“This year [1992], scientists proved definitively that in males, NO translates sexual excitement into potency by causing erections. Key pelvic nerves get a message from the brain and make nitric oxide in response. NO dilates blood vessels throughout the crucial areas of the penis, blood rushes in, and the penis rises to the occasion.” 22. One of the Pfizer witnesses, Dr. Challiss, described this as tabloid journalism, and so it is, but he also said it made a nice story. I have no doubt that it reflects the excitement that the elucidation of nitric oxide’s role in the body, and in relation to male sexual activity, generated by the end of 1992.”
“Impotence can be defined literally as a lack of power, in the male, to copulate and may involve an inability to achieve penile erection or ejaculation, or both. More specifically, erectile impotence or dysfunction may be defined as an inability to obtain or sustain an erection adequate for intercourse.”
“The compounds of the invention are potent inhibitors of cyclic guanosine 3’, 5’ monophosphate phosphodiesterases (cGMP PDEs) in contrast to their inhibition of cyclic adenosine 3,5-monophosphate phosphodiesterases (cAMP PDEs). This selective enzyme inhibition leads to elevated cGMP levels which, in turn, provides the basis for the utilities already disclosed for the said compounds in [Bell I] and [Bell II], namely in the treatment of stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency e.g. post- percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS).”
“Unexpectedly, it has now been found that these disclosed compounds are useful in the treatment of erectile dysfunction. Furthermore the compounds may be administered orally, thereby obviating the disadvantages associated with i.c. administration.”
“ Claim 1 . The use of a compound of formula (I): [ Diagram or picture not reproduced in HTML version - see .rtf file to view diagram or picture ] wherein R 1 is H; C 1 -C 3 alkyl; C 1 -C 3 perfluoroalkyl; or C 3 -C 5 cycloalkyl; R 2 is H; C 1 -C 6 alkyl optionally substituted with C 3 -C 6 cycloalkyl; C 1 -C 3 perfluoroalkyl; or C 3 -C 6 cycloalkyl; R 3 is C 1 -C 6 alkyl optionally substituted with C 3 -C 6 cycloalkyl; C 1 -C 6 perfluoroalkyl; C 3 -C 5 cycloalkyl; C 3 -C 6 alkenyl; or C 3 -C 6 alkynyl; R 4 is C 1 -C 4 alkyl optionally substituted with OH, NR 5 R 6 , CN, CONR 5 R 6 or CO 2 R 7 ; C 2 -C 4 alkenyl optionally substituted with CN, CONR 5 R 6 or CO 2 R 7 ; C 2 -C 4 alkanoyl optionally substituted with NR 5 R 6 ; (hydroxy)C 2 -C 4 alkyl optionally substituted with NR 5 R 6 ; (C 2 -C 3 alkoxy)C 1 -C 2 alkyl optionally substituted with OH or NR 5 R 6 ; CONR 5 R 6 ; CO 2 R 7 ; halo; NR 5 R 6 ; NHSO 2 NR 5 R 6 ;NHSO 2 R 8 ; SO 2 NR 9 R 10 ; or phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl any of which is optionally substituted with methyl; R 5 and R 6 are each independently H or C 1 -C 4 alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino, 4-N(R 11 )-piperazinyl or imidazolyl group wherein said group is optionally substituted with methyl or OH; R 7 is H or C 1 -C 4 alkyl; R 8 is C 1 -C 3 alkyl optionally substituted with NR 5 R 6 ; R 9 and R 10 together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperdino, morpholino or 4-N(R 12 )-piperazinyl group wherein said group is optionally substituted with C 1 -C 4 alkyl, C 1 -C 3 alkoxy, NR 13 R 14 or CONR 13 R 14 ; R 11 is H; C 1 -C 3 alkyl optionally substituted with phenyl; (hydroxy)C 2 -C 3 alkyl; or C 1 -C 4 alkanoyl; R 12 is H; C 1 -C 6 alkyl; (C 1 -C 3 alkoxy)C 2 -C 6 alkyl; (hydroxy)C 2 -C 6 alkyl; (R 13 R 14 N)C 2 -C 6 alkyl; (R 13 R 14 NOC)C 1 -C 6 alkyl; CONR 13 R 14 ; CSNR 13 R 14 ; or C(NH)NR 13 R 14 ; and R 13 and R 14 are each independently H; C 1 -C 4 alkyl; (C 1 -C 3 alkoxy)C 2 -C 4 alkyl; or (hydroxy)C 2 -C 4 alkyl. or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the curative or prophylactic treatment of erectile dysfunction in a male animal, including man. Claim 5: “The use according to claim 4 wherein the compounds of formula (1) is selected from. …”
“The use according to claim 5 wherein the compound of formula (I) is 5-[2-ethoxy-5-(4-methyl-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.”
