordingly, the characteristics and reactivity of the bromo-diol are not materially different to the characteristics and reactivity of the cyano-diol.

...

31. It is clear to me, and I believe that it would have been apparent to me and any chemist in 1988, that the cyano-diol of the Lundbeck Process could be replaced by the bromo-diol or indeed a diol with any halogen or pseudohalogen in the place of the cyano group, without making any material difference to the way in which the process works. This is because (i) these different substituents have very similar properties, (ii) none of the chemistry involved in the Lundbeck Process involves interaction with these substituents and (iii) these substituents can be replaced with the desired cyano group by a straightforward and well known cyanation process at any stage in the synthetic route.
  1. In Exhibit MGB-8 to Professor Banwell’s affidavit of 6 March 2007, Professor Banwell addresses Mr Petersen’s comparison of the A Process and Claim 6(b) of the Patent. Professor Banwell’s main disagreement with Mr Petersen is expressed in paras 5-10 of Exhibit MGB-8 which are as follows :
5. ... the two processes represented by Mr Petersen in paragraph 13 have very fundamental and significant differences. The step of the [A] Process described in paragraph 13 (which corresponds to ECT-III in the [A] Documents) shows the aromatic group containing a hydroxymethyl substituent at the 2 position and a bromine (Br) atom substituent at the 4 position. In comparison, the Lundbeck Process involves a cyano (CN) or nitrile group at the same 4 position within the relevant molecule. Bromine and cyano groups are fundamentally different substituents. This difference necessarily changes the inherent chemistry of both compounds, resulting, amongst other things, in different:

(a) solubility;
(b) melting point;
(c) boiling point;
(d) rates of crystallisation; and
(e) reactivity.

6. The two compounds shown in paragraph 13 of the Petersen Affidavit are not chemically equivalent and, as a result, their respective chemistries are different.

7. The bromo ([A] Process) and cyano (Lundbeck Process) substituents attached to the 4 position on the aromatic group result in different chemical properties that Mr Petersen has overlooked in his analysis.

8. In organic chemistry a cyano group attached to a benzene ring ‘behaves’ as an electron-withdrawing group and is regarded as a meta-directing group. On the other hand, bromo substituents attached to a benzene ring are considered inductively electron-withdrawing groups but act mesomerically as electron donating groups. Bromo substituents in this chemical arrangement are ortho- and/or para- directing groups. In lay terms this means that these two substituents (CN vs Br) are known to exert quite different effects on the associated aromatic ring and other groups attached to this ring. The replacement of a bromo substituent for a cyano substituent has fundamental chemical consequences.

9. The fundamental chemical differences between bromo and cyano substituents were well known to a skilled addressee well before 14 June 1988 and reported in standard chemistry textbooks such as Morrison and Boyd.

10. It is also noteworthy that Mr Petersen’s 3D representation in paragraph 13 of chemical structures in both the [A] Process and Lundbeck Process confirming the stereochemistry of the diastereomeric salts are not in Claim 6 of the Patent. Indeed, the word diastereomer does not appear in Claim 6 at all. Mr Petersen’s representation also includes the absolute configuration of S-diol and R-diol in the [A] Process although this is not reported in the [A] documents. Unless Mr Petersen has performed a crystal structure on these respective compounds or, alternatively, carried out spectroscopic or chemical correlation studies, neither Mr Petersen ([n]or anyone else) can assign these absolute configurations as Mr Petersen has done.

  1. In his affidavit, Professor Davies expressed general agreement with Mr Petersen’s affidavit. He states that in 1988, if he had known the content of the Patent in suit and Lundbeck’s previously published patents concerning citalopram and had been trying to arrive at a single enantiomer of citalopram without making use of the cyano-diol, the first thing he would have tried would have been to use the bromo-diol instead, conducting the other steps described in the Patent on the bromo-diol, and, if successful, cyanating bromo-citalopram to citalopram.
  2. Professor Davies disagrees with much of Professor Banwell’s evidence in Exhibit MGB-8.
  3. Professor Davies agrees with Professor Banwell, however, that there can be significant reactivity differences between a bromo and a cyano group, but maintains that such differences have no material effect on the kind of chemistry involved in the patented process. He agrees with Professor Banwell’s explanation of the characteristics of a cyano group as being meta-directing, whereas bromo substituents are ortho- or para-directing, but he maintains that this is of relevance only in relation to electrophilic aromatic substitution reactions. The Lundbeck and A processes do not, he explains, involve electrophilic aromatic substitution.
  4. Professor Davies says that Professor Banwell overplays the significance of the differences between the bromo and cyano substituents on the relevant chemistry involved in the Lundbeck and A processes, in para 5 of Exhibit MGB-8. Professor Davies agrees that there will be differences in solubility, melting point and so on, but does not believe that there will be any relevant differences in reactivity.
  5. Professor Davies strongly disagrees with Professor Banwell’s contention in para 8 of Exhibit MGB-8 that the replacement of a bromo-substituent for a cyano-substituent in the A process has relevant fundamental chemical consequences.
  6. In relation to Professor Banwell’s evidence in para 9 of Exhibit MGB-8, Professor Davies states that both bromo and cyano substituents are electron withdrawing, the only real difference manifesting itself in the product orientation seen in electrophilic aromatic substitution reactions which are not involved in the present case.
  7. The step ECT-IV that Professor Banwell, in para 11 of Exhibit MGB-8, states has been omitted by Mr Petersen, relates, according to Professor Davies, to liberation of the salt to return to the free base. Professor Davies says that this is not a step that is material to the processes in question. However, he points out that, at para 23 of Mr Petersen’s affidavit, Mr Petersen refers to the resolution steps generally and that it is clear from Example 2 in the Patent specification that the reaction proceeds on the basis of a liberated salt as a base.
  8. Professor Davies’s conclusions are expressed in paras 30-33 of his affidavit as follows:
30. The Lundbeck and [A] Processes are, in essence, identical with each other. The only differences are that:
a. in the [A] Process, resolution and ring-closure are performed on the bromo-diol, rather than the cyano-diol of the Lundbeck Process; and
b. in the [A] Process, there is a final cyanation step, derived from a previous Lundbeck patent, to convert the single enantiomer of bromo-citalopram to the single enantiomer of citalopram.

31. The differences between the bromo and cyano substituents are not, in my view, likely to have a material effect on the way the processes work. The differences identified by Professor Banwell in paragraph 5 of MGB-8, would be relevant only if electrophilic aromatic substitution reactions were required, which they are not in the process in question.

32. As I noted in paragraph 9 above, had I, in 1988, knowledge of the patent in suit and Lundbeck’s previous published patents concerning citalopram and been trying to arrive at a single enantiomer of citalopram without making use of the cyano-diol, I believe that the first thing that I would have tried would have been substituting the bromo-diol in place of the cyano-diol, conducting the other steps described in the patent in suit on the bromo-diol and, if successful, cyanating bromo-citalopram to citalopram. This is what is described in the [A] Process.

33. I have made all enquiries which I believe are desirable and appropriate. No matters of significance which I regard as relevant have, to my knowledge, been withheld from the Court.

