G3.3 The 341 patent
207 The complete specification for the 341 patent is entitled "An isoxazole derivative, processes for its preparation, compositions containing it, and its use for combating rheumatism". As noted, the derivative described as formula 1 in the 341 patent is leflunomide. It will be recalled also that the 341 patent notes that the compound, by virtue of its pharmacological properties, "can be used especially as an antirheumatic, antiphlogistic, antipyretic and analgesic agent, and for the treatment of multiple sclerosis." The specification further records that experiments with the three animal models (the Adjuvant Arthritis or AA model, the Adjuvant Arthritis Perper modification or AAP model and the Allergic Encephalomyelitis or AE model) showed that the compound "is superior to known compounds to a surprising degree" in terms of antiphlogistic action, effect on immunological processes, ulcerogenic activity and acute toxicity. As set out above, the specification summarises the results of the animal model experiments as follows:
The above pharmacological findings show that the compound according to the invention, of the formula I differs advantageously in its pattern of action from the tested antiphlogistic agents, in particular in respect of the inhibition of immunopathological processes on animal models which are also relevant to human illness. This is probably equally true relative to other antiphlogistic agents hitherto employed in therapy. This fact opens up the possibility of tackling, by medication, rheumatic illnesses in man by more nearly treating the cause, instead of purely symptomatic treatment as with the antiphlogistic agents used hitherto.
208 The claims of the 341 patent include the compound leflunomide in claim 1 and claim 4 as follows:
4. Method for the treatment of inflammations, rheumatic complaints or multiple sclerosis by administering to the patient an effective amount of the compound as claimed in claim 1.
209 Dr Shumack's evidence confirmed that the skilled addressee of the 341 patent would have been a rheumatologist rather than a dermatologist. Dr Shumack, a dermatologist, said that the animal models in the 341 patent all concerned immune processes. On his reading of the 341 patent it related to a compound, leflunomide, which might be useful in treating arthritic and inflammatory conditions and multiple sclerosis. As the 341 patent said nothing about proliferative processes, Dr Shumack would not have considered the 341 patent to be relevant to psoriasis. As noted, in 1993 and for a number of years thereafter, psoriasis was generally understood to be a proliferative disease and not an inflammatory or immune-mediated response. It follows that Dr Shumack's evidence is not that of the skilled addressee.
210 Professors Smith and Brooks are both rheumatologists. Contrary to Apotex's submissions, Professor Smith did not read the 341 patent as encompassing PsA within the general terms "rheumatic illnesses" and "rheumatic complaints". Rather, it is apparent from his evidence as a whole that Professor Smith considered those terms to be so broad as to be nearly meaningless if read in isolation. Professor Smith, however, did not do so. As a skilled addressee he had regard to the animal models in order to give meaning to the very general references in the 341 patent to "rheumatic illnesses" and "rheumatic complaints". Professor Smith was adamant that none of the animal models was relevant to PsA. The models were relevant to RA and, in the case of the AE model, multiple sclerosis. On this basis Professor Smith read the 341 patent as dealing with potential treatments for RA and multiple sclerosis. No material was put to Professor Smith in cross-examination suggesting that his view about the animal models was wrong.
211 Professor Brooks had a different view. As noted, Professor Brooks had used animal models in his own research. He considered the AA model to be relevant to the seronegative arthropathies, including PsA, because of his own research using such models. In his words, however, rheumatologists generally "don't know too much about animal models". In common with Professor Smith, Professor Brooks considered various references in the 341 patent to be very broad or, as he put it, capable of including "all of the 150 or so types of arthritic disease". However, in light of his view of the animal models Professor Brooks concluded that the 341 patent was concerned with inflammatory rheumatic diseases including RA, PsA and other seronegative arthropathies. Professor Brooks thus described claim 4 of the 341 patent as involving a method of treatment of inflammatory rheumatic diseases including RA, PsA and other seronegative arthropathies. Nevertheless, Professor Brooks acknowledged that animal models rarely mimic human disease. Accordingly, the ability to extrapolate from them is limited to an indication that the treatment may work in the relevant human disease. Substantial further work would be required to determine whether leflunomide would be safe or effective to treat any disease in humans.
