By Mark Engstrom, J.D.
In a lawsuit involving the alleged infringement of extended-release formulations of memantine, brand name Namenda XR—a drug that was developed by Adamas Pharmaceuticals to prevent calcium buildup in Alzheimer’s patients with overactive receptors for NMDA (N-methyl-D-aspartate)—a federal district court did not err in finding that all of the asserted claims were indefinite, the U.S. Court of Appeals for the Federal Circuit has ruled. Because the district court had properly construed a phrase describing a change in memantine concentration as a function of time, and had properly concluded that the intrinsic and extrinsic evidence both showed that the relevant claims were invalid as indefinite, the judgment of the district court was affirmed (Forest Laboratories, Inc. v. Teva Pharmaceuticals USA, Inc., December 11, 2017, Taranto, R.).
Lawsuit. Adamas and its exclusive licensee, Forest Laboratories (collectively, "Forest"), sued Teva Pharmaceuticals USA for the infringement of six patents. According to the plaintiffs, Teva’s generic version of Namenda XR infringed U.S. Patent Nos. 8,168,209; 8,173,708; 8,283,379; 8,329,752; 8,362,085; and 8,598,233. The patents described and claimed pharmaceutical compositions—and methods of administering those compositions—containing extended-release formulations of memantine, a substance that blocks NMDA receptors.
Prevention of calcium buildup. When activated by the neurotransmitters glutamate and glycine, NMDA receptors open calcium ion channels. In patients with overactive NMDA receptors, however, the channels stay open too long, causing calcium buildup and neurodestructive effects. Memantine, however, prevents that build-up and its associated side effects.
Memantine was traditionally administered through an immediate-release formulation, but the side effects of quick release required a dosing regimen that was difficult for many to follow. An extended-release formulation addressed those problems. Unlike the immediate-release formulation, an extended-release version did not require a low starting dose followed by dose escalation. Instead, patients could achieve the desirable "steady-state concentration levels"— with a simple dosing schedule and decreased side effects—soon after therapy began.
Claim construction. The representative claim described a composition that included an extended-release formulation of 5 to 40 mg memantine (or a pharmaceutically acceptable salt), which provided a plasma memantine concentration profile as measured in a single-dose human pharmacokinetic (PK) study, characterized by "a change in memantine concentration as a function of time (dC/dT) that is less than 50% [of] that of an immediate release dosage form comprising the same dose of memantine as the composition …"
The district court construed that 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 PK studies. The court concluded that the intrinsic evidence did 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 showed that measurements from human PK studies varied widely in terms of the concentration profiles they generated for any particular memantine formulation.
Because a person of ordinary skill in the art would not know, with reasonable certainty, which human PK study to rely on when considering whether a formulation of memantine would infringe, and because human-study results were so variable, the district court found that claim 1 and the claims it represented were all indefinite. It thus entered a final judgment of invalidity based on indefiniteness.
Forest’s contentions. Forest argued that the district court had erred by construing the representative claim to require that the profiles of the extended- and immediate-release formulations be derived from measurements in human PK studies. According to Forest, the profile for the immediate-release formulation had to be the computer-generated profile that was shown in two figures: Figures 1A and 2D. The Federal Circuit rejected that argument.
The circuit court acknowledged that: (1) the claim language required "a plasma memantine concentration profile, as measured in a single-dose human PK … study," and (2) it was grammatically possible to read that phrase as referring to "only the profile of the extended-release formulation." That reading was unreasonable, however, in the context of the intrinsic evidence. According to the court, the specification described Figures 1A and 2D as showing concentration profiles of a 20-mg memantine immediate-release formulation and a 20-mg memantine extended-release formulation that was generated by a predictive PK software program called GastroPlus. In addition, the descriptions of Figures 1A and 2D were the only intrinsic evidence that Forest had used to support its argument that the immediate-release profile in the figures supplied the immediate-release profile that was recited in the claim.
In the Federal Circuit’s view, the intrinsic evidence was insufficient to support Forest’s argument. The descriptions of the figures were no more than what they purported to be: descriptions of the figures. They were not a definition, the court explained, and they were not directed to the meaning of the claim terms. The figures were simply computer-to-computer comparisons that illustrated a possible relation between an immediate-release and extended-release formulation.
Similarly, Figures 1A and 2D did not define a fixed baseline for the claim-required comparison simply because they provided the only immediate-release concentration profile that was disclosed in the specification. Finally, the prosecution history did not provide any support for Forest’s proposed construction.
For those reasons, Forest’s claim construction was contrary to the intrinsic evidence. Further, Forest did not argue that the extrinsic evidence—including usage and other facts that were external to the patent—required that the claims called for a comparison of a human-study profile to a computer-generated profile. According to the Federal Circuit, human-study comparisons were required.
The district court, having concluded that the claims required human-study comparisons, found that no study design was specified in the patents, that the patents were not limited to the particular human study that was reported in the prosecution history, that Forest’s extrinsic evidence did not persuasively identify particular human studies that a relevant skilled artisan would know to use, and that different human pharmacokinetic studies produced widely varying concentration profiles for particular formulations.
In those circumstances, the Federal Circuit concluded, the district court’s indefiniteness ruling was supported by precedents that held claims indefinite in particular circumstances; i.e., when the claims required measured quantities (absolute or relative), when different techniques for the measurements were known in the art and some produced infringing results while others did not, when the intrinsic evidence did not adequately specify the technique or techniques to use, and when extrinsic evidence did not show that a relevant skilled artisan would know what technique to use.
Forest argued that, if the claim required that both the extended and immediate-release profiles be measured in a human study, then the claim required that both profiles be measured in the same study. The court rejected that argument. Forest had affirmatively opposed that very position before the district court, the circuit court explained, when Teva had raised it. And Forest had repeatedly argued that it would be improper to read into the claim a requirement that the dC/dT of both the extended- and immediate-release formulations be measured in the same human study.
The proposed position was not merely different from any other position that Forest had urged the district court to adopt; it was a position that Forest had affirmatively and unequivocally urged the district court to reject. In the Federal Circuit’s view, judicial efficiency supported a finding that Forest had waived that position.
The case is No. 2016-2550; 2016-2553.
Attorneys: Jeffrey B. Elikan (Covington & Burling LLP) for Forest Laboratories Inc. and Forest Laboratories Holdings, Ltd. Mark David Schuman (Carlson, Caspers, Vandenburgh, Lindquist & Schuman, PA) for Teva Pharmaceuticals USA, Inc.
Companies: Forest Laboratories Inc.; Forest Laboratories Holdings, Ltd.; Adamas Pharmaceuticals, Inc.; Merz Pharma GmbH & Co. KGaA; Merz Pharmaceuticals, GmbH; Teva Pharmaceuticals USA, Inc.
MainStory: TopStory Patent FedCirNews
Interested in submitting an article?
Submit your information to us today!Learn More