Tuesday, February 27, 2024

Tension in the Sanofi Disclosure Analysis

Takeda Canada Inc v Apotex Inc 2024 FC 106 Furlanetto J

2,570,916 / dexlansoprazole / DEXILANT / NOC

Proton pump inhibitors (PPIs) are a class of compounds that decrease gastric acid level in the stomach [5]. PPIs are now a well-established treatment for GI disorders related to increased gastric acid [7]. It is desirable to have a once daily dosing regimen, but the formulations known at the time of the patent could result in nocturnal breakthrough events if used on a once-daily basis, resulting increased gastric acid production [12]. Takeda’s 916 patent aimed to address this problem with a “pulsatile” release formulation, comprising a PPI with “a first and a second dose,” which are released from the dosage form as “discrete pulses,” resulting in specified blood plasma concentrations [90], [92]. Takeda’s DEXILANT product is a pulsatile release formulation of the claimed type, which includes two types of delayed-release beads containing dexlansoprazole [6]. Apotex sought to sell a dexlansoprazole oral dose capsule product and Takeda brought this NOC action in response [2].

Furlanetto J addressed three claim construction issues, which all turned on the evidence. One question in particular turned on the meaning of “a first and a second dose” in the claims. Apotex argued that this means distinct amounts of PPI in the dosage form itself [97], as with the two types of delayed-release beads in DEXILANT. Takeda argued that the reference to two doses was not the amount of PPI in the formulation, but the amount of PPI released from the formulation [97]. In other words Takeda argued that even if there was only one form of PPI in the product, if it was released in two waves resulting in two distinct blood plasma peaks, that would fall within the claims. Furlanetto J accepted Apotex’s construction, for reasons that strike me as being straightforward and compelling [98]–[104]. (Her conclusions on the other two claim construction issues also strike me as being sound.)

In light of that construction, Apotex prevailed on infringement because it does not contain two different types of dexlansoprazole: “Characteristic of a single continuous, delayed release dosage form, each of the mini-tablets in the Apotex Product are identical” [119]. There was also an extended discussion of various labs tests which was a bit difficult to follow because of redactions. My impression is that Takeda was arguing that if you squint really hard, you can see two peaks in the plasma concentration curves. In any event, in the end Furlanetto J held that Apotex’s product would not infringe as Takeda failed to established that Apotex’s product comprised a first and a second dose of dexlansoprazole from the dosage form as two discrete pulses: “Rather, the evidence indicates that there is only one dose of dexlansoprazole in each 30 mg or 60 mg capsule of the Apotex Product that is released from the Apotex Product in a single, continuous delayed release fashion” [147].

To this point, the decision turned on the facts with no novel points of law. The conclusion on claim construction and infringement would have been sufficient to dismiss the action [148]. Furlanetto J nonetheless went on to address Apotex’s validity arguments, “which formed a significant portion of the parties’ arguments at trial” [148].


The anticipation argument raised a tricky point which turns ultimately on a tension in Sanofi 2008 SCC 61.

The focus was solely on the disclosure branch of the two part test for anticipation [151]. The key piece of prior art was Application 2,499,574, and in particular Example 57 which “provides a formulation that is close to DEXILANT® except that it includes the excipient PEG as part of the formulation” [168]. Apotex introduced evidence that the PEG would not affect the pharmacokinetics and that the blood plasma reached would exceed the threshold specified in the claims [169]–[170]. Furlanetto J held that Example 57 did not anticipate because “the heart of the invention of the 916 Patent is the recognition of the threshold plasma concentration and how to achieve and maintain it,” and “There was no suggestion in the 574 Application of any recognition of these properties, nor of their significance” [176]. Moreover, Example 57 did not disclose the blood plasma concentrations that would result, and for that to be determined, the capsules of example 57 would have had to be administered to humans and the PK properties would have to be identified and studied” [176]. It is not entirely clear to me if Example 57 comprised two different types of granules (see [202], suggesting it did), but it is clear that Example 11 did have two types [161], and Furlanetto J held that Example 11 did not anticipate because, inter alia, “there was no disclosure of any plasma concentration being a threshold which must be surpassed for pharmacological effect” [166].

