Case No: HC 1999 No 01110

IN THE HIGH COURT OF JUSTICE

CHANCERY DIVISION

PATENTS COURT

Before: The Hon. Mr Justice Laddie

IN THE MATTER OF European Patent (UK) No. 0,702,555

in the name of PFIZER LIMITED (the Respondent)

AND IN THE MATTER of the Patents Act 1977

AND IN THE MATTER of a Petition to revoke

The same by LILLY ICOS LLC (the Petitioner)

Mr Simon Thorley QC, Mr Andrew Waugh QC and Mr Colin Birss

instructed by Taylor, Joynson, Garrett for the Claimant/Petitioner

Mr David Kitchin QC and Mr Richard Meade

instructed by Bird & Bird for the Defendant/Respondent

Hearing date: 4 - 18 October, 2000

JUDGMENT (subject to revision to correct typographical and clerical errors)

DATED: 8 November 2000

Mr Justice Laddie:

Introduction

By this action, Lilly ICOS LLC (ëLillyí) seeks to invalidate and revoke European Patent (UK) 702,555 (ëthe Patentí) which is registered in the name of Pfizer Limited. The patent seeks protection for the medical use of a number of chemicals in the treatment of impotence. One of these has the chemical name, sildenafil citrate. It is the active ingredient in the anti-impotence drug known as Viagra. Indeed it is part of Pfizerís case that this is the patent ëforí Viagra. It argues that the commercial success of Viagra is testimony to its inventiveness. Lilly is in the course of producing its own anti-impotence drug and it fears that the patent will stand in its way. It says that the patent is invalid because it is anticipated by a single piece of prior art, obvious over a number of pieces of prior art, insufficient and contains added matter. Before considering the patent and the attacks levelled at it, it will be useful to have a basic understanding of the anatomical, physiological and chemical background against which the issues have to be decided.

Technical Background

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.

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.

Anatomy.

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

Figure 1:

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

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.

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 cavernosum. 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 emissery 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. t he 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.

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.

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 ëvoluntaryí 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 ëinvoluntaryí control. These muscles are made to contract or allowed to relax by the background housekeeping systems which exists in mammals (and other animals). The smooth muscles which surround the sinusoids and small arteries in the corpora cavernosa are part of this ëinvoluntaryí 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.

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.

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 paint or priapism. This form of administration of the drug is frequently referred to as intracavernosal or ëi.c.í As an alternative to i.c. treatment, some drugs were injected into the urethra. Again there were side effect.

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 not5withstanding 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

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.

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 ëmessengerí 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 1980ís that this produced a ërelaxing factorí, 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 1980ís.

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.

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 5íGMP. Thus turning cGMP into 5íGMP 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:

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 ëfront endí of the pathway and is dependent, amongst other things, on the generation of NO. It is removed by the ëback endí 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.

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 (ëPGE1í). 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 show the PDEs, what they acted on and examples of selective inhibitors which were known by June 1993. The relevant data are as follows:

PDE type	Substrate	Inhibitors
PDE_I	Hydrolyses cAMP and cGMP	None known
PDE_II	Hydrolyses cAMP and cGMP	None known
PDE_III	Hydrolyses cAMP and cGMP	Amrinone (Sterling Winthrop) Milrinone (Sterling Winthrop)
PDE_IV	Hydrolyses cAMP	Rolipram (Schering) Ro 20-1724 Denbufylline
PDE_V (including PDE_{V B} and PDE_{V C})	Hydrolyses cGMP	Zaprinast (M&B22948) (although also inhibits PDE_I to a lesser extent.)

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.

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

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."

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 oxideís role in the body, and in relation to male sexual activity, generated by the end of 1992.

The Patent

The patent is for the second medical use of certain compounds. As I have mentioned, one of these is sildenafil citrate, the active ingredient in Viagra. In fact sildenafil citrate and a very large number of the other chemicals covered by the patent are the subject of two earlier Pfizer patent applications, namely EP 0463 756 and EP 0526 004, referred to respectively as Bell I and Bell I. Those applications were published before June 1993 and they are relied on in this case as prior art. In Bell I and II, sildenafil citrate and the other chemicals were proposed for a number of other medical applications, but not the treatment of male erectile impotence. That is why the patent in suit is, in part at least, for second medical use.

(a) The specification general description of the invention

It is particularly important in this case to construe the patent without regard to after acquired knowledge. The first line of the patent states that the "invention relates to the use of a series of pyrazolo[4,3-d]pyrimidin- 7-ones for the preparation of a medicament for the treatment of impotence". This is consistent with the title of the patent which is "Pyrazolopyrimidones for the treatment of impotence." The chemicals which are the subject of the Bell I and II applications are pyrazolo[4,3-d]pyrimidin- 7-ones and they are the subject of some of the claims in the patent, but the patent and its claims cover a much wider field. At page 2 lines 5 to 22 there is a brief discussion of male impotence and some of the prior art methods for treating it. As far as impotence is concerned, the specification says:

"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." (p 2 line 5 to 7)

The specification then states that the efficacy of orally administered drugs is low. It refers to the current treatment consisting of i.c. injection of various drugs "either alone or in combination" (page 2 line 15) but it also points out the existence of undesirable side effects, including pain and fibrosis of the penis. Other forms of treatment are touched upon briefly. Again, the specification records that they suffer from side effects. The specification then addresses what it says is the invention in the following terms:

"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 dys-function. Furthermore the compounds may be administered orally, thereby obviating the disadvantages associated with i.c. administration."

A number of points should be noticed. First, at least up to this point in the specification, there is little doubt that the expression "compounds of the invention" and "these disclosed compounds" alike refer back to the pyrazolo[4,3-d]pyrimidin- 7-ones referred to in the opening line which are the subject of the two Bell applications. Secondly, the first paragraph in the last quoted extract asserts that "the compounds of the invention" are both potent inhibitors of cGMP PDEs as compared to their inhibition of cAMP PDEs and that it is this selective inhibition which leads to the elevated cGMP levels said to give rise to the effectiveness of these compounds in the treatment of diseases such as angina, pulmonary hypertension and so on. So, if one looks back at the flow chart set out in Figure 2 above, the compounds of the invention block step 4, namely the ability of the phosphodiesterase enzyme (PDE) to turn cGMP into 5íGMP. The result is that cGMP levels remain high and it is this high level of cGMP which is asserted to be responsible for the medicinal properties of the compounds (i.e. anti angina etc) which are set out in the Bell applications. Thirdly it said that these compounds ëmay beí administered orally. It is not suggested that all of the compounds are suitable for oral administration and it is not Pfizerís position that they all are.

The specification then goes on to identify a group of compounds which are said to embody the invention. They are described by reference to a structural formula, referred to as "Formula I", which is set out in Figure 3 below. In it the letters R¹ to R⁴ represent a large number of identified chemical groups. It is not in dispute that the number of chemicals covered by Formula I is very large indeed.

Figure 3

The specification then goes on to identify a "preferred group of compounds" within Formula I, a "more preferred group", and a "particularly preferred group", each of which is a smaller subset of the previous group of compounds. Reference is then made to "specially preferred individual compounds of the invention" which "include" 9 named chemicals. One of those is sildenafil citrate.

