Lacosamide – USA

On Feb 01, 2019 Federal Circuit affirmed PTAB’s decision of upholding the compound patent on epileptic drug Vimpat® challenged by three generic-drug makers.

Mylan, Breckenridge and Alembic appealed from the final written decision of the PTAB in an inter partes review concluding that claims 1–13 of U.S. Reissue Patent 38,551 (“the ’551 patent”) are not unpatentable. Research Corporation Technologies, Inc. (“RCT”) owns the ’551 patent, which discloses and claims enantiomeric compounds and pharmaceutical compositions useful in the treatment of epilepsy and other central nervous system (“CNS”) disorders. Claim 1 recites the lacosamide compound generically in R configuration. Claim 8 depends from claim 1 and recites “[t]he compound according to claim 1 which is (R)-N-benzyl-2-acetamido-3- methoxypropionamide,” referred to in the patent as “BAMP” and referred to herein as lacosamide.

On Nov. 23, 2015, Argentum Pharmaceuticals LLC filed IPR against ’551 patent. In its petition, Argentum challenged claims 1–13 on eight grounds. The Board only instituted on two grounds involving three references: (1) obviousness of claims 1–9 over Kohn 1991 and Silverman and (2) obviousness of claims 10–13 over Kohn 1991, Silverman, and U.S. Patent 5,378,729 (“the ’729 patent”). Three days after the Board instituted Argentum’s petition, Mylan, Breckenridge, and Alembic each filed their own petitions for review with concurrent motions for joinder. The Board issued its final written decision, concluding that each challenged claim had not been shown to be unpatentable. Contrary to its views in the institution decision, the Board disagreed with Petitioners. It “assumed arguendo, that an ordinary artisan would have selected compound 3l of Kohn 1991 as a lead compound” but found that converting the methoxyamino group (NH-O-CH3 ) would have been viewed as undesirable because the compounds in Kohn 1991 without a methoxyamino or nitrogen-containing moiety at the α-carbon had reduced activity.

The Board also credited evidence suggesting that an ordinary artisan would have understood the methoxyamino moiety to confer significant activity to the compound and that substitution of nitrogen for carbon would have led to a significantly different conformation and biological activity. While the Board “acknowledge[d] Silverman’s teaching . . . that bioisosterism has been shown to be useful to attenuate toxicity in lead compounds,” it found a lack of “specific evidence suggesting an ordinary artisan would have understood that modifying the methoxyamino group of Kohn 1991’s compound 3l would have reduced that compound’s toxicity.” Proceeding to the second ground relating to the dependent claims Board concluded that independent claim 1 would not have been obvious over Kohn 1991 and Silverman, the Board reasoned that it could not conclude that the more limited dependent claims 10–13, the only claims at issue in the second ground, would have been obvious. Of the four petitioners, Mylan, Breckenridge and Alembic appealed. RCT challenges whether Appellants have standing to challenge the Board’s decision.

STANDING:

RCT did not assert that Appellants lack Article III standing. However, RCT submitted that each Appellant lacks standing because it does not fall within the zone of interests of 35 U.S.C. § 319. According to RCT, Appellants fall outside that zone because RCT brought an infringement action against each Appellant more than a year before it filed its IPR petition, and each Appellant’s petition was therefore time-barred. In its institution and joinder decision, the Board exercised its discretion to join each Appellant as a party to Argentum’s IPR as permitted by 35 U.S.C. § 315(c). RCTs argument was that the initial Petitioner, Argentum, would have lacked Article III standing to appeal the Board’s decision, because “its IPR was limited to an agency matter.”