212 On the basis of this evidence it is apparent that the 341 patent, at its priority date, disclosed nothing to the skilled addressee about the skin disease psoriasis. No one at the priority date considered psoriasis to be a form of rheumatic illness or rheumatic complaint (the terms used in the 341 patent). Thus nothing in the 341 patent would have suggested to the skilled addressee that leflunomide might be a potential treatment for psoriasis. However, as the competing submissions of the parties disclose, this conclusion is not the end of the matter. As noted, while a prior art document is to be read through the eyes of the skilled addressee, the effect of the document is objective. While Apotex disavowed the concept of "inevitable result" and urged the aptness of the symmetry of the "reverse infringement" test, in the present context the distinction between the two is more apparent than real. The reverse infringement test asks whether the alleged anticipation would infringe the claim. The test presupposes the proper identification of both the alleged anticipation and the claim, and requires consideration of the relationship between the two. The concept of "inevitable result" is concerned with the nature of the relationship between the alleged anticipation and the claim which is required to deprive the claim of novelty.
213 Apotex's principal argument about lack of novelty is to be assessed with these considerations in mind. The argument involves the following steps:
(1) The 341 patent discloses the administration of leflunomide as a method of treatment of (at least) RA and PsA in humans.
(2) The alleged anticipation is thus the administration of leflunomide as a method of treatment of (at least) RA and PsA in humans.
(3) Sanofi-Aventis asserts that the claim of the patent will be infringed by Apotex's proposed supply of leflunomide for use as a method of treatment for PsA.
(4) If, as Sanofi-Aventis asserts, the claim of the patent includes the use of leflunomide as a method of treatment for PsA, the claim is the same as the alleged anticipation.
(5) It follows that the alleged anticipation, on Sanofi-Aventis's own case, infringes the claim of the patent.
(6) The reverse infringement test is satisfied. Accordingly, the claim of the patent is not novel.
214 Each step of this argument involves controversy. Steps (1) and (2) involve the proper identification of the disclosure of the 341 patent, which is in issue between the parties. Step (3) equates the proper construction of the claim of the patent with Sanofi-Aventis's description of the conduct said to constitute infringement, an equation which Sanofi-Aventis disputes. Steps (5) and (6) assume the result (infringement of the claim) from the fact that the alleged anticipation and conduct said to constitute infringement of the claim are the same.
215 For present purposes (and contrary to Sanofi-Aventis's case), assume that the 341 patent discloses (in the sense of teaches) a method of treatment of PsA by the administration of leflunomide to a person suffering from that disease. Inherent in that teaching is the idea that the treatment will be effective in the sense that the administration of leflunomide will in fact treat the disease PsA. If this is so, the reverse infringement test cannot yield a positive answer unless performance in accordance with the teaching of the 341 patent must result in infringement of the claim of the patent. Such infringement must be "necessarily entailed" before a conclusion of infringement can be reached. Possible or even likely infringement is insufficient. Awareness of the fact of infringement is irrelevant; if following the teaching of the prior art inevitably results in the infringement of the claim of the patent, the latter cannot be novel (SmithKline Beecham at [22]-[23]). On this basis, the distinction Sanofi-Aventis sought to draw between product and method claims is beside the point. It is true that, taken literally, it is meaningless to speak of disclosure of a method that inevitably leads to production of the method. The relevant point for present purposes is that if performing the teaching of the 341 patent inevitably results in the use of the method claimed in the patent then it must follow, by reference to the relevant principles, that the method claimed in the patent is not novel.
216 On the assumption set out above about the 341 patent (namely, that it teaches a method of treatment of PsA by the administration of leflunomide to a person suffering from PsA), the inescapable conclusion on the evidence is that following that teaching would infringe the claim of the patent. The evidence establishes that: - (i) psoriasis is a diagnostic criterion of PsA, (ii) almost every person suffering from PsA either has or will develop psoriasis, and (iii) administering an effective amount of leflunomide to a person suffering from PsA will therefore prevent or treat psoriasis in that person in almost all cases. Otherwise put, if the teaching of the 341 patent is a method of treatment of PsA by the administration of leflunomide to a person suffering from PsA then the following of that teaching will inevitably result in the use of the method claimed in the patent (namely, preventing or treating the skin disease psoriasis by the administration of an effective amount of leflunomide). The fact that the evidence described the proportion of persons suffering from PsA who also have or will develop psoriasis as "almost all" rather than "all" is immaterial. The evidence is sufficient to reach the required certainty of infringement being the "inevitable result" of or "necessarily entailed" by the assumed alleged anticipation. Consistent with principle, on this analysis, it does not matter that no one would have been aware that the administration of leflunomide to a person with PsA would also prevent or treat psoriasis in that person. The skilled addressee's knowledge of the different aetiology of PsA and psoriasis is relevant to the substance of the disclosure of the 341 patent (which is presently being assumed for the purpose of this discussion), but not to the effect of the disclosure. This analysis also does not equate (impermissibly according to Sanofi-Aventis) the claimed invention with the conduct alleged to constitute infringement. From this analysis it becomes apparent that the real issue is identifying the alleged anticipation or, in other words, determining what it is that the 341 patent discloses. As such, in order to determine whether Apotex has made out its case on novelty, it is necessary to consider whether the 341 patent does in fact disclose a method of treatment of PsA by the administration of leflunomide to a person suffering from PsA.
