England and Wales Court of Appeal (Civil Division) Decisions

The Proceedings

The Background

2. The following technical background is derived in part from the primer agreed by the parties and supplied to me before the trial and partly from the written reports, witness statements and oral testimony given by the witnesses at the trial. I believe it to be uncontroversial. It represents part of the common general knowledge at the priority date of the patent in June 1993.PRIVATE 

3. The penis, like any other living organ or tissue in a mammal, is supplied with nutrient-rich and oxygen-rich blood in vessels called arteries. The flow is maintained by allowing the exit of the blood from the organ through vessels called veins. In an adult male human the penis has to grow in length and become rigid in order to facilitate sexual intercourse. This is called erection, or tumescence. After sexual intercourse or removal of the sexual stimulation which led to tumescence, in normal males the penis will return to its more flaccid and shorter resting state. This is called detumescence. Tumescence and detumescence are caused by changes in the blood flow inside the penis. To understand how this is achieved, it is necessary to know something of the basic anatomy of the normal penis.

(a) Anatomy.

4. Set out below is a diagrammatic representation of a cross-section of the penis.

Figure 1:

5. Towards the bottom of the figure the urethra is identified. This is the channel through which urine and semen can travel. Above and to each side of the urethra are two symmetrical compartments, or corpora, each of which is called a corpus cavernosum. It is changes in the blood flow inside these compartments which lead to tumescence and detumescence. The corpora cavernosa consist of vascular sinusoids. That is to say they contain a network of very small blood vessels or passages. The sinusoids are surrounded by a type of muscle known as cavernous smooth muscle which, like any other muscle, can contract or relax. The corpora cavernosa also contain a matrix of supporting connective tissue. Blood is supplied to the vascular sinusoids in the copora cavernosa through a network of arteries. The blood drains out again through a network of small veins or venules which drain into larger veins, called emissary veins. The latter veins lie on the outer surface of each corpus cavernosum. Surrounding the corpora cavernosa is a fibrous layer called the tunica albuginea. Rather like a sausage skin, it is not very elastic. The emissary veins are located between the corpora cavernosa and their respective tunica albugineas.

(b) function

6. When the penis is in its flaccid resting state, the flow of blood into the corpora cavernosa is restricted or throttled back by constriction of the smooth muscle which surrounds vessels in the incoming arterial network. These muscles act rather like ligatures. When they contract they reduce the internal diameter of the vessels in the arterial network. Of course they do not completely close the arteries or the penis would be completely starved of blood. When the smooth muscles are contracted like this, less blood can flow into the corpora cavernosa. Similarly the cavernous smooth muscle is contracted to the same effect. On the other hand the venules and veins are unaffected. They continue to be able to remove blood from the penis with comparative ease.

7. When an erection is triggered, the smooth muscles surrounding the vessels in the arterial network and the cavernous muscles relax. The arteries open up. It is now easier for them to supply blood to the corpora cavernosa. Blood floods in to the sinusoids. The sinusoids start to swell and each corpus cavernosum presses up against the surrounding tunica albuginea. The swelling of the sinusoids squeezes the venules, thereby reducing the size of their internal passages. This reduces their ability to drain blood from the corpora cavernosa. Similarly, as the corpora cavernosa expand and press against the tunica albuginea, the emissary veins located between these two tissues are squeezed and are less able to drain blood from the penis. The result is that the penis becomes engorged with blood and stiff. A state of full erection is achieved when the pressure in the corpora cavernosa equals mean systolic pressure (i.e. the pressure of the blood leaving the heart). When the erectile process works in reverse the smooth muscles contract and the arteries again become constricted. This reduces influx of blood. At the same time the smooth muscle of the sinusoids become constricted which, in turn, reduces the external pressure on the venules and the emissary veins and allows the blood to flow out. So, during an erection inflow of blood is facilitated and outflow hindered and during detumescence outflow is facilitated and inflow is hindered.

8. It should be noticed that contraction of the smooth muscles results in relaxation or detumescence. On the other hand relaxation of the smooth muscles results in tumescence/erection. This is because the smooth muscle is being used to throttle back the blood which, if allowed to flow in at arterial pressure, would result in the penis being gorged with blood and erect.

(c) Smooth muscles

9. The body of a mammal contains a number of different types of muscle. For example the muscles which result in one being able to raise or lower an arm are part of the ‘voluntary’ system of the body and are under conscious control of the brain. On the other hand there are muscles in the body which are under ‘involuntary’ control. These muscles are made to contract or allowed to relax by the background housekeeping systems which exist in mammals (and other animals). The smooth muscles which surround the sinusoids and small arteries in the corpora cavernosa are part of this ‘involuntary’ system. They are supplied and brought into operation by a separate system of nerves to those used in the voluntary system. Various types of smooth muscle are to be found in different tissues and organs of mammals.

(d) Male Erectile Dysfunction (MED) and its treatment.

