IP Law Daily Actavis’ generic seizure drug would infringe Oxtellar XR patents
Monday, February 8, 2016

Actavis’ generic seizure drug would infringe Oxtellar XR patents

By Jody Coultas, J.D.

A generic version of the seizure treatment Oxtellar XR would infringe Supernus Pharmaceuticals, Inc.’s patents covering the drug, according to the federal district court in Camden, New Jersey (Supernus Pharmaceuticals, Inc. v. Actavis Inc., February 5, 2016, Bumb, R.). Therefore, the court entered judgment in favor of Supernus in its infringement suit against Actavis Inc., Watson Laboratories, Inc. - Florida n/k/a Actavis Laboratories FL, Inc., Actavis Pharma, Inc., Watson Laboratories, Inc., and ANDA, Inc.

Oxtellar XR® is a once-daily extended release oxcarbazepine tablet used to treat partial epilepsy seizures in adults and children above the age of six. The drug is covered by U.S. Patent Nos. 7,722,898 (the ’898 patent), 7,910,131 (the ’131 patent), and 8,617,600 (the ’600 patent). The patents describe and claim a specific type of oxcarbazepine formulation for the treatment of seizures with a “homogenous matrix” containing the active ingredient, oxcarbazepine, and excipients. After Actavis submitted an Abbreviated New Drug Application (ANDA) seeking approval to market its generic ANDA product prior to the expiration of the patents, Supernus filed suit for infringement.

Claim construction. The court construed the term “homogeneous matrix” as “a matrix in which the ingredients or constituents are uniformly dispersed.” Cmin and Cmax are the minimum and maximum concentration, respectively, in blood or plasma at steady-state.

Infringement. Supernus asserts that the ANDA product would infringe claims 1, 6 to 8, 11, 18, and 19 of the ’898 patent and claims 6 to 8, 11, 18, 19, and 21 of the ’131 patent. Actavis conceded that its Actavis Tablets would infringe certain elements of claims 1 of the ‘898 and ‘131 patents because it was also a once-a-day administration of seizure treatment medication. However, Actavis disputed the presence of a homogeneous matrix and an agent that enhanced the solubility of oxcarbazepine.

All of the asserted claims require a pharmaceutical formulation of oxcarbazepine “comprising a homogeneous matrix.” The manufacturing process confirmed Supernus’ argument that the constituents were uniformly dispersed in the Actavis Tablets such that the tablet comprised a homogeneous matrix. Prior to receiving FDA approval, all pharmaceutical formulations must pass blend uniformity testing and content uniformity testing. The Actavis Tablets passed both tests. These tests demonstrated that the Actavis Tablets were comprised of a homogenous matrix in which the constituents were uniformly dispersed. Finally, Supernus’ presented evidence of chemical imaging of the Actavis Tablets, which confirmed that both tablets were comprised of a homogeneous matrix. Although the constituents were dispersed more uniformly in the Oxtellar XR® tablets than the Actavis Tablets, this had no bearing on whether the Actavis Tablets comprised a homogeneous matrix.

The court found that the Actavis Tablets infringed Claim 1 of the ’898 patent and Claim 1 of the ’131 patent. Element 1(c) of the patents required “at least one agent that enhances the solubility of oxcarbazepine selected from the group consisting of surface active agents complexing agents, cyclodextrins, pH modifying agents, and hydration promoting agents.” The court found there was sufficient evidence that two excipients in the Actavis Tablets acted as an agent that enhances the solubility of oxcarbazepine in the Actavis Tablets. Therefore, the Actavis Tablets comprised an element 1(c) solubility enhancing agent. Actavis’ argument that the excipients were merely “binders” and not agents that enhanced the solubility of oxcarbazepine, the functions listed in Actavis’s ANDA were merely proposed functions and a single compound may have several functions.

Some of the dependent claims at issue were also infringed, according to the court. Actavis’ 150 mg tablets did not infringe Claims 6 and 8 of the ’898 and ’131 patents, nor do the Actavis 300 mg tablets infringe Claim 8 of the ’898 and ’131 patents. However, all three dosage sizes infringe Claim 7 of the ’898 and ’131 patents. The 300 mg and 600 mg tablets infringed Claim 6 of the ’898 and ’131 patents, and the 600 mg tablets infringed Claim 8 of the ’898 and ’131 patents.

