Pfizer Overseas Pharmaceuticals v Eli Lilly and Company [2005] FCAFC 224 (31 October 2005)

Last Updated: 10 January 2006

FEDERAL COURT OF AUSTRALIA

Pfizer Overseas Pharmaceuticals v Eli Lilly and Company
[2005] FCAFC 224

PATENTS – validity – construction – lack of inventive step – novelty – fair basis – sufficiency of description of invention – disclosure of best method of invention – date of assessment – false suggestion – patent for treatment of erectile dysfunction – common general knowledge at priority date – relevant prior art – use of evidence of overseas witnesses


Patents Act 1990 (Cth) s 18(1), s 40, s 7, s 138

Eli Lilly and Company v Pfizer Overseas Pharmaceuticals [2005] FCA 67; (2005) 218 ALR 408 cited
Bristol-Myers Squibb Company v FH Faulding & Co Limited [2000] FCA 316; (2000) 97 FCR 524 applied
Canadian General Electric Co Limited v Fada Radio Limited [1930] AC 97 cited
Hill & Evans (1862) 4 De G F & J 288; 45 ER 1195 cited
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Welch Perrin & Co Pty Ltd v Worrel [1960] HCA 91; (1961) 106 CLR 588 cited
Interlego AG v Toltoys Pty ltd [1973] HCA 1; (1972) 130 CLR 461 applied
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Catnic Components Ltd v Hill & Smith Ltd [1982] RPC 183 cited
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Société Des Usines Chimiques RhônePoulenc v Commissioner of Patents (1958) 81 ALR 79 cited
Rehm Pty Ltd v Websters Security Systems (International) Pty Ltd (1988) 81 ALR cited
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WR Grace v Asahi Kasei [1993] FCA 84; (1993) AIPC 90-974 cited
Firebelt Pty Ltd v Brambles Pty Ltd [2002] HCA 21; (2002) 188 ALR 280 cited
Tidy Tea Ltd v Unilever Australia Ltd (1995) 32 IPR 405 cited
Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12; (1981) 148 CLR 262 cited
Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157 followed
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Flour Oxidizing Co Ltd v Carr & Co Ltd (1908) 25 RPC 428 cited
General Tire & Rubber Co v Firestone Tyre and Rubber Co Ltd [1972] RCP 457 cited
Imperial Chemical Industries Pty Ltd v Commissioner of Patents [2004] FCA 1658; (2004) 213 ALR 399 cited
AMP Inc v Utilux Pty Ltd (1971) 45 ALJR 123 cited
British Dynamite Co v Krebs [1879] 13 RPC 190 cited
Esber v The Commonwealth [1992] HCA 20; (1992) 174 CLR 430 cited
Frederikshavn Vaerft A/S v Stena Rederi Aktiebolag [2002] FCA 1024; (2002) 124 FCR 243 cited
Rescare Limited v Anaesthetic Supplies Pty Ltd (1992) 111 ALR 205 discussed
C Van Der Lely NV v Ruston’s Engineering Co Ltd [1993] RPC 45 followed
Rediffusion Simulation Ltd v Link-Miles Ltd [1993] FSR 369 followed
Prestige Group (Australia) Pty Ltd v Dar Industries Inc (1990) 26 FCR 197 followed
Cooper Brookes (Wollongong) Pty Ltd v Federal Commissioner of Taxation [1981] HCA 26; (1981) 147 CLR 297 cited
Illinois Tool Works Inc v Autobars Co (Services) Limited [1974] 91 RPC 337 cited




Laddie, ‘Patents – what’s invention got to do with it?’ In Vavere and Bently (eds) Intellectual Property in the New Millennium, Cambridge University Press (2004) 91
Monotti – ‘Sufficiency of Description; At what time is adequacy to be considered?’ (2005) 16 AIPJ 152








FRENCH, LINDGREN and CRENNAN JJ
31 OCTOBER 2005
MELBOURNE

IN THE FEDERAL COURT OF AUSTRALIA
VICTORIA DISTRICT REGISTRY	VID 337 OF 2005

On Appeal from a Single Judge of the Federal Court of Australia

BETWEEN:	PFIZER OVERSEAS PHARMACEUTICALS FIRST APPELLANT PFIZER PTY LIMITED (ACN 008 422 348) SECOND APPELLANT CP PHARMACEUTICALS INTERNATIONAL CV THIRD APPELLANT PFIZER MANUFACTURING LLC FOURTH APPELLANT PFIZER PRODUCTION LLC FIFTH APPELLANT
AND:	ELI LILLY AND COMPANY FIRST RESPONDENT ELI LILLY AUSTRALIA PTY LTD (ACN 000 233 992) SECOND RESPONDENT ELI LILLY AND COMPANY LIMITED THIRD RESPONDENT
JUDGES:	FRENCH, LINDGREN AND CRENNAN JJ
DATE OF ORDER:	31 OCTOBER 2005
WHERE MADE:	PERTH (HEARD IN MELBOURNE)

THE COURT ORDERS THAT:

1. The appeal be dismissed.

2. The parties bear their own costs of the appeal.





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

Index

Introduction 1 - 3
Physiological and Bio-chemical Background 4 - 11
The Patent 12 – 17
Important Prior Publications 17 – 23
The Evidence at Trial 23 – 25
The Lilly Witnesses – (i) Dr Gristwood 25 – 29
The Lilly Witnesses – (ii) Dr Cherry 29 – 31
The Lilly Witnesses – (iii) Mr Pryor 32
The Lilly Witnesses – (iv) Professor Charman 33
The Lilly Witnesses – (v) Dr McMahon 33- 34
The Lilly Witnesses – (vi) Dr Kruse 34 – 37
The Lilly Witnesses – (vii) Professor Aversen 37
The Bayer Witnesses – (i) Professor Brown 37 – 41
The Bayer Witnesses – (ii) Dr Silver 41
The Bayer Witnesses – (iii) Professor Scammells 41 – 43
The Bayer Witnesses – (iv) Professor Goldie 43 – 45
The Bayer Witnesses – (v) Dr Cartmill 45 – 46
The Bayer Witnesses – (iv) Dr Warrington 46 – 47
The Pfizer Witnesses – (i) Peter Ellis 47 – 50
The Pfizer Witnesses – (ii) Michael Allen 50 – 51
The Pfizer Witnesses – (iii) Martyn Burslem 52 – 53
The Pfizer Witnesses – (iv) Richard Palmer 53 – 54
The Pfizer Witnesses – (v) Rodolphe Fischmeister 54
The Pfizer Witnesses – (vi) Alan Robertson 54 - 55
The Pfizer Witnesses – (vii) Donald Moss 55
The Pfizer Witnesses – (viii) Zdzisilaw Wisniewski 55 - 56
The Pfizer Witnesses – (ix) Steven Pittler 56
The Pfizer Witnesses – (x) Ciara McKenna 56 – 57
The Reasons for Judgment at First Instance 57 – 65
The Orders at First Instance 65 - 66
The Grounds of the Appeal 66
The Notice of Contention 66 - 67
Statutory Framework – The Patents Act 1990 (Cth) 67 – 71
Constructional Questions 71 – 78
Infringement 78 - 79
Fair Basing 79 – 82
Lack of Inventive Step – Obviousness 82 – 92
Novelty 93 – 97
Sufficiency 97 – 102
Best Method 102 – 112
False Suggestion 112 – 116
Conclusion 116 - 117
Diagram – Contraction Relaxation 118
Diagram – Obvious? 119

IN THE FEDERAL COURT OF AUSTRALIA
VICTORIA DISTRICT REGISTRY	VID 337 OF 2005

On Appeal from a Single Judge of the Federal Court of Australia

BETWEEN:	PFIZER OVERSEAS PHARMACEUTICALS FIRST APPELLANT PFIZER PTY LIMITED (ACN 008 422 348) SECOND APPELLANT CP PHARMACEUTICALS INTERNATIONAL CV THIRD APPELLANT PFIZER MANUFACTURING LLC FOURTH APPELLANT PFIZER PRODUCTION LLC FIFTH APPELLANT
AND:	ELI LILLY AND COMPANY FIRST RESPONDENT ELI LILLY AUSTRALIA PTY LTD (ACN 000 233 992) SECOND RESPONDENT ELI LILLY AND COMPANY LIMITED THIRD RESPONDENT

JUDGES:	FRENCH, LINDGREN AND CRENNAN JJ
DATE:	31 OCTOBER 2005
PLACE:	PERTH (HEARD IN MELBOURNE)

REASONS FOR JUDGMENT

FRENCH AND LINDGREN JJ:
Introduction

1 Pfizer Overseas Pharmaceuticals is a company incorporated in Ireland. It is the registered patentee of Australian Patent No 676571 (the Patent). The title of that Patent is ‘Pyrazolopyrimidinones for the treatment of impotence’. Pfizer Pty Ltd is a company incorporated in Australia and was granted an exclusive licence in Australia in respect of the Patent on 29 January 2003 and 27 May 2003. A product said to embody the invention claimed in the Patent is the well known anti-impotence drug, Viagra. Eli Lilly and Company (Lilly USA) is a company incorporated under the laws of Indiana in the United States of America. Eli Lilly Australia Pty Ltd (Lilly Australia) is incorporated in Australia. Eli Lilly and Company Limited (Lilly UK) is a company incorporated under the laws of the United Kingdom. Lilly USA and Lilly Australia market, in Australia, an anti-impotence drug called Cialis. The Lilly parties are collectively referred to as ‘Lilly’ in these reasons. The Pfizer group of companies, which are the appellants in this case, is referred to as ‘Pfizer’ which term will also encompass individual members of the group.

2 On 17 September 2002 Lilly commenced proceedings in the Victorian District Registry of the Court for revocation of each of the claims in the Patent. It also sought a declaration that the Patent was and always had been invalid. The bases upon which invalidity was alleged included:

1. The invention as claimed in claim 10 did not involve an inventive step.
2. The invention as claimed in claim 10 was not fairly based on the matter described in the specification.
3. The invention as claimed in claim 10 was not novel.
4. The invention as claimed in claim 10 was not sufficiently described.
5. The specification did not describe the best method of performing the invention as claimed in claim 10.
6. The grant of the Patent was obtained by false suggestion or misrepresentation.

Pfizer cross-claimed against Lilly alleging that it had infringed the Patent with its product Cialis.

3 A further revocation proceeding was instituted by Bayer Aktiengesellschaft (Bayer) in March 2003. Pfizer cross-claimed against Bayer for infringement of the Patent arising out of the sale and supply in Australia by Bayer of its product, Levitran. Orders were made by consent in both proceedings on 10 September 2004 that evidence in one proceeding would be evidence in the other.

4 The Lilly and Bayer proceedings were heard together by Heerey J over 25 days in November and December 2004. On the second day of final addresses the Bayer proceeding was settled. Bayer was given leave to withdraw its application and Pfizer its cross-claim. On 10 February 2005 his Honour gave judgment – Eli Lilly and Company v Pfizer Overseas Pharmaceuticals [2005] FCA 67; (2005) 218 ALR 408. He found that one of the claims in the Patent, namely claim 10, was invalid because it was obvious, that is to say, it did not disclose an inventive step in the light of common general knowledge in the area. He also found that claim 10 was not fairly based on matter disclosed in the specification in the Patent. Otherwise his Honour rejected the Lilly contentions. He found that claim 10 was novel and not invalid on any of the other grounds advanced by Lilly. He also found that were the claim valid, then Lilly’s sales of Cialis would have constituted an infringement.

5 A notice of appeal against his Honour’s decision was lodged by Pfizer on 14 April 2005. Lilly filed a notice of contention on 20 May 2005.

6 The appeal involved challenges from both sides to his Honour’s findings. Pfizer argued that his Honour ought to have found that the invention as claimed in claim 10 of the Patent was not obvious and was fairly based on matter disclosed in the Patent specification. Lilly argued that his Honour ought to have found that the invention as claimed was not novel, not sufficiently described, that the best method of performing the invention was not disclosed and that the grant of the Patent was obtained by false suggestion. Lilly also contended that, assuming claim 10 to be valid, its product, Cialis, did not infringe it.

7 For the reasons that follow we are of the view that:

1. The invention as claimed in claim 10 did involve an inventive step.

2. The invention as claimed in claim 10 was not fairly based on the matter described in the specification.
3. The invention as claimed in claim 10 was novel.
4. The invention as claimed in claim 10 was sufficiently described.
5. The specification described the best method of performing the invention as claimed in claim 10.
6. The grant of the Patent was not obtained by false suggestion.
7. The Lilly product, Cialis, would have infringed claim 10 if that claim were valid.

Crennan J agrees with us on all points save for fair basing.

8 In the result claim 10 is invalid for want of fair basing. The appeal must therefore be dismissed. However as Lilly has failed on all the other points it has raised, the appropriate order is that each party bear its own costs of the appeal.

Physiological and Bio-chemical Background

9 In order to appreciate the issues on the appeal it is necessary to have a basic understanding of the physiological and biochemical processes at work in the erectile function of the human penis. Pfizer and Lilly prepared technical primers for the trial which, it was said, set out current knowledge. There was contention about whether some of the matters contained in the primers were known or formed part of general scientific knowledge as at June 1993 and May 1994. It was apparent, however, that the general descriptions of the processes at work in relation to erectile function as known at the time of the trial were not in dispute. The Court was also assisted by a PowerPoint presentation setting out essential elements of the relevant biochemical pathways. Two key diagrams from that presentation are set out at the end of these reasons so that the reader can better follow the discussion of the evidence and the submissions.

10 The penis has three cylindrical masses of erectile tissue. They are enclosed in a fibrous membrane. The bulk of the penis comprises two erectile cylinders called the corpora cavernosa. They are paired and lie side by side. They are separated by an incomplete fibrous wall or septum. They communicate along three quarters of their length through small holes in the septum which allow them to operate as a single unit. A third cylinder called the corpus spongiosum surrounds and supports the urethra and sits in a groove created by the other two cylinders. It also keeps the urethra open during ejaculation. The three erectile cylinders comprise largely highly vascularised sinusoidal tissue. When the sinusoidal tissue fills with blood during sexual excitement the penis enlarges, becoming rigid and erect. Blood is supplied to the penis by arteries and exits the penis by veins.

11 The process of erection or tumescence occurs when smooth muscle in the penis relaxes allowing the blood vessels to open up and blood to flow into the corpus cavernosum. Detumescence, which is the resting state, occurs when smooth muscle is contracted restricting blood flow to the penis and acting like a ligature. During tumescence the swelling of the corpus cavernosum reduces the ability of blood to drain from the penis so maintaining erection. The relaxation of smooth muscle is therefore critical to the erectile functioning of the penis.

12 Smooth muscle is one of three basic types of muscle tissue found in vertebrates. The other two are skeletal muscle and cardiac muscle. Smooth muscle is found in many tissues and organs throughout the vascular system surrounding blood vessels. It is also found in the lungs, surrounding the airways such as bronchioles, in the gastrointestinal tract and in the uterus. It contracts or relaxes, without voluntary control, according to impulses from the autonomic nerve system. That is the part of the peripheral nervous system which is responsible, inter alia, for controlling the function of organs and other tissues within the body. The smooth muscle which surrounds the sinusoids and small arteries and in the corpora cavernosa is under the control of the autonomic nervous system.

13 Smooth muscle comprises separate cells. The cells, acting together, cause relaxation or contraction of smooth muscle tissue as a whole. The processes of relaxation and contraction can be described by reference to events in a single smooth muscle cell.

14 Cellular action flows from cascades of biochemical reactions which generally take place within the cell but for the most part are initiated outside the cell. The cascade of reactions from a specific initiator to a specific response is called a ‘pathway’. A pathway may involve a number of biological chemicals or ‘mediators’ within the cell. They are often involved in functionally distinct pathways. A class of protein known as enzymes catalyse many biochemical reactions in the cell.

15 Contraction and relaxation of smooth muscle cells is controlled by nerves in the autonomic nervous system. Three classes of nerves which are important to the erectile process are:

1. Adrenergic nerves. This nerve type is generally responsible for releasing mediators, such as norepinephrine (also known as noradrenaline), which lead to contraction of smooth muscle.
2. Cholinergic nerves which release acetylcholine, a mediator which antagonises the effect of the adrenergic mediators responsible for contraction.
3. Non-adrenergic, non-cholinergic (NANC) nerves which release nitric oxide (NO) in response to sexual stimulation.

16 The initiation of a biochemical pathway relevant to the contraction or relaxation of smooth muscle cells occurs when a ‘first messenger’ such as a hormone or nitric oxide is released by a nerve. That first messenger either enters the cell or interacts with receptors on its external surface to trigger a pathway within the cell commencing with a second messenger chemical. Among cellular second messengers are the cyclic nucleotides known as cyclic adenosine-3’5’–monophosphate (cAMP) and cyclic guanosine – 3’5’ – monophosphate (cGMP).

17 In the resting state of the penis, penile smooth muscle is contracted. The contraction is controlled by a number of mechanisms involving alpha–adrenoreceptors. Norepinephrine is released by adrenergic nerves together with messengers from endothelial cells. Those messengers are prostaglandin F_2a and endothelins. They activate specific receptors on the smooth muscle cell membrane which initiate a cascade of reactions. Norepinephrine activates alpha₁ – adrenoreceptors. The reactions so initiated generate inositol triphosphate (IP₃). That causes calcium concentration in the cell to be elevated. That in turn activates an enzyme called myosin light chain kinase (MLCK). The activation of MLCK allows the interaction of two intracellular proteins, myosin and actin, which results in contraction.

18 The relevant interaction occurs in the movement of myosin relative to actin. Myosin can bind to actin. When there is a low concentration of calcium the ‘head’ of the myosin molecule cannot make contact with its binding site on the actin molecule and so the muscle is relaxed. However, where calcium concentration is high the myosin ‘head’ can come into contact with actin allowing contraction. This occurs in the pathway involving calcium and MLCK which results in phosphorylation of the myosin and enables it to interact with the actin. Phosphorylation is a form of molecular bond breaking which commonly occurs in biological systems. Myosin is a complex molecule which alters its three dimensional shape depending on whether other mediators are bound or not bound to it. A rolling process of alteration of the configuration of myosin combined with contact and non-contact with actin is what allows the muscle cell to contract.

19 It follows from the preceding that the state of relaxation or contraction of a smooth muscle cell is a function of calcium ion concentration in the cell. Calcium is also stored in the sarcoplasmic reticulum within the cell and is released when IP₃ is generated. Where IP₃ is present the calcium concentration will rise resulting in contraction. The flow of potassium ions in and out of the cell also controls the level of calcium in it. Stimulation of potassium channels causes relaxation of the cell because it gives rise to hyperpolarisation preventing calcium channels, which are voltage-dependent, from opening.

20 Continual nerve stimulation from adrenergic nerves maintains the contracted state of the smooth muscle. That adrenergic stimulation is balanced by stimulation from other nerves which control the relaxation of the smooth muscle.

21 Pathways contributing to smooth muscle relaxation include the NO/cGMP pathway and two cAMP pathways. One involves epinephrine (also known as adrenaline) and the other vasoactive intestinal polypeptide (VIP) and alternative prostaglandin E₁ (PGE₁). According to Pfizer’s primer, in the late 1980s and early 1990s research was conducted on these pathways and other mechanisms relating to penile erection, particularly the inhibition of alpha-adrenoreceptors with a view to blocking contraction.

22 One mode of smooth muscle relaxation occurs via the NO/cGMP pathway. The external stimulus or the first messenger for that pathway is NO. It consists of one nitrogen atom bound to one oxygen atom. It is responsible for triggering a large number of different physiological occurrences. It has a short life in the body of up to six seconds and is only capable of acting locally near the site of its release. It is produced in the body close to the tissue on which it acts. The NO relevant to penile smooth muscle is produced or released from at least two sources. One of those is the NANC nerves. The other source is vascular endothelial cells comprising the tissue known as the endothelium.

23 Endothelial cells line smooth muscles. They are located throughout the cardiovascular system lining every blood vessel in the body. In the 1980s it was found that endothelial cells produced an endothelium derived relaxing factor (EDRF), an unidentified mediator favourably affecting the relaxation of smooth muscle. Research in the late 1980s showed that EDRF was in fact NO. Endothelial cells appear to have a basal production of NO. However it is not thought to be responsible for sufficient relaxation to result in erection. The principal source of NO for penile smooth muscles is said to be the NANC nerves.

24 Neurotransmission through the NANC nerves in response to sexual stimulation provides penile smooth muscle with an NO ‘rush’. Broadly, sexual stimulation triggers a cascade of reactions within the brain leading to neurotransmission through the sacral NANC nerves and the release of NO. The rush of NO from the NANC nerves is primarily responsible for erection. So much appears to be common ground. Lilly’s primer states:

‘In summary, NO released from the vascular endothelium cells lining the smooth muscle (nitric oxide was previously referred to as EDRF) and the non-adrenergic non-cholinergic (NANC) nerves supplying the smooth muscle causes elevation of cGMP levels, which causes relaxation of smooth muscle and dilation of blood vessels, which causes or contributes to erection ...’

Lilly further states:

‘Nitric oxide is the principal mediator of penile erection, relaxing the corpus cavernosum in response to NANC neurotransmission.’

25 NO molecules produced in the endothelium or NANC nerves enter smooth muscle cell and bind to an enzyme known as soluble guanylate cyclase (GC). GC is responsible for converting guanosine triphosphate (GTP) which is a common intra-cellular molecule, into cGMP. cGMP binds to, and activates, a cGMP-specific protein kinase (PKG) which in turn regulates the activity of other cellular proteins. It inhibits MLCK, stimulates potassium channels and inhibits calcium channels. This causes the concentration of calcium in the cell to fall, the myosin head to detach from actin and relaxation to result. PKG and cAMP-specific protein kinase (PKA), also reduce the sensitivity of contractile ‘machinery’ to calcium by acting on enzymes (phosphatases) which regulate MLCK.

26 The concentration of the cyclic nucleotides cGMP and cAMP in smooth muscle cell depends upon two main factors. The inflow of NO controls the production of cGMP by guanylate cyclase. Secondly, and importantly, a specific enzyme known as phosphodiesterase (PDE) determines the extent to which cGMP is subsequently broken down. PDEs modify the chemical composition of cyclic nucleotides, creating a 5’-monophosphate nucleotide (AMP or GMP) which is inert with respect to proteins upon which the cyclic nucleotide acts.

27 cAMP is also involved in penile smooth muscle relaxation. The hormone epinephrine (adrenaline) triggers activation of adenylate cyclase, which converts ATP into cAMP. cAMP activates PKA and can also activate PKG when present in high concentrations. PKA in turn activates potassium channels in the cellular membrane and inhibits MLCK. As a result the myosin ‘head’ detaches from actin. This causes relaxation. cAMP concentrations in the cell are regulated by PDEs. Some therapies based on manipulation of the cAMP pathway were used for erectile dysfunction prior to 1993, including intracavernosal injection of papaverine and PGE₁.

28 A tabular summary of the key information about neurotransmission and cellular responses was set out in the Pfizer primer as follows:

Neurotransmitter	Source	Second Messenger	Ca++ Concentration	Smooth muscle cell response
Neurogenic
Norepinephrine	Adrenergic nerves	IP3/Ca2+	Increased	Contraction
Acetylcholine	Cholinergic nerves	NO/GC/cGMP/PKG	Decreased	Relaxation
NANC NO	NANC (nitrergic)	GC/cGMP/PKG	Decreased	Relaxation
VIP	NANC (vipergic)	AC/cAMP/PKA	Decreased	Relaxation
Endothelial
Endothelin-1	Endothelium	IP3/Ca2+	Increased	Contraction
Endothelial NO	Endothelium	GC/cGMP/PKG	Decreased	Relaxation
PGE1	Endothelium	AC/cAMP/PKA	Decreased	Relaxation

29 The role of PDEs is of importance in lowering the concentration of cGMP produced by NO inflows and as a result the extent to which relaxation of the smooth muscle of the penis occurs. Five different types of PDE enzyme are referred to in the primers. Each regulates concentrations of cGMP and cAMP or both to varying degrees. Five PDE enzyme families were known in 1990. A classification system was adopted to discriminate between them. Some could be inhibited, that is to say their catalysing function could be completely or significantly blocked by chemicals called PDE inhibitors.

30 The 1990 classification of PDEs divided them into families designated by the Roman numerals I to V. In 1994, a further classification divided PDE_V into two parts, added newly discovered families of PDE isoenzymes and replaced the Roman numeral system of nomenclature with one based on Arabic numerals. Both Pfizer and Lilly set out, in their primers, a table of PDE families in the 1990 classifications. The Pfizer table, largely replicated in the Lilly table, was as follows:

Name	Description	Activity
PDEI	Calcium/calmodulin dependent PDE	Hydrolyses cAMP and cGMP but some subtypes are cGMP preferring
PDEII	cGMP-stimulated PDE	Hydrolyses cAMP and also cGMP at high concentrations
PDEIII	cGMP-inhibited PDE	cAMP preferring
PDEIV	cAMP-specific PDE	Almost exclusively hydrolyses cGMP
PDEV	cGMP-specific PDE	Almost exclusively hydrolyses cGMP

The PDE enzymes have varying distributions through the body of tissues. The exact tissue distribution was not known in June 1993.

31 PDE inhibitors are compounds which block a PDE’s ability to convert cGMP into GMP or cAMP into AMP. By preventing a PDE from lowering the concentration of cGMP or cAMP in the cell, relaxation can occur or be potentiated. A number of PDE inhibitors with varying degrees of selectivity had been developed and used by June 1993 to treat conditions such as asthma and heart failure. Among the inhibitors said to have been known at 1990 were Dipyridamole and zaprinast (M&B22,948) in respect of PDE_V. Different PDEs are prevalent in different tissues and organs of the body. Their prevalence provides the basis for systematic therapeutic use of PDE inhibitors to relax smooth muscle in specific tissues and organs.

32 The Lilly primer contained a useful flowchart showing the pathway whereby the production of NO leads to production of cGMP and the effect of PDEs on the concentration of cGMP.

33 As appears from the evidence referred to later in these reasons, the relevant family of PDEs, namely PDE_V went through a taxonomical development which led initially to its subdivision into PDE V_A PDE V_B and PDE V_C. The first of these was the penile smooth muscle PDE. The second and the third were located in retinal tissue. The latter two, PDE V_B and PDE V_C were subsequently reclassified as PDE_VI. PDE V_A reverted to PDE_V – see the evidence of Dr Gristwood summarised below. For ease of reference in these reasons, PDE_V will be the nomenclature adopted for the relevant PDE in smooth muscle in the penis unless the earlier taxonomical subdivision is specifically mentioned in the evidence as quoted or summarised.

The Patent

34 The Patent was granted on an application filed pursuant to the Patent Cooperation Treaty on 13 May 1994. It shows a priority date of 9 June 1993, claiming priority from a United Kingdom patent application no GB9311920 filed on that date. It is common ground that because of various amendments the priority date for the claim in contention in these proceedings, namely claim 10, is 13 May 1994.

35 On 19 September 2003 the Court ordered that the Patent be amended pursuant to s 105 of the Patents Act 1990 (Cth) (the Act) by deletion of the existing claim 9 and consequential amendments to claim 10. As the claims were not renumbered there is no claim 9 in the Patent as it now stands. On the first day of the trial before Heerey J claims 12 to 18 were also deleted by consent.

36 The Patent specification describes the invention as one which ‘relates to the use of a series of pyrazolo[4,3-d]pyrimidin-7-ones for the treatment of impotence’. Erectile impotence or dysfunction is defined as ‘an inability to obtain or sustain an erection adequate for intercourse’.

37 According to the specification a number of drugs previously shown to induce penile erections only operated effectively upon direct injection into the penis. Medical treatment current at the time of the lodgement of the specification was based upon intracavernosal injection of vasoactive substances. While some good results had been claimed, there were side effects of pain, priapism and fibrosis of the penis associated with their intracavernosal administration. Potassium channel openers (KCO) and VIP had been shown to be active but their development was limited by their cost and stability. The application of glyceryl trinitrate patches to the penis had been shown to be effective but produced side effects in both patient and partner. Penile prostheses had a short term success rate but gave rise to problems with infection and ischaemia, particularly in diabetic men. The use of this type of treatment was described in the specification as a final option rather than a first-line option.

38 The compounds comprising the invention are described in the specification as:

‘... potent inhibitors of cyclic guanosine 3’,5’-monophosphate phosphodiesterases (cGMP PDEs).’

Their selective enzyme inhibition is said to lead to elevated cGMP levels which provide the basis for utilities already disclosed for these compounds in two other patents known as Bell 1 (EP-A-0463756) and Bell 2 (EP-A-0526004), namely in the treatment of various conditions including conditions of the cardiovascular system. Then it is said:

‘Unexpectedly, it has now been found that these disclosed compounds are useful in the treatment of erectile dysfunction.’

The word ‘unexpectedly’ was added by amendment on 13 May 1994. The specification states that the compounds are able to be administered orally obviating disadvantages associated with intracavernosal administration.

39 The class of compounds covered by the specification is described by reference to a molecular diagram and descriptions of alternative groups of atoms which may be substituted for each other at particular points on the molecular structure. The number of compounds so defined is very large. The alternative descriptions are followed by the words:

‘... or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the curative or prophylactic treatment of erectile dysfunction in a male animal, including man.’

The underlined words were added on 13 May 1994.

40 Examples of pharmaceutically acceptable salts of the defined class of compounds include non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulphuric and phosphoric acid, with organo-carboxylic acids or with organo-sulphonic acids. Compounds in the defined class can also provide pharmaceutically acceptable metal salts, particular non-toxic alkali metal salts with bases. Examples are said to include the sodium and potassium salts.

41 The specification sets out descriptions of subsets of the class of compounds defined in formula (I) in ascending levels of preference. Thus there is:

1. A preferred group of compounds.
2. A more preferred group of compounds.
3. A particularly preferred group of compounds.
4. Especially preferred individual compounds.

The last group contains nine compounds one of which is sildenafil. Sildenafil monocitrate is the active ingredient of Viagra. It is however not one of the compounds identified as ‘especially preferred’.

42 By words added on 13 May 1994 the specification goes on to state:

‘A preliminary investigation was carried out with a view to isolating and characterising the cyclic nucleotide PDEs of human corpus cavernosum, relaxation of which leads to penile erection. Studies of substrate specificity, response to activators and inhibitor sensitivity, have demonstrated that human corpus cavernosum contains three distinct PDE enzymes.’