10. A significant part of the adult male population suffers from male erectile dysfunction. An accurate figure for the numbers affected is not known, partly because some sufferers are reluctant to acknowledge the existence of the problem or to discuss it with third parties. However the sufferers of one form or another of MED in Britain may be in the millions. MED becomes more prevalent in older men. In some males MED takes the form of a total inability to achieve an erection. In others the erection may be incomplete or last insufficiently long to achieve any or satisfactory sexual intercourse. In others the penis may stay erect for a long time or permanently (priapism). It is probable that there are a number of different causes of MED, with some males having one defect and others having others.

11. There were, at June 1993, a number of well know treatments for men who were unable to achieve satisfactory erections. The most widely used consisted of the self administration, by injection directly into the corpora cavernosa, of various drugs. The injection had to be effected shortly before sexual intercourse was desired. The drugs deployed included phenoxybenzamine, phentolamine, papaverine and prostaglandin E₁. In England papaverine was the most widely used of these agents. For obvious reasons this form of treatment did not suit everyone. Some males disliked the act of self injection and sometimes one or both partners found the treatment discouraging. Furthermore the injections were not without side effects. For example frequent injections directly into the penis cause scarring. Sometimes treatment caused pain or priapism. This form of administration of the drug is frequently referred to as intracavernosal or ‘i.c.’ As an alternative to i.c. treatment, some drugs were injected into the urethra. Again there were side effects.

12. Another type of treatment consisted of the oral administration of a drug known as yohimbine. Although it was accepted before me by all the witnesses that the oral administration of a drug was the avenue of choice, there was much doubt as to the efficacy of yohimbine. As a result, i.c. injections were used widely not withstanding their obvious disadvantages. A number of other treatments were used in a minority of cases. These included the use of suction devices and prostheses, the use of glyceryl trinitrate patches applied to the penis and sometimes increases in arterial supply to the penis effected by surgical intervention. All suffered from some side effects even in those cases where they were effective in curing or reducing MED.

(d) The Chemistry of Smooth Muscle Relaxation

13. At this point it will also be convenient to explain what is going on inside smooth muscle which makes it contract and relax. All the matters set out below were known at the priority date and were common general knowledge.

14. Muscle is made up of living cells. In the case of the type of muscles distributed in the penis, each cell is made to relax when it receives a chemical ‘messenger’ which triggers the series of chemical reactions in the cell which cause the relaxation. In smooth muscles the creation of such a chemical messenger can be traced back to the production of a short lived gas, called nitric oxide (chemical formula: NO). Nitric oxide is produced or released from at least two sources. First smooth muscle is lined with cells called endothelium cells. It was known in the 1980’s that this produced a ‘relaxing factor’, that is to say something which affected the contraction of the muscle. Because of its source and effect this was known as EDRF (i.e. Endothelium Derived Relaxing Factor). EDRF was discovered to be nitric oxide in the late 1980’s.

15. Secondly the nerves which service smooth muscle also release nitric oxide. These nerves are sometimes called non-adrenergic non-cholinergic (to distinguish them from certain other nerves in the body which are adrenergic or cholinergic) or NANC nerves. In both cases the nitric oxide is produced by a reaction from a chemical called L-arginine. The chemical reaction is catalysed by an enzyme called nitric oxide synthase.

16. The nitric oxide produced by these two methods enters the smooth muscle cells and activates another enzyme (called guanylate cyclase) which converts another chemical called guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP in turn activates certain other intracellular enzymes (called protein kinases) which cause or promote chemical reactions which relax the smooth muscle. cGMP can itself be inactivated. A group of enzymes, called phosphodiesterases or (PDEs), cause cGMP to be turned into a chemical which is ineffective to relax muscle. This ineffective chemical is known as 5’GMP. Thus turning cGMP into 5’GMP has the effect of removing the agent which causes the muscle to relax. This sequence of chemical reactions can be represented in abbreviated and diagrammatic form as follows.

Figure 2:

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17. This is known as the NANC pathway. Notice that the agent which is believed to cause relaxation is cGMP. That agent is produced by the ‘front end’ of the pathway and is dependent, amongst other things, on the generation of NO. It is removed by the ‘back end’ of the reaction - i.e. the part which is dependent, amongst other things, on the action of the PDE enzymes. As will be recalled, relaxation of the smooth muscle results in erection. So, production of cGMP should cause or contribute towards an erection and removal of it should cause or contribute towards detumescence.

18. What goes on in the penis is more complex than this. Penile smooth muscle is also relaxed by other agents. In particular there is another chemical called cyclic adenosine monophosphate or cAMP which relaxes the smooth muscle like cGMP does. It is produced from a different starting material to cGMP in response to different messengers. In particular the messengers which trigger the creation of cAMP are called vasoactive intestinal peptide (VIP) and prostaglandin E1 (‘PGE1’). Like cGMP, cAMP is turned into an ineffective chemical by the action of a PDE enzyme. By the priority date it was well known that there were a number of PDEs. Each one regulates the level of cGMP, cAMP or both to varying degrees. By June 1993, five different PDE enzymes or enzyme groups were recognised by scientists and a classification system was adopted to discriminate between them. By that time it was also known that some of these PDEs could be inhibited (i.e. their catalysing function could be completely or significantly blocked) by certain other chemicals, called PDE inhibitors. A table set out at the back of the primer shows the PDEs, what they acted on and examples of selective inhibitors which were known by June 1993. The relevant data are as follows:

