Wednesday, August 10, 2022

Skinny Label and Swiss Claims

Janssen Inc v Apotex Inc 2022 FC 996 (reasons) 2022 FC 995 (judgment) Pallotta J

            2,659,770 / macitentan / OPSUMIT / NOC

There are three known biological pathways affecting pulmonary blood pressure, namely the prostacyclin, nitric oxide, and endothelin pathways. PDE5 inhibitors, such as tadalafil, work through the nitric oxide pathway. Macitentan is an endothelin receptor antagonist (ERA), which, as the name suggests, works through the endothelin pathway. The 770 patent relates to the use of combination therapy consisting of macitentan and a PDE5 inhibitor (PDE5-I) to treat diseases involving vasoconstriction, particularly pulmonary arterial hypertension (PAH). Most PAH patients are treated with combination therapy, but a non-trivial number of patients — around 20% — are treated with macitentan monotherapy [162]. Janssen markets OPSUMIT, a 10 mg tablet, for use alone or in combination therapy. Apotex sought to market a 10mg tablet of macitentan, which is not itself patented, and in this NOC action, Pallotta J held that Apotex’s macitentan product would infringe Janssen’s 770 patent. Validity was not at issue [9]. The 770 patent was also at issue in Janssen v Sandoz 2022 FC 715, in which infringement was conceded and validity was at issue: see here.

This is in many ways a typical ‘skinny label’ case, in which a generic seeks to sell a drug that is itself unpatented, but which may be used in a manner that is patented, eg as part of a patented combination, or for a patented indication. The generic in such cases is not normally a direct infringer, so infringement by inducement must be established under the three-part Corlac test, 2011 FCA 228 [162]. This typically reduces to the question of whether the generic’s product monograph (PM) will induce infringement by prescribing physicians, who will read the monograph and thereby be induced to prescribe the generic product for use in an infringing manner. A central question is therefore whether the generic’s skinny label has been sufficiently scrubbed clean of any reference to the infringing use. This inquiry turns on the details of the PM. Sometimes the generic wins, sometimes it loses—as in this case. The generic will also sometimes argue that even if its PM does instruct an infringing use, that doesn’t constitute infringement because the prescribers don’t pay any attention to the generic PM in any event. Whether prescribers heed the generic PM is a fact-specific inquiry, but so far as I know, no generic has ever prevailed on this argument. (Please leave a comment with a case cite if I am wrong about that.) Apotex made that argument in this case, and, unsurprisingly, lost. The result was that Apotex was enjoined from marketing Apo-macitentan until after the expiry of the 770 patent. While the case was typical in broad outlines, there are a few issues of interest in this decision, particularly on the construction of Swiss-type claims.

Three types of claims were at issue in this case [86]:

Product for use

Claims 1–5 eg “A product containing [macitentan] . . . in combination with [a PDE5-I] . . . for therapeutic use. . . in the treatment of [PAH].”

Use for treatment — sometimes referred to as German-style claims

Claims 21–31 eg “A use of [macitentan] in combination with [a PDE5-I] for treating [PAH].”

Use in manufacture of a medicament for — commonly called Swiss-form claims

Claims 10–20 eg “A use of [macitentan] in combination with [a PDE5-I] . . . for the manufacture of a medicament intended to treat [PAH].

A variety of claim types are employed because many jurisdictions have some kind of prohibition on patenting of methods of medical treatment, and consequently a variety of claim forms are used in claiming the use of a compound to treat a disease. A fourth type of claim that is often used in the US is straightforward: “A method of treating disease Y, comprising administering compound X.” This type of claim is not allowed in Canada as it is considered to fall afoul of the prohibition on patenting methods of medical treatment.

A preliminary issue was as to the construction of “combination,” which Pallotta J construed as including any scenario in which macitentan and the PDE5-I work in concert to treat the disease in question. In particular, it does not matter whether the macitentan and PDE5-I are combined in the same dosage form [120]; and it includes a scenario in which the patient is started on macitentan monotherapy and then moved to a combination therapy of macitentan and PDE5-I [116].