The study referred to was carried out by Mr Burslem of Pfizer in 1994. It identified three PDE isoenzymes in human corpus cavernosum tissue. The predominant PDE is the cGMP-specific PDE_V , whilst cGMP-stimulated cAMP PDE_II and cGMP-inhibited cAMP PDE_III are also present.

43 It is then said that:

‘The compounds of the invention have been tested in vitro and found to be potent and selective inhibitors of the cGMP-specific PDE_v .’

44 One of the especially preferred compounds of the invention has a strongly inhibitory action against PDE_V. It has an IC₅₀ = 6.8 nM against the PDE_V enzyme, but demonstrates only weak inhibitory activity against the PDE_II and PDE_III enzymes with IC₅₀ = >100 μM and 34 μM respectively. IC₅₀ measures the concentration of an inhibitor necessary to reduce enzyme activity by 50%. So it is said in the specification:

‘Thus relaxation of the corpus cavernosum tissue and consequent penile erection is presumably mediated by elevation of cGMP levels in the said tissue, by virtue of the PDE inhibitory profile of the compounds of the invention.’

45 The specification states that in man, certain especially preferred compounds have been tested orally in both single and multiple dose volunteer studies. Patient studies confirmed that one of the especially preferred compounds induced penile erection in impotent males. It suggests that the compounds of the invention might also be useful for the treatment of female sexual dysfunction including orgasmic dysfunction related to clitoral disturbances.

46 The specification states:

‘Generally, in man, oral administration of the compounds of the invention is the preferred route, being the most convenient and avoiding the disadvantages associated with i.c. administration. A preferred dosing regimen for a typical man is 5 to 75 mg of compound three times daily.’

47 In what was said by the learned trial judge to be ‘arguably a consistory clause’ the specification states a number of attributes of the invention. First the invention provides a process for the preparation of a pharmaceutical composition for:

‘... the curative or prophylactic treatment of erectile dysfunction in a male animal, including man, comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.’

Secondly, there is provided a process for preparing such a composition. These first and second elements of what his Honour referred to as ‘a consistory clause’ were added on 13 May 1994.

48 The ‘consistory clause’ thirdly states:

‘The invention also provides a method of treating a male animal, including man, to cure or prevent erectile dysfunction which comprises treating said male animal with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity.’

In a further and fourth aspect it is said that the invention:

‘...includes the use of a cGMP PDE inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the oral treatment of erectile dysfunction in man’.

The specification continues:

‘The invention also includes a method of orally treating man to cure or prevent erectile dysfunction, which comprises treatment with an orally effective amount of a cGMP PDE inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity.’

The invention is said also to include the use of a cGMP inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing either entity ‘... for the manufacture of a medicament for the curative or prophylactic oral treatment of erectile dysfunction in man’.

49 At the commencement of the proceedings there were eighteen claims set out in the specification. The claims as they stood following the deletion of claim 9 and claims 12 to 18, and not including claim 11 which is not relevant for present purposes, are as follows:

‘1. A method of treating a male animal requiring such treatment, including man, to cure or prevent erectile dysfunction which comprises treating said male animal with an effective amount of a compound of formula (I) wherein ....’

These words were added on 3 October 1996. The chemical formulae which followed, and which are not reproduced here, were added on 13 May 1994.

50 Claims 2, 3 and 4 each narrows claim 1 by limiting the various groups of substitutable atoms in formula (I). The form of claim 2 is thus:

‘The method according to claim 1 wherein in the compound of formula (I) R¹ is H, methyl or ethyl; R² C₁-C₃ alkyl; R³is C₂-C₃ alkyl or allyl; R⁴ is C₁-C₂ alkyl optionally substituted with OH, NR⁵R⁶, CN, CONR⁵R⁶ or CO₂R⁷; ...’

Claim 3 begins:

‘The method according to claim 2 wherein in the compound of formula (I) R¹ is methyl or ethyl; R² is C₁-C₃ alkyl; ...’

Claim 4:

‘The method according to claim 3 wherein in the compound of formula (I), R¹is methyl or ethyl; R² is n-propyl; R³ is ethyl, n-propyl or allyl; ...’

51 Claim 5 sets out nine particular compounds in the following form:

‘The method according to claim 4 wherein the compound of formula (I) is:

5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one; ....’

The nine compounds referred to in claim 5 are the ‘especially preferred individual compounds’ mentioned earlier. The formulae in the claims 2 to 5 were all added on 13 May 1994.

52 Claims 6, 7 and 8 are:

‘6. The method according to claim 5, wherein the compound of formula (I) is: 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo-[4,3-d] pyrimidin-7-one.
7. The method according to claim 5, wherein the compound of formula (I) is: 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo[4,3-d] pyrimidin-7-one.
8. The method according to claim 5, wherein the compound of formula (I) is the monocitrate salt of 5-[2-ethoxy-5-(4-methyl-1-pipereazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo[4,3-d] pyrimidin-7-one.’

Those claims were added on 6 January 1997. They each specify a particular compound of formula (I). The compound in claim 7 is the free base known as sildenafil. That in claim 8 is sildenafil monocitrate. It is the active ingredient of Viagra. The words ‘The method’ which open each of claims 2 to 8 inclusive were added on 3 October 1996.

53 Claim 10 is as follows:

‘A method of orally treating man to cure or prevent erectile dysfunction in man in need of such treatment, which comprises treatment with an orally effective amount of cGMP PDE_v inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity.’

The claim in its present form reflects an amendment ordered by Heerey J on the application of Pfizer on 19 September 2003 – Eli Lilly & Company v Pfizer Research and Development Company [2003] FCA 988. Before that amendment, which also deleted claim 9, claims 9 and 10 were as follows:

‘9. A method of orally treating man to cure or prevent erectile dysfunction in man in need of such treatment, which comprises treatment with an orally effective amount of a cGMP PDE inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity.

10. The method according to claim 9 wherein the inhibitor is cGMP PDE_v inhibitor.’

54 The claims that followed were not relevant for the purposes of the proceedings before his Honour.

Important Prior Publications

55 Three publications predating the priority date of the patents were the focus of contention at trial and on the appeal. They were as follows:

1. J Rajfer et al – Nitric Oxide as a Mediator of Relaxation of the Corpus Cavernosum in Response to Nonadrenergic, Noncholinergic Neurotransmission – New England Journal of Medicine, January 9, 1992, Vol 326 No 2 pp 90-94
2. SG Korenman and SP Viosca – Treatment of Vasculogenic Sexual Dysfunction with Pentoxyfilline – Journal of the American Geriatrics Society, April 1993, Vol 41 No 4 pp 363-366.
3. KJ Murray – Phosphodiesterase V_A Inhibitors – Drug News and Perspectives, April 1993 Vol 6(3) pp 150-156

56 The abstract to the Rajfer paper set out the background to the research which it reported. It stated that nitric oxide had been identified as an endothelium derived relaxing factor in blood vessels. The researchers tried to determine whether it was involved in the relaxation of the corpus cavernosum which allows penile erection. The relaxation of that smooth muscle was known at that time to occur in relation to stimulation by NANC neurons.

57 The researchers studied strips of corpus cavernosum tissue obtained from 21 men in whom penile prostheses had been inserted because of impotence. The smooth muscle specimens were pre-treated with guanethidine and atropine and sub-maximally contracted with phenylephrine. Smooth muscle relaxant responses to stimulation by an electric field and to nitric oxide were then studied.

58 The reported results were that electrical field stimulation caused a marked transient, frequency-dependent relaxation of the corpus cavernosum which was inhibited in the presence of n-nitro-L-arginine and n-amino-L-arginine, which selectively inhibit the biosynthesis of nitric oxide from L-arginine. The addition of excess L-arginine, but not D-arginine, largely reversed the inhibitory effects. A nitric oxide generating chemical called S-nitroso-N-aectylpenicillamine (SNAP) was added and caused ‘... rapid, complete, and concentration-dependent relaxation of the corpus cavernosum’. The abstract then stated the following further result:

‘The relaxation caused by either electrical stimulation or nitric oxide was enhanced by a selective inhibitor of cyclic guanosine monophosphate (GMP) phosphodiesterase (M&B22,948). Relaxation was inhibited by methylene blue, which inhibits cyclic GMP synthesis.’

M&B22,948 is the inhibitor also known as zaprinast. The conclusion as stated in the abstract was that the findings supported the hypothesis that nitric oxide was involved in the NANC neurotransmission which leads to smooth muscle relaxation in the corpus cavernosum that permits penile erection. Defects in that pathway might cause some forms of impotence.

59 The detailed description of the method indicated that the strips of corpus cavernosum taken from 21 men treated by prosthesis for impotence, were mounted longitudinally in 25-ml-organ-bath chambers with fine nichrome wires, with the upper wire of each strip attached to a force-displacement transducer. Changes in isometric force were measured and recorded on a Grass polygraph. The bathing mediums used contained guanethidine to produce adrenergic blockade and atropine to produce cholinergic blockades. Electrical stimulation was provided with parallel platinum electrodes.

60 It was found that the addition of zaprinast, a cGMP PDE inhibitor augmented the relaxant responses elicited by electrical field stimulation. The use of SNAP, which liberated nitric oxide elicited pharmacologic actions attributed exclusively to nitric oxide and gave rise to rapid concentration dependent relaxation of pre-contracted strips of corpus cavernosum. The relaxation was enhanced by the zaprinast.

61 In their discussion of the results, the researchers observed that electrical field stimulation of isolated pre-contracted strips of corpus cavernosum from men with impotence caused smooth muscle relaxation by mechanisms which they attributed to the formation and release of a relaxing factor which had the properties of NO. The addition of NO in the form of labile SNAP caused similar rapid relaxant responses that were inhibited by methylene blue, enhanced by zaprinast and unaffected by N-nitro-L-arginine. They observed that zaprinast ‘... is a selective inhibitor of cyclic GMP but not cyclic AMP phosphodiesterase’ This was indicated by its capacity to augment the relaxation elicited by electrical field stimulation and NO, coupled with its inability to augment PGE₁ elicited smooth-muscle relaxation attributed to cAMP formation.

62 The researchers referred to the complete blockade of electrically elicited relaxation of corporal smooth muscle with the addition of tetrodotoxin as consistent with the hypothesis that electrically elicited relaxation was mediated by the NANC pathway. Their observations suggested that NANC neurotransmission was coupled in some manner to the activation of the L-arginine-nitric oxide pathway in human corpus cavernosum. In this respect the findings in humans paralleled those made in rabbits. They said (at 93):

‘Nitric oxide may be synthesized and released as a neurotransmitter by the nonadrenergic, noncholinergic neurons. Its labile chemical nature, however, makes it unlikely that nitric oxide could be stored as a preformed neurotransmitter. Alternatively, an unidentified neurotransmitter, such as vasoactive intestinal polypeptide, may interact with either endothelial or smooth-muscle cells in the corpus cavernosum to trigger the local formation of nitric oxide.’

63 The study was not designed to address any possible difference between impotent and normal patients with regard to the magnitude of the relaxation of corpus cavernosum by elicited electrical field stimulation. The researchers said (at 94):

‘Although the present study did not address such differences, the data suggest that the nonadrenergic, noncholinergic L-arginine-nitric oxide pathway may be involved physiologically in mediating penile erection. It is conceivable that impairment of this pathway could account for the impairment in relaxation elicited by electrical-field stimulation that has been described in certain impotent men. Smooth-muscle relaxation is the mechanism by which papaverine and prostaglandin E_1, when injected intracavernosally, cause tumescence in impotent patients. In view of the previous finding that electrically elicited relaxation of the corpus cavernosum is impaired in men with diabetes and impotence, interference with the L-arginine-nitric oxide pathway could be one cause of impotence that is treatable by the administration of direct-acting vasodilators.’

64 The Korenman study published in the Journal of the American Geriatrics Society in April 1993 had as its objective an evaluation of the use of pentoxifylline to treat impotency in men with mild to moderate penile vascular insufficiency. The participants were couples and the mode of intervention involved twelve weeks of treatment with a placebo or doses of pentoxifylline. It was found that pentoxifylline therapy regularly increased the penile-brachial pressure index (PBPI) in impotent men in comparison with the placebo frequently into the normal range. The therapy was particularly useful in restoring PBPI in men with pelvic steal syndrome. Nine men were able to re-establish coital function and three had no improvement. Their conclusions were that the promising preliminary results suggested a well-tolerated alternative therapy for erectile dysfunction in patients with mild to moderate penile vascular disease.

65 The introduction to the Korenman paper observed that pentoxifylline renders red blood cells more deformable allowing them to pass more readily through partially obstructed arterial channels. This had led to its use in the management of intermittent claudication. The study tested the possibility that the drug would be similarly effective in improving blood flow through the penis and thereby facilitating the erectile process in older men with a vascular component of impotence.

66 In their discussion of the results the researchers observed (at 366):

‘The significant increase in penile blood pressure due to pentoxifylline ... suggests that it increased blood flow through the penis via its hemorheological effects. However, pentoxifylline was recently shown to have direct vasodilator properties, offering another possible mechanism of action. The potent tumor necrosis factor-suppressing effects of pentoxifylline, which result in inhibition of the inflammatory response, may or may not play a role in pentoxifylline’s effect on impotence; ultrastructural examination of corpora cavernosal tissues of impotent men failed to demonstrate an inflammatory response.’

67 The paper by Kenneth J Murray in Drug News & Perspectives was a review of existing literature. A brief outline of its essential proposition appeared on the title page of the article:

‘The therapeutic potential of PDE V_A inhibitors as, for example, vasodilators, bronchodilators and modulators of gastrointestinal motility, is largely based on the effects of one compound, zaprinast, and a clearer picture will be obtained when other rationally designed inhibitors become available.’

68 The article opened with the observation that PDEs had long been regarded as potential targets for therapeutic agents. Interest in the area had been renewed by the recognition of five distinct PDE isoenzyme families, and the fact that tissues had different complements of those isoenzymes. There was, therefore, a logical foundation for selective PDE inhibitors to be used to increase cyclic nucleotide levels in specific target tissues or organs. Selective PDE III inhibitors were being used clinically for the treatment of congestive heart failure and as antithrombotic agents. This success had given hope that inhibitors of other PDE isoenzymes would also be useful drugs. The stated purpose of the review was to discuss briefly the PDE isoenzyme families and to describe one of those, namely PDE V. The physiological and pharmacological effects of PDE V_A inhibitors were reviewed and their potential therapeutic indications discussed.

69 The cGMP-specific PDE isoenzyme (designated PDE V) family was said to consist of several members or isoforms. PDE V_A is located in a number of nonretinal tissues. PDE V_B and PDE V_C with similar properties are exclusively located in the retina where they play an important role in visual transduction. The author said (at 150):

‘PDE V_A contains a noncatalytic binding site for cGMP, and this property was used in the initial purification and naming of the enzyme. Therefore, the first reports of PDE V_A were as cGMP-binding PDEs in lung and platelets. In addition to these tissues, PDE V_A is also found in various smooth muscle types and spleen. This is not to say that PDE V_A is exclusive to these tissues, as small amounts of PDE V_A may have escaped detection in other tissues. However, when compared to some other PDEs (eg PDE IV), PDE V_A exhibits a rather limited tissue distribution.’

70 The most salient feature of PDE V_A is its specificity for cGMP as a substrate. This means that an inhibition of PDE V_A would result in elevation in cGMP but not cAMP levels. PDE IV inhibitors, on the other hand, would cause an elevation of cAMP but not cGMP. PDE III inhibitors could increase the levels of both cyclic nucleotides. Murray said (at 151):

‘The combination of a limited tissue distribution and substrate specificity suggests that a specific PDE V_A inhibitor could have a narrow range of physiological and pharmacological actions.’

71 Murray identified the most frequently studied PDE V_A inhibitor as zaprinast. There was nevertheless considerable confusion regarding its selectivity for PDE V_A with respect to PDE I. It was difficult to compare results of different groups of workers due to the marked differences in purification methods, assay conditions and the analysis used to calculate the final kinetic parameter. There were, however, a number of reports which indicated that zaprinast could inhibit both PDE V_A and PDE I. There was no doubt that zaprinast was a potent inhibitor of PDE V_A. There was also evidence that it could inhibit PDE I.

72 In referring to the physiological effects of PDE V_A inhibition Murray observed that in general PDE V_A had been shown to relax a variety of vascular smooth muscles from a number of species in an agonist-independent manner, although guinea pig aorta was not relaxed by zaprinast. The results also strongly indicated that relaxation by zaprinast was endothelium dependent. The majority of studies in airway smooth muscle had utilized zaprinast and bovine trachaelis. There was a consensus that zaprinast was a very weak relaxant of that tissue. It did not relax canine trachea. Both zaprinast and another substance, SK&F-96231, caused an agonist-independent relaxation of guinea pig trachea. Potential species differences were indicated.

73 Referring to Rajfer, Murray said (at 153):

‘The effects of zaprinast have also been studied in a number of other smooth muscle types. With strips of human corpus cavernosum, zaprinast alone caused a relaxation and enhanced the relaxation caused by nitric oxide or electrical stimulation.’

He referred to its relaxant effects on muscle in other species and also its effect on platelet function.

74 Turning to potential therapeutic use of PDE V_A inhibitors, Murray observed that the only PDE V_A inhibitor that had been clinically evaluated to the time of publication of his article was zaprinast. It had been used for adult asthmatics, to reduce bronchoconstriction induced by exercise but not that provoked by histamines. It had no effect on exercise induced asthma in children. He said (at 154):

‘However, when evaluating these results, it should be remembered that these were small clinical trials using a compound that may have actions other than PDE V_A inhibition. Therefore, at present, PDE V_A inhibitors must be considered to be compounds with potential rather than established clinical use.’

He went on (at 154-155):

‘Smooth muscle relaxation appears to be the most promising of the potential uses of PDE V_A inhibitors, and possible therapeutic utilities could include vasodilation, bronchodilation, modulation of gastrointestinal motility and treatment of impotence. Although PDE V_A inhibitors will relax most smooth muscle types in vitro, this does not necessarily mean that a nonselective action will be seen in vivo. Selective actions could be achieved by virtue of the fact that many of the effects of PDE V_A inhibitors in a particular tissue are dependent on the level of guanylate cyclase activity. Thus, PDE V_A inhibitors will have the greatest effect in cells and tissues that have a high guanylate cyclase activity, and there could be considerable value in a therapeutic agent that has little activity in its own right, but potentiates the effects of endogenous mediators.’

In his final paragraph, Murray said:

‘In addition to smooth muscle relaxation, other therapeutic properties of PDE V_A inhibitors could include analgesia and effects on platelet function. At present, the therapeutic potential of PDE V_A inhibitors is largely based on the effects of one compound (ie, zaprinast), and a clearer picture will be obtained when other rationally designed PDE V_A inhibitors become available.’

The Evidence at Trial

75 The reasons for judgment of the learned trial judge were succinct and it is necessary in considering them, on appeal, to have an appreciation of the range and content of the evidence that was placed before him. What follows identifies the witnesses and provides an overview of their evidence-in-chief and some responses in cross-examination.

76 Witnesses at the trial gave their evidence on affidavit subject to cross-examination.

77 The Lilly witnesses were:

1. Robert Gristwood – Research and Development Director of Arachnova Limited, a British pharmaceutical company.
2. Denis Cherry – Medical Director of the Perth Human Sexuality Centre.
3. John Pryor – a medical specialist in the field of uroandrology (relating to the male genital tract).
4. William Charman – Professor of Pharmaceutics at the Victorian College of Pharmacy, Monash University.
5. Christopher McMahon – a Genito-Urinary Sexual Health Physician at the Australian Centre for Sexual Health, St Leonards, Sydney.
6. Lawrence Kruse – a medicinal chemist, consultant to the pharmaceutical and biotechnology industry and former Senior Vice President of Sterling Winthrop.
7. Philip Iversen – Principal Research Scientist with Eli Lilly and Company.
8. Lothar Uher – a Technical Scientist at ICOS Corporation in the United States.

78 The Bayer witnesses were:

1. Lindsay Brown – a Pharmacologist and Associate Professor in the Department of Physiology and Pharmacology at the University of Queensland.
2. Paul Silver – Senior Director Project Manager Neuro Sciences and Womens’ Health at Wyeth Research (USA).
3. Peter Scammells – Professor of Medicinal Chemistry and Head of the Department of Medicinal Chemistry at Monash University.
4. Roy Goldie – Executive Dean in the Faculty of Health, Sciences at Flinders University in Adelaide.
5. Ross Cartmill – a practising neurologist and a member of the Neurology Department at the Princess Alexandra Hospital in Brisbane.
6. Brian Warrington – the Vice President, Technology Development UK for GlaxoSmithKline Plc.

79 The Pfizer witnesses were:

1. Peter Ellis – Executive Director of Exploratory Development at Pfizer.

2. Michael Allen – Vice President Pfizer Global Research and Development, Head of the Exploratory Development Management team in Europe and the Therapy Area Leader for Gastroenterology and Genito-Urinary Products in world wide development.

3. Martyn Burslem – Executive Director, Discovery Biology at Pfizer.

4. Richard Palmer – Chief Executive Officer of Alizyme Plc, a drug development company in the United Kingdom.
5. Rodolphe Fischmeister – Director of Research at INSERM (Institut National de la Santé et de la Recherche Medicale) and Head of the Cellular and Molecular Cardiology Laboratory at the Faculty of Pharmacy at the University of Paris-Sud, Chatenay-Malabry, France.
6. Alan Robertson – Chief Executive Officer of Pharmaxix Ltd.
7. Donald Moss – a Consultant Urologist and Senior Urologist at Ballarat Base Hospital.
8. Zdzisilaw Wisniewski – a Clinical Urologist and currently Chairman of the Western Australian Section of the Urological Society of Australasia.
9. Steven Pittler – Professor in the Department of Physiological Optics and the Department of Ophthalmology at the University of Alabama, USA.
10. Ciara McKenna – Marketing Manager, Pfizer Australia Pty Ltd for Endocrinology/Gastroenterology/Urology/Ophthalmology.
11. Anna Young – Solicitor whose evidence related to searches of prior art literature.

The Lilly Witnesses - (i) Dr Gristwood

80 Dr Gristwood resides in Cambridge in the United Kingdom. He set out matters which were known to him and which he believed would have been known to other pharmacologists in the UK as well as elsewhere in the world, including Australia before June 1993. They were matters widely presented in journals and at meetings.

81 He described the functioning of smooth muscle in the body generally and the importance of understanding pharmacological pathways associated with its relaxation. In 1983 a research team had demonstrated that vascular smooth muscle relaxation through an Endothelium Derived Relaxing Factor (EDRF) was mediated by activation of guanylyl cyclase which consequently increased the concentration of cGMP. In 1985 another study showed that the effect of EDRF was blocked by haemoglobin and by methylene blue which is a guanylyl cyclase inhibitor. This was consistent with EDRF being NO because haemoglobin binds strongly to NO. The blocking effects of methylene blue demonstrated that the EDRF induced relaxation was mediated through cGMP. A study conducted in 1987 demonstrated, using cultured endothelial cells, that EDRF was NO. This was confirmed by independent studies in the same year.

82 Dr Gristwood first became aware of the strong possibility that EDRF was NO at a meeting in Sydney in 1987. From 1989, shortly after the confirmation of EDRF as NO, there was speculation among pharmacologists that it could also be a neurotransmitter of the NANC nervous system which was known to innervate a number of peripheral tissue systems including urogenital systems.

83 There was substantial publicity about the role of NO in various biological mechanisms in the early 1990s. The publicity was not restricted to specialist pharmacology journals but appeared in more widely read scientific publications such as The Lancet, Science and New Scientist. Science named NO as its ‘Molecule of the Year’ in 1992 and summarised its role in vasodilation, immune responses, sexual dysfunction and the learning and memory processes. Under the title ‘NO sex’, the article said:

‘This year, scientists proved definitively that in males, NO translates sexual excitement into potency by causing erections ... NO dilates blood vessels throughout the crucial areas of the penis, blood rushes in, and the penis rises to the occasion.’

By the end of 1992, many physiologists, biochemists and pharmacologists would have been aware that NO contributed to erections. By then also, most would have been aware that it caused an increase in cGMP levels and had the effect of relaxing smooth muscle.

84 Dr Gristwood discussed the relationship between cyclic nucleotides and PDEs. He referred to the classification of PDEs into five families in 1990 by the researchers Beavo and Reifsnyder. The cGMP-specific PDEs (PDE IA and the retinal enzymes) were reclassified as PDE V. PDE V was later subdivided into PDE V_A, PDE V_B and PDE V_C. PDE V_B and V_C, under the Beavo classification, became the new terms for the retinal PDEs. They were later reclassified together as PDE VI.

85 He set out in his affidavit a table representing his understanding in June 1993 of the known PDE families of isoenzymes as they were then classified along with their substrate specificity, their selective inhibitors and the human tissue in which they were located. He identified PDE V as found in lung platelets and blood vessels and the corpus cavernosum. He named its selective inhibitor as zaprinast.

86 It became apparent in the 1980s to pharmacologists and biochemists that PDEs had different tissue distributions. By 1992 Dr Gristwood knew that zaprinast was a selective inhibitor of PDE V. He also knew from the Rajfer paper, which he read before February 1993, that zaprinast enhanced smooth muscle relaxation of human corpus cavernosum tissue. He said:

‘From this information it was apparent to me that a PDE V enzyme was present in that tissue and played a functional role in the mediation of smooth muscle in human corpus cavernosum.’

He referred to Rajfer in a presentation he gave in Nice, France on 27 February 1993 on the cardiovascular effects of PDE inhibitors. Papers arising from the symposium were reproduced in the Excerpta Medica publication in 1993. Dr Gristwood said in his paper:

‘Since PDE V is specific for the metabolism for cGMP, it can be expected that the inhibitors of PDE V will potentiate the relaxant effect of the endothelium- derived relaxing factor EDRF (nitric oxide), which acts by stimulating guanylate cyclase. In fact some studies have demonstrated that zaprinast augments the responses which are dependent on nitric oxide.’

87 On reading Rajfer, Dr Gristwood appreciated that impotence was a new therapeutic possibility for PDE V inhibitors in light of the fact that zaprinast, a known selective PDE V inhibitor was shown to enhance smooth muscle relaxation of human corpus cavernosal tissue. The importance of PDE V in the erectile process emerged clearly from Rajfer. If he were looking for a new treatment for impotence, Rajfer would have strongly suggested to him the use of PDE V inhibitors. Having read the paper there was nothing to deter him from pursuing an oral delivery of a selected PDE V inhibitor as a treatment of impotence. The preferred mode of administration for a new medicine would always be oral. He knew, in 1993, that zaprinast had been administered orally in humans without adverse side effects. He expected that most people working in the field of PDE V inhibitors at the time would have been aware of this. In this respect he referred to the studies of the use of oral administration of zaprinast in patients with exercise-induced bronchial asthma reported in 1983, which he read in 1985. He also knew before June 1993 that selective inhibition of PDE V would only produce a narrow range of effects in vivo. This was because of its substrate specificity, its absence from important organs such as the heart and the fact that PDE inhibitors in general produce much less dramatic effects in vivo than activators of adenylyl or guanylyl cyclases. So although in 1993 he knew PDE V was present in tissues in the human body, he would not have been deterred from pursuing an oral route as the means of administration of a PDE V inhibitor as a treatment for impotence.

88 In cross-examination he accepted that the defect in the NANC pathway explored by Rajfer could occur at any point in it. If the defect lay in inadequate generation of NO the logical treatment would remedy that problem. That, however, would suggest using zaprinast to increase the efficiency of such NO as was generated.

89 Dr Gristwood also accepted that work beyond that undertaken by Rajfer would be necessary to ascertain whether relaxation from a PDE_V inhibitor working on basal levels of cGMP was going to be sufficient to achieve a usable erection.

90 Dr Gristwood referred to the Murray paper and its disclosure of the oral administration of PDE V inhibitors. Murray referred to actual human clinical trials of a selective inhibitor of PDE V against asthma where oral administration was used. The information he gained from reading Murray in 1993 was that PDE V inhibitors could be administered orally to humans and that they could be useful in the treatment of impotence. He said:

‘Given this information this is the only method of administration for PDE V inhibitors that I would have contemplated for treatment for erectile dysfunction. I would only have moved to other methods of administration if for some reason the oral route was ineffective.’

91 He agreed that the paper identified four therapeutic utilities and that there was nothing in the paper to identify a potential treatment for impotence as having greater prospectivity than the potential treatments for those other utilities. They were all ‘fair game’.

92 Dr Gristwood also referred to the Korenman paper. He knew in 1993 that pentoxifylline was a non-selective PDE inhibitor. From his reading of Murray ‘by definition’ the term ‘cGMP PDE V (PDE V_A) inhibitor’ included methylxanthine-non-selective PDE inhibitors such as pentoxifylline’.

93 In a second affidavit Dr Gristwood said that the phrase ‘a cGMP PDE V inhibitor’ had a clear meaning in 1993/94. It referred to compounds that inhibited cGMP PDE V also known simply as PDE_V or PDE V. The phrase embraced both selective and non-selective inhibitors so long as they had PDE V inhibitory activity. He found support for this conclusion in the Murray review which clearly used the phrase ‘PDE V_A inhibitor’ to include non-selective as well as selective PDE V inhibitors.

94 In January 1993 Dr Gristwood co-authored a publication in the British Journal of Pharmacology relating, among other things, to the PDE inhibitory activity of pentoxifylline. The purpose of the research reported was to examine in vitro bronchodilator effects of two selective PDE IV inhibitors and the PDE inhibitory activities of two non-selective PDE inhibitors, one of which was pentoxifylline. He expressed his opinion that pentoxifylline was a cGMP PDE_V inhibitor. He also said that, in his opinion, the term ‘cGMP PDE_V inhibitor’ as used in claim 10 of the patent covered both selective and non-selective inhibitors.

95 In a third affidavit, Dr Gristwood took issue with evidence given by Drs Fischmeister and Palmer in their comments on the Rajfer and Murray publications. Two possible treatments for erectile dysfunction presented themselves as a result of Rajfer. One was to increase the level of cGMP by increasing NO activation, eg by using an NO donor. The other was to increase the level of cGMP by preventing its breakdown by PDE V enzymes. This would involve the use of an agent inhibiting the action of those enzymes. That is to say of those enzymes, a PDE V inhibitor.