19. It will be seen that PDE_IV only acts as a catalyst for the destruction of cAMP. It can therefore be said to be a cAMP specific PDE. Similarly PDE_V can be called cGMP specific. The other PDEs are not specific, but can catalyse reactions which destroy both cAMP and cGMP. However, a PDE which catalyses the destruction of both cAMP and cGMP, and therefore is not specific, may be more effective in helping to destroy one type of substrate than the other. For example PDE_III is more effective in destroying cAMP than in destroying cGMP, so it can be called a cAMP selective PDE. Similarly an inhibitor may be more effective in blocking the enzymatic activity of one type of PDE than of another. In such a case it can be said to be a selective inhibitor of the former. So zaprinast, a chemical which figures extensively in this case, is a selective PDE_V inhibitor. In fact the inhibition of an enzyme is a reversible effect which is dependent on the concentration of the inhibitor used. The more inhibitor present, the greater the inhibition. For this reason, one measure of the power of an inhibitor is to find the figure which causes 50% inhibition of the enzyme activity. This is called its IC₅₀ value.

20. It was common general knowledge before the priority date that cGMP and cAMP also regulate a variety of functions in other organs and tissues of the body, not just the relaxation of smooth muscles in the penis.

21. Finally I should mention that the importance of nitric oxide became so well known that in the 18 December 1992 issue of the eminent journal Science it was named “Molecule of the Year”. In the editorial of that issue, it was stated that NO “is a major biochemical mediator of penile erection” and in an article in the same issue under the heading “Molecule of the Year”, it was said:

“This year [1992], scientists proved definitively that in males, NO translates sexual excitement into potency by causing erections. Key pelvic nerves get a message from the brain and make nitric oxide in response. NO dilates blood vessels throughout the crucial areas of the penis, blood rushes in, and the penis rises to the occasion.”

22. One of the Pfizer witnesses, Dr. Challiss, described this as tabloid journalism, and so it is, but he also said it made a nice story. I have no doubt that it reflects the excitement that the elucidation of nitric oxide’s role in the body, and in relation to male sexual activity, generated by the end of 1992.”

The Patent

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

“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 which, in turn, provides the basis for the utilities already disclosed for the said compounds in [Bell I] and [Bell II], namely in the treatment of stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency e.g. post- percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS).”

“Unexpectedly, it has now been found that these disclosed compounds are useful in the treatment of erectile dysfunction. Furthermore the compounds may be administered orally, thereby obviating the disadvantages associated with i.c. administration.”

“In summary, the above investigation identified three PDE isoenzymes in human corpus cavernosum tissue. The predominant PDE is the cGMP-specific PDE_v, whilst cGMP-stimulated cAMP PDE₁₁ and cGMP-inhibited cAMP PDE₁₁ cAMP PDE₁₁₁ are also present.

The compounds of the invention have been tested in vitro and found to be potent and selective inhibitors of the cGMP-specific PDE_v. For example, one of the especially preferred compounds of the invention has an IC₅₀ = 6.8 nM v, the PDE_v enzyme, but demonstrates only weak inhibitory activity against the PDE₁₁ and PDE₁₁₁ enzymes with IC₅₀ = > 100µM and 34µM respectively. Thus relaxation of the corpus cavernosum tissue and consequent penile erection is presumably mediated by the elevation of cGMP levels in the said tissue, by virtue of the PDE inhibitory profile of the compounds of the invention.

Furthermore, none of the compounds of the invention tested in rat and dog, both intravenously (i.v.) and orally (p.o.) at up to 3 mg/Kg, has shown any overt sign of adverse acute toxicity. In mouse, no deaths occurred after dose of up to 100 mg/Kg i.v.. Certain especially preferred compounds showed no toxic effects on chronic p.o administration to rat at up to 10 mg/Kg and to dog at up to 20 mg/Kg.

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.”

“Moreover, 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 manufacture of a medicament for the curative or prophylactic oral treatment of erectile dysfunction in man.” (page 5 lines 23 to 25)

“Claim 1. The use of a compound of formula (I):

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wherein

R¹ is H; C₁-C₃ alkyl; C₁-C₃ perfluoroalkyl; or C₃-C₅ cycloalkyl;

R² is H; C₁-C₆ alkyl optionally substituted with C₃-C₆ cycloalkyl; C₁-C₃ perfluoroalkyl;

or C₃-C₆ cycloalkyl;

R³ is C₁-C₆ alkyl optionally substituted with C₃-C₆ cycloalkyl; C₁-C₆ perfluoroalkyl; C₃-C₅ cycloalkyl; C₃-C₆ alkenyl; or C₃-C₆ alkynyl;