Federal Circuit said that a statutory cause of action extends only to litigants that “fall within the zone of interests protected by the law invoked.” Lexmark Int’l, Inc. v. Static Control Components, Inc., 572 U.S. 118, 129 (2014) (quoting Allen v. Wright, 468 U.S. 737, 751 (1984)). The “zone of interests” limitation “always applies and is never negated.” To determine whether an appellant falls within the zone of interests, we apply traditional principles of statutory interpretation, asking not “whether in our judgment Congress should have authorized [the appeal], but whether Congress in fact did so.” Federal circuit further said that Section 315 contemplates the joining of petitioners as “parties.” Section 319 then provides that “[a] party dissatisfied with the final written decision” of the Board “may appeal the decision pursuant to sections 141 through 144. Any party to the inter partes review shall have the right to be a party to the appeal.” Joined parties, as provided in § 315, may appeal pursuant to § 319. Accepting RCT’s argument would require us to read the word “party” differently between § 315 and § 319, an argument for which RCT provides no support. Accordingly, Federal circuit concluded that Appellants fall within the zone of interests of § 319 and are not barred from appellate review.

MERITS:

On the merits, Appellants challenged the Board’s non-obviousness conclusion. Regarding claims 1–9, Appellants asserted a lead compound analysis, proposing compound 3l in Kohn 1991 as the lead. In its final written decision, the Board did not resolve whether compound 3l was an appropriate lead compound. Instead, it accepted compound 3l as the lead and concluded that Petitioners did not meet their burden to establish a motivation to modify that compound. For this analysis, federal circuit assumed, as the Board did, that compound 3l was an appropriate lead compound.

Appellants first argued that an ordinary artisan would have recognized the methoxyamino group in compound 3l to be uncommon and to have potential synthetic and stability problems. According to Appellants, a person of skill in the art would then have been motivated to modify compound 3l by replacing the amine of its methoxyamino group with a methylene link to yield a more stable, synthetically accessible, pharmaceutically common and acceptable moiety. In proposing this modification, Appellants rely on the principles of bioisosterism as recited in Silverman. Appellants submitted that, of the “classical bioisosteres” in Silverman, only methylene would result in a more pharmaceutically common and acceptable compound and resolve the potential stability and synthesis concerns presented by the methoxyamino moiety. Appellants maintained that Silverman would have motivated a person of skill in the art to replace the amine in the methoxyamino group with a methylene link and have a reasonable expectation of success having done so. Appellants further contend that their proposed modification to compound 3l would have been expected to have excellent potency. Specifically, Appellants pointed to Kohn 1991’s teaching that a terminal methoxy group added to compound 3a resulted in compound 3l, which was ten times more potent than compound 3a. As a final point, Appellants argued that a person of skill in the art would have had reason to isolate the R enantiomer from its “racemic lacosamide” mixture because Kohn 1991 teaches that the “anticonvulsant activity resided primarily with the R stereoisomer.”

Federal Circuit however, agreed with RCT that the Board’s findings are supported by substantial evidence. Even if a person of skill in the art would have been motivated to modify compound 3l, the record evidence suggests that compounds without a methoxyamino or nitrogen-containing group at the αcarbon had reduced activity. The evidence also suggests that replacing the methoxyamino in compound 3l would have yielded a different conformation. Such a conformational change may have affected interaction with receptors and altered biological activity. Kohn 1991 itself explains that “stringent steric and electronic requirements exist for maximal anticonvulsant activity,” which would counsel against modifying compound 3l in a way that would change its conformation significantly. The Board also was entitled to reject bioisosterism as a basis for a motivation to modify compound 3l. While Silverman does disclose that that bioisosterism may be useful to attenuate toxicity in a lead compound, the record does not indicate why bioisosterism would have been used to modify compound 3l in particular, which already had a high potency and low toxicity, and why methylene was a natural isostere of methoxyamino. In light of the reductions in potency and the significant conformational changes that would have been expected, the Board’s finding that a person of skill in the art would not have been motivated to modify the methoxy amino group in compound 3l was supported by substantial evidence. As Appellants did not meet their burden to show that claims 1–9 would have been obvious over Kohn 1991 and Silverman, federal circuit concluded that the Board did not err in concluding that Appellants failed to meet their obviousness burden regarding claims 10–13, which depend therefrom.

Thus, Federal Circuit affirmed the Board’s conclusion that Appellants have failed to show that claims 8–13 would have been obvious.

Previously, on May 23, 2018, Federal Circuit affirmed a Delaware court's finding that a UCB Inc's same patent is not invalid (reported here on this blog).