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Grunenthal Gmbh v. Alkem Laboratories Ltd.

United States Court of Appeals, Federal Circuit

March 28, 2019


          Appeals from the United States District Court for the District of New Jersey in Nos. 2:13-cv-04507-CCC-MF, 2:13-cv-06929-CCC-MF, 2:13-cv-07803-CCC-MF, 2:14-cv-03941-CCC-MF, 2:14-cv-04617-CCC-MF, 2:15-cv-06797-CCC-MF, Judge Claire C. Cecchi.

          Michael Sitzman, Gibson, Dunn & Crutcher LLP, San Francisco, CA, argued for all plaintiffs-cross-appellants. Plaintiff-cross-appellant Assertio Therapeutics, Inc. also represented by Jaysen Chung; Christine Ranney, Denver, CO; Timothy P. Best, Los Angeles, CA.

          Linda A. Wadler, Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, Washington, DC, for plaintiff-cross-appellant Grunenthal GmbH. Also represented by Krista E. Bianco.

          Michael E. Joffre, Sterne Kessler Goldstein & Fox, PLLC, Washington, DC, argued for defendant-appellee. Also represented by William H. Milliken.

          Robert J. Gajarsa, Latham & Watkins LLP, Washington, DC, argued for defendants-appellants Hikma Pharmaceuticals International Limited, Hikma Pharmaceuticals USA Inc. Also represented by Kenneth G. Schuler, Chicago, IL; Gregory Sobolski, San Francisco, CA.

          Imron T. Aly, Schiff Hardin, Chicago, IL, argued for defendant-appellant Alkem Laboratories Limited. Also represented by Cindy Ahn, Jason Harp, Neil Lloyd; Ahmed M.T. Riaz, New York, NY.

          Before Reyna, Taranto, and Chen, Circuit Judges.


         Alkem Laboratories Limited, Hikma Pharmaceuticals International Limited, and Hikma Pharmaceuticals USA Inc. appeal the judgment of the district court that U.S. Patent No. 7, 994, 364 is not invalid for obviousness or lack of utility. Grünenthal GmbH and Assertio Therapeutics, Inc., formerly Depomed, Inc., cross-appeal the finding that Hikma Pharmaceuticals International Limited, Hikma Pharmaceuticals USA Inc., and Actavis Elizabeth LLC do not infringe U.S. Patent No. 8, 536, 130. Because the district court did not err in its conclusions, we affirm.


         A. Patents at Issue

         Grünenthal GmbH ("Grünenthal") is the assignee of U.S. Patent Nos. 7, 994, 364 ("the '364 patent") and 8, 536, 130 ("the '130 patent"). Assertio Therapeutics, Inc., formerly Depomed, Inc. ("Depomed"), is an exclusive licensee of both patents. Each patent is listed in the U.S. Food and Drug Administration's ("FDA") Approved Drug Products with Therapeutic Equivalence Evaluations (the "Orange Book") for NUCYNTA® ER (extended release), a tapentadol hydrochloride tablet. J.A. 52853, 52856. The '364 patent is directed to the Form A polymorph[1] of the chemical compound tapentadol hydrochloride and a method of treating pain and/or urinary incontinence.[2] See '364 patent, Abstract; id. col. 18 l. 66-col. 19 l. 4. The '364 patent states that Form A "is very stable at ambient conditions and therefore useful for producing a pharmaceutical composition." Id. col. 1 ll. 63-67. The asserted claims of the '364 patent, claims 1, 2, 3, and 25, recite various X-ray powder diffraction (XRPD) patterns. See, e.g., id. col. 18 l. 65-col. 19 l. 4. XRPD is a method for measuring the X-rays scattered by a polycrystalline sample as a function of scattering angle. Each polymorph has a unique XRPD.

         The '130 patent describes a method of using tapentadol and tapentadol hydrochloride for the treatment of polyneuropathic pain. Polyneuropathic pain is a type of pain caused by damage to multiple nerves. In contrast, mononeuropathic pain is pain associated with damage to a single nerve.

         Claim 1 of the '130 patent is directed to the method of treating "polyneuropathic pain" with tapentadol or "a pharmaceutically acceptable salt thereof," i.e., tapentadol hydrochloride. '130 patent, col. 18 ll. 2-7. Claim 2 is directed to the method of treating polyneuropathic pain using "a hydrochloric salt" of tapentadol, i.e., tapentadol hydrochloride. Id. col. 18 ll. 8-10.

