Ranbaxy's submissions
341 Ranbaxy submitted that the answer to this question is 'yes', as there was good reason to do so (and it had become routine to do so) for any racemate. Further, Ranbaxy submitted that there were "particular reasons" to do so for omeprazole.
342 Dr Stevenson's answer to question 28 of the document entitled, "ORGANIC CHEMISTRY: Second meeting" (which asked how common it was at the priority date to separate the enantiomers of a racemate when dealing with a chiral molecule of interest) was as follows:
My experience at May 1993 was that separation of enantiomers was a routine part of the drug design process.
The reasons for pursuing single enantiomers can be found in the basis of drug design methods, namely that a successful drug has to be active, efficacious, and pharmacologically significant. This profile includes the relevant selectivity profile, toxicity profile and pharmacokinetic profile all of which enable the drug molecule to be delivered in vivo and demonstrate the desired therapeutic effect. The single enantiomers of a compound can have significantly different profiles in all of the above or only some of the above.
The only way to determine this is to engage in resolution and profile the individual enantiomers to look for evidence for these differences. Although in terms of primary activity there is only a potential twofold advantage (and in the specific case of Omeprazole no advantage in primary activity at all), this is not the case for the other parameters, which in some ways are the more difficult aspects of drug design. Therefore the use of single enantiomers was at May 1993 and is today an essential part of the drug design process.
343 Ranbaxy submitted that Dr Stevenson's evidence in this regard should be accepted, as he had considerable practical experience to be able to say so, including the separations he personally conducted prior to 1993 whilst at Merck. Ranbaxy submitted that the 'Second meeting' document is consistent with his oral evidence and with his affidavit, and that Dr Stevenson was not squarely challenged on any of that evidence. As Dr Stevenson points out, there were three related pharmacological reasons for resolution of enantiomers, namely, the potential for improvements in efficacy (selectivity); the potential for improvements in safety (toxicity); and the potential for improvement in pharmacokinetic profile. The evidence of the pharmacologists, Professor Evans and Dr Reece, expanded on these reasons (this is addressed further below).
344 Further, Ranbaxy contended that Dr Stevenson's evidence was consistent with the growing interest in the separation of enantiomers from the mid 1980s, reflected in the scientific literature including the 1992 Food and Drug Administration Guidance document entitled "Development of New Stereoisomeric Drugs" ('1992 FDA Guidance document').
345 Ranbaxy then relied upon a number of publications in support of their argument. I set out the main publications.
346 In 1984, an article written by Mr E J Ariens entitled "Stereochemistry, a Basis for Sophisticated Nonsense in Pharmacokinetics and Clinical Pharmacology" was published in the European Journal of Clinical Pharmacology (volume 26, p 663), in which he strongly advocated the investigation of the optically active forms of racemic drugs. He stated that "in clinical pharmacology, particularly in pharmacokinetics, neglect of stereo-selectivity in action leads to the performance of expensive "highly sophisticated scientific nonsense".
347 Mr Ariens returned to the theme in 1987 in an article entitled "Bias in pharmacokinetics and clinical pharmacology", published in Clinical Pharmacology & Therapeutics (volume 42(4), p 361), in which he stated that (at 363):
[a]s overwhelmingly documented, stereoisomers as a rule differ markedly in their pharmacodynamic and pharmacokinetic properties. From the point of view of biology, enantiomers are essentially different compounds.
348 Also in 1987, a paper co-written by Professor Davies entitled "The highly stereoselective conversion of N,N-dimethylamphetamine into N-methylpseudoephedrine; a mimic of the enzyme mediated stereospecific benzylic hydroxylation" was published in Tetrahedron (volume 43(19), p 4463). This publication referred to the "growing appreciation" of the different biological effects of enantiomeric molecules. He and his co-author said (at p 4463):
Whilst many pharmaceuticals are still produced in racemic form there is a growing appreciation of the different biological effects of enantiomeric molecules and as a result the preparation of optically pure β-amino-alchols [sic] has attracted considerable attention.