“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.”
“The use according to any one of claims 1 to 8 wherein the medicament is adapted for oral treatment.”
“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.”
“The use according to claim 10 wherein the inhibitor is a cGMP PDE v inhibitor.””
“58. My findings on the construction of the claims are therefore as follows: (A) Claim 1 covers the use of a Formula I compound (a) either alone or with some other agent, (b) by any means of administration, (c) for the purpose of treating male animals who have the inability to obtain or sustain an erection and (d) where such use is effective, at least in some cases, in treating that disorder. (B) Claim 10 covers the use of (a) any compound which inhibits cGMP PDE enzymes (whether selective or not), (b) either alone or with some other agent, (c) by oral administration, (d) for the purpose of treating males who have the inability to obtain or sustain an erection and (e) where such use is effective, at least in some cases, in treating that disorder. (C) Claim 11 is of the same scope as claim 10 save that it is restricted to compounds which inhibit cGMP PDE V .”
“I think that having regard to the statement which Pfizer is prepared to make, set out in paragraph 4 of Mr Meade’s skeleton argument [the same as in the June letter], and having regard to what he told me in response to a direct question from me this morning – which will appear on the transcript – that screening forms no part of any positive case of inventiveness which is being made on behalf of Pfizer, the process of screening forms no positive case which would be advanced in support of the contention of non-obviousness, it seems to me that it would be wrong for me, on this aspect of the objection, to make the order for disclosure which is sought.”
“There are, we think, four steps which require to be taken in answering the jury question. The first is to identify the inventive concept embodied in the patent in suit. Thereafter, the court has to assume the mantle of the normally skilled but unimaginative addressee in the art at the priority date and to impute to him what was, at that date, common general knowledge in the art in question. The third step is to identify what, if any, differences exist between the matter cited as [forming part of the state of the art] and the alleged invention. Finally, the court has to ask itself whether, viewed without any knowledge of the alleged invention, those differences constitute steps which would have been obvious to the skilled man or whether they require any degree of invention.”
“The therapeutic potential of PDE V A inhibitors as, for example, vasodilators, bronchodailtors and producers of gastrointestinal motility, is largely based on the effects of one compound, Zaprinast, and a clearer picture will be obtained when other rationally designed inhibitors become available.”
“The effects of zaprinast have also been studied in a number of other smooth muscle types. With strips of human corpus cavernosum, zaprinast alone caused a relaxation and enhanced the relaxation caused by nitric oxide or electrical stimulation. [At this point there is a footnote reference to the Rajfer paper.] … Zaprinast is a weak relaxant of lower esophageal sphincter muscle from a number of species, including humans, but potently relaxes guinea pig colon and Taenia coli preparations. Contracted rat gastric fundus is also relaxed by zaprinast, and the compound potentiates the sodium nitroprusside (SNP)-induced relaxation of this tissue. In vivo studies of PDE V A inhibitors have largely been on the effects of zaprinast on mean arterial blood pressure (MABP) in anesthetized rats or dogs, and again, the results give a reasonably consistent picture. Zaprinast lowered MABP mainly by decreasing total peripheral resistance, and there is evidence for selective vasodilatation. Zaprinast increased cardiac output and also caused a marked natriuresis, but had little effect on heart rate. In a rat aortavenocaval fistula model of cardiac failure, infusion of zaprinast caused natriuresis with little effect on MABP. Treatment of spontaneously hypertensive rats with zaprinast caused a fall in MABP to control levels. SK&F-96231 did not affect heart rate or MABP in conscious dogs, whereas bronchodilating effects of the compound were observed in anesthetized guinea pigs.”