R⁴ is C₁-C₄ alkyl optionally substituted with OH, NR⁵R⁶, CN, CONR⁵R⁶ or CO₂R⁷; C₂-C₄ alkenyl optionally substituted with CN, CONR⁵R⁶ or CO₂R⁷; C₂-C₄ alkanoyl optionally substituted with NR⁵R⁶; (hydroxy)C₂-C₄ alkyl optionally substituted with NR⁵R⁶; (C₂-C₃ alkoxy)C₁-C₂ alkyl optionally substituted with OH or NR⁵R⁶; CONR⁵R⁶; CO₂R⁷; halo; NR⁵R⁶; NHSO₂NR⁵R⁶;NHSO₂R⁸; SO₂NR⁹R¹⁰; or phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl any of which is optionally substituted with methyl;

R⁵ and R⁶ are each independently H or C₁-C₄ alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino, 4-N(R¹¹)-piperazinyl or imidazolyl group wherein said group is

optionally substituted with methyl or OH;

R⁷ is H or C₁-C₄ alkyl;

R⁸ is C₁-C₃ alkyl optionally substituted with

NR⁵R⁶;

R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperdino, morpholino or 4-N(R¹²)-piperazinyl group wherein said group is optionally substituted with C₁-C₄ alkyl, C₁-C₃ alkoxy, NR¹³R¹⁴ or CONR¹³R¹⁴;

R¹¹ is H; C₁-C₃ alkyl optionally substituted with phenyl; (hydroxy)C₂-C₃ alkyl; or C₁-C₄ alkanoyl;

R¹² is H; C₁-C₆ alkyl; (C₁-C₃ alkoxy)C₂-C₆ alkyl; (hydroxy)C₂-C₆ alkyl; (R¹³R¹⁴N)C₂-C₆ alkyl; (R¹³R¹⁴NOC)C₁-C₆ alkyl; CONR¹³R¹⁴; CSNR¹³R¹⁴; or C(NH)NR¹³R¹⁴;

and

R¹³ and R¹⁴ are each independently H; C₁-C₄ alkyl; (C₁-C₃ alkoxy)C₂-C₄ alkyl; or (hydroxy)C₂-C₄ alkyl.

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.

Claim 5: “The use according to claim 4 wherein the compounds of formula (1) is selected from. …” There follows a list of 9 chemical compounds.

Claim 6: “The use according to claim 5 wherein the compound of formula (I) is 5-[2-ethoxy-5-(4-methyl-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.”

Claim 7: “The use 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.”

Claim 9: “The use according to any one of claims 1 to 8 wherein the medicament is adapted for oral treatment.”

Claim 10: “The use of a cGMP PDE 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.”

Claim 11: “The use according to claim 10 wherein the inhibitor is a cGMP PDE_v inhibitor.””

“58. My findings on the construction of the claims are therefore as follows:

(A) Claim 1 covers the use of a Formula I compound (a) either alone or with some other agent, (b) by any means of administration, (c) for the purpose of treating male animals who have the inability to obtain or sustain an erection and (d) where such use is effective, at least in some cases, in treating that disorder.

(B) Claim 10 covers the use of (a) any compound which inhibits cGMP PDE enzymes (whether selective or not), (b) either alone or with some other agent, (c) by oral administration, (d) for the purpose of treating males who have the inability to obtain or sustain an erection and (e) where such use is effective, at least in some cases, in treating that disorder.

(C) Claim 11 is of the same scope as claim 10 save that it is restricted to compounds which inhibit cGMP PDE_V.”

Obviousness

“I think that having regard to the statement which Pfizer is prepared to make, set out in paragraph 4 of Mr Meade’s skeleton argument [the same as in the June letter], and having regard to what he told me in response to a direct question from me this morning – which will appear on the transcript – that screening forms no part of any positive case of inventiveness which is being made on behalf of Pfizer, the process of screening forms no positive case which would be advanced in support of the contention of non-obviousness, it seems to me that it would be wrong for me, on this aspect of the objection, to make the order for disclosure which is sought.”

That conclusion was recorded in the court’s order of 17th August 2000.

“There are, we think, four steps which require to be taken in answering the jury question. The first is to identify the inventive concept embodied in the patent in suit. Thereafter, the court has to assume the mantle of the normally skilled but unimaginative addressee in the art at the priority date and to impute to him what was, at that date, common general knowledge in the art in question. The third step is to identify what, if any, differences exist between the matter cited as [forming part of the state of the art] and the alleged invention. Finally, the court has to ask itself whether, viewed without any knowledge of the alleged invention, those differences constitute steps which would have been obvious to the skilled man or whether they require any degree of invention.”

“The therapeutic potential of PDE V_A inhibitors as, for example, vasodilators, bronchodailtors and producers 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.”

Clearly the author is suggesting that other PDE_v inhibitors should be investigated.

“Cyclic nucleotide phosphodiesterases (PDEs) have long been regarded as potential targets for therapeutic agents. More recently, interest in this area has been renewed by the recognition that there are five distinct PDE isoenzyme families, and that tissues have different complements of these isoenzymes. There is, therefore, a logical foundation for selective PDE inhibitors to be used to increase cyclic nucleotide levels in specific target tissues or organs. Indeed selective PDE III inhibitors (see below for nomenclature) are currently used clinically for the treatment of congestive heart failure and as antithrombotic agents, and this success has given hope that inhibitors of other PDE isoenzymes will also be useful drugs. The purpose of this review is to discuss briefly the PDE isoenzyme families and to describe one of these isoenzyme families, PDE V. The physiological and pharmacological effects of PDE V_A inhibitors are reviewed and their potential therapeutic indications discussed.”

