Wednesday, September 27, 2017

"The Ability to Inhibit a Biological Target Implicated in Disease" Establishes Utility

Bristol-Myers Squibb Canada Co v Apotex Inc 2017 FCA 190 [Dasatinib FCA] Gleason JA: Webb, Near JJA var’g 2017 FC 296 [Dasatinib FC] Manson J
            2,366,932 / 2,519,898 / dasatinib / SPRYCEL / NOC
            FC double patenting / FC promise

Dasatinib FCA is the first decision of the FCA on utility following the SCC’s Esomeprazole 2017 SCC 36 decision, which “abolished the promise doctrine” [35]. The FCA’s holdings flow straightforwardly from Esomeprazole. This is not surprising, since the scintilla requirement, which is now the only remaining branch of the utility requirement, is of long standing, so it is unnecessary to create new law in the aftermath of Esomeprazole. With that said, pharmaceutical patent litigation only really took off in Canada after compulsory licensing was abolished in 1993, and the promise doctrine has been the primary battleground in utility attacks for much of the period since, so there is little case law on what exactly constitutes a “scintilla” of utility in the pharmaceutical context. The FCA’s statement that “Establishing that a compound has the ability to inhibit a biological target implicated in disease is doubtlessly a useful discovery” [40], is important guidance on this issue.

Both patents at issue relate to dasatinib, which is used to treat chronic myelogenous leukemia (CML). The claim at issue from the ‘932 patent is to the compound dasatinib as such [22]. Dasatinib FC was decided prior to Esomeprazole, and, applying the promise doctrine, Manson J held that the patent promised, inter alia, that dasatinib would be therapeutically useful [31], and that was the standard against which utility was to be assessed. As discussed here, it was undisputed that therapeutic efficacy was not demonstrated or soundly predicted as of the claim date, and the holding that the ‘932 patent lacked utility followed directly [34]. (The ‘898 patent was also held invalid for different reasons, but this was a rare NOC proceeding which was not moot on appeal because the Minister has not yet issued the NOC to Apotex [6]. I’ll discuss the issues raised by ‘898 patent in a subsequent post.)

With the promise doctrine abolished, Manson J’s holding on this point could not stand [8]. The main issue on appeal was therefore whether the claimed invention was useful in light of Esomeprazole.

The SCC in Esomeprazole summarized the correct approach as follows [35]:

[54] First, courts must identify the subject-matter of the invention as claimed in the patent. Second, courts must ask whether that subject-matter is useful — is it capable of a practical purpose (i.e. an actual result)?

[55] The Act does not prescribe the degree or quantum of usefulness required, or that every potential use be realized — a scintilla of utility will do. A single use related to the nature of the subject-matter is sufficient, and the utility must be established by either demonstration or sound prediction as of the filing date (AZT, at para. 56).

On the first point, the FCA held that

[37] [C]ontrary to what Apotex asserts in its supplemental written submissions, the subject-matter of claim 27 of the 932 patent is not the potential therapeutic uses for dasatinib. Rather, the subject-matter of claim 27 is merely the compound, dasatinib, itself. This is all that claim 27 claims, and it is erroneous to expand the subject-matter of the claim beyond what it says.

This is a straightforward reading of Esomeprazole: it is “the invention as claimed” that must be useful, just as it is the claimed invention which must be new and non-obvious. A contrary holding would have re-established the promise doctrine through the back door, by making properties – those disclosed or promised in the disclosure, no doubt – the measure of utility.

At the second stage, the question is whether dasatinib had “at least a scintilla of utility” as of the filing date. But how much is a scintilla? It is a low bar, as the word indicates, but it is more than zero.

On the facts, it was conceded that BMS had established that dasatinib acted in vitro to inhibit a certain class of cellular enzymes, specifically “Src-family PTKs” [39]. It was also known that abnormal activity of PTKs was linked to a variety of diseases, including CML [Dasatinib FC 200]. Apotex argued that this was not enough to establish the requisite scintilla of utility. The FCA disagreed (my emphasis):

[40] Establishing that a compound has the ability to inhibit a biological target implicated in disease is doubtlessly a useful discovery. Here, it was known as of the relevant date that enhanced activity of PTK was involved in many diseases, as stated in the specification and confirmed in the evidence of several of the experts. Thus, discovery of a substance that acted to inhibit certain PTKs represented an important advance and certainly meets the minimal utility requirements that are now applicable following the decision of the Supreme Court in Esomeprazole.