The Lilly Witnesses – (ii) Dr Cherry

96 The next Lilly witness, Dr Cherry, established the Perth Human Sexuality Centre in 1992 with the assistance of a urologist, Dr Alistair Tulloch. He had kept up to date with the development of erectile dysfunction pharmacotherapies since about 1987. Such pharmacotherapy had its origins in 1982 when a French vascular surgeon by the name of Virag reported for the first time an entirely pharmacologically induced erection caused by a papaverine administered by intracavernous injection. Before this discovery, papaverine was known as a non-selective PDE inhibitor which operated by increasing smooth muscle levels of secondary messengers such as cAMP and cGMP thereby causing a relaxation effect in smooth muscles. Virag’s discovery brought together two previously unrelated fields, namely vascular medicine and urology. Dr Cherry described the development of therapies for erectile dysfunction and the increasing understanding of the pathways for the development of erections. He read the Rajfer paper in late 1992. He regarded it as a ‘clincher’. It was a seminal paper that drew together for him much of the research to which he referred in his affidavit evidence. At the time he was working at the Reproductive Medicine Research Institute (RMRI) at Queen Elizabeth II Medical Centre, now called the Keogh Institute for Reproductive Medicine in honour of the late Professor Ted Keogh.

97 When Dr Cherry read the Rajfer paper he understood that zaprinast was a selective inhibitor of cGMP PDEs but not cAMP PDEs. The data presented allowed him to understand that by using a cGMP PDE inhibitor relaxation of smooth muscle in human penile tissue would be enhanced. Rajfer established to his mind the NO-cGMP pathway that was responsible for the human erectile response. He believed, following Rajfer, that all the basic elements for developing a new human pharmacotherapeutic for the treatment of erectile dysfunction via the NO-cGMP pathway were available in the scientific literature. He also referred to the publication in Science magazine in 1992 which described NO as the ‘Molecule of the Year’. He said:

‘In my opinion, all that was needed was for a pharmaceutical company to identify a compound that was capable of working systematically (when orally administered) to affect the NO-cGMP pathway and thereby affect the response of the smooth muscle in the penis, inducing relaxation and hence an erection.’

98 He agreed in cross-examination however that the paper was ‘essentially ... about nitric oxide in the NANC neurotransmission’. He did not think he had been familiar with zaprinast before reading the paper. He didn’t see it then as a PDE_V inhibitor.

99 Dr Cherry agreed that Rajfer’s statement that it was ‘conceivable’ that impairment of the L-arginine nitric oxide pathway could account for impairment in relaxation stimulated by electrical fields, was a ‘signal’ that Rajfer still thought himself at the early stage of an investigative process. He saw the Rajfer observation of the effect of the cGMP PDE inhibitor as:

‘... no more than an interesting observation ... the story between this and eventually arriving at a drug is a long and arduous task, but this is an observation that says, "Well, that’s interesting, there is further relaxation engendered by this product, maybe it has a role to play," maybe.’

He would not necessarily translate the results of an in vitro experiment to an in vivo situation. However Rajfer provided the ‘best ex vivo data that a researcher could obtain’.

100 Dr Cherry had not read the Murray paper prior to preparing his second affidavit in these proceedings.

101 He was asked to comment on the meaning of some terms used in the Patent. In particular he referred to the word ‘cure’ as indicating that a patient had been treated for a medical condition in such a way that the condition would not return or that the prospect of it returning was so long that there was no reasonable expectation of it returning during the lifetime of the patient. He expressed the view that Viagra neither cures nor prevents the disease that causes erectile dysfunction. It treats the disorder in such a way that an erection can occur. However the disease is still present after treatment.

102 In a second affidavit, Dr Cherry referred to the Korenman paper. That paper, he said, allowed him to understand and would also have done so in June 1993, that oral administration of pentoxifylline could be used for the treatment of erectile dysfunction. Murray would have allowed him to understand in June 1993 that a possible therapeutic use of PDE V_A inhibitors was a treatment for impotence.

103 In a further affidavit, Dr Cherry discussed the interest in erectile dysfunction by Australian practitioners in the field in 1993. Many urologists were more surgically oriented than he was. He was more pharmacologically or medically oriented. So far as he was aware in 1993, neither he nor any of his urologist colleagues had any capacity, either commercial or scientific, to explore future possible erectile dysfunction treatments based on information contained in the scientific literature. There was therefore no specific forum to discuss or develop basic research knowledge into a viable commercial or non-commercial proposition. He also gave evidence responding to other witnesses.

The Lilly Witnesses - (iii) Mr Pryor

104 John Pryor, a medical specialist in the field of uroandrology gave evidence, inter alia, that he had association with urologists from Australia before June 1993. There had been a close association between the Urological Association of Australasia and the British Association of Urological Surgeons for many years and since well before 1993. Based on his contact with Australian urologists, it was his opinion that their knowledge of urology was and continued to be similar to that of urologists in the United Kingdom.

105 He referred to publications and meetings in which the treatment of erectile dysfunction had been considered. Between 1982 and 1992 a better understanding of the physiological mechanism of erections meant that pharmacological treatment of erectile dysfunction became possible. For the first time it was clear to him that developing an improved oral drug to treat erectile dysfunction was a feasible proposition.

106 In cross-examination he characterised the Rajfer paper as the first of a whole series of papers explaining various elements of the ‘puzzle’ – a reference to the precise role of NO and how it was generated in the NANC pathway. The work was done primarily to demonstrate the physiological mechanism rather than with the aim of therapeutic treatment.

107 In December 1992 an independent panel convened by the National Institute of Health of the United States prepared a consensus statement on erectile dysfunction. It legitimised erectile dysfunction as a suitable area of medical practice. It made no reference to the use of cGMP PDE inhibitors in the treatment of that condition.

108 Had Mr Pryor been consulted in early 1993 by a company considering a program for the development of a cGMP PDE inhibitor to treat erectile dysfunction, he would have advised the priority development of orally active drug. The success of any drug would depend on its efficacy and safety. However, based on what he knew in June 1993, there was no reason not to believe that such a compound could be developed that would be both safe and efficacious. He also offered a construction of the word ‘cure’ as removing a disease condition. The way in which Viagra worked in respect of impotence or erectile dysfunction did not remove any underlying disease condition.

The Lilly Witnesses - (iv) Professor Charman

109 Professor Charman reviewed the Patent in the light of two questions which he was asked to address:

(a) Whether, and if so, how he could have identified a compound described in the Patent as a cGMP PDE V inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, that was orally effective to cure or prevent erectile dysfunction in man, within claims 9 and 10 of the Patent;
(b) Whether, and if so, how he could have identified a compound not described in the Patent as a cGMP PDE V inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, that was orally effective to cure or prevent erectile dysfunction in man, within claims 9 and 10 of the Patent.

He set out the various steps that he would have taken and concluded, on his review of the data in the Patent alone, that even if his investigations were limited to the nine ‘especially preferred compounds’ named, he could not be certain that he would be able to identify a compound described in the Patent as a cGMP PDE V inhibitor or a pharmaceutically acceptable salt thereof or composition containing either entity that was orally effective to cure or prevent erectile dysfunction in man. Moreover the resources required to identify a compound, not described in the Patent, which was such a cGMP PDE V inhibitor were only slightly less than for a completely new drug discovery program.

110 Professor Charman considered whether sildenafil citrate was described or referred to in the Patent or in the two British patents EP-1 or EP-2. With the exception of claim 8 there was nothing in the Patent that led him to conclude or even infer that a pharmaceutically acceptable salt was particularly desirable, let alone an organo-carboxylic acid salt, and specifically a citric acid salt. None of the nine named ‘especially preferred’ compounds are salts.

The Lilly Witnesses - (v) Dr McMahon

111 Dr McMahon began treating patients for erectile dysfunction in 1981. By June 1993, apart from the Australian Centre for Sexual Health of which he is Director, the only other established clinic in Australia was the Keogh Clinic in Western Australia. At that time the treatment options available were counselling, penile injection therapy, surgery or vacuum erection devices. Prior to June 1993 his treatment of choice was patient-administered penile injection therapy using papaverine. Papaverine was a PDE inhibitor which acted as a vasodilator. The work relevant to erectile dysfunction that was foremost in his mind before June 1993 was that of Dr Rajfer and Dr Peggy Bush. He attended a meeting in Washington of the American Urological Association in May 1992 when Dr Rajfer made a presentation in which he discussed the studies performed by his group using zaprinast on human corpus cavernosum. He was impressed and enthused by Rajfer’s presentation. One of the conclusions offered in the presentation was that there was a potential place for PDE V inhibitors as an oral treatment for erectile dysfunction. Dr McMahon recognised that an oral medication of a PDE V inhibitor, capable of reaching sufficient concentration within the corpora and being specific enough to penile PDE V isoenzyme, was a potential new erectile dysfunction treatment. He discussed the research and its oral application with Professor Keogh on his return to Australia. By September 1992 he understood that the mechanism of erection involved NO and cGMP as neurotransmitters and that PDE V enzymes had a regulatory function.

112 He agreed in cross-examination with the proposition that the Rajfer paper was about basic research as distinct from research in living human beings. The paper was about whether NO had a role to play in the NANC pathway. He could not say that any frequency of electrical stimulation of the tissue would have a direct correlation in the human body. The data from Rajfer pertained ‘purely to an organ bath study’. The level of relaxation demonstrated in the paper could not really be translated to the level of relaxation or the concentration of zaprinast necessary in vivo. He described the paper as a ‘proof of concept’ type paper. It suggested, inter alia, that there might be a potential role for zaprinast in the treatment of erectile dysfunction.

The Lilly Witnesses - (vi) Dr Kruse

113 Dr Kruse worked with Smith Kline & French Laboratories in the United States and subsequently in the United Kingdom. He was made Director and later Group Director of Medicinal Chemistry in that organisation. He remained with them until August 1989 supervising their 60 strong Medicinal Chemistry Department. In August 1989 he was recruited by Sterling Winthrop, then a subsidiary of Eastman Kodak, to be its Vice President of Chemical Research and Development. He was later appointed Senior Vice President and remained with that company until March 1995 when the company was sold to the French pharmaceutical company, Sanofi. At Sterling Winthrop he had responsibility for a large number of scientists.

114 Dr Kruse had connections with Australian scientists from about 1975 when he shared a laboratory bench at MIT with Dr James Reiss. In 1988 he presented a series of lectures at academic institutions in Australia. In 1986 his research group commenced working on PDE inhibitors. He did not discuss the details of that research when he visited Australia. He maintained contact with two Australian researchers through the 1980s. His Australian research colleagues appeared to him to be very knowledgeable about the literature in their scientific field.

115 Dr Kruse described the development of his own research in the field of PDE V inhibitors and his knowledge of them prior to 1993. In 1993 he knew the PDE family was a large and increasingly well characterised family of isoenzymes and that the field had moved to a rational categorisation based upon related protein sequence and catalytic function. He believed that the PDE area was ripe to bring forth novel therapeutic agents.

116 He learned about the NO pathway in the mid 1980s. In 1987 he read a paper that confirmed for him that NO was endothelium-derived relaxing factor and was a neurotransmitter. He was familiar with the 1992 Science journal article which named NO the ‘Molecule of the Year’. He read the article in December 1992 shortly after its publication. By June 1993 he knew that the release of NO from the endothelium caused a specific activation of guanylate cyclase which produced relaxation of vascular smooth muscle through elevation of cGMP.

117 Dr Kruse was given a copy of the Rajfer paper for the purpose of preparing his evidence in proceedings in the United Kingdom. He did not recall having read it at the time it was published. He believed however, given the significance of the information, that one of his co-workers at Sterling Winthrop had drawn it to his attention. Rajfer’s work illustrated that smooth muscle relaxation induced by NO is mediated through an increase in cGMP concentration and could be enhanced by the use of the cGMP PDE inhibitor, zaprinast. He was aware by 1992 that zaprinast was a selective inhibitor of PDE V. Importantly, from his perspective, Rajfer also used the most relevant experimental model possible, namely actual human penile muscle tissue from patients suffering erectile dysfunction. Because of that data he would have had a high level of confidence that Rajfer’s results would have been directly transferable to the in vivo human situation. The information from Rajfer would have made it clear to him in 1993 that there were two choices for manipulation of the NO cGMP pathway. One was to develop a compound which produced NO and the other was to inhibit the PDE enzymes known to hydrolyse cGMP. Both approaches would maintain the concentration of cGMP in the corpus cavernosum. He would, in June 1993, have approached the task of developing a therapeutic for treating impotence from Rajfer by looking for a cGMP PDE inhibitor like zaprinast or some analogue of it.

118 In cross-examination he acknowledged that there is no case in which one could take an in vitro experiment and jump to an efficacious dose in man. What could be done was to take the reasonable step of going forward with a PDE_V inhibitor and doing appropriate clinical trials.

119 Had he wished to pursue Rajfer teaching in June 1993 he would have focussed on oral administration as the preferred and most widely used route of administration. It best ensured patient compliance which meant a wider market. It also enabled delivery of pharmaceuticals in the home as opposed to a hospital setting.

120 Dr Kruse also referred to Murray. The technical information that he would have taken from Murray was that PDE V_A inhibitors could be used to treat erectile dysfunction and that they could be used orally for that purpose.

121 He then turned to a consideration of the Patent. The especially preferred list of compounds included sildenafil, but did not include sildenafil citrate which would be a pharmaceutically acceptable salt. The Patent did not actually identify which of the very many compounds within the compounds of the invention were in fact effective orally. He contended it was impossible to predict on the basis of structure whether a compound would work orally in humans. The Patent did not provide clear evidence that any of the compounds of the invention worked orally. Nor did it provide any information about dosage level.

122 Claim 10 did not disclose or describe which classes of PDE V inhibitors other than the compounds of formula (I) might be orally effective in humans. It provided no assistance as to the nature of such other PDE V inhibitors that might be of value in the oral therapy of erectile dysfunction. It was not possible to predict from the Patent that Tadalafil, the active ingredient of the Lilly product Cialis, would be an orally effective PDE V inhibitor in humans or would be useful in the oral treatment of erectile dysfunction.

123 In further evidence, Dr Kruse said he would have construed the term ‘cGMP PDE V inhibitor’ as meaning exactly what it says, that is a compound that inhibits cGMP PDE V to some extent. He understood the term to cover both selective and non-selective PDE inhibitors, the sole criterion being that they should inhibit cGMP PDE V. He referred to the Murray review which covered both selective and non-selective inhibitors.

The Lilly Witnesses - (vii) Professor Aversen

124 Philip Iversen is a former Professor of Statistics, employed at the time of trial by Eli Lilly & Company as Principal Research Scientist. He worked at Lilly as a Senior Statistician from 1994 until 1999. In connection with proceedings before the US Patent Office, Dr Iversen did a statistical analysis of data produced by Dr Vincent Florio concerning the inhibition by pentoxifylline of various PDE enzymes to see whether the data were statistically significant. He concluded, in effect, that there was a statistically significant difference between the effect of the IC₅₀ for the pentoxifylline action on PDE V and the IC₅₀ in respect of its action on the other PDEs. The experiments conducted by Dr Florio were carried out under his supervision by Mr Lothar Uher who also gave evidence.

The Bayer Witnesses - (i) Professor Brown

125 The first Bayer witness was Lindsay Brown, an Associate Professor in the Department of Physiology and Pharmacology at the University of Queensland. His principal area of research is cardiovascular pharmacology. A number of his published research papers were concerned with vascular smooth muscle. He studied the effects of a PDE_III called milrinone. He had been asked, in preparing his evidence, to explain what was known to him and to other Australian pharmacologists in June 1993 about the pharmacology of smooth muscle relaxation and more particularly penile erection. He was also asked to comment on what was disclosed in Rajfer and Murray and a paper by Trigo-Rocha et al entitled ‘Nitric Oxide and cGMP: mediators of pelvic nerve-stimulated erection in dogs’ which appeared in the American Journal of Physiology in 1993.

126 Professor Brown set out what he understood to be the basic general pharmacology knowledge in Australia in 1993 in the relevant area.

127 From 1987 NO was unequivocally known to be the mediator or messenger produced by endothelial cells which caused vascular smooth muscle relaxation. From about 1998 NO was described as a NANC nerve neurotransmitter. A review article published by Professor Rand in the Journal of Clinical and Experimental Pharmacology and Physiology in March 1992 described NO as the mediator of NANC nerve neurotransmission. He described it as activating the enzyme soluble guanylate cyclase in smooth muscle with a consequent increase in cGMP resulting in smooth muscle relaxation. The article included a section on penile erectile tissue. In that section Professor Rand set out the evidence for NO being the mediator of NANC nerve neurotransmission relating in penile erection. Professor Brown referred to Professor Rand’s review published in early 1992 and the conclusion in that review that:

‘The evidence for a nitrergic mechanism in tumescence of erectile tissue sheds new light on the observation that topical application of the nitrovasodilator glyceryl nitrate to the penis produces erection (Talley and Crawley 1985).’

128 At a meeting in Perth in 1991, Professor Brown attended a talk by Professor Black, Professor of Pharmacology at the University of Sydney, who spoke of NO as the NANC neurotransmitter in the airways. What she said in 1991 was well understood by Professor Brown as applying to smooth muscle anywhere in the body. That is to say NO was a key effector in smooth muscle relaxation. Smooth muscle was also relaxed when cellular levels of cAMP increased.

129 PDEs were well known as enzymes which broke down cyclic nucleotides which caused smooth muscle relaxation. They were drug targets with inhibition and various drugs were known to inhibit PDEs. There were known to be different types of PDEs found in smooth muscles in different locations in the body. Professor Brown was aware by 1990 of the families of PDEs designated I through V and of their sub-families. Compounds which inhibited PDEs were well known, at least to pharmacologists, as pharmacological agents. The selective PDE_III inhibitor milrinone had been used in cardiovascular medicine from the early 1980s. A non-selective PDE inhibitor, theophylline, had been used for many years in the treatment of asthma and acted through the relaxation of airways smooth muscle. Professor Brown described PDE inhibitors in the 1980s as ‘a hot topic in pharmacology as potential therapy for heart failure and in respiratory medicine’. He was generally familiar, from the mid to late 1980s, with the PDE_V inhibitor zaprinast which had been used in respiratory disorders. It was also well known to other Australian pharmacologists at the time. Prior to 1993 Professor Brown was aware that Pfizer had a development program to create novel PDE inhibitors based on theophylline for use as vasodilators in angina treatment. He also observed that before 1993 oral administration was the preferred way in Australia and internationally for the delivery of pharmaceutical agents.

130 Professor Brown read the Rajfer paper at about the time it was published. It was the type of paper in which he was particularly interested as a pharmacological study with clear clinical implications. The experimental method of adding a drug to an organ bath and measuring a response enabled inferences to be drawn about what was happening in the human body. When he read the paper Professor Brown assumed that the cGMP PDE inhibitor used was zaprinast. He based that assumption on the fact that zaprinast was the only PDE_V inhibitor which had been widely studied at the time.

131 Professor Brown referred to the last sentence of the Rajfer paper which said:

‘In view of the previous finding that electrically elicited relaxation of the corpus cavernosum is impaired in men with diabetes and impotence, interference with the L-arginine-nitric oxide pathway could be one cause of impotence that is treatable by the administration of direct-acting vasodilators.’

He regarded this as a strong statement even though expressed in conservative ‘science-speak’. Rajfer had shown that a direct-acting vasodilator also relaxed isolated cavernosal tissue. His study showed that interference with the NO pathway by PDE inhibitors and SNAP achieved this relaxation of cavernosal tissue. The reference to the vasodilator as ‘direct-acting’ did not imply any particular route of administration. It could be oral, intravenous or topical. Clinical use of direct-acting vasodilators in Australia and overseas prior to 1992 (for hypertension) was by oral administration. On this basis he believed Rajfer was referring to oral administration. He said:

‘Thus, what Rajfer is saying is to use an orally administered direct acting vasodilator which interferes with the L-arginine-NO pathway to treat impotence. The only direct acting vasodilators described by Rajfer were the PDE_V inhibitor and S-nitroso-N-acetylpenicillamine.’

132 According to Professor Brown, once it was known that smooth muscle relaxation is essential for penile erection, that such relaxation results from NANC nerves releasing NO to raise cGMP levels and that PDE V inhibition increases cGMP levels, it logically followed that one should use a PDE_V inhibitor to treat impotence. This was quite apparent to him and he believed it would have been quite apparent to other pharmacologists. He said:

‘The pharmacology in Rajfer shows that the PDE_V inhibitor potently relaxes the corpus cavernosum tissue, and it thus stands out to use the PDE_V inhibitor to relax penile smooth muscle to treat erectile dysfunction patients.’

His mindset, and he believed that of other pharmacologists, when faced with a biological pathway was ‘how can I modulate or manipulate this pathway to get a desired pharmacological outcome?’. The obvious pharmacological approach in the light of Rajfer was to use a PDE_V inhibitor as an orally active direct acting vasodilator interfering with the L-arginine NO pathway to relax the smooth muscle.

133 It was put to him in cross-examination that it was not possible from Rajfer to draw the conclusion that the reported effect of the PDE_V inhibitor in that case would be greater in penile tissue than in any other tissue in the body. He agreed. Rajfer had ‘only done penile tissue’.

134 Professor Brown agreed that by 1992 much less was known about cGMP PDEs than about cAMP PDEs. It was known that cGMP PDEs were present in large areas of the vascular system, in the retina, the penis and in the respiratory system.

135 He accepted that it was not known from Rajfer whether in vivo responses would be different nor whether an impotent man could generate enough NO for a cGMP PDE_V inhibitor to have a therapeutic effect. It was not possible to forecast from Rajfer whether a particular treatment would provide a solution, but one could so hypothesise and test the hypothesis and undertake a further research program.

136 Professor Brown also referred to the Murray review. Murray’s description of the selective actions of PDE V_A inhibitors was, in the context of systemic administration, such as oral administration where the PDE V inhibitor was distributed throughout the body but only had its action at a particular target tissue. The Trigo-Rocha paper, which was a follow-on study from that of Rajfer, supported the case made in Rajfer for the treatment of erectile dysfunction in a live animal model using a direct-acting vasodilator which was a PDE_V inhibitor.

The Bayer Witnesses - (ii) Dr Silver

137 The next Bayer witness was Paul Silver, Senior Director, Project Management, Neurosciences and Women’s Health at Wyeth Research. He had held a number of positions in the Pharmaceutical Research Division of Sterling Winthrop primarily as a pharmacologist. He had worked on the development of therapies for cardiovascular diseases. The compounds he worked on included an orally active PDE_V inhibitor for coronary angina with additional potential use in pulmonary disorders and impotence. He and his group had experimented using zaprinast as a comparator with other compounds being tested. From their results his team concluded that PDE_V inhibitors were more potent and selective than zaprinast. They tested their effects on the blood pressure of spontaneously hypertensive rats and dogs. A consistent finding in the dog experiments was that some of the PDE_V inhibitors produced penile erections in male dogs even when anaesthetised.

138 From about mid 1992 Dr Silver and members of his group appreciated that Sterling Winthrop’s PDE_V inhibitor compounds had the potential for treating impotence. They did not initiate any research program in that area because urology was not of great interest to the company at that time. Nevertheless, in an article which he and others wrote in late 1993 or early 1994, in the Journal of Pharmacology and Experimental Therapeutics, they expressly included impotence among the list of possible therapeutic uses for a Sterling Winthrop selective cGMP inhibitor known as WIN 58237.

139 At a talk which he gave in 1994 at the Conference of the Federation of American Society of Experimental Biology in California, Dr Silver discussed the potential use of PDE inhibitors for different conditions including impotence. He produced as part of his evidence a slide which summarised work by Professor Ignarro on corpus cavernosum tissue. He explained that Professor Ignarro’s group had shown that a deficit in NO could be the cause of impotence and therefore that either NO donors or cGMP PDE inhibitors could be used to treat impotence.

The Bayer Witnesses - (iii) Professor Scammells

140 Professor Peter Scammells is Professor of Medicinal Chemistry and Head of the Department of Medicinal Chemistry at Monash University. He was asked to comment on the Patent and the two European patents EP-A-0463756 and EP-A-0526004. Professor Scammels obtained his PhD in 1991. He was familiar with the class of compounds referred to in the Patent as pyrazolo[4,3-d]pyrimidine-7-ones. He had discussed them in the literature review section of his PhD thesis. He was aware during his PhD studies that such compounds had inhibitory activity against PDEs. He cited a reference from his thesis to that effect.

141 The Patent makes reference to the therapeutic uses of the compounds which it covered as having been described in the two European patents. There they are described as potent and selective inhibitors of the calcium/calmodulin-independent cGMP PDE and the calcium/calmodulin-dependent cGMP PDE. The potent and selective inhibition of both of the cGMP PDEs is said to be based on IC₅₀ values. The compounds in the European patents are described as orally administered.

142 Although the compounds described in the European patents were said to be orally administrable, the statement of the invention in the Patent did not define any mode of administration. Professor Scammells referred to the statement in the specification that:

‘Unexpectedly, it has now been found that these disclosed compounds [the compounds described in EP-A-0463756 and EP-A-0526004] are useful in the treatment of erectile dysfunction.’

In his opinion that statement was not limited to any mode of administration. Oral availability of a compound is strictly determined by its chemical structure. Versions of the Pfizer compounds involving ester or amide group substituents may not be orally active.

143 Professor Scammells described formula (I) of the Patent as being ‘of a very generic nature" and the descriptions of the groups R₄, R₅ and R₆ as ‘exceptionally broad’. He described the Patent as a ‘greedy grab’. He said that the meaning ‘cGMP PDE inhibitor’ is not defined anywhere. There is no description of the chemical structure or formula of any such compounds or whether the inhibitors are potent and selective inhibitors or not. The term ‘is as vague as it could possibly be’. Without a chemical structure for the compounds he could not tell what compounds are and are not cGMP PDE inhibitors, let alone how he would synthesize those unknown compounds. He asserted that if he were to undertake a search of chemical literature to try and determine what compounds were cGMP inhibitors which might be useful in treating erectile dysfunction, there were simply no criteria for any such search in the Patent apart from the reference ‘cGMP PDE inhibitor’. A researcher would be facing a drug discovery project to synthesize compounds within that class that he might find in a scientific paper or other reference, to test them pharmacologically and then test them in a model for erectile dysfunction before he could ascertain whether or not they were effective to treat erectile dysfunction. In Professor Scammells’ opinion the term ‘cGMP PDE inhibitor’ in claim 9 (as it then was) referred to any compound at all which inhibited a cGMP PDE to any extent. He then referred to the previous claim 10 and the reference in it to a cGMP PDE_V inhibitor. His comments applied equally to the use of that term. The compounds were not defined in any way chemically and their biological properties were undefined apart from the fact that they inhibit cGMP PDE_V. He said that claim 10 would include, in his opinion, any compound which inhibited cGMP PDE_V to any extent as well as any other PDE without any reference to potency or selectivity. His comments on the amended form of claim 10 were the same.

The Bayer Witnesses - (iv) Professor Goldie

144 Professor Roy Goldie, currently Executive Dean in the Faculty of Health Sciences at Flinders University in Adelaide also provided affidavit evidence for Lilly. He collaborated with the late Dr Ted Keogh on studies of penile tissue in 1982 and 1984. These involved investigation of the pharmacology of the erectile process and of the effect of different drugs on penile tissue and nerve systems in the corpora cavernosum. The object was to develop a model for human penile erection. The latter study was carried out on dogs. Its results were published in 1985 in the Pharmacological Research Communications entitled ‘Pharmacology of the Erectile Tissue of the Canine Penis’. The result was that the researchers had many of the components of the mechanism of NANC neurotransmission of penile erection but not enough information to fully elucidate it. They knew there were receptors for the NANC neurotransmitter, but did not know where they were. They suspected that they were on the smooth muscle tissue. The paper indicated that there were some agents already available that might be administered to therapeutic advantage in erectile dysfunction because they induced relaxation of the cavernosal tissue. These included vasointestinal peptide.

145 Against that background Professor Goldie set out what was known to pharmacologists in Australia about the pharmacology of penile erection in June 1993. The NO pathway and the five PDE enzymes were then very well known. The selective expression of the PDEs in different tissues of the body and the ability to target specific PDE isoenzymes provided a capacity to achieve a pharmacological result in one tissue without impacting adversely on another. The general approach was described by Beavo and Reifsnyder in a 1990 review paper and reflected what is and was then a basic pharmacological approach to finding new therapeutic agents. Professor Goldie was familiar at the time with milrinone and amrinone as selective inhibitors for PDE_III. He identified dipyridamole and zaprinast as selective PDE_V inhibitors at the time.

146 The New England Journal of Medicine in which the Rajfer paper was published is a clinical peer-reviewed journal which, according to Professor Goldie, is widely read by medical scientists, including pharmacologists. It is one of the best places to publish clinically oriented research. He had a copy of Rajfer in a stack of photocopied papers outside his office which indicates he read the paper and copied it for general interest or teaching purposes or both around about the time it was published. He said:

‘The overall message from the Rajfer et al paper is that NO released by NANC nerves is essential to penile erection. It also clearly sets the scene for clinical intervention to treat impotence with substances which act on the NO pathway, either as an NO donor or as a cGMP PDE inhibitor.’

147 Professor Goldie referred to the statement in the Rajfer paper that interference with the L-arginine-nitric-oxide pathway could be one cause of impotence treatable by the administration of direct acting vasodilators. He said that what really leapt out of that conclusion for him was the suggestion that a direct acting vasodilator could be used to treat impotence via action on the NO pathway which is critically important to penile erection. He said:

‘The use of a cGMP PDE inhibitor appears to me to be what is meant in this context. ... This section of the paper describes that an 84 to 96% increase in relaxation of corpus cavernosal smooth muscle tissue was seen in impotent men using a cGMP PDE inhibitor.’

In cross-examination Dr Goldie said that in learning about the paper some people would say ‘"Aha" .... in addition, what we ought be doing is looking at the potential for PDE 5s (sic) as a potential therapy’. He was not saying that was his reaction. However other people who read the paper at the time might well have picked up on the fact that zaprinast had been doing a good job of relaxing a quite strongly contracted preparation and ‘made that leap these authors weren’t prepared to make.’

148 The 1993 Murray review reiterated and reinforced what was in the Rajfer paper. According to Professor Goldie it clearly provided the rationale for using PDE V_A inhibitors in treating impotence.

149 Professor Goldie also undertook an examination and review of the specification and claims in the Patent. He said that it was meaningless to talk about something being simply a ‘cGMP PDE_V inhibitor’. He said:

‘You have to go further and specify the relevant concentration in order to speculate on its likely potency as an inhibitor. This is generally defined as the IC₅₀ which gives you the molar concentration at which you can expect 50% of the enzyme to be inhibited. Even then, potency alone of an inhibitor does not indicate whether that compound would be selective.’

