Wednesday, April 22, 2020

An Active Ingredient Is a Medicinal Ingredient

Glaxosmithkline Biologicals S.A. v. Canada (Health) 2020 FC 397 Barnes J
            2,600,905 / SHINGRIX

I believe this is the first decision interpreting the provisions of the Patent Act relating to the Certificate of Supplementary Protection (CSP) (s 104ff), which came into force in Sept of 2017 in order to meet Canada’s commitment under Art 20.27 of CETA [18]. Section s 106(c) of the Act, in combination with s 3(2) of the CSP Regulations, provides that a CSP may be only be granted for a patent that “contains a claim for the medicinal ingredient or combination of all the medicinal ingredients contained in a drug.” GSK sought a CSP in respect of the 905 Patent and the drug SHINGRIX. Claim 1 of the 905 patent is to a composition consisting of a truncated antigen and an adjuvant. The Minister refused the CSP on the basis that (i) an adjuvant is not a medicinal ingredient; and (ii) a CSP may only be granted for a patent directed solely to a medicinal ingredient or ingredients.

Both the Minister’s decision and that of Barnes J focused on the first point. Barnes J held that a medicinal ingredient means a biologically active ingredient; he considered the Minister’s position, that a medicinal ingredient must have some independent biological activity, even if only to a negligible extent, to be unreasonable. Because Barnes J held that an adjuvant is a medicinal ingredient, and because the 095 patent was directed solely to the antigen and an adjuvant, it was unnecessary for Barnes J to consider whether a CSP may only be granted for a patent directed solely to a medicinal ingredient. This issue will surely be raised in future cases, and Barnes J’s remarks on the point, though very brief, are worth noting.

Barnes J’s decision makes it clear that the Minister’s position on the definition of “medicinal ingredient” was entirely divorced from the text of the Act and CSP Regulations (as well as being unsupported by purposive considerations). I will suggest that the same appears to be true in respect of the second issue. I get the distinct impression that the Minister’s policy was developed by people who thought they already knew what the Act said, and so didn’t bother to actually read it, either before or after developing the policy.

An adjuvant is an ingredient used in some vaccines to enhance the immune response. As WHO has noted in its Guidelines on Vaccine Adjuvants, some antigens used in vaccines “are weakly immunogenic and require the presence of adjuvants for the induction or enhancement of an adequate immune response.” In this case, the undisputed scientific evidence was that the adjuvant used in SHINGRIX “is biologically active and essential to its clinical efficacy” [7], and Barnes J remarked that the adjuvant was a “necessary ingredient” of the medicine [43]. This was not disputed by the Minister. In the Minister’s view, the fact that the adjuvant was essential to the clinical efficacy is irrelevant to whether it is a medicinal ingredient: “the determination of whether a drug component is a medicinal or non-medicinal ingredient is not made based on the biological activity” [9, answer 119], and “a vaccine adjuvant can never be a medicinal ingredient, whatever its biological activity may be and regardless of its significance in achieving a desired clinical response “ [32]. The Minister’s position was that an adjuvant in SHINGRIX is not a medicinal ingredient because it does not independently trigger an immune response: [30], [31.29]. Conversely, the truncated antigen in SHINGRIX is a medicinal ingredient because it can induce an immune response, even though that response might be “negligible” (decision under appeal, as quoted [5], p5 last paragraph).

The question then, was whether the Minister properly interpreted the Act and CSP Regulations as meaning that an ingredient is a “medicinal ingredient” only if it is capable of independently triggering some immune response, even if negligible and clinically ineffective on its own, and that an adjuvant is therefore not a medicinal ingredient even though it is essential to the clinical efficacy of the vaccine. Barnes J’s decision was to the effect that there was no support for the Minister’s position in the text of the Act, or its context, or its purpose. The decision is short enough that I might just say that I agree entirely with Barnes J’s analysis, and leave it at that; but since this is my first post on CSP issues, I can’t resist a deeper dive.

So far as the text goes, there are three links in Barnes J’s reasoning: (1) a “medicinal ingredient,” is the ingredient responsible for the drug’s desired effect in the body; (2) the desired effect is a clinically meaningful effect; (3) the adjuvant is essential to the clinical effect of vaccine in question. From this is follows that the adjuvant is a medicinal ingredient.