While it is well-established that a “scintilla” of utility is the minimum that is required, the underlined sentence provides important guidance as to what exactly this means in the context of pharmaceuticals. The FCA remarked “parenthetically” that “a similar sort of discovery was found to satisfy the utility requirement in Esomeprazole and Teva Canada Limited v. Novartis AG, 2013 FC 141 [imatinib].” I’m not sure Esomeprazole is helpful. Esomeprazole is the (-) enantiomer of omeprazole, and omeprazole was known to be therapeutically effective in the treatment of gastric acid-related diseases. Moreover, it was known that the active inhibitory agent was an achiral metabolite of omeprazole, so from that it could be very confidently predicted that esomeprazole, which would be transformed into the very same metabolite, would be therapeutically effective: see Esomeprazole FC 2014 FC 638, [165]; and see here. Thus, in Esomeprazole therapeutic utility itself could be soundly predicted, which was not the case for dasatinib. Imatinib, on the other hand, is indeed a close parallel, in my view: see here. I’ll also note that in Moxifloxacin 2014 FC 462 Phelan J held that “good in vitro activity” was sufficient to establish utility. There are also a few other cases with statements indicating a similar standard, those most are strictly distinguishable one way or the other. On the other hand, I am not aware of any cases at all indicating that a “scintilla” of utility is higher. Thus, in my view the FCA’s statement is consistent with the prior cases. But because the promise doctrine has so dominated the law of utility since pharmaceutical litigation took off with the abolition of compulsory licensing, there is remarkably little case law directly on this point. The FCA’s guidance is therefore particularly welcome.

While the FCA did not mention it, this holding is also consistent with the decision of the UKSC in HGS v Lilly [2011] UKSC 51, in which the UK Supreme Court held that the requirement of industrial applicability, the European equivalent of utility, was satisfied when the claimed compound was a member of a family of compounds which were known to have a role in immune and inflammatory responses: see here; and Siebrasse, HGS v Lilly: How Soon Is Too Soon to Patent? (2011) 24 IPJ 41-52. HGS v Lilly is of course not binding on Canadian courts, but as Lord Neuberger discussed [96]-[102], international consistency is very desirable. While patent law is national, the patent incentive is international. Patentees rely on expected profits from multiple jurisdictions when deciding whether it is worthwhile pursuing a particular avenue of research, and an inventor should not have to give up her patent in one jurisdiction to get it in another. Seeking consistency with other jurisdictions, to the extent that our law and sound policy permits, is an important policy consideration. In large part for that reason the UKSC followed the lead of the EPO in setting the standard for industrial applicability. Having taken a step towards harmonization with the rejection of the promise doctrine in Esomeprazole, it is welcome to see that we are not departing from it in the definition of a “scintilla” of utility.

The exact threshold will likely be further refined in subsequent cases. The FCA’s statement that “the ability to inhibit a biological target implicated in disease” establishes utility, has to be read in context. As I understand it, and as indicated by the FCA [40], the link between enhanced activity of PTK and disease was well established: see Dasatinib FC [200]. There is room to argue that proven in vitro activity against target does not establish utility if the target itself is not as firmly “implicated” in disease. On other hand, the utility accepted in HGS v Lilly was arguably a lower standard, the compound was a member of a family known to have a role in immune and inflammatory responses, but the connection between the compound and a specific disease was perhaps not as clear as in this case. There is also room to argue in that direction, as the reasons in Dasatinib FCA are clear on their face that “the ability to inhibit a biological target implicated in disease” is not necessarily the minimum required by the “scintilla”. Rather it is “ doubtlessly a useful discovery” and “certainly” sufficient to meet the standard. While not the final word on the subject, the guidepost established by the Court in Dasatinib FCA is both very helpful, and planted in the right spot.

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