“To date, the only PDE V A inhibitor that has been clinically evaluated is zaprinast. In adult asthmatics, zaprinast reduced bronchoconstriction induced by exercise, but not that provoked by histamine 51 . In contrast, zaprinast had no effect on exercise-induced asthma in children 52 . However, when evaluating these results, it should be remembered that these were small clinical trials using a compound that may have actions other than PDE V A inhibition. Therefore, at present, PDE V A inhibitors must be considered to be compounds with potential rather than established clinical use. Smooth muscle relaxation appears to be the most promising of the potential uses of PDE V A inhibitors, and possible therapeutic utilities could include vaso dilatation, bronchodilatation, modulation of gastrointestinal motility and treatment of impotence. Although PDE V A inhibitors will relax most smooth muscle types in vitro , this does not necessarily mean that a nonselective action will be seen in vivo . Selective actions could be achieved by virtue of the fact that many of the effects of PDE V A inhibitors in a particular tissue are dependent on the level of guanylate cyclase activity. Thus, PDE V A inhibitors will have the greatest effect in cells and tissues that have a high guanylate cyclase activity, and there could be considerable value in a therapeutic agent that has little activity in its own right, but potentiates the effects of endogenous mediators. An example of this has been demonstrated in the rat model of cardiac failure described above, where the operated animals were more sensitive to the effects of zaprinast than their sham-operated controls. An explanation for this is that higher levels of the guanylate cyclase-activating ANP are found in the former group.” … At present the therapeutic potential of PDE V A is largely based on the effects of … zaprinast, and a clearer picture will be obtained when other rationally designed PDE V A inhibitors become available.”
“Nitric oxide has been identified as an endothelium – derived relaxing factor in blood vessels. We tried to determine whether it is involved in the relaxation of the corpus cavernosum that allows penile erection.”
“71. Under the heading ‘conclusions’ in the abstract, the authors say that defects in the NANC pathway may cause some forms of impotence. The main text of the paper records that failure of penile erection could be due to impaired relaxation of the smooth muscle of the corpus cavernosum (p. 90 left column) and states that the purpose of the study it reports was to ascertain whether nitric oxide plays a part in relaxation of the corpus cavernosum in humans and therefore in penile erection (p. 90 right column). It then reports a series of experiments. It is not necessary to go into the detail of those experiments but they can be split into two broad groups. In the first, the effect of modification of the nitric oxide generating part of the NANC pathway was examined. For example the generation of nitric oxide was impaired by swamping the tissue samples with an analogue of L-arginine which is not turned into NO. This had the effect of preventing L-arginine from being turned into NO (see step 1 in the flow diagram at paragraph 16 above). The second was concerned with looking at the chemical processes by which the cGMP produced by NO was removed from the tissue. To do this it used a cGMP PDE inhibitor identified as M&B 22,948 – this is the pharmaceutically active molecule known as zaprinast produced by May & Baker (see the table at paragraph 18 above). The authors report that they took strips of fresh human corpus cavernosum tissue and subjected them either to electrical field stimulation (i.e. to emulate the effect of the nerves when a man is sexually aroused) or to treatment with a chemical called SNAP which liberates NO. In both cases the NO released made the corpus cavernosum relax. The authors then applied the selective cGMP PDE inhibitor, zaprinast, to the tissue samples to see what effect it had on the NO-generated relaxation. It records that the inhibitor augmented or enhanced the relaxant responses. For example under the rubric “Preliminary Observations in Men without Impotence”
“Corporal tissue from two men without impotence and tissue from impotent patients responded similarly with regard to the … enhancing effects of M&B 22,948 on electrically elicited relaxation. … M&B 22,948 … caused increases of 72 to 86 percent and 84 to 96 percent, respectively, in the relaxation response of corporal strips from 2 normal patients and 11 impotent patients.” 72. In the discussion section of the paper, Rajfer says: “… the addition of nitric oxide … caused similar rapid relaxant responses that were … enhanced by M&B 22,948 … M&B 22,948 is a selective inhibitor of cyclic GMP but not cyclic AMP phosphodiesterases…” [i.e. it is a selective inhibitor of cGMP PDE but not cAMP PDE] and ends by concluding that the NANC pathway “…may be involved physiologically in mediating penile erection. It is conceivable that impairment of this pathway could account for the impairment in relaxation elicited by electrical-field stimulation that has been described in certain impotent men. Smooth-muscle relaxation is the mechanism by which papaverine and prostaglandin E 1 , when injected intracavernosally, cause tumescence in impotent men. … interference with the L-arginine-nitric oxide pathway could be one cause of impotence that is treatable by the administration of direct-acting vasodilators.” 73. There is one other passage in Rajfer which should be referred to. It is on the second page of the paper in the detailed description of the experimental procedure being used. It reads as follows: “When [zaprinast], an experimental drug prepared by May and Baker (Dagenham, United Kingdom) was tested, it was added to the strips at a concentration of either 1 or 3 (mol per liter (whichever caused a relaxation of 10 to 15 percent, sufficient to ensure that enough [zaprinast] had been added).””