         B. Prior Art References

         There are two different polymorphs of tapentadol hydrochloride: Form A and Form B. Form B of tapentadol hydrochloride was known in the art and previously disclosed in U.S. Patent No. 6, 248, 737 ("the '737 patent"), also assigned to Grünenthal. See '364 patent, col. 1 ll. 58-63. The '737 patent discloses a number of compounds, including tapentadol hydrochloride, intended to have an analgesic effect suitable for the treatment of pain. See, e.g., '737 patent, col. 1 l. 52-col. 2 l. 36; id., Example 25, col. 20 ll. 1- 20.[3] Specifically, Example 25 of the '737 patent discloses the steps for synthesizing tapentadol hydrochloride. The '737 patent states that tapentadol hydrochloride was crystallized, but it does not describe the resulting crystal structure, nor does it discuss polymorphs.

         Also known in the art at the time of filing was the concept of polymorph screening, which is the practice of characterizing all crystal forms of a chemical compound. A 1995 article by Byrn et al.[4] ("Byrn") "describes a conceptual approach to the characterization of pharmaceutical solids," including a flow chart describing investigative steps to determine whether polymorphs are possible. J.A. 57372-73. Byrn does not outline a particular method to definitively test for polymorphism.[5] Instead, it provides a decision tree outlining, among other things, different ways to gain additional information about whether polymorphs exist for a particular chemical compound and lists various analytical tests to identify polymorphs. J.A. 57373.

         To determine whether polymorphs are possible, Byrn lists a number of solvents to be used in recrystallizing the substance in question. The listed solvents are water, methanol, ethanol, propanol, isopropanol, acetone, acetonitrile, ethyl acetate, and hexane. Id. Other variables such as temperature, concentration, agitation, and pH could affect the solids produced by recrystallization with these various solvents. Id., Figure 1. This case focuses on the extent and limits of what the disclosure in Byrn teaches about discovering polymorphs, if any, of a known compound, and ultimately, whether a skilled artisan would reasonably expect the recrystallization of tapentadol hydrochloride to result in any polymorph, let alone one with the physical properties of Form A.

         C. Proceedings in District Court

         Grünenthal and Depomed (collectively, "Cross-Appellants") brought suit against Alkem Laboratories Limited ("Alkem"), Hikma Pharmaceuticals International Lim-ited, [6] Hikma Pharmaceuticals USA Inc. (collectively, "Hikma"), and Actavis Elizabeth LLC ("Actavis"), [7] alleging infringement of the '364 and '130 patents stemming from their respective Abbreviated New Drug Application ("ANDA") filings seeking to market generic versions of immediate and extended release tapentadol hydrochloride tablets.[8] All defendants subsequently stipulated to infringement of the '364 patent. Alkem and Hikma challenged the validity of the '364 and '130 patents.

         After a bench trial, the district court concluded that Alkem infringes the '130 patent, but that Actavis and Hikma do not. In re Depomed Patent Litig., No. 13-cv-4507-CCC-MF, 2016 WL 7163647, at *2 (D.N.J. Sept. 30, 2016) ("Depomed Litigation"). The district court also determined that the '364 patent is not invalid as obvious, that the '130 patent is not invalid as anticipated, and that the '130 patent is not invalid due to obviousness-type double patenting in light of U.S. Patent No. RE39, 593. Id.

         Alkem and Hikma each appeal different aspects of the district court's invalidity rulings. Grünenthal and Depomed collectively appeal the district court's finding of noninfringement of the '130 patent. We have jurisdiction under 28 U.S.C. § 1295(a)(1).


         Much of Hikma's argument on appeal is made in the alternative and many of its arguments become moot should we hold Hikma does not infringe the '130 patent. Therefore, we will first address Cross-Appellants' arguments regarding noninfringement. We will then address Alkem's appeal of the finding that the '364 patent is not invalid as obvious and Hikma's challenge to the utility and validity of the '130 patent.

         A. Infringement

         We begin with a discussion of Grünenthal and Depomed's cross-appeal. Because neither Hikma's nor Ac-tavis's proposed label is indicated to treat polyneuropathic pain, and the case made by Grünenthal and Depomed for indirect infringement depended on the proposed label indications, we agree with the trial court that Hikma and Ac-tavis ...

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