(b) The specification experimental data.

The specification contains a limited amount of data to explain and support the invention. It explains that preliminary investigations were carried out for the purpose of isolating and identifying the PDEs in human corpus cavernosum and describes the experiments used. It reports that three distinct PDEs were present. They are identified as PDEs _II, _III and _V. The implicit teaching is that PDEs _I and _IV are not present, or not present in detectable amounts. The specification says that the major PDE present is PDE_V. Rather confusingly it states at one point that this PDE is "highly selective" for cGMP (page 4 line 46) while at another it identifies it as "cGMPspecific" (page 4 line 55). There appears to be no doubt amongst the witnesses and the parties that this PDE is PDE_V according to the accepted nomenclature and would be so understood by the skilled man in the art. In accordance with the terminology discussed at paragraph 18 above, it would be best described as cGMPspecific. As far as the second PDE isolated is concerned, the specification states that it destroys both cAMP and cGMP (page 4 line 48) and it identifies it at PDE_II. Although it does not expressly state that this PDE is cAMP selective, it does refer to it as cAMP PDE_II (page 4 line 55). The better view is, therefore, that the reader is being informed that PDE_II destroys both cAMP and cGMP, but is particularly effective against the former. As to the third PDE, the reader is told that it is cAMP selective (page 4 line 49). It is identified as PDE_III. In summary, the reader is being told that there are three PDEs present and that they all destroy cGMP. However the most prevalent PDE is PDE_V which only destroys cGMP.

Having explained that only three PDEs have been detected in human corpus cavernosum, the specification turns to explain how the compounds of the invention work. It says:

"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 PDE_II and PDE_III enzymes with IC₅₀ = >100 µM and 34 µM respectively". (p 4 line 57 to p 5 line 2)

The teaching of this passage is that some of the compounds within Formula I have been tested. They strongly and selectively inhibit cGMP-specific PDE_V. This means that they block that PDE much more than the other two PDEs which are also inhibited, but to a much smaller degree. Therefore use of the inhibitor will inactivate much of PDE_V but leave most of PDE_II and _III unaffected. We can see therefore that much of the PDE activity which destroys cGMP, namely that caused by PDE_V, is removed. However some cGMP destroying activity remains because most of the PDE_II and _III activity survives and both of them destroy cGMP to some extent, although less so than they destroy cAMP. To the very small extent that PDE_II and _III are inhibited, their ability to destroy cAMP will also be diminished. Because most of the cGMP destroying activity has been removed, cGMP should rise. This is addressed in the next passage 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."

This passage is important. The compounds of the invention cause a rise in cGMP levels in the corpus cavernosum, because they prevent some of the cGMP from being destroyed. They also cause the relaxation of the muscle in that tissue which leads to erection of the penis. On the basis of this, the patentee states that the erection is "presumably" caused by the increased cGMP levels. This is, no doubt, a reasonable deduction. But the patentee does not say that he has done anything by way of experimentation to prove this theory is right. It is his explanation of the likely reason why the PDE_V selective inhibitors of Formula I work.

The specification then goes on to deal briefly with toxicity, oral availability and efficacy trials. Somewhat surprisingly none of this identifies any particular compound as having been tested. For example it says that patient studies were conducted on one of the especially preferred compounds and showed that it induced penile erection in impotent males. It does not identify which of the nine listed especially preferred Formula I compounds was tested.

At page 5 line 15 the patentee 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."

The whole of the specification up to this point appears to have been written by reference to the large number of pyrazolo[4,3-d]pyrimidin-7-ones covered by Formula I and described in the earlier Bell applications. These are the selective enzyme inhibitors referred to on page 2 of the specification. However the specification ends with a paragraph which co nsiderably widens the disclosure and which is of particular significance in this case since it is the basis for the most important claims in the patent. It reads as follows:

"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)

It should be noticed that, notwithstanding the title to the patent, this passage is not restricted to pyrazolopyrimidones (whether of Formula I or otherwise). Furthermore, unlike earlier passages in the specification, it is not restricted, at least expressly, to selective or specific inhibitors. It appears to be directed at any cGMP PDE inhibitor, whether selective, specific or not. In other words it is directed at any inhibitor which will cause increases in cGMP levels. Thus it appears to cover inhibitors of all the cGMP PDEs listed in the table set out in paragraph 18 above except inhibitors for PDE_IV, because that PDE does not destroy cGMP.

(d) The claims

The patent has eleven claims. Attention during the trial was directed to claims 1, 10 and 11, but reference was also made to claims 6, 7 and 9. These claims are as follows:

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

wherein

R¹ is H; C₁-C₃ alkyl; C₁-C₃perfluoroalkyl; 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;NHSO₂R^{8;
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 wherei n 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, mor-pholino 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 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-prop yl-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."

Claim 1 is directed to the use of PDE inhibitors published in the Bell Applications. Although its validity is attacked, Lilly is not so concerned with this claim, or any of the claims dependent on it, because it has no current commercial interest in any inhibitor falling within the scope of Formula I. Claim 6 is directed to the second medical use of sildenafil citrate (Viagra) and Claim 7 is directed to a proposed back-up product to Viagra. Claims 10 and 11 are, potentially, much wider than Claim 1 because they are not limited to a specific series of chemicals. They cover any chemical, whether known now or not, which is a cGMP PDE inhibitor (claim 10) or a cGMP PDE_V inhibitor (claim 11). It is these claims which most concern Lilly.

Construction of the Claims

A number of differences exist between the parties as to the proper construction of these claims. However all of the disputes relating to the scope of claims 1, 6, 7 and 9 apply equally to claims 10 and 11 and in relation to the latter there are additional areas of disagreement. For this reason it is more convenient to consider the scope of the latter two claims first.

(a) "The use of for the curative or prophylactic treatment of "

Two points arise for consideration here. Pfizer says that these words are only fulfilled by the use of a compound which is both for the purpose of trying to treat the target illness and which also is suitable for treating that illness, that is to say that in relation at least some individuals the treatment works. In support of this it relies on the decision of the Court of Appeal, Bristol-Myers Squibb Co v. Baker Norton Pharmaceuticals [2000] IP & T 908. Furthermore they say that the success of the treatment must be attributable to the use of the identified compounds alone. A successful treatment which involves the use of the identified compounds and other agents in combination, save where the latter are merely colourable, does not fall within the claim. Lilly argue that it is sufficient if the use of the compound is for trying to treat the illness, efficacy is not necessary. It says that if someone uses a product with the intention of treating the illness and is confident it works, then this requirement is met even if, in reality, the product has no relevant pharmacological effect. If the patientís condition improves because he has been told by a doctor that he is going to get better a placebo effect then that falls within the claim. For this Pfizer relies Bristol-Myers Squibb as well. It also disagree on the issue of combined treatments. If the target compound is successful to treat the illness, it does not matter that such success involves the collaboration of the compound with other agents. In such cases each and all the ingredients in the combined therapy are used for the curative or prophylactic treatment.

