On February 7, 2024, the Federal Court dismissed Takeda's action under subsection 6(1) of the Patented Medicines (Notice of Compliance) Regulations in relation to dexlansoprazole (Takeda's DEXILANT). Justice Furlanetto determined that the Asserted Claims of Canadian Patent No. 2,570,916 (916 patent) were not infringed and were invalid for insufficiency and failure to disclose the factual basis and line of reasoning for sound prediction of utility: Takeda Canada Inc v Apotex Inc, 2024 FC 106.
Background
DEXILANT is a "pulsatile release formulation ... that includes two types of delayed-release beads containing dexlansoprazole", and releases dexlansoprazole, a proton pump inhibitor (PPI) in "two discrete pulses". DEXILANT "is used to treat heartburn associated with gastroesophageal reflux disease (GERD), as well as to heal damage to the esophagus from stomach acid."
The 916 patent describes a need for a once-a-day PPI dosage form that can provide a full day of effect, without "nocturnal breakthrough events" experienced by some patients. The 916 patent teaches "that alleviation of nocturnal breakthrough is a function of the concentration of the PPI in the patient" and "there is a threshold concentration that must be surpassed in a second dose" for therapeutic effect.
Construction and Infringement
The Asserted Claims of the 916 patent all depend on claim 1 (the sole independent claim), which contains the following elements:
- A dosage form that includes a PPI;
- the PPI is released as a first and a second dose;
- the first and second dose are released as discrete pulses;
- each pulse of the PPI is sufficient to raise plasma concentrations above a threshold concentration of at least 100 ng/mL;
- the second dose contains at least 10% more of the PPI than the first dose; and
- the first and the second dose independently comprise between 5 mg and 300 mg of the PPI.
The PPI of claim 16 is dexlansoprazole.
The Apotex Product dosage forms "are capsules filled with the same, identical mini-tablets". The Court determined that the Asserted Claims were not infringed as the Apotex Product "is not a dosage form with a first and a second dose that has pulsatile release." Dissolution testing, bioequivalence testing and other redacted analysis of the Apotex Product were all consistent with a single dose released in a single, continuous delayed release fashion.
Not anticipated
The Court determined that the 916 patent was not anticipated by Canadian Application No. 2,499,574 (574 Application). First, the examples of interest in the 574 Application contained a first dose of 4.25 mg, below the 5 mg to 300 mg doses required by claim 1 of the 916 patent. Second, these examples did not disclose a threshold plasma concentration of 100 ng/mL required by claim 1 as they do not identify any threshold and only provide plasma concentrations from beagle dogs. Third, example 57 did not inherently anticipate the Asserted Claims. While Apotex argued that example 57 contained a formulation close to DEXILANT, it did not contain pharmacokinetic data; thus, to arrive at the threshold concentration, the capsules of example 57 would have to be administered to humans and the pharmacokinetic properties identified and studied. The Court indicated that the 574 application did not include "the heart of the invention", which was "the recognition of the threshold plasma concentration and how to achieve and maintain it (i.e., with a pulsatile release dosage form that has a second dose that is at least 10% greater than the first dose)."
Not obvious
The Asserted Claims were not invalid for obviousness. The Court identified two aspects of the inventive concept. First, the Asserted claims included dosage forms "designed around the recognition that there is a threshold plasma concentration to achieve therapeutic effect." Second, "to maintain the threshold plasma concentration for a PPI pulsatile release dosage form, the second dose must be greater than the first dose to account for absorption differences in the GI tract."
The Court agreed with Takeda that the prior art did not directly identify any particular plasma concentration threshold as a target for therapeutic effect. Further, the prior art did not teach that the second dose in a pulsatile dosage form should be larger to address regional absorption differences in the GI tract. Justice Furlanetto determined that there was no motivation to focus development on PPIs' pharmacokinetic properties and a threshold plasma concentration, or to consider absorption differences in the GI tract. The Court concluded, "[t]here was no direct path to the inventive concept and no basis for the PSA to embark on experimentation to arrive at the inventive concept without the need for inventiveness."
Lacks sound prediction of utility
The Court rejected Takeda's position that Apotex's experts conceded utility, i.e., that the claimed dosage forms would have a pharmacological effect (an effect on gastric acid pH). While Apotex's experts acknowledged that they would expect such an effect with the claimed dosage forms, these statements did not specify timing or what was known at the filing date.
The Court also rejected Takeda's argument that Example 1 of the 916 patent could serve as the factual basis for the sound prediction of utility. Example 1 related to PK-PD modelling involving IV administration of lansoprazole in humans. Apotex's pharmacokinetics expert identified flaws in the modelling assumptions and opined that an IV infusion could not form the basis of a prediction for the claimed pulsatile oral dosage form. The Court did not have any contrary expert opinion on pharmacokinetics.
While an inventor performed additional modelling and simulation work on the impact of oral dual-pulse dosing regimens on gastric pH pulsatile formulations, this work was not referenced in the 916 patent. The Court concluded that without this data in the patent, the skilled person could not predict the practical utility would be achieved by the claimed dosage form.
Accordingly, the Asserted Claims were invalid for failure to disclose a factual basis and line of reasoning to support a sound prediction of utility.
Insufficient
The Court determined that the Asserted Claims were invalid for insufficiency for two reasons. First, for reasons similar to those discussed for inutility, Example 1 does not provide sufficient information for the skilled person "to understand how the inventors arrived at the oral dosage data and steady state plasma concentrations in the patent." Second, the 916 patent does not teach or include any example of a particular dosage form of the Asserted Claims, i.e., that "achieves a particular pharmacokinetic threshold plasma concentration through pulsatile release of drug." Takeda's expert acknowledged that work required to arrive at such a dosage form would include "formulation work, administration of the dosage form to a human, bioavailability and bioequivalence studies, followed by dose adjustments", that is at least as much work as contemplated in Teva Canada Ltd v Pfizer Canada Inc, 2012 SCC 60.
Overbreadth
The Asserted Claims were not invalid for overbreadth. Apotex argued that the inventors established that at least 1 hour was required between pulsed doses, which limitation was not claimed. The Court disagreed. The report relied on by Apotex "does not state that there must be any particular time gap between pulses", and the Asserted Claims refer to "discrete pulses of the PPI", which contemplates a "noticeable time period between pulses".
Ambiguity
Apotex's argument on ambiguity was based on a claim construction not adopted by the Court. Accordingly, the Court determined that the Asserted Claims were not invalid for ambiguity.
Unpatentable subject-matter
The Court determined that the Asserted Claims were not unpatentable subject matter. Apotex argued that the Asserted Claims claim a desired result, i.e., any pulsed release dosage form that achieves the claimed pharmacokinetic results. The Court disagreed. The claims are directed to a physical dosage form loaded with a first and second dose with specified ranges of PPI.
Conclusion
In summary, the Court determined that the Asserted Claims of the 916 patent were not infringed and invalid on the basis of insufficiency and lack of disclosure of a factual basis and line of reasoning to support a sound prediction of utility. Justice Furlanetto dismissed Apotex's arguments relating to obviousness, overbreadth, ambiguity, and unpatentable subject matter.
Takeda may appeal as of right.
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