The most interesting claim construction issue concerned the interpretation of the Swiss-type claims. Swiss claims were originally developed to avoid the European prohibition on patenting of methods of medical treatment. Since a Swiss claim is, on its face, a claim to the product, not its use, and the physician who prescribes a drug does not manufacture it, physicians are excluded from the scope of infringement. However, in Hoffmann-La Roche v Sandoz 2021 FC 384, [95]–[109], Manson J held that the Swiss claims should be construed as use claims on the basis of a purposive interpretation; in effect, the idea is that what was really discovered was a new use, not a new method of manufacture, and the claim should be construed in light of what was actually discovered [97]. The result was that the generic, Sandoz, could not be liable as a direct infringer. As discussed here, this is a bit of a strange result, because it means that prescribers are direct infringers and the manufacturer is not, even though the original purpose of Swiss claims was to ensure that the manufacturer a direct infringer and the prescriber is not an infringer at all.

In this case, Apotex, relying on Hoffmann-La Roche, argued that the Swiss claims should be construed as use claims, so that Apotex could only be liable, if at all, on the basis of inducement. Pallotta J did not accept this argument. While a purposive construction may consider the nature of the inventive concept, “a purposive construction focuses on the language of the claims,” and “[t]he words chosen by the patentee necessarily play a key role” [128]. The importance of the text is consistent with the general law of statutory interpretation: Canada Trustco 2005 SCC 54 [10]; Canada v Utah 2020 FCA 224 [9]; Biolyse v Bristol-Myers Squibb 2003 FCA 180 [13]. It is also well-established as a principle of claim construction: Free World 2000 SCC 66 [39]–[40]; ABB Technology 2015 FCA 181 [42]–[43] (cited by Pallotta J at [128]. The words of the Swiss claims clearly claim the use “for manufacture of a medicament” [128].

While I’ve waffled a bit on this (see my comments on Warner-Lambert) I think Pallotta J is right on this. The key doctrinal point is that the words play a “dominant role” in the interpretive process, as the SCC put it in Canada Trustco. This is important in the context of statutory interpretation because the legislature must be able to rely on the courts to carry out the legislature’s intent, and the words, when clear, are the best reflection of that intent. The parallel point in the context of claim construction is that the patentee should be able to decide what it wants to claim—taking the risk that the claim may be invalid—and again, the words it uses are the best guide to that intent. If there is some public policy reason that Swiss form claims should not be permitted at all, then this should be implemented through a substantive legal rule, which can then be debated and subject to appeal.

Even though Pallotta J came to a different conclusion than Manson J, she did not have to expressly disagree with his analysis, as Manson J held that the meaning was context specific [103] and his holding of law was only that Swiss claims do not “automatically benefit[] from a literal construction” [102]. I must say I am not very enthused about that approach. Patent agents take great pains with the words used in a claim. While some terms used will be specific to the invention, and so may require considerable context, there are some terms, such as “comprising,” which are effectively terms of art with a specific meaning, and which should accordingly be given a consistent meaning. To my mind, Swiss claims are sufficiently common and established as a claim form, that they should be given a standard construction, so that patent agents will be able to predict the consequences of using Swiss claims.

Even though Palotta J construed the Swiss claims as product claims, she nonetheless held that neither the Swiss claims, nor the product-for-use claims, were directly infringed by Apotex. She noted that Apotex only intended to sell macitentan itself, not a product that contains macitentan in combination with a PDE5-I. Consequently, she held that Apotex did not infringe the product-for-use claims, which claim ‘A product containing [macitentan] in combination with [PDE5-I]’ because the product sold by Apotex would not contain the drugs in combination [144]. This reasoning seems right to me. She held that the Swiss claims were not infringed for the same reason [144]. This also seems right, given the structure of the Swiss claims at issue: “A use of [macitentan] in combination with [a PDE5-I] . . . for the manufacture of a medicament intended to treat [PAH].” This indicates that macitentan and the PDE5-I are used in combination for manufacture of the medicament.