349 Professor Evans agreed with Mr Ariens' views. Further, he made this fact known at various conferences at around that time, and co-authored a paper on the topic in 1988, entitled "Stereoselective drug disposition: potential for misinterpretation of drug disposition data". It was published in the British Journal of Clinical Pharmacology (volume 26, p 771). He and his co-authors pointed out that:
Although enantiomers have essentially identical physico-chemical properties in a non-chiral environment, they may behave differently when exposed to an optically discriminating environment such as the human body. Consequently, they may differ in their pharmacodynamics, pharmacokinetics or both.
350 Reference was also made to the 1984 and 1987 Ariens' articles, the latter of which was said to indicate "the need for an increased appreciation of stereoselectivity in the field of clinical pharmacology".
351 Professor Evans and his co-authors conclude in that publication by expressing the hope that (at 778):
this paper will contribute to the recent move within the literature to promote awareness in clinical pharmacology of stereoselectivity. This awareness should be applied to re-evaluate the results of previous studies on chiral drugs which have failed to consider stereoselective drug disposition, and to anticipate potential complications of using non-stereoselective drug analysis in future studies.
352 In 1988, Wainer and Dreyer published a text book entitled "Drug Stereochemistry", one chapter of which was devoted to the topic "Pharmacokinetic differences between drug enantiomers in man". That book, which Professor Evans consulted regularly before the priority date, recalled Pasteur's observation made over 100 years earlier that the essential products of life are asymmetric. They pointed out the pharmacokinetic as well as the pharmacodynamic reasons for separation of racemates and concluded that "many drug enantiomers have different pharmacological properties in man, and there seems to be substantial intersubject variation in the ratios of the concentration of the individual drug enantiomers in plasma in man". The view was expressed that "it probably is a good idea for individual drug enantiomer plasma levels to be determined and correlated with effect to see if any extra clinical benefit is gained by this additional analytical step".
353 The work sets out, in table 2, evidence for stereoselective biotransformation of drug enantiomers in man. 'Biotransformation' is another word for metabolism. The listed stereoselective drugs include mephenytoin (about which more will be said shortly), and it is stated that "in extensive metabolizers, the S-(+) enantiomer undergoes p-hydroxylation exclusively, while the R (-) enantiomer is biotransformed equally by p-hydroxylation and N-demethylation".
354 In 1989, in a review article in Nature (volume 342, p 631) entitled "Chemical Asymmetric Synthesis", Professor Davies wrote (at p 636):
The differing pharmacological effects of the two enantiomers of chiral molecules are now well documented. Even if the inactive enantiomer lacks undesirable side effects, administering the potent enantiomer alone halves the dose and alleviates stress on the patient's already compromised metabolism. We are at the watershed of asymmetric synthesis - in the near future it will be common practice to synthesize all potential new drugs as single enantiomers and there is already pressure from regulatory agencies in this direction.
355 In an article entitled "Enantioselective pharmacodynamics and pharmacokinetics of chiral non-steroidal anti-inflammatory drugs" written in 1991 (but published in 1992 in the European Journal of Clinical Pharmacology, volume 42, p 237), Professor Evans wrote that (at 237):
it is becoming generally accepted that studies in which the complexities of chirality are neglected may be misinformative. At the same time substantial advances have been made in the technology required to resolve and quantify the enantiomers of chiral drugs and biological specimens. Because of these recent developments in attitudes and analytical capabilities, it is becoming more common for pharmacokinetic studies of racemic drugs to generate data for individual enantiomers rather than unresolved species.
356 Professor Evans confirmed the accuracy of these statements in his oral evidence. The article also stated:
[t]he consequences of using a chiral drug as a racemate can be established only after careful consideration of the pharmacodynamic and pharmacokinetic properties of its individual enantiomers.
357 Under the heading "Enantioselective Pharmacodynamics", Professor Evans said that:
[p]harmacodynamic differences between enantiomers arise from enantioselective interactions with the chiral macromolecules which constitute the biological receptors. Typically, both enantiomers will elicit similar pharmacological effects but one will be more active than the other. In other cases, the individual enantiomers of a chiral drug may exhibit qualitatively different and sometimes opposing pharmacological properties.
