Takeda Canada Inc v Apotex Inc 2024 FC 106 Furlanetto J
2,570,916 / dexlansoprazole / DEXILANT / NOC
As discussed in my last post, the patent at issue in this case related to a “pulsatile”
dosage form of proton pump inhibitors (PPIs) 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]. As discussed in my last post, Furlanetto J held that Takeda had not
established infringement. That aspect of her decision was entirely straightforward, and
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 last post discussed the novelty argument. This
post deals with the remaining validity issues. It raises the thorny issue of whether the factual basis for a sound prediction must be disclosed in the patent; I review the debate, though in the end this decision adds nothing new, as the point was not contested. The other interesting issue is the treatment of sufficiency, which strikes me as problematic in apparently requiring a patentee to disclose in the patent the amount of active ingredient necessary for clinical efficacy.
Obviousness
There is nothing notable in the obviousness analysis, but a brief description is useful in understanding the utility argument. While pulsatile dosage forms were known in the prior art for dealing with the breakthrough effect, there were some differences between the prior art and the asserted claims: in particular, the asserted claims specified the plasma concentrations needed to prevent breakthrough [209] and also required the second dose to be larger, to compensate for reduced absorption in the lower digestive tract [213]–[215]. Furlanetto J held that these differences would not have been obvious, in an analysis that turned on the facts [217]–[227].
Utility
Furlanetto J stated that “where the utility is founded on a sound prediction, the factual basis for the prediction must be set out in the patent disclosure” to the extent it is not based on the CGK [231]. Whether the factual basis for a sound prediction needs to be disclosed in the patent is a long running debate seeming from an enigmatic statement in Wellcome / AZT 2002 SCC 77 [70]:
Thirdly, there must be proper disclosure. Normally, it is sufficient if the specification provides a full, clear and exact description of the nature of the invention and the manner in which it can be practised. . . . In this sort of case, however, the sound prediction is to some extent the quid pro quo the applicant offers in exchange for the patent monopoly. Precise disclosure requirements in this regard do not arise for decision in this case because both the underlying facts (the test data) and the line of reasoning (the chain terminator effect) were in fact disclosed, and disclosure in this respect did not become an issue between the parties. I therefore say no more about it.
The Federal Courts initially understood this as requiring only the standard disclosure of how to make and use the invention: see eg Aventis Pharma v Apotex 2006 FCA 64 [28]–[35] affg 2005 FC 1283 [178]–[254]. Then, in Raloxifene 2008 FC 142 [164] affd 2009 FCA 97 [15], Hughes J interpreted this paragraph of Wellcome / AZT as requiring disclosure of the factual basis for the sound prediction in the patent itself. (There’s also a separate issue as to what is meant by “this sort of case”: see AstraZeneca FC 2014 FC 638 [141], discussed here.)
There are two main problems with this. First, the factual basis for sound prediction was not disclosed in the patent in the leading cases: see my post “The underlying facts were NOT in fact disclosed,” showing that the factual basis for the sound prediction was not disclosed in Wellcome / AZT itself; and see my comments to that post showing that the factual basis was not disclosed in Olin Mathieson [1970] RPC 157 (Ch) either, which Wellcome / AZT [60] identified as the case which gave “serious shape and substance” to the doctrine. Second, it seems clear that there is no duty to disclose the factual basis for demonstrated utility in the patent. (Initially it was entirely clear that there was no such duty, but after the enhanced disclosure requirement was advanced for sound prediction, there have been some hints that there is an enhanced disclosure requirements for demonstrated utility as well.) There is only one utility requirement in the Act, and it is often a very fine line between demonstrated utility and sound prediction — the difference will turn on exactly how much data has been collected. So, if the facts A, B, C and D are enough to demonstrate utility, but the facts A, B & C are only enough to establish a sound prediction, if the applicant is in possession of the facts A, B, C and D, it will not need to disclose any of them, but if the applicant is only in possession of the facts the facts A, B & C, they will need to be disclosed. It is difficult to see any rationale for this distinction. The only rationale that has been provided for the heightened disclosure requirement for sound prediction is the statement in Wellcome / AZT [70] that “the sound prediction is to some extent the quid pro quo the applicant offers in exchange for the patent monopoly.” This statement is completely opaque, which is entirely understandable, given that it was expressly obiter. As a result, it is not clear what the rationale is for a heightened disclosure requirement for sound prediction; and it is double unclear as to what the rationale might be for distinguishing the disclosure requirement in a case of sound prediction from that when utility is demonstrated.