On the first of these points, I have no doubt that Pfizerís argument is correct. This point was considered by the Court of Appeal in Bristol-Myers Squibb in which Aldous LJ said:

"The words ëfor treating cancerí have to be construed in context. The skilled addressee would realise that drugs which were suitable for treatment would not always be successful. However, drugs which had no effect were not suitable. The phrase means ësuitable for trying to treat cancerí. What is suitable is a question of fact, not one of perception. If the drug has a beneficial effect in the treatment of cancer it will be suitable. If not, it will not be." (paragraph 21)

A second medical use claim only survives because the compound is effective to achieve a new treatment. If it is not effective, or not discernibly so, it is not suitable for that treatment. If administration of the compound results in some patients getting better, but the same improvement would be achieved by the administration of any placebo, that is not enough. The patient benefit is achieved simply because the patient believes he is being treated, not because of any peculiar feature or efficacy of the patented compound.

On the second point, in my view Lillyís construction is to be preferred. When two or more agents are used together to treat a disease then each is "used for the treatment of" the disease. Were someone to use a compound within Formula I of the patent in a dose which did not produce full erections in a patient and boosted its performance by the addition of another agent, not within Formula I, I think it would be fanciful to say that the first compound was not being used in the treatment. The point can be made by reference to a real example. It will be recalled that on page 2 of the specification the patentee states that good results in the treatment of MED had been based on the i.c. injection of drugs such as phenoxybenzamine, phentolamine, papaverine and prostaglandin E₁, "either alone or in combination". It would not make sense to say that papaverine, for example, was being used in the treatment of MED when injected alone, but not when it was injected with other agents.

(b) "The use of a cGMP PDE inhibitor" (claim 10) and "a cGMP PDE_V inhibitor" (claim 11)

These are the words which have generated the greatest dispute on construction between the parties. Its outcome has a major impact on the experiments which were carried out on the issue of anticipation. Lilly argues that the words should be given their natural unqualified meaning. Therefore any compound which inhibits cGMP PDE falls within claim 10. It does not matter whether it also inhibits cAMP PDEs as well, nor does it matter whether it inhibits cGMP PDEs more effectively than cAMP PDEs. Similarly, in relation to claim 11, Lilly argues that any compound which inhibits cGMP PDE_V is covered, whether or not it also inhibits other PDEs and, in particular, whether or not it inhibits PDE_V more or less than other PDEs. .

Pfizerís position on this issue has changed. A dispute arose between the parties as to whether certain experiments should be allowed to be carried out in relation to the issue of anticipation. The matter came on for hearing before Pumfrey J. He ordered Pfizer to serve on Lilly a statement of its case effectively requiring it to explain its construction of claims 10 and 11. This was complied with in June of this year. The Pfizer statement reads as follows:

"Claim 10

In order for its use to fall within claim 10, a substance (or its pharmaceutically acceptable salt, or a composition containing either) must have the following properties:

- It must be a selective cGMP PDE inhibitor, which is to say it must be a potent inhibitor of cGMP PDEs in contrast to its inhibition of cAMP PDEs.

- In addition, the medicament produced using the said substance (or salt or composition) must be for the curative or prophylactic oral treatment of erectile dysfunction in man, which includes the requirement that oral administration should result in an improvement of erectile dysfunction (as compared with the level of dysfunction encountered or to be expected had the substance not been administered). It is not a requirement that the medicament bring about such improvement in all subjects to whom it is administered.

- In addition, the said improvement of erectile dysfunction must be achieved substantially as a result of cGMP PDE inhibition.

Claim 11

In addition to the requirements of claim 10, for the use of a substance to fall within claim 11 it must be a PDE_V inhibitor."

Thus, in relation to claim 10, the substance has to be (i) selective, in the sense that it inhibits cGMP PDEs more than cAMP PDEs, (ii) potent in its inhibition, (iii) effective in treating MED and (iv) that effectiveness must have been caused by the inhibition of the cGMP PDE. Claim 11, w hich is dependent on claim 10, is said to incorporate all these features but is restricted to inhibitors which are selective to PDE_V.

This construction gave rise to a number of difficulties. Amongst them was the consequence that, if it was correct, claim 10 only covered selective, potent PDE_V inhibitors and therefore had identical width to claim 11. This was unlikely to be the proper construction and towards the end of the trial Mr Kitchin advanced a somewhat modified view. He said that both claims still required selectivity and potency (and causation) but that claim 10 covered only inhibitors of PDE_I and PDE_V whereas claim 11 covered inhibitors of the latter enzyme only. The way he arrived at this conclusion ran something like this; In 1993 it was thought that cGMP PDE was specific in its effect, that is to say it only destroyed cGMP. It was also thought that PDE_IV was specific to the destruction of cAMP see the table in paragraph 18 above. It was also known that the other PDEs destroyed both cAMP and cGMP. There was no understanding at that time that PDE_II or PDE_III were in any way selective towards the destruction of cGMP over the destruction of cAMP. However it was said that there was at least one "school of thought" at the time that PDE_I was selective towards cGMP. Mr Kitchin did not rely on this to justify his clientís construction of claims 10 and 11. Rather he said that a reader of the patent in suit would realise that the reference to cGMP PDE inhibitor in claim 10 must be a reference back to the discussion of such inhibitors on page 2 of the specification (see the quotation set out in paragraph 25 above) where there is reference to the Bell applications. One would therefore refer to the latter applications. They refer to the presence of PDE_I, PDE_III and PDE_V (under their then current names) and states that the compounds of Formula I are effective anti-angina agents because they inhibit PDE_I and PDE_V. Therefore a reader of the patent in suit would assume that the efficacy of the Formula I compounds in the treatment of MED would similarly be due to the fact that they inhibit PDE_I and PDE_V. From this it would be assumed that similar efficacy could be obtained from any other compound which inhibited PDE_I and PDE_V. Thus the reference in claim 10 to cGMP PDEs must cover any compound (not just Formula I compounds) which can inhibit PDE_I, PDE_V or either of them.

This construction at least has the attraction that, unlike others put forward by Pfizer, it appears to give claim 10 a wider scope than claim 11, which is clearly what the draughtsman intended. However, if it were correct, it would have a result which is surprising indeed. As noted already (see paragraph 29 above), the patentee reports that there is no detectable PDE_I in human corpus cavernosum. Therefore claim 10 would, apparently, include medical treatments which involve the inhibition of an enzyme which is not even present in the penis and for that reason presumably would not work. If, of course, such uses are excluded from the claim because they do not work, then one gets back to the situation where claim 10 and claim 11 are of identical width.

But in addition to this criticism, it appears to me that Pfizerís approach is wrong in principle. There is nothing in these claims or the specification which suggests that determination of the scope of protection is to be discovered by reference to the Bell applications which are concerned with the treatment of quite different diseases. Furthermore, read in context, Bell I and II tie in with the title of the patent and are identified as the source of the group of chemicals which are the subject of claims 1 to 9. Claims 10 and 11 are based on the much more general wording inserted at the end of the specification (see paragraph 35 above) which has been inserted to widen the disclosure away from the Bell applications. Thus the latter claims are not put forward as based upon or restricted to what is disclosed in those applications.