He contended that the Patent simply claimed what Murray had recommended, that is the promising potential of PDE_V inhibitors in the treatment of impotence.

150 Professor Goldie also gave affidavit evidence in response to affidavits filed by Pfizer witnesses.

The Bayer Witnesses - (v) Dr Cartmill

151 Dr Ross Cartmill is a Urologist who practises in Brisbane. He discussed the general state of knowledge of erectile pharmacology in the early 1990s. He referred to a paper by Dr Peggy Bush et al entitled ‘Comparison of nonadrenergic, noncholinergic and nitric oxide-mediated relaxation of corpus cavernosum’ published in the International Journal of Impotence Research (1992) 4, 85-93. That study compared the effects of NANC stimulation and NO on rabbit corpus cavernosum. It reported that responses to electrical field stimulation and NO in precontracted strips of rabbit corpus cavernosum were enhanced by zaprinast and inhibited by haemoglobin. Dr Bush referred to the Rajfer paper which had been published earlier in the year. Dr Cartmill had not read the Rajfer paper before his preparation for these proceedings. He said that the use of cGMP PDE inhibitors to treat impotence stood out from Rajfer as an obvious thing to do from a urological perspective. Drug development would, of course, have to follow. The European Patents, known as Bell 1 and Bell 2, spoke of compounds useful in the treatment of peripheral vascular disease. Given the incidence of peripheral vascular disease in impotence he would have expected that the compounds of Bell l would have use in treating erectile dysfunction associated with vascular disease of the penis.

152 In relation to oral treatment, he noted that before 1993 non-surgical treatments were principally intracavernosal. Such treatment was clearly disadvantageous in the sense that patients would rather take a tablet. In his opinion a goal for non-surgical patient therapy for erectile dysfunction in 1993 was a tablet rather than an intracavernosal injected substance.

The Bayer Witnesses - (vi) Dr Warrington

153 Brian Warrington, the Vice President Technology Development UK for GlaxoSmithKline plc (GSK), worked with Smith Kline & French (SKF) from November 1965. Through a sequence of mergers it became GSK. He gave evidence of research programs in which he had been involved. From 1986 SKF ran a program investigating possible therapeutic treatments by PDE inhibition. He ran the PDE program in the UK from 1998 until it was closed down in 1992. In the UK, SKF focussed on PDE V inhibitors. In the US it was investigating PDE IV.

154 In the course of the PDE V program a large number of compounds were prepared as potential PDE V inhibitors. Some 500 structurally congruent compounds exhibiting PDE inhibitory activity were made using zaprinast as the starting point. The more promising compounds became the subject of a number of patent applications. In the course of the program they considered as potential applications of their PDE V inhibitors a number of areas including male penile erectile dysfunction.

155 In a document which he prepared in August 1992, Dr Warrington noted that PDE V_A inhibitors could potentially be used for treating impotence. He wrote at the time:

‘Potential uses were perceived to be as bronchodilators in asthma or spasmolytics in IBS provided sufficient selectivity for these effects over general vascular effects could be achieved. Other possibilities (not explored) were urinary incontinence and impotence.’

IBS refers to irritable bowel syndrome. The focus of SKF’s research was in this area because it already had relevant existing expertise and knowledge. However, according to Dr Warrington, other potential therapeutic applications for PDE V inhibitors were kept in mind including male penile erectile dysfunction.

156 In another paper which he prepared in July 1992, Dr Warrington discussed PDE V_A inhibitory activity for the purpose of assisting the SKF Patent Department in the preparation of a patent specification. In the course of that paper he said, referring to the PDE V_A inhibitors:

‘The compounds have smooth muscle relaxant activity and may be useful in the treatment of urinary incontinence or impotence. In such treatment, the compound may be administered by any suitable route, eg by the oral, respiratory tract, parenteral or topical routes, in manner known per se.’

157 In September 1992, SmithKline Beecham, as SKF had become, decided to cease all gastrointestinal work throughout the company. The entire PDE V program was categorised for management as being gastrointestinal despite its potential application to conditions outside that therapeutic area.

The Pfizer Witnesses - (i) Peter Ellis

158 Doctor Ellis is Executive Director of Exploratory Development in Pfizer. He holds a doctorate in pharmacology from the University of Edinburgh. He was employed from 1981 to 1984 as a Deputy Team Leader in Discovery Biology of Pfizer at its premises in Sandwich. From 1985 he was a Team Leader and from 1992 to 1994 a Section Head overseeing several teams.

159 He described the progress of the project which led to the discovery of the compound, sildenafil monocitrate, known within Pfizer as UK-92,480. The project began in 1986. At the outset it was directed to finding an anti-hypertensive drug that relaxed blood vessels and increased renal excretion of fluid and sodium. In late 1998 it changed direction and involved investigation of a possible agent for the treatment of stable and unstable angina. In 1993 when the angina project was about to be closed as a consequence of limited efficacy and report of lower back pains experienced by patients and volunteers, the compound UK-92,480 was tested on a small scale patient trial as a treatment for male erectile dysfunction. Following the success of that trial the project changed focus again to the development of a treatment for male erectile dysfunction. Dr Ellis set out the progress of the project in some detail in his affidavit. It is not necessary to reproduce that detail here.

160 By July 1990 Dr Ellis and his co-workers knew that UK-92,480 was a cGMP PDE_V inhibitor. They also knew that it was orally bioavailable in rats and dogs. It had a predicted oral bioavailability in man of 70% and a half life of five hours. In late 1989, according to Dr Ellis, they knew that UK-92,480 enhanced EDRF-dependent vascular smooth muscle relaxation in blood vessels. The potential of EDRF in mediating erection was not yet elucidated.

161 In or around mid to late December 1991, Per Andersson of the Pfizer Urogenitals group arranged for UK-92,480 to be sent to test its erectile activity under the Gorm Wagner monkey model in Copenhagen. This model for erectile response involved intracavernosal injection of a drug into the penis of an anesthetised monkey. A ligature was placed around the penis prior to injection. A short time after injection the ligature was released to see whether or not the drug had produced an erection.

162 In January 1992 the hypertension task force of which Dr Ellis was a member reported to the Discovery Leadership on new approaches to the treatment of hypertension. One of those approaches involved the identification of an orally delivered NO releasor. There was a brief reference, in the appendix to the report, to the potential for an NO releasor to be of assistance in the treatment of impotence. The report set out the team’s understanding of the physiological explanation of impotence as a failure to produce adequate quantities of NO in the penis. The hypertension task force recommended that NO releasing agents be tested in animal models of impotence. At that time UK-92,480 was still awaiting evaluation in the Gorm Wagner monkey model.

163 Dr Ellis received a copy of the Rajfer paper in January 1992. He did not recall whether he had seen it prior to its circulation by Dr Ringrose. Its circulation did not cause a stir within the project team as Dr Ringrose frequently circulated literature. However Dr Brown, the Manager of Pfizer’s Chemistry Group at the time, wrote on a yellow Post-it note attached to the Rajfer article:

‘UK-92,480 is going to Wagner for ic dosing to his monkeys – scheduled for next week I believe. No ‘beneficial S/E’s’ were reported to the ECMT but I’ll check again with Clinical.’

164 At the time Dr Ellis was aware from other papers that penile erection required relaxation of the corpus cavernosum and that smooth muscle contained NO synthase which produced NO which in turn produced cGMP. He knew this to be true for a variety of smooth muscles, including the corpus cavernosum from animal species. He said that what Rajfer reported was evidence for the presence of one pathway only, NANC (NO as neurotransmitter), but provided no data to suggest an intervention in that pathway would overcome the other pathways operating and have any effect on erection in an intact physiological system if there were a defect in another pathway.

165 In March 1992 Per Andersson informed Dr Ellis that the results of the testing in the Gorm Wagner monkey model were negative. UK-92,480 did not elicit a significant erectile response. From this testing Dr Ellis and his team concluded that further investigation of UK-92,480 as a potential treatment for erectile dysfunction was not warranted.

166 In March 1992 Pfizer commenced a double blind placebo controlled multiple dose study of UK-92,480 in 36 healthy male volunteers, designated ‘Study 207’. It was carried out by Simbec, a clinical research organisation under the supervision of Dr Allen. On 14 and 15 May 1992 a report was prepared of a monitoring list including a list of adverse events. It was reported that some volunteers had suffered miscellaneous aches and muscle pain (myalgia), some had suffered headaches and there were reports of spontaneous erections. Subsequent discussion of the drug focussed on the myalgia problem. A later study, ‘Study 211’, which was commenced in October 1992, reported spontaneous erections in five out of seven subjects.

167 Dr Ellis discussed pursuing UK-92,480 for the treatment of erectile dysfunction as he believed it was worthwhile. The drug was first formally considered as a potential treatment for impotence at a meeting held on 26 June 1992. It was followed up by Dr Allen on 4 August 1992. He prepared a planning document proposing clinical studies necessary to evaluate the drug as a treatment for impotence. Study 350 was commenced in July 1993 after being twice postponed. Sixteen impotent patients with no known organic cause for their impotence were studied. They were dosed three times a day. They were admitted to a private hospital and were connected to a device used to measure the rigidity and duration of penile erection (Rigiscan). They were shown a pornographic video before they retired to bed. In November 1993 Dr Allen reported that efficacy against impotence was shown through the patients’ diaries and with the Rigiscan measurements. There was some evidence that an improvement in erectile dysfunction was noted on the first day of dosing. This raised the possibility that UK-92,480 might be effective when administered in single doses.

168 In February 1994 Dr Ellis moved from Pfizer’s Biology Group to Clinical and at the same time the UK-92,480 program was passed to the Urogenital Group. Dr Ellis said that by June 1993 they understood that UK-92,480 was effecting an erection through inhibition of a high affinity cGMP metabolising enzyme, either PDE_I or PDE_V. He asked Mr Burslem to determine the mechanism that was at work. Mr Burslem reported his preliminary results on 1 March 1994. He reported three PDEs present in the corpus cavernosum with the greatest activity being that of PDE_V. Mr Burslem found that UK-92,480 was a potent inhibitor of PDE_V. It was more than 10,000 times more selective for PDE_V than for other PDEs present in the human corpus cavernosum. His memo noted that PDE_V inhibition most likely represented the mechanism of action underlying the efficacy of UK-92,480 in impotence.

169 A further study was carried out in February 1994 using twelve patients given three escalating doses of the drug and the placebo in random order with at least three days in between each dose. They were subject to visual sexual stimulation while being monitored by a Rigiscan device for periods of three hours. Initial reports in May 1994 indicated that there may have been a dose related increase in rigidity at 10mg, 25mg and 50mg. However the erectile response was modest and only of short duration. A complete patent specification was lodged on 13 May 1994. At that time Dr Ellis believed that the data available and properly tested supported chronic three times a day dosing as the most effective in providing treatment for erectile dysfunction.

170 In a second affidavit Dr Ellis reviewed the Korenman paper. He pointed out that pentoxifylline was not described as a PDE_V inhibitor in that study. He attacked its reliability noting that more than half (53 out of 90) of the successful episode data reported in the study related to one patient. To achieve IC₅₀ for pentoxifylline against PDE_V the dose would have to be at least 100 times higher than the dose administered in Korenman. It would not be possible to administer that amount as the highest reported dose of pentoxifylline in a man, which was 80mg/kg (about 5.6 grams to a 70 kg man), produced severe side affects including convulsions and loss of consciousness. Pentoxifylline was ineffective as an inhibitor of PDE_V at clinical concentrations and did not even approach the required threshold for activity demonstrated by other PDE_V inhibitors.

The Pfizer Witnesses - (ii) Michael Allen

171 Dr Allen is Vice President of Pfizer Global Research and Development and Head of Exploratory Development at the Sandwich Laboratories. Since July 2003 he has been the Genitourinary and Gastrointestinal Therapeutic Area Leader for Worldwide Development. He first became aware that the Pfizer Discovery Group was developing a compound UK-92,480 as a possible agent for the treatment of angina in July or August 1989. This was shortly after he joined Pfizer. He described the history of the project relating to the UK-92,480. Much of it was as covered in Dr Ellis’ evidence. In late July 1992 Dr Allen had his first discussion with Mr Gingell, a consultant urologist, about the possible trial of UK-92,480 as a treatment for erectile dysfunction. In early August 1992 he attended an Early Candidate Management Team (ECMT) meeting and reported on the ongoing clinical trials for the drug. The meeting was losing its enthusiasm for the angina project at that stage. A well tolerated dose could not be found that reached the target plasma concentration without accompanying incidents of myalgia.

172 In August 1992 Dr Allen was given approval to conduct a small clinical trial to assess UK-92,480 as a potential oral treatment for impotence. The trial was scheduled for January 1993. On 18 August 1992 he contributed to a status report to the ECMT. He reported on spontaneous erections experienced by volunteers in Study 207 following his report on dose related myalgia. He referred to Study 211 in October 1992 in which spontaneous erections were recorded. This Study was related to determination of the operation of a slow release preparation and its effect on the incidence of myalgia.

173 The first erectile dysfunction trial of UK-92,480 was Study 350. The protocol was developed by Dr Allen and Mr Gingell in 1993. The study commenced in July 1993 involving sixteen patients with erectile dysfunction. At the conclusion of the Study it appeared that UK-92,480 taken as a three times a day dose of 25mg improved erectile function. At a meeting held in August 1993 it was decided to put all studies involving the drug for angina indication on hold. Clinical work continued on the drug in relation to its possible effects on impotence.

174 A second erectile dysfunction trial, Study 351, was commenced in March 1994. The early results were encouraging. They were reported to the ECMT on 10 May 1994 by a Dr Boolell.

175 In a second affidavit, Dr Allen offered a critique of the Korenman paper to substantially the same effect as that offered by Dr Ellis.

The Pfizer Witnesses - (iii) Martyn Burslem

176 Mr Burslem is Executive Director, Discovery Biology of Pfizer. He generally verified Dr Ellis’ affidavit so far as it related to things he had done. He was aware, early in 1988, of mixed reports in the literature on whether PDE_I was the only PDE enzyme in vascular smooth muscle. There were reports of both PDE_I and PDE_V. Zaprinast, which was weakly selective for PDE_V over PDE_I, was commonly used to test for cGMP PDE activity. Its weak selectivity explained the mixed reports in the early literature. He hypothesised that PDE_V were present in smooth muscle and proposed to isolate it to compare the potency of Pfizer’s inhibitors against it and their activity in vascular smooth muscle.

177 In pursuit of this proposal Mr Burslem studied PDE enzymes in rabbit platelet cells. At this time the project with which he was concerned sought to potentiate antral natriuretic factors (ANF) in the kidney with a view to treatment for hypertension and heart failure. The emphasis of the inquiry in so far as it related to therapeutic applications of cGMP PDE inhibitors shifted to the treatment of angina early in 1989. UK-92,480 was screened, apparently for the first time in May 1989, and found to be ‘... the most potent and selective PDE_V inhibitor of the compounds tested in that screening round’.

178 Mr Burslem was involved with studies of the operation of UK-92,480 until January 1992 when he became Team Leader of the Pfizer Cardiovascular Biology Group. He continued as an ad hoc member of the ECMT until mid 1993. He was asked by Dr Ellis in February 1994 to isolate and characterise the PDE isoenzymes in the human corpus cavernosum. He was not aware then of any reported investigations on that question. In a memorandum written in March 1994 about the preliminary results of his isolation and characterisation work, he reported three PDE isoenzymes in human corpus cavernosum tissue. cGMP specific PDE_V was predominant. He was surprised to find that PDE_V was the peak PDE.

179 As at 1992 the reports of erectile responses to orally administered UK-92,480 were unexpected so far as Mr Burslem was concerned. He thought that any vasodilator given systematically would give rise to major hemodynamic changes well before any erectile response was detected. He said:

‘It was surprising and unexpected to me to discover subsequently in 1994 that the human corpus cavernosum was rich in PDE_V when compared with other smooth muscle. This explains how, upon generation of nitric oxide as a consequence of sexual stimulation, a PDE_V inhibitor present at a concentration which is sufficiently low that it does not cause any major hemodynamic effect can nevertheless lead to an improvement in erectile response.’

The Pfizer Witnesses – (iv) Richard Palmer

180 Dr Palmer is Chief Executive Officer of Alizyme plc, a drug development company based in Cambridge in the United Kingdom. He has held senior positions in pharmacological research in Wellcome Foundation and Glaxo Wellcome. Alizyme plc of which he is now Chief Executive Officer, is a speciality pharmaceutical development company.

181 After reviewing the history of developing understanding of the function of NO in smooth muscle relaxation he made the point that it is one thing to know that NO is an important mediator which contributes to a particular physiological effect. However, translating this into a potential target and getting a therapeutic agent out of it is an entirely different matter. He thought it ‘worth a try’ in the late 1980s and early 1990s to use highly selective PDE inhibitors as therapeutic drugs to lower blood pressure. But:

‘To be able to use one to treat a specific problem in a specific tissue, as is the case with erectile dysfunction, without creating masses of other undesirable side effects is a surprise.’

It seemed to like ‘serendipity’ that sildenafil, developed for the treatment of angina, happened to favourably affect men with erectile dysfunction without other effects.

182 Dr Palmer reviewed a number of articles including the Rajfer paper. He noted that the paper left unanswered the question whether increasing relaxation by a high concentration of zaprinast would be capable of facilitating a usable erection. In his opinion the data in the paper would not lead one to attempt to treat impotence with zaprinast or to develop another cGMP PDE inhibitor for this indication by first intent. He took issue with different conclusions offered by other witnesses. He made the point that Rajfer was oriented to show that the L-arginine/NO/cGMP pathway was involved in NANC relaxation. The cGMP PDE inhibitor was ‘merely another tool, together with L-nitroarginine and methylene blue, to support the conclusion that NO is the NANC transmitter responsible for relaxation of this tissue preparation’.

183 The Murray paper suggested there was potential for selective PDE_VA inhibition. However it was not possible to predict from it whether there would be any therapeutic use assuming that new inhibitors could be created based on that rationale.

The Pfizer Witnesses - (v) Rodolphe Fischmeister

184 Dr Fischmeister is Director of Research of INSERM in France and Head of the Cellular and Molecular Cardiology Laboratory in the Faculty of Pharmacy of the University of Paris-Sud.

185 Dr Fischmeister said that the term cGMP PDE_V inhibitor conveyed to him that the inhibitor was more selective for a PDE_V than for any other known inhibitor.

186 In reviewing the state of scientific knowledge in 1993/94 Dr Fischmeister said that in 1994 as an experienced scientist in the PDE field he would not have understood Rajfer to be referring in any way to the use of PDE inhibitors to treat erectile dysfunction orally or otherwise. The results of the experiments conducted by Rajfer gave good grounds for the view that NO was involved in the relaxation of corpus cavernosum tissue.

187 Dr Fischmeister did not find support in the Rajfer paper for the inference drawn by Murray that zaprinast alone caused a relaxation and enhanced that caused by NO or electrical stimulation. After reviewing a number of papers he said that the concept of using a cGMP PDE_V inhibitor as a therapeutic agent for erectile dysfunction was not straightforward in 1993. The possibility that such an inhibitor could achieve an effect as an accelerator like NO required consideration of the possibility that muscle cells in the corpus cavernosum had a significant basal production of cGMP. This was ‘...certainly not an obvious issue’.

The Pfizer Witnesses – (vi) Alan Robertson

188 Dr Alan Robertson of New South Wales was the Chief Executive Officer of Pharmaxis Ltd. He did his doctorate in synthetic organic chemistry. He described himself as a ‘medicinal chemist’ which is ‘a scientist who conceives new molecules with a view to achieving a given therapeutic effect’. He expressed the view that in 1992 there was simply not the same kind of depth of pharmaceutical research in Australia as in the Northern Hemisphere. There was no research in Australia at a high level of scientific knowledge in the area of EDRF and NO relevant to the present case.

189 Dr Robertson gave extensive evidence about how he would put the Patent into effect based upon the specification and claims in it. In so doing he responded to difficulties raised by some other witnesses. He also undertook a review of the prior art. He observed that the Rajfer paper did not disclose where the problem (if there were one) in the NO pathway, occurred in the case of erectile dysfunction. The Murray article did not suggest how a drug might be developed for relaxing a specific smooth muscle in a specific organ without affecting other smooth muscle in the body. For a scientist reading the Murray article prior to the Pfizer invention, impotence would simply be one of the possible therapeutic targets mentioned, with a lot more research to be done on them.

The Pfizer Witnesses – (vii) Donald Moss

190 Donald Moss is a Urologist working in Ballarat. He was President of the Urological Society of Australia in 1998 and 1999. He said that before the Viagra mode of action was publicised, neither he nor anyone with whom he spoke connected PDEs or PDE inhibitors with a treatment for erectile dysfunction. In 1994 it was clear that NO had an important role in the corpus cavernosum, but even as late as September 1994, at a meeting of the Societie International D’Urologie (SIU) in Sydney there was no consensus on the specifics of the mechanisms for erection. His first awareness of the possible clinical relevance of PDE and PDE_V inhibitors was at a meeting he attended in Paris in 1996. He did not recall reading the Rajfer paper. He thought he might have consigned it to the ‘yes that’s interesting but of no import to me’ bin.

191 Dr Moss was of the view, contrary to that of Dr Pryor, that as far as he and other Australian urologists were concerned in the early to mid 1990s they did not have the knowledge of theoretical concepts and research disclosed in Dr Pryor’s affidavits.

The Pfizer Witnesses – (viii) Zdzisilaw Wisniewski

192 Dr Wisniewski is a Clinical Urologist. He describes his expertise as that of ‘a surgeon providing a clinical practice for patients and frequently surgical intervention for erectile dysfunction and other penile disorders’. Referring to Rajfer’s paper and other publications in 1991 and 1992 he said that he understood from them that NO was accepted as a neurotransmitter for erectile tissue and part of the NANC pathway. He also remembered reading that smooth muscle relaxation was mediated through an increase in cGMP. Neither he nor anyone he spoke to in Australian urology circles made the connection between the NO/cGMP pathway and the possible oral treatment for erectile dysfunction. He also disagreed with Dr Pryor’s evidence about the knowledge of Australian urologists at the time.

193 Rajfer’s paper did not talk about PDE_V inhibition to the level of saying there was an oral therapy that might work. He did not see Viagra as having stemmed from Rajfer’s work.

The Pfizer Witness – (ix) Steven Pittler

194 Dr Pittler is a Professor in the Department of Physiological Optics and the Department of Ophthalmology at the University of Alabama in Birmingham. His particular interest lay in the role of PDEs in retinal tissue. He said that the term cGMP PDE inhibitor in claim 10 of the Patent indicated a greater selectivity for inhibiting cGMP PDE_V than for inhibiting any other cGMP PDE known at the time. He also reviewed the evidence of a number of other witnesses.

The Pfizer Witnesses – (x) Ciara McKenna

195 Ciara McKenna is the Marketing Manager for Endocrinology/Gastroenterology/Urology/Ophthalmology for Pfizer. At the time of the trial she had held that position for over 18 months.

196 She said that Viagra had been granted regulatory approval in the USA on 27 March 1998. In the week ending 24 April 1998, which was its fourth week of release in the USA, it was reported that around 206,246 prescriptions had been filled for it.

197 In 1998 more than 200,000 physicians wrote more than 7 million prescriptions for more than 50 million tablets of Viagra for more than 3 million patients. On 1 May 1998. Viagra had taken a 94% share of all dispensed new prescriptions for erectile dysfunction products. That year gross sales in the USA amounted to $US718 million. She set out a table showing sales in subsequent years. In 2004 to July, the gross sales were $US0.549 billion. Since the grant of marketing authorisation for Viagra in the European Union in September 1998 it enjoyed similar commercial success. It has since obtained marketing approval in over 100 countries.

198 Viagras annual sales of $US1.7 billion comprised 92% of the $US1.8 billion worldwide market for erectile dysfunction therapies in 2002. It was the 25^th highest selling prescription drug by worldwide sales in 2002. Ms McKenna also set out worldwide sales figures.

199 Viagra was given marketing approval in Australia in September 1998. Its gross sales were $28.9 million in 2003 and were forecast to be $26.3 million in 2004.

The Reasons for Judgment at First Instance

200 The learned primary judge reviewed the physiological and biochemical processes involved in the erectile functioning of the penis as discussed in the Pfizer and Lilly primers. He set out the relevant terms of the Patent and summarised the contents of the Rajfer, Murray and Korenman articles. His Honour then dealt with the issues before him by formulating and discussing a series of questions which he had to decide.

201 The first of the questions was constructional, namely the meaning of ‘cGMP PDE_V inhibitor’ in claim 10. Pfizer contended that the term referred to a PDE_V inhibitor which was selective for PDE_V. Lilly’s submission was that it referred to any inhibitor that had any activity against PDE_V regardless of whether it was more or less selective for that PDE than any of the other known PDEs.

202 His Honour observed that as a matter of ordinary language the term ‘cGMP PDE_V inhibitor’ in claim 10 conveys the concept of a substance identified only by the presence of a particular function or capacity, namely that it inhibits cGMP PDE_V. Pfizer’s construction involved reading a limitation or qualification into the ordinary language so that the reader would understand that the author of the document was intending to convey a narrower meaning. He referred to Herbert Adams Pty Ltd v Federal Commissioner of Taxation [1932] HCA 27; (1932) 47 CLR 222 and cited Dixon J at 228-229:

‘... it is always less difficult to show that a word has a wider meaning than it is to establish a specialized use. For an extension of meaning involves no abandonment of the use in respect of things to which it would in any case apply; but a uniformly restricted application among any class of persons is necessary in order to establish that it has among them a narrower meaning and that meaning only.’

His Honour regarded the ‘linguistic logic’ of the passage as compelling particularly once it appeared that the suggested narrower meaning was not a matter of uniform expert opinion or usage and not consistent with the language of the document as a whole.

203 His Honour referred to expert evidence relied upon by Pfizer noting that evidence as to the meaning of technical terms is admissible although the construction of the specification is a matter of law and belongs to the Court. There was evidence of usage supporting Lilly’s view. The word ‘selective’ was commonly used to identify the PDE against which an inhibitor has the most activity. If Pfizer’s strictly were correct, the term ‘selective PDE_V inhibitor’ would be tautologous. There was evidence that the term was often used if context required it. Indeed Pfizer had done so in its Canadian Viagra patent in which claim 25, corresponding to claim 10 in the Patent, claimed ‘The use of an effective amount of a cGMP PDE inhibitor ... wherein the cGMP PDE inhibitor is a selective inhibitor of cGMP-specific PDE_v.’ Similarly, claim 24 of the Pfizer US patent spoke of ‘an effective amount of a selective cGMP PDE_V inhibitor’. His Honour concluded that where the context was appropriate the qualifier ‘selective’ could be used in conjunction with ‘cGMP PDE_V inhibitor’. He also found support for Lilly’s contention in the context of the Patent. He concluded that while sometimes ‘cGMP PDE_V inhibitor’ may, without more, connote an inhibitor selective for PDE_V in claim 10, when read in the context of the Patent as a whole it did not.

204 The next question was as to the priority date of claim 10. It was accepted by Pfizer that the priority date was 13 May 1994, which was the date of filing of the PCT application.

205 His Honour then turned to the attack on claim 10 based on want of novelty. He referred to s 138(3)(b) and s 18(1)(b)(i) of the Act as well as the statutory definitions of the concepts of novelty and prior art base found in s 7(1) and the Dictionary in Sch 1 of the Act. He referred to the discussion of the authorities on novelty by Black CJ and Lehane J in Bristol-Myers Squibb Company v FH Faulding & Co Limited [2000] FCA 316; (2000) 97 FCR 524 and observed (at 24 [90]):

‘For present purposes it is sufficient to say that the question is whether the alleged anticipation would, if the patent were valid, constitute an infringement (the "reverse infringement test"). Where the alleged anticipation takes the form of a publication (a "paper anticipation"), the hypothetical infringement does not arise because of the publication per se; rather one asks whether the publication teaches, in the sense of directing, recommending or suggesting, the invention under consideration.’

He cited a passage from the judgment of the Privy Council in Canadian General Electric Co Limited v Fada Radio Limited [1930] AC 97 at 104:

‘... it is not enough to prove that an apparatus described in an earlier specification could have been used to produce this or that result. It must also be shown that the specifications contain clear and unmistakable directions so to use it.’

His Honour then set out a number of questions and answers relevant to the novelty issue. It is not necessary to set out all of those questions here but rather the conclusions at which he arrived in responding to them.

206 His Honour found that the Murray paper did not teach the use of a cGMP PDE_V inhibitor to treat impotence. Its pervading tone was hypothetical, cautious, abstract and speculative. It gave no particular prominence to the treatment of impotence among potential users of cGMP PDE_V inhibitors. If, contrary to his conclusion, Murray taught the method of claim 10, that teaching would be taken to include oral administration.

207 It was common ground that the Korenman paper was publicly available before the priority date of claim 10, which was 13 May 1994. The Korenman study was carried out to test the possibility that pentoxifylline would be effective in improving blood flow through the penis thereby facilitating the erectile process. It taught away from the pith and substance of claim 10 of the Patent which was the use of a substance identifiable by a particular function, namely the inhibition of cGMP PDE_V. There was no reference to pentoxifylline as such an inhibitor. Nor was there in the relevant product information leaflet. Footnotes to the paper referring to two 1989 papers dealing with the effect of pentoxifylline in rabbit pulmonary circulation and in canine arteries and veins did not teach the method of claim 10. The tentative terms in which the footnoted papers were couched and the fact that they dealt with animal rather than human studies and with conditions other than impotence, confirmed the conclusion that Korenman, read as a whole, did not contain clear and unmistakeable directions to use the method of claim 10. In any event, pentoxifylline did not, it seemed, act via a cGMP PDE_V inhibitory mechanism of action.

208 Because he had rejected Pfizer’s construction claim that claim 10 referred to a selective cGMP PDE_V inhibitor, it was not necessary for his Honour to discuss an experiment which Lilly had conducted designed to show that pentoxifylline was in fact a selective cGMP PDE_V inhibitor. Had that been so then Korenman could have been treated as in anticipation of claim 10. In any event he was not persuaded that at the relevant time pentoxifylline would have been identified as a selective cGMP PDE_V inhibitor. Korenman would have needed to disclose PDE_V inhibitory activity to be an anticipation. Otherwise there would not have been disclosure of ‘specific details necessary for the practical working and real utility of the alleged invention’ – citing Hill v Evans (1862) 4 De G F & J 288 at 301, 45 ER 1195 at 1199. His Honour concluded that claim 10 was not liable to be revoked for want of novelty. He then turned to the question of obviousness.

