Patentable Subject-Matter and Combinations

Apotex Inc v Janssen Inc 2021 FCA 45 Locke JA: Webb, Boivin JJA affg Janssen Inc v Apotex Inc 2019 FC 1355 Phelan J

            2,661,422 / abiraterone acetate & prednisone / ZYTIGA / old NOC

In this decision Locke JA for the FCA has affirmed Phelan Js decision under the old NOC regulations that Janssen’s 422 patent, to a combination of abiraterone acetate and prednisone for the treatment of a prostate cancer, to be valid and infringed by Apotex’s APO-ABIRATERONE product: see here and here for discussion of Phelan J’s decision. Locke JA's decision on appeal is relatively brief, but there are important developments in respect of demonstrated utility, a significant clarification of the obvious-to-try analysis, as well as observations on patentable subject-matter as it relates to combinations.

In this post I’ll outline the facts and discuss patentable subject-matter: the key point is simply that there is an open question as to whether a synergistic effect is required for a combination to constitute patentable subject-matter.

The technology is complicated [6], and I’m not sure the facts outlined below are entirely accurate, but I believe it is good enough to understand the issues. 

Facts

The invention relates to a treatment for prostate cancer, in particular a combination of abiraterone acetate and prednisone. Testosterone, produced primarily in the testes, was known to promote the growth of cancer cells. The primary treatment for prostate cancer was therefore suppression of androgens, specifically testosterone, in the testes. [7] However, testosterone is also produced in the adrenal gland, and patients will often see a resumption in the progress of their cancer even after testicular androgen production is suppressed. This is known as castration resistant prostate cancer (CRPC) [7].

It was known that CRPC could be treated by suppressing residual androgen production in the adrenal gland using adrenal androgen inhibitors, such as ketoconazole (KC) and aminoglutethimide (AG) [8]. However, the adrenal gland also produces other hormones, such as glucocorticoids, and suppression of androgen production in the adrenal gland could cause serious side effects due to suppressed glucocorticoid production [8]. Consequently, glucocorticoid replacement therapy, by co-administration of a glucocorticoid, such as prednisone and dexamethasone, was known to be desirable to minimize the side effects [9].

Abiraterone acetate (AA) was a known adrenal androgen inhibitor, though it seems to have been relatively new at the relevant time. It was known to have a different mechanicism of action from KC and AG, and consequently was not expected to require glucocorticoid replacement therapy [10]. The 422 patent claimed the combination of AA and prednisone for the treatment of prostate cancer [FC 38]. Apotex is seeking to market AA, but the product monograph will instruct that it be used in combination with prednisone, so inducing infringement [55]–[58] if the claims are valid.

On validity, Apotex argued (inter alia) that administering prednisone with an adrenal androgen inhibitor was known to be desirable, AA was an adrenal androgen inhibitor, and so it would be obvious to administer prednisone in combination with AA. Phelan J rejected this on the basis that AA’s different mechanism of action meant that it was not obvious that AA would have side effects that would require glucocorticoid replacement therapy with prednisone [FC 197]. This is even though, as it turns out, AA does have side effects, and glucocorticoid replacement therapy is required, and that is in fact why prednisone is administered in combination with AA in clinical practice today [5].

Even so, just throwing in prednisone along with AA would not constitute invention. Janssen argued that the combination was inventive because the inventors had discovered that, surprisingly, prednisone was useful in combination with AA because of synergistic anti-cancer effects, and not merely to treat side effects. Phelan J found that even though prednisone is in fact co-administered primarily to treat the side effects, there is a scintilla of synergistic effect [221].

As I noted in my post on Phelan J’s decision, “The result is that Janssen is able to prevent Apotex from marketing abiraterone in combination with prednisone to control side effects, on the basis of a mostly wrong ‘discovery’ that prednisone acts synergistically with abiraterone.”

Patentable Subject Matter

As discussed here, at first instance Phelan J indicated that in the case of a combination invention there is a requirement for a synergistic effect as a matter of “patentable subject matter” [132]. In my post I had suggested that any requirement for synergy in a combination should be addressed as a matter of obviousness, and not by a distinct requirement of patentable subject matter. Janssen made a similar argument in the FCA [21]. Locke JA remarked that the argument “is an interesting one,” but “this is not the case to decide the issue,” as Phelan J had accepted that there was a synergistic effect, and the point would not affect the outcome [22]. This is very welcome, as it shows that there is a live issue as to whether there is a separate subject-matter requirement in respect of combination inventions. The point can therefore be addressed in a suitable case without assuming that the law is settled.

While that’s all that can be drawn from this decision, I can’t resist the urge to elaborate on the issue. As I understand it, when patentable subject matter arises as a separate requirement, it means that the claimed subject-matter is of a nature that it cannot be patented, even if it is new, useful, non-obvious and fully disclosed. That was the case, for example in Harvard Mouse 2002 SCC 76, where a claim to an a “transgenic mouse” was held to be unpatentable, even if it was new, useful, inventive and fully disclosed. Similarly, it is substantively controversial whether methods of medical treatment—such as a claim of the form “use of compound X in range from A to B to treat disorder Y”—are patentable subject-matter, but the debate itself turns on the same concept of patentable subject-matter as Harvard Mouse; whether claims to subject-matter of that nature are unpatentable, even if the claimed subject-matter is new, useful and non-obvious.

I have difficulty seeing that kind of issue here. I think it is clear that a combination of the type claimed in this case may be patented. For example, suppose the cause of castration resistant prostate cancer was entirely unknown, and in a scientific breakthrough the inventors had discovered that the source was adrenal androgen production; they realized that AA could inhibit that production, and they also did enough testing to discover the side-effects, and realized that adding prednisone would relieve those side effects. On those facts, the combination of AA and prednisone would be new, useful and inventive, and I think it is uncontroversial a claim of exactly the same form as was at issue in this case would be patentable subject-matter. If that is right, then the objection on the facts in this case is not based on the same type of subject-matter objection that was addressed in Harvard Mouse. Another type of subject-matter objection is the rule against abstract claims, set out in s 27(8); but the claims in this case are clearly not abstract. So if there is actually a subject-matter objection here somewhere, it is of an entirely new type. As suggested in my previous post, rather than making up a new kind of subject-matter objection, the better way to proceed is treat the matter as a question of obviousness.

Locke JA also remarked that “An aggregation is problematic because it does not provide more than was already available to the public,” and in this case “there is no dispute that the combination in issue provides improved results over what was previously known” [23]. This seems right to me on the facts of the case, but I would suggest that the question should be simply whether the combination was obvious; this implies that while improved results are relevant — a combination that gives exactly the same results as the individual components is unlikely to be inventive—but it is not necessarily determinative. It may be obvious that the combination will give improved results, as when an adjuvant is used in combination with a vaccine, but that does not mean that the combination of a well-known adjuvant with an existing vaccine is inventive. Alternatively, it may be obvious to use the combination for other reasons, and the improved results is a “golden bonus” that does not transform the obvious into the non-obvious. In either of these scenarios, the claimed invention might be obvious even though it gives improved results.

On appeal, Apotex argued that in the case of a combination invention, the comparison should not be with the results of either drug alone, but with “the sum of the two component drugs” [19]. I’m not sure I understand this argument, which was set out only briefly, and in any event Locke JA rejected it [22]–[23].