INVENTIVE STEP
8 Apotex formulated the relevant question (the so-called "Cripps question") for the present case in these terms:
Would the hypothetical addressee or team at the relevant date, possessed of the common general knowledge within the field at that time, which included the nature and use of other corticosteroids as an intra-nasal treatment of allergic rhinitis, directly be led as a matter of course to try mometasone furoate as an intra-nasal once-daily initial or maintenance treatment of allergic rhinitis, with the substantial absence of systemic levels of mometasone furoate in the bloodstream, in the expectation that it might well produce a useful result or a better alternative than existing intranasal corticosteroid treatments of allergic rhinitis?
9 As formulated this question avoids the effect of some of the disputed evidence. Professor Hogger, for example, says that the relevant field of discourse about the treatment of allergic rhinitis would not have been confined to corticosteroids. She thus takes issue with the starting point assumed by Dr Weiner on behalf of Apotex who was asked what he would have done if confronted with the problem of finding a corticosteroid therapeutically effective for the treatment of allergic rhinitis. Professor Hogger's evidence is that she would have considered not just corticosteroids but also leukotriene antagonists and antihistamines and possibly some other new therapy altogether. Further, certain factors at the priority date would have led her away from corticosteroids. Although known for topical use, the nasal passage is different from the skin and one could not extrapolate from the skin to the nose (a point made also by Dr Yan). There were also concerns about the long term use of corticosteroids and their use in children or pregnant women. According to Professor Hogger MF had also been reported at the time to have several metabolites and had very low solubility in water. Although Apotex noted that it is not apparent that Professor Hogger would have been aware of the metabolites at the time there is evidence (including from experts on which Apotex relied) of the type of literature searches that would have been carried out and which might reasonably be inferred to have disclosed the information to which Professor Hogger refers.
10 Professor Hogger's evidence indicates that there is a real issue between the parties as to the relevant starting point for the inquiry. It provides a rational basis for querying whether Apotex's evidence involves the correct starting point or not.
11 Apotex emphasised the evidence of Professor Archer that it was well known at the priority date that MF has low systemic bioavailability "either through topical absorption or oral ingestion. In practice, it was widely used and prescribed for inflammatory conditions and highly effective with very few adverse side effects". Apotex noted that if, as Professor Archer said, MF was safe for oral ingestion it was obvious that it would be safe for nasal inhalation. As Merck submitted, however, there are some difficulties with Professor Archer's reference to oral ingestion. Although these difficulties ultimately may be capable of resolution they are not able to be resolved in the present context. First, although Professor Archer refers to the oral ingestion of other corticosteroids he does not give examples of the oral ingestion of MF other than in the statement on which Apotex relies. Second, none of the literature to which Professor Archer refers (including the patent and certain documents relied on by Apotex as forming prior art) identifies oral ingestion of MF as opposed to topical application. Third, none of the other experts refer to oral ingestion of MF as opposed to topical application. These circumstances indicate that this statement of Professor Archer may not be capable of bearing the weight which Apotex sought to place upon it. The circumstances call into question the reliability of the statement or, at the least, demand explanation which is not presently available.
12 Taking into account these circumstances it is apparent that Merck's arguments to the effect that corticosteroids were not the obvious starting point for the treatment of allergic rhinitis at the priority date and that MF was not an obvious candidate for a once-daily dose for such treatment cannot be dismissed as specious or unconvincing. Nor is it apparent that Merck's experts require some degree of scientific certainty not justified by relevant principle. On the evidence Merck has real arguments to counter those of Apotex as to invalidity on the basis of common general knowledge in the art. There is evidence of other agents being relevant candidates for development, not just corticosteroids and not necessarily MF. There is evidence that the nasal passages are different from the skin and that low systemic bioavailability from topical application could not be assumed to mean low systemic bioavailability from nasal inhalation at the priority date. There is evidence that MF was known by at least some skilled in the art to have metabolites. There is evidence that because of its low solubility formulation of the nasal spray would not be anywhere near as straightforward as Dr Rowe suggests.
