Apotex Inc. v. Merck Sharpe & Dohme Corp., IPR2015-00419, Patent 5,691,336, Institution of IPR denied, 6/25/2015
Merck owns US patent 5691336, directed to tachykinin receptor antagonists. This patent is listed in the Orange Book as claiming the drug substance and drug product of fosaprepitant dimeglumine, sold under the brand name “Emend.” Fosaprepitant is a phosphoramidate prodrug of aprepitant, an antiemetic drug. The ‘336 patent received a patent term extension on under 35 USC § 156 for five years, so it expires on March 4, 2019. Merck has asserted this patent against several other generic copyists, but not against Apotex. It’s not stated if Apotex has already filed a PIV certification against this product.
Petitioner Apotex asserted that claims directed to the marketed product were obvious. The primary argument was that the Dorn ‘699 patent disclosed the structure of aprepitant, and that the Murdock ‘082 patent disclosed phosphoramidate prodrugs to improve the aqueous solubility of a parent nitrogenous compound. Apotex argued that it was obvious modify the parent compound aprepitant with the Murdock ‘082 prodrugs to arrive at the claimed invention (fosaprepitant).
The opinion cited the two-part analysis elucidated in Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291–93 (Fed. Cir. 2012) for this kind of analysis. The Otsuka test asks of a person of ordinary skill would (1) select an appropriate lead compound, and (2) if there is a reason to modify the lead compound to arrive at the claimed compound.
The PTAB finds that the lead compound selection prong fails in this case. Dorn ‘699 disclosed a broad genus of compounds. Aprepitant was compound 96 in Dorn ‘699. Apotex argued that there was a narrowed range of preferred substituents that encompassed compound 96, but the PTAB agreed with Merck that a “skilled artisan would not have picked compound 96 from the hundreds of compounds listed in [Dorn ‘699].” Slip op. at 8–9. Dorn ‘699 disclosed 600 specific compounds. There was no biological data pointing to compound 96, and other leads at the time of the ‘336 patent invention pointed to other likely compounds. So “compound 96 could not have served as ‘a natural choice for further development efforts.’” Slip op. at 9. An additional factor is that aprepitant was not a known active drug until well after the ‘336 patent issued (see fn 9).
Other obviousness arguments all relied on Dorn ‘699 for selecting compound 96 as the lead compound, and therefore all fail also.
The Board concludes that Petitioner (Apotex) did not establish a reasonable likelihood that it would prevail in showing the unpatentability of the claims in dispute, so the IPR is dismissed. The ‘336 patent is not obvious.
This decision is in contrast to Bristol Myers Squibb v Teva, 752 F.3d 967 (Fed. Cir. 2014), where the Federal Circuit held the structure of entecavir to be obvious. The court in BMS determined that there was a valid lead compound, and valid reasons to modify that compound. Apotex made similar arguments in this fosaprepitant case.
So why did the court in BMS find a lead compound where none was found by the PTAB in this fosaprepitant case? There is no clear conclusion here. On one hand, the references providing potential lead compounds for entecavir were not the kind expansive disclosure that the Dorn ‘699 patent appears to be. So the court was able to focus on a much narrower set of structures. But on the other hand, entecavir was not a prodrug. An argument could be made that there are a limited set of moieties useful to impart useful features on a parent structure, for example increasing solubility, increasing bioavailability, and preventing metabolism in the gut. So modifying a parent to form a pro-drug is more likely to be obvious, assuming the parent is an identified lead compound. Of course, in this fosaprepitant case, the Board held that there was no valid lead compound.
This case suggests that patent challengers seeking to invalidate a novel chemical structure patent will have a tough time at the PTAB.
Citation: Apotex Inc. v. Merck Sharpe & Dohme Corp., IPR2015-00419, Patent 5,691,336, Institution of IPR denied, 6/25/2015
Download the decision here: Apotex v Merck IPR2015-00419 -14
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