To elaborate, s 106(c) of the Act provides that a CSP may be only be granted for a patent that pertains to “a medicinal ingredient, or combination of medicinal ingredients,” and s 3(2) of the CSP Regs defines this to mean that the patent “contains a claim for the medicinal ingredient or combination of all the medicinal ingredients contained in a drug.” The term “medicinal ingredient” is not defined in either the Act or CSP Regs [26], but the same term appears in s 4(2)(b) of the PM(NOC) Regulations, in the listing eligibility provisions. “Medicinal ingredient” as used in that context had been judicially interpreted to mean “the substance in the formulation which, once administered, is responsible for the drug’s desired effect in the body”: Bayer Inc v Canada, 2009 FC 1171 [86-87] aff’d 2010 FCA 161, [2009] FCJ No 1471. This definition was taken directly from the RIAS accompanying the PM(NOC) Regulations, SOR/2006-241, which states at 1516 “The term ‘medicinal ingredient,’ in turn, refers to the substance in the formulation which, once administered, is responsible for the drug’s desired effect in the body.” The RIAS stated that the term was “intended to bear [its] established meaning under the extensive body of case law interpreting ‘a claim for the medicine itself.’” Thus, the PM(NOC) RIAS indicates that the term “medicinal ingredient” already had an “established meaning” at least by 2006; it must be presumed that the drafters of the CSP provisions of the Act were aware of that meaning. The Minister therefore properly conceded that this definition of medicinal ingredient was applicable [30].

Thus, it is clear that a medicinal ingredient is a substance responsible for the drug’s “desired effect.” Barnes J noted that “[p]resumably the desired effect in the body is a clinically meaningful effect and not a negligible immune response that the administration of the antigen alone would prompt” [38]. This must be right; the desired effect of a drug is that it cures, prevents or ameliorates a disease or disorder; sometimes a drug may not work, in the sense that it provokes a barely detectable physiological response, but that is certainly not what is desired, and a compound that never provokes any clinically meaningful effect is certainly not desirable.

The third link in the interpretive chain is that in this case, the antigen itself does not have a clinically meaningful effect when administered alone [38]. If the adjuvant is not a medicinal ingredient, then neither is the antigen, and that is absurd. Rather than saying that neither the antigen nor the adjuvant is a medicinal ingredient because neither is capable of independently producing a clinical effect, we must conclude that the antigen and the adjuvant are both medicinal ingredients because they are both necessary to produce a clinical effect. Thus the Minister’s position that the antigen was a medicinal ingredient, but the adjuvant was not, is not logically tenable given the definition of “medicinal ingredient’ that was properly accepted by the Minister as being correct.

A separate interpretive point, which is also compelling in its own right, is that the CSP provisions were enacted to meet Canada’s commitment under Art 20.27 of CETA [18], as the CSP RIAS expressly states in the first paragraph. As Barnes J noted, [27], s 3 of the CETA Implementation Act provides that any provision implementing CETA “ is to be interpreted in a manner consistent with the Agreement.” Art 20.27 CETA provides that each Party “shall” provide a period of sui generis protection in respect of a “product” that is protected by a basic patent in force, and “product means the active ingredient or combination of active ingredients of a pharmaceutical product” [21]. It follows that “medicinal ingredient” must be interpreted as including an “active” ingredient [34-35]. As noted, it was undisputed that the adjuvant at issue is biologically active.

Turning from textual to purposive considerations, as noted above some antigens used in vaccines are weakly immunogenic on their own and require an adjuvant to be clinically effective. Barnes J point out that “If the Minister’s position were to be applied uniformly, any new and useful vaccine that requires an adjuvant to be effective would be excluded for supplementary protection,” and “Inasmuch as many useful vaccines are adjuvanted and patented as such, this would exclude CSP protection for many novel vaccines” [39]. (Vaccines requiring an adjuvant are presumably patented as such in order to satisfy the utility requirement.) Barnes J remarked, with considerable restraint, that “It is at least doubtful that such a result was intended by CETA” [39]. I might add that such an interpretation would certainly be absurd, in the technical statutory interpretation sense; in the current situation, “grotesque” and “bizarre” might be more to the point.