Conclusion on the claim of infringement of the method claim (claim 6(b))

  1. I think it is true to say, as the Lundbecks say in their closing submissions on infringement, that the parties agree that the only difference between the A process and the process of claim 6(b) is that the cyano-diol of claim 6(b) is replaced by the bromo-diol in the A process, and that the 5-cyano substituent is later replaced in the compound by a cyanation process accepted as well known and routine.
  2. I find that although in other contexts there are differences between using the cyano-diol as against the bromo-diol, there are none in the context of the present process.
  3. I accept Professor Davies’s evidence that in 1988 he would have chosen to use the bromo-diol rather than the cyano-diol for the purpose to hand if he had been instructed that the cyano-diol was not available.
  4. Although Professor Banwell pointed to differences between the use of the two diols, his evidence did not establish how those differences were of any relevance in the present context.
  5. In substance, what Alphapharm has done has been to create an additional step, the product of which it later removes. Apart from that evanescent substitution, the A process is the same as that spelt out in claim 6(b).
  6. Accordingly, subject to Alphapharm’s other defences, I find that use of the A process used to produce the (+)-enantiomer of escitalopram would infringe claim 6(b).

Consideration of Alphapharm’s defences

The definition of “exploit” and importation

  1. I set out Alphapharm’s submission at [659] above. There is no dispute that the acts of infringement must occur within the patent area, which is for present purposes, Australia (see [659] above). In relation to claim 6(b), “exploit” has the meaning identified in para (b) of the definition of “exploit”. Accordingly, in general terms, Alphapharm submits that para (b) provides for two classes of exploitation of a method or process invention:
    1. in Australia, using the method or process; and
    2. in Australia, making, hiring, selling or otherwise disposing of, offering to make, sell, hire or otherwise dispose of, using or importing, or keeping for the purpose of doing any of those things, a product resulting from the use referred to in (1).
  2. The difference between the constructions supported by Alphapharm and the Lundbecks concerns the meaning of the expression “the use referred to in (1)”. According to Alphapharm, that notion includes the “in Australia” element, whereas according to the Lundbecks it does not.
  3. A consequence of the construction supported by Alphapharm is that in the case of an invention which is a method or process, importation is not a form of exploitation unless the product imported had resulted from the use of the method or process in Australia. However, as the Lundbecks submit, where the product results from the use of the method or process in Australia, the very making of the product, having occurred in Australia, would itself be a contravention of the patented method or process (para (a) of the definition of “exploit”). Accordingly, the effect of Alphapharm’s submission would be that in the case of an invention of a method or process, the reference to importing is superfluous.
  4. I do not think that the construction supported by Alphapharm is correct. There is no suggestion in the express terms of the definition of “exploit” that importation, with nothing more, is not to be a form of exploitation in the case of a patented method or process. The territorial connection with Australia is one that is implied, and the proper construction of the definition of “exploit” has the territorial connection attaching twice, but not three times. The notion of “in Australia” does not follow the expression “from such use” at the end of para (b). The correct construction is, in my view, as follows:
exploit, in relation to an invention includes:
(a) where the invention is a product – [in Australia, or more accurately, in the patent area] make, hire, sell or otherwise dispose of the product, offer to make, sell, hire or otherwise dispose of it, use or import it, or keep it for the purpose of doing any of those things; or
(b) where the invention is a method or process – [in Australia, or more accurately, in the patent area] use the method or process or do any act mentioned in paragraph (a) in respect of a product resulting from [the use, anywhere, of the method or process].

Alphapharm’s s 78(2) defence

  1. It is unfortunate that Alphapharm did not lead any affidavit evidence directed to establishing its s 78(2) defence. However, I do not think it is open to the Lundbecks to seize on part of the admissions made by Alphapharm and to ignore the qualifications subject to which those admissions were made, one of which was that the only purpose for which Alphapharm manufactured the pharmaceutical substance in question was to have the goods included in the ARTG.
  2. In my view, Alphapharm’s s 78(2) defence succeeds in relation to the period after 27 May 2004 to 25 October 2006, and s 119A would apply to any exploitation by Alphapharm that has occurred in the period on or after 26 October 2006.

Conclusion on infringement generally

  1. In relation to Lundbeck’s claim of infringement of claims 1, 3, 5 and 6 of the Patent, I have held that Alphapharm “exploited” the inventions the subject of those claims, and therefore infringed those claims from November 2002 to 27 May 2004, after which time there was no infringement by Alphapharm by reason of s 78(2) (and, if it be relevant, s 119A) of the Act.

SECTION N – ADMISSIBILITY OF CERTAIN EVIDENCE

General

  1. I deferred ruling on objections that certain evidence tendered was not admissible. The objection to which most submissions were addressed was an objection by Alphapharm and Arrow to large parts of the affidavit of Professor Montgomery sworn 20 December 2006 in which he expressed opinions based on reports of clinical studies carried out by other persons. However, before dealing with that objection, I will deal with the others that are outstanding.

Objections by Lundbeck to documents tendered by Alphapharm

  1. Alphapharm tendered the following documents as listed in the “Index to Applicant’s Supplementary Tender Bundle”:
4
Extract of Danish file wrapper for patent 2599/8929 “New enantiomers and their isolation”
5
Patent application WO 03/006449 A1 “Method for the Preparation of Escitalopram”
6
...
7
ICH Harmonised Tripartite Guideline, Statistical Principles for Clinical Trauls [sic – Trials] E9.
8
ICH Harmonised Tripartite Guideline, Choice of Control Group and Related Issues in Clinical Trials E10.
  1. In my opinion, none of these documents are admissible.
  2. Documents 4 and 5 relate to foreign patent applications. In each case, the applicant is Lundbeck. Document 4 comprises a Danish patent application that was apparently made on 24 May 1989 in respect of (+)-citalopram and a method for its preparation, and subsequent correspondence between Lundbeck and the Danish Patent Office (DPO). The DPO refused the application, expressing the opinion that the product had not been shown to differ substantially from what was already known prior to the application filing date, including the racemic citalopram, and the fact that almost the entire therapeutic effect resided in one of the optically active antipodes of a racemic compound. The DPO referred to ss 2 and 16 of the Danish Patents Act. The DPO also rejected method claims that were included in the application.
  3. While Alphapharm may be encouraged by the fact that the Danish Patent Office accepted arguments somewhat similar to submissions it has put to me, this does not make the Danish file wrapper rationally probative in relation to the issues I have to decide under the Act. In other words, the relevance of the document is not shown.
  4. Document 5 is an International Application published under the Patent Cooperation Treaty bearing an international filing date of 12 July 2002 and entitled “Method for the Preparation of Escitalopram”. Likewise, its relevance to the issues I have to decide under the Act is not shown.
  5. I note that my rulings in relation to Documents 4 and 5 are consistent with certain observations made on applications for orders for discovery by Burchett J in F Hoffmann-La Roche AG v Chiron Corporation (2000) 47 IPR 516 at [19]–[21] and by Branson J in Lubrizol Corporation Inc v Imperial Chemical Industries plc [2000] FCA 1464; (2000) 50 IPR 526 at [33] (although, unlike the present case, those cases involved the exercise of a discretion and a balancing exercise).
  6. Documents 7 and 8 were tendered in order to diminish the effect of Professor Montgomery’s evidence, but neither of them was put to him. Their probative value is substantially outweighed by the danger that the evidence might be unfairly prejudicial to Lundbeck, and I refuse to admit them (see s135(a) of the Evidence Act).

Certain objections by Arrow

Objection to the last sentence of para 40 of Dr Bøgesø’s affidavit sworn 21 December 2006

  1. Arrow raises form and relevance objections to this sentence in which Dr Bøgesø states: “To my knowledge, no-one has, even today, managed to solve citalopram with a resolving agent via a fractional crystallisation of diastereomeric salts”.
  2. In the light of Dr Bøgesø’s qualifications, experience and position, this testimony is admissible, although subject to the question of the weight to be given to it. Dr Bøgesø was not put forward as an expert witness, but as a witness of fact. I certainly accept that his evidence does not exclude the possibility that someone, somewhere may have “managed to solve citalopram with a resolving agent via a fractional crystallisation of diastereomeric salts”.