The patentee clearly knew how to refer to specificity, potency and selectivity in relation to PDEs and their inhibitors and did so in the specification where that was his intention. Furthermore there are compelling reasons to construe claims 10 and 11 without the addition of the words ëselectiveí or ëpotentí. The only teaching in the specification which suggests how the patented inhibitors cure or act as prophylactics for MED is that which refers to the inhibition of cGMP PDEs and the consequent rise in cGMP levels. Therefore there is no reason why the patentee should be thought to have avoided seeking protection for second medical uses of any inhibitor which could cause such raised cGMP levels. In other words it makes sense that claim 10 covers any cGMP PDE inhibitor since all such inhibitors will, by definition, increase cGMP levels. The only reason to exclude cGMP PDE inhibitors which also inhibit cAMP PDEs (i.e. non-selective cGMP PDEs) would be if the resultant and simultaneous rise in cAMP levels caused by the use of such compounds would give rise to unacceptable and unavoidable adverse effects. As Mr Kitchin concedes, there is no statement in the specification that raised cAMP levels would be harmful at all, let alone significantly so. This is a point which ties in directly to Pfizerís argument that the claims must cover ëselectiveí cGMP PDEs. Both parties agreed that there is no magic in the word ëselectiveí. Mr Kitchin putí opening skeleton argument states:

" persons developing drugs know that they want specific effects and they constantly strive to get them - because non-specific effects tend to give rise to side effects. Hence, by saying a cGMP PDE inhibitor, the patent indicates that that effect rather than any other effect is desired. In fact, of course, the patent also explicitly states that, by contrast to cGMP PDE inhibition, cAMP inhibition is not desired.

The extent to which a compound must inhibit cGMP PDEs in preference to cAMP PDEs to fall within the claim is a question of degree. It is, however, a question of degree which the skilled reader can easily answer; what is desired is a level of selectivity for cGMP PDE inhibition relative to cAMP PDE inhibition so that the former is inhibited enough to give the desired effect, without inhibiting the latter appreciably (thus avoiding non-specific activity).

A secondary point taken by Lilly appears to be that, if the claim does call for selectivity, any degree of preference for cGMP PDE will do, so that a compound with a cGMP PDE:cAMP PDE inhibition ratio of 2:1 would do. Again, this is an approach which ignores the realities. If the ratio were 2:1, then at drug concentrations sufficient to inhibit cGMP PDE enough to get the desired effect, there would also be very substantial, and undesirable, non-specific effects." (emphasis added)

(Note that the last sentence in the first of these three paragraphs is incorrect. There is no such explicit statement.)

The whole of this passage emphasises that what would amount to acceptable selectivity is dependent on the existence not just of side effects attributable to the increase of cAMP levels but also the extent to which such side effects are undesirable. If the patentee had intended to make selectivity a feature of his claims, he would have been expected to give the reader some guidance as to the degree of selectivity needed. He did not do so. He did not suggest that there would be side effects if cAMP levels rise, he does not identify any such side effects and, most importantly, he gives the reader no clues as to how rigorously they need to be avoided. Very similar considerations apply to Pfizerís assertion that claims 10 and 11 should be construed as if they contained the word ëpotentí before ëinhibitorí.

It seems to me that the problem is reinforced by the stance adopted by Pfizer in its closing written submissions where it says:

"Dr Kruse did not agree that cAMP elevation would be dangerous, but thought it might be (XX 4/488-9) and that is good enough for our purposes, since it shows that the skilled man could not read the patent as being indifferent to cAMP elevation (provided that cGMP was elevated). [emphasis as in the original]

The fact that the reader of the patent would not be indifferent to cAMP elevation does not mean that he would assume that it must be prohibited at all costs. As Dr Kruse was explaining, elevated cAMP might or might not be undesirable to some extent. The patent includes no indication one way or the other.

It follows that I reject Pfizerís suggestion (see paragraph 46 above) that claims 10 and 11 should be construed as if they contained the words ëselectiveí and ëpotentí. For reasons already given, I agree that these claims, and all the others, should be construed so as to cover only such second medical uses as are effective in treating MED. It should be noticed that this involves a degree of potency as a drug. It does not translate into a degree Pfizer potency as an inhibitor to cGMP PDEs as compared with cAMP PDEs.

This leaves only Pfizerís fourth point, namely that claims 10 and 11 should be construed so as to require the efficacy in treating MED to be caused by the inhibition of the cGMP PDE. This again has impact on the experiments. Pfizerís point is that a use of a cGMP PDE inhibitor does not fall within these claims, even if the use is effective to treat MED, unless it is proved that the mechanism by which the beneficial result was achieved was attributable to that inhibition. Therefore to prove infringement it would be necessary to prove that it was the PDE inhibition which was the cause and not some other activity of the inhibitor. Of course similar proof of causation would need to be provided before any use of a cGMP PDE inhibitor in the prior art could amount to anticipation hence the impact on the experiments in this case.

In my view there is nothing in this point. Nowhere in the claims or the specification does the patentee tie himself down to any particular mode of action of the inhibitor. All that he does (see paragraphs 31 and 32 above) is speculate, no doubt reasonably and probably accurately, that elevation of the cGMP levels caused by the inhibition is the reason for the beneficial effect claimed. If it subsequently were to be found that cGMP PDE inhibitors were effective in curing or reducing MED but by a chemical route other than the elevation of cGMP levels, the claims would have the same width and, in particular, would cover anyone who used a suitable inhibitor to effect the same treatment. Consistent with this, the patent contains no teaching as to what the reader is supposed to do to demonstrate whether or not a particular successful treatment owes its efficacy to elevation of the levels of cGMP. It follows that I do not accept Pfizerís arguments on this point.

Finally on construction I should mention one other matter. All the claims are restricted to second medical uses leading to the "curative or prophylactic treatment of erectile dysfunction" in male animals or man. As pointed out at paragraph 24 above, "erectile dysfunction" is defined in the specification as meaning the inability to obtain or sustain an erection. That it is what those words mean in the claims.

Summary on construction:

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.

Attacks on validity.

It is now possible to turn to the attacks on validity. Although anticipation, obviousness, insufficiency and added matter were all relied on by Lilly, the objections under the last two heads were closely tied in to Pfizerís construction of the claims. In the event they are no longer of great importance. Anticipation was advanced on the basis of one document; "Treatment of Vasculogenic Sexual Dysfunction with Pentoxifylline" by Korenman & Viosca - Journal of the American Geriatrics Society (41:363-366) (April 1993). ("Korenman"). Obviousness was pleaded on the basis of a number of prior publications, not including Korenman. However at the trial Lilly concentrated its attention on three documents;

(A) "Nitric oxide as a mediator of relaxation of the corpus cavernosum in respect to nonadrenergic, noncholinergic neurotransmission" by Rajfer et al - New England Journal of Medicine Vol. 362 No. 2 at p. 90 (9 January 1992) ("Rajfer"),

(B) "Phosphodiesterase V_A Inhibitors" by K. J. Murray in Drug News and Perspectives (DN&P) at Vol 6(3) p150-156 (April 1993) ("Murray") and

(C) "The Role of the L-arginine-Nitric Oxide-Cyclic GMP pathway in Relaxation of Corpus Cavernosum Smooth Muscle" a PhD dissertation of Dr Margaret Ann Bush of the University of California ("Bush").