I must say that the Minister’s interpretation strikes me as so completely far-fetched that I have considerable difficulty understanding what motivated the Minister to take that position. The decision under review suggests an answer. It states at the very outset:

The single medicinal ingredient approved in SHINGRIX is Varicella Zoster Vials (VZV) g1ycoprotein E (gE).
The Notice of Compliance (NOC) for Submission No. 200244 dated October 13, 2017 lists “Varicella Zoster Virus (VZV) glycoprotein E (gE)” as the single medicinal ingredient for the drug SHINGRIX.
The submission application form (HC-SC 3011) for Submission No. 200244 lists under item 56 gE antigen as the single medicinal ingredient.
The Product Monograph (“PM”) for SHINGRIX on page 3 in the table labeled “Summary Product Information” lists “Varicella Zoster Virus (VZV) glycoprotein E (gE)” as the single medicinal ingredient under the heading “Dosage Form / Strength per 0.5 mL dose.”

This seems to be saying that the adjuvant is not a medicinal ingredient because it is not listed on the NOC for SHINGRIX. The basic logic is to the effect that if the antigen was the medicinal ingredient for the purposes of the NOC and PM, it must be the medicinal ingredient for the purposes of the CSP as well. But as Barnes J noted, “[t]he fact that the Minister obtains some degree of administrative efficiency by treating vaccine adjuvants as though they are excipients for licensing purposes does not dictate or inform the legal obligations that pertain to extending patent-like protection for an already approved drug” [36].

Moreover, neither the Minister’s decision nor any of the guidance documents provide any statutory basis for such a position. On my own reading of the provisions, I can see only the barest glimmer of a textual argument supporting the Minister’s position. Section 106(c) of Act provides that a CSP may be issued for a medicinal ingredient or ingredients “contained in a drug for which an authorization for sale of the prescribed kind was issued.” This is a limitation on eligibility which is distinct from the requirement that the patent be for a medicinal ingredient. This passage might conceivably have been the background basis for the view that a CSP can only be issued for a patent claiming solely to the medicinal ingredient or ingredients listed on the NOC. (That’s speculation on my part; as noted, there is no suggestion to that effect in the guidance documents). But such an interpretation strikes me as clearly wrong. The point of this limitation is evidently that a CSP cannot be issued for a drug that is not approved for use in Canada; that is consistent with Art 20.27.2.a of CETA which provides that sui generis protection shall be provided on the condition that marketing authorisation has been granted.

Given that the adjuvant was an active ingredient and therefore a medicinal ingredient, Barnes J set aside the Minister’s decision refusing to issue the CSP and ordered a redetermination.

While this conclusion was sufficient to dispose of the application, another issue is raised, though it received less attention. As mentioned at the outset, even if an adjuvant was not a medicinal ingredient, the Minister’s decision to refuse the CSP would only be justified if a CSP may only be granted for a patent directed solely to a medicinal ingredient or ingredients. Barnes J noted that some kind of eligibility limitation might make some sense to prevent forms of evergreening, particularly with respect to minor variations that do not affect the performance of the drug [44]. Such a limitation would be permitted by CETA. Art 20.27 of CETA, which provides that sui generic protection “shall” be granted in respect of a product that is protected by (reading the definitions together) a patent that protects “the active ingredient or combination of active ingredients . . . as such.” The phrase “as such” evidently means that it is not necessary to provide sui generic protection for any patent that would be infringed by a medicine containing the specified active ingredient. Beyond that, it is not entirely clear what “as such” means. No doubt there is some body of preparatory documents that might shed light on this question. But it is not necessary to address that now. CETA does not on its face prohibit a party from providing sui generic protection to a broader range of patents. So even if Canada is permitted to restrict the patents eligible for a CSP to those directly solely to a medicinal ingredient or ingredients, did Parliament actually do so?

As Barnes J noted:

[44] There is also nothing in the CSP provisions of the Patent Act or in the CSP Regulations that expressly excludes from eligibility patent claims directed to a formulation. The applicable provisions only require that the patent contain a claim for the medicinal ingredient included in a drug authorized for sale under a Notice of Compliance. It is only in the RIAS that the formulation exclusion appears and there the example given concerns a claim for an improvement to the stability of a known medicinal ingredient.

S 106(1)(c) of the Act provides that a patent is eligible if it “pertains in the prescribed manner to a medicinal ingredient, or combination of medicinal ingredients, contained in a drug.” That language is clearly not limiting. Section 3(2)(a) of the CSP Regs defines “pertains” to mean “the patent contains a claim for the medicinal ingredient or combination of all the medicinal ingredients contained in a drug.” There is no evident textual limitation here, unless the word “for” is made to do a great deal of work.