“138. I accept Mr Thorley’s arguments of obviousness. If anything, the case of obviousness based on Murray is even stronger than in relation to Rajfer. It could be said that Pfizer’s patent is little more than a putting into practice of the recommendations and suggestions of Dr Murray. Those recommendations and suggestions would have been appreciated by a man skilled in the art at the priority date as being sound and worth trying.”
“Should we not try out UK 92480 [sildenafil citrate] on impotence? Have we seen any beneficial side effects?”
“90. … What is clear from the evidence is that the Pfizer workers involved did not know, to use Dr Ellis’ words, that the mechanism of action of cGMP PDE inhibitors is fundamentally different from other direct acting vasodilators. They had not appreciated that the production of cGMP is not increased by an inhibitor but that its breakdown is countered. However these are matters which a skilled man in the art would have understood from Rajfer (and from Murray or Bush). It should be remembered that even the abstract at the beginning of the Rajfer article points out the different mode of action because it states that “The relaxation caused by either electrical stimulation or nitric oxide was enhanced by a selective inhibitor of cylcic guanosine monophosphate (GMP) phosphodiesterase.”
“99. … The starting point in considering this issue is an awareness of what those in the art thought of oral treatment of MED at the priority date. In my view this was an area in which there was close to consensus between the witnesses. There is no doubt that a high priority in the search for any new treatment of MED was that it should be administered orally. This was considered to be the ideal form of treatment by Dr. Gristwood. Dr. Challis, said that oral delivery was clearly the preferred route of administration and, under cross-examination, he said: “…if you can achieve oral administration I am sure that there are a myriad of reasons why you would pursue it” (Day 5 Transcript page 659 –660) 100. Some of those reasons were given by Dr. Kruse in a passage in his report which was not seriously challenged: “The ultimate aim of most drug research program is to produce a drug which can be taken orally. … Oral administration is the preferred and most widely used route of administration for the simple reason that it best ensures patient compliance and can be used at home, as opposed to in a hospital setting. Oral drugs can easily be self-administered by a patient. Swallowing a pill is a relatively non-invasive and non-threatening event for most patients and it is a fairly easy task to ensure one is taking the correct quantity of the drug, i.e. it is easier to count pills than say measure out a quantity of solution to take intravenously. Of course there are some circumstances where other routes of administration (e.g. intravenous or intramuscular) might be preferred, for example for the administration of a very potent, short acting drug following a stroke or an anaphylactic shock. Non-oral methods of administration might also be preferred for certain organs, for example administration directly into the eye for the treatment of glaucoma. However, in the vast majority of cases of drugs being administered to treat non-life threatening conditions the oral route of administration is the best and the most widely used. In a disease such as erectile dysfunction, where male self-image, and perceptions of performance are important, oral activity is almost certainly a requirement for a commercially successful drug. It is difficult to imagine an injectable or other mode of administration competing effectively with the discretion and simplicity of an orally acting therapeutic.” 101. Similar evidence was given by Mr Pryor, a urologist called by Lilly who was a most impressive witness. He said that by early 1993 the vast majority of clinicians had recognised the disadvantage of penile injection therapy and the desirability of having an oral preparation and that he would have advised any company involved in finding a new treatment for MED that it should make it a priority to develop an orally active drug. He said: “The oral route of administration is generally the most convenient and most acceptable to a patient for any drug. It enables the patient to manage easily and in the safest way possible the treatment of his particular disorder. It is suitable for acute, chronic or prophylactic treatment. With respect to the treatment of erectile dysfunction, oral administration of a medicament was generally recognised as being the obvious goal to aim for since it would overcome the unpleasant and potentially hazardous procedures associated with intracavernosal injections. In fact, at the NIH consensus meeting in 1992 it was stated that amongst the needs and directions for future research was the development of new therapies, including pharmacologic agents, and with the emphasis on oral agents that may address the cause of male erectile dysfunction which greater specificity (page 194)”. (Pryor Expert Report paragraph 5.4) (The NIH referred to in that passage is the American National Institute of Health which held a meeting on impotence in December 1992.) 102. I accept Mr Pryor’s evidence as fair and reliable. Indeed Pfizer accepts that at the priority date an effective oral treatment for impotence was known to be desirable “in the abstract”.”