So, Furlanetto J is saying that these examples did not anticipate because they did not disclose the properties of the compound described in the examples. This is contrary to the basic rule that “what infringes if later, anticipates if earlier”: Consolboard [1981] 1 SCR 504, 534. There is no requirement that anyone at the time would know of all the properties. As Lord Hoffmann said in Synthon [2005] UKHL 59 [22], in a passage quoted with approval in Sanofi 2008 SCC 61 [25], “whether or not it would be apparent to anyone at the time, whenever subject matter described in the prior disclosure is capable of being performed and is such that, if performed, it must result in the patent being infringed, the disclosure condition is satisfied.” So, if a pharmaceutical company were to market a pill that in fact had two types of PPI and resulted in plasma concentrations that were in fact above the specified thresholds, that pill would infringe if sold after the patent issued, regardless of whether anyone had measured the plasma concentrations prior to litigation. By the same token, such a pill would anticipate if sold prior to the date of the patent, also regardless of whether anyone had ever measured the plasma levels. As Lord Hoffmann explained in Merrell Dow [1995] UKHL 14 [47], “whether or not a person is working a product invention is an objective fact independent of what he knows or thinks about what he is doing”; similarly in Synthon [2005] UKHL 59 [22], quoting Merrell Dow, Lord Hoffmann noted that “[t]he flag has been planted, even though the author or maker of the prior art was not aware that he was doing so.”

All of this is settled law, with Sanofi as the leading case, and indeed, it was expressly recognized as such by Furlanetto J [153]. Why then did she hold that the plasma concentrations had to be disclosed in order to anticipate? The problem lies in Sanofi itself. The quotes from Sanofi that I have given above are all from the discussion of general principles relating to anticipation. When the SCC in Sanofi discussed the disclosure requirement in particular, and in applying those principles to the facts, the SCC did indeed imply that the properties have to be disclosed in order to anticipate.

Recall that the question in Sanofi was whether the prior art disclosure of the racemate anticipated the claim to the enantiomer. The answer was no. But why? Under the general principles set out in Sanofi, the answer would have been that making the racemate would not infringe a claim to the enantiomer, and so the test that “the matter relied upon as prior art must disclose subject-matter which, if performed, would necessarily result in an infringement of the patent” (Sanofi [25], quoting Synthon [2005] UKHL 59 [22]) would not be satisfied. More broadly, the question in Sanofi was framed as being whether disclosure of the genus can anticipate the species. The answer is no, because someone practising the genus would not inevitably infringe, as the genus might be practised without infringing, by selecting another species from the pool: see Sanofi [21].

But while that answer would have been straightforward on the general principles set out in Sanofi, the SCC changed its approach when it came to the discussion of the disclosure requirement specifically. The SCC said:

[31] Section 27(1) of the Act requires as a condition for obtaining a patent that the invention was not “known or used” and was not “described” in any patent or any publication more than two years before the patent application was filed. In the context of genus and selection patents, in E. I. Du Pont de Nemours & Co. (Witsiepe’s) Application, [1982] F.S.R. 303 (H.L.), Lord Wilberforce stated, at p. 311:

It is the absence of the discovery of the special advantages, as well as the fact of non-making, that makes it possible for such persons to make an invention related to a member of the class.

The compound made for the selection patent was only soundly predicted at the time of the genus patent. It was not made and its special advantages were not known. It is for those reasons that a patent should not be denied to the inventor who made and discovered the special advantages of the selection compound for the first time.

This is all true, but it runs together anticipation and obviousness.

