1,340,794 / pemetrexed / ALIMTA
In this decision Barnes J held Takeda’s ‘794 patent (licensed by Lilly ) covering pemetrexed to be invalid for lack of sound prediction of utility. The most interesting legal point is that Barnes J rejected Rennie J’s view, expressed in Apotex / esomeprazole 2014 FC 638, that the heightened disclosure requirement for sound prediction applies only in new use cases.
The ‘794 patent relates to a class of compounds including pemetrexed, which, according to the patent “are useful as anti-tumor agents” . All the claims at issue are compound claims. Pemetrexed is not specifically claimed or disclosed, but it falls within Claims 7 and 9 , which claim a class of compounds. Only some compounds falling within those claims had been tested as of the filing date, and the key question was therefore whether “the person of skill in 1989 [the filing date] could have soundly predicted the promised utility of the untested compounds falling within Claims 7 and 9 from the test data reported in the Patent and from what was known in the art” . Whether pemetrexed itself was useful was not even discussed, and even if established would have been relevant, at most, as one more data point in a prediction of utility of the untested compounds.
The parties had the usual dispute over the promise of the patent, with Hospira arguing for an elevated promise and Lilly for a much lower one . Barnes J held that the promise was of “in vivo activity in relation to abnormal tissue” , which fell in between the position of the parties. The exact basis for his construction of the promise is not entirely clear. Barnes J found the opinions of the experts to be “largely unhelpful” , and he emphasized the statement in the patent that the invention relates to “which are useful as anti-tumor agents,” as well as mentioning similar references to “excellent” or “remarkable” antitumor effect , . This is consistent with the trend that any phrase stating that the compounds “are useful”, without a qualifier, will be taken as promise, but it is not clear from his brief discussion why Barnes J construed “anti-tumor agent” to mean in vivo activity (though he did note some expert evidence to that effect ). The passages in the patent describing “excellent” or “remarkable” effects that were evidently being referenced by Barnes J mixed specific references to in vitro effect with general statements regarding in vivo effect. So, the specification stated that the compounds “have toxicities highly specific to tumor cells and excellent antitumor effects” (p2),; they “show excellent antitumor effects in mouse tumor cell strains (. . .) and human tumor cell strains (...), decrease the tumors carried by warm-blooded animals . . . and prolong the life-span of tumor-carrying warm-blooded animals” (p25); they “are excellent in inhibition of cell growth of [specified cell lines], while they do not exert a toxicity against [specified cell line]. The compounds (I) of this invention and the salts thereof are of low toxicity, having remarkable antitumor effect. Therefore, the preparations containing the compound (I) or salts thereof can be employed as antitumor agents for the treatment of tumors in warm-blooded animals, particularly mammals. . . .” (p27). The examples of the effects disclosed in the patent all referred to cell lines.
While the references to treatment of tumours in mammals support the view that the patent promised in vivo activity, recall that in Plavix 2013 FCA 186 (here), the FCA encouraged a restrained approach to construction of the promise of the patent, requiring that a promise be explicit ,  and cautioned against ignoring “the distinction drawn in the jurisprudence between the potential use of an invention and an explicit promise to achieve a specific result is considered.” . In Plavix the FCA held that the statement in the ‘777 patent that “the medicine of the invention can be usefully administered in the treatment and prevention of platelet disorders due to extracorporeal blood circuits or the consequence of complications in atheroma,” relied on by the trial judge  as indicating an explicit promise of use in humans, was no more than an indication of the “potential use in humans” which was “foreshadowed” in the patent . It strikes me that it is at least arguable that the promise of the ‘794 patent could have been construed similarly, with the specific references to in vitro activity constituting the promise, and the more general references to in vivo treatment cell being foreshadowing of the potential use in humans. Barnes J’s construction of the promise in this case illustrates two points. First, while Plavix seemed to be a signal from the FCA that a more restrained approach should be taken to construing the promise of the patent, the reality seems to be that Plavix has had little effect; as I put it in the title of an earlier post, the “Promise of the Patent is Alive and Well Post-Plavix FCA.” The very brevity of Barnes J’s analysis of the promise emphasizes this point. Despite Plavix, he did not consider it necessary to explicitly consider the possibility that references to in vivo use were merely references to a potential use. The second point is the difficulty in predicting how the courts will construe the promise of the patent, in light of the variety of language touching on utility that is typically found in the disclosure. In this case, as noted above, the court considered that neither party’s submissions were even helpful.