“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. [At this point there is a footnote reference to the Rajfer paper.]

…

Zaprinast is a weak relaxant of lower esophageal sphincter muscle from a number of species, including humans, but potently relaxes guinea pig colon and Taenia coli preparations. Contracted rat gastric fundus is also relaxed by zaprinast, and the compound potentiates the sodium nitroprusside (SNP)-induced relaxation of this tissue.

In vivo studies of PDE V_A inhibitors have largely been on the effects of zaprinast on mean arterial blood pressure (MABP) in anesthetized rats or dogs, and again, the results give a reasonably consistent picture. Zaprinast lowered MABP mainly by decreasing total peripheral resistance, and there is evidence for selective vasodilatation. Zaprinast increased cardiac output and also caused a marked natriuresis, but had little effect on heart rate. In a rat aortavenocaval fistula model of cardiac failure, infusion of zaprinast caused natriuresis with little effect on MABP. Treatment of spontaneously hypertensive rats with zaprinast caused a fall in MABP to control levels. SK&F-96231 did not affect heart rate or MABP in conscious dogs, whereas bronchodilating effects of the compound were observed in anesthetized guinea pigs.”

“To date, the only PDE V_A inhibitor that has been clinically evaluated is zaprinast. In adult asthmatics, zaprinast reduced bronchoconstriction induced by exercise, but not that provoked by histamine⁵¹. In contrast, zaprinast had no effect on exercise-induced asthma in children⁵². However, when evaluating these results, it should be remembered that these were small clinical trials using a compound that may have actions other than PDE V_A inhibition. Therefore, at present, PDE V_A inhibitors must be considered to be compounds with potential rather than established clinical use.

Smooth muscle relaxation appears to be the most promising of the potential uses of PDE V_A inhibitors, and possible therapeutic utilities could include vaso dilatation, bronchodilatation, modulation of gastrointestinal motility and treatment of impotence. Although PDE V_A inhibitors will relax most smooth muscle types in vitro, this does not necessarily mean that a nonselective action will be seen in vivo. Selective actions could be achieved by virtue of the fact that many of the effects of PDE V_A inhibitors in a particular tissue are dependent on the level of guanylate cyclase activity. Thus, PDE V_A inhibitors will have the greatest effect in cells and tissues that have a high guanylate cyclase activity, and there could be considerable value in a therapeutic agent that has little activity in its own right, but potentiates the effects of endogenous mediators. An example of this has been demonstrated in the rat model of cardiac failure described above, where the operated animals were more sensitive to the effects of zaprinast than their sham-operated controls. An explanation for this is that higher levels of the guanylate cyclase-activating ANP are found in the former group.”

… At present the therapeutic potential of PDE V_A is largely based on the effects of … zaprinast, and a clearer picture will be obtained when other rationally designed PDE V_A inhibitors become available.”

“Nitric oxide has been identified as an endothelium – derived relaxing factor in blood vessels. We tried to determine whether it is involved in the relaxation of the corpus cavernosum that allows penile erection.”

“The relaxation [of human corpus cavernosum tissue] caused by either electrical stimulation or nitric oxide was enhanced by a selective inhibitor of cyclic guanosine monophosphate (GMP) phosphodiesterase (M&B 22,948).” [i.e. by a selective cGMP PDE inhibitor]

“71. Under the heading ‘conclusions’ in the abstract, the authors say that defects in the NANC pathway may cause some forms of impotence. The main text of the paper records that failure of penile erection could be due to impaired relaxation of the smooth muscle of the corpus cavernosum (p. 90 left column) and states that the purpose of the study it reports was to ascertain whether nitric oxide plays a part in relaxation of the corpus cavernosum in humans and therefore in penile erection (p. 90 right column). It then reports a series of experiments. It is not necessary to go into the detail of those experiments but they can be split into two broad groups. In the first, the effect of modification of the nitric oxide generating part of the NANC pathway was examined. For example the generation of nitric oxide was impaired by swamping the tissue samples with an analogue of L-arginine which is not turned into NO. This had the effect of preventing L-arginine from being turned into NO (see step 1 in the flow diagram at paragraph 16 above). The second was concerned with looking at the chemical processes by which the cGMP produced by NO was removed from the tissue. To do this it used a cGMP PDE inhibitor identified as M&B 22,948 – this is the pharmaceutically active molecule known as zaprinast produced by May & Baker (see the table at paragraph 18 above). The authors report that they took strips of fresh human corpus cavernosum tissue and subjected them either to electrical field stimulation (i.e. to emulate the effect of the nerves when a man is sexually aroused) or to treatment with a chemical called SNAP which liberates NO. In both cases the NO released made the corpus cavernosum relax. The authors then applied the selective cGMP PDE inhibitor, zaprinast, to the tissue samples to see what effect it had on the NO-generated relaxation. It records that the inhibitor augmented or enhanced the relaxant responses. For example under the rubric “Preliminary Observations in Men without Impotence” Rajfer says:

“Corporal tissue from two men without impotence and tissue from impotent patients responded similarly with regard to the … enhancing effects of M&B 22,948 on electrically elicited relaxation. … M&B 22,948 … caused increases of 72 to 86 percent and 84 to 96 percent, respectively, in the relaxation response of corporal strips from 2 normal patients and 11 impotent patients.”

