Lacosamide - USA

On May 23, 2018, Federal Circuit affirmed a Delaware court's finding that a UCB Inc's patent on the epilepsy drug Vimpat® is not invalid for double patenting or obviousness or anticipation.

This case arises under the Hatch-Waxman Act. UCB holds NDA that cover its lacosamide anti-epileptic drug approved by USFDA and marketed under the tradename Vimpat®. Appellants are generic drug manufacturers who filed Abbreviated New Drug Applications (“ANDAs”), seeking approval for generic versions of Vimpat® before expiration of U.S. Patent No. RE38,551. The ’551 patent covers lacosamide compound. As disclosed in the ’551 patent, lacosamide is the R-enantiomer of N-benzyl-2-acetamido-3-methoxypropionamide. The specification teaches that “the R stereoisomer is unexpectedly more potent than the corresponding S stereoisomer and the racemic mixture.” The claims of the ’551 patent at issue in this case are dependent claims 9, 10, and 13.Claim 9 covers (R) N-Benzyl 2-Acetamido-3-methoxypropionamide containing at least 90% (w/w) R stereoisomer. Claim 10 covers therapeutic composition & claim 13 covers method of treating human.

Before the district court, Appellants asserted that claims 9, 10, and 13 of the ’551 patent are invalid for obviousness-type double patenting, alleging that they are not patentably distinct from claims 44–47 of the U.S. Patent No. 5,654,301 (continuation-in-part of the 5,378,729). Appellants also argued that the compound described in the asserted claims of the ’551 patent is merely an obvious species of the genus claimed in the ’301 patent. Following a bench trial, the district court found that it would not have been obvious to a person of ordinary skill in the art to make lacosamide by placing an unsubstituted benzyl at R or an unsubstituted methyl at R1 in combination with methoxymethyl at R3. Appellants also asserted that LeGall’s disclosure of the racemic mixture compound 107e alone, or in combination with the ’729 patent’s disclosure of the genus and Kohn 1991’s disclosure of compound 3l rendered the asserted claims of the ’551 patent obvious. The district court applied a lead compound analysis and concluded that, as of March 1996, a skilled artisan would not have selected any Functionalized Amino Acid (FAA) genus, let alone compound 107e (LeGall) or compound 3l (Kohn 1991), as a lead compound. Finally, Appellants asserted that the ’551 patent was anticipated by LeGall’s disclosure of the racemic mixture of compound 107e, which necessarily discloses the enantiomers of that mixture, including the R enantiomer. The district court held that LeGall does not anticipate the asserted claims because, while it discloses the racemic mixture compound 107e, it does not explicitly disclose the R-enantiomer or its characteristics. Thus, district court made exhaustive fact findings based on the trial evidence and concluded that the asserted claims (9, 10, and 13) of the ’551 patent are not invalid. Appellants appealed.

Obviousness-type double patenting:

Appellants asserted that claims 9, 10, and 13 of the ’551 patent are not patentably distinct from claims 44–47 of the ’301 patent and are thus invalid for obviousness-type double patenting. Because these claims only have a common methoxymethyl group at the R3 position, the question before court was whether a person of ordinary skill in the art, starting with claim 45 of the ’301 patent, would have been motivated to place an unsubstituted benzyl at R and an unsubstituted methyl at R1 in combination with the methoxymethyl group at R3 with a reasonable expectation of success.

Claim 9 of the ’551 patent requires the R-enantiomer with 90% or greater purity; while claim 45 of the ’301 patent allows for any substituted or unsubstituted group. Focusing on these differences, the district court found that as of the priority date, a person of ordinary skill in the art would not have had a reasonable expectation that placing an unsubstituted benzyl at R or an unsubstituted methyl at R1 with a methoxymethyl group at R3 would have yielded an efficacious anticonvulsant FAA. Also by the priority date not a single reference disclosed any anticonvulsant data for any compound comprising a methoxymethyl group at R3 let alone lacosamide. Because these findings are supported by expert testimony and the record, Federal circuit concluded that they are not clearly erroneous & affirmed that the asserted claims of the ’551 patent are not invalid for obviousness-type double patenting.

Obviousness:

Appellants next asserted that claim 9 of the ’551 patent would have been obvious based on LeGall’s disclosure of compound 107e as a racemic mixture. Appellants further asserted that LeGall alone, or in combination with the ’729 patent and Kohn 1991, render claim 9 obvious. Applying a lead compound analysis, the district court concluded that a person of ordinary skill in the art would not have selected any FAA, let alone the compounds disclosed in LeGall and Kohn 1991, as lead compounds in the lead compound analysis. Appellants argued that because Aventis did not apply a lead compound analysis, no such analysis is required in this case. Federal circuit said that we are not aware of any authority holding that a lead compound analysis is or is not required in cases involving purifying mixtures. LeGall contains no data that would have led a person of ordinary skill in the art to select compound 107e among the many compounds disclosed in LeGall as a lead compound. Dr. Roush also testified that based on LeGall’s disclosure, a person of ordinary skill in the art would not have been motivated to develop compound 107e. Federal circuit saw no clear error in the district court’s factual findings based on such evidence.  Based on this evidence, Federal circuit sustained district court's conclusion that the asserted claims of the ’551 patent would not have been obvious.

Anticipation:

Only Appellants Accord Healthcare, Inc. and Intas Pharmaceuticals Ltd. raised anticipation on appeal. They argued that because LeGall discloses the chemical structure of the racemic compound 107e, it necessarily discloses the R-enantiomer (lacosamide) recited in claim 9 of the ’551 patent. Relying principally decision in Sanofi, 550 F.3d at 1084, the district court found claim 9 of the ’551 patent not anticipated, concluding that LeGall discloses neither the R-enantiomer of compound 107e nor any of its characteristics. Federal circuit held that the district court did not clearly err in finding that LeGall does not anticipate claim 9 of the ’551 patent. “[T]he knowledge that enantiomers may be separated is not ‘anticipation’ of a specific enantiomer that has not been separated, identified, and characterized.” Federal circuit stated that “the novelty of an optical isomer is not negated by the prior art disclosure of its racemate.” In re May, 574 F.2d 1082, 1090 (CCPA 1978). Thus, Federal circuit found no clear error in the district court’s finding of no anticipation.

PROST, Chief Judge, dissenting:

Chief Judge, Prost dissented mainly on double patenting issue addressed by district court. Specifically, she said that the district court clearly erred when it found there would not have been a reasonable expectation of success in selecting unsubstituted benzyl for R and unsubstituted methyl for R1. She said that although we cannot reject the district court’s finding that drug development is unpredictable, “obviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success.” Pfizer, 480 F.3d at 1364. In reality, “there were many tests conducted on FAAs with benzyl at R and methyl at R1.” And indeed, as the district court found 75% of Dr. Kohn’s experimental compounds contained benzyl at R and methyl at R1, and most of these were unsubstituted. The district court’s findings of fact as to the prior art provided ample evidence showing that a person of skill in the art would have had a reasonable expectation of success in creating an FAA with anticonvulsant activity by selecting an unsubstituted benzyl for R and an unsubstituted methyl for R1.

She further said that the district court also erred when it found that the limited data that did exist at the time would not have led a person of ordinary skill to place an unsubstituted benzyl at R or an unsubstituted methyl at R1. Indeed, the data that were available showed that unsubstituted benzyl at R and an unsubstituted methyl at R1 were comparable to, if not better than, any other substituents tested.

Finally, and perhaps most importantly, the district court erred when it did not consider the LeGall Thesis in its primary double-patenting analysis. For purposes of this litigation, the parties agreed that the LeGall Thesis constitutes a “printed publication” within the meaning of 35 U.S.C. § 102(b). Importantly, the LeGall Thesis disclosed compound 107e which, exactly like lacosamide, has a methoxymethyl group at R3, an unsubstituted benzyl at R, and an unsubstituted methyl at R1. Compound 107e is identical to lacosamide except that it contains both the R- and Senantiomers in a mixture, rather than just the Renantiomer. Thus, to the extent the district court found that there was no indication in the prior art that benzyl and methyl would have been successful with a methoxymethyl group, it clearly erred.

She further held that "taking the district court’s clear error together with the remainder of its fact findings, I would have concluded that claims 9, 10, and 13 of the asserted ’551 patent are not patentably distinct from the reference claims. Thus, I would reverse the district court’s conclusion and hold that the asserted claims of the ’551 patent are invalid for obviousness-type double patenting. I therefore respectfully dissent".