In any event, in the end, Barnes J expressly rejected Lilly’s position that “any measurable in vitro antifolate activity would satisfy the promise of the Patent” , which he characterized as “effectively read[ing] the promise down to a ‘scintilla’ of utility” , so that Barnes J clearly held utility should be measured against a higher standard of utility than the scintilla that would be required in the absence of an express promise (though it is not clear that Lilly’s position really did amount to asserting a mere scintilla of utility as contrasted with a low promised utility).
On the main legal point of interest, recall that in Apotex / esomeprazole Rennie J, drawing in part of Gauthier J’s concurring remarks in Plavix 2013 FCA 186, held that the effect of the SCC’s obiter remarks in Viagra 2012 SCC 60 was to overturn previous FCA decisions, such as Raloxifene 2009 FCA 97 aff’g 2008 FC 142, which had held that there is a heightened disclosure requirement in all cases where utility is established by sound prediction, such that the factual basis for that prediction and the line of reasoning must be disclosed in the patent itself . On Rennie J's view, the heightened disclosure requirement is now “limited to the context of ‘new use’ patents, assuming such a utility disclosure requirement exists at all” . Barnes J disagreed, saying:
 While I have some sympathy for Justice Rennie's and Justice Gauthier's views, I am not persuaded that the state of the law on this issue has changed. In particular, it would take something more than Justice LeBel's apparent reservations [in Viagra] to displace the requirement for disclosure described by Justice Binnie in [AZT 2002 SCC 77] and, later, as clearly endorsed by the Federal Court of Appeal in [Raloxifene 2009 FCA 97], in [Olanzapine (No 1) 2010 FCA 197] and in many decisions of this Court.
Banres J therefore held that “where utility is based on a sound prediction, there remains an obligation to disclose in the patent specification the factual basis and a sound line of reasoning supporting the prediction”  I can’t agree with Barnes J’s suggestion that the cryptic comments of Binnie J in AZT established a requirement to set out the factual basis for a sound prediction in the patent itself, but the FCA decisions cited by Barnes J certainly did. And while Rennie J’s interpretation of AZT is very interesting in its own right, Barnes J makes a fair point in doubting whether the effect of Justice LeBel’s comments in Viagra was to overrule the FCA’s line of authority on this point. With both Rennie JA and Gauthier JA now on the FCA, this issue will no doubt be authoritatively decided at that level in due course.
Having accepted the established FCA case law, Barnes J held that Lilly could not rely on in house testing or a line of reasoning not found in the patent in order to establish a sound prediction of antitumour activity . He noted that Lilly’s expert “based his opinion of a sound prediction of utility substantially on data that was not disclosed in the Patent” , and also that the patent “provides no line of reasoning from which the person of skill could draw a prima facia reasonable inference that the thousands of untested claimed compounds would be useful as antitumor agents in vivo or even in vitro” , or that would allow an inference of in vivo activity to be extrapolated from the reported in vitro data . These “fundamental flaws in Lilly’s case”  would have sufficed to dispose of the case on the law as set out by Barnes J, but he nonetheless went on to address the evidence relied on by Lilly . After reviewing the evidence of Lilly’s main expert on utility, including evidence not found in the patent (eg ), he concluded that “I do not agree with Lilly that a person of skill would have made a prediction of utility for the thousands of untested compounds included in the asserted claims. This is equally the case if one accepts Lilly’s assertion of the promise of the subject claims as being merely some antifolate activity in some cell line in vitro”  (and see similarly ). This indicates that Barnes J would have reached the conclusion that the patent is invalid even if he assessed utility against the standard proposed by Lilly and in light of all the evidence presented by Lilly.