OBVIOUSNESS

Obviousness was the major attack advanced by Lilly and I will consider it first. As usual, the parties referred to Windsurfing International Inc. v. Tabur Marine (Great Britain) Ltd [1985] RPC 59. That case sets out a structured approach to the question of obviousness and can simplify analysis. The first step is to identify the inventive concept embodied in the paten t in suit. Then one must 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 the date, common general knowledge in the art in question. Third, it is necessary to identify what if any differences exist between the matter acted as being "known or used" and the alleged invention. Finally, one must ask whether, viewed without 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. Windsurfer is a particular help where the inventive concept is buried in obscure language in the claims. Here that is not so. Mr Kitchin set out the relevant concepts as follows: claim 1 is to the use of the compounds of Formula I for the manufacture of medicaments for the treatment of MED. Note that there is no limitation to any particular form of administration. Claim 10 is to the use of a cGMP PDE inhibitor for the manufacture of a medicament for oral treatment of MED. So claim 1 covers any mode of administration, but is restricted to Formula I compounds only whereas claim 10 covers use any cGMP PDE inhibitor but only if administered orally. Both claims cover sildenafil citrate but, because of its much greater width, the more important claim is the latter (and claim 11).

A considerable volume of evidence was advanced in support of and to counter the case on obviousness. Central to this exercise was the evidence given by a number of impressive experts including a Nobel Laureate, Professor Ignarro, who was called on behalf of Pfizer. In the light of the heavy reliance placed by the parties on their respective lead expertsí evidence, I think it might be useful to identify and restate the task facing the court.

The question of obviousness has to be assessed through the eyes of the skilled but non-inventive man in the art. This is not a real person. He is a legal creation. He is supposed to offer an objective test of whether a particular development can be protected by a patent. He is deemed to have looked at and read publicly available documents and to know of public uses in the prior art. He understands all languages and dialects. He never misses the obvious nor stumbles on the inventive. He has no private idiosyncratic preferences or dislikes. He never thinks laterally. He differs from all real people in one or more of these characteristics. A real worker in the field may never look at a piece of prior art for example he may never look at the contents of a particular public library or he may be put off because it is in a language he does not know. But the notional addressee is taken to have done so. This is a reflection of part of the policy underlying the law of obviousness. Anything which is obvious over what is available to the public cannot subsequently be the subject of valid patent protection even if, in practice, few would have bothered looking through the prior art or would have found the particular items relied on. Patents are not granted for the discovery and wider dissemination of public material and what is obvious over it, but only for making new inventions. A worker who finds, is given or stumbles upon any piece of public prior art must realise that that art and anything obvious over it cannot be monopolised by him and he is reassured that it cannot be monopolised by anyone else.

Of particular importance in this case, in view of the way that the issue has been developed by the parties, is the difference between the plodding unerring perceptiveness of all things obvious to the notional skilled man and the personal characteristics of real workers in the field. As noted above, the notional skilled man never misses the obvious nor sees the inventive. In this respect he is quite unlike most real people. The difference has a direct impact on the assessment of the evidence put before the court. If a genius in a field misses a particular development over a piece of prior art, it could be because he missed the obvious, as clever people sometimes do, or because it was inventive. Similarly credible evidence from him that he saw or would have seen the development may be attributable to the fact that it is obvious or that it was inventive and he is clever enough to have seen it. So evidence from him does not prove that the development is obvious or not. It may be valuable in that it will help the court to understand the technology and how it could or might lead to the development. Similarly evidence from an uninspiring worker in the field the he did think of a particular development does not prove obviousness either. He may just have had a rare moment of perceptiveness. This difference between the legal creation and the real worker in the field is particularly marked where there is more than one route to a desired goal. The hypothetical worker will see them all. A particular real individual at the time might not. Furthermore a real worker in the field might, as a result of personal training, experience or taste, favour one route more than another. Furthermore evidence from people in the art as to what they would or would not have done or thought if a particular piece of prior art had, contrary to the fact, been drawn to their attention at the priority date is, necessarily, more suspect. Caution must also be exercised where the evidence is being given by a worker who was not in the relevant field at the priority date but has tried to imagine what his reaction would have been had he been so.

This does not mean that evidence from those in the art at the relevant time is irrelevant. It is not. As I have said, it may help the court to assess the possible lines of analysis and deductions that the notional addressee might follow. Furthermore, sometimes it may be very persuasive. If it can be shown that a number of ordinary workers in the relevant field at the relevant time who were looking for the same goal and had the same prior art, missed what has been patented then that may be telling evidence of non-obviousness. This is particularly the case where the commercial benefits of the development would have been apparent and a long time had passed between the publication of the prior art and the priority date of the patent. Hence the impact and interrelationship between the familiar concepts of long felt want and commercial success. Likewise evidence that ordinary men in the art and working from the same prior art at the relevant time independently came to the same development may be some evidence that the notional skilled man would have done likewise. However the evidence is rarely that simple. In most substantial patent cases the technology at issue is sophisticated and the witnesses called are experts in their fields. In most cases, of which this is a good example, they are either renowned academics or researchers who have been immersed in the R&D departments of major companies. In either case they come to the issues not only with a profound understanding of the technology but also frequently with knowledge of additional private and relevant information which is not deemed to be known to the notional addressee. For example a research worker in the field will almost always have knowledge of highly confidential prior work done in his department which cannot but affect his attitude to the prior art. This is all material of which the notional man skilled in the art will be ignorant.

The actions of the notional skilled man also reflects on a topic sometimes called by British patent lawyers "mosaicing". To what extent is it possible to patch together the teaching or disclosures from different sources? On this topic I was reminded of what is said in Terrell, 15^th Edition, starting at paragraph 7.13:

"Each document must be interpreted on its own in order to determine the information it contains. It is not legitimate to piece together a number of prior documents in order to produce an anticipation of the invention. However, a series of papers which form a series of disclosures and refer to each other, so that ëanyone reading one is referred by cross-reference to the othersí, do not form an impermissible mosaic and can be relied upon together as an attack on novelty."

This passage is directed particularly at the issue of mosaicing when applied to the law of novelty. The same approach applies to obviousness. There may well be invention in patching together disclosures from unrelated sources (see Von Heyden v. Neustadt (1880) 50 L.J.Ch. 126). But, at least in relation to obviousness, the second part of this statement does not represent a rigid but limited exception. When any piece of prior art is considered for the purposes of an obviousness attack, the question asked is "what would the skilled addressee think and do on the basis of this disclosure?" He will consider the disclosure in the light of the common general knowledge and it may be that in some cases he will also think it obvious to supplement the disclosure by consulting other readily accessible publicly available information. This will be particularly likely where the pleaded prior art encourages him to do so because it expressly cross-refers to other material. However I do not think it is limited to cases where there is an express cross-reference. For example if a piece of prior art directs the skilled worker to use a member of a class of ingredients for a particular purpose and it would be obvious to him where and how to find details of members of that class, then he will do so and that act of pulling in other information is itself an obvious consequence of the disclosure in the prior art.