358 Under the heading "Enantioselective Pharmacokinetics", he said:
Interactions with chiral macromolecules may be involved in the absorption of a drug, its distribution throughout the body, its metabolism, and its excretion, and each process may be enantioselective.
359 Under the heading "Metabolism", he said:
"It is well recognised that stereochemical factors play an important role in xenobiotic metabolism, and that enantioselective metabolism has important consequences for many chiral drugs."
360 Xenobiotic refers to the introduction of foreign matter, such as a synthetic chemical, into the body.
361 In May 1992, the FDA published the Guidance document referred to above, that said:
To evaluate the pharmacokinetics of a single enantiomer or mixture of enantiomers, manufacturers should develop quantitative assays for individual enantiomers in in vivo samples early in drug development. This will allow assessment of the potential for interconversion and the absorption distribution, biotransformation, and excretion (ADBE) profile of the individual isomers. When the drug product is a racemate and the pharmacokinetic profiles of the isomers are different, manufacturers should monitor the enantiomers individually to determine such properties as dose linearity and the effects of altered metabolic or excretory function and drug-drug interactions.
362 It also stated, under the heading "Policy in General":
FDA invites discussion with sponsors concerning whether to pursue development of the racemate or the individual enantiomer. All information developed by the sponsor or available from the literature that is relevant to the chemistry, pharmacology, toxicology, or clinical actions of the stereoisomers should be included in the IND and NDA submissions.
363 Further, under the heading "Pharmacology/Toxicology", and the subheading "Pharmacokinetic Profile", the document stated:
To monitor in vivo interconversion and disposition, the pharmacokinetic profile of each isomer should be characterized in animals and later compared to the clinical pharmacokinetic profile obtained in phase 1.
364 In his affidavits, Dr Reece drew attention to the following statement from the 1992 FDA Guidance document:
Where little difference is observed in activity and disposition of the enantiomers, the racemates may be developed.
365 His evidence on this point was that "in order to obtain regulatory approval for a chiral compound at May 1993, the individual enantiomers of the compound would normally be tested". Professor Evans' evidence was that it would be a brave (not to say foolhardy) drug developer who, after May of 1992, would pursue the development of a racemate without characterising the enantiomers, and that from May 1992 (12 months before the priority date of the Purity Patent) "any company submitting a registration dossier for a racemic drug would have been expected to comment on the activity of the enantiomers".
366 The evidence of Dr Pyter, who had extensive experience with Abbott Laboratories, was that if a molecule contained a chiral centre, resolution to single enantiomers would normally take place during the discovery process.
367 The evidence of Dr Reece, who also had extensive experience in drug companies, was that prior to initiation of clinical trials, potential differences in metabolism of the enantiomers of a racemic drug candidate would be tested.
368 Ranbaxy submitted that the proposition that the skilled team would routinely have attempted to separate the enantiomers of omeprazole to investigate their pharmacokinetic profile is further supported by the evidence in relation to the gastroenterology and pharmacology of omeprazole, in that:
(a) Dr Prichard and Professor Dent both agreed that there was known to be a variability in clinical response to the recommended dose of 20 mg of omeprazole.
(b) A clinical trial conducted by Professor Dent in 1986 showed that a minority of patients did not respond, although his view was that at that time the mechanism for that lack of response was not well known. Extensive clinical trials in or around 1988 also disclosed variability of response to the recommended dose.
(c) Dr Prichard and Professor Dent agreed that the variability of effect of omeprazole 20 mg on acid secretion was "of considerable clinical importance, as it has been shown to be the most important underlying mechanism for failure of healing of oesophagitis by omeprazole and so the most important variable to tackle in order to improve the results of initial therapy".
(d) The pharmacologists, Professor Evans and Dr Reece, also agreed in the Joint Expert Report: Pharmacology that it was known to be desirable to reduce interindividual variability in the pharmacokinetic properties of a drug "if that led to improved efficacy (or acceptable efficacy in a greater proportion of patients) or if it led to reduced toxicity or risk of toxicity, or if it simplified the use of the drug (eg making it easier to determine what dose to use in a specific patient)".