209 His Honour referred to s 7 of the Act and the criteria of obviousness set out in ss 7(2) and (3). The test for obviousness, as his Honour stated it, was whether a hypothetical skilled person, constituted by a research team or group would, in all the circumstances, including a knowledge of all the relevant prior art, directly be led as a matter of course to try something in the expectation that it might well produce a useful result. He cited Aktiebolaget Hassle v Alphapharm Pty Ltd [2002] HCA 59; (2002) 212 CLR 411. If it could be said that upon doing so the group would arrive at the alleged invention then obviousness would be made out. To become part of common general knowledge in the relevant field a publication would need to be not just accessible but to have been assimilated into the consciousness of the hypothetical skilled worker or team.

210 It was common ground before his Honour that the notional team would include a pharmacologist and a chemist with experience in drug discovery and development. He also accepted Lilly’s submission that the team would include a medical practitioner experienced in the treatment of impotence.

211 It was not easy to isolate what facts were disputed as within common general knowledge or otherwise. He accepted that the Rajfer and Murray publications formed part of the common general knowledge. He rejected Pfizer’s assertion that as at 13 May 1994 there was an incomplete and inaccurate knowledge of the presence of PDEs and their types in corpus cavernosum.

212 His Honour then considered whether the hypothetical skilled person constituted by a research team would, on reading Rajfer, be led directly as a matter of course to try an oral PDE_V inhibitor to cure or prevent impotence in the expectation that it might well produce a useful alternative to existing methods of treatment. He referred to evidence of what Rajfer conveyed to various witnesses. He noted that immediately after publication of Rajfer, Dr Ringrose, the Head of Discovery at Pfizer UK, circulated a copy to his management team with a comment written on it:

‘Should we not try out UK-92,480 in impotence? Have we seen any beneficial s/e’s [side effects]?’

UK-92,480 which was Pfizer’s internal designation for sildenafil monocitrate was then being considered as a potential angina treatment. He saw this as a contemporaneous actual reaction by a skilled reader to the Rajfer paper. He mentioned in this context also a paper by Dr Gristwood. Dr Gristwood read Rajfer no later than February 1993 and gave a paper at a conference in Nice in which he referred to Rajfer saying:

‘Since PDE_V is specific for the metabolism of cGMP, it can be expected that the inhibitors of PDE_V will potentiate the relaxant effect of the endothelium-derived relaxing factor EDRF (nitric oxide), which acts by stimulating guanylate cyclase. In fact some studies have demonstrated that zaprinast augments the responses which are dependent on nitric oxide.’

Dr Gristwood had given evidence that on reading Rajfer he appreciated that impotence was a new therapeutic possibility for PDE_V inhibitors in light of the fact that zaprinast, a known selective PDE_V inhibitor, was shown to enhance smooth muscle relaxation of human corpus cavernosum tissue. Were he looking for a new treatment for impotence Rajfer would have ‘strongly suggested’ the use of PDE_V inhibitors.

213 His Honour said that Dr Gristwood’s Nice paper and Dr Ringrose’s note were strong indications that Rajfer would, when published, have taught a skilled reader that compounds that inhibit cGMP PDE_V were likely to be useful in the treatment of impotence. He held that Rajfer conveyed not certainty, which was not required, but a well-founded expectation that further testing of cGMP PDE_V inhibitors might well provide a treatment for impotence or be likely to have that effect.

214 His Honour then dealt with and rejected a number of arguments against obviousness advanced by Pfizer. He concluded that Rajfer could be relied upon to establish a lack of inventive step. He also concluded that Murray formed part of the common general knowledge of the addressee in Australia at the priority date. Pfizer’s main answer to Murray was that it did not state that cGMP PDE_V inhibitors should be administered orally. His Honour had already observed in rejecting this argument in connection with Rajfer, that oral administration would self-evidently be the preferred route. He concluded that Murray also could be relied upon to establish a lack of inventive step.

215 His Honour then considered whether there were secondary indicia establishing inventive step. He referred to the enormous commercial success of Viagra but found that Pfizer’s change of direction with UK-92,480 from angina to impotence was due not to serendipity but to the impact of Rajfer. He referred to Study 207 which Pfizer commenced on UK-92,480 for angina in March 1992. This was a study using healthy volunteers designed to test dosage levels for angina treatment. There were reports of spontaneous erections at higher dose levels. Dr Ellis had given evidence that this was the first occasion upon which spontaneous erections had been reported to him as an adverse effect during clinical trials of UK-92,480. The results of the Study were formally reported within Pfizer on 26 June 1992. It was then said that UK-92,480 would be ‘considered for the treatment of impotence on the basis of the spontaneous erection seen in Phase I multiple dose study’.

216 Dr Ellis and Dr Terrett of Pfizer made a Request for Patent Application within Pfizer on 18 January 1993 in relation to the use of cGMP PDE inhibitors for impotence. The request referred to ‘recent literature disclosures’ which had proposed that NO was an important mediator of penile erection. His Honour found that the reference to ‘recent literature disclosures’ was an obvious reference to Rajfer, notwithstanding Dr Ellis’ reluctance to concede as much. Dr Ellis and Dr Terrett signed a Record of Inventorship on 22 June 1993.

217 This history demonstrated how intimately the ideas conveyed by Rajfer were bound up in Pfizer’s work which led to the alleged invention. Pfizer was lucky in having its existing angina project which could be steered in the new direction of impotence treatment. The headstart it was thereby given helped to explain its commercial success. But the story of stumbling by chance on a solution which fulfilled a long-felt want did not fit the historical facts. Nor did the story take into account the rapid developments in scientific knowledge in the area.

218 His Honour considered whether claim 10 was fairly based on the matters described in the specification. He referred to Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58; (2004) 212 ALR 1. The relevant inquiry is what the body of the specification as a whole discloses as the invention. He observed that claim 10 was an awkward fit in the specification. The Patent in its body and in claims 1 to 8 deals with the use of compounds identified by their chemical structure. There is a detailed hierarchy of compounds.

219 His Honour found it to be common ground that claim 10 is not confined to ‘compounds of the invention’ or ‘compounds of formula (I)’. When in the body of the specification there is an account of the ‘preliminary investigation’ and the recording of a finding of ‘potent and selective’ inhibition of the cGMP-specific PDE_V it is ‘compounds of the invention’ that is referred to. In the six components of the consistory clause the only reference to compounds defined not by chemical structure but by inhibitory function is to the inhibition of cGMP PDE, not cGMP PDE_V. That reference was written to support the subsequently abandoned claim 9. His Honour observed (at [174]):

‘Mere coincidence of language between a claim and part of the body of a specification does not establish fair basing if that part of the language of the specification does not reflect the description of the invention in the light of the specification as a whole ... In the present case however there is not even coincidence of language.’

He concluded that claim 10 was not fairly based on the matter described in the body of the specification.

220 He next considered sufficiency and the requirement under s 40(2)(a) of the Act that a complete specification must ‘describe the invention fully, including the best method known to the applicant of performing the invention ...’. He held that the earliest date for determining sufficiency was the date of grant. Claims 6, 7 and 8 and the other amendments made on 6 January 1997 were therefore to be taken into consideration. The common general knowledge and prior art which could be taken into account by the skilled addressee was that at that date for determining sufficiency. The relevant question then was whether the specification provided sufficient information to enable a skilled addressee to use a single embodiment of a cGMP PDE_V inhibitor in applying the method claimed in claim 10. His Honour accepted the evidence of Pfizer’s witness, the medicinal chemist, Dr Robertson. He accepted Dr Robertson’s evidence that the skilled addressee reading the Patent as a whole and noting the progressive narrowing of claims would be likely to focus on claim 8. If the embodiment selected by the addressee for working came within claim 10, it did not matter that it also might fall within claim 8. There was no justification for requiring the one embodiment of claim 10 relied on to be outside the compounds of formula (I). His Honour concluded that Lilly’s ground of insufficiency was not made out.

221 His Honour then considered whether the description of the invention included the best method known to the applicant of performing the invention. The first issue to be determined under that heading was the relevant date for determining whether the best method had been disclosed. His Honour concluded that the relevant date was, at the earliest, the date of grant. Lilly had contended that the date was the date of filing of the PCT application on 13 May 1994. His conclusion was based upon his construction of the requirements of s 40(2)(a) and the definition of ‘complete specification’ in the Dictionary in Sch 1 of the Act. He identified the best method known to Pfizer to be the use of sildenafil monocitrate. He concluded, based on Dr Robertson’s evidence, that to a skilled reader the Patent does disclose the freebase and salt of the especially preferred compound.

222 The next question was whether the claimed invention was ‘a manner of new manufacture’ within the meaning of s 6 of the Statute of Monopolies (UK). He rejected the proposition advanced by Lilly that claim 10 claimed a ‘mere desideratum’. The Patent specification told the reader the manner in which the desired object was to be achieved, namely by use of an orally effective cGMP PDE_V inhibitor. This could not be characterised as a ‘bare idea’. He noted that in the Bell patents, which were referred to in the complete specification, Pfizer disclosed a number of compounds including formula (I) compounds, suggested to be useful for a number of indications including the treatment of angina within a particular dosage range. They were disclosed in those two patents as potent and selective inhibitors of PDE_I and PDE_V. The Patent therefore disclosed patentable subject matter.

223 The next question was whether there had been a false suggestion which materially contributed to the decision to grant the Patent. Lilly submitted that the specification gave the false impression that one of the nine ‘especially preferred individual compounds’ had been tested and worked and that the patentee was disclosing its best method. This was based on the statement in the Patent:

‘Moreover patient studies conducted thus far have confirmed that one of the especially preferred compounds induces penile erection in impotent males.’

His Honour acknowledged that the compound which achieved the experimental result referred to in that passage was not a freebase compound as were the ‘especially preferred individual compounds’. However Dr Robertson’s evidence established that a skilled addressee would not draw a distinction between a compound in its freebase form and the same compound in its salt form. There was no false suggestion.

224 His Honour then considered whether the Lilly product, Cialis, infringed Pfizer’s Patent. Certain formal admissions had been made for the purposes of the case. They were the following:

(a) Cialis is an inhibitor of cGMP PDE_V;

(b) Cialis tablets are intended to be prescribed by doctors in Australia as a treatment to be taken orally for the treatment of erectile dysfunction in men;
(c) Cialis (in 10mg and 20mg tablet form) has been approved by the Australian Therapeutic Goods Administration (TGA);
(d) Lilly imports, sells, offers for sale or otherwise disposes of Cialis tablets in Australia; and
(e) Cialis:
(i) inhibits PDE_V;

(ii) is >10,000–fold more potent for PDE_v than for PDE_I, PDE_II, PDE_III and PDE_IV;
(iii) is approximately 700-fold more potent for PDE_V than for PDE_VI.

225 Lilly argued that Cialis does not ‘cure or prevent erectile dysfunction’ because it treats such dysfunction on an ad hoc basis for a limited period of up to 36 hours. This, it was said, is not a ‘cure’ because the person treated is not restored to health in the sense that he no longer has the disease. His Honour however held that claim 10 was concerned with a ‘performance problem’. Cialis would treat that problem and thus ‘cure’ or ‘prevent’ it in the sense that a man taking Cialis would not have the problem for 36 hours. Cialis therefore cured or prevented impotence within the meaning of claim 10. His Honour also rejected Lilly’s argument that ‘mere sale or importation’ did not infringe a method claimed. He concluded that if claim 10 of the Patent were valid, Lilly’s conduct would have constituted an infringement of it.

The Orders at First Instance

226 The learned primary judge delivered judgment on 10 February 2005 and directed counsel to submit minutes of proposed orders. On 11 March 2005 he made orders in the following terms:

‘The Court declares that:

1. Claim 10 of Australian Patent No 676571 is and always has been invalid.

The Court orders that:

2. Australian Patent No 676571, so far as it relates to claim 10, be revoked.
3. The Cross-Claim be dismissed.
4. The Respondents/Cross-Claimants pay 72.5% of the Applicants/Cross-Respondents’ costs of and incidental to these proceedings, including all costs reserved in these proceedings or to be dealt with in these proceedings, such costs to be taxed in default of agreement.
5. The time within which the Respondents/Cross-Claimants may file and serve a Notice of Appeal be extended to 14 April 2005.
6. Order 2 be stayed:

(a) initially until 14 April 2005; and

(b) if an appeal is lodged within that period, until the determination of that appeal, or further Order.’

227 The Court also noted undertakings by Pfizer to prosecute any appeal expeditiously and to serve a copy of the relevant orders on the Commissioner of Patents and not to threaten any person with proceedings or commence proceedings for infringement of claim 10 of the Patent during the period of the stay. The Court also noted Pfizer’s undertaking not to seek to amend the Patent otherwise than in the course of or in connection with the proceedings.

The Grounds of the Appeal

228 The grounds of the appeal were set out in some detail and it is not necessary to reproduce them in full here. It is sufficient to say that Pfizer asserted in the grounds that the learned primary judge erred in finding:

1. that in claim 10, in the context of the Patent as a whole, the term ‘cGMP PDE_V inhibitor’ does not connote an inhibitor which is selective for PDE_V (grounds 20 to 23);
2. that claim 10 was not fairly based on matter described in the specification in the Patent (grounds 24 to 28);

3. that claim 10 of the Patent was invalid because it was obvious (grounds 1 to 19).

The issues are set out in the order in which they will be dealt with in the reasons that follow.

The Notice of Contention

229 In its notice of contention Lilly asserted that the learned primary judge:

1. should have held that claim 10 of the Patent was not novel when compared with the prior art base as it existed before the priority date of the claim, as required by s 18(1)(b)(i) of the Act;
2. should have held that the date for determining whether the best method known to the patentee of performing the invention is described in the specification of the Patent, is the date of filing of the complete specification (namely, in the case of the Patent, the date of filing the PCT application on 13 May 1994);
3. should have held that the specification of the Patent did not describe the best method known to the patentee of performing the invention claimed in claim 10 of the Patent at 13 May 1994;
4. erred in his findings as to sufficiency in relation to the relevant date for determining sufficiency, the construction of claim 10, and the test applied to determining sufficiency;
5. assuming that the specification of the Patent did not describe the best method, should have held that there was a false suggestion made by the patentee which materially contributed to the decision to grant the Patent;
6. should have held that the importation or sale of Cialis by the respondents would not infringe claim 10 of the Patent if that claim was valid because it does not ‘cure or prevent’ male erectile dysfunction within the meaning of claim 10 of the Patent. If he were correct in so construing claim 10, then it was not open to find that the importation and sale of Cialis by the respondents would infringe claim 10 of the Patent as Pfizer did not lead evidence that Cialis cures or prevents erectile dysfunction by cGMP PDE_V inhibition.

Statutory Framework – The Patents Act 1990 (Cth)

230 The Patents Act 1990 which is the statute applicable to this appeal repealed the Patents Act 1952 (Cth). The 1990 Act commenced on 30 April 1991. Some of the provisions of that Act which are relevant to this appeal have been amended by subsequent legislation. Textual alterations to accommodate the innovation patent system were introduced by the Patents Amendment (Innovation Patents) Act 2000 (Cth). They came into effect on 24 May 2001. Significant amendments relating to novelty and inventive step were introduced by the Patents Amendment Act 2001 (Cth). These amendments apply to the making of complete applications and to patents for which the complete applications are made on or after the day on which Schedule 1 to that Act commenced. Schedule 1 commenced on 1 April 2002 – see s 13 Patents Amendment Act 2001.

231 The Court is concerned with the Patents Act 1990 as it stood prior to the amendments introduced by the amending Acts of 2000 and 2001. Other earlier amendments are not material for present purposes.

232 A patent for an invention confers upon the patentee the exclusive rights, during the term of the patent, to exploit the invention and to authorise another person to exploit the invention (s 13(1)). The relevant rights are personal property capable of assignment and devolution by law (s 13(2)). A patent for an invention may only be granted to a person who is the inventor or a person who derives or is entitled to derive title to the patent from the inventor (s 15(1)).

233 The class of inventions which are patentable inventions under the Act is described in s 18. Section 18 as it stood prior to the amending Act of 2000 was as follows:

‘(1) Subject to subsection (2), a patentable invention is an invention that, so far as claimed in any claim:

(a) is a manner of manufacture within the meaning of section 6 of the Statute of Monopolies; and

(b) when compared with the prior art base as it existed before the priority date of that claim:

(i) is novel; and
(ii) involves an inventive step; and

(c) is useful; and
(d) was not secretly used in the patent area before the priority date of that claim by, or on behalf of, or with the authority of, the patentee or nominated person or the patentee’s or nominated person’s predecessor in title to the invention.

(2) Human beings, and the biological processes for their generation, are not patentable inventions.’

234 Nothing done under the Act guarantees the granting of a patent or that a patent is valid in Australia or anywhere else (s 20(1)). The invalidity of a patent in relation to a claim does not affect its validity in relation to any other claim (s 22).

235 Section 40 of the Act sets out the requirements for specifications for patents thus:

‘(1) A provisional specification must describe the invention.

(2) A complete specification must:

(a) describe the invention fully, including the best method known to the applicant of performing the invention; and
(b) where it relates to an application for a standard patent – end with a claim or claims defining the invention; and
(c) where it relates to an application for a petty patent – end with a single claim, or a single independent claim and not more than 2 dependent claims, defining the invention.

(3) The claim or claims must be clear and succinct and fairly based on the matter described in the specification.

(4) The claim or claims must relate to one invention only.’

236 Section 43(1) requires that each claim of a specification have a priority date. By s 43(2) the priority date of a claim is the date of filing of the specification or a different date determined under the Regulations where they so provide. Section 43(4) provides that the priority date of a claim of a specification may be different from the priority date of any other claim of the specification.

237 Schedule 1 to the Act sets out a dictionary of expressions which, by virtue of s 3 of the Act, are defined for the purposes of the Act or of a particular chapter of the Act. The definitions contained in the dictionary include the following:

‘invention means 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.

prior art base means:

(a) in relation to deciding whether an invention does or does not involve an inventive step::

(i) information in a document, being a document publicly available anywhere in the patent area; and
(ii) information made publicly available through doing an act anywhere in the patent area; and
(iii) where the invention is the subject of a standard patent or an application for a standard patent – information in a document publicly available outside the patent area;

(b) in relation to deciding whether an invention is or is not novel:

(i) information of a kind mentioned in paragraph (a); and
(ii) information contained in a published specification filed in respect of a complete application where:

(A) if the information is, or were to be, the subject of a claim of the specification, the claim has, or would have, a priority date earlier than that of the claim under consideration; and
(B) the specification was published after the priority date of the claim under consideration; and
(C) the information was contained in the specification on its filing date and when it was published.’

‘prior art information means:

(a) for the purposes of subsection 7(1) – information that is part of the prior art base in relation to deciding whether an invention is or is not novel; and
(b) for the purposes of subsection 7(3) – information that is part of the prior art base in relation to deciding whether an invention does or does not involve an inventive step.’

238 Section 7 of the Act as it stood at the relevant time provided:

‘(1) For the purposes of this Act, an invention is to be taken to be novel when compared with the prior art base unless it is not novel in the light of any one of the following kinds of information, each of which must be considered separately:

(a) prior art information (other than that mentioned in paragraph (c)) made publicly available in a single document or through doing a single act;
(b) prior art information (other than that mentioned in paragraph (c)) made publicly available in 2 or more related documents, or through doing 2 or more related acts, if the relationship between the documents or acts is such that a person skilled in the relevant art in the patent area would treat them as a single source of that information;
(c) prior art information contained in a single specification of the kind mentioned in subparagraph (b)(ii) of the definition of prior art base in Schedule 1.

(2) For the purposes of this Act, an invention is to be taken to involve an inventive step when compared with the prior art base unless the invention would have been obvious to a person skilled in the relevant art in the light of the common general knowledge as it existed in the patent area before the priority date of the relevant claim, whether that knowledge is considered separately or together with either of the kinds of information mentioned in subsection (3), each of which must be considered separately.

(3) For the purposes of subsection (2), the kinds of information are:

(a) prior art information made publicly available in a single document or through doing a single act; and
(b) prior art information made publicly available in 2 or more related documents, or through doing 2 or more related acts, if the relationship between the documents or acts is such that a person skilled in the relevant art in the patent area would treat them as a single source of that information;

being information that the skilled person mentioned in subsection (2) could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant to work in the relevant art in the patent area.’

239 Section 138 of the Act provides for revocation of patents and in particular s 138(3) provides that the court may by order revoke a patent either wholly or so far as it relates to a claim on one or more of the following grounds, but on no other ground:

‘(a) that the patentee is not entitled to the patent;
(b) that the invention is not a patentable invention;
(c) that the patentee has contravened a condition in the patent;
(d) that the patent was obtained by fraud, false suggestion or misrepresentation;
(e) that an amendment of the patent request or the complete specification was made or obtained by fraud, false suggestion or misrepresentation;
(f) that the specification does not comply with subsection 40(2) or (3).’

Constructional Questions

240 The construction of the Patent is logically antecedent to all other issues. In this case however, the constructional debate was narrowly focussed on two questions:

1. Whether the term ‘cGMP PDE_V inhibitor’ in claim 10 refers only to inhibitors which are selective for PDE_V (grounds 20 to 25).
2. Whether the term ‘cure or prevent’ in claim 10 covers a method of treatment which temporarily overcomes the effects of erectile dysfunction.

241 The first question was raised by Pfizer in its attack upon the finding by the learned trial judge that the term ‘cGMP PDE_V inhibitor’ covers PDE_V inhibitors which are not selective for that enzyme as well as inhibitors which are. Pfizer submitted in effect that the wide construction adopted by his Honour underpinned his finding that claim 10 was not fairly based on the matter described in the body of the specification. It did not demonstrate how his Honour’s construction impinged upon his fair basis conclusion. Lilly submitted that there was no connection. The fair basing question depended solely on whether the specification read as a whole disclosed as the invention the use of the compounds of the invention, that is the compounds of formula (I).

242 In his reasons for judgment the learned trial judge observed that much of the discussion on the construction point was relevant to the issue of fair basing – [170]. Part of that discussion, at [85] and [86], did turn upon the proposition that claim 10 was not limited to the compounds of the invention or compounds of formula (I). His Honour’s reasons, however, did not otherwise make any connection between the construction of claim 10 and the fair basis holding.

243 On novelty, Lilly relied upon an experiment designed to show that pentoxifylline was a selective cGMP PDE_V inhibitor and thus that Korenman anticipated claim 10. Because of the broader construction of claim 10 which his Honour had adopted he found it unnecessary to discuss the Lilly experiment – [90]. He was, in any event, not persuaded that at the relevant time pentoxifylline would have been identified as a selective cGMP PDE_V inhibitor.

244 It may be seen from the foregoing that the question whether claim 10 covered non-selective cGMP PDE_V inhibitors played virtually no part in the outcome of the case.

245 The second constructional question was relevant to the asserted infringement of claim 10 by the Lilly product in the event that claim 10 were valid. Lilly argued that its product, Cialis, did not ‘cure or prevent erectile dysfunction in man in need of such treatment’ within the meaning of claim 10 because it treated such dysfunction ‘on an ad hoc basis for a limited period of up to 36 hours’. This was not a ‘cure’ because even after using Cialis the person treated still had the disease. Similarly it was argued that the word ‘prevent’ in the context of claim 10 meant to forestall the onset of the disease so as to keep it from occurring. His Honour held, however, that the Patent defined ‘impotence’ by reference to the inability to achieve penile erection or ejaculation. Cialis treated that problem and thus cured or prevented it in the sense that a man taking Cialis would not have the problem for 36 hours. On that basis his Honour held that Cialis would ‘cure or prevent’ impotence within the meaning of claim 10.

246 Notwithstanding the marginal relevance of the first constructional question, it is desirable to deal with both as they were fully argued. This requires a consideration of some general principles.

247 Underlying any approach to the construction of a patent is its character as a document conferring a public monopoly not to be construed merely as a written document inter partes. This requires ‘... a description which is not reasonably capable of misunderstanding’ – Martin v Scribal Pty Ltd [1954] HCA 48; (1954) 92 CLR 17 at 59 (Dixon CJ); Welch Perrin & Co Pty Ltd v Worrel [1960] HCA 91; (1961) 106 CLR 588 at 610 (Dixon CJ, Kitto and Windeyer JJ). Plain language is to be given its plain meaning. The clear words of a claim are not to be distorted by importing passages from the specification – Martin v Scribal at 97 (Taylor J). It was put thus in the joint judgment in Welch Perrin (at 610):

‘Nevertheless, it is to be remembered that any purely verbal or grammatical question that can be resolved according to ordinary rules for the construction of written documents, does not, once it has been resolved, leave uncertain the ambit of the monopoly claimed.’

So when a claim is clear it is not to be glossed or obscured by reference to the specification. Barwick CJ and Mason J reiterated the rule in Interlego AG v Toltoys Pty Ltd [1973] HCA 1; (1972) 130 CLR 461 at 478:

‘... the settled rule is that in ascertaining the width of a particular claim it is not permissible to vary or qualify the plain and unambiguous meaning of the claim by reference to the body of the specification.’

248 Construction should not be unduly narrow (Martin v Scribal (at 97)):

‘... it is right to construe a claim with an eye benevolent to the inventor and with a view to making the invention work – this is an application of the old doctrine ut res magis valeat quam pereat – and it is illustrated in Nobel’s Case [(1894) 11 RPC at 524]; and, where the language of a claim is obscure or doubtful, the doubt may sometimes be resolved by referring to words in the body of the document to explain it. This is known as the dictionary principle.’

A re-statement of the latter part of that proposition may be found in the joint judgment of Barwick CJ and Mason J in Interlego (at 479):

‘If the expression is not clear it is then permissible to resort to the body of the specification to define or clarify the meaning of words used in the claim without infringing the rule that clear and unambiguous words in the claim cannot be varied or qualified by reference to the body of the specification.’

249 In Décor Corp Pty Ltd v Dart Industries Inc (1988) 13 IPR 385, Sheppard J reviewed the authorities and set out ten principles of construction:

1. The claims define the invention which is the subject of the patent. These must be construed according to their terms upon ordinary principles. Any purely verbal or grammatical question that can be answered according to ordinary rules for the construction of written documents is to be resolved accordingly.

2. It is not legitimate to confine the scope of the claims by reference to limitations which may be found in the body of the specification but are not expressly or by proper inference reproduced in the claims themselves. To put it another way, it is not legitimate to narrow or expand the boundaries of monopoly as fixed by the words of a claim by adding to those words glosses drawn from other parts of the specification.

3. Nevertheless, in approaching the task of construction, one must read the specification as a whole.

4. In some cases the meaning of the words used in the claims may be qualified or defined by what is said in the body of the specification.

5. If a claim be clear, it is not to be made obscure because obscurities can be found in particular sentences in other parts of the document. But if an expression is not clear or is ambiguous, it is permissible to resort to the body of the specification to define or clarify the meaning of words used in the claim.

6. A patent specification should be given a purposive construction rather than a purely literal one.

7. In construing the specification, the court is not construing a written instrument operating inter partes, but a public instrument which must define a monopoly in such a way that it is not reasonably capable of being misunderstood.

8. The body, apart from the preamble, is there to instruct those skilled in the art concerned in the carrying out of the invention; provided it is comprehensible to, and does not mislead, a skilled reader, the language used is seldom of importance.

9. Nevertheless, the claims, since they define the monopoly, will be scrutinised with as much care as is used in construing other documents defining a legal right.

10. If it is impossible to ascertain what the invention is from a fair reading of the specification as a whole, it will be invalid. But the specification must be construed in the light of the common knowledge in the art before the priority date.

In Nesbit Evans Group Australia Pty Ltd v Impro Ltd (1997) 39 IPR 56, Lindgren J cited the ten principles with evident approval. Hill J, in a separate judgment, agreed. Wilcox J differed on one point not related to the relevant principles of construction and otherwise agreed with Lindgren J’s reasons.

250 Lindgren J added the following to the propositions enunciated by Sheppard J in Décor Corp:

1. There is a danger in considering the integers of a claim individually and in isolation. This could yield a literal rather than a purposive construction – see Catnic Components Ltd v Hill & Smith Ltd [1982] RPC 183 at 243 (Lord Diplock).

2. The Court should avoid too technical or narrow a construction of claims.

3. A construction according to which the invention will work is to be preferred to one according to which it may not do so.

251 The learned trial judge in the present case was of the opinion that, as a matter of ordinary language, the term ‘cGMP PDE_V inhibitor’ in claim 10 conveys to the reader the concept of a substance identified only by the presence of a particular function or capacity, namely that it inhibits cGMP PDE_V. On that view the proposition that it describes only selective inhibitors of cGMP PDE_V would impose a limitation or qualification upon the ordinary language.

252 His Honour referred to expert evidence on either side of the constructional debate. He also found evidence of usage contrary to the Pfizer contention. In Pfizer’s Canadian Viagra Patent claim 25 referred to:

‘The use of an effective amount of a cGMP PDE_V inhibitor ... where the cGMP PDE_V inhibitor is a selective inhibitor of cGMP-specific PDE_V.’

Claim 24 of the Pfizer US Patent also referred to ‘an effective amount of a selective cGMP PDE_V inhibitor.

253 The specification refers to ‘selective enzyme inhibition’ by the compounds of the invention but the selectivity there identified relates to the effect of the inhibitor on cGMP PDEs by way of contrast with its effect on cAMP PDEs. However later in the specification it is said:

‘The compounds of the invention have been tested in vitro and found to be potent and selective inhibitors of the cGMP-specific PDE_V. For example, one of the especially preferred compounds of the invention has an IC₅₀ = 6.8nM _v the PDE_V enzyme, but demonstrates only weak inhibitory activity against the PDE_II and PDE_III enzymes....’

It may be seen from these passages in the specification that selectivity against cGMP PDE_Vs is said to be a demonstrated feature of the compounds of the invention. Its importance, as it emerged from the evidence, was that administration of a selective inhibitor would not unduly affect the functioning of smooth muscle in organs other than the penis. Minimising the risk of adverse smooth muscle effects in cardiac, respiratory, bowel and retinal tissue was an important purpose of the invention.

254 Reading claim 10 in a way that is consistent with the terms of the specification to which reference has been made and the state of common general knowledge at the time and with an eye to its utility yields the narrower construction advanced by Pfizer. In this respect it may be said that his Honour erred. However, as already noted, if there were an error, it was not one which was shown to have had any affect upon his overall conclusions.