The passage from the CSP RIAS that was the primary basis for the view that claims must be directly solely to medicinal ingredients states as follows [25]:

Also, claims that are directed to a formulation containing the medicinal ingredient, including compositions, preparations or similar claim types, do not make a patent eligible for a CSP. A claim to a formulation does not protect the medicinal ingredient or combination of medicinal ingredients per se. A claim to a formulation may be directed, for example, to the improvement of the stability of medicinal ingredients. This is consistent with CETA, which only requires the protection of the medicinal ingredient or combination of medicinal ingredients when claimed “as such.”

The first sentence only says that formulation patents are not necessarily eligible; it does not say that a formulation patent is defined as meaning any patent directed to anything more than the medicinal ingredient alone. As Barnes J noted at [44], the only example given in the RIAS is an improvement directed to extended shelf life. It is not possible to extrapolate from that to a general prohibition on any patent claiming more than the medicinal ingredient as such.

Moreover, the view that CSPs are restricted to patents claiming solely medicinal ingredients strikes me as problematic from a purposive construction. For example, new use patents are eligible for a CSP under Reg 3(2)(c), but most use claims are for the use of the drug in combination with a pharmaceutically acceptable carrier, presumably to satisfy the utility requirement: see eg the key claim 22 of the 277 patent to the use of AZT to treat HIV/AIDS. It would seem wrong to exclude all such claims because they are directed to an excipient in addition to the medicinal ingredient. And indeed, the Guidance document does not say this, as it refers only to “formulations.” But the logic of the Guidelines, and its interpretation of the words “as such” implies the same result. And I don’t see how to distinguish 3(2)(a) from (c), in this respect — that is far more work that the word “for” can be made to bear.

Overall, I have considerable difficulty seeing anything in the text, context, or purpose, to support the Minister’s view that a patent is eligible only if it claims solely the medicinal ingredient or ingredients. With that said, the point does not appear to have been the focus of the argument in this case, and it was not fully explored by Barnes J, given his conclusion on the meaning of “medicinal ingredient.”

Finally, I’ll turn to the standard of review. I long ago gave up trying to keep abreast of developments in admin law, as the SCC jurisprudence in the area is both impenetrable and constantly changing; it is consistent only in its incoherence. I’ve heard it said that Vavilov 2019 SCC 65, marks a step forward, but I must say that’s not apparent to me. In this case, it was uncontroversial that the presumptive standard of reasonableness applies to the issues of statutory interpretation that were before the Minister [11]; there was no suggestion that this was a case in which the presumption of reasonableness was rebutted. (GSK made a very strained argument that the issue was really one of claims construction, but this was easily rejected by Barnes J [12]). However, Barnes J at [15] quoted passages from Vavilov stating that the administrative decision maker must interpret the statute in accordance with accepted principles of statutory interpretation: “in a manner consistent with the text, context and purpose” [Vavilov 121]. Moreover, the administrative decision maker “cannot adopt an interpretation it knows to be inferior — albeit plausible — merely because the interpretation in question appears to be available and is expedient” [Vavilov 121]: see also Vavilov [108], [110] stating that administrative decision makers are not “permitted to disregard or rewrite the law as enacted by Parliament” and “It will, of course, be impossible for an administrative decision maker to justify a decision that strays beyond the limits set by the statutory language it is interpreting” (both noted by Barnes J at [15]). This is particularly important in this case, because, as noted above, the CSP Regulations were clearly intended to implement the corresponding CETA provisions, as the RIAS explicitly states, and, as noted by Barnes J [27], the CETA Implementation Act at s 3 provides that any provision implementing CETA “is to be interpreted in a manner consistent with the Agreement.” (**Perhaps the concern being addressed by this provision is that the government might enter into CETA and then seek to subtly resile from its requirements by political pressure on administrative decision makers who are employees of the government.) While the standard is nominally “reasonableness,” given all these constraints — sound though they are — this all strikes me as a kind of “reasonableness minus” standard for reviewing questions of law. Not that I see anything wrong with that; frankly, I have never understood what was wrong with applying the Housen standard of correctness — on matters of law / palpable and overriding error on matters of fact — to administrative decision makers; but no doubt I’m just a legal dinosaur. In any event, it seems to me that the Minister’s interpretation in this case was so clearly wrong that it would not have been upheld even on the most deferential standard of review that we have seen over the past decades.

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