(e) The pharmacologists also agreed in their Joint Expert Report at question 12 that there were a number of motivating factors to investigate and separate the enantiomers of omeprazole, and that none of the deterrents would have prevented them from pursuing the enantiomers. Professor Evans identified one deterrent (knowledge that the enantiomers of omeprazole are both converted to the same achiral active species) as having "extra significance"; however he agreed that this would not prevent him from separating the enantiomers if that was his intention. But Dr Reece pointed out that, regardless of whether the enantiomers were converted to the same active species, differences in the AUC of the enantiomers due to polymorphic drug metabolism would result in varying pharmacological effect.
369 On this basis, Ranbaxy submitted that this presents a compelling reason to resolve the enantiomers of omeprazole to test the extent to which the hydroxylation metabolism of omeprazole was stereoselective.
370 Ranbaxy submitted that at trial, the "lone voice" holding out against the separation of enantiomers being a routine part of the drug design process at least by 1993 was Professor Davies. Ranbaxy submitted that his evidence that it was not "common" by 1993 to resolve the enantiomers was not convincing, and he did not have the same level of practical experience as Dr Stevenson.
371 Ranbaxy further submitted that Professor Davies' evidence that the skilled addressee would not be motivated to resolve the enantiomers of omeprazole was also unconvincing. They contended that he never squarely addressed the point that the desirability of investigating the pharmacokinetic profiles of the enantiomers supplied a reason to resolve them. Instead he kept resorting to the proposition that because the safety and efficacy of omeprazole was known and the enantiomers of omeprazole might racemise, there would be no motivation to resolve them. It was Ranbaxy's case that this proposition "fails to meet all the reasons for resolution", and that its constant repetition "suggested Professor Davies had (no doubt unconsciously) taken on the role of advocate" for AstraZeneca.
372 A similar argument was made in respect of the proposition that the enantiomers might racemise. Ranbaxy noted that Professor Davies' initial evidence was that there was a risk of racemisation, but that this "quickly increased to an expectation". They further submitted that despite acknowledging the experimental fact that the enantiomers do not racemise in alkaline conditions to any significant extent, his evidence then shifted and he asserted many times that racemisation was occurring under basic conditions. When challenged directly on this issue, it was said that he reverted to it being a risk only, before again shifting back to the stronger proposition. Again, Ranbaxy submitted that these "slides" suggest "an unfortunate lack of objectivity".
373 Ranbaxy also noted the answer given by Professor Davies to question 3 in the Joint Expert Report: Organic Chemistry, where he added (in the context of speaking of expected racemisation under basic conditions) that "[t]his concurs with the inventors [sic] expectation described in AU 337 p 5 lines 11-14". Ranbaxy submitted that this addition was unnecessary, and again suggests that Professor Davies had taken on the role of an advocate. A further reason for caution in relation to Professor Davies' evidence was said to arise from his "enthusiasm" in suggesting that his own views would be shared by the "person of ordinary skill". It was said that he used the expression many times when the question did not call for such a reference, although such usage declined following him being questioned about it.
374 Ranbaxy submitted that leaving aside the disagreement between the experts as to whether racemisation would be expected under certain conditions, the reality is that until separation was attempted, one could not predict with certainty whether racemisation would occur or, if it did, to what extent. In fact, Ranbaxy contended that the evidence of Dr Stevenson in particular suggests that the quite moderate rate of racemisation of the enantiomers of omeprazole in neutral conditions disclosed in Erlandsson 1990 (130 hours) would encourage rather than discourage resolution in light of the much shorter known time for absorption and elimination (four hours). They submitted that any expectation that it would occur could never, realistically, have caused a medicinal chemist not to attempt the separation. It did not deter Mr von Unge from doing so. In fact, he liberated the enantiomers under strongly basic conditions.
375 Ranbaxy also pointed to the fact that it was accepted by all of the experts in this case that racemisation is not inevitable. Rather, there is a "risk" or a "fear" that racemisation might occur, the likelihood of which is something upon which reasonable minds may (and do in fact) differ. Dr Stevenson, Dr Reece and Dr Pyter all considered that the risk of racemisation of omeprazole under basic conditions would be inconsequential.