“105. However, there are additional reasons why Mr Kitchin’s arguments must be rejected. On the facts here there was overwhelming pressure on workers in the field to try oral administration with any new pharmaceutical candidate for MED treatment. I have already referred to the very unpleasant nature of the primary treatment for male impotence, namely self injection into the penis immediately before sexual intercourse, and the general appreciation by 1992 if not before that oral treatment was what was needed. Pfizer suggests that the perceived risks of oral administration of a PDE inhibitor were so great that they would not even be tried. This argument reached its high point in Professor Ignarro’s warning that oral administration risked killing the patients. Because some PDE inhibitors were known to have an effect on the peripheral vascular system which could result in lowered blood pressure, so any systemic treatment would be likely to be potentially life-threatening. 106. It is all too easy in a case like this to raise a lurid fear and for that to obscure the issues. That, in my view, is what Pfizer have done here. It is well known and not in dispute that regulatory authorities exercise immense care before they will license drugs for human use. The prospect of an orally administered impotence treatment being allowed on the market which has a significant risk of killing patients or even causing them significant harm must be regarded as very small indeed. As Mr Kitchin is anxious to point out, most drugs go through extensive testing, including testing on live animals, before they are allowed even to be clinically tested on humans. The risk, if there is one, therefore is not a risk of killing patients so much as of failing to make it through the trials which always have to be undertaken to prove efficacy and lack of relevant or unacceptable toxicity and side effects. The question is, therefore, whether it would be obvious to try to use a cGMP PDE inhibitor in oral treatment or were the risks of failing so great as to deter the notional skilled worker before he set off down that path. Whether something is obvious to try depends to a large extent on balancing the expected rewards if there is success against the size of the risk of failure. Here it was apparent that the rewards for finding an oral treatment would be substantial. The risk was not, as indicated above, the risk of killing anyone, but the risk that trying oral administration would not work so that the research would be unproductive. … 107. I have come to the conclusion that the skilled team would not have been put off trying oral administration of a PDE inhibitor. On the contrary, on balance there is much in the evidence which suggests that trying oral administration was a worthwhile, and perhaps the first, avenue to pursue. The skilled team would have included PDE expertise. It would have known that the oral administration of PDE inhibitors was already being tried in a number of fields. As Dr. Challis agreed, it was well known by 1993 that a number of PDE inhibitors were bioavailable orally. Further Lilly produced a document (X17) which referred to 25 patents to PDE inhibitors applied for before the priority date of the patent in suit. The patentees included Warner-Lambert Co., SmithKline Beecham, Pfizer and Schering – all well known names in the pharmaceutical field. Every one of them suggested that the inhibitors should be administered orally. In some cases they contain a suggested daily dose for human ingestion. Even by the time of Rajfer in January 1992, it would have been apparent that it was worth trying oral administration of any candidate compound. The reasons for this are not difficult to understand. On the one side there was the pressure to find an oral treatment for MED. On the other there was nothing to suggest that these inhibitors as a class were necessarily ineffective or toxic when so administered. Dr. Gristwood gave evidence on this issue. He said: “Having read Rajfer et. al., there was nothing to deter me from pursuing an oral delivery of a selective PDE V inhibitor as a treatment of impotence. Although cardiovascular effects have been reported in anaesthetised rats and dogs with intravenous administration of zaprinast, I was not then, and still am not, aware of any reported adverse side effects associated with oral administration of zaprinast to humans. I was aware in 1993 that zaprinast had been administered orally in humans (both adults and children) without adverse side effects. I would expect most people working in the field to have been aware of this.” 108. I accept that evidence. The fact that zaprinast (May & Baker’s PDE V inhibitor) which was discussed and used in Rajfer was the subject of clinical trials and had been administered orally for that purpose would have been known to all those involved in the potential use of PDE inhibitors as a drug candidate. Anyone who had any fears about the use of it, or other PDE inhibitors, for oral administration would have found that out from the published literature. Furthermore, even if the skilled man was not aware that PDE inhibitors had actually been used in such clinical trials, he would not have been put off trying oral administration. He would have been unable to predict whether there would be a problem associated with oral administration, or if there was its nature and magnitude and he would be reassured that if any significant problem did exist it would surface during the course of the tests necessary for regulatory approval, that is to say tests specifically designed as a filter to ensure no appreciable risk to the public. The result is that the skilled man or team in the art would not have been put off from trying to use a PDE inhibitor for oral administration. 