72. In the discussion section of the paper, Rajfer says:

“… the addition of nitric oxide … caused similar rapid relaxant responses that were … enhanced by M&B 22,948 … M&B 22,948 is a selective inhibitor of cyclic GMP but not cyclic AMP phosphodiesterases…” [i.e. it is a selective inhibitor of cGMP PDE but not cAMP PDE]

and ends by concluding that the NANC 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 men. … interference with the L-arginine-nitric oxide pathway could be one cause of impotence that is treatable by the administration of direct-acting vasodilators.”

73. There is one other passage in Rajfer which should be referred to. It is on the second page of the paper in the detailed description of the experimental procedure being used. It reads as follows:

“When [zaprinast], an experimental drug prepared by May and Baker (Dagenham, United Kingdom) was tested, it was added to the strips at a concentration of either 1 or 3 (mol per liter (whichever caused a relaxation of 10 to 15 percent, sufficient to ensure that enough [zaprinast] had been added).””

“138. I accept Mr Thorley’s arguments of obviousness. If anything, the case of obviousness based on Murray is even stronger than in relation to Rajfer. It could be said that Pfizer’s patent is little more than a putting into practice of the recommendations and suggestions of Dr Murray. Those recommendations and suggestions would have been appreciated by a man skilled in the art at the priority date as being sound and worth trying.”

“When deciding whether a claimed invention is obvious, it is often necessary to decide whether a particular avenue of research leading to the invention was obvious. In such circumstances the extent of the different avenues of research and the perceived chances of any one of them providing a successful result can be relevant to the decision whether the invention claimed was obvious. Whether the subject matter was obvious may depend upon whether it was obvious to try in the circumstances of that particular case and in those circumstances it will be necessary to take into account the expectation of achieving a good result. But that does not mean that in every case the decision whether a claimed invention was obvious can be determined by deciding whether there was a reasonable expectation that a person might get a good result from trying a particular avenue of research. Each case depends upon the invention and the surrounding facts. No formula should be substituted for the words of the statute. In every case the Court has to weigh up the evidence and decide whether the invention was obvious. This is the statutory task.”

“90. … What is clear from the evidence is that the Pfizer workers involved did not know, to use Dr Ellis’ words, that the mechanism of action of cGMP PDE inhibitors is fundamentally different from other direct acting vasodilators. They had not appreciated that the production of cGMP is not increased by an inhibitor but that its breakdown is countered. However these are matters which a skilled man in the art would have understood from Rajfer (and from Murray or Bush). It should be remembered that even the abstract at the beginning of the Rajfer article points out the different mode of action because it states that

“The relaxation caused by either electrical stimulation or nitric oxide was enhanced by a selective inhibitor of cylcic guanosine monophosphate (GMP) phosphodiesterase.” (emphasis added)

91. That message is reinforced by the rest of the document. It explains that the inhibitor does not produce the muscle relaxing factor (cGMP) but enhances or amplifies its action if it is already there. Dr Ellis is correct to say that the different mode of action of cGMP PDE inhibitors to NO donors makes it clear why the experiment did not work. However once Rajfer (or Murray or Bush) was published and had been read carefully, that difference was no longer a matter of hindsight.”

“99. … The starting point in considering this issue is an awareness of what those in the art thought of oral treatment of MED at the priority date. In my view this was an area in which there was close to consensus between the witnesses. There is no doubt that a high priority in the search for any new treatment of MED was that it should be administered orally. This was considered to be the ideal form of treatment by Dr. Gristwood. Dr. Challis, said that oral delivery was clearly the preferred route of administration and, under cross-examination, he said:

“…if you can achieve oral administration I am sure that there are a myriad of reasons why you would pursue it” (Day 5 Transcript page 659 –660)

100. Some of those reasons were given by Dr. Kruse in a passage in his report which was not seriously challenged:

“The ultimate aim of most drug research program is to produce a drug which can be taken orally. … Oral administration is the preferred and most widely used route of administration for the simple reason that it best ensures patient compliance and can be used at home, as opposed to in a hospital setting. Oral drugs can easily be self-administered by a patient. Swallowing a pill is a relatively non-invasive and non-threatening event for most patients and it is a fairly easy task to ensure one is taking the correct quantity of the drug, i.e. it is easier to count pills than say measure out a quantity of solution to take intravenously. Of course there are some circumstances where other routes of administration (e.g. intravenous or intramuscular) might be preferred, for example for the administration of a very potent, short acting drug following a stroke or an anaphylactic shock. Non-oral methods of administration might also be preferred for certain organs, for example administration directly into the eye for the treatment of glaucoma. However, in the vast majority of cases of drugs being administered to treat non-life threatening conditions the oral route of administration is the best and the most widely used. In a disease such as erectile dysfunction, where male self-image, and perceptions of performance are important, oral activity is almost certainly a requirement for a commercially successful drug. It is difficult to imagine an injectable or other mode of administration competing effectively with the discretion and simplicity of an orally acting therapeutic.”