Objection to the first and last sentences of para 59 of Professor Davies’s affidavit sworn 21 December 2006

  1. Again, Arrow raises form and relevance objections. In the first sentence, Professor Davies states that the average skilled person, if he or she, in 1988, had embarked on a project to obtain the individual enantiomers of citalopram, would not “have gone to anything like” the lengths to which Dr Bøgesø and his colleagues went, and “even less if the task was to develop an improved anti-depressant”. In the last sentence Professor Davies states that such a person would not have had such a depth of knowledge of the molecule as Dr Bøgesø and his colleagues had, and would not have pursued synthesis of the enantiomers with their “determination, vigour and tenacity”.
  2. Counsel for Arrow submits: “I don’t think it’s going to be a significant matter, but it’s not really a matter for an expert in Professor Davies’s position to give an opinion on that. That’s really a matter for the court.”
  3. In my opinion the evidence is admissible. Professor Davies’s training, study and experience in the field, including, in particular, his knowledge of the interests and concerns of the pharmaceutical industry as at the priority date, was considerable. He knew the state of relevant research at that time. It does not matter that the opinion expressed is about “a fact in issue or an ultimate issue”: s 80(a) of the Evidence Act. Again, however, the question as to the weight to be given to the testimony remains.

Objections to certain paragraphs of Professor Montgomery’s affidavit

  1. Lundbeck relies on Professor Montgomery’s opinions that:
  2. Alphapharm classified its objections to the paragraphs in question of Professor Montgomery’s affidavit as a “General Relevance Objection” and a “Factual Basis Objection”.
  3. In a table in its submissions, Alphapharm identified 13 passages in Professor Montgomery’s affidavit to which it objected. However, to speak of “13 passages” is apt to mislead by way of understatement. The passages objected to were extensive. Nine of the 13 each embraced numerous paragraphs of the affidavit
  4. Arrow also objected to certain paragraphs of Professor Montgomery’s affidavit (not all of which were identical to those objected to by Alphapharm), and adopted the submissions made by Alphapharm.
  5. In so far as I should decide that the passages or any of them are admissible, Alphapharm and Arrow seek a direction pursuant to s 136 of the Evidence Act limiting the use to be made of the passages.
  6. I will begin by giving a brief overview of Professor Montgomery and his affidavit. I will then address, in general terms, the General Relevance Objection, the Factual Basis Objection and the application for the s 136 direction.

Professor Montgomery

  1. Like all other expert witnesses in the case, Professor Montgomery has an impressive curriculum vitae. He graduated with a Bachelor of Science (Honours) degree from the University of London in 1960 and a Bachelor of Medicine and Bachelor of Surgery (MBBS) from University College Hospital, London, in 1963. He received a Diploma in Psychological Medicine (DPM) from the Royal College of Physicians and Surgeons in 1973 and a Doctor of Medicine (MD) from the Karolinska Institute in Stockholm, Sweden, in 1978. Professor Montgomery became a Member in 1973, and then a Fellow, in 1982, of the Royal College of Psychiatrists (FRCPscych).
  2. I will not trace the whole of Professor Montgomery’s career and experience. In 1978 he, together with a colleague, developed the Montgomery-Asberg Depression Rating Scale (MADRS) to measure levels of depression. Professor Montgomery describes the MADRS as “the most sensitive rating scale for depression” and as being “widely used”.
  3. Professor Montgomery was successively Senior Lecturer, Reader and then Professor in Psychiatry at St Mary’s Hospital Medical School, London (now part of Imperial College School of Medicine, University of London) from 1979 to 1998. In 1999 he was appointed as Emeritus Professor of Psychiatry at the Imperial College of Science, Technology and Medicine, London.
  4. Professor Montgomery was a Member of the Council of the Royal College of Psychiatrists from 1980 to 1992, President of the British Association of Psychopharmacology from 1990 to 1992, and President of the European College of Neuropsychopharmacology from 1992 to 1995.
  5. Professor Montgomery was a member of the Committee on Safety of Medicines UK (CSM) from 1987 to 1993 and, as the only psychiatrist on the Committee, he considered all applications in the field of psychiatry and neurology at that time, including all of the antidepressants for which marketing approval was sought. He estimates that he completed a total of about 40 expert reports (now called “clinical overviews”) to support regulatory applications for central nervous system medication, including for SSRIs and other antidepressants.
  6. For 16 years Professor Montgomery has been the editor of International Clinical Psychopharmacology and European Neuropsychopharmacology. He is also on the editorial boards of other scientific journals.
  7. Professor Montgomery has published several hundred scientific papers, research reports, reviews and book chapters and has authored some 25 books.
  8. Professor Montgomery was awarded the Prix Erasme de Psychiatrie in 1999 by the Free Erasmus University of Brussels, the Neuroscience Award in 2001 by the European College of Neuropsychopharmacology, and a Lifetime Achievement Award in 2006 by the British Association of Psychopharmacology.
  9. For more than 30 years, Professor Montgomery’s work has involved treating patients suffering from psychiatric illnesses and research into those illnesses, with a particular focus on depression.
  10. Professor Montgomery has been consulted by most pharmaceutical companies (he names 15) and chairs Lundbeck’s “Global Advisory Board of Experts”.

Professor Montgomery’s affidavit

  1. I will now give some examples of the passages objected to (except where indicated otherwise, the passages set out below or summarised below, are objected to by either Alphapharm or Arrow, or both).
  2. In para 4 of his affidavit, Professor Montgomery refers to a list of publications constituting Exhibit SAM-1 to his affidavit. There are 61 of them, including 12 authored by Professor Montgomery alone, or with co-authors. In relation to the 61 articles, Professor Montgomery states:
I have read and am familiar with each of these publications and have considered them for the purposes of preparing this affidavit. Where I refer to a publication in this affidavit, I am referring to the publication as referred to in the list contained in Exhibit SAM-1. Where I refer to each of these publications in the body of my affidavit, unless I or the context indicates to the contrary, I intend to indicate that the cited publication provides, in my view, sound scientific support for the proposition in relation to which I cite the publication. [my emphasis]

As foreshadowed in this passage, in later paragraphs, Professor Montgomery made statements followed simply by a citation of author’s name and year of publication.

  1. In para 6 of his affidavit, Professor Montgomery states that he has been asked by Lundbeck’s solicitors to provide a report in relation to :
(a) depression and its treatments, including selective serotonin reuptake inhibitors (SSRIs); and
(b) the benefits of escitalopram over other SSRIs in general and citalopram in particular.

  1. In some instances in his affidavit, Professor Montgomery makes statements of a general conclusory nature without tying them to any particular article or articles. For example, in para 52, he states:
The effects of the different SSRIs on neurotransmitter systems and on the liver microsomal oxidase systems involved in drug metabolism are as follows:
(a) Citalopram was the most selective of the SSRIs, before the introduction of escitalopram. It is well tolerated by elderly patients and is the one least likely to cause drug-drug interactions.
(b) Escitalopram is even more selective and potent and is as well tolerated as citalopram. ...

Again, in para 53, Professor Montgomery states:

The SSRIs in general, with the exception of escitalopram, have shown a relatively flat dose-response relationship in the fixed dose comparisons with no advantage in producing a better response with higher doses and with some disadvantage in a heavier side-effect burden. With escitalopram, there is evidence that the higher doses are more helpful in severe depression.
  1. Paragraphs 70-76 of Professor Montgomery’s affidavit were not objected to, except for the last sentence of para 76, which was objected to by Arrow. Although somewhat lengthy, I think it desirable to set out these paragraphs. They appeared under the heading “Overview of Escitalopram” and were as follows:
70. Escitalopram is the active enantiomer of citalopram...

