Memantine – USA

On Dec 11, 2017, The Federal Circuit affirmed a Delaware judge's decision that Forest Laboratories’ six patents on the Alzheimer's drug Namenda are invalid as indefinite in a win for Teva Pharmaceuticals. During claim construction, Delaware district court determined that all of the asserted patent claims are invalid for indefiniteness and on that basis entered judgment against Forest. During appeal CAFC agreed with district court’s finding that the Delaware Court’s construction was reasonable and as such, the claims were indeed indefinite.

Forest Laboratories, Inc., holds New Drug Application No. 22–525 covering Namenda XR® (Namenda Extended Release formulation), a memantine hydrochloride formulation “indicated for the treatment of moderate to severe dementia of the Alzheimer’s type.” Adamas is the owner, and Forest Laboratories Holdings, Ltd., is the exclusive licensee, of six related patents: U.S. Patent No. 8,168,209; U.S. Patent No. 8,173,708; U.S. Patent No. 8,283,379; U.S. Patent No. 8,329,752; U.S. Patent No. 8,362,085; and U.S. Patent No. 8,598,233. The patents describe and claim pharmaceutical compositions, and methods of administering pharmaceutical compositions, that contain extended-release formulations of memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist. According to the specification, the rate that the memantine in a particular formulation enters a patient’s bloodstream is measured in terms of a ratio: “dC” designates the change in concentration of memantine in blood during a specified time; “dT” designates the length of the specified time.

In December 2013, Teva filed an abbreviated new drug application seeking approval to sell a generic version of Namenda XR® and provided Forest with its Paragraph IV certification stating that the six patents were invalid or will not be infringed by Teva’s generic. Forest then sued Teva & the parties addressed issues of claim construction. The parties agreed that the language in claim 1 of the ’209 patent is representative & claim 1 reads:

1. A solid pharmaceutical composition in a unit dosage form for once daily oral administration comprising an extended release formulation of 5 to 40 mg memantine or pharmaceutically acceptable salt thereof, wherein administration of a dose of the composition to a human subject provides a plasma memantine concentration profile, as measured in a single-dose human PK [pharmacokinetic] study, characterized by a change in memantine concentration as a function of time (dC/dT) that is less than 50% that of an immediate release dosage form comprising the same dose of memantine as the composition, wherein the dC/dT is measured between the time period of 0 to Tmax of the immediate release form of memantine.

Forest proposed that the highlighted language either be left unconstrued or be construed to mean a “change in plasma memantine concentration of the extended [sustained] release dosage form as a function of time (dC/dT) that is less than 50% that of an immediate release dosage form comprising the same dose of memantine as the extended [sustained] release dosage form.” Teva contended that the claim term is indefinite under 35 U.S.C. § 112. According to Teva, the term requires the comparison of a concentration profile of an immediate-release formulation and a concentration profile of an extended-release formulation, as measured in human pharmacokinetic studies. Teva asserted, neither the claim language nor the specification adequately describes how to conduct the studies to obtain those concentration profiles, and differences in study design lead to variable results in the claim-required comparison. Forest argued that, under the claim language, the dC/dT of the extended-release formulation is to be derived from a human study, and then compared to the dC/dT from the computer-derived curve of the immediate-release formulation shown for Namenda 20 mg in Figures 1A and 2D of the specification.

The district court construed the claim to require that the concentration profile of the extended-release formulation and the concentration profile of the immediate-release formulation be measured in human pharmacokinetic studies. The court concluded that the intrinsic evidence does not disclose a specific human-study design or provide guidance as to how to design a human study. The court also found that the extrinsic evidence of how a person of skill in the art would understand the language at issue, including undisputed expert testimony, showed that “measurements from human [pharmacokinetic] studies vary widely in terms of the concentration profiles they generate” for any particular memantine formulation. Because “[a] person of ordinary skill in the art would not know, with reasonable certainty, which ‘human [pharmacokinetic] study’ on which to rely when considering whether a formulation of memantine might infringe” and because human-study results are so variable, the court ruled, claim 1 and the other claims it represented are indefinite. Thus Delaware court entered a final judgment of invalidity based on indefiniteness.

CAFC reviewed de novo a district court’s determination of indefiniteness, but reviewed for clear error any of the district court’s underlying findings of fact based on extrinsic evidence. Forest contended that the district court erred by construing the claim to require that both of the concentration profiles being compared—the profiles of the extended- and immediate-release formulations—be derived from measurements in human pharmacokinetic studies. CAFC agreed with the district court & rejected Forest’s argument. Court said that language of claim 1 requires “a plasma memantine concentration profile”, as measured in a single-dose human PK [pharmacokinetic] study. The specification describes Figures 1A and 2D as showing concentration profiles of a 20 mg memantine immediate-release formulation and a 20 mg memantine extended-release formulation generated by a predictive pharmacokinetic software program called GastroPlus. The descriptions of the figures are no more than what they purport to be: descriptions of the figures. They do not constitute a definition and are not even directed to the meaning of the claim terms. Elsewhere, the specification does expressly define terms, such as “dC/dT”. Indeed, the merely illustrative character of the figures is confirmed by the fact that the figures show profiles only for particular doses, not profiles for the full range of doses covered by the claims—for which immediate-release profiles are needed but not found in those figures. The prosecution history also provides no support for Forest’s proposed construction. The inventor declaration submitted during prosecution describes the results of a human pharmacokinetic study from which both immediate-release and extended-release profiles were derived. The inventor compared those two profiles measured in the human study; he did not compare the extended-release profile from the human study to the immediate-release profile in Figures 1A and 2D.

Moreover the district court’s indefiniteness ruling is supported by precedents that hold claims indefinite in particular circumstances where the claims require measured quantities (absolute or relative), different techniques for such measurements are known in the art and some produce infringing results and others not, the intrinsic evidence does not adequately specify the technique or techniques to use, and extrinsic evidence does not show that a relevant skilled artisan would know what technique or techniques to use. Thus finally CAFC affirmed the judgment of the district court & found patents invalid as indefinite.