Finally on the issue of the characteristics and behaviour of the skilled addressee, mention should be made of the skilled team. For many years now it has been well accepted law that in some cases the addressee for the purpose of testing obviousness is considered to be a team made up of notional skilled but uninventive members from different disciplines. Although both parties accepted that this was a case where the skilled addressee should be considered to consist of a team, at one stage it appeared that there was a dispute between them as to the nature of the expertise of the members of the team. Both sides accept that the relevant fields of expertise would encompass pharmacology, medicinal chemistry and urology. However Pfizer suggest that, at least at first, the notional team would only have a very general background knowledge of PDEs rather than the knowledge of a skilled but unimaginative worker in the PDE field. On the other hand Lilly says that such expertise should be attributed to the notional team from the outset. In the end there was no substantial difference between the parties on this topic. As Mr Kitchin put it in his skeleton:

"one should consider [the notional teamís] reaction to the prior art item by item, but bearing in mind that if the art specifically flags a technology in which they would regard themselves as inadequately skilled, they would consider getting help from someone else."

I have come to the conclusion that the notional skilled addressee or team in this case would have relevant but unimaginative expertise and knowledge in the fields of pharmacology, chemistry and urology and that would include knowledge of most treatments for MED which were publicly available at the priority date in June 1993 together with non-inventive expertise in relation to PDEs.

(A) Rajfer

This document was described as creating a furore and being very exciting. Professor Ignarro said that it had played a role in making Science magazine declare nitric oxide the Molecule of the Year (see paragraph 21 above). It is the product of work carried out by Professor Ignarroís team and it lists Professor Ignarro, Dr Bush (of the Bush Thesis) and others in addition to Dr. Rajfer as authors. It is not in dispute that the skilled reader at the time would have thought of this as reporting an important and high quality piece of research.

The brief extract at the beginning of the paper reports:

"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]

Under the heading ëconclusionsí 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."

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."

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 m mol per liter (whichever caused a relaxation of 10 to 15 percent, sufficient to ensure that enough [zaprinast] had been added)."

Mr Thorley argues that a skilled team would have appreciated the significance of the teaching that use of a selective cGMP PDE inhibitor could enhance or augment the erectile response. It would have taken that as an encouragement to try such inhibitors as candidates for medical treatment of impotence, including impotence consisting of an inability to sustain a complete erection. Once it had reached that conclusion it would have been obvious to try any known cGMP PDE selective inhibitor including any of those in the Bell applications (so that claim 1 and its dependents are obvious). Furthermore it would have been obvious to try to use any cGMP PDE orally (so that claims 10 and 11 are obvious).

He also argues that the proof of the pudding is in the eating. On seeing the Rajfer paper a number of individuals in the art thought of using these inhibitors to treat impotence. Thus it is known from Pfizer internal documents that a Dr Ringrose of Pfizer read Rajfer and annotated it in manuscript with the words "Should we not try out [sildenafil citrate] in impotence? Have we seen any beneficial S[ide]/e[effect]s." Similarly we know from Dr. Murrayís paper which is the second main piece of prior art that he, a senior biologist at SmithKline Beecham, had thought of it, as had a Dr. Silver of Sterling Winthrop, Dr. Gristwood of Almirall and Dr. Hyafil of Glaxo. To these should be added Dr. Bush who made the same suggestion in her thesis. This is an impressive list. However only Drs Gristwood and Hyafil gave oral evidence. Dr Bush provided a witness statement but she was not cross-examined. It is likely that all of these individuals were highly qualified researchers. It may be that some of them were inventive people. It is apparent that all, with the possible exception of Professor Ignarro and Dr. Bush, were involved in the research departments of major pharmaceutical companies. It may be that their reaction to the Rajfer paper was conditioned by the confidential information in this field which they may have had access to inside their respective companies. As far as Dr Hyafil is concerned, his deduction was not made on the basis of the Rajfer paper itself but from hearing it described by Professor Ignarro at a public lecture. Having heard the evidence of the Professor, it is likely that the lecture gave no further relevant information than is to be found in the paper, but one cannot now be sure. In view of these uncertainties, I think it is not possible to say that these actions by other parties prove the case of obviousness, they are merely not inconsistent with it.

Mr Kitchinís response to the case based on Rajfer involves a number of submissions. Most of them apply equally to all the claims in issue. However one is directed to demonstrating the validity of claim 1 and its dependents while another is directed to claims 10 and 11. It is convenient to consider them one by one.

(a) Alternative routes to a treatment

Mr Kitchin says that there was no reason to start with the L-arginine-NO-cGMP pathway. There were many alternative routes which could have been of interest. For example other forms of i.c. injection might prove interesting, because it would amount to a refinement of an existing successful treatment. Or it might be that someone would be more interested in trying to develop a topically applied treatment.

Even were Mr Kitchinís first point good on the facts, it is wrong in law. The fact that there are alternative routes is no answer to a case of obviousness based on a particular piece of prior art. On the contrary, the notional skilled addressee is expected to have read the pleaded prior art carefully and to bring to it his interest in the field. If he does that and finds the patented step was an obvious one to make, it is no answer to say that if he had started with other prior art other solutions would have come to mind. Furthermore this argument does not succeed on the facts. The reaction to Rajfer was explained by Pfizerís witness, Professor Ignarro:

"I recall that shortly before publication of the [Rajfer] article the editor of the New England Journal of Medicine warned me of the likely furore and said that impotent men would be asking where could they get nitric oxide. The paper was front page news in the New York Times for 9 January 1992. For two days we were bombarded, and I got interviewed on TV, on Good Morning America or some equivalent of the time. I declined an interview with Hustler magazine."

In my view that popular response would have been mirrored by a skilled man in the field in the sense that he would realise that now a quite different cure for some forms of impotence might be available. What Rajfer did was elucidate the whole pathway including the final step involving the use of cGMP PDE. As Professor Ignarro commented during his cross examination, in the 1980s, the pathway responsible for causing smooth muscle relaxation was known as the NANC pathway. He said that these were:

" very interestingly named for what they are not, which always impressed me, not adrenergic and not cholinergic, nobody knew what they were so they were called nonadrenergic, noncholinergic nerves." (Day 3 Transcript page 352)

What Rajfer did was elucidate the whole pathway. As Mr. Pryor said, he nailed the pathway and completed the jigsaw. (Day 4 Transcript page 590)

Once a worker understands what is going on in a process it is possible to make logical decisions on how to tackle defects. He is no longer restricted to the pharmaceutical equivalent of banging on the side of the set when the television does not work. Rajfer not only elucidated the full pathway but also told the reader that the vital smooth muscle relaxing agent, cGMP, could be increased either by increasing NO production or by preventing or reducing its destruction by cGMP PDE. There is no doubt that the treatments available in the early 1990ís were either of low efficacy or unpleasant. The need for an alternative route was apparent. It follows that if developing Rajfer was obvious, it does not cease to be so because of the existence of other possible routes.

(b) Only the front end of the NANC pathway would have been of interest

Mr Kitchin also argues that if one did seek to manipulate the L-arginine-NO-cGMP pathway in impotent males, the "only logical thing to do", to use his words, would be to administer a treatment which would increase NO production i.e. boost the front end of the pathway. There was no reason to think that there was a functioning NO-drive in impotent males so interfering with cGMP PDE would be pointless there might be no cGMP to enhance.