109. The evidence supports the view that any worries about possible side effect or contra indications would not have been sufficient to prevent a worker in the field from trying out PDEs for administration to man, whether orally or otherwise. For example Dr. Challis’ evidence was: “Q. Coming back again to paragraph 46 you are unable to point my Lord to any known PDE5 as at 1993 which was known to have life-threatening side-effects. A. I am sorry, I have gone to the .... We are on 46? Q. Did I say 46. I should not have done. … MR. THORLEY: I do apologize; it is my fault. Paragraph 65, top of page 29, you were talking about life-threatening consequences. That is what we were talking about and I am trying to ensure that I have got your evidence accurately. Do you want me to put the question again? A. No. I am quite happy. I am saying that, I think the point that I am trying to get across there is that if one is thinking about the treatment of MED one has a good idea of what the patient population is going to be. It is going to be generally more elderly. I think the incidence of impotence increases essentially exponentially beyond the age of around 40, so we are dealing here with a group of patients that have potentially other health problems in their lives. We are dealing with a disorder that is in itself not life-threatening and, therefore, I think that anyone developing drugs in this area is going to be acutely aware of any side-effects, never mind life-threatening side-effects, but there is the potential of these drugs, I think, to cause life-threatening effects in people with particular other complicating disorders. Q. Are you saying that that concern would deter you from doing any development work in the field or are you saying that you would conduct development research with caution? A. The latter.” (Day 5 Transcript page 700) 110. He returned to the same theme on the next day: “MR. THORLEY: … doctor, you said, if I recall rightly that because of these complications there could be no guarantee that a beneficial therapy could be produced. A. No. Q. By pursuing any particular route of potential treatment. A. That is absolutely the case, yes. Q. That is the point that you are seeking to make. A. The point is that I believe .... The sildenafil example gives us a clear example of where, despite all of my provisos, a drug is extremely effective. Therefore, all I am doing is trying to make you aware of the complexities of the field. I am not saying that there was no point in travelling towards that therapeutic goal at all.” (Day 6 Transcript page 720) 111. In addition to these points, I should refer to the evidence of Dr. Dennis Smith, the Senior Director of Pfizer’s Drug Metabolism Department and whose entire industrial career has been in the area of Drug Metabolism and Pharmacokinetics. He was asked by Pfizer to comment on what procedures would have formed a routine part of drug development programmes in order to assess the oral bioavailability of a compound, as at June 1993 . In particular, he was asked to comment on the use of conscious animals for this purpose as at that date. 112. He stated that oral bioavailability assessment of compounds using animals, such as the dog had certainly become a well known and routine part of drug development programmes by 1992. He said that this was due to fundamental similarities between animals and man in the processes governing absorption of compounds from the gastrointestinal tract and subsequent appearance in the systemic circulation (from where the drug molecule exerts its pharmacological effect). He also said that such assessments are a routine aspect of selecting the appropriate drug molecules for clinical development. He supported that view by a reference to numerous published articles from various workers, from a large number of pharmaceutical companies. His report also contains the following: “I should say that in practice, oral bioavailability studies are not carried out on the full range of compounds studied in the course of a drug discovery programme, but only those which are considered to be the more promising candidates for further development. For each compound being tested, such studies normally took approximately two to three weeks to carry out in 1993. I should also point out that species differences in bioavailability between man and animal species, including dog, have been identified, which may mean that the data needs interpretation for prediction to man. However, the assessment of oral bioavailability in animal species in 1993 and today remains an essential element of the preclinical assessment of novel drug candidates. Increasingly in vitro systems have been put into place which facilitate this interpretation, but these are used alongside data on bioavailability in conscious animals. Other animal species are used in addition to the dog in the assessment of oral bioavailability. These include mice, rats and monkeys. However, the extensive use of the dog in pharmacology studies and in drug safety evaluation within the pharmaceutical industry, results in the dog being amongst the most commonly used of the animal species.” 113. Unsurprisingly, Lilly chose not to cross examine this witness. His evidence supports the view that it would have been a matter of course to try out any potential anti-MED candidate by oral administration to conscious animals, including dogs, and that any such testing would have taken a comparatively short time. That is what the skilled man in the art would have done.”