71. Citalopram is a 50:50 racemic mixture of two mirror image molecules, or enantiomers (see below). In 1992 it was believed that only one enantiomer was responsible for the therapeutic effect (Hyttel 19922) [the footnote states “Although published some years after the patent in suit, the Hyttel 1992 paper is based upon the data contained in the patent in suit”.]. In those circumstances, eliminating the enantiomer which is not responsible for producing the desired therapeutic effect, could have been expected to result in a more specific drug with potentially fewer side effects but without improved clinical effect. The interpretation of adverse reactions and drug-drug interactions is also easier if only one enantiomer is present. The issue of drug-drug interactions is of particular importance in patient populations, such as depressed patients, in which polypharmacy frequently occurs. Furthermore, regulatory authorities favoured enantiomerically pure drugs.

72. In 1988, knowledge of the importance of, and different effects of, individual enantiomers was not widespread.

73. At that time (1988), there was no information publicly available as to whether both enantiomers or only one of them was responsible for the therapeutic effect of Citalopram. There was no publicly available information suggesting that the R enantiomer of citalopram had a negative effect. If only one enantiomer was responsible for the therapeutic effect, by eliminating the enantiomer which was not responsible for producing the desired therapeutic effect, I, and I believe other clinicians, would have expected that a drug would be more specific with potentially fewer side effects, but without improved clinical effect. In other words, I, and I believe other clinicians, would have expected that where one enantiomer is practically devoid of therapeutic effect, separating a racemate into its individual enantiomers would result in similar efficacy at half the dose.

74. As I have noted ... above, I sat on the Committee on Safety of Medicines UK (CSM) from 1987 to 1993. The approach taken by the CSM in 1988 to racemates and separate enantiomers was that it was nice to receive data in relation to separate enantiomers of pharmaceutical products. However, if the data in relation to a racemate was that the racemate was therapeutically active and there was no pressing rationale, such as toxicity or other unwanted side effects, to separate the racemate, then there was no reason to do so.

75. I was aware in 1988 of pharmaceutical industry practice to try to separate a chiral compound into its individual enantiomers in order to check for unwanted receptor affinities and potential deleterious side effects. However, this practice did not extend to separating chiral compounds into their individual enantiomers to ascertain whether one had a beneficial or deleterious effect on the compounds efficacy. In 1988 close attention was not yet paid to enantiomers and I would not have expected an active enantiomer with the same or similar receptor affinities as the racemate to have any benefits over and above a racemate which did not have deleterious or unwanted effects.

76. In 1988, knowledge that one enantiomer was practically devoid of 5-HT reuptake inhibitory potential, had it been available, would have led me, and I believe other clinicians, to the expectation that the drug profile would be at least as good as citalopram at half the dose. On this basis, the ratio of predicted efficacy would be that a half-dose of escitalopram would produce the same degree of inhibition of 5-HT reuptake as a full dose of citalopram. However, as discussed below unexpected differences in favour of escitalopram have been found.

It will be noted that these paragraphs describe the position as at the priority date.

  1. In paras 77-78, Professor Montgomery states:
Serotonin Uptake Inhibition
77. In vitro and in vivo studies have shown that escitalopram is a more potent SSRI than citalopram, and that the R-enantiomer is practically devoid of 5-HT uptake inhibitory potency.

Animal Models and the Attenuating Effects of the R-Enantiomer
78. Citalopram is active in several well-accepted animal models predictive for antidepressant effect. It is therefore not surprising that escitalopram has also been found to be active in these same animal models. The R-enantiomer was practically devoid of 5-HT reuptake effects, confirming the in vitro data.

Senior counsel for Lundbeck said that he relied on para 77 only to introduce the subject and not as independent opinion evidence in its own right.

  1. In many places in his affidavit, Professor Montgomery cites articles in support of statements, thereby indicating acceptance of the conclusions in those articles (as contemplated by para 4 of his affidavit set out at [728] above). For example, paras 79–81 of his affidavit are as follows:
79. The surprising finding in studies with some of these animal models has been the earlier response to escitalopram compared with citalopram. In the rat model of chronic mild stress (Willner 1997), administration of TCAs such as imipramine, or conventional SSRIs, normalizes sucrose intake after three to four weeks of treatment. This is in line with the characteristic delayed onset of antidepressant effect observed in the clinic. In contrast, escitalopram produced a complete antidepressant-like effect after only one week of treatment (Sanchez 2000, Montgomery 2001). This earlier response with escitalopram was unexpected, suggesting that the R-enantiomer might modulate the effect of the S-enantiomer, delaying the antidepressant action.

80. The role of the R-enantiomer has been investigated further in a series of preclinical studies, which have shown that the R-enantiomer reduces the positive effect of the S-enantiomer (Mork 2003). Consequently, escitalopram shows earlier and greater efficacy than when the R- and S-enantiomers are given together (Mork 2003, Chen 2005, Sanchez 2004).

Serotonin Transporter Allosteric Binding Site

81. Escitalopram, compared to other SSRIs and SNRIs, is unique in having, in addition to its 5-HT reuptake inhibitory effects, a pronounced effect via an affinity-modulating allosteric site (Chen 2005). The allosteric binding site has been reported to modulate the binding to the primary site and thereby enhance the binding (Plenge 1991). Escitalopram has been shown to increase the stabilization of the binding to the serotonin transporter via the allosteric mechanism compared to other SSRIs and venlafaxine (Chen 2005). This unique self-enhancing effect on the serotonin transporter goes a long way to explain the obvious clinical superiority of escitalopram as an antidepressant and as an anxiolytic.
  1. Alphapharm makes the point that parts of the paragraphs set out above come almost directly from a booklet written by Professor Montgomery, Pocket Pharma: Escitalopram and Depression (Science Press Ltd, 2003, pp 24–25), and suggests that this may explain the form that the affidavit takes. While I acknowledge that there is a danger in assuming that the content of a book written by the deponent of an affidavit can simply be put into affidavit form, I must assess the affidavit and objections to it on their merits.

The nature of Alphapharm’s General Relevance Objection

  1. The General Relevance Objection relates to paragraphs directed to showing that escitalopram has proved to be therapeutically far more effective than citalopram. Alphapharm submits, firstly, that a difference in therapeutic effect as between the two is irrelevant to the questions arising under s 25A of the TG Act. Alphapharm emphasises that the statutory question arising under the TG Act is whether, when Lundbeck lodged its application for TGA approval of escitalopram oxalate, another therapeutic good “consisting of, or containing” the same active component was already included in the ARTG. According to Alphapharm’s submission, that question is not answered by reference to the superior efficacy of escitalopram over citalopram.
  2. Secondly, and for a similar reason, Alphapharm submits that in the Lundbeck Appeal (Extension of Term) Proceeding, the statutory question for consideration under s 70 of the Act and reg 10.7 of the Patents Regulations for the purpose of ascertaining the “first regulatory approval date” is not answered by evidence of the present kind.
  3. Thirdly, Alphapharm submits that in so far as evidence of the kind mentioned is said to be relevant to the validity of the Patent in the Revocation Proceeding, “after-acquired knowledge” concerning the superior benefits of the invention cannot buttress a claim for the presence of an inventive step.
  4. Accordingly, Alphapharm submits that Professor Montgomery’s evidence of the kind mentioned is not relevant in any of the three proceedings mentioned. Arrow supports Alphapharm’s objection made in the Revocation Proceeding for the purposes of the Arrow Proceeding.
  5. Lundbeck countered the General Relevance Objection in the Revocation Proceeding and the Arrow Proceeding on the basis that the evidence was relevant to the issue of obviousness. Lundbeck submits that Professor Montgomery’s evidence goes to, for example:
(i) there having been little motivation to separate and test the enantiomers of citalopram when the racemate was safe and effective
(ii) the unexpected superior clinical properties of escitalopram, including its superior efficacy, earlier onset of action, it being more effective in the more severely depressed patients, and it being effective in a greater number of patients than citalopram and other SSRIs; ...
  1. Lundbeck also submitted that Professor Montgomery’s evidence is relevant to showing that escitalopram has different pharmacological and clinical effects, which, it says, is relevant, in relation to TGA (Protected Information) Proceeding, to the issue whether citalopram consists of or contains the same active component as escitalopram, and, in relation to the Lundbeck Appeal (Extension of Term) Proceeding, to the issue whether escitalopram is a different pharmaceutical substance per se from citalopram.

Consideration of Alphapharm’s General Relevance Objection

  1. In relation to inventive step, it is the common general knowledge, understandings and expectations of the hypothetical skilled non-inventive addressee or team as at the priority date that matter. As noted in Section E at [224], I accept Professor Montgomery’s evidence and that of other witnesses:

I do not accept, however, that it was part of common general knowledge at that time that it was possible that one enantiomer might be many times more therapeutically effective than the racemate.

  1. The Patent specification accords with the position as I have described it in the preceding paragraph. It states:
Furthermore, it was shown to our surprise that almost the entire 5 H-T uptake inhibition resided in the (+)-citalopram enantiomer.

If it surprised the inventors that “almost the entire 5 H-T uptake inhibition resided in the (+)-enantiomer” [my emphasis] it must have also been very surprising to them to learn after the priority date that the (+)-enantiomer gave many times the therapeutic benefits given by citalopram.

  1. There is a series of decisions of the various courts of the United States in which it has been accepted that unexpected superiority in effectiveness is probative of non-obviousness: see, for example, Sterling Drug Inc v Watson 135 F Supp 173 (1955) at 175-176; In re Gershon, 372 F 2d 535 (1967) at 537; In re Skoner, 517 F 2d 947 (1975) at 950; Ex parte Sohda 2002 WL 519757 at 2-3; In re Chupp, 816 F 2d 643 (1987) at 646-647; Ortho-McNeil Pharmaceutical Inc v Mylan Laboratories Inc 348 F Supp 2d 713 at 755-756.
  2. In some of these cases it has been said that the evidence of unexpected superior clinical benefits has been admitted to counter prima facie obviousness arising from other evidence. I do not find other evidence in the present case raising a prima facie case of obviousness. In any event, this was not a basis of admissibility relied upon by Lundbeck.
  3. In Canada, it has been suggested that in relation to obviousness, little weight should be given to “subsequently recognised advantages”: see Janssen-Ortho Inc v Novapharm Ltd [2006] Carswell Nat 3249 at [113](8), [114](8).
  4. In oral submissions, senior counsel for Lundbeck stated:
In terms of obviousness, the opinion as to how predictable this material was is relevant. It’s not advanced for the proposition that because there was this unexpected benefit, that somehow makes it inventive. That’s not what we’re saying. We’re simply not advancing that argument. But we are advancing the argument on motivation. If you didn’t expect this unexpected benefit, then the fact that you have this massive benefit doesn’t mean that you were motivated to move mountains to get there.

The problem with this basis of admissibility is that Alphapharm does not rely upon escitalopram’s having far superior therapeutic benefits to those of citalopram as establishing motivation. In fact, by its objection, Alphapharm is seeking to keep out Professor Montgomery’s evidence that escitalopram was later found to have therapeutic benefits far superior to those of citalopram.

  1. In Wellcome, Aickin J, with whom the other members of the High Court agreed, stated (at 287):
... not all inventions are to be classified as fulfilling a long-felt want. Those which reveal an “unfelt want” are as likely, or sometimes more likely, to involve an inventive step.

In Astra at [38], Gleeson CJ, Gaudron, Gummow and Hayne JJ approved of this passage. However, neither Aickin J in Wellcome nor their Honours in Astra were saying that evidence of unexpected benefits is admissible. Rather, the point they were making was that evidence of previous unsuccessful attempts to satisfy a long-felt want, while admissible, might not be entitled to much weight since inventive step can be present, not only in the presence of a long-felt want and associated motivation, but also in their absence.

  1. It seems to me that Lundbeck has set up a “straw man” to knock down. In the light of the nature of the case that Lundbeck had to counter, it was only evidence of what was commonly known and expected at the priority date that it was entitled to seek to prove. Evidence of post-priority date surprises did not fall within that description.
  2. Since arriving at the conclusion expressed in the last paragraph, I have read what Kitchin J has said on the present issue in Generics v Lundbeck at [231]–[237] and the passages from the authorities to which his Lordship refers, namely, Richardson-Vicks Inc’s Patent [1995] RPC 568 at 581 and Glaxo Group Ltd’s Patent [2004] EWHC 477; [2004] RPC 43 at [113]. I note that my conclusion is generally in line with those three authorities.
  3. In summary, while I would admit any parts of Professor Montgomery’s affidavit that go to the pre-priority date common general knowledge and expectations of the hypothetical skilled but non-inventive addressee or team as to the benefits to be found in a separate enantiomer, I do not admit the passages tendered to prove that the post-priority date clinical studies and data established that in fact the therapeutic benefits of escitalopram far exceeded those expectations.
  4. In relation to the Lundbeck Appeal (Extension of Term) Proceeding, Professor Montgomery’s evidence showing that escitalopram has different pharmacological and clinical effects was initially potentially relevant to the question of whether Cipramil consisted of or contained the pharmaceutical substance (+)-citalopram because of submissions made by Lundbeck as to the meaning and application of provisions of the TG Act. However, I have now rejected Lundbeck’s submissions in that respect (see Section K above), and the evidence is therefore shown to be irrelevant.
  5. Finally, in relation to the TGA (Protected Information) Proceeding, Lundbeck Australia contended that Professor Montgomery’s evidence showing that citalopram and escitalopram have different pharmacological properties and effects was relevant to the question whether Cipramil can be said to consist of or contain (+)-citalopram. According to the submission, his evidence was relevant to that question because of Lundbeck Australia’s submission as to the meaning and application of the expression “active component”. However, again, I have now rejected Lundbeck’s submission in that respect too (see Section L above), and so the evidence is shown to be irrelevant.
  6. In sum, the General Relevance Objection is sustained in the Lundbeck Appeal (Extension of Term) Proceeding and the TGA Proceeding and, to the extent mentioned, in the Revocation Proceeding and the Arrow Proceeding.

The nature of Alphapharm’s Factual Basis Objection

  1. Alphapharm submits:
415. ... Professor Montgomery articulates a series of opinions regarding the efficacy of citalopram vs (+) citalopram on the basis of his interpretation of reports or articles, which in turn report the results of certain clinical studies (most of which were conducted by or on behalf of Lundbeck).

416. No person has given evidence regarding the conduct of those studies, the underlying data concerning the studies has not been provided and there has been no disclosure of primary documents that might reveal (for instance) the aims, objectives or methodology of those studies. The authors of the Journal Articles relied upon have not given evidence. As submitted above, Alphapharm was able to call the pooled studies seriously into question, on the basis of limited material.

417. The Journal Articles themselves constitute reports of selected information taken from and summarized as the results from clinical studies. Further, there is no evidence as to the existence of other unpublished studies the results of which may be unhelpful to the Lundbeck arguments. Professor Montgomery does not refer to the underlying data, but relies on the results as reported in the Articles.

418. The Journal Articles themselves are at times opaque as to the studies upon which their conclusions are based ... Further, not all of the studies upon which the Montgomery expert evidence is based were published.

419. Accordingly, the basis upon which Professor Montgomery has expressed his opinions is hearsay evidence which cannot be admitted as evidence of the truth of its contents.

420. Alphapharm submits that, in the absence of proof of that factual basis, the evidence of Professor Montgomery in this regard is inadmissible.

  1. Alphapharm relies on a passage from the well-known judgment of Heydon JA (as his Honour then was) in Makita (Australia) Pty Limited v Sprowles (2001) 52 NSWLR 705 (Makita) at [85]:
In short, if evidence tendered as expert opinion evidence is to be admissible, it must be agreed or demonstrated that there is a field of “specialised knowledge”; there must be an identified aspect of that field in which the witness demonstrates that by reason of specified training, study or experience, the witness has become an expert; the opinion proffered must be “wholly or substantially based on the witness’s expert knowledge”; so far as the opinion is based on facts “observed” by the expert; they must be identified and admissibly proved by the expert, and so far as the opinion is based on “assumed” or “accepted” facts, they must be identified and proved in some other way; it must be established that the facts on which the opinion is based form a proper foundation for it; and the opinion of an expert requires demonstration or examination of the scientific or other intellectual basis of the conclusions reached: that is, the expert’s evidence must explain how the field of “specialised knowledge” in which the witness is expert by reason of “training, study or experience”, and on which the opinion is “wholly or substantially based”, applies to the facts assumed or observed so as to produce the opinion propounded. If all these matters are not made explicit, it is not possible to be sure whether the opinion is based wholly or substantially on the expert’s specialised knowledge. If the court cannot be sure of that, the evidence is strictly speaking not admissible, and, so far as it is admissible, of diminished weight.
  1. Lundbeck submits that it has not been accepted in this Court that an expert’s opinion is inadmissible if it is based on assumed or accepted facts that are not identified and proved, citing: Sydneywide Distributors Pty Ltd v Red Bull Australia Pty Ltd [2002] FCAFC 157; (2002) 55 IPR 354 (Sydneywide) at [16] per Branson J and [87] per Weinberg and Dowsett JJ); Neowarra v Western Australia (No 1) [2003] FCA 1399; (2003) 134 FCR 208 at [16], [21]–[27] per Sundberg J; Jango v Northern Territory (No 4) (2004) 214 ALR 608 at [19] per Sackville J; NutraSweet Australia Pty Ltd v Ajinomoto Co Inc [2005] FCA 1524; (2005) 67 IPR 381 at [33] per Finkelstein J; Cadbury Schweppes Pty Ltd v Darrell Lee Chocolate Shops Pty Ltd [2006] FCA 363; (2006) 228 ALR 719 at [7] per Heerey J.
  2. I do not think it necessary to review all of these cases.
  3. It is necessary to distinguish between two potential meanings of the notion of a “basis rule”. The expression may be used to refer to a supposed rule that evidence of expert opinion is not admissible unless the expert identifies the assumed factual basis for his or her opinion, thereby distinguishing between what is opinion and what is not. This goes to the form taken by the expert’s evidence. The provisions of s 79 of the Evidence Act tend to have the practical effect of requiring attention to the form that expert evidence takes: HG v The Queen [1999] HCA 2; (1999) 197 CLR 414 at [39] per Gleeson CJ. As I noted in Harrington-Smith v State of Western Australia (No 2) [2003] FCA 893; (2003) 130 FCR 424 at [25], in the absence of a distinction between opinion and assumed factual basis, the Court may not be able to be satisfied:
  4. On the other hand, the expression “basis rule” may be used to refer to a supposed rule that evidence of expert opinion is not admissible unless the factual basis of the opinion is proved by admissible evidence.
  5. Generally speaking, Professor Montgomery’s evidence is not criticised for not identifying the basis of his opinions: he identifies precisely enough the journal articles on which he relies, and where he does not attribute a statement to a particular article, he is making only an introductory statement (for example, para 77 of his affidavit which was set out at [732] above) or giving an overall summary of the effect of all of the articles. What is put by Alphapharm is that Professor Montgomery’s opinions are not admissible because the factual basis for them, being the actual carrying out and recording of the results of the clinical studies reported in the journal articles, were not proved by admissible evidence (see para 416 of Alphapharm’s submissions set out at [754] above).

Consideration of Alphapharm’s Factual Basis Objection

  1. The starting point for resolution of Alphapharm’s General Relevance Objection is a particular group of exceptions to the hearsay rule that were recognised under the general law as being dictated by necessity. In the Law Reform Commission’s Interim Report on Evidence (ALRC No 26, 1985), the Commission described these exceptions as (a) the expert’s accumulated knowledge, (b) the reported data of fellow scientists, and (c) information commonly relied upon in an industry, trade or calling (ALRC No 26 vol 1 at [131], vol 2 at [91]). The Commission cited in support: English Exporters (London) Ltd v Eldonwall Ltd [1973] 1 Ch 415; R v Abadom [1983] 1 WLR 126; Borowski v Quayle [1966] VR 382 (Borowski); H v Schering Chemicals Ltd [1983] 1 All ER 849 (Schering Chemicals); Reid v Kerr [1974] 9 SASR 367; Rowley v London and North Western Railway Co [1852] EngR 1037; (1873) LR 8 Exch 221; Dickins v Randerson [1901] 1 KB 437; R v Perryman (1907) 147 CCC Sess Pap 109 (Lawrence J). There is some overlap between the three categories.
  2. The Commission referred, as an illustration of (b), to Borowski, in which the following passage from Wigmore on Evidence, Chadbourn JH (ed) (Little, Brown & Co, Boston, 1979) vol 2 at [665b], was cited with approval:
The data of every science are enormous in scope and variety. No one professional man can know from personal observation more than a minute fraction of the data which he must every day treat as working truths. Hence a reliance on the reported data of fellow scientists, learned by perusing their reports in books and journals. The law must and does accept this kind of knowledge from scientific men...[T]o reject a professional physician or mathematician because the fact or some facts to which he testifies are known to him only upon the authority of others would be to ignore the accepted methods of professional work and to insist on finical and impossible standards.....In general, the considerations which define the (professional) are (a) a proper source of information, (b) an extent of personal observation in the general subject, enabling him to estimate the general plausibility, or probability of soundness, of the views expressed, and (c) the impossibility of obtaining information on the particular technical detail except through reported data in part or entirely. The true solution must be to trust the discretion of the trial judge, exercised in the light of the nature of the subject and the witness’ equipments. The decisions show in general a liberal attitude in receiving technical testimony based on professional reading.

In Borowski, his Honour found (at 386) that evidence given by the expert in that case:

...would have been directed to matter travelling outside opinion and dependent to a degree upon knowledge based upon hearsay. But this is an area where the hearsay rule does not apply and the matter dealt with in the evidence would clearly have been admissible.
  1. This passage was cited with approval in Reid v Kerr [1974] 9 SASR 367, 370, and the necessity of the approach reflected in it was noted in Schering Chemicals at 854.
  2. The same judge-made exception to the hearsay rule was recognised in the standard texts on evidence at that time: see, for example, D Byrne QC and JD Heydon, Cross on Evidence (3rd Australian Edition, Butterworths, 1986) at [15.31], [17.161], citing, in addition to Borowski and Schering Chemicals, See v Milner (1980) 2A Crim R 210 (FCA); Holt v Auckland City Council [1980] 2 NZLR 124; Cuthill v State Electricity Commissioner of Victoria [1981] VR 908 at 915 (FC); Baker v Australian Asbestos Insulations Pty Ltd [1984] 3 NSWLR 595 at 607.
  3. The Law Reform Commission dealt with the present issue under the heading “Evidence Admissible for a Non-hearsay Purpose” (ALRC No 26 Vol 1 at [685]) stating (footnotes omitted):
Under existing law hearsay evidence that is admissible for a non-hearsay purpose is not excluded, but may not be used by the court as evidence of the facts stated. This involves the drawing of unrealistic distinctions. The issue is resolved by defining the hearsay rule as preventing the admissibility of hearsay evidence where it is relevant by reason only that it would affect the court’s assessment of the facts intended to be asserted. This would have the effect that evidence relevant for a non-hearsay purpose – eg to prove a prior consistent or inconsistent statement, or to prove the basis of the expert’s opinion – will be admissible also of evidence of the facts stated:

Tender of Prior Consistent and Inconsistent Statements
...............

Expert’s evidence of Basis of Opinion
Reference has been made above to the uncertainties that exist as to the admissibility of such evidence and to the unclear exceptions which have had to be created to meet the problems created by the hearsay rule. Under the proposal, evidence by an expert of the facts on which his opinion is based will be admissible as evidence of those facts. Potential dangers have been raised. First, there is the danger that false evidence may be placed before the court. However, the expert will usually form a judgment about the accuracy of what he is told. In addition the tactical pressure on the parties to verify the facts relied upon by the expert should ensure that problems of assessment of the evidence will not arise. They will either call more direct evidence or have to face adverse comment. When assessment problems do arise, the exclusionary discretions may be used. This is similar to the present approach. Another danger suggested is that it could result in an increase in evidence adduced – particularly that which is adduced in the Family Court and is of marginal relevance. As at present, the expert will do no more than adduce evidence of the basis of his opinion – what he was told will be relevant to that opinion and the assessment of it. However, the relevance proposal and relevance discretion will apply and give the courts express control where now that control and its extent is unclear. It has also been suggested that parties will want to answer the allegations of marginal relevance and this will give rise to an increase in the evidence given. However, this should not occur. First the party against whom the evidence is led can object to the relevance of the facts related by the expert – only those affecting his opinion will be relevant. As to such facts, that party will have to decide, as at present, whether he accepts those facts or wishes to challenge them. He would have to do this whether the evidence was admitted as the basis of the expert’s opinion or to prove the facts asserted – it would be a foolish party who relied on that distinction in relation to key factual elements and did not call rebutting evidence. The proposal in fact has the potential to save time and costs. At present, the party leading the expert evidence should lead non-hearsay evidence to confirm all the statements made to and relied upon by the court. If he does not, it will be open to the opposing party to argue that the opinion should be rejected – the hearsay rile will lie in wait. Under the proposal he can call witnesses to confirm the key material, and leave it up to the opposing party to cross-examine the witness to raise the matters in issue. If he does not and leads evidence in rebuttal, it will be possible for the first party to call further evidence.
  1. The result of the Commission’s deliberations was s 60 of the Evidence Act. The hearsay rule itself is set out in s 59 of that Act. Section 59(1) provides:
Evidence of a previous representation made by a person is not admissible to prove the existence of a fact that the person intended to assert by the representation.
  1. Section 60 provides for an exception to the hearsay rule as follows:
The hearsay rule does not apply to evidence of a previous representation that is admitted because it is relevant for a purpose other than proof of the fact intended to be asserted by the representation.
  1. A “previous representation” is defined in the Dictionary to the Evidence Act to be a representation made otherwise than in the course of the giving of evidence in the proceeding in which evidence of the representation is sought to be adduced.
  2. The representations made by the authors of the articles cited by Professor Montgomery are “previous representations” as to the carrying out of the clinical studies and the results of them.
  3. Sections 59 and 60 are perhaps an odd way of grappling with the present issue. It seems clear, however, that it was intended that in a case like the present one, statements of the bases for expert opinions like those made by Professor Montgomery were to be characterised as being relevant for a purpose other than proof of the facts intended to be asserted by the representations by the authors of the articles. Prior to the enactment of s 60, the summaries given by Professor Montgomery of the effect of the journal articles would have been ruled admissible as falling within the exceptions dictated by necessity referred to at [761]-[765] above.
  4. In their joint report, Uniform Evidence Law: Report of December 2005, the Australian, New South Wales and Victorian Law Reform Commissions have recognised that s 60 had the effect of excluding from the hearsay rule an expert’s statement of the factual basis of his or her opinion (see [7.74] ff). The Commissions recognised (at [7.74]) that an expert relies on “statements made to him or her by others about their observations of events which are facts in issue, together with a wide range of factual information from more remote sources”. The Commissions gave as illustrations:

The Commissions also recognised that, through necessity, there existed those judge-made exceptions to the hearsay rule referred to at [761] above. In addition to Borowski, they cited PQ v Australian Red Cross Society [1992] 1 VR 19; R v Vivona (Unreported, Victorian Court of Criminal Appeal, Crockett, Tadgell and Teague JJ, 12 September 1994); R v Fazio (1997) 93 A Crim R 522. The Commissions then stated at [7.77], [7.78] (footnotes omitted):

7.77 The proposal that became s 60 was formulated with these exceptions in mind, with the intention that s 60 would perform the role the miscellaneous common law exceptions had performed and the complication of specific exceptions for these kinds of evidence avoided.

7.78 Section 60 also applies to representations of fact unique to the particular case upon which the expert bases his or her opinion. Such evidence is hearsay at common law, but s 60 lifts the statutory hearsay rule in that situation.

  1. It will be recalled that the Law Reform Commission noted at [685] of ALRC No 26 Vol 1 (set out at [765] above) that “[p]otential dangers [of the application of s 60] have been raised”, including that false evidence may be placed before the Court. However, it stated that “the expert will usually form a judgment about the accuracy of what he is told”. It also stated that when “assessment problems [in relation to the evidence] do arise, the exclusionary discretions [a reference to Part 3.11 of that Evidence Act] may be used”. Such a use of s 136 of the Evidence Act (which falls within Part 3.11 of the Evidence Act) was referred to by Finkelstein J in Quick v Stoland at 382 and by Nicholson J in Daniel v State of Western Australia [2000] FCA 858; (2000) 178 ALR 542 at [30]- [34].
  2. Section 136 of the Evidence Act is entitled “General discretion to limit use of evidence” and provides:
The court may limit the use to be made of evidence if there is a danger that a particular use of the evidence might:
(a) be unfairly prejudicial to a party; or
(b) be misleading or confusing.
  1. As noted earlier, Alphapharm and Arrow ask the Court to exercise its discretion under s 136 in relation to the evidence constituting the factual basis of Professor Montgomery’s opinion.
  2. In a sense, it is true, as Alphapharm submits, that the relevant parts of Professor Montgomery’s evidence consist of a review of scientific literature. This characterisation, however, does not adequately reflect the significance of his testimony. A person lacking his “specialised knowledge based on [his] training, study or experience” (see s 79 of the Evidence Act) would not know how to go about locating relevant articles, would not be able to distinguish between relevant and the irrelevant ones, would not be able to interpret the articles, and would not be able to assess their overall effect in the light of the questions on which his opinion evidence is required. Part of Professor Montgomery’s specialist knowledge is precisely knowledge of the identity of the scientific journals that publish research carried out within his area of expertise, knowledge of the clinicians who have been working and publishing in the area, and knowledge of the relevance and reliability of their published work in relation to the questions raised.
  3. Professor Montgomery gave evidence of the peer-review process that is followed in the case of the two journals of which he has been the editor for approximately the last 16 years. Three or four reviewers are approached, with the possibility of substitutes if any of those approached initially prove to be too slow in providing their comments as reviewers. The article will be accepted for publication if the reviewers so recommend. The reviewers may suggest amendments which, in Professor Montgomery’s experience, only rarely have authors declined to adopt. If, for any reason, reviewers cannot be found for an article, it will not be accepted for publication. Professor Montgomery said that, in the case of both of the journals of which he is editor, approximately 75%  of the articles submitted are rejected, some of them out of hand.
  4. While Professor Montgomery did not give evidence of the peer-review process that is followed in the case of the other journals in which the articles he cited were published, I infer that all of those journals in which they were published were peer reviewed and that their editors followed a generally similar peer review process to that followed by Professor Montgomery himself.
  5. It is true that when the Parliament enacted s 60, it was considered that Part 3.11 of the Evidence Act, which contains s 136, would act as a safeguard to limit the operation of s 60 in appropriate circumstances (see [765], [772] above). However, I will not make an order under s 136. The evidence with which I am concerned is the evidence of Professor Montgomery’s opinions. If the opinions were otherwise admissible, I would not think it appropriate to limit the use to be made of them pursuant s 136.
  6. Ultimately, if the scientific community, represented here by Professor Montgomery, accepts as a sufficient basis for the forming of opinions, the reportings of clinical studies published in peer-reviewed articles in scientific journals of high repute, I do not see why the Court should interfere by limiting the use to be made of the opinions.
  7. The weight to be accorded to Professor Montgomery’s opinions remains a matter for the Court. Criticisms made by Alphapharm of particular opinions expressed by him are to be taken into account as going to the weight to be given to those opinions (see Quick v Stoland at 378 per Branson J; Welsh v The Queen (1996) 90 A Crim R 364 at 369, 371). Indeed, as Lundbeck itself states in its submissions:
If Alphapharm doubts the validity of the reports or articles to which Lundbeck’s expert witnesses have referred, it is entitled to question the credibility of these reports or articles (as has been done by Dr Mitchell in his affidavit). His Honour is then invited to make a determination of the validity of these arguments based upon the cross-examination of Dr Mitchell and of Professor Montgomery and use this determination as one of the factors in deciding the weight to be afforded to a particular expert’s evidence.

In fact, Alphapharm adduced evidence from Professor Mitchell countering that of Professor Montgomery and addressing the post-priority date studies mentioned by him. Because Alphapharm’s General Relevance Objection has succeeded, that evidence of Professor Mitchell was rendered irrelevant.

  1. This seems to me to reflect the only practicable way in which opinion evidence of the kind given by Professor Montgomery can be dealt with. In this respect, I note the statement made by Cooke J in Seyfang v G D Searle & Co [1973] QB 148 at 151:
It does appear to me with the greatest respect that a system which does not permit experts to refer in their expert evidence to the publications of other experts in the same field is a system which puts peculiar difficulties in the way of proof of matters which depend on expert opinion.
  1. I have not overlooked the decision of the High Court in Lee v The Queen [1998] HCA 60; (1998) 195 CLR 594 or Cadbury Schweppes Pty Ltd v Darrell Lea Chocolate Shops Pty Ltd (No 3) (2006) 229 ALR 179. I do not think, however, that they stand against the approach that I have taken above.
  2. In my opinion, for the reasons given above, s 60 of the Evidence Act defeats the Factual Basis Objection. I would have declined to make an order under s 136 of that Act if the passages objected to had not succumbed to the General Relevance Objection.

SECTION O – CONCLUSION

  1. As the parties requested, I will publish these reasons and give them an opportunity to make submissions as to the orders (including orders as to costs) to be made. The four proceedings will be fixed for a date for the making of such orders. Directions will be made for the filing and service of submissions as necessary.
  2. While the reasons set out above were being proofread in preparation for delivery of judgment, the English Court of Appeal on 10 April 2008 gave judgment in H Lundbeck A/S v Generics (UK) Ltd [2008] EWCA Civ 311, the appeal from the judgment of Kitchin J in Generics v Lundbeck previously noted. With respect, I do not think it necessary to incorporate references to their Lordships’ reasons, which are, generally speaking, consistent with what I have written above.
I certify that the preceding seven hundred and eighty-five (785) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Lindgren.

Associate:


Dated: 24 April 2008


Proceeding NSD 1120 of 2005


Counsel for the Applicant/Cross Respondent (Alphapharm Pty Ltd):
Mr DK Catterns QC, Mr S Burley SC and Mr JS Cooke
Solicitor for the Applicant/Cross Respondent (Alphapharm Pty Ltd):
Mallesons Stephen Jaques


Counsel for the Respondent/First Cross Claimant
(H Lundbeck A/S) and for the Second Cross Claimant (Lundbeck Australia Pty Ltd):
Mr D Shavin QC and Ms KJ Howard SC


Solicitor for the Respondent/First Cross Claimant
(H Lundbeck A/S) and for the Second Cross Claimant (Lundbeck Australia Pty Ltd):
Corrs Chambers Westgarth

Proceeding NSD 1870 of 2005


Counsel for the Applicant (Lundbeck Aust Pty Ltd):
Mr D Shavin QC and Ms KJ Howard SC
Solicitor for the Applicant (Lundbeck Aust Pty Ltd):
Corrs Chambers Westgarth


Counsel for the First Respondent (the Secretary of the Department of Health & Ageing of the Commonwealth of Australia):
Mr G Kennett
Solicitor for the First Respondent (the Secretary
of the Department of Health & Ageing of the Commonwealth of Australia):
Australian Government Solicitor
Counsel for the Second Respondent
(Alphapharm Pty Ltd):
Mr DK Catterns QC, Mr S Burley SC
and Mr JS Cooke


Solicitor for the Second Respondent
(Alphapharm Pty Ltd):
Mallesons Stephen Jaques

Proceeding NSD 954 of 2006


Counsel for the Applicant
(Arrow Pharmaceuticals Pty Ltd):
Mr C Dimitriadis


Solicitor for the Applicant
(Arrow Pharmaceuticals Pty Ltd):
Blake Dawson Waldron


Counsel for the Respondent (H Lundbeck A/S):
Mr D Shavin QC and Ms KJ Howard SC
Solicitor for the Respondent (H Lundbeck A/S):
Corrs Chambers Westgarth

Proceeding NSD 1078 of 2006


Counsel for the Applicant (H Lundbeck A/S):
Mr D Shavin QC and Ms KJ Howard SC


Solicitor for the Applicant (H Lundbeck A/S):
Corrs Chambers Westgarth


The First Respondent (Commissioner of Patents) did not appear, having filed a submitting appearance.


Counsel for the Second Respondent
(Alphapharm Pty Ltd):
Mr DK Catterns QC, Mr S Burley SC
and Mr JS Cooke


Solicitor for the Second Respondent
(Alphapharm Pty Ltd):
Mallesons Stephen Jaques


Dates of Hearing:
11, 12, 13, 16, 17, 18, 19, 23, 24, 26 April 2007; 1, 7, 8, 9, 10, 11 May 2007


Date Last Written Submission Received:
21 November 2007


Date of Judgment:
24 April 2008

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