In my view this point is also bad both in law and on the facts. I am not persuaded that the notional skilled worker in the field would only consider the front end of the NANC pathway. What was apparent in the evidence filed in this case was that some workers would, for understandable reasons, prefer to look at the downstream end of the pathway (i.e. the PDE end) and others favoured the upstream end (i.e. the NO production end). Professor Ignarro was the most determined of the latter group. I will consider his evidence with some care when I come to consider the Bush thesis. However the fact that there were alternative ways of looking at the problem and that some real life workers preferred to consider one course rather than the other does not answer a case of obviousness. Tied in with this part of Mr Kitchinís argument is the assertion that there was no reason to think that there was functioning NO production in impotent males. If there was no such production, then cGMP would not be produced. If that was what was happening, then there was no cGMP for the cGMP PDE to destroy and inhibiting the latter PDE would be ineffective. This was put by way of an analogy by Dr. Ellis, one of Pfizerís witnesses. He likened the process of production and destruction of cGMP to filling and emptying a bath. The production of NO was equivalent to opening the tap. The PDE which destroys the cGMP is like the plughole which lets the water out of the bath. A cGMP PDE inhibitor therefore acts to put the plug back in. As he put it "there is no use putting in the bath plug unless you turn on the taps as well". Therefore if the breakdown of the NANC pathway was at the NO-production end, using a PDE inhibitor would be pointless. The important word here is ëifí. As all the witnesses appeared to agree, it was not known where the breakdown in the NANC pathway (assuming that to be the cause of the impotence) was in impotent males. Furthermore it appears to have been accepted that there were likely to be different defects in different impotent males. It seems to me that the notional skilled worker in the field at the priority date would have thought it likely that in some impotent males it would be likely that the breakdown was caused by production of cGMP in insufficient quantities, for example because NO was produced but in less than necessary quantities, or for too short a period or by defects in the control of cGMP breakdown. It should be remembered that MED includes those cases where the patient achieves a full erection but is unable to sustain it or only achieves partial erection. In all these cases, using an inhibitor to stop or slow down cGMP breakdown might well result in higher levels of cGMP and therefore more successful erections. It was worth a try.

To use Dr Challisí analogy, it was quite possible that in some cases there was no water being poured into the bath because the tap was turned off. But in other cases it was just as likely that the tap was only partly on so that insufficient water entered the bath or the size of the waste outlet was too big, or both of these. It would only be where the tap was completely closed that blocking the outlet would be expected to have no effect. When that analogy is translated to MED, there was no reason to believe, and no witness asserted that it was believed, that all cases of MED attributable to failure of the NANC pathway were cases in which there was total failure of NO production.

Mr Kitchin develops his argument further. He says that even if the worker in the art thought of trying to use a cGMP PDE inhibitor, and assuming he had got through the sort of successful in vitro experiments used by Rafjer, he would first consider injecting the chosen agent into an animal subject. For example he would try injecting it into anaesthetised dogs or monkeys. Such treatment works in relation to the injection of nitrovasodilators because they cause an increase in NO production and a consequent increase in cGMP levels. However the base level of NO production in the penis is very low in anaesthetised dogs, so there is likely to be little or no cGMP for the inhibitor to enhance. No erection would be caused and the course of research would be brought to an abrupt end. This is not an unreal suggestion because it is what Pfizer did at first and it produced no discernible effects in the subject animals.

In my view this is far too bleak a picture. One of the things that Rafjer teaches is that, unlike nitrovasodilators, which generate cGMP, the cGMP PDE inhibitors only help to potentiate the cGMP which is already there. If there is no basal level of cGMP, then the inhibitors will have nothing to enhance. That is why in many of the experiments reported in the paper, the strips of corpus cavernosum were first subject to electrical field stimulation or SNAP before zaprinast was applied to them. This was to ensure that there was NO present. That message would have been understood by a skilled worker in the field. In fact the passage in Rajfer set out at paragraph 73 above discloses that some strips of corpus cavernosum relaxed 10% to 15% when treated with zaprinast even when no NO source was supplied, presumably because there was base level of NO production in the untreated tissue. This point might well have been missed by the skilled addressee. As we shall see, it was not missed by Dr. Murray. Nevertheless the message that zaprinast or other similar inhibitors would only work if sufficient NO was already present would have been understood by the man skilled in the art. The man skilled in the art would have realised this before he started injecting anaesthetised animals because those subjects are unlikely to be producing NO because they are not sexually stimulated. Furthermore, even if he made the mistake of injecting anaesthetised animals, he would not be put off by failure to see penile er ections. He would immediately realise that the likely cause of the negative result was the absence of anything for the inhibitor to enhance. Evidence touching on this subject was given by Mr. Pryor. He said:

"MR. KITCHIN: Could I please take you on to page 181, where you will see a summary. Could I draw your attention, please, to the right-hand column. The author writes: "The development of effective pharmacological means of inducing erections has revolutionized the treatment of erectile dysfunction, but has in no way produced a panacea." By inducing erections, am I correct in understanding that the therapies used produced an erection on administration?

A. Yes, within the limitation that that was not always the case. By that stage [i.e. 1993], it was accepted that if you wanted to maximize the response, you needed some form of sexual stimulation as well." (Day 4, Transcript page 563)

How, then, does this marry up with what happened in Pfizer? In early 1992 it injected sildenafil citrate into anaesthetised monkeys. Mr. Kitchin suggests that if a major pharmaceutical company with a considerable research department failed to see the necessity for some form of sexual stimulation in the animal models, so surely would the skilled and non-inventive man in the art. Even were this the totality of the Pfizer story, it would not disprove Lillyís case. Sometimes large companies make mistakes. But the full story is not as simple as it may seem. What happened is that Pfizer had decided in 1990 to look at sildenafil citrate for potential use as a drug. Initially it thought that the compound might have application in the treatment of, amongst others, intermittent claudication, transient ischaemic attacks, hypertension (all circulatory problems) and osteoporosis. According to Dr. Ellis, by August 1991, that is to say well before the publication of Rajfer, sildenafil citrate had been informally scheduled for evaluation in a model of erectile function. At about that time, it was decided to test the compound in monkeys. The nature of the experiments to be undertaken were explained by Dr Ellis:

"the Urogenitals group were working on impotence and were investigating novel a -blockers, injected intracavernosally, for the treatment of MED. Gorm Wagner was a sex therapist who had developed a model in the monkey to assess compounds as potential treatments for MED. The model involved the use of an anaesthetised monkey. A ligature was placed around the penis and the compound under test injected intra cavernosally. After a few minutes to allow absorption of the compound the ligature was released and any erections recorded. Compounds acting directly to induce erections, such as a -blockers and prostaglandins, are effective in this model inducing full and maintained erections."

Therefore the experimental model used was designed to find direct inducers of erections. In those circumstances it was of no consequence that the animal was anaesthetised since it was not required to supply any sexual input. The direct acting compounds would mimic that input. Sildenafil citrate was added to the a -blockers being tested. In other words it was being tested to see if it also was a direct acting compound. One week before these experiments were due to be carried out Dr. Ringrose saw the Rajfer for the first time and circulated it with the manuscript note referred to in paragraph 73 above. There is no suggestion that anyone on the team had any knowledge of the details of the NANC pathway before Rajfer was forwarded by Dr Ringrose nor was it suggested that anyone on the team considered the contents of that paper either in detail or at all.