In this case, the parties evidently accepted that the factual basis must be disclosed in the patent, as Furlanetto J did not indicate that her statement at [231] was disputed. I’m not convinced that the the point is settled. Furlanetto J relied on Eurocopter 2013 FCA 219 [153], Apotex v Allergan 2015 FCA 137 [9] and Pharmascience v Teva 2022 FCA 2 [5]. Eurocoper says only that disclousre of the factual basis “may” be required and Apotex v Allergan merely paraphrased this in a brief decision affirming the decision below on the facts. Pharmascience v Teva 2022 FCA 2 is more directly on point, but even there Locke JA’s remarks are ambiguous, as discussed here. Since the parties did not dispute the point, this decision doesn’t add any authority to the debate. The issue will eventually have to be clarified by the FCA.
Given that position, the question was whether two examples provided a sufficient factual basis for a sound prediction of utility. The parties agreed that the requisite utility was simply “to give a pharmacological effect (i.e., as agreed by the parties in this context, an effect on gastric acid pH)” [233]. Furlanetto J found that a scintilla of utility had not been established on the facts [248], apparently because “the effect of a pulsatile release dosage form on gastric pH could not have been predicted” [244].
I have to admit, I find this very suprising. It is very well known that PPIs are effective in treating GI issues, at least when given in a large enough dose to meet threshold blood plasma levels. Claim 11, which was one of the assserted claims [2], specifies blood plasma levels of at least 450 ng/ml, which I take it is well over the threshold. Presumably if this concentration were achieved with a single dose, it would be effective. I find it very difficult to understand how it makes any difference if the same plasma level is achieved with pulsatile dose. But I have to admit that I couldn’t really follow the technical evidence reviewed by Furlanetto J, and anyway, it is a finding on the evidence.
Sufficiency
Furlanetto J held the disclosure was insufficient for two reasons.
[258] First, Example 1 does not provide sufficient information for the PSA to understand how the inventors arrived at the oral dosage data and steady state plasma concentrations in the patent. As highlighted earlier and explained by Dr. Davies, the experimentation said to underlie Example 1 yielded modelled results that would be known to the PSA to be significantly lower than actual steady state plasma concentration values. Further, the data was from an IV study alone at one time point and did not include the subsequent oral dosage modelling data that was necessary for the inventors to translate the results of the modelling to threshold concentrations for a pulsatile release oral dosage form to be used over a 24 hour time period.
I find this passage a bit difficult to understand. The second sentence suggests that the problem is that the data is misleading. If that is the issue, Takeda was right in saying that this was a disguised s 53 attack [260]. Alternatively, Furlanetto J might be saying that the defect was simply the failure to disclosure how the inventors “arrived at the oral dosage data and steady state plasma concentrations.” This seems to be saying that the inventors must disclose in the patent the experiments and reasoning process that led them to arrive at their invention. If that is what was meant, it is not correct. As it happens, this point was addressed by Manson J in his very recent decision in Proslide v WhiteWater 2024 FC 175, in which WhiteWater argued that “the key principle” of the law of sufficiency is that “information known by the patentee may be considered in assessing whether the disclosure is sufficient,” and that “[f]acts known by the inventor, and intentionally omitted or not communicated in the description of a patent can result in disclosure being insufficient”. Manson J rejected this argument, encapsulating the established law of sufficiency as follows:
[19] WhiteWater’s position broadens the scope of sufficient disclosure beyond what the law actually supports. Section 27(3) of the Patent Act, RSC, 1985, c P-4, requires the patent to make a full disclosure, but that requirement pertains to “the invention and its operation or use as contemplated by the inventor” in the patent. Therefore, the extent of the obligation to make sufficient disclosure is limited in two ways. First, the information need only pertain to the invention as disclosed and claimed by the patent. Second, that information must enable the skilled person to make or use that invention (Teva at paras 50-52, 70). Further disclosure is not necessary to meet the requirements of sufficiency as contemplated by section 27(3).
On the whole, I suspect that what Furlanetto J was really getting at in this paragraph was similar to her second point, which is easier to understand, so I’ll turn to that.
The second point turned on the fact that the patent claims a dosage form containing an amount of PPI that results in a specified plasma concentration, but it does not disclose the amount of the PPI that is required to achieve that concentration. The amount of PPI required to achieve the specified plasma levels would depend on a variety of factors, such as the exact dosage form, as the excipients can affect absorption [263]–[264]. Consequently, determining the exact amount of PPI to achieve the specified levels would require a non-trivial amount of routine research, albeit not rising to the level of invention.
Furlanetto J cited Idenix v Gilead 2017 FCA 161 [19] for the proposition that “[a] disclosure is insufficient if it necessitates the working out of a problem,” and Seedlings 2021 FCA 154 [68], Leo Pharma 2017 FCA 50 [59] and Teva 2012 SCC 60 [75] for the proposition that “a minor research project is too much,” though some non-inventive trial and error experimentation may be permitted [257]. Applying this threshold to the facts, she held on the facts that the effort requires was too much [268].