217 Sanofi-Aventis's first argument against characterising the 341 patent as making such a disclosure is that, for reasons similar to those given in respect of the Bartlett article and the Rozman abstract, the skilled addressee would not read the 341 patent as directing, recommending or suggesting the administration of leflunomide for the treatment of any disease. The 341 patent refers to experiments with animal models. Professors Smith and Brooks agreed that the ability to extrapolate from animal models to human diseases is limited. Experiments with animal models can provide an indication that a treatment might work for a particular human disease but no more. Further investigations would always be required before any conclusions about the safety and efficacy of the relevant drug in the treatment of human diseases could be drawn. As Professor Brooks said, on reading the 341 patent, he would have concluded that "…this is a very interesting drug. We need to do a clinical trial. And, before that, we need to make sure that it is not going to kill anybody when they take it, first." According to Sanofi-Aventis (adopting the language of General Tire at 485-486), the evidence falls far short of establishing a clear and unmistakable direction, recommendation or suggestion to administer leflunomide as a method of treating any disease in humans; putting it another way, the "flag" planted by the 341 patent is distant from the "precise destination" marked out by the method claimed in the patent.
218 It may be acknowledged, as Apotex submitted, that the disclosure in the 341 patent need not persuade the skilled addressee to administer leflunomide to treat a particular disease before it can be said to teach such administration. This is the point made by the Full Court in Merck v Arrow Pharmaceuticals at [109]-[111] (referred to above) in the context of pharmaceutical patents and the need for clinical trials. The question remains whether the invention has "been before made known" (Hill v Evans at 301), the invention in the present case being the claimed method of preventing or treating the skin disease psoriasis in humans by administering an effective amount of leflunomide. With this in mind, I find persuasive Sanofi-Aventis's argument that the 341 patent - like the Bartlett article and the Rozman abstract - falls well short of teaching the administration of leflunomide for the treatment of any disease. The 341 patent identifies the compound leflunomide and records that by virtue of its pharmacological properties it can be used as an agent having a wide range of broadly described effects - as an "antirheumatic, antiphlogistic, antipyretic and analgesic agent, and for the treatment of multiple sclerosis." In context, the focus of the 341 patent is the pharmacological properties of leflunomide and its potential for use in a wide range of possible treatments. The experiments with animal models show that leflunomide differs advantageously in its pattern of action from other tested antiphlogistic agents in respect of the inhibition of immunopathological processes "on animal models which are also relevant to human illness." This is said to open up "the possibility of tackling, by medication, rheumatic illnesses in man by more nearly treating the cause…". In light of the terms of the specification, the treatment of any disease in humans is a possibility supported by the pharmacological properties of leflunomide and the results of the experiments with the animal models. On this basis, the evidence of Professors Smith and Brooks, as a whole, does not support construing the 341 patent, including claim 4, as in fact teaching the administration of leflunomide to treat any disease in humans.