The general point of Witsiepe’s Application is that a species may be patented over the genus. It is now understood that two separate hurdles must be overcome. The prior art disclosing the genus must not have specifically disclosed the species, or it will be anticipated. This is true even if it turns out that the species had special properties that were not appreciated in the prior art. Suppose that the genus patent specifically disclosed five especially preferred compounds by structure, and disclosed in vitro tests showing they were all effective in treating a disease. One of those, the lead compound, was commercialized and sold. It would not be possible to get a subsequent species patent on that compound, even if it was subsequently discovered, surprisingly and unexpectedly, that it had no side effects at all, while every other known member of the genus had significant side effects. That would be true even if no one had known that this was the only compound with no side effects (perhaps because the lead compound was the only one which was commercialized and the others had never been tested in humans). The same is true if the especially preferred compound had not been commercialized, but merely specifically disclosed, as there is no difference in principle between prior sale and prior publication. (If it were surprisingly and unexpectedly discovered that the compound was useful in treating an entirely different disease, it would be possible to get a patent on the use to treat that disease. That is not because the prior art must disclose the properties to anticipate; it is because making and using the compound for uses known in the prior art would not infringe the new use patent.) On the other hand, even if the species was not specifically disclosed, it must also have special properties. There is no “invention” in picking one member of the genus at random and finding that it has exactly the same properties as all the other known members. If it does not have special properties, it will be obvious, even if it is not specifically disclosed.

The quoted passage from Witsiepe’s Application’s runs these together: “It is the absence of the discovery of the special advantages [non-obviousness], as well as the fact of non-making [anticipation], that makes it possible for such persons to make an invention [new, useful and non-obvious subject matter] related to a member of the class.” And the following sentence from the SCC is to the same effect: “It was not made [not anticipated] and its special advantages were not known [not obvious].” It is true that both of these requirements must be satisfied for a selection patent to be valid. The problem is that in the heading to that section — “i. Disclosure” — and in the following paragraph, the SCC in Sanofi identified both of these separate requirements with the disclosure branch of anticipation:

[32] Where there is no such disclosure [of the special advantages], there is no discovery of the special advantages of the selection patent as compared to the genus patent, and the disclosure requirement to prove anticipation fails.

The SCC also ran obviousness and anticipation together in dealing with the disclosure requirement when applying the law to the facts. The special properties of the enantiomer were better activity and lower toxicity. The SCC said there was no anticipation because “[t]here was no evidence that the person skilled in the art would know from reading the [prior art genus patent] that the more active dextro-rotatory isomer would be less toxic than the racemate or levo-rotatory isomer or any of the other compounds made and tested” [40] and “[s]ince the ‘875 patent did not disclose the special advantages of the dextro-rotatory isomer and of its bisulfate salt, as compared to the levo-rotatory isomer or the racemate and their salts, or the other compounds made and tested or otherwise referred to in the ‘875 patent, the invention of the ‘777 patent cannot be said to have been disclosed” [41]. The approach set out on the facts in Sanofi was picked up in comments in Novo Nordisk 2010 FC 746 [170]–[174] and in Allergan 2022 FC 260, which were relied on by Takeda and quoted by Furlanetto J at [174], [175].

So, the reason that Furlanetto J’s analysis of disclosure in this case was inconsistent with the general test set out in Sanofi, is that the SCC’s analysis of disclosure in Sanofi was also inconsistent with the general test that it had just set out. The reason for this internal inconsistency in Sanofi is that it was a selection patent case. When the SCC addressed the broad principles of anticipation, it relied on the leading cases on anticipation generally. But when it got to the specifics, it turned to cases on selection patents specifically, which run anticipation and obviousness together.

I can’t fault Furlanetto J for following the SCC’s lead. But this case illustrates the problem with the view that the special properties must be disclosed in order to anticipate. The focus on disclosure of the properties didn’t make any difference in Sanofi itself because the enantiomers were not specifically described in the prior art in any event. But in this case, the focus on the properties may have made the difference. Because Furlanetto J held that the claims were not anticipated because the plasma concentrations were not disclosed, it is not entirely clear to me whether she would have held them to be anticipated on the “what infringes if later, anticipates if earlier” test. So suppose that the prior art did indeed disclose a formulation that would indeed infringe, so that the claims would be anticipated on that test. In particular, suppose that even though the plasma levels were not disclosed, the formulation disclosed in the prior art would in fact result in clinically effective plasma levels, exceeding the threshold set out in the claims. And since there is no difference between a prior publication and prior practice, suppose that the prior patentee had marketed its product to thousands of patients, who had taken it to successfully treat their GI disorders, all without measuring the plasma levels. Would the 916 patent be valid, so that the prior manufacturer would have to withdraw its product and turn the market over to Takeda? That can’t be.

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