255 The second constructional question related to the term ‘cure or prevent’ in claim 10.

256 On the appeal Lilly contended that his Honour erred on the infringement issue by wrongly holding that its product, Cialis, did ‘cure or prevent erectile dysfunction in men in need of such treatment’ within the meaning of claim 10. Lilly submits that by the use of the expression ‘cure or prevent’, claim 10 claims more than Cialis achieves. Cialis treats erectile dysfunction ‘on an ad hoc basis for a limited period of up to about 36 hours’, whereas, according to Lilly’s submission, to ‘cure’ is to produce the result that a man no longer has the underlying disease and ceases to be an impotent man, while to ‘prevent’ is to forestall the onset of the disease.

257 We were taken to dictionary definitions of ‘cure’ and ‘prevent’ but we do not find them particularly helpful. For example, the word ‘remedy’ is given as one synonym for ‘cure’, but the question simply becomes whether claim 10 claims a once and for all remedy.

258 We take as our staring point that which his Honour took: the Patent’s definition of impotence (page 1, lines 6-11):

‘... a lack of power, in the male, to copulate and may involve an inability to achieve penile erection or ejaculation, or both. More specifically, erectile impotence or dysfunction may be defined as an inability to obtain or sustain an erection adequate for intercourse.’

His Honour’s reasoning is succinctly expressed in the following passage which follows his quoting of this definition ([230]):

‘This would accord with the understanding of the term "impotence" (or its more scientific sounding synonym "erectile dysfunction") in ordinary speech. Accordingly claim 10 is not referring to some underlying physiological or psychological condition. In the vernacular, it is concerned with a performance problem. Cialis will treat that problem and thus "cure" or "prevent" it in the sense that a man taking Cialis will not have the problem for 36 hours. This question must be answered in the affirmative.’

259 We agree that impotence, as defined in the Patent and as commonly understood, is an inability to ‘perform’ from time to time when desired. Intervening periods do not give rise to any problem, even though the underlying condition exists during them too.

260 In our opinion, an ‘inability to obtain or sustain an erection adequate for intercourse’ is ‘cured or prevented’ not only by a once and for all remedy which is directed to the underlying condition, but also by the maintenance of an ongoing dosing regimen which is directed to the condition’s manifestations from time to time. The words ‘cure or prevent’ in claim 10 are not limited to the former. It is no reason to limit them in that way that a once and for all treatment is preferable to a treatment which must be regularly repeated. Of course, the body of the specification makes it clear that the latter is the treatment method to which claim 10 refers: ‘A preferred dosing regimen for a typical man is 5 to 75 mg of compound three times daily’ (page 10, lines 28-30). If the meaning of the expression ‘cure or prevent’ in claim 10 were unclear (we do not think it is) it would be permissible to look to those words in the body of the specification to resolve the ambiguity: Interlego AG at 479; Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8; (2001) 207 CLR 1 at 12 [15].

261 Lilly submits that the draftsperson should be treated as having chosen the words and syntax of claim 10 with skill and care (Lilly cited Sachtler GmbH & Co KG v RE Miller Pty Ltd [2005] FCA 788 at [61]), and that if intermittent relief from impotence dependent on a course of treatment had been intended, some words such as ‘A method of orally treating men for erectile dysfunction’ would have been used. Lilly also refers to the fact that the corresponding claim in Pfizer’s US Patent No 6,469,012 has been rewritten to refer to ‘a method of treating erectile dysfunction in a male human’.

262 The fact that claim 10 might have been expressed in a way which, it might be suggested, more clearly excludes a claim of a once and for all remedy is not determinative of the present question. Nor is the different formulation of the corresponding claim in Pfizer’s US patent.

263 Lilly refers to the disjunctive form, ‘cure or prevent’, in claim 10 (and to the disjunctive curative or prophylactic treatment at pp 4 and 11 of the Patent). But Lilly’s submission that in claim 10, ‘cure’ means ‘treat an existing disease so that the person treated no longer has the disease’, and ‘prevent’ means ‘forestall the onset of the disease to keep it from occurring’, erroneously treats claim 10 as stating what it does not state: ‘A method of orally treating men to cure to prevent the disease which gives rise to erectile dysfunction’.

264 Importantly, claim 10 states that it is concerned with ‘men in need of [treatment to cure or prevent erectile dysfunction]’. Thus, the claim is concerned with men who already have the underlying disease. It follows that claim 10 can not be construed as a claim of a method of forestalling the onset of the disease at all. Since ‘prevent’ cannot be read as relating to the underlying disease, why should ‘cure’ be?

265 Lilly’s submission does not give due weight to the word ‘dysfunction’. Claim 10 is directed to inability to function, operate or perform from time to time when desired, not to the underlying disease which is the cause of that inability.

266 The draftsperson may have chosen the expression ‘cure or prevent’ in an attempt to focus attention on both the course of successive occasions of dysfunction (‘cure’) and the individual occasion of dysfunction (‘prevent’).

Infringement

267 For the purpose of the proceedings before the learned primary judge, Lilly made a number of formal admissions about the operation of its product Cialis in the treatment of erectile dysfunction. Those admissions have been summarised earlier in the discussion of his Honour’s reasons for judgment. Given the admissions and his Honour’s correct construction of the term ‘cure or prevent erectile dysfunction’ in claim 10, it follows that Lilly’s product would infringe that claim if the claim were to be found valid.

Fair Basing

268 It is a requirement for the specification of a patent that the claim or claims made in it must be ‘fairly based on the matter described in the specification’ (s 40(3)). The history and content of the term ‘fairly based’ was discussed at some length in the judgment of the Full Court in CCOM Pty Ltd v Jiejing Pty Ltd (1994) 122 ALR 417 at 432-437 (Spender, Gummow and Heerey JJ). It became part of Australian patent law with the enactment of ss 40 and 45 of the Patents Act 1952 (Cth). As the Full Court said in CCOM (at 496):

‘It was used to describe the relationship between the claims defining the invention and the matter described in the complete specification ..., and as a criterion for fixing the priority date of the claim of a complete specification fairly based on matter disclosed in the preceding provisional specification....’

It is only the former sense which is relevant for present purposes. It has been carried over into the 1990 Act.

269 The question whether an invention as claimed in any claim is fairly based on the matter described in the specification is a distinct question and not to be conflated with other issues going to validity, such as novelty, utility or obviousness:

‘A patent can be successfully challenged on the ground that the claims are not fairly based even though ever other possible ground of challenge fails.’
Lockwood Security Products Pty Ltd at 13 [48].

The process of assessment of fair basing mandated by the judgment in Lockwood Security lends emphasis to the proposition that it stands alone as a ground going to validity (at 14 [49]):

‘... when assessing whether there is fair basing within the meaning of s 40(3), it is necessary to split the patent into the claims and the body of the specification in order to see whether the former are fairly based on the matter described in the latter.’

270 The question posed by the fair basing requirement is that formulated by Barwick CJ in Olin Corporation v Super Cartridge Co Pty Ltd [1977] HCA 23; (1977) 180 CLR 236 at 240:

‘... whether the claim to the product being new, useful, and inventive, that is to say, the claim as expressed, travels beyond the matter disclosed in the specification.’

That is to say, assuming novelty, utility and inventive step, does the claim travel beyond the specification. That statement of the question was approved by the High Court in Kimberly-Clark at 12 [15]. The Court put it thus:

‘... where the issue is one under a 40(3) of "fair basing" of a claim, what the 1990 Act requires is a comparison between the matter described in the specification and the claim which defines the scope of the monopoly.’

271 In Lockwood Security the court said that the comparison called for by s 40(3) is not analogous to that between a claim and an alleged anticipation or infringement. It is wrong to apply an ‘over meticulous verbal analysis’ or isolate in the body of the specification essential integers or features of an invention and inquire whether they correspond with the essential integers of a claim – at 20 [69]. What is required is ‘a real and reasonably clear disclosure’, words taken from the judgment of Fullagar J in Société Des Usines Chimiques Rhône-Poulenc v Commissioner of Patents [1958] HCA 27; (1958) 100 CLR 5 at 11. The court in Lockwood Security quoted with approval a passage taken from the judgment of Gummow J in Rehm Pty Ltd v Websters Security Systems (International) Pty Ltd (1988) 81 ALR 79 (at 95), where his Honour said, inter alia:

‘... the question is whether there is a real and reasonably clear disclosure in the body of the specification of what is then claimed, so that the alleged invention as claimed is broadly, that is to say in a general sense, described in the body of the specification.’

272 The learned primary judge found that claim 10 was not fairly based on the specification. That finding appears largely to have been grounded in his opinion that the specification dealt only with the compounds of the invention or compounds of formula (I), whereas claim 10 was not so limited. Applying the words from the judgment of Gummow J in Rehm he said that the issue of fair basing required a focus on the ‘text of the patent’. He found the Patent to direct ‘the reader away from further investigation and testing because what it does disclose are the specified "compounds of the invention".’ It was the generality of claim 10 extending to substances outside the group defined as the ‘compounds of the invention’ which appears to have underpinned the fair basing finding in this case.

273 Pfizer’s submissions on fair basing involved the following propositions:

1. The learned trial judge’s conclusion on fair basis was tied to his construction of the term ‘cGMP PDE_V inhibitor’. He should have found that that term connoted selectivity.

2. The learned trial judge wrongly concluded that the compounds of the invention were confined to the compounds of formula (I).

3. Whether or not proposition 2 is correct, the principle claimed in claim 10 was broadly described in the specification.

274 As to the first proposition Lilly correctly submitted that it bore no relationship to his Honour’s reasons for his finding on fair basis. That is the conclusion already reached earlier in these reasons in the section relating to the construction of claim 10. Lilly further submitted that the basis of his Honour’s reasoning was that the Patent does not contain a real and reasonably clear description of the use of cGMP PDE_V inhibitors outside the compounds of formula (I). What it does disclose as the invention is the use of the specified compounds of the invention.

275 The specification opens with the statement that the invention relates to ‘... the use of a series of a pyrazolo [4,3-d] pyrimidin – 7 – ones for the treatment of impotence’. In so doing it makes clear that the invention relates to a defined class of drugs. It does not, on those words, extend to any class of drugs which inhibits cGMP PDE_V activity selectively or otherwise. The broad identification of the class of drugs to which the invention relates is linked to the reference on page 2 of the specification to ‘The compounds of the invention ...’ which are said to be ‘potent inhibitors of cyclic guanosine 3, 5-monophosphate phosphodiesterases (cGMP PDEs) in contrast to their inhibition of cyclic adenosine 3, 5-monophosphate phosphodiesterases (cAMP PDEs)’. Reference follows in the next paragraph to ‘... these disclosed compounds ...’. There follows the statement that ‘the present invention concerns the use of a compound of formula (I):’. That is then elaborated by various molecular substitutional possibilities. It is also widened to incorporate ‘... a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity ...’. There follow repeated references to compounds of formula (I). The term ‘compounds of the invention’ reappears later in the specification. It is clear however that his Honour was correct in finding, on the proper construction of the specification, that the compounds of the invention are referred to interchangeably with the compounds of formula (I). There is no basis disclosed, upon a reasonable reading of the specification, for any distinction to be drawn between those two terms. Pfizer’s second proposition fails.

276 The third proposition depends upon finding in the specification a broad statement of a range of cGMP PDE_V inhibitors which can accommodate the range claimed in claim 10. Such a range of compounds is not to be found in the specification. Indeed the whole of its text may be read as limited by the class of compounds referred to in the opening sentence. Any limitation in the specification upon the class of compounds comprising the invention (other than by reference to their effects as cGMP PDE_V inhibitors) is fatal to claim 10. For on its face, claim 10 applies to any compound, however defined, which is ‘a cGMP PDE_V inhibitor’. It makes no difference to that reasoning whether the term ‘cGMP PDE_V inhibitor’ is read as referring only to selective inhibitors. The claim, read as a whole, travels well beyond the range of compounds, large as it may be, which is disclosed in the body of the specification. Pfizer’s third proposition fails.

277 His Honour was right to conclude that the invention as claimed in claim 10 is not fairly based on the matter described in the specification.

Lack of Inventive Step – Obviousness

278 It is a necessary condition of patentability that an invention, so far as claimed in any claim, is one which, when compared with the prior art base as it existed before the priority date of the claim, involved an inventive step (s 18(1)(b)(ii)). Section 7(2) has the effect that a claimed invention lacks an inventive step compared with the prior art base only if ‘... the invention would have been obvious to a person skilled in the relevant art in the light of the common general knowledge as it existed in the patent area before the priority date of the relevant claim’.

279 The term ‘common general knowledge’ is not defined in the Act but has been the subject of judicial exegesis reflecting:

‘... 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.’
Minnesota Mining and Manufacturing Co v Beiersdorf (Australia) Ltd [1980] HCA 9; (1980) 144 CLR 253 at 292 (Aickin J)

Or as the Federal Court put it in WR Grace v Asahi Kasei [1993] FCA 84; (1993) AIPC 90-974 at 39,271:

‘The common general knowledge of the art or science represents the matters that the skilled person will have at the back of his or her mind when coming to consider the prior art, so that each document alleged to constitute the prior art is to be regarded as the addressee would regard it in the light of common general knowledge. Common general knowledge is relevant as distinct from mere public knowledge.’

280 In addition to the state of common general knowledge, s 7(2) and (3) requires consideration to be given to prior art information publicly available through one document or act or one or more related documents or acts which the skilled addressee could ‘be reasonably expected to have ascertained, understood and regarded as relevant to the work in the relevant art in the patent area’. The hypothetical skilled person will not confine himself or herself to the common general knowledge in considering the question answered by the allegedly inventive step. He or she can be expected to carry out literature searches using relevant contemporary search facilities including on-line data bases.

281 The effect of the 1990 amendments was discussed in the context of obviousness in Firebelt Pty Ltd v Brambles Pty Ltd [2002] HCA 21; (2002) 188 ALR 280. Under the 1952 Act, as expounded in Minnesota Mining, a prior disclosure ‘did not provide a basis for a conclusion as to obviousness without evidence that the disclosure in question was part of the common general knowledge at the relevant priority date – Firebelt at [35]. The report of the Industrial Property Advisory Committee dated August 1984 entitled ‘Patents Innovation and Competition in Australia’ recommended that:

‘For the purpose of determining inventiveness, any single prior disclosure or use should be capable of being considered against the background of all that is common general knowledge in the relevant field of art. On this basis the requirement of inventiveness will not be fulfilled if the knowledge imputed by the disclosure or use, combined with what is common general knowledge in the art would render the claimed invention obvious to a person reasonably skilled in the art.’

The Committee recommended that it not be possible to combine two disclosures or uses when neither lay within the common general knowledge unless one of the disclosures referred to another disclosure or use. The Committee further said:

‘On the other hand we see as being treated within the common general knowledge of the art, not merely information which is generally known and used in the art but information publicly available or recorded from anywhere in the world which a skilled person working in the art at the relevant time should reasonably have been expected to find, understand, and regard as relevant.’

The Court in Firebelt noted that the latter recommendation was accepted for standard patents albeit not for petty patents which it was considering in that case.

282 Their Honours quoted with approval (at [36]) an observation by Burchett J in Tidy Tea Ltd v Unilever Australia Ltd (1995) 32 IPR 405 at 414 that:

‘The new provisions are limited by the words "being information that the skilled person ... could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant to work the relevant art in the patent area". And if a prior [disclosure] passes those tests, it must still be able to be said that, if that [disclosure] had been considered by the hypothetical skilled person together with the common general knowledge at the relevant time, "the invention would have been obvious".’

283 In Alphapharm a revocation claim on the ground of obviousness fell for consideration under the 1952 Act. The joint judgment of the majority referred in passing to the 1990 Act as providing relaxation of the rules forbidding the use of prior disclosures which, while publicly available, were not part of the common general knowledge at the priority date (at 422). This, of course, was the relaxation effected by s 7(2) and (3). The prior position reflected in the Minnesota Mining case would not, for example, allow obviousness to be established by an online search of the Patent Office library. The issue would not have been, was it obvious to search there, but whether ‘what a search would have disclosed had entered the body of common general knowledge’ (Alphapharm at 430).

284 The language of s 7(2) ‘indicates that the onus to establish the absence of an inventive step rests upon the party challenging validity’ (Firebelt at [31]).

285 The content of the concept of ‘inventive step’ was not changed by the 1990 amendments. The class of things that might be relied upon to prove its absence were widened, as already discussed, to include a prior disclosure or use or related disclosures or uses considered in the light of common general knowledge before the priority date.

286 The point of departure for determining whether a claimed invention was obvious at the priority date is the statement by Aickin J in Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12; (1981) 148 CLR 262 at 286 that:

‘The test is whether the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not.’

The idea of ‘routine’ in this passage was elaborated in Alphapharm by reference to an earlier passage of Aickin J’s judgment in Wellcome Foundation which was extracted at [51]. That passage referred to:

‘... experiments were of a routine character which the uninventive worker in the field would try as a matter of course.’
Wellcome Foundation at 281

287 The Alphapharm majority saw an affinity between the approach adopted by Aickin J and the so-called Cripps Question posed by Graham J in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157. The approach enunciated by Graham J in the passage that follows was expressly approved by the majority in Alphapharm:

‘Would the notional research group at the relevant date, in all the circumstances, which include a knowledge of all the relevant prior art and of the facts of the nature and success of chlorpromazine, directly be led as a matter of course to try the -CF₃ substitution in the "2" position in place of the – CI atom in chlorpromazine or in any other body which, apart from the – CF₃ substitution, has the other characteristics of the formula of claim 1, in the expectation that it might well produce a useful alternative to or better drug than chlorpromazine or a body useful for any other purpose?’

The approval of this passage in Alphapharm did not involve any acceptance of the proposition that a claimed invention is obvious if the steps that led to it would have been seen by a skilled addressee as ‘worth while to try’ in the light of common general knowledge at the priority date. The majority expressly rejected that criterion. They regarded the decisions of the United States’ courts, which also rejected that approach, as reflecting an approach closer to that adopted in the Minnesota Mining and Wellcome Foundation decisions.

288 There was no dispute in Alphapharm that the hypothetical non-inventive worker in the field could be represented by a team of persons experienced in the practical work of formulating drugs for pharmaceutical use. Such persons would be highly qualified chemists usually with a demonstrated capacity for original research. Assuming, as seems to have been common ground in the present case, that a PhD qualification would be an entry level requirement for participation in the notional team of skilled addressees, that would certainly be correct. The majority in Alphapharm paraphrased the approach taken by the learned trial judge in that case (at [30]):

‘The hypothesis which the case law required fixed upon members of that class who were not "particularly imaginative or inventive". There are conceptual difficulties in applying what is said in some of the older authorities respecting "workmen" and the like to modern conditions in the pharmaceutical and other industries. But the employment of highly skilled research teams as a matter of course, was noted over seventy years ago, well before the 1952 Act.’

The Court noted that there was no challenge to the approach of the trial judge. It was therefore not required to pass upon that approach but did not criticise it in any way.

289 The essential steps in the reasoning of the learned trial judge in the present case involved the following steps:

1. The notional team of skilled addressees would include a pharmacologist, a medical chemist and a medical practitioner experienced in the treatment of impotence.
2. Rajfer and Murray formed part of the common general knowledge at the priority date.
3. Rajfer could be relied upon to establish a lack of inventive step. It provided an unusually powerful indication that further examination of the PDE_V inhibitor possibility was ‘worth trying and that the expectation that such examination might produce a worthwhile result was a very reasonable one’.
4. Murray formed part of the common general knowledge of the priority date but also qualified as a s 7(3) document.
5. Murray could be relied upon to establish a lack of inventive step.

290 As Lilly observed in its submissions on the question of inventive step, Pfizer’s submissions related almost entirely to evidentiary matters. Pfizer contended that there was no evidence at trial justifying the conclusion that the invention as claimed in claim 10 was obvious. There was no evidence as to the state of common general knowledge of skilled addressees within Australia. If it were proper to rely upon evidence of the knowledge of persons overseas, that did not establish that a skilled addressee, by taking routine steps, would have been led directly to the invention. Moreover, it was submitted, that the evidence of widespread demand for an oral treatment for erectile dysfunction and the failure of anybody to disclose the use of a cGMP PDE_V inhibitor in an oral treatment for erectile dysfunction until after the publication of Pfizer’s Patent spoke strongly against the trial judge’s conclusions.

291 Pfizer identified what it said were a number of incorrect factual findings on the part of the learned trial judge. It summarised its position thus:

(a) Each of Dr Cherry, Dr McMahon and Dr Cartmill, was not capable of giving relevant and admissible evidence of the state of common general knowledge of the skilled addressee working in the field in Australia in 1993/94.

(b) Each of the overseas witnesses, Dr Gristwood, Dr Kruse and Mr Pryor, was not capable of giving relevant and admissible evidence of the state of common general knowledge of the skilled addressee working in the field in Australia in 1993/94.

(c) Murray was not part of the common general knowledge of the skilled addressee in Australia as at 1993/94.

(d) It was not an overstatement to say that as at the relevant priority date each of cGMP PDE_V and PDE_I ‘were known to be located in tissues situated throughout the body, including in the smooth muscle of the vasculature platelets and lung tissue’.

(e) As at 13 May 1994 there was not a complete and accurate knowledge of the presence of PDEs and their types in corpus cavernosum.

(f) The Pfizer team’s discovery of the invention claimed in claim 10 was:

(i) not due to the impact of Rajfer; and
(ii) serendipitous.

(g) As at 1993/94 the skilled addressee (overseas, there being no evidence from Australian addressees) was concerned about potential dangerous effects from an orally administered PDE_V inhibitor; and

(h) The term ‘compounds of formula (I)’ is not synonymous with the term ‘compounds of the invention’.

292 Pfizer’s submissions involved the contention that the learned trial judge should not have had regard to the evidence of expert witnesses from outside Australia as proxies for people who worked in the relevant field in Australia. That submission is not accepted. But it was open to his Honour to have regard to such evidence in assessing the state of common general knowledge of an hypothetical skilled team in Australia at the priority date. He could also have regard to such evidence in assessing the significance of prior art information in Australia. The linkage to be made between the evidence of overseas witnesses and the position in Australia was a matter of fact and inference.

293 There was ample evidence before his Honour of the international character of research in the field of erectile dysfunction. By way of example, Dr Gristwood gave evidence of matters known to him and which he believed would have been known to other pharmacologists in the United Kingdom and elsewhere, including Australia, in 1993. Evidence as to the global nature of a particular field of scientific inquiry can properly be given by one who is an expert in the field. It is the kind of thing which, in the ordinary course of his research and communication with other scientists, he could be expected to know. Whether or not it is to be accepted, is a matter for the trial judge.

294 Mr Pryor was based in the United Kingdom, but gave evidence of contacts with urologists in Australia before 1993 and the close links that existed between the British and Australian Urological Associations. It is not necessary to multiply examples of the evidence which has already been summarised in these reasons. It is sufficient to say that it supported the inference of a global pool of common general knowledge on issues relevant to the invention which would have been known to the skilled hypothetical addressee in Australia and that Rajfer and Murray were, as found by his Honour, part of that common general knowledge.

295 The present case is not to be decided by niceties of the location of particular expert witnesses. That kind of approach would place the fields of pharmacology, medicinal chemistry and urology in Australia in a rather unreal state of isolation from the rest of the world.

296 As to the evidence of clinical urologists, which it was suggested should not have been accepted as they were not properly part of any hypothetical team of skilled addressees, that submission is not accepted. Dr Cherry, who is a Perth urologist, gave evidence of his knowledge of the field which of itself was a good indicator of the common general knowledge that other relevant skilled addressees on the hypothetical team would have. The Pfizer submissions would have excluded relevant clinicians from the team looking for a mode of treatment for impotence. But clinicians and, in particular, urologists, were in a position to offer a practical, clinical perspective, albeit rooted in the necessary theoretical learning which was necessary for the development of an effective treatment.

297 So much having been said, the critical question in this case was whether Rajfer and Murray regarded as part of the common general knowledge or as s 7(3) documents, jointly or severally, rendered the development of the claimed invention obvious. For it was on the foundation of those two works that his Honour held the claimed invention to lack the necessary inventive step.

298 The learned trial judge reviewed, in his reasons for judgment, what Rajfer conveyed to various expert witnesses. His findings in this respect may be summarised as follows:

1. Dr McMahon saw Rajfer as clarifying the role of NO as part of a cascade of neurotransmitters in the development of penile erection. Beyond that the main conclusion he drew was that there may be a role for zaprinast and perhaps for PDE_V drugs as a treatment for men with erectile dysfunction.

2. Dr Cherry concluded from Rajfer that the NO/cGMP pathway was responsible for the human erectile response and that, at an in vivo level, the pathway could be manipulated by potentiating NO formation or by the use of a cGMP PDE inhibitor such as zaprinast.

3. Mr Pryor saw the paper as demonstrating that zaprinast was potentially useful in the treatment of erectile dysfunction because it elicited the immediate physiological response, ie smooth muscle relaxation in penile tissue taken from impotent human patients.

4. Dr Gristwood said that on reading Rajfer he appreciated that impotence was a new therapeutic possibility for PDE_V inhibitors in light of the fact that zaprinast, a known selective PDE_V inhibitor, was shown to enhance smooth muscle relaxation of human corpus cavernosum tissue. Rajfer would have strongly suggested to him the use of PDE_V inhibitors as a new treatment for impotence.

5. Dr Kruse did not recall reading Rajfer at the time of its publication. He thought Rajfer completely elucidated the NANC pathway leading to erection. Smooth muscle relaxation induced by NO was mediated through an increase in the cGMP PDE inhibitor, zaprinast, which he knew was a selective inhibitor of PDE_V. Because Rajfer used actual human penile muscle tissue from men suffering from erectile dysfunction he would have had a ‘high level of confidence’ that Rajfer’s results would have been directly transferable in vivo.

6. Dr Ellis said that all Rajfer did was to confirm early animal results and demonstrate that NO was a neurotransmitter in the NANC pathway. He agreed in cross-examination that Rajfer showed that zaprinast used as a tool potentiated or augmented or enhanced the effect of electrical field stimulation and NO under experimental conditions defined.

7. Dr Palmer had not read Rajfer before the present proceedings. Its whole thrust was consistent with a focus on confirming the features of the NANC/L-arginine/NO/cGMP pathway. It did not disclose a logical therapeutic use of PDE inhibitors for the treatment of impotence.

8. Dr Robertson said that Rajfer proved to him that NO was the key mediator and that something which mimicked it or supplied it to the penis would be likely to give an erection.

299 His Honour did not refer to that part of Dr McMahon’s evidence in which he described the Rajfer paper as a ‘proof of concept’ type paper which suggested a ‘potential role’ for zaprinast in the treatment of erectile dysfunction. Dr McMahon also pointed out that the level of relaxation demonstrated in the paper could not be translated to the level of relaxation or the concentration of zaprinast necessary in vivo.

300 Dr Kruse had said in cross-examination that there was no case in which one could take an in vitro experiment and leap to an efficacious dose in man. What could be done was to take the reasonable step of going forward with a PDE_V inhibitor and doing appropriate clinical trials.

301 His Honour did not refer to the Bayer witness, Dr Brown. Dr Brown said in his evidence that the obvious pharmacological approach in the light of Rajfer was to use a PDE_V inhibitor as an orally active direct acting vasodilator interfering with the L-arginine NO pathway to relax the smooth muscle. However he agreed in cross-examination that it was not possible from Rajfer to draw the conclusion that the reported effect of the PDE_V inhibitor in that case would be greater in penile tissue than in any other tissue in the body.

302 His Honour did not canvass Professor Goldie’s evidence which was that the overall message from the Rajfer paper was that NO released by NANC nerves is essential to penile erection. It also set the scene for ‘clinical intervention to treat impotence with substances which act on the NO pathway either as an NO donor or as a cGMP PDE inhibitor’. Dr Goldie accepted in cross-examination that in learning about the paper some people would say that in addition what they ought to be doing is looking at the potential for PDE_V inhibitors as a potential therapy. He was not saying that that was his reaction.

303 Dr Cartmill, another Bayer witness, had not read the Rajfer paper before his preparation for the present proceedings. He said that the use of cGMP PDE inhibitors to treat impotence stood out from Rajfer as an obvious thing to do from a urological perspective.

304 His Honour made the global statement that he accepted the evidence of Lilly and Bayer witnesses as to what Rajfer would have conveyed. However, with respect to his Honour, it cannot be said that the message conveyed by the Lilly and Bayer witnesses was consistent and unambiguous as to what Rajfer would have conveyed to them. It must of course be acknowledged that his Honour made the point that scientific papers have a ‘cautious tone of voice’ with a ‘liberal sprinkling of qualifications’ and that (at [135]):

‘In a discourse in that style and tone Rajfer conveys, not certainty, for that is not required, but a well-founded expectation that further testing of cGMP PDE_V inhibitors might well provide a treatment for impotence or, in Dr Robertson’s words, would be likely to have that effect.’

305 In concluding that Rajfer could be relied upon to establish a lack of inventive step, his Honour came close to adopting the ‘worthwhile to try’ approach eschewed by the High Court in Alphapharm. For he said that Rajfer provided an unusually powerful indication that further examination of the PDE_V inhibitor possibility was ‘worth trying and that the expectation that such examination might produce a worthwhile result was a very reasonable one’.

306 So far as Murray was concerned, his Honour accepted, correctly, that it was probably unnecessary and artificial to consider Murray without Rajfer as the former specifically referred to the latter. Murray, of course, was a review article, not one reporting research in its own right. Murray really stands or falls with Rajfer in this connection.

307 Rajfer was an in vitro organ bath experiment using strips of penile tissue subjected to electrical stimulation and exposure to different chemicals including methylene blue and zaprinast. Its principal objective was clarification of the NANC L-arginine NO pathway in erectile function. While the evidence of the expert witnesses might well support a conclusion from Rajfer that investigation of the effects of a cGMP PDE_V inhibitor on erectile function was worth a try, it could not be said, given the uncertainties attending such further investigation, that it would be routine or ‘a matter of course’. The same is true of Murray.

308 The fact that Dr Ringrose suggested to his management team that they ‘try out UK-92,480, in impotence’ does not of itself establish that any such try out would have been a matter of routine or of course. It might well be, as his Honour said, that the ideas conveyed by Rajfer were intimately bound up in Pfizer’s work which led to the alleged invention the subject of the Patent. But the facts as found by his Honour do not, with respect, support the notion of a mere routine process of investigation leading to the invention claimed in claim 10.

309 In a recent essay, Sir Hugh Laddie criticised the concept of ‘obvious to try’ as the criterion of want of inventive step expounded by the English Courts. He said:

‘On its face, this produces an unworkable or irrational test. If the reward for finding a solution to a problem and securing a monopoly for that solution is very high, then it may well be worthwhile for large players to examine all potential avenues to see if one gives the right result, even though the prospects of any one of them succeeding are much less than 50/50. What makes something worth trying is the outcome of a simple risk to reward calculation. Yet, if the reward is very large, the avenues worth trying will be expanded accordingly. So, the more commercially attractive the solution and the more pressing the public clamour for it, the harder it will be to avoid an obviousness attack. In those circumstances a solution which is quite low down a list of alternatives, all of which are more or less worth trying, will fail for obviousness; a consequence which is consistent with the decision in Brugger v Medic-Aid [1996] RPC 635’.

Laddie, ‘Patents – what’s invention got to do with it?’ In Vaver and Bently (eds) Intellectual Property in the New Millennium, Cambridge University Press (2004) 91 at 93.

310 As a more general critique of the obviousness requirement he observed (at 95):

‘For example, in the world of medicine and genetics, not only do we now have great understanding of how chemicals and genes work but there are now new disciplines which allow the technician to determine what shape of molecule exhibits a particular beneficial property and how to make molecules of that shape.

It is this type of technology which will be used to tackle diseases in the future, yet in many cases it may be said that the application of such technology to solve known problems is not inventive. It appears that the field of pharmaceuticals, the example which is most often used to demonstrate the necessity of patent protection to delivery of new and valuable products to the public, also illustrates how ill-suited the law is for achieving that goal.

It has been said that patents are not granted simply for coming first in the race to achieve an obvious product or process. Yet in many cases, absent the commercial incentive of a patent, there will not be a race at all.

In this case, on accepted tests of obviousness as enunciated most recently in Alphapharm, his Honour erred in reaching the conclusion that he did. The evidence did not disclose lack of an inventive step in relation to the invention claimed in claim 10. On that point Pfizer succeeds.



Novelty

311 It is a requirement, for the patentability of an invention as claimed in any claim, that it be novel when compared with the prior art base as it existed before the priority date of the claim (s 18(1)(a)(i)). For the purpose of novelty the ‘prior art base’ is as defined in the dictionary set out in Schedule 1.

312 Section 7(1), like s 7(2) with respect to want of inventive step, places the onus of showing want of novelty on the party seeking to establish the absence of that condition of patentability. Novelty may be negatived by reference to prior art information in a single publicly available document or act or two or more documents or acts so related that a skilled addressee would treat them as a single source of the information. Prior art contained in an earlier specification may also negative novelty but that category is not relevant for present purposes. The prior art base which may be regarded for the purpose of determining novelty was significantly extended by the 1990 Act. In the case of a standard patent it covers ‘information in a document publicly available outside the patent area’. Under the 1952 Act the only relevant prior art comprised publications or uses in Australia.

313 The law relating to novelty under the 1990 Act was considered by the Full Court in Bristol-Myers Squibb. In the joint judgment of Black CJ and Lehane J, their Honours referred to what had been said by Aickin J 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 or 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.’

In the case of a paper anticipation such as a specification or publication, there can be no direct application of the reverse infringement test. An hypothetical infringement may be posited on the assumption that somebody does or makes what the alleged anticipation suggests. Their Honours cited Lord Westbury in Hill v Evans (at 546 [63]):

‘... 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. If something remains to be ascertained which is necessary for the useful application of the discovery, that affords sufficient room for another valid patent.’

Their Honours also referred to Flour Oxidizing Co Ltd v Carr & Co Ltd (1908) 25 RPC 428; Canadian General Electric Co Ltd at 104 and General Tire & Rubber Co v Firestone Tyre and Rubber Co Ltd [1972] RPC 457. After reviewing those authorities, they said (at 548 [67]):

‘What all those authorities contemplate, in our view, is that a prior publication, if it is to destroy novelty, must give a direction or make a recommendation or suggestion which will result, if the skilled reader follows it, in the claimed invention. A direction, recommendation or suggestion may often, of course, be implicit in what is described and commonly the only question may be whether the publication describes with sufficient clarity the claimed invention or, in the case of a combination, each integer of it.’

314 The learned trial judge referred to the judgment in Bristol-Myers Squibb and cited in particular the statement of the Privy Council in the Canadian General Electric Co case that (at [90]):

‘... it is not enough to prove that an apparatus described in an earlier specification could have been used to produce this or that result. It must also be shown that the specifications contain clear and unmistakable directions to use it.’

His Honour then considered whether or not Murray or Korenman anticipated the invention. Murray gave no particular prominence to the treatment of impotence and did not mention that use in its statement of the theme of the article. Korenman taught away from the pith and substance of claim 10 of the Patent which relates to the use of a substance identifiable by a particular function, namely the inhibition of cGMP PDE_V. There was no reference in Korenman to pentoxifylline as a cGMP PDE_V inhibitor. His Honour held claim 10 not liable to be revoked for want of novelty.

315 In challenging his Honour’s conclusions as to novelty, Lilly accepted that he had correctly set out the test. However it contended that with respect to each of the Murray and Korenman publications he had erred in its application.

316 Lilly submitted that his Honour took an over-literal approach to the question whether Murray directed, recommended or suggested the invention under consideration. It submitted that the statutory question is whether the invention, so far as claimed in claim 10, is novel in the light of the information contained in Murray. This does not demand any particular level of emphasis, prominence, proof or certainty. Nor does the phrase ‘direct, recommend or suggest’ used in the Bristol-Myers Squibb case. The question, according to Lilly, is whether Murray ‘teaches’ the claimed invention. In approaching that question it was necessary to consider whether a skilled addressee following the ‘teaching’ of the publication would perform the invention and therefore infringe claims to it.

317 Lilly referred to observations by Crennan J in Imperial Chemical Industries Pty Ltd v Commissioner of Patents [2004] FCA 1658; (2004) 213 ALR 399. Her Honour there quoted Sachs LJ in General Tire & Rubber Co that (at 411 [61]):

‘... 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.’

She said that ‘clear and unmistakable directions’ to do what the patentee claims to have invented are ‘necessary’. Even allowing for implicit disclosures of the kind contemplated by the joint judgment in Bristol-Myers Squibb, as her Honour said (at 412 [63]):

‘... skilled addressees are not required to rummage through the prior patentee’s "flag locker" to find a "flag which the [prior patentee] possessed and could have planted".’ – citing ICI Chemicals v Lubrizol Corp [2000] FCA 1349; (2000) 106 FCR 214.

318 Lilly submitted that his Honour had misapplied the ‘teaches’ test for novelty and that applying the correct test he ought to have found that Murray taught the use of a cGMP PDE_V inhibitor to treat erectile dysfunction. Its teaching was not a mere hypothetical assertion. It clearly taught that zaprinast is an inhibitor of PDE_VA. Lilly referred to the discussion in Murray of the therapeutic utility of PDE_VA inhibitors for the treatment of impotence as based, among other things, on:

(a) the relaxation caused by zaprinast on strips of human corpus cavernosum described in Rajfer;
(b) examples of the oral use of zaprinast in humans.

The article, it was submitted, was authoritative and persuasive on its face. Murray taught all of the integers of the claim in combination including oral administration. Indeed, the disclosure in Murray was at least equivalent to the disclosure in the patent in suit. An anticipation, it was said, need only reveal the claimed invention to the same level of specificity as the patent in suit. These contentions however considerably overstated the content and effect of Murray.

319 Murray was a review article which focussed upon the therapeutic potential of PDE_V inhibitors as vasodilators, bronchodilators and modulators of gastrointestinal motility. This therapeutic potential was largely based on the effects of zaprinast. The paper discussed PDE families and their nomenclature generally and the cGMP specific PDE isoenzyme PDE_V, its family members and isoforms.

320 It referred to PDE_V inhibitors and zaprinast, noting that there was considerable confusion about its selectivity for PDE_V with respect to PDE_I. Its effect on various in vitro smooth muscle preparations was set out in Table V of the paper. That table did not include reference to human corpus cavernosum. The reference to Rajfer was brief and in the following terms (at 153):

‘The effects of zaprinast have also been studied in a number of other smooth muscle types. With strips of human corpus cavernosum, zaprinast alone caused a relaxation and enhanced the relaxation caused by nitric oxide or electrical stimulation.’

321 In relation to its potential therapeutic use, the article stated (at 154-155):

‘Smooth muscle relaxation appears to be the most promising of the potential uses of PDE V_A inhibitors, and possible therapeutic utilities could include vasodilation, bronchodilation, modulation of gastrointestinal motility and treatment of impotence.’

322 Having regard to the generality of the discussion in Murray and to the brevity of the references to the use of PDE_V inhibitors in the treatment of human erectile dysfunction, it cannot be said on any application of the novelty tests referred to, that Murray anticipated the invention as claimed in claim 10.

323 A fortiori Korenman did not anticipate the invention as claimed in claim 10. His Honour was correct to hold, as he did, that it taught away from the pith and substance of that claim. It made no reference to pentoxifylline as a cGMP PDE_V inhibitor. Moreover as his Honour found, pentoxifylline did not act via any such inhibitory mechanism. As the Korenman paper explicitly recognised, the design of the experiment was based on the fact that pentoxifylline treatment altered red cell membrane at formation and therefore had a delayed onset of action. Viagra and Cialis, as his Honour observed, had effect shortly after the administration of a single dose.

324 Lilly’s contention that the invention as claimed in claim 10 wants novelty fails.

Sufficiency

325 Section 40(2)(a) of the Act requires that a complete specification ‘describe the invention fully including the best method known to the applicant of performing the invention’. The first limb of that requirement, namely that the invention be described ‘fully’ imports the requirement of sufficiency of description.

326 The complete specification referred to in s 40(2)(a) is the whole document inclusive of the claims – Kimberly-Clark at 19 [31]. The Court there said (at 12-13 [16]):

‘The question then is whether the invention has been fully described in the complete specification. The text speaks here of the complete specification, not any one part thereof. From the distinction drawn in s 40(2) between describing the invention in the complete specification and defining the invention in any claims with which the complete specification ends, it does not follow that the description is to be gleaned solely from one part (the body) and that it is forbidden to obtain any assistance by regard to the remainder (the claims) of the complete specification. Rather, the text indicates that the specification must be read as a whole and that reference to the claims may dispel ambiguity or uncertainty from the body of the specification concerning the description of the invention.’

327 The requirement of full description of the invention depends for its content, in part, upon the meaning of the word ‘invention’ as used in s 40(2)(a). The relevant meaning was stated by McTiernan J in respect of s 40(1) of the 1952 Act in AMP Inc v Utilux Pty Ltd (1971) 45 ALJR 123 at 127:

‘I take it to mean ‘the embodiment which is described, and around which the claims are drawn’.’

The High Court in Kimberly-Clark approved that formulation and its application to s 40(2)(a) of the 1990 Act.

328 For the purpose of assessing sufficiency the complete specification is to be read in the light of the common general knowledge and the art before the priority date. The Court is required to place itself ‘in the position of some person acquainted with the surrounding circumstances as to the state of [the] art and manufacture at the time’ – Kimberly-Clark at 16 [24] citing British Dynamite Co v Krebs [1879] 13 RPC 190 at 192. The relevant question formulated by the High Court in Kimberly-Clark at 17 [25] is:

‘... will the disclosure enable the addressee of the specification to produce something within each claim without new inventions or additions or prolonged study of matters presenting initial difficulty?’

329 The learned trial judge referred to the principles stated in Kimberly-Clark. He identified the skilled addressee as the hypothetical team mentioned earlier albeit possibly without the medical practitioner experienced in sexual medicine. His Honour considered that such a person might not be necessary for the purpose of assessing the workability of the patent.

330 In Lockwood Security the High Court held at 17 [60] that for the purposes of s 40(2)(a) it is not necessary for the inventor to disclose all alternative means of performing the invention. It is enough that the disclosure enables the addressee ‘to produce something within each claim without new inventions or additions or prolonged study of matters presenting additional difficulty’. In so doing the Court repeated what had been said in Kimberly-Clark. The learned trial judge adopted the latter statement. Whether or not obiter, as Lilly contended, it was a considered statement by a unanimous bench of the High Court and should be followed by a judge at first instance. His Honour was, with respect, quite correct to adopt that approach.

331 In determining sufficiency, his Honour referred to the evidence of Dr Robertson that the skilled addressee reading the Patent as a whole would be likely to focus on claim 8. He referred to Dr Robertson’s affidavit evidence which included the statement:

‘If I wanted to make a compound which was already known, and claimed in the Patent, then I would simply make one which was described in the Patent. I found the Patent to be very typical of those that I read and worked upon in 1993.’

He said that if he were setting out to manufacture a generic pharmaceutical based on the Patent he would manufacture the compound described in claim 8. If a citrate salt had not been made and mentioned in the claims, then claims 6 and 7 described two of the nine especially preferred compounds listed on page 6-7. If, in the absence of claim 8, he had to determine which of the compounds in claims 6 and 7 he most preferred he would, on balance, have favoured the compound in claim 7. That in claim 6 had a morpholine structure and could not be made into a salt very readily. It can also be metabolically vulnerable. Accordingly, he would prefer the piperazine in claim 7. This was the free base of the salt in claim 8 which was sildenafil monocitrate.

332 His Honour observed that Dr Scammells, Professor Charman and Dr Kruse were all prepared to accept that the addressee would narrow the area of interest down to the nine ‘especially preferred individual compounds’. He did not however find their evidence convincing in their steadfast refusal to go any further. He said (at [188]):

‘Apart from the fact that, as Dr Robertson said, one might reasonably take it that the data at page 9 line 30 was likely to refer to the compound which the structure of the text otherwise indicated was of particular interest, the issue here is not whether the Patent on its face provides a complete scientific rationale for a particular embodiment but rather whether the Patent identifies among a theoretically vast number of alternatives (apparently a common feature of chemical patents) one, or a reasonable number, which the addressee can select and work.’

333 His Honour observed that if the embodiment selected by the addressee for working came within claim 10 it would not matter that it also fell within claim 8. There was no justification for requiring the one embodiment of claim 10 relied upon to be outside the compounds of formula [1]. He also observed that the Bell patents are incorporated by reference into the Patent and contain sufficient instructions to enable a medicinal chemist to synthesise the compounds described in them.

334 Although it would be necessary to test any compound for oral bioavailability, toxicity and effectiveness, his Honour found that the evidence showed that while those steps called for skill, they were essentially routine for those skilled in the area. This did not necessarily equate to ease and simplicity. He noted that there was no evidence that anyone attempting to make something falling within claim 10 had failed. Lilly succeeded. Its product was within claim 10, hence the cross-claim for infringement.

335 In its submissions on sufficiency, Lilly reserved the right to argue before the High Court that the test in Kimberly-Clark and Lockwood Security was obiter and not intended to lay down a universally applicable principle for determining sufficiency.

336 It was submitted that his Honour had considered only the first limb of the test and incorrectly applied it. In this respect Lilly referred to his Honour’s observation that the task of determining oral bioavailability, toxicity and effectiveness might be a difficult one but that fact did not of itself mean that the Patent could not be worked without further invention. Contrary to Lilly’s submission this does not, in context, reflect any incorrect application of the test in Kimberly-Clark.

337 Lilly then turned to the question of the date upon which sufficiency should be determined. His Honour said (at [182]):

‘Consistently with the conclusion I have reached on the similar issue arising in relation to fair basing ... the date is, at the earliest, the date of grant. This means that claims 6, 7 and 8 and the other amendments made on 6 January 1997 must be taken into consideration.’

For the reasons set out in the next section dealing with ‘BEST METHOD’ his Honour’s conclusion as to the relevant date for the assessment of sufficiency was correct (see the discussion of the present question in Monotti: ‘Sufficiency of Description; At what time is adequacy to be considered’ (2005) 16 AIPJ 152 at 153-157). The question is whether he erred in the assessment of sufficiency.

338 Lilly attacked the assessment of sufficiency submitting that the specification only describes the results of tests undertaken on some compounds and failed to identify any tested compound identified. On some occasions the compound is described as being one of a sub-set of nine ‘especially preferred’ compounds. Sildenafil monocitrate is not identified in the specification.

339 Lilly also made the point that his Honour relied exclusively on Dr Robertson’s evidence as to the identification of the compound subjected to testing and for which results are claimed in the Patent. It argued, however, that part of Dr Robertson’s evidence quoted by his Honour was ruled inadmissible and part was admitted as opinion only. It may be noted that the parts cited earlier in this judgment were not so excluded.

340 One of the passages from Dr Robertson’s affidavit quoted by his Honour, which Lilly pointed out, was not admitted into evidence, read as follows (at 46 [187]):

‘I would infer that the tests and data referred to in the Patent relate to sildenafil, which is the third compound listed in the nine especially preferred compounds on page 6-7 of the Patent.’

It was pointed out that in the balance of the quoted paragraph Dr Robertson did not make such a specific inference. Accordingly it was said his Honour erred in concluding from this evidence that the compound tested and for which results were given in the Patent was sildenafil citrate. The evidence otherwise supported the view that the compound tested was either sildenafil or sildenafil citrate.

341 Professor Charman had given evidence that even if the choice were limited to sildenafil or sildenafil citrate he would still need to evaluate both compounds for their suitability for development and clinical study because ‘if the compound tested for clinical development and study was sildenafil this would not suffice for the citrate salt and vice versa’.

342 It was not disputed that a range of tests would have to be performed before the compound was administered to a human to determine whether it were efficacious. Lilly submitted therefore that a considerable investment in time and resources was required before any compound could be tested for efficacy in humans. Given that time and cost it submitted that forcing a skilled addressee to discriminate between even two compounds by not identifying that for which the patentee generated a result constituted a requirement that the skilled addressee undertake prolonged study of matters presenting initial difficulty within the meaning of Kimberly-Clark. A fortiori, it was argued, the evidence supported the view that, without claims 6, 7 and 8, the skilled addressee could not have made something within the claim without prolonged study of matters presenting initial difficulty.

343 In response, Pfizer contended that Lilly had misstated the proper test in its argument that the Patent invalidly failed to identify the compound which had been subjected to testing and for which particular results were claimed. The High Court in Lockwood Security had been at pains to identify ‘that the grounds of invalidity themselves are, and must be kept, conceptually distinct’. The effect of the contentions by Lilly was to confuse the requirement under s 40(2)(a) to disclose the best method of performing the invention known to the inventor with the requirement to provide a sufficient description of the invention to enable it to be performed. Given, however, that the ‘best method’ is an inclusion in the sufficiency criterion, it is not clear that the warning in Lockwood Security applies to require a sharp distinction between these two aspects of s 40(2)(a).

344 Pfizer pointed to the principle articulated in Kimberly-Clark and repeated in Lockwood Security that the patentee is required only to give sufficient disclosure to enable an addressee to produce something within each claim. There is no requirement that the ‘something’ must be the ‘best method’ known to the patentee at the priority date of performing the invention.

345 The trial judge had held as a question of fact that the Bell patents were incorporated by reference into the Patent and that they contained sufficient instructions to enable a medicinal chemist to synthesise the compounds described in them. This was conceded by Drs Scammells, Kruse and Robertson. The trial judge found that at least with respect to nine specifically identified compounds there was sufficient information either in the Patent or incorporated by the reference to the Bell patents to synthesise each of those PDE_V inhibitors. A skilled addressee could test and screen those compounds. This was not challenged and could not be challenged in the evidence.

346 Having regard to the evidence to which Pfizer pointed in its submissions and the evidence upon which his Honour relied (even allowing for the inadmissibility of two portions of the paragraph quoted from the evidence of Dr Robertson), there was more than an adequate basis for him to come to the conclusion that he did, that the specification gave a sufficient description for the purposes of s 40(2)(a) of the Act.

347 His Honour’s conclusion depended in part upon his finding that the date for assessment of sufficiency was the date of the grant of the Patent. The same question arises under s 40(2)(a) in relation to disclosure of the best method for performing the invention. For the reasons that follow the relevant date for that purpose is the date of grant. Those reasons apply equally to the issue of sufficiency. The Lilly submissions as to sufficiency are not accepted.

Best Method

348 Section 40(2)(a) of the Act provides:

‘A complete specification must:

(a) describe the invention fully, including the best method known to the applicant of performing the invention; ...’

349 The active ingredient of Viagra is sildenafil monocitrate. It was added to the specification in the form of claim 8, which was introduced by way of an amendment on 6 January 1997. Claims 6 and 7 were added on the same date.

350 Lilly submitted that ‘the best method known to the applicant of performing the invention’ must be included in the complete specification at the ‘filing date’, in this case, the international filing date of the PCT application, 13 May 1994 (see s 88 of the Act), and no later. If this is right, so Lilly’s submission went, s 40(2)(a) was not complied with; the purported complete specification filed on 13 May 1994 was not a complete specification within the meaning of the Act; and the Patent is invalid.

351 Pfizer submitted that the date as at which s 40(2)(a) must be complied with, that is to say, by which disclosure of the best method must be made, is either the date of grant (10 July 1997) or the date of commencement of the proceeding before his Honour (17 September 2002).

352 In his reasons for judgment the learned trial judge referred to the definition of ‘complete specification’ in the Act’s Dictionary in Sch 1:

‘Complete specification means (other than in section 116) a specification filed in respect of a complete patent application or, if the specification has been amended, the complete specification as amended.’

He saw no reason why the definition did not apply in s 40(2)(a). He thought it to be expected that the Act would make it clear if, in a particular context, the Dictionary meaning was not intended, as it did in ss 41(1), 42(1)(b), 79B(1)(a) and 102(2A).

353 The learned trial judge referred to s 138(3) which sets out the grounds of revocation, and noted that some of them were expressed in the past tense and the others in the present tense, that relevant to the present case, ground (f) (‘that the specification does not comply with s 40(2) or (3)’), being expressed in the present tense. His Honour thought that this rather suggested that the Court was required to look at the specification at the time when the proceeding (for revocation) was commenced.

354 His Honour referred to the general principle that ‘judicial proceedings to enforce alleged rights are determined according to the law existing at the time when the proceedings are instituted, unless the statute otherwise provides’, citing Esber v The Commonwealth [1992] HCA 20; (1992) 174 CLR 430 at 448-449 per Brennan J, and Frederikshavn Vaerft A/S v Stena Rederi Aktiebolag [2002] FCA 1024; (2002) 124 FCR 243 at 249 per Sundberg J. His Honour therefore saw ‘force in Pfizer’s primary argument that the court must consider the validity of the Patent at the time of commencement of the proceeding’ (at [202]).

355 While his Honour accepted that if the matter were unconstrained by statute, persuasive reasons could be advanced favouring the date of filing, he saw the question as being, not which of various solutions was preferable, but whether the plain meaning of the Act led to a result that was ‘irrational, absurd, extraordinary, capricious or obscure’, citing Cooper Brookes (Wollongong) Pty Ltd v Federal Commissioner of Taxation [1981] HCA 26; (1981) 147 CLR 297 at 304, 321. The construction supported by Pfizer (date of commencement of proceeding) was not, according to his Honour, of that kind. Alternatively, he said, there was much to be said for the date of grant, citing Illinois Tool Works Inc v Autobars Co (Services) Limited [1974] 91 RPC 337 at 369.

356 His Honour’s conclusion was that the relevant date was, at the earliest, the date of grant. By that date, of course, the best method of claim 8 was included in the specification.

357 Lilly’s submissions proceeded along the lines set out in [358] to [364] below.

358 Subsections 29(1)-(4) provide:

‘(1) A person may apply for a patent for an invention by filing, in accordance with the regulations, a patent request and such other documents as are prescribed.
(2) An application may be a provisional application or a complete application.
(3) A patent request in relation to a provisional application must be in the approved form and accompanied by a provisional specification.
(4) A patent request in relation to a complete application must be in the approved form and accompanied by a complete specification.’

What distinguishes a complete specification from a provisional specification is compliance with s 40(2).

359 Patents have always dated from the date of the filing of the complete specification: see s 65(a) of the Act. This reflects a policy that the consideration for the grant of the monopoly is the disclosure to the public of the invention, including the best method known to the applicant of performing it. This policy would be frustrated if disclosure of the best method could be made later than the date of the patent. Lilly submitted:

‘Put shortly, the 1990 Act expressly provides that, before a patent is granted, the patent specification must be determined to comply with s 40(2), including the best method as part of s 40(2)(a), at each of these stages. If Pfizer is right, the absurd position would be reached that it would be a valid answer at the stage of s 45(1)(a) (examination), s 49(1)(b) (acceptance) or s 59(c) (opposition), or on an appeal under s 51 or s 60, that even though the applicant has not provided its best method – and satisfied the mandatory requirement of s 40(2)(a) – it proposes to do so by way of an amendment to the specification which is to be filed (and presumably allowed) at some later date – upon grant, or even at the commencement of proceedings. On his Honour’s construction, a patent could be obtained without ever providing the consideration for the grant of the patent. With respect, this cannot be correct.’

Again, an outcome of his Honour’s conclusion is that s 59(c) would have no work to do. That provision is as follows:

‘The Minister or any other person may, in accordance with the regulations, oppose the grant of a standard patent on one or more of the following grounds, but on no other ground:
(a) ... ;
(b) ... ;

(c) that the specification filed in respect of the complete application does not comply with subsection 40(2) or (3).’

If the primary Judge’s conclusion is correct, opposition on this ground, in so far as it relates to s 40(2)(a), would be rendered futile.

360 Accordingly, the second part of the definition of ‘complete specification’ (see [352] above) does not apply to s 29(4) or s 40(2)(b).

361 A historical review of the cases shows that even before statute expressly required it, a statement of the best method of performance of the invention was required by the courts: Liardet v Johnson (1778) 1 WPC 53 (reproduced in Hayward’s Patent Cases, vol 1, 196–201) at 198 per Lord Mansfield LJ; R v Arkwright (1785) 1 CPC 53 (reproduced in Hayward’s Patent Cases, vol 1, 261–311) at 261, 266, 288, 294; Morgan v Seaward (1835) 1 WPC 174–175 (reproduced in Hayward’s Patent Cases, vol 1, 682–683) at 200; British Dynamite at 192, 195.

362 A practice developed of distinguishing in complete specifications between the definition of the invention in ‘claims’, and the disclosure of practical directions for the use or performance of it. The distinction was made obligatory by s 5(5) of the Patents, Designs and Trade Marks Act 1883 (UK) (cf s 40(2)(b) of the Act).

363 In Australia, the Patents Act 1903 (Cth) provided in s 36:

‘A complete specification must fully describe and ascertain the invention and the manner in which it is to be performed, and must end with a distinct statement of the invention claimed.’

and in s 86(3):

‘Every ground on which a patent might at common law be repealed by scire facias shall be available as a ground of revocation.’

An express requirement that a complete specification ‘fully describe the invention, including the best method of performing the invention which is known to the applicant, appeared in s 40(1) of the Patents Act 1952 (Cth) (‘the 1952 Act’), which is, in effect, re-enacted as s 40(2)(a) of the 1990 Act.

364 In its historical review of the authorities and statutory provisions relating to disclosure of best method, Lilly referred to Vidal Dyes Syndicate Ltd v Levinstein Ltd [1912] 29 RPC 245 at 269, 273, 280; Firebelt Pty Ltd v Brambles Australia Ltd [2002] HCA 21; (2002) 188 ALR 280; Blanco White, Patents for Inventions (5^th ed) at [4-507]; and Colgate-Palmolive Co v Cussons Pty Ltd (1993) 26 IPR 311 at 354-355, as well as authorities on SS112 of the US Patents Act, USC Title 35 (which requires the specification to ‘set forth the best mode contemplated by the inventor of carrying out his invention’), namely, In re Gay 309 F 2d 769, 772; 135 USPQ 311 (CCPA 1962); Amgen Inc v Chugai Pharmaceutical Co Ltd (1991) 927 F 2d 1200; 18 USPQ 2d 1016 (Fed Cir 1991); cert denied, 112 S Ct 169 (1991), at 927 F 2d 1209-10, 18 USPQ 2d at 1024; Spectra-Physics Inc v Coherent Inc 827 F 2d 1524 at 1535; 3 USPQ 2d 1737 at 1745 (Fed Cir 1987); cert denied, 484 US 954 (1987), Nobelpharma AB v Implant Innovations Inc 141 F 3d 1059 at 1064; 46 USCQ 2d 1097 at 1101 (Fed Cir 1998); cert denied, 119 S Ct 178 (1998).

365 Pfizer’s submissions proceeded along the lines set out in [366] to [372] below.

366 There is a distinction between the date at which the best method known to the applicant is to be identified and the date by which that method must be disclosed in the complete specification in satisfaction of s 40(2)(a). Lilly’s submissions erroneously blur the two, to arrive at the one date (date of filing) for both. In truth, the former is the date of filing, but the latter is the date of acceptance or the date of grant.

367 Lilly challenged the correctness of the latter, but not the former date. As a matter of statutory construction and longstanding authority, including Rescare Limited v Anaesthetic Supplies Pty Ltd (1992) 111 ALR 205 at 220-233 per Gummow J, and Kimberly-Clark, as well as United Kingdom authority consistent with the Act, the date is no earlier than the date of grant and is probably as late as the date of commencement of the proceeding.

368 The Act allows for amendment of a specification up to acceptance by the Commissioner, up to grant, and even subsequently: ss 102, 104. Lilly’s submission would require the making of an exception in the case of one aspect of the requirement of s 40(2)(a) (the inclusion in the complete specification of a statement of best method) where the terms of the Act do not suggest this.

369 As his Honour observed (see [353] above), within s 138(3) the various grounds on which the Court may revoke a patent differ in their use of the present and past tenses, the relevant ground being expressed in the present tense.

370 There are provisions of the Act which specify times at or by which particular conditions must be satisfied, such as ss 6(a) and 42(1)(b) (relating to micro-organisms), 79B (relating to divisional applications) and 102(2)(a) (amendments). If Parliament had intended a requirement that s 40(2)(a) be complied with at the time of filing and not later, it would similarly have said so. In the absence of such an express limitation, the requirement can be satisfied at any time down to grant.

371 In England it is accepted that the date of publication of the complete specification is the date at which sufficiency of disclosure is to be tested, citing Terrell on the Law of Patents (13^th ed 1982) at [5.04]; Anxionnaz v Rolls Royce Limited [1967] 84 RPC 419 at 471 per Lloyd-Jacob J, followed by Graham J in Illinois Tool Works Inc at 369.

