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Bayer Intellectual Property GMBH v. Aurobindo Pharma Ltd.

United States District Court, D. Delaware

July 13, 2018



          STENGEL, C.J. [1]

I. Introduction

         This is a consolidated patent infringement action arising under the Hatch-Waxman Act. The plaintiffs, Bayer Intellectual Property GMBH, Bayer Pharma AG, and Janssen Pharmaceuticals, Inc. (collectively “Bayer”) allege infringement of claim 16 of U.S. Patent No. 7, 157, 456 (the “'456 patent”), which claims the compound rivaroxaban. The parties concede infringement. Defendants, Mylan Pharmaceuticals Inc. and Sigmapharm Laboratories, LLC submit that the patent is invalid as obvious. I held a four-day bench trial beginning on March 5, 2018 through March 9, 2018.[2]

         Presently before me are the parties' proposed findings of fact and conclusions of law. Pursuan t to Federal Rule of Civil Procedure 52(a), having considered the entire record and the relevant law, I find that the asserted claim of the '456 patent is not invalid due to obviousness. The findings of fact and conclusions of law are set forth in further detail below.

         II. Procedural History

         On October 9, 2015, plaintiffs filed a complaint alleging infringement of the '456, '860, and '339 patents. (Doc. No. 1.) Sigmapharm filed its answer on October 30, 2015, alleging that the patents were invalid. (Doc. No. 26.) On January 19, 2016, Mylan filed its answer, also asserting as an affirmative defense that the patents were invalid. (Doc. No. 66.)

         The parties filed separate stipulations stating that the products that are the subject of defendants' ANDAs infringe any valid claims of the '456, '860, and '339 patents, including claim 16 of the '456 patent. (Doc. Nos. 232, 236.) Plaintiffs later notified defendants that, for purposes of narrowing the issues for trial, they would only assert claim 16 of the '456 patent. (Doc. No. 286 at ¶ 8; Doc. No. 287 at ¶ 15.)

         Beginning on March 5, 2018, I held a four-day bench trial. The parties submitted post-trial briefing and on April 25, 2018 I heard closing arguments.

         III. Findings of Fact

         A. The parties

         1. The Bayer plaintiffs are corporations organized and existing under the laws of the Federal Republic of Germany. (Doc. No. 286-1, Ex. 6, ¶¶ 6-7.)

         2. Janssen is a corporation organized and existing under the laws of the Commonwealth of Pennsylvania. (Id. at ¶ 8.)

         3. Mylan is a corporation organized and existing under the laws of the State of West Virginia. (Id. at ¶ 18.)

         4. Sigmapharm is a limited liability company organized and existing under the laws of the Commonwealth of Pennsylvania. (Id. at ¶ 14.)

         5. Janssen is the holder of approved New Drug Application No. 22406 for Xarelto® (rivaroxaban). (Id. at ¶ 12.)

         6. Xarelto® is a factor Xa inhibitor which is indicated to (1) reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; (2) for the treatment of deep vein thrombosis (DVT); (3) for the treatment of pulmonary embolism (PE); (4) for the reduction in the risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months; and (5) for the prophylaxis (prevention) of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery. (Id. at ¶ 10.)

         B. The patent-in suit

         7. The '456 patent is entitled “Substituted Oxazolidinones and Their Use in the Field of Blood Coagulation.” (Id. at ¶ 1.)

         8. The named investors are Alexander Straub, Thomas Lampe, Jens Pohlmann, Susanne Roehrig, Elisabeth Perzborn, Karl-Heinz Schlemmer, and Joseph Pernerstorfer. (Id.)

         9. The patent was issued on January 2, 2007, expires on August 28, 2024, and is currently assigned to Bayer Intellectual Property GmbH. (Id. at ¶¶ 1, 2.) The priority date for the patent is December 24, 1999. (3/5/18 a.m. Tr. 33:12-19.)

         C. ANDA No. 208546

         10. Sigmapharm submitted Abbreviated New Drug Application (“ANDA”) No. 208546 to the FDA seeking approval of its proposed rivaroxaban tablets under § 505(j)(2)(A)(vii)(IV) of the Federal Food, Drug and Cosmetic Act (“Paragraph IV Certification”) that the claims of the '456 patent and U.S. patent Nos. 7, 585, 860 (the “'860 patent”) and 7, 592, 339 (the “'339 patent”) were invalid, unenforceable, and/or will not be infringed by the commercial manufacture, use, or sale of Sigmapharm's proposed rivaroxaban tablets. (Doc. No. 286-1, Ex. 6, ¶ 16.)

         11. By letter dated August 31, 2015, Sigmapharm notified plaintiffs that it submitted ANDA No. 208546. (Id. at ¶ 15.)

         D. ANDA No. 208561

         12. Mylan submitted ANDA No. 208561 also seeking approval of its proposed rivaroxaban tablets contained in a Paragraph IV Certification that the '456, '860, and '339 patents were invalid, unenforceable, and/or would not be infringed by the commercial manufacture, use, or sale of Mylan's proposed rivaroxaban tablets. (Id. at ¶ 20.)