376 Further, Ranbaxy contended, Dr Stevenson, Dr Reece and Dr Pyter all gave evidence that in the face of an apparent risk of racemisation, they would nevertheless take steps to attempt to resolve the enantiomers. Professor Evans also agreed in the Joint Expert Report: Pharmacology that he would still attempt to separate the enantiomers. Even Professor Davies acknowledged that if there was a sufficient motivation to resolve the material (ie putting aside the fact that omeprazole is a prodrug and "safe and efficacious"), the skilled team would try to resolve the enantiomers. Indeed, the co-inventor of the Purity Patent, Mr von Unge, "nevertheless went ahead and did the experiments".
377 Ranbaxy also noted that in the book chapter entitled "An Innovative Asymmetric Sulfide Oxidation: The Process Development History Behind the New Antiulcer Agent Esomeprazole" written by the AstraZeneca employees Messrs Hans-Jürgen Federsel and Magnus Larsson (published in "Asymmetric Catalysis on Industrial Scale: Challenges, Approaches and Solutions" (2004), H U Blaser and E Schmidt (eds)), there is no suggestion that an expectation that racemisation would occur was a reason for not having earlier resolved the enantiomers of omeprazole.
378 Finally, Ranbaxy asserted that the proposition that at May 1993 the skilled team would have routinely attempted to separate the enantiomers of omeprazole is supported by what AstraZeneca themselves did. They separated the enantiomers of omeprazole in 1987 and tested them. Those tests were done on gastric glands for differences in pharmacodynamics. Such confirmatory tests were performed, in spite of the fact that the mechanism of action of the enantiomers was known. The evidence does not disclose any tests carried out on liver microsomes for differences in pharmacokinetics at the priority date. Perhaps this was because of the small quantities of the enantiomers that had been obtained in 1987 (although only small amounts would be required to conduct the liver microsome experiments), or because 1987 was relatively early days in the development of knowledge about the desirability of doing such tests. However, by the early 1990s the desirability of doing such tests was apparent as is recognised in the book chapter written by the AstraZeneca employees Messrs Federsel and Larsson. At p 415 of the chapter, Federsel and Larsson refer (with what Ranbaxy described as "justified embarrassment") to the strangeness of not having earlier investigated the pharmacokinetics of the enantiomers. They said (citations omitted):
Later on, one of the single enantiomers of omeprazole, esomeprazole, was selected as a CD [candidate drug]. This may seem strange and poses the question as to why had the single enantiomers not been investigated at an earlier stage? Omeprazole displays chirality by virtue of its sulfoxide functionality and a couple of analytical separations of the two isomers were performed during the 1980s. However, early on a single isomer was not considered for development. The reason being that the accepted mechanism of acid inhibition led to the prediction that both isomers of omeprazole would have exactly the same effect at the site of action because acid catalyzed conversion of either isomer to the same non-chiral sulphenamide species would occur at the same rate for both isomers. Thus while it was known that the isomers of chiral drugs often have different activities, the logical assumption was that this was not the case here. Furthermore, before 1990 only milligram amounts of the single isomers had been prepared, which was not enough for in vivo testing. For these reasons the "single-isomer concept" did not look very attractive. However, the Hässle scientists could not turn away from the idea of a possible difference in metabolism between the two isomers.
379 Later the authors say:
Switching back to the early days at the beginning of the 1990s when the hunt for a suitable omeprazole-successor was still vigorously being pursued, the pre-clinical evaluation including in vivo testing, required access to at least 100 mg of each investigated compound. In the case of the stereoisomers, the task was addressed in a way that must be regarded as most straightforward under the circumstances, since the racemate was abundantly available (commercial production on a multi-ton scale), namely by applying a conventional resolution procedure.
380 Ranbaxy contended that the "Two of a Kind" article of which Mr von Unge was a co-author (published in Chemistry in Britain in May 2002, p 118), explained that the availability of larger amounts of the pure isomers of omeprazole allowed testing in rats which demonstrated significant pharmacokinetic differences. This then led to testing in humans which identified the superiority of the (-)-enantiomer.