219 Apotex's argument to the contrary, relying upon the proposition that the animal tests in the 341 patent provide better safety and efficacy data than that the patent in suit (in which, submitted Apotex, the human trial data is based on a trial involving RA), is not persuasive. The 341 patent, construed as a whole, discloses the possibility of treating diseases in humans by administration of leflunomide. The patent in suit discloses a method of treatment of the skin disease psoriasis by the administration of leflunomide. The specification of the patent in suit identifies that leflunomide is well tolerated by human beings with a better risk-benefit ratio than other immunosuppressive agents in terms of resistance to infections, kidney dysfunction, and laboratory values such as liver enzymes, blood count and body weight. Further, and as noted above, the inference that the human trial data in the patent in suit is based on a trial for RA is not one which I draw on the evidence. For these reasons Apotex's suggestion that, in terms of safety and efficacy in the treatment of human diseases, the 341 patent and patent in suit contain disclosures equal "for the purposes of practical utility" (Hill v Evans as cited above) is not convincing. The result is that the 341 patent does not deprive the patent in suit of novelty, as the assumption on the basis of which I would be prepared to find that the various tests for anticipation have been satisfied (as set out above) is not supported by the evidence.
220 If, contrary to this conclusion, the 341 patent does teach a method of treatment of a disease or diseases in humans by the administration of leflunomide, the next question is the identification of the relevant disease(s). Sanofi-Aventis's second argument is that the skilled addressee would not read the 341 patent as directing, recommending or suggesting the administration of leflunomide for the treatment of PsA.
221 The formula in claim 4 of the 341 patent is "inflammations, rheumatic complaints or multiple sclerosis". The focus of the evidence, as noted, was the phrase "rheumatic complaints" (and the equivalent general references to "rheumatic illnesses" in the specification). In short, Professor Smith read this as a reference to RA but not PsA. Professor Brooks read this as a reference to at least RA and PsA. Both relied on their view of the animal models to support their reading. The difficulty with the evidence about the animal models is twofold. Insofar as Professor Smith is concerned, he was adamant that none of the models was relevant to PsA. Moreover, nothing was put to Professor Smith to suggest that his opinion in this regard was incorrect. Insofar as Professor Brooks is concerned, he considered that the AA model was relevant to PsA - and that he would have considered it to be so at the priority date of both the 341 patent and the patent in suit - because he had used that model in his own research. However, he accepted that he was "ahead of the pack" (the "pack" being rheumatologists generally) and had particular knowledge of animal models when most rheumatologists knew little if anything about them. This evidence founded Sanofi-Aventis's submission that Professor Brooks was not the skilled addressee in the sense of the typical non-inventive skilled worker in the field. Professor Brooks, rather, was himself inventive and was bringing to bear his own experiments to support his conclusions. When all of this evidence is weighed I am satisfied it supports the inference for which Sanofi-Aventis contends: the skilled addressee would not have read the 341 patent as saying anything about PsA.
222 This conclusion is supported by other evidence relevant to the substance of what the 341 patent would have communicated to the skilled addressee. It is apparent that neither Professor Smith nor Professor Brooks read the references in the 341 patent to "rheumatic complaints" and "rheumatic illnesses" literally. If read literally then, as Professor Brooks said, the phrases would encompass all of the 150 or so types of arthritic disease. However, drawing upon the context presented by the animal models, Professor Brooks read the words as referring to the inflammatory rheumatic conditions (RA, PsA and the other seronegative arthropathies) whereas Professor Smith read them as referring to RA alone. The large number of potential diseases encompassed by the concept of "rheumatic complaints" and "rheumatic illnesses" speaks against a literal construction. Whatever is being disclosed by the 341 patent, it would not be understood by the skilled addressee as communicating a method of treatment of all types of rheumatic illness.
223 The choice which the evidence presents, accordingly, is between reading the 341 patent's reference to "rheumatic complaints" as meaning either all forms of inflammatory arthritis or RA alone (the most common form of inflammatory arthritis). To assist in the task of construction it is relevant to note that the 341 patent was published in 1980. It is not necessary to decide whether the relevant date for construction of the 341 patent is 1980 or the priority date of the patent in suit (March 1993) because, on the evidence, there is no material difference between those two dates. The relevant point is that the 341 patent nowhere mentions PsA or the seronegative arthropathies, but it does refer to "arthritis", "inflammation", and "rheumatic" illnesses and complaints. With this in mind a number of other key facts must be recalled. First, "arthritis" is a general term applying to numerous types of joint disorders. Second, rheumatologists distinguish between non-inflammatory and inflammatory arthropathies, with the latter term reserved for those forms of arthritis where inflammation of the joint tissues is the underlying cause of damage to the joints. Third, there are two types of inflammatory arthritis, rheumatoid arthritis and the seronegative arthropathies (PsA, ankylosing spondylitis, reactive arthritis and inflammatory bowel disease-associated arthritis). Fourth, RA is associated, amongst other things, with the presence of the positive rheumatoid factor in the blood. The seronegative forms of arthritis, by definition, are associated with a negative RF test. Fifth, and as Professors Smith and Brooks said, for a number of years after the priority date of the claim in the patent (March 1993) little was known about PsA. By March 1993 (and for some years thereafter) most research efforts had focussed on RA as the most common form of inflammatory (as opposed to non-inflammatory) arthritis. The aetiology of RA and PsA was thought to be different. RA was known to be T cell-mediated. PsA was not. The mechanisms underlying RA were known, but those underlying PsA were merely in the course of being investigated and understood. For example, the role of TNF α in RA was emerging but its similar role in PsA was unknown until the late 1990s. Moreover, RA was known to be by far the most common form of inflammatory arthritis (accounting for about 70% of cases of inflammatory arthritis). As Professor Brooks said, research was largely driven by the pharmaceutical industry and the principal focus was thus RA and not PsA.