The ‘600 patent. Actavis’ generic tablets did not infringe the ’600 patent, according to the court. Claim 1 of the ’600 patent requires a “solid oral pharmaceutical formulation for once-a-day administration of oxcarbazepine comprising a homogeneous matrix.” The issue was whether the percent weight limitations found in the ’600 patent were infringed. The court found that the Actavis Tablets did not infringe those limitations.

Obviousness. Actavis failed to prove that the patents were invalid as obvious, according to the court. Actavis alleged that the asserted claims were obvious in light of a combination of prior art references setting forth oxcarbazepine and extended-release carbamazepine formulations for the treatment of seizures. However, the prior art did not disclose all of the elements of the invention and there was insufficient evidence to establish that a person of ordinary skill in the art would have had a motivation to combine the prior art references with a reasonable expectation of success. Prior to the creation of Oxtellar XR®, immediate release oxcarbazepine formulations and both immediate and extended release carbamazepine formulations were available to treat seizures. Tt was well known that significant and material differences existed between carbamazepine and oxcarbazepine, and that there were obstacles to creating an effective once daily oxcarbazepine formulation. None of the prior art references directly taught each element of the patent claims at issue, nor was it obvious that oxcarbazepine was suitable for an extended release formulation based on a combination of the prior art.

The relevant secondary considerations were insufficient to sway the court’s conclusion of nonobviousness. Supernus identified a long felt need for an extended release, once daily formulation of oxcarbazepine to treat seizures that results in an improved side effect profile, as well as increased tolerability and patient compliance. Despite industry skepticism that an effective once daily oxcarbazepine formulation could be developed, met this need. Before Supernus succeeded, others had attempted to formulate a once daily oxcarbazepine to treat seizures and failed.

Written description. Actavis argued that because the “homogeneous matrix” limitation was not described in the patents, the patents were invalid for lack of written description. However, the court found that the patent explicitly discloses the step by step manufacturing process used by the inventors to produce a homogeneous matrix tablet. The prosecution history demonstrated that the inventors amended Claim 1 to recite a homogeneous matrix derived according to the protocols set forth in the examples of the patents.

Indefiniteness. The patents were not invalid as indefinite, according to the court. Actavis argued that the patents were indefinite because the specification and prosecution history did not contain guidance on how to determine if a matrix is homogeneous. A patent must inform those skilled in the art about the scope of the invention with reasonable certainty. A person skilled in the art understood that “homogeneous” meant a mixture of two or more ingredients that are uniformly dispersed in a pharmaceutical formulation. Also, persons skilled in the art understood that perfect homogeneity was not achievable because perfect molecular uniformity in a pharmaceutical formulation was not possible. The FDA uniformity testing confirmed to skilled persons that a particular manufacturing process worked as intended.

The cases are Nos. 13-4740 (RMB/JS) and 14-1981 (RMB/JS).

Attorneys: Charles M. Lizza, William C. Baton, and Sarah A. Sullivan (Saul Ewing, LLP), Edgar H. Haug, Sandra Kuzmich, Jason A. Lief, Nicholas F. Giove, Andrew S. Roper, Laura A. Chubb, Jonathan Herstoff. Rachel P. McClure, and Kevin J. Georgek (Frommer Lawrence & Haug) for Supernus Pharmaceuticals, Inc. Charles A. Weiss, Howard S. Suh, Michael B. Eisenberg, Eric H. Yecies, Leisa Smith Lundy, Christopher M. Scott, and Nicholas P. Chiara (Holland & Knight), and Liza M. Walsh, Jennifer Critchley, Eleonore Ofosu-Antwi, and Christopher J. Borchert (Connell Foley LLP) for Actavis Inc., Watson Laboratories, Inc. - Florida n/k/a Actavis Laboratories FL, Inc., Actavis Pharma, Inc., Watson Laboratories, Inc., and ANDA, Inc.

Companies: Supernus Pharmaceuticals, Inc.; Actavis Inc.; Watson Laboratories, Inc. - Florida n/k/a Actavis Laboratories FL, Inc.; Actavis Pharma, Inc.; Watson Laboratories, Inc.; ANDA, Inc.

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