101. Similar evidence was given by Mr Pryor, a urologist called by Lilly who was a most impressive witness. He said that by early 1993 the vast majority of clinicians had recognised the disadvantage of penile injection therapy and the desirability of having an oral preparation and that he would have advised any company involved in finding a new treatment for MED that it should make it a priority to develop an orally active drug. He said:

“The oral route of administration is generally the most convenient and most acceptable to a patient for any drug. It enables the patient to manage easily and in the safest way possible the treatment of his particular disorder. It is suitable for acute, chronic or prophylactic treatment. With respect to the treatment of erectile dysfunction, oral administration of a medicament was generally recognised as being the obvious goal to aim for since it would overcome the unpleasant and potentially hazardous procedures associated with intracavernosal injections. In fact, at the NIH consensus meeting in 1992 it was stated that amongst the needs and directions for future research was the development of new therapies, including pharmacologic agents, and with the emphasis on oral agents that may address the cause of male erectile dysfunction which greater specificity (page 194)”. (Pryor Expert Report paragraph 5.4)

(The NIH referred to in that passage is the American National Institute of Health which held a meeting on impotence in December 1992.)

102. I accept Mr Pryor’s evidence as fair and reliable. Indeed Pfizer accepts that at the priority date an effective oral treatment for impotence was known to be desirable “in the abstract”.”

“105. However, there are additional reasons why Mr Kitchin’s arguments must be rejected. On the facts here there was overwhelming pressure on workers in the field to try oral administration with any new pharmaceutical candidate for MED treatment. I have already referred to the very unpleasant nature of the primary treatment for male impotence, namely self injection into the penis immediately before sexual intercourse, and the general appreciation by 1992 if not before that oral treatment was what was needed. Pfizer suggests that the perceived risks of oral administration of a PDE inhibitor were so great that they would not even be tried. This argument reached its high point in Professor Ignarro’s warning that oral administration risked killing the patients. Because some PDE inhibitors were known to have an effect on the peripheral vascular system which could result in lowered blood pressure, so any systemic treatment would be likely to be potentially life-threatening.

106. It is all too easy in a case like this to raise a lurid fear and for that to obscure the issues. That, in my view, is what Pfizer have done here. It is well known and not in dispute that regulatory authorities exercise immense care before they will license drugs for human use. The prospect of an orally administered impotence treatment being allowed on the market which has a significant risk of killing patients or even causing them significant harm must be regarded as very small indeed. As Mr Kitchin is anxious to point out, most drugs go through extensive testing, including testing on live animals, before they are allowed even to be clinically tested on humans. The risk, if there is one, therefore is not a risk of killing patients so much as of failing to make it through the trials which always have to be undertaken to prove efficacy and lack of relevant or unacceptable toxicity and side effects. The question is, therefore, whether it would be obvious to try to use a cGMP PDE inhibitor in oral treatment or were the risks of failing so great as to deter the notional skilled worker before he set off down that path. Whether something is obvious to try depends to a large extent on balancing the expected rewards if there is success against the size of the risk of failure. Here it was apparent that the rewards for finding an oral treatment would be substantial. The risk was not, as indicated above, the risk of killing anyone, but the risk that trying oral administration would not work so that the research would be unproductive. …

107. I have come to the conclusion that the skilled team would not have been put off trying oral administration of a PDE inhibitor. On the contrary, on balance there is much in the evidence which suggests that trying oral administration was a worthwhile, and perhaps the first, avenue to pursue. The skilled team would have included PDE expertise. It would have known that the oral administration of PDE inhibitors was already being tried in a number of fields. As Dr. Challis agreed, it was well known by 1993 that a number of PDE inhibitors were bioavailable orally. Further Lilly produced a document (X17) which referred to 25 patents to PDE inhibitors applied for before the priority date of the patent in suit. The patentees included Warner-Lambert Co., SmithKline Beecham, Pfizer and Schering – all well known names in the pharmaceutical field. Every one of them suggested that the inhibitors should be administered orally. In some cases they contain a suggested daily dose for human ingestion. Even by the time of Rajfer in January 1992, it would have been apparent that it was worth trying oral administration of any candidate compound. The reasons for this are not difficult to understand. On the one side there was the pressure to find an oral treatment for MED. On the other there was nothing to suggest that these inhibitors as a class were necessarily ineffective or toxic when so administered. Dr. Gristwood gave evidence on this issue. He said:

“Having read Rajfer et. al., there was nothing to deter me from pursuing an oral delivery of a selective PDE V inhibitor as a treatment of impotence. Although cardiovascular effects have been reported in anaesthetised rats and dogs with intravenous administration of zaprinast, I was not then, and still am not, aware of any reported adverse side effects associated with oral administration of zaprinast to humans. I was aware in 1993 that zaprinast had been administered orally in humans (both adults and children) without adverse side effects. I would expect most people working in the field to have been aware of this.”