224 These five considerations support the conclusion that the skilled addressee reading the 341 patent either in 1980 or at the priority date of the patent would have understood the 341 patent to concern the most common form of inflammatory arthritis, being RA, and multiple sclerosis (which is expressly mentioned), but not the seronegative arthropathies PsA, ankylosing spondylitis, reactive arthritis and inflammatory bowel disease-related arthritis. Hence, if (contrary to the conclusion above) the 341 patent discloses a method of treatment of diseases in humans, it does not disclose as a method of treatment of PsA by the administration of leflunomide. The administration of leflunomide to treat RA or multiple sclerosis, on the evidence, may or may not also treat psoriasis and thus, for the reasons given above, is not a disclosure sufficient to anticipate the invention claimed in the patent. Accordingly, on this basis the 341 patent cannot be said to deprive the patent of novelty.
225 Insofar as Apotex sought to rely upon Dr Shumack's evidence to support the contrary conclusion, three points need to be made. The first is that, for the reasons given above, I do not consider Dr Shumack (a dermatologist) to be the skilled addressee of the 341 patent (as at the priority date of either the 341 patent or the patent in suit). The second is that the parts of Dr Shumack's evidence on which Apotex relied (that is, that Dr Shumack would understand references in the 341 patent to rheumatic illnesses and the like as references to diseases that would be treated by a rheumatologist such as RA, seronegative arthritis, lupus and connective tissue diseases; that the assertions in the 341 patent are "fairly wide-ranging or far-reaching"; and that it sounds reasonable to a non-rheumatologist that animal models for RA might also work for PsA) did not involve consideration of the phrases to which Dr Shumack was taken in the context of the 341 patent as a whole. The third is that the evidence, when analysed, does not touch upon the first and third of Sanofi-Aventis's arguments.
226 Sanofi-Aventis's third argument was that even if, as a matter of proper construction through the eyes of the skilled addressee, the 341 patent teaches a method of treatment of "rheumatic complaints", and the term "rheumatic complaints" would have been understood to encompass or include PsA, the disclosure is too broad to deprive the claim of novelty. Sanofi-Aventis relied on the reasoning in ICI Chemicals, IGT v Aristocrat and EI Du Pont to support this argument. None of these cases provides an exact analogy to the present case. Nevertheless, on the evidence, the reference to "rheumatic complaints" in claim 4 of the 341 patent, if read literally, would include all 150 or so types of arthritic disease. So read, Sanofi-Aventis's case that the disclosure is too broad to undermine the novelty of the claim is persuasive. The question is then whether it is possible to identify a basis upon which the 341 patent can be read as dealing with not only RA but also with all the seronegative arthropathies, which include but are not limited to PsA. For the reasons given above, Professor Brooks' evidence in this regard is not that of the skilled addressee. Nothing else in the evidence supports reading "rheumatic complaints" as meaning all or even the two most common types of inflammatory arthritis (as opposed, for example, to all 150 or so types of arthritic disease). It follows that Sanofi-Aventis's argument - that if the 341 patent teaches a method of treating rheumatic complaints in humans (including, amongst 150 or so possible diseases, PsA) by the administration of leflunomide, the disclosure is too broad and lacks sufficient clarity to deprive the patent of novelty - is persuasive and should be accepted.
227 For these reasons, the three prior art documents on which Apotex relied do not have the effect of anticipating the patent and thereby depriving the claim of the patent of novelty.