The following week the experiments were conducted. Dr Ellis explains that:

"[sildenafil citrate] did not work in this model, inducing only a very transient partial erection . This indicated that the basal nitric oxide drive was insufficient for sildenafil to be effective in this model. We were disappointed at this result and did not have the conviction to continue exploring the utility of [sildenafil citrate] in MED in the absence of other supportive data. Indeed, I do not recall seeing any formal report of this study."

The reason for the failure of this model is then explained by Dr Ellis:

"Subsequently we discovered that an adequate supply of nitric oxide, such as that released during sexual arousal, is essential for a cGMP PDE inhibitor to work. Thus the mechanism of action of cGMP PDE inhibitors is fundamentally different from other (directly acting) vasodilators. The fact, now appreciated, that the production of cGMP is not increased, but the breakdown of cGMP is countered, means that the drug does not in itself cause an erection (like the injected vasodilators) but only enhances the natural erectile response to sexual arousal. Thus, it simply enhances the natural response to arousal. It is essential that this level of nitric oxide is achieved in patients with MED for cGMP PDE inhibitors to be effective. This makes it clear in hindsight, (which it was not at the time) why [sildenafil citrate] did not prove effective in the monkey model."

The failure of the experiment is understandable. What is clear from the evidence is that the Pfizer workers involved did not know, to use Dr Ellisí 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)

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.

Mr Kitchinís third argument goes as follows: if one thought of using a cGMP PDE inhibitor one would only think of doing so in combination with an NO donor. This is because, again, the notional skilled worker would assume that more NO needed to be produced in the corpus cavernosum in all impotent men. So the tap had to be turned on as well as the plug put in the bath. I did not understand this to amount to a concession on behalf of Pfizer that a combined treatment would be obvious.

In my view, this argument also fails on the facts and the law. First, it appears to me that if a man in the art thought of harnessing the knowledge provided by the Rajfer paper to the development of a treatment for impotence, he would have considered both ends of the NANC pathway alone and together. The idea of using two or more agents together is neither new nor surprising. As noted above, the patent itself refers to the fact that existing treatments for MED included administration of drugs in combination. This was touched upon by Dr. Ellis under cross-examination:

"A. Sure. The phentolamine story started in the late 80s when there was a very small trial published in the American literature suggesting that phentolamine, taken orally, might be an effective treatment. I think they studied 20 patients at most. At about that time phentolamine was being widely used as an injectable although, interestingly, as an injectable it is not very effective when it is used on its own. It does not produce a very good erection and historically it has always been combined with something else. Initially it was papaverine, subsequently prostaglandin E1 and laterally VIP." (Day 6 Transcript page 769).

No-one offered a reason why a combined treatment would not be acceptable. Nor was any reason put forward as to why a man skilled in the art would have failed to think of such a treatment after reading Rajfer. On the contrary, it appears to me that Professor Ignarro came close to saying that a combined treatment, at least applied intracavernosally, was something which would have been expected to have occurred to him

"Thus I never thought at that time that a selective cGMP PDE inhibitor would have any use on its own in the treatment of impotence. I would have thought for this reason that for it to be of any use it would have to be combined with an nitric oxide donor, but that to administer such a combination orally (or for that matter either component on their own) and thereby systemically, with the attendant loss in blood pressure would risk killing the patient. I was surprised to hear that erectile dysfunction could be effectively treated by the oral administration of a cGMP PDE inhibitor."

The Professorís references to ëkilling the patientí which was tied in to his worries about oral administration of PDE inhibitors will be considered below. For the purpose of dealing with this part of Mr Kitchinís submissions, it is sufficient to note that there appears to be no material which undermines the view that Rajfer would suggest, at the least, a combined treatment of a NO donor and a PDE inhibitor applied intracavernosally. However, as explained above, the claims cover the use of PDE inhibitors in combined treatments, so this is not an answer to the argument of obviousness. But more than this, I have already explained that it would have been apparent to the skilled worker that some impotent males were likely to have functioning or partially functioning NO production in their corpora cavernosa and that the administration of a cGMP PDE inhibitor alone might well work.

(d) No reason to find the Bell applications

Mr Kitchinís fourth argument is directed at claim 1 and the claims dependent on it. Although these claims are broad in the sense that they directed to any mode of treatment, including oral and intracavernosal administration of the drug, they are restricted to the very large class of chemicals encompassed by Formula I. Mr Kitchin says that even were it obvious to think of trying PDE inhibitors for the treatment of MED, there was no reason for a skilled worker to stumble on the Bell applications which include all or substantially all of the Formula I PDE inhibitors.

I reject this argument also. It should be borne in mind that Mr Kitchin conceded, as he had to, that none of the claims in the patent were said to cover a selection invention. In particular, he conceded that he could not say that the act of selecting the vast number of chemicals covered by Formula I out of the even larger number of possible PDE inhibitors was inventive. Not only is there nothing in the patent to support an invention based on selection, but any such argument would be inconsistent with claim 10 which covers all cGMP PDE inhibitors, as long as they are capable of being taken orally. If this is correct, and it is obvious in the light of Rajfer to try to use cGMP PDE inhibitors to treat impotence, it is obvious to try any such inhibitor and there is no invention in listing some but not all of the possible inhibitors. In these circumstances it is obvious to try all the inhibitors including, but not limited to, those disclosed in the Bell applications. It follows that it is not necessary to show that a man in the art would have searched for and found the Bell applications. Nevertheless, if that had been a requirement, it would have been met here. It is not in dispute that a literature search at the priority date for PDE inhibitors would have turned up at least Bell I. It would have been obvious to a skilled man to conduct such a search and to limit it, in the initial stages, to a patent search so as to see what other pharmaceutical companies were doing since it was apparent at the priority date that a considerable number of such companies were engaged in PDE research. Again, a search so limited would have turned up Bell I.

(e) Oral administration would be shunned

Mr Kitchin argues that there were strong reasons to avoid oral administration. This was directed to the validity of claims 10 and 11. He says that it would have been apparent to a skilled worker that the tissue concentrations in the penis which he would have assumed were necessary to get an effect were likely to be so high that oral doses would be very large. Furthermore he says that because nitric oxide, cAMP and cGMP are to be found all over the body, to give a PDE inhibitor systemically in large doses would be highly likely to lead to most undesirable, widespread and dangerous effects. Such effects would include falling blood pressure. Hence Professor Ignarroís fear of "killing patients". In addition to this, Mr Kitchin says that there was no established practice of giving oral treatments for impotence; quite the opposite.

In my view none of these arguments bears close scrutiny. 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 concensus 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 659660)

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."

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.)

I accept Mr Pryorís 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". It will be seen, therefore, that claim 10 covers the use of any cGMP PDE inhibitor in achieving a well recognised goal, namely the oral treatment of MED. Before addressing the factual question of whether or not it was obvious to try to use such inhibitors for that type of treatment, it appears that a point of principle arises in relation to this claim and claim 11. Assuming that it was obvious to use a cGMP PDE inhibitor or a cGMP PDE_V inhibitor to treat male impotence, is it possible for Pfizer to obtain valid patent protection where the only distinguishing feature between what is obvious and what is claimed consists of the fact that the treatment is orally administered? In addressing this issue it should be borne in mind that it is not su

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