108. I accept that evidence. The fact that zaprinast (May & Baker’s PDE_V inhibitor) which was discussed and used in Rajfer was the subject of clinical trials and had been administered orally for that purpose would have been known to all those involved in the potential use of PDE inhibitors as a drug candidate. Anyone who had any fears about the use of it, or other PDE inhibitors, for oral administration would have found that out from the published literature. Furthermore, even if the skilled man was not aware that PDE inhibitors had actually been used in such clinical trials, he would not have been put off trying oral administration. He would have been unable to predict whether there would be a problem associated with oral administration, or if there was its nature and magnitude and he would be reassured that if any significant problem did exist it would surface during the course of the tests necessary for regulatory approval, that is to say tests specifically designed as a filter to ensure no appreciable risk to the public. The result is that the skilled man or team in the art would not have been put off from trying to use a PDE inhibitor for oral administration.

109. The evidence supports the view that any worries about possible side effect or contra indications would not have been sufficient to prevent a worker in the field from trying out PDEs for administration to man, whether orally or otherwise. For example Dr. Challis’ evidence was:

“Q. Coming back again to paragraph 46 you are unable to point my Lord to any known PDE5 as at 1993 which was known to have life-threatening side-effects.

A. I am sorry, I have gone to the .... We are on 46?

Q. Did I say 46. I should not have done. …

MR. THORLEY: I do apologize; it is my fault. Paragraph 65, top of page 29, you were talking about life-threatening consequences. That is what we were talking about and I am trying to ensure that I have got your evidence accurately. Do you want me to put the question again?

A. No. I am quite happy. I am saying that, I think the point that I am trying to get across there is that if one is thinking about the treatment of MED one has a good idea of what the patient population is going to be. It is going to be generally more elderly. I think the incidence of impotence increases essentially exponentially beyond the age of around 40, so we are dealing here with a group of patients that have potentially other health problems in their lives. We are dealing with a disorder that is in itself not life-threatening and, therefore, I think that anyone developing drugs in this area is going to be acutely aware of any side-effects, never mind life-threatening side-effects, but there is the potential of these drugs, I think, to cause life-threatening effects in people with particular other complicating disorders.

Q. Are you saying that that concern would deter you from doing any development work in the field or are you saying that you would conduct development research with caution?

A. The latter.”

(Day 5 Transcript page 700)

110. He returned to the same theme on the next day:

“MR. THORLEY: … doctor, you said, if I recall rightly that because of these complications there could be no guarantee that a beneficial therapy could be produced.

A. No.

Q. By pursuing any particular route of potential treatment.

A. That is absolutely the case, yes.

Q. That is the point that you are seeking to make.

A. The point is that I believe .... The sildenafil example gives us a clear example of where, despite all of my provisos, a drug is extremely effective. Therefore, all I am doing is trying to make you aware of the complexities of the field. I am not saying that there was no point in travelling towards that therapeutic goal at all.” (Day 6 Transcript page 720)

111. In addition to these points, I should refer to the evidence of Dr. Dennis Smith, the Senior Director of Pfizer’s Drug Metabolism Department and whose entire industrial career has been in the area of Drug Metabolism and Pharmacokinetics. He was asked by Pfizer to comment on what procedures would have formed a routine part of drug development programmes in order to assess the oral bioavailability of a compound, as at June 1993 . In particular, he was asked to comment on the use of conscious animals for this purpose as at that date.

112. He stated that oral bioavailability assessment of compounds using animals, such as the dog had certainly become a well known and routine part of drug development programmes by 1992. He said that this was due to fundamental similarities between animals and man in the processes governing absorption of compounds from the gastrointestinal tract and subsequent appearance in the systemic circulation (from where the drug molecule exerts its pharmacological effect). He also said that such assessments are a routine aspect of selecting the appropriate drug molecules for clinical development. He supported that view by a reference to numerous published articles from various workers, from a large number of pharmaceutical companies. His report also contains the following:

“I should say that in practice, oral bioavailability studies are not carried out on the full range of compounds studied in the course of a drug discovery programme, but only those which are considered to be the more promising candidates for further development. For each compound being tested, such studies normally took approximately two to three weeks to carry out in 1993. I should also point out that species differences in bioavailability between man and animal species, including dog, have been identified, which may mean that the data needs interpretation for prediction to man. However, the assessment of oral bioavailability in animal species in 1993 and today remains an essential element of the preclinical assessment of novel drug candidates. Increasingly in vitro systems have been put into place which facilitate this interpretation, but these are used alongside data on bioavailability in conscious animals. Other animal species are used in addition to the dog in the assessment of oral bioavailability. These include mice, rats and monkeys. However, the extensive use of the dog in pharmacology studies and in drug safety evaluation within the pharmaceutical industry, results in the dog being amongst the most commonly used of the animal species.”

113. Unsurprisingly, Lilly chose not to cross examine this witness. His evidence supports the view that it would have been a matter of course to try out any potential anti-MED candidate by oral administration to conscious animals, including dogs, and that any such testing would have taken a comparatively short time. That is what the skilled man in the art would have done.”

Lord Justice Buxton:

Lord Justice Longmore: