Earlier this month, the Federal Circuit affirmed a decision by the Patent Trial and Appeal Board (PTAB) that the claims of U.S. Reissue Patent No. RE38,551 challenged in inter partes review were not unpatentable for obviousness, in Mylan Pharmaceuticals Inc. v. Research Corporation Technologies, Inc.
The claims of the '551 reissue patent were directed to compounds for treating epilepsy (as well as other central nervous system disorders). The compounds have the generic structure:
Ar-CH2NH-C(O)-HC(CH2Q)-NH-C(O)-Q1
where Ar is a phenyl group optionally substituted with a halo group; Q is a lower alkoxy substituent; and Q1 is methyl. This compound is chiral and the claims encompass enantiomeric embodiments and pharmaceutical compositions thereof. A specific embodiment claimed in challenged claims 8-13 the '551 reissue patent is (R)-N-benzyl-2-acetamido-3-methoxypropionamide having the trade name lacosamide. Petitioners Mylan Pharmaceuticals, Breckenridge Pharmaceutical, and Alembic Pharmaceutical (a fourth company, Argentum Pharmaceuticals, filed the initial petition in which the other three joined and took the lead; each of the joining Petitioners had been sued for infringement in ANDA litigation more than a year before their petitions were filed Argentum did not join in the appeal) pursued the IPR on two grounds asserting obviousness. The first ground relied on a scientific publication to Kohn (the Kohn reference) and a treatise on drug design by Silverman (the Silverman treatise). The second ground combined these references with U.S. Patent No. 5,378,729 (the '729 patent). Petitioners' argument was based on "a lead compound analysis," where Petitioners identified the Kohn reference as disclosing a lead compound (R,S)-2-acetamido-N-benzyl-2-methylacetamide:
CH3C(O)C-NH-N(X)C*-(CO)-NH-CH2-Ph
derivatized by introduction of the X component, which is "a functionalized nitrogen, oxygen, or sulfur substituent." The Kohn reference disclosed that these compounds had an effectiveness for treating convulsions in mice. The reference taught that the most potent compound contained a functionalized oxygen atom two atoms removed from the alpha carbon (designated with an asterisk in the formula above). Petitioners relied upon Silverman for the motivation to modify this compound to produce lacosamide based on the drug development approach termed bioisosterism, purported in the reference to be useful for attenuating toxicity or modifying bioactivity. Here this drug development tool was purportedly relevant for groups having the same number of valence electrons but (perhaps) different atoms, such as -CH2-, -NH-, -O-, -S- and -Se-. The '729 patent, was directed to antiepileptyic compounds including racemic N-benzyl 2-acetamido-3-methoxypropionamide.
Despite being sufficiently persuaded to initiate an IPR on these grounds, the Board refused to provide a Final Written Decision that the claims were in fact unpatentable for obviousness. The Board was unpersuaded by the reasons asserted by Petitioner under Ground 1 for modifying the lead compound: "(1) that the methoxyamino moiety was not a common moiety in compounds that result in commercial pharmaceutical compounds and (2) that the methoxyamino moiety may present synthetic and stability problems." The skilled worker would have been motivated to substitute a -CH2- group for the -NH- group in the lead compound. Moreover, the Kohn reference had disclosed a 10-fold higher anticonvulsant activity when a compound having an -NH2 group was substituted with a compound having a -CH2OCH3 moiety. The Board disagreed, based on disclosure in the Kohn reference that "compounds [] without a methoxyamino or nitrogen-containing moiety at the α-carbon had reduced activity." In addition, the Board accepted Patent Owner's evidence 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." The bioisosterism teachings of Silverman did not cure these deficiencies, according to the Board, because the was "a lack of 'specific evidence suggesting an ordinary artisan would have understood that modifying the methoxyamino group of [the lead compound] would have reduced that compound's toxicity."
The Federal Circuit's affirmance was written by Judge Lourie joined by Judges Bryson and Wallach and first addressed the issue of standing, wherein all the appellants had joined the IPR more than one year after being sued by Patent Owner under 35 U.S.C. § 319. The panel held that the Board had exercised its discretion to permit joinder (permitted under 35 U.S.C. § 315(c)) and the absence of Petitioner Argentium (which would have lacked standing to bring this appeal for lack of Article III standing) vitiates the remaining Petitioners' capacity to pursue the appeal. (Interestingly, these parties apparently agreed that Argentium would not have had standing to appeal.) The Court agreed with the remaining Petitioners that, once joined under § 319, they that had "an express, statutory right to appeal." The Court made its determination under the "zone of interests" standard (which the Court assesses under "traditional principles of statutory interpretation, asking not 'whether in our judgment Congress should have authorized [the appeal], but whether Congress in fact did so,'" citing Lexmark Int'l, Inc. v. Static Control Components, Inc., 572 U.S. 118, 128 (2014). Using these rubrics, the Court found support in the plain language of § 315, which contemplates joining as a party "any person who properly files a petition under section 311" (emphasis in opinion). Combined with the provisions of § 319, granting parties the right to appeal, it was an easy exercise in statutory interpretation for the Court to find standing.
Turning to the merits, the panel accepted without analysis whether the compound disclosed in the Kohn reference was properly considered a lead compound. Performing its review under that assumption, the Court (after reciting the parties' competing arguments) found that the Board's decision was supported by substantial evidence. This finding was enough by itself for the Federal Circuit to affirm the PTAB's decision under In re Gartside, 203 F.3d 1305, 1316 (Fed. Cir. 2000), the Court's decision implementing the Supreme Court's apportionment of deference due the PTO under Dickinson v. Zurko, 527 U.S. 150 (1999). The Court held that substantial evidence supported the Board's determination that "compounds without a methoxyamino or nitrogen-containing group at the α- carbon had reduced activity" and that making he substitution would have resulted in a conformational change that "may have affected interaction with receptors and altered biological activity." The panel also deferred to the Board's crediting RCT's expert over Petitioners' expert with regard to differences between the three-dimensional structure of the lead compound and racemic lacosamide, citing Yorkey v. Diab, 601 F.3d 1279, 1284 (Fed. Cir. 2010). And the opinion noted that the Board:
[W]as 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.
Finally, the opinion rejected Petitioners' contention, at oral argument (and rebuttal at that, timing that seemed to annoy the Court), that the Court should remand the case to the PTAB in view of the Supreme Court's intervening decision in SAS Institute, Inc. v. Iancu, 138 S. Ct. 1348 (2018), finding that issue to have been waived as in PGS Geophysical AS v. Iancu, 891 F.3d 1354, 1362–63 (Fed. Cir. 2018), due to untimeliness.
In addition to the SAS aspect, this case illustrates the capacity of the PTAB to enter a decision, after oral argument and Patent Owner's opportunity to present evidence, contrary to the decision to institute. This makes invalidation much less of a foregone conclusion in IPRs, which must be seen by Patent Owners as a welcome development.
Mylan Pharmaceuticals Inc. v. Research Corporation Technologies, Inc. (Fed. Cir. 2019)
Panel: Circuit Judges Lourie, Bryson, and Wallach
Opinion by Circuit Judge Lourie