372 Pfizer submits that the Court should not follow the obiter dicta of Gummow J in Rescare.

373 The Court’s consideration of the competing submissions on the relevant date for the purpose of best method disclosure follows.

374 Disclosure of the ‘best method known to the applicant of performing the invention’ (a subjective notion) is a part of describing the invention ‘fully’: s 40(2)(a) provides that a complete specification must ‘describe the invention fully, including the best method known to the applicant of performing the invention’ (our emphasis). The best method known to the applicant need not be identified as such in the specification: Eli Lilly & Co at [206], approving C Van Der Lely NV v Ruston’s Engineering Co Ltd [1993] RPC 45 at 56. The requirement that an applicant disclose the best method known to the applicant of performing the invention safeguards against an applicant’s holding back with a view to getting the benefit of the patent monopoly without conferring on the public the full consideration for the grant of that monopoly: cf Firebelt Pty Ltd v Brambles Australia Ltd at 544.

375 The date as at which the best method known to the applicant is to be identified is conceptually distinct from the date by which the specification’s full description of the invention must include a disclosure of it. The parties correctly proceeded on the basis that it is the best method known to the applicant as at the filing date that must be disclosed. In Rescare, Gummow J expressed the opinion (at 223) that this was so under s 40 of the 1952 Act, and s 40(2)(a) is to the same effect as s 40(1)(a) of the 1952 Act.

376 The facts of Rescare call for careful consideration. In that case, a ‘one tube’ apparatus provided a better method than a ‘two tube’ apparatus for performing the invention (a device for treating ‘snoring sickness’ or ‘obstructive sleep apnoea’). The one tube apparatus was not known to the applicant on the international filing date, 23 April 1982. The respondent contended that the relevant date was the date of publication, 4 November 1982, and that the patentee knew of the one tube method by that date but failed to disclose it. Gummow J found that it had not been established that by the date of publication, the best method known to the applicant was the one tube method. This finding made it unnecessary for his Honour to determine the question of law whether it was the best method known to the applicant as at the earlier international filing date, 23 April 1982, which was required to be disclosed. His Honour went on, however, to express his opinion on the point.

377 Gummow J traced the history of the requirement of disclosure of best method, and concluded (at 223):

‘Sections 67 and 68 of the 1952 Act provided for a term of a standard patent of 16 years, reckoned from the date of the patent, this being the date on which the complete specification was lodged. The adequacy of the disclosure should be judged by reference to the time from which dated the monopoly granted the applicant in exchange for the disclosure. In the present case that is the international filing date, 23 April 1982. This is the date from which the term of the patent runs.’

378 In Rescare his Honour was concerned with the date as at which the best method known to the applicant for the patent is to be identified. This is shown by the genesis of the issue described above: was the specification deficient for disclosing only the two tube method and not the better one tube method?

379 Once it is accepted, however, that an applicant for a patent must disclose the best method known to the applicant at the date of filing, it is also not difficult to think, as Gummow J appears to have done and as we do, that disclosure must be made in the complete specification when it is filed. Lest there be any doubt, we would make it clear that s 40(2)(a) requires an applicant for a patent to disclose in the complete specification at the time of filing it the best method of performing it known to the applicant at that time: cf C Van Der Lely NV at 56 and Rediffusion Simulation Ltd v Link-Miles Ltd [1993] FSR 369 at 405, which were decided on ss 4(3)(b) and 32(1)(h) of the Patents Act 1949 (UK).

380 In our view, however, this does not resolve the issue raised by Lilly’s notice of contention, which is whether a failure to disclose on that date the best method then known to the applicant cannot in any circumstances be overcome by later amendment of the specification. In Rescare, Gummow J did not have to consider this question.

381 Lilly’s submission was that a document which purports to be a complete specification but which does not disclose from the outset the best method of performance then known to the applicant is simply not a ‘complete specification’ at all and can never become one by amendment. However, there appears to be no basis for carving out of the scope for amendment the disclosure of best method. Lilly’s submission must therefore be that if the purported complete specification as originally filed does not ‘describe the invention fully’ (s 40(2)(a)), or ‘where it relates to an application for a standard patent – end with a claim or claims defining the invention’ (s 40(2)(b)), or ‘where it relates to an application for an innovation patent – end with at least one and no more than five claims’ (s 40(2)(c)), it is no complete specification at all. Perhaps the submission must also be that unless ‘[t]he claim or claims [are] clear and succinct and fairly based on the matter described in the specification’ as required by s 40(3), and ‘[t]he claim or claims ... relate to one invention only ‘as required by s 40(4), again, irremediably, the document does not qualify as a complete specification and any patent issued on the basis of it is ineluctably invalid.

382 The questions arise then, consistently with Lilly’s submission:

•	What work, apart from allowing correction of a clerical error or obvious mistake (see s 104(1)(b)), is left for the power of amendment to do? and
•	What did the legislature have in mind when it defined ‘complete specification’ to be, ‘if the specification has been amended, the complete specification as amended’ (see [352] above)?

383 As noted above, Lilly submitted that the justification for a carving out from the possibility of amendment is the general principle that full disclosure of the invention, including the best method of performing it, is the consideration for the grant of the patent’s monopoly, and the date of the patent is, relevantly, the date of filing of the relevant complete specification (s 65(a)). But the complete specification is not published at filing. The logic of Lilly’s present submission would indicate the date when a complete specification first becomes open to public inspection.

384 We agree with the primary Judge that the present issue is not to be resolved by reading down the Act’s provisions for amendment so as to make them yield what may be thought to be a desirable policy. Rather, the answer is found in the Act’s express limitation on the power of amendment, and on questions of timing.

385 The Act’s régime providing for amendment of a complete specification, coupled with the Dictionary definition of ‘complete specification’, signify that in the examination process (see esp s 45(1)(a)), in opposition proceedings (see esp s 59(c)), and in revocation proceedings (see esp s 138(3)(f)), it is the specification as amended that must be regarded in order to determine whether s 40(2)(a) is complied with.

386 Subsection 104(1) entitles an applicant for a patent or a patentee, subject to the Act and the regulations, to ask the Commissioner for leave, relevantly, to amend the complete specification for the purpose of removing a lawful ground of objection to it, for any purpose including either or both of the following:

‘(a) removing a lawful ground of objection to the request or specification, whether that objection is raised in the course of an examination or re-examination or otherwise;

(b) correcting a clerical error or an obvious mistake.’

That a complete specification does not include in its description of the invention, the best method known to the applicant (at date of filing) of performing it, is a ‘lawful ground of objection’. Importantly, for present purposes, however, s 102 identifies amendments which are not allowable. Leaving aside innovation patents and amendments to correct clerical errors or obvious mistakes, the restrictions on permissible amendments increase according to whether the amendment is to be made:

• at any time, including prior to acceptance (s 102(1));
• at any time after acceptance of the specification (s 102(2)); and
• after the patent is granted (s 102(2C)).

387 Subsection 102(1) provides:

‘An amendment of a complete specification is not allowable if, as a result of the amendment, the specification would claim matter not in substance disclosed in the specification as filed.’ (our emphasis)

388 The verb ‘claim’ is defined in the Act’s Dictionary by reference to the noun ‘claim’. The reference is to s 40(2)(b)’s ‘claim or claims defining the invention’. If a proposed amended disclosure of best method somehow caused the specification to ‘claim’ matter not in substance disclosed in the specification as filed, the proposed amendment would not be allowable. It is perhaps difficult to imagine how this might occur in the case of an amendment in the disclosure of best method. A possibility, albeit perhaps a remote one, is that the amendment might lead to the claim or claims being construed more expansively than they were prior to the amendment. Be this as it may, it is the claiming of matter in substance disclosed in the specification as filed that is the operative limitation.

389 Subsection 102(2) additionally makes amendment after acceptance not allowable if, as a result of the amendment:

‘(a) a claim of the specification would not in substance fall within the scope of the claims of the specification before amendment; or

(b) the specification would not comply with subsection 40(2) or (3).’

390 Whether any of the amendments which were in fact allowed in the present case fell foul of s 102 is an issue not before the Court: cf Kimberly-Clark at [5]. The issue before the Court under s 138(3) is simply whether the complete specification in its present (amended) form, that is, as granted, complies with s 40(2)(a) by, relevantly, including in its description of the invention the best method of performing the invention which was known to Pfizer at the date of filing: cf Kimberly-Clark at [5]. It is not in dispute that the complete specification, as amended, discloses that best method. Accordingly, the ground of revocation provided for in s 138(3)(f) (‘that the specification does not comply with subsection 40(2) or (3)’) is not made out in the present respect.

391 In view of this conclusion, we are not required to decide whether there is a latest date applicable to all cases, by which s 40(2)(a) may be complied with, or, to express the matter differently, after which the Commissioner may never allow an amendment in order to overcome a specification’s failure to state best method as required by s 40(2)(a). As indicated above, the question is to be resolved by reference to the régime of amendments that are and are not allowable under ss 102 and 104 of the Act and the regulations, and to the application of those provisions to the facts of the particular case.

392 Lilly’s contention that the Patent should be revoked for failure to state the best method as required by s 40(2)(a) is not sustained.

False Suggestion

393 Section 138(3) of the 1990 Act provides, as a ground for revocation of a patent, that the patent was obtained by false suggestion.

394 In Prestige Group (Australia) Pty Ltd v Dart Industries Inc (1990) 26 FCR 197, Lockhart J held that the words ‘false suggestion’ in s 100(1)(k) of the 1952 Act did not require that fraud, in the sense of deliberate intent to deceive, be established. Nor was it necessary that the conduct constituting the false suggestion or representation must be such that in its absence the patent would not have been granted. On the test as his Honour formulated it the question was whether the conduct constituting the false suggestion or representation materially contributed to the Commissioner’s decision to grant the patent even if other circumstances or causes also played a part in the making of that decision. His Honour said, at 201:

‘It is sufficient if the conduct is a material inducing factor which led to the grant. It goes too far to say that the false suggestion or representation must be material in the sense that without it the Patent would not have proceeded to grant.’

At 218 Gummow J agreed with Lockhart J that it would be sufficient that the false suggestion was a material inducing factor which led to the grant. Northrop J agreed with the reasons published by Gummow J.

395 Lilly’s case for false suggestion depended upon the statement in the specification in which it was asserted that patient studies had confirmed that one of the especially preferred compounds induced penile erection in impotent males. The full text of the relevant paragraph of the specification was as follows:

‘In man, certain especially preferred compounds have been tested orally in both single dose and multiple dose volunteer studies. Moreover, patient studies conducted thus far have confirmed that one of the especially preferred compounds induces penile erection in impotent males.’

396 Lilly submitted that this assertion was calculated to give the false impression that one of the specified compounds identified earlier in the Patent (none of which were salts of any kind) had been tested and worked. The impression conveyed to the Commissioner of Patents was that the patentee was disclosing as one of the nine free amines (not salts) its best method, as it was obliged to do. The specified compounds referred to by Lilly were those mentioned in the body of the specification where it identified ‘especially preferred individual compounds of the invention’. Under this heading there were some nine compounds identified one of which, it is common ground, was sildenafil. In fact, according to Lilly, the patentee was not disclosing one of the nine free amines in the passage cited. It was referring to a salt and did not disclose that fact.

397 In dealing with Lilly’s false suggestion case, his Honour identified the ‘especially preferred compounds’ mentioned in the cited passage as the nine especially preferred individual compounds previously described in the body of the specification. He identified the especially preferred compound referred to in the passage cited as sildenafil which is the compound mentioned in claim 7. In answer to the question whether the Patent contained a false suggestion, his Honour said (at [220]):

‘True it is that the compound which achieved the experimental results referred to on page 10 was not a freebase compound, as were the "especially preferred individual compounds". But, as Dr Robertson’s evidence established, a skilled addressee would not in this context draw a distinction between a compound in its freebase form and the same compound in its salt form. Sildenafil monocitrate on administration to man gets converted by the stomach from the citrate into the hydrochloride and then absorbed as the freebase, so it is the freebase or, to use Dr Robertson’s expression, the unfettered molecule, that is absorbed and causes the response, not the citrate itself.’

398 Lilly submitted that there was inconsistency in this finding with his Honour’s earlier finding that it was not disputed that the best method known to Pfizer was the use of sildenafil monocitrate. Lilly challenged his conclusion that a skilled addressee would not draw a distinction between the freebase form of the compound and the same compound in salt form. Pfizer itself had applied for a patent for the monocitrate salt form because it was superior and patentably distinct. Lilly also submitted that his Honour’s holding went beyond Dr Robertson’s evidence. He had accepted Dr Robertson’s evidence that the skilled addressee would be likely to focus on claim 8. But Dr Robertson said this because he inferred from the presence of claim 8 that the monocitrate was the compound of significant interest.

399 As Pfizer pointed out in its submissions however, Lilly’s false suggestion allegation was tied to its attack on best method. The citrate salt form of sildenafil was expressly disclosed in the Patent through claim 8 which had been incorporated in it by the date of grant. In any event it was understood by the skilled addressee that the citrate form of sildenafil and the freebase form were bioequivalent in the body. This evidence was said to be supported by other witnesses. Counsel for Lilly had pressed Dr Ellis in cross-examination with the distinction between sildenafil and sildenafil citrate. However, Dr Ellis said:

‘When in solution, sildenafil is as it is listed on page 7 and is the active moiety.’

400 Pfizer submitted that the fact that the patentee did not disclose that the especially preferred compounds administered to healthy volunteers and the especially preferred compound which induced penile erection in impotent males was administered in the form of a salt, did not amount to a false representation. It said so for the following reasons:

(a) The patentee identified the especially preferred compounds in a way which was consistent with their understanding of those compounds. For example, sildenafil (the generic name for the compound in claims 7 and 8) was known by Pfizer to be the active species which induced penile erection in impotent men.

(b) A skilled addressee upon reading the Patent would not draw a distinction between a compound in its freebase form and the same compound in its salt form.

(c) The especially preferred compounds, and in particular the especially preferred compound salt in claim 8, would be recognised by the skilled addressee to be absorbed into the body in its freebase form following oral administration.

(d) A skilled addressee would immediately understand that each of the especially preferred compounds in freebase form constitute the ‘active ingredient’ which can be formulated into a pharmaceutical dose form for administration to impotent men. A skilled addressee would further understand that an active ingredient could be formulated into a dose form in either its freebase form, or in one of the many possible salt forms depending on the dose form contemplated.

401 In Dr Ellis’ evidence in cross-examination he said:

‘Sildenafil citrate, when administered to the body, the sildenafil is the active moiety available. What is actually acting on the corpus cavernosal tissue is sildenafil, not sildenafil citrate.’

He accepted that the subjects in the study swallowed sildenafil citrate. It was put to him that sildenafil citrate was nowhere identified in the document and that was a deliberate strategy on Pfizer’s part. He said:

‘If I answer the second question first, I have no knowledge of any strategy to deliberately exclude the citrate from this patent. The first question you asked me the day before yesterday – and we went through the patent and identified, I believe, one area where it referred to a carboxylic acid salt form and a second one where it made reference back to the Bell patents which specifically mentioned the citrate salt, so my knowledge is that from those two aspects, it is contained in this patent.’

402 In Dr Robertson’s evidence in cross examination the following exchanges occurred:

‘Q. Sildenafil citrate is not one of the especially preferred compounds, is it?

A. Sildenafil is one of the especially preferred compounds; whether it’s a citrate or not doesn’t really make much difference to me.

Q. But sildenafil citrate itself is not one of those compounds?

A. Sildenafil citrate is a salt. That means the salt is not joined to sildenafil itself, it just is a salt held together by electrostatic forces, so I don’t know. That’s a pretty difficult question.

Q. Dr Robertson, you’d agree that the salt form of a compound is a different compound?

A. In this case, sildenafil citrate on administration to man, or any amine citrate on administration to man, gets converted by the stomach from the citrate into the hydrochloride and then absorbed as the freebase, so it’s the free base here, the unfettered molecule, if you like, that is absorbed and causes the response, not the citrate itself.

Q. If you look at the claims, Dr Robertson, they refer to sildenafil the compound and sildenafil citrate as different entities, don’t they?

A. They make two special claims to the citrate salt of sildenafil, that’s right. Whether it is the citrate or not, it’s a salt that obviously was of interest to Pfizer. The fact that it’s citrate versus fumarate didn’t really make much significance to me at the time.’

403 Having regard to this evidence, it cannot be said that his Honour went beyond what it stated in his reliance upon it. In any event the Patent at claim 8 specified the monocitrate salt and that was disclosed as at the date of grant, complying with the best method disclosure requirement. As at the date of grant, the specification did not contain a false suggestion. Even absent claim 8, we are not persuaded that the reference to the freebase compound rather than the salt has been shown by Lilly to have materially contributed to the grant of the Patent. Lilly’s contention on false suggestion fails.

Conclusion

404 As appears from the preceding reasons, Pfizer succeeded in demonstrating error on the part of the learned trial judge in his finding as to lack of inventive step. On the other hand it has not succeeded in its challenge to his Honour’s finding that claim 10 was not fairly based on the specification. None of the Lilly contentions is made out. In the result, however, because of a lack of fair basis, claim 10 is invalid and the orders made by his Honour should stand. The appeal must be dismissed. Having regard to the distribution of success and failure and the ultimate outcome of the appeal, the appropriate order is that each party should bear its own costs of the appeal.

I certify that the preceding four hundred and four (404) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justices French and Lindgren.

Associate:

Dated: 31 October 2005

Biochemical pathways related to smooth muscle relaxation and erection absent a cGMP PDE
Inhibitor

Biochemical pathways related to smooth muscle relaxation and erection with a cGMP PDE inhibitor

IN THE FEDERAL COURT OF AUSTRALIA
VICTORIA DISTRICT REGISTRY	VID 337 OF 2005

On Appeal from a Single Judge of the Federal Court of Australia

BETWEEN:	PFIZER OVERSEAS PHARMACEUTICALS FIRST APPELLANT PFIZER AUSTRALIA PTY LIMITED SECOND APPELLANT CP PHARMACEUTICALS INTERNATIONAL C.V. THIRD APPELLANT PFIZER MANUFACTURING LLC FOURTH APPELLANT PFIZER PRODUCTION LLC FIFTH APPELLANT
AND:	ELI LILLY AND COMPANY FIRST RESPONDENT ELI LILLY AUSTRALIA PTY LIMITED SECOND RESPONDENT ELI LILLY AND COMPANY LIMITED THIRD RESPONDENT

JUDGES:	FRENCH, LINDGREN AND CRENNAN JJ
DATE:	31 OCTOBER 2005
PLACE:	PERTH (HEARD IN MELBOURNE)

REASONS FOR JUDGMENT

CRENNAN J:

405 I have had the advantage of reading the judgment of French and Lindgren JJ in draft and agree with their Honours’ summary of the facts and the history of these proceedings. I agree also with their account of the arguments as presented by the parties to this appeal.

406 I agree with their reasoning in respect of the issues of infringement and construction and agree also with their conclusion that the importation into or sale in Australia of Cialis would infringe claim 10 of the Patent if that claim is found to be valid.

407 I also agree with French and Lindgren JJ that the primary judge erred in finding that claim 10 of the Patent was invalid because it was obvious or disclosed no inventive step. Further, I agree with their findings in relation to the notional addressee of the Patent, and with their Honours’ assessment of the weight of the evidence concerning obviousness and a lack of inventive step by Pfizer in developing the invention disclosed in the Patent.

408 I also agree with their conclusions in respect of the issues of sufficiency, best method and false suggestion, and their conclusion that none of Lilly’s contentions in the notice of contention is made out.

Fair basis

409 While I agree with French and Lindgren JJs’ description of Pfizer’s submissions on the issue of fair basis set out in their draft judgment, I respectfully do not agree with the conclusions they have reached on that issue.

410 Claim 10 is fairly based on the matters disclosed in the body of the specification of the Patent. I have reached this conclusion following an assessment of how the specification of the Patent is to be construed in the light of the common general knowledge and the art as at the priority date. A specification is not to be construed in the abstract. In performing such an analysis, it is well established that the Court is to place itself in the position of some person acquainted with the surrounding circumstances as to the state of the art and manufacture at the time: Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58; (2004) 217 CLR 274 at 302 [72]; Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd & Ors (2001) CLR 1 at [24]; see also the judgments of Lockhart and Sheppard JJ in Décor Corporation Pty Ltd v Dart Industries Inc (1998) 13 IPR 385, respectively at 391 and 400.

411 Having regard to the evidence which is already set out in the decision at first instance, and also in the draft judgment of French and Lindgren JJ, I understand the context of the Patent specification, and the state of the common general knowledge in the relevant field at the present time, governs the construction of the technical term ‘cGMP PDE_V inhibitor’, as connoting an inhibitor which is selective for PDE_V. The specification of the Patent emphasises selectivity throughout its text. The body of the specification discloses a principle that utilises the particular activity of a class of compounds which would be understood by the hypothetical skilled addressee to be selective for PDE_V. The complete specification is entitled ‘PYRAZOLOPYRIMIDINONES FOR THE TREATMENT OF IMPOTENCE’. I note in passing Pyrazolopyrimidinones are not confined to the compounds of formula (I) referred to in the body of the specification. While I agree with French and Lindgren JJs’ recognition that the first sentence in the body of the specification refers to formula (I) compounds, at page 2, paragraph 2 of the body of the specification it is stated:

‘... the compounds of the invention are potent inhibitors of cyclic guanosine 3’, 5’ – monophosphate phosphodiesterases (cGMP PDEs) in contrast to their inhibition of cyclic adenosine 3’, 5’ – monophosphate phosphodiesterases (cAMP PDEs). This selective enzyme inhibition leads to elevated cGMP levels...’

A skilled reader would interpret claim 10 in the light of this explanation which indicates that the compounds of the invention selectively inhibit cGMP PDE over cAMP PDE. The invention taught by the Patent and its specification is described by reference to such qualifications: the invention is effective because of the action of ‘potent and selective inhibitors of the cGMP-specific PDE_V’ (as per the Results section of the investigation, at page 9 at line 30, set out in the Patent’s specification).

412 The trial judge recognised that the expression ‘cGMP PDE_V inhibitor’ may connote an inhibitor which is selective for PDE_V but he concluded that in the context of the Patent as a whole, the expression does not have such a meaning. There was evidence from Pfizer’s witnesses, Dr Fischmeister, Professor Pittler and Dr Robertson and some evidence from Bayer’s witnesses, Professor Brown and Dr Silver as to their understanding of the expression and, in particular, the Pfizer witnesses gave evidence that a reference to a ‘PDEx inhibitor’ immediately conveys selectivity to a person skilled in the art.

413 However, more critical to the appeal are the second and third propositions of Pfizer’s submissions on this issue set out in French and Lindgren JJs’ draft judgment.

414 The critical question on the appeal in relation to the issue of fair basis is whether the trial judge erred in finding that the body of the specification does not contain a real and reasonably clear disclosure of the use of cGMP PDE_V inhibitors, outside the ‘compounds of formula (I)’, which he found to be an expression used interchangeably, in the body of the specification, with the expression ‘compounds of the invention’.

415 It is necessary to set out relevant parts of the body of the specification which follow the title and the paragraph extracted in paragraph 411 above. The body of the specification at the bottom of page 2 and over on page 3 states: ‘Thus, the present invention concerns the use of a compound of formula (I) [which is then followed by formulae] or a pharmaceutically accepted salt thereof, or a pharmaceutical composition containing either entity.’ That reference to the use of a compound of formula (I) is an introduction to the text on the pages 4, 5, 6 and 7 which contain numerous references to the compounds of formula (I). It can be noted that there is a hierarchy of preferred groups of compounds of formula (I) on pages 5 and 6, followed at the bottom of page 6 to a reference to ‘(e)specially preferred individual compounds of the invention’, which includes a reference at the top of page 7 to sildenafil monocitrate.

416 Two thirds of the way down page 7, there is a reference to the fact that the compounds of formula (I) and their pharmaceutically acceptable salts are described in the Bell patents. It is clear from what then follows that the essence of the inventive step, over the Bell patents, is next described, because at the bottom of page 7, the body of the specification recites:

‘A preliminary investigation was carried out with a view to isolating and characterising the cyclic nucleotide PDEs of human corpus cavernosum, relaxation of which leads to penile erection. Studies of substrate specificity, response to activators and inhibitor sensitivity, have demonstrated that human corpus cavernosum contains three distinct PDE enzymes.’

417 A discussion of methods then follows on page 8. Then the results of the investigation and an explanation of why the compounds of the invention are effective is to be found on pages 9 and 10 of the body of the specification as follows:

‘In summary, the above investigation identified three PDE isoenzymes in human corpus cavernosum tissue. The predominant PDE is the cGMP-specific PDE_V whilst cGMP-stimulated cAMP PDE_II and cGMP-inhibited cAMP PDE_III are also present.

The compounds of the invention have been tested in vitro and found to be potent and selective inhibitors of the cGMP-specific PDE_{V .} For example, one of the especially preferred compounds of the invention has an IC₅₀ = 6.8 nM v. the PDE_V enzyme, but demonstrates only weak inhibitory activity against the PDE_II and PDE_III enzymes with IC₅₀ = >100 μM and 34 μM respectively. Thus relaxation of the corpus cavernosum tissue and consequent penile erection is presumably mediated by elevation of cGMP levels in the said tissue, by virtue of the PDE inhibitory profile of the compounds of the invention.’

418 That explanation followed a disclosure that human corpus cavernosum soluble PDEs were separated into three distinct fractions of activity. The first, fraction 1 (designated by order of elution) represents the major PDE present. This was disclosed to be PDE_V which was found to be insensitive to stimulation by calcium/calmodulin. There was evidence from Mr Burslem that a person skilled in the art would be aware that PDE_I and PDE_V are known to co-elute in fraction 1 and that PDE_I is sensitive to stimulation by calcium/calmodulin. PDE_II and PDE_III were also disclosed. The body of the specification at this point has established that the compounds of the invention are potent and selective inhibitors of PDE_V.

419 Then page 11 of the body of the specification contains consistory clauses. The first three of these refer to compounds of formula (I) and the third can be matched to claim 1. The next three consistory clauses are introduced by the respective phrases ‘In a further aspect . . .’, ‘The invention also includes . . .’ and ‘Moreover, the invention includes . . .’. The fourth consistory clause read in the context of the disclosures extracted here from pages 2, 9 and 11 of the body of the specification is apt to cover the disclosures in those pages directed to the principle claimed in claim 10. Those specified disclosures on pages 2, 9 and 11 refer to ‘compounds of the invention’ in apparent or possible contradistinction to the references to the ‘compounds of formula (I)’ on pages 2, 4, 5 and 6, although the passages disclose a principle or activity which does not turn on any apparent or possible distinction between the two expressions, and it is clearly a principle or activity of the compounds of the invention. Whilst the two expressions do not seem to me to be used interchangeably in the body of the specification, that may not matter.

420 For the purposes of determining the fair basis issue, it matters not that there is no coincidence of language between a consistory clause and the language of a claim. While coincidence of language and a match between a consistory clause and a claim is convenient and often sufficient for establishing fair basis, such a match is not a necessary requirement for a claim to be found to be fairly based on a reasonably clear disclosure in the body of the specification.

421 It also matters not that the last three consistory clauses on pages 11 and 12 including the fourth consistory clause on page 11, may also have been apt for ‘field of use’ claims ultimately abandoned. Further, it does not matter if, as the trial judge found ‘claim 10 (and the abandoned claim 9) are an awkward fit.’ Claim 7 and claim 10 are a logical fit, claim 7 matching the disclosure to which I have referred at the top of page 7 and claim 10 matching the disclosure of the use of the compounds of the invention on pages 9 to 11 and the fourth consistory clause on page 11.

422 The whole specification shows the draftsman has referred to ‘compounds of formula (I)’ frequently by reference to their structure and to ‘compounds of the invention’ generally, although not exclusively, by reference to their activity. Where there is a discussion of the activity of selective inhibitors on page 9 the draftsman refers to ‘compounds of the invention’ and ‘one of the especially preferred compounds of the invention’. It seems to me that a contradistinction between ‘compounds of formula (I)’ and ‘compounds of the invention’ is deliberately made as part of the explanation of the essence of the inventive step, over and above the disclosures in the Bell patents, and this explanation teaches the skilled addressee about the essence of the invention, which is the selective activity of the compounds of the invention as described on pages 9 to 11. Even if that is not correct, or if any distinction between the two expressions is really a distinction without a difference, it seems to me that the results described on page 9 disclose a principle, namely the use of cGMP PDE_V inhibitors, which expression would be understood as synonymous with selective cGMP PDE_V inhibitors, to cure or prevent erectile dysfunction. The disclosure of the explanation of why the compounds of the invention Pyrazolopyrimidinones work, as a treatment of impotence, is a further aspect of, or broader disclosure in, the body of the specification, than the disclosures by reference to the structure of various compounds of formula (I). Therefore, it seems to me claim 10 broadly claims what is reasonably clearly disclosed in the body of the specification on pages 2 and 9 to 11 and in the fourth consistory clause on page 11.

423 The specification read fairly, as a whole, by a skilled addressee familiar with both the state of the art and common general knowledge in the field (which included an understanding that the disclosure on page 9 indicates an absence of PDE_I) reasonably clearly discloses the use of cGMP PDE_V inhibitors (synonymously, selective cGMP PDE_V inhibitors) for the oral treatment of erectile dysfunction in men with the result that claim 10 is fairly based on ‘the matter described in the specification’ as required by s 40(3) of the Patents Act 1990 (Cth).

Orders

424 Given my agreement with French and Lindgren JJ in relation to all issues other than the issue of whether claim 10 is fairly based on matter described in the specification and my findings on that issue, I would make the same orders as them in respect of Lilly’s notice of contention. I would allow the appeal by Pfizer and order that the respondents pay the appellants’ costs of and incidental to this appeal and the hearing below and otherwise remit the matter to the trial judge for such further orders as are necessary and appropriate to be made to dispose of all outstanding matters.

I certify that the preceding twenty (20) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Crennan.

Associate:

Dated: 31 October 2005

Counsel for the Appellants:	Mr D Shavin QC, Ms J Baird and Ms H Rofe
Solicitor for the Appellants:	Corrs Chambers Westgarth
Counsel for the Respondents:	Mr D Catterns QC and Ms K Howard
Solicitor for the Respondents:	Blake Dawson Waldron
Date of Hearing:	8, 9 and 10 August 2005
Date of Judgment:	31 October 2005