Pfizer Overseas Pharmaceuticals v Eli Lilly and Company
[2005] FCAFC 224
•31 OCTOBER 2005
FEDERAL COURT OF AUSTRALIA
Pfizer Overseas Pharmaceuticals v Eli Lilly and Company
[2005] FCAFC 224PATENTS – 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) 218 ALR 408 cited
Bristol-Myers Squibb Company v FH Faulding & Co Limited (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
Aktiebolaget Hassle v Alphapharm Pty Ltd (200r) 212 CLR 411 applied
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (2004) 212 ALR 1 applied
Martin v Scribal Pty Ltd (1954) 92 CLR 17 applied
Welch Perrin & Co Pty Ltd v Worrel (1961) 106 CLR 588 cited
Interlego AG v Toltoys Pty ltd (1972) 130 CLR 461 applied
Décor Corp Pty Ltd v Dart Industries Inc (1988) 13 IPR 385 cited
Nesbit Evans Group Australia Pty Ltd v Impro Ltd (1997) 39 IPR 56 cited
Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd (2001) 207 CLR 1 cited
Catnic Components Ltd v Hill & Smith Ltd [1982] RPC 183 cited
CCOM Pty Ltd v Jiejing Pty Ltd (1994) 122 ALR 417 cited
Olin Corporation v Super Cartridge Co Pty Ltd (1977) 180 CLR 236 cited
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
Minnesota Mining and Manufacturing Co v Beiersdorf (Australia) Ltd (1980) 144 CLR 253 cited
WR Grace v Asahi Kasei (1993) AIPC 90-974 cited
Firebelt Pty Ltd v Brambles Pty Ltd (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) 148 CLR 262 cited
Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157 followed
Meyers Taylor Pty Ltd v Viccar Industries Ltd (1977) 137 CLR 228 cited
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Imperial Chemical Industries Pty Ltd v Commissioner of Patents (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) 174 CLR 430 cited
Frederikshavn Vaerft A/S v Stena Rederi Aktiebolag (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) 147 CLR 297 cited
Illinois Tool Works Inc v Autobars Co (Services) Limited [1974] 91 RPC 337 citedLaddie, ‘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 152FRENCH, 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 APPELLANTPFIZER PTY LIMITED (ACN 008 422 348)
SECOND APPELLANTCP PHARMACEUTICALS INTERNATIONAL CV
THIRD APPELLANTPFIZER MANUFACTURING LLC
FOURTH APPELLANTPFIZER PRODUCTION LLC
FIFTH APPELLANTAND:
ELI LILLY AND COMPANY
FIRST RESPONDENTELI LILLY AUSTRALIA PTY LTD (ACN 000 233 992)
SECOND RESPONDENTELI LILLY AND COMPANY LIMITED
THIRD RESPONDENTJUDGES:
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 APPELLANTPFIZER PTY LIMITED (ACN 008 422 348)
SECOND APPELLANTCP PHARMACEUTICALS INTERNATIONAL CV
THIRD APPELLANTPFIZER MANUFACTURING LLC
FOURTH APPELLANTPFIZER PRODUCTION LLC
FIFTH APPELLANTAND:
ELI LILLY AND COMPANY
FIRST RESPONDENTELI LILLY AUSTRALIA PTY LTD (ACN 000 233 992)
SECOND RESPONDENTELI 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
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.
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.
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.
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) 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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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).
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 F2a 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.
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.
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.
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.
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.
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.
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.
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.’
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.
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.
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.
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++
ConcentrationSmooth 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
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.
The 1990 classification of PDEs divided them into families designated by the Roman numerals I to V. In 1994, a further classification divided PDEV 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 cGMPPDEV cGMP-specific PDE Almost exclusively
hydrolyses cGMPThe PDE enzymes have varying distributions through the body of tissues. The exact tissue distribution was not known in June 1993.
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 PDEV. 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.
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.
L-Arginine
Nitric Oxide (NO)/ EDRF
Guanylate Cyclase
Enzyme catalysed reaction
To produce cGMP5’GMP
Guanosine
Triphosphate
(GTP)cyclic Guanosine
Monophosphate
(cGMP)(Causes muscle relaxation)
Enzyme catalysed reaction
To remove cGMPcGMP hydrolysing
Phosphodiesterase
Enzyme (PDE)(Does not cause
muscle relaxation)Activates enzyme precursor
Enzyme catalysed reaction
1
2
3
4
L-Arginine
Nitric Oxide (NO)/ EDRF
Guanylate Cyclase
Enzyme catalysed reaction
To produce cGMP5’GMP
Guanosine
Triphosphate
(GTP)cyclic Guanosine
Monophosphate
(cGMP)(Causes muscle relaxation)
Enzyme catalysed reaction
To remove cGMPcGMP hydrolysing
Phosphodiesterase
Enzyme (PDE)(Does not cause
muscle relaxation)Activates enzyme precursor
Enzyme catalysed reaction
1
2
3
4
As appears from the evidence referred to later in these reasons, the relevant family of PDEs, namely PDEV went through a taxonomical development which led initially to its subdivision into PDE VA PDE VB and PDE VC. The first of these was the penile smooth muscle PDE. The second and the third were located in retinal tissue. The latter two, PDE VB and PDE VC were subsequently reclassified as PDEVI. PDE VA reverted to PDEV – see the evidence of Dr Gristwood summarised below. For ease of reference in these reasons, PDEV 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
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.
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.
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’.
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.
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.
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.
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.
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’.
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 PDEV , whilst cGMP-stimulated cAMP PDEII and cGMP-inhibited cAMP PDEIII are also present.
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 PDEv .’
One of the especially preferred compounds of the invention has a strongly inhibitory action against PDEV. It has an IC50 = 6.8 nM against the PDEV enzyme, but demonstrates only weak inhibitory activity against the PDEII and PDEIII 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.’
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.
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.’
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.
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’.
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.
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; …’
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.
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.
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 PDEv 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 PDEv inhibitor.’
The claims that followed were not relevant for the purposes of the proceedings before his Honour.
Important Prior Publications
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 VA Inhibitors – Drug News and Perspectives, April 1993 Vol 6(3) pp 150-156
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.
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.
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.
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.
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.
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.
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.’
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 E1, 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.’
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.
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.
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.’
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 VA 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.’
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 VA inhibitors were reviewed and their potential therapeutic indications discussed.
The cGMP-specific PDE isoenzyme (designated PDE V) family was said to consist of several members or isoforms. PDE VA is located in a number of nonretinal tissues. PDE VB and PDE VC with similar properties are exclusively located in the retina where they play an important role in visual transduction. The author said (at 150):
‘PDE VA 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 VA were as cGMP-binding PDEs in lung and platelets. In addition to these tissues, PDE VA is also found in various smooth muscle types and spleen. This is not to say that PDE VA is exclusive to these tissues, as small amounts of PDE VA may have escaped detection in other tissues. However, when compared to some other PDEs (eg PDE IV), PDE VA exhibits a rather limited tissue distribution.’
The most salient feature of PDE VA is its specificity for cGMP as a substrate. This means that an inhibition of PDE VA 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 VA inhibitor could have a narrow range of physiological and pharmacological actions.’
Murray identified the most frequently studied PDE VA inhibitor as zaprinast. There was nevertheless considerable confusion regarding its selectivity for PDE VA 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 VA and PDE I. There was no doubt that zaprinast was a potent inhibitor of PDE VA. There was also evidence that it could inhibit PDE I.
In referring to the physiological effects of PDE VA inhibition Murray observed that in general PDE VA 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.
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.
Turning to potential therapeutic use of PDE VA inhibitors, Murray observed that the only PDE VA 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 VA inhibition. Therefore, at present, PDE VA 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 VA inhibitors, and possible therapeutic utilities could include vasodilation, bronchodilation, modulation of gastrointestinal motility and treatment of impotence. Although PDE VA 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 VA inhibitors in a particular tissue are dependent on the level of guanylate cyclase activity. Thus, PDE VA 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 VA inhibitors could include analgesia and effects on platelet function. At present, the therapeutic potential of PDE VA inhibitors is largely based on the effects of one compound (ie, zaprinast), and a clearer picture will be obtained when other rationally designed PDE VA inhibitors become available.’
The Evidence at Trial
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.
Witnesses at the trial gave their evidence on affidavit subject to cross-examination.
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.
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.
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
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.
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.
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.
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.
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 VA, PDE VB and PDE VC. PDE VB and VC, under the Beavo classification, became the new terms for the retinal PDEs. They were later reclassified together as PDE VI.
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.
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.’
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.
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.
Dr Gristwood also accepted that work beyond that undertaken by Rajfer would be necessary to ascertain whether relaxation from a PDEV inhibitor working on basal levels of cGMP was going to be sufficient to achieve a usable erection.
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.’
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’.
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 VA) inhibitor’ included methylxanthine-non-selective PDE inhibitors such as pentoxifylline’.
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 PDEV 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 VA inhibitor’ to include non-selective as well as selective PDE V inhibitors.
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 PDEV inhibitor. He also said that, in his opinion, the term ‘cGMP PDEV inhibitor’ as used in claim 10 of the patent covered both selective and non-selective inhibitors.
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
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.
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.’
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 PDEV inhibitor.
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’.
Dr Cherry had not read the Murray paper prior to preparing his second affidavit in these proceedings.
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.
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 VA inhibitors was a treatment for impotence.
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
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.
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.
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.
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.
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
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.
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
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.
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)?
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.
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.
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.
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)).
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)
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.
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).’
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.
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.
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
Section 138(3) of the 1990 Act provides, as a ground for revocation of a patent, that the patent was obtained by false suggestion.
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.
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.’
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.
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.’
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.
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.’
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.
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.’
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.’
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
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
Adrenergic
NerveVIP
VIP
β2
α2
α1
Adenylate
CyclaseSarcoplasmic
ReticulumCa++
Ca++
MLCK
Guanylate
CyclaseATP
cAMP
cAMP PDE
Relaxation
PKA
K+
Potassium channel
Calcium channel
Smooth muscle
cellK+
PGE1
PKG
PGF
ET1
Cholinergic
NerveEndothelial cell
Ca++
Ca++
NANC
nerveEPINEPHRINE
PDE
inhibitorPGE1
PAPAVERINE
AMP
NOREPINEPHRINE
Adrenergic
Nerveα2
α1
Adenylate
CyclaseSarcoplasmic
ReticulumCa++
Ca++
Ca++
MLCK
Guanylate
CyclaseRelaxation
PKA
IP3
Calcium channel
PKG
PGF
ET1
ENDOTHELIN
PROSTAGLANDIN F2α
Endothelial cell
Ca++
Ca++
cGMP
PDEAdrenergicNerve
α2
α1
Adenylate
CyclaseIP3
ET1
NOREPINEPHRINE
ACETYLCHOLINE
PHENTOLAMINE
PHENOXY-
BENZAMINEYOHIMBINE
Guanylate
CyclaseGTP
cGMP
Endothelial cell
NO
NANC
nerveGMP
cGMP
PDENO
Endothelial cell
ACETYLCHOLINE
CONTRACTION +
RELAXATION:Biochemical pathways related to smooth muscle relaxation and erection absent a cGMP PDE
Inhibitor
Adrenergic
NerveVIP
VIP
β2
α2
α1
Adenylate
CyclaseSarcoplasmic
ReticulumCa++
Ca++
Ca++
MLCK
Guanylate
CyclaseATP
cAMP
cAMP PDE
Relaxation
PKA
K+
Potassium channel
Calcium channel
Smooth muscle
cellK+
PGE1
PKG
PGF
ET1
Cholinergic
NerveEndothelial cell
Ca++
Ca++
NANC
nerveEPINEPHRINE
PDE
inhibitorPGE1
PAPAVERINE
AMP
NOREPINEPHRINE
Adrenergic
Nerveα2
α1
Adenylate
CyclaseSarcoplasmic
ReticulumCa++
Ca++
Ca++
MLCK
Guanylate
CyclaseRelaxation
PKA
IP3
Calcium channel
PKG
PGF
ET1
ENDOTHELIN
PROSTAGLANDIN F2α
Endothelial cell
Ca++
Ca++
cGMP
PDEAdrenergicNerve
α2
α1
Adenylate
CyclaseIP3
ET1
NOREPINEPHRINE
ACETYLCHOLINE
PHENTOLAMINE
PHENOXY-
BENZAMINEYOHIMBINE
Guanylate
CyclaseGTP
cGMP
Endothelial cell
NO
NANC
nerveGMP
cGMP
PDENO
Endothelial cell
ACETYLCHOLINE
PDE
inhibitorOBVIOUS?
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 APPELLANTPFIZER AUSTRALIA PTY LIMITED
SECOND APPELLANTCP PHARMACEUTICALS INTERNATIONAL C.V.
THIRD APPELLANTPFIZER MANUFACTURING LLC
FOURTH APPELLANTPFIZER PRODUCTION LLC
FIFTH APPELLANTAND:
ELI LILLY AND COMPANY
FIRST RESPONDENTELI LILLY AUSTRALIA PTY LIMITED
SECOND RESPONDENTELI 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:
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.
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.
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.
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
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.
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) 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.
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 PDEV inhibitor’, as connoting an inhibitor which is selective for PDEV. 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 PDEV. 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 PDEV’ (as per the Results section of the investigation, at page 9 at line 30, set out in the Patent’s specification).
The trial judge recognised that the expression ‘cGMP PDEV inhibitor’ may connote an inhibitor which is selective for PDEV 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.
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.
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 PDEV 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’.
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.
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.’
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 PDEV whilst cGMP-stimulated cAMP PDEII and cGMP-inhibited cAMP PDEIII 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 PDEV . For example, one of the especially preferred compounds of the invention has an IC50 = 6.8 nM v. the PDEV enzyme, but demonstrates only weak inhibitory activity against the PDEII and PDEIII 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.’
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 PDEV 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 PDEI and PDEV are known to co-elute in fraction 1 and that PDEI is sensitive to stimulation by calcium/calmodulin. PDEII and PDEIII 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 PDEV.
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.
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.
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.
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 PDEV inhibitors, which expression would be understood as synonymous with selective cGMP PDEV 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.
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 PDEI) reasonably clearly discloses the use of cGMP PDEV inhibitors (synonymously, selective cGMP PDEV 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
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
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