This is problematic. Novel drugs are often patented very early in the R&D process, often on the basis of in vitro tests only, at a point where identifying the actual dose and dosage form necessary for clinical efficacy is a very long way off. This is typically true when utility is based on a sound prediction, and is often true even when utility has been demonstrated. While the patent will typically state the quantity needed, this is normally little more than guesswork. For example, in ZYTIGA 2021 FCA 45, concerning the 2,661,422 patent, which related to a combination of abiraterone acetate & prednisone for treating prostate cancer (discussed here), the specification stated that the amount to be administered was “about 0.01 mg/kg/day to about 100 mg/kg/day of abiraterone acetate” — a range of four orders of magnitude, and that for a compound that was already known. Similarly, in Rosiglitazone 2011 FC 239 (discussed here), the specification stated that the unit dose “normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg.” In HGS v Lilly [2011] UKSC 51, concerning EP(UK)0,939,804, relating to neutrokine alpha and related anitbodies, the specification stated that “[0125] As a general proposition, the total pharmaceutically effective amount of Neutrokine-α polypeptide administered parenterally per dose will be in the range of about 1 µg/kg/day to 10 mg/kg/day of patient body weight, although, as noted above, this will be subject to therapeutic discretion.”
It might be suggested that this case is different because the claims specified the requisite
blood plasma concentration of the active ingredient and determining this concentration
was part of the inventive concept. But sufficiency requires that the patentee disclose how
to use the invention. Even when the plasma concentration is not specified, the skilled
person still has to be able to practice the invention by determining an effective amount
of the drug, so this doesn’t seem to be a difference in principle. A patent is sufficient if some trial and error is needed to find the clinically effective dose when a new compound is claimed, and the trial and error needed to find the dose needed to find the plasma concentration in this cases seems to be of the same nature, and if anything less extensive, given that the desired concentration is specified. But maybe there is more to this point that I am not seeing.
In coming to her conclusion, Furlanetto J relied primarily on the SCC Teva decision [267], which invalidated the patent for requiring what the decision repeatedly referred to as a “minor research project.” More specifically, and crucially, in Teva the skilled person would have to “undertake a minor research project to determine what the true invention was” [75] (my emphasis). This reference to determining the “true invention” was repeated consistently, in all the SCC’s references to a “minor research project”: see [17], [74], [75]. The issue in Teva was that the patent disclosed that one of the especially preferred compounds had been tested in humans and found to be effective, but the patent did not disclose which one. It was the failure to disclose which compound had been tested that constituted the failure to disclose “the true invention.” As the SCC noted in Teva, the trial judge felt that requiring the skilled person to undertake “a minor research project in order to determine which of the claims describes the true invention. . . plays games with the reader.” And as the FCA noted in Leo Pharma, the issue in Teva was that “the patentee had deliberately omitted essential information, thereby obscuring the fact that only one of the compounds claimed actually worked. Thus, the invention itself was not even properly disclosed” [58]. (See also Proslide [26], to the same effect.)
Thus the disclosure requirement at issue in Teva was not about disclosure of how to make the invention, it was disclosure of “the true invention.” And as the FCA pointed out in BRP v Arctic Cat 2018 FCA 172 [78], “[e]nablement (how to practice the invention) is a concept completely distinct from the disclosure of the invention itself, the latter of which was at issue in [Teva].” In this case there was no suggestion that Takeda had tried to conceal the true invention. The disclosure requirement at issue in this case was not disclosure of the true invention, but standard enablement, or how to practice the invention. And as the FCA further pointed out in Leo Pharma [58]–[59] and in BRP v Arctic Cat [78], the SCC in Teva did not change the traditional standard for sufficiency of disclosure of how to make the invention. In BRP v Arctic Cat [78], the FCA held that it was an error of law to apply the Teva standard for disclosure of the invention to the completely distinct context of enablement. With respect, it appears that Furlanetto J may have made that error in this case.
With all that said, I would return to the s 53 point. If Takeda actually knew the amount of active ingredient necessary to achieve the specified plasma concentrations and failed to disclose it, it is possible that there might be some kind of wilful misleading argument to be made. I don’t want to explore this further since it wasn’t at issue; the point is simply that a s 53 objection should be dealt with under s 53, and not by a strained interpretation of the sufficiency requirement.
Claims Broader
Apotex argued that the claims were overbroad “because the work of the inventors established that at least 1 hour was required between the pulsed doses; however, this 1 hour was not claimed” [270]. This seems to be redundant with utility, but in any event, it failed on the facts [274].
Ambiguity
A weak ambiguity attack also failed on the facts: [275]–[279].
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