As an aside, it occurs to me that a more difficult question would arise if the Swiss claims were of the form “A use of [macitentan] for the manufacture of a medicament intended to treat [PAH] in combination with [a PDE5-I].” In that claim, the question is whether the macitentan is intended for combination use, which, given Pallotta J’s holding that “in combination” encompasses any scenario in which the drugs work in concert, would include administration of separate pills in combination therapy. In that hypothetical, the question would be whether the generic product was intended for use in combination therapy. As discussed here, in Warner-Lambert v Generics (UK) [2018] UKSC 56 the UKSC split three ways in trying to decide what “for” means, with two variations on an objective intent test, plus a subjective intent test, not to mention the modified objective foreseeability test endorsed by the EWCA. Using the hypothetical claim, the generic might be a direct infringer on either the objective or subjective intent approach, depending on whether, on the facts, it subjectively or objectively intended macitentan to be administered in combination with a PDE5-I. I would stress that I am not endorsing either of these approaches, but simply pointing out that a more difficult issue would have arisen had the Swiss claims been framed differently.

With construction settled, Apotex argued that its PM did not instruct the use of macitentan in combination therapy. Pallotta J rejected this argument on the facts. It’s a bit hard to follow because of redactions, which, though brief, obscure the precise nature of the references. If I understand correctly, the main trial which established the safety and efficacy of macitentan as a monotherapy – “SERAPHIN” — also established its efficacy as a combination therapy [153]. The Apotex PM contained clinical trial data from SERAPHIN [192], [193], and SERAPHIN was so well known [187] that the references to it in the Apotex PM would be enough to alert physicians to the fact that macitentan is effective in combination therapy, and so would induce infringement [192], [199]. This is even though the APO-MACITENTAN PM “removed all mentions to the use of macitentan as a combination therapy that are present in the OPSUMIT PM, and only mentions SERAPHIN results that reported macitentan was useful as a monotherapy” [164]. It is true that the courts have been stringent about ensuring that the generic PM is scrubbed clean of references to the infringing use, but this seems pretty harsh on Apotex, given that it had to include the clinical trial data to establish efficacy as a monotherapy. I must say that I suspect that one factor in Pallotta J’s analysis is the fact that combination therapy is the primary use for macitentan, with only 10–30% of patients getting monotherapy [162]. If the opposite were true, so that eg only 10% of the use was in the patented combination, then I wonder if it would have gone the other way. Of course, in that scenario, it is perhaps unlikely that the main clinical trial data would be for the combination therapy.

Apotex also argued that even if the PM did instruct infringing combination therapy, this did not matter because prescribers don’t pay attention to the PM anyway: “In the field of PAH, the physicians know SERAPHIN very well and it does not matter what is contained in APO-MACITENTAN PM” [166]. This argument failed on the facts [197], as it always does. (If anyone knows a case where this argument has succeeded, please let me know in the comments.) The argument makes sense in theory, given the requirement that the influence be the “but for” cause of direct infringement, but if successful, it would mean that generic would in theory be able to sell a drug with the infringing use plastered all over the PM, on the basis that the PM is irrelevant anyway. I suspect that a desire to avoid this strongly counter-intuitive result might help explain why the courts invariably come to the conclusion that at least some prescribers are influenced by the PM. (Of course, it’s also possible that it’s simply true that at least some prescribers are influenced by the PM.)

Finally, Pallotta J emphasized that in light of this influence, Apotex would induce infringement “even if a physician applies their own skill and judgment to the decision to prescribe combination therapy” [156]: see similarly [181]. Pallotta J remarked that “[i]f it were otherwise, inducing infringement could never be found in the context of pharmaceutical patents” [156]. In any event, I don’t really see any difficulty with this position. As Pallotta J also noted, “a ‘but for’ test does not mean that Apotex’s activities must be the sole cause of the infringement” [156]. A physician who learns from the PM that macitentan is useful in combination therapy to treat PAH must still use their skill and judgment to determine that their patient is suffering from PAH. Conversely, a physician who has determined that their patient is suffering from PAH will not prescribe macitentan combination therapy unless they have learned somewhere that it is effective in treating PAH; and if they learn that from the PM, the information in the PM is the ‘but for’ cause of the infringement, even if it is not the sole cause of the infringement.

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