13 As a result I am not persuaded that Apotex has a strong case that as at the priority date, by reason of the common general knowledge, the notional research group would have been directly led as a matter of course to try MF as an intra-nasal once-daily treatment of allergic rhinitis with the substantial absence of systemic levels of MF in the bloodstream in the expectation that it might well produce a useful product or process. On analysis of the expert evidence there are certain matters assumed by the expert evidence adduced by Apotex which may be found questionable (the starting point for the exercise) and certain assertions (that of oral ingestion and the ease of formulation) which at the least require explanation. Accordingly, insofar as it is possible to weigh the competing evidence at this stage it is the evidence of Merck which appears to carry greater persuasive force.
14 The same conclusion applies to the question of the prior art. Apotex identified three key documents as ones which have been ascertained and understood by a person skilled before the priority date and which would have made the invention obvious in the sense of lacking any inventive step. The documents are United States Patent No 4,472,393 (the Shapiro patent), International Patent Application No PCT/US91/06249 (Yuen) and an article by Chang-Jin Wang et al "A Competitive Enzyme Immunoassay for the Direct Determination of Mometasone Furoate (SCH 32088) in Human Plasma (1992) 10 Journal of Pharmaceutical & Biomedical Analysis 473-479 (Wang).
15 There were issues between the parties as to whether the Shapiro patent and Yuen would have been ascertained by the hypothetical skilled addressees at the priority date and, if ascertained, understood in combination as Apotex contended. Let those matters be assumed in Apotex's favour. There was evidence from the experts upon whom Apotex relied that these publications would have led them as a matter of course to try MF as an intra-nasal once-daily treatment of allergic rhinitis with the substantial absence of systemic levels of MF in the bloodstream in the expectation that it might well produce a useful product or process. There was also evidence from the experts upon whom Merck relied to the contrary. Again, accordingly, it is necessary to examine the substance of the documents relied upon as prior art.
16 The Shapiro patent relates to novel compounds including MF useful for the treatment of inflammatory conditions. It refers to the compounds' high topical anti-inflammatory properties. It says the compounds may be applied topically or locally in any of the conventional pharmaceutical forms including topically in creams, lotions, aerosols or ointments in the treatment of all corticosteroid responsive dermatoses "or in the form of ophthalmic suspensions or nasal sprays". It says that the steroid may be formulated into a preparation suitable for topical application in a conventional manner and examples include "ointments, lotions, creams, sprays, drops…and aerosols". Yuen concerns the novel compound MF monohydrate and refers to MF as known to be useful in the treatment of inflammatory conditions. It refers to the pharmaceutical compositions of particular interest as "aqeous suspension compositions of [MF] monohydrate, eg for nasal inhalation". Wang refers to MF as a synthetic corticosteroid which has topical anti-inflammatory activity and is a "promising new candidate by oral and nasal inhalation for the treatment of asthma and allergic rhinitis".
17 Dr Yan makes the point that the Shapiro patent does not refer to the safety or efficacy of any of the compounds for the treatment of allergic rhinitis, Yuen does not include any information from clinical trials about the aqueous suspension or whether the nasal suspension is safe and efficacious, and Wang describes the development of an assay for measuring the content of MF in blood plasma and, while Wang states MF is a promising candidate for the treatment of allergic rhinitis, also identifies that its metabolism, pharmacokinetics and toxicokinetics have not been evaluated. Accordingly, none of these documents (if ascertained at all) would have directly led Dr Yan as a matter of course to try MF as an intra-nasal once-daily treatment of allergic rhinitis with the substantial absence of systemic levels of MF in the bloodstream in the expectation that it might well produce a useful product or process.
18 Apotex's arguments about the prior art are plainly not without substance. The references upon which Apotex relied provide a real foundation for the argument that the invention claimed lacked an inventive step. The countering evidence of Merck, however, also has persuasive force, at least on its face. That evidence, properly analysed, cannot be reduced to a position that nothing can be known without clinical trials. The evidence relates specifically to MF and the lack of clear direction in the documents in respect of the use of MF to treat allergic rhinitis without substantial side effects.
19 Accordingly, although I do not accept Merck's arguments that Apotex's case for invalidity is so weak that it fails to raise a triable issue, I am not satisfied that Apotex's case is of sufficient strength to deny the existence of a prima facie case of infringement on Merck's part. Merck has established a prima facie case of infringement. When dealing with the strength of that prima facie case in assessing the balance of convenience I recognise that Merck's position on infringement is not unassailable. There are real arguments against validity which, if established, would remove the foundation of Merck's claimed right to final and thus interlocutory relief.