         13. On September 15, 2015, Mylan notified plaintiffs that it submitted ANDA No. 208561. (Id. at ¶ 19.)

         E. Expert Witnesses

         14. Dr. Steven Brickner, defendants' medicinal chemistry expert, received a Ph.D. in organic chemistry from Cornell University; worked in the pharmaceutical industry as a medicinal chemist for 27 years, and has another nine years' experience as a medicinal chemistry consultant and is a named inventor on thirty (30) U.S. Patents and Patent Applications. (Defs. FF. ¶ 12 (citing 3/5/18 a.m. Tr. 9:20-11:11; 12:14-13:7; DTX-1266).) Dr. Brickner is accredited with discovering linezolid. (Id. (citing 3/5/18 a.m. Tr. 10:12-11:13).)

         15. Dr. Spada, plaintiffs' medicinal chemistry expert, was the medicinal chemistry head of a factor Xa inhibitor program from 1993 through 1999; he is the coauthor/inventor on numerous publications and patent applications in the factor Xa space, including the Ewing II article, discussed infra; and was familiar with the factor Xa field in December of 1999 including by reviewing the literature and attending conferences. (Pltffs. FF. ¶ 16 (citing 3/8/18 a.m. Tr. 57:2-59:1; PTX-9).)

         16. Although both Dr. Spada and Br. Brickner are experienced medicinal chemists, I find that Dr. Spada's testimony is credible and reliable and it informs my obviousness analysis.[3]

         F. The Person of Ordinary Skill in the Art

         17. The POSA pertaining to the '456 patent as of December 24, 1999 (the priority date), is defined as follows,

A scientist with a Ph.D. in organic chemistry, or an equivalent discipline, with approximately seven (7) years of experience with the synthesis of organic compounds; the purification of organic compounds; and designing pharmaceutical compounds. The POSA would also understand the general principles of drug design and delivery, including pharmacology, pharmacokinetics, metabolism, toxicology and formulation, as well as the role of compounds that inhibit the enzyme factor Xa and other anticoagulants in the treatment and prevention of thromboembolic disorders and the ability to understand work presented by others in these fields.

(Defs. FF ¶ 22 (citing 3/5/18 a.m. Tr. 34:16-35:20).)[4]

         G. Scope and Content of the Prior Art

         18. As of the priority date, there were 18 companies and hundreds of researchers working in the factor Xa field. (3/8/18 a.m. Tr. 70:5-15.)

         19. Among the hundreds of articles published in the field, plaintiffs rely on four review articles published in 1999 that summarize the state of the art: Al-Obeidi, Ewing III, Zhu, and Fevig. (Id. at 71:4-9; PTX-3 (Al-Obeidi); PTX-4 (Ewing III); PTX-6 (Zhu); PTX-325A (Fevig).)

         20. Anticoagulants are compounds that prevent or treat problematic blood clots.[5](3/5/18 a.m. Tr. 16:17-23.)

         21. Anticoagulants work by suppressing either the synthesis or function of various clotting factors. (Id.)

         22. A factor Xa inhibitor is one such anticoagulant that prevents blood clot formation. Factor Xa inhibitors bind to factor Va, which prevents the formation of a prothombinase complex that converts prothrombin to thrombin. (Id. at 20: 10-16.) By preventing the formation of thrombin, there is no thrombin to convert fibrinogen to fibrin. (Id.) Without fibrin, a clot cannot form. (Id.)

         23. Factor Xa inhibitors have two key binding sites: the S1 and S4 pockets. (Id. at 22: 11-16.)

         24. The portion of the factor Xa inhibitor that interacts with the S1 site is known as the “P1 group, ” and the portion that interacts with the S4 pocket is known as the “P4 group.” (Pltff. FF. ¶ 20.) The central scaffold is known as the “core.” (Id.)

         25. The conventional wisdom in December of 1999 was that in order to be a potent factor Xa inhibitor a compound required a basic P1 group and an aromatic or basic P4 group. (3/8/18 a.m. Tr. 60:12-17; 60:22-61:4, 77:25-81:15; see PTX-3 at 949; see also PTX-325A at 89, 93, 95.)

         26. The conventional wisdom for designing factor Xa inhibitors was based on the knowledge of the structure of S1 and S4 pockets. The S1 pocket was known to contain a negatively charged aspartic acid and the idea was to use a positively charged residue with at least some basicity[6] to interact with the negatively charged aspartic acid, like opposite magnetic poles attracting to each other. (3/8/18 a.m. Tr. 77:25-79:4.)

         27. The S4 pocket was known to have three aromatic rings with a strong affinity for other aromatic rings, and also had a cation hole. (Id. at 79:5-81:5.) Conventional wisdom taught that “aromatic and/or basic residues were tolerated and important for binding in the P4 pocket.” (Id. 80:13-15.)

         IV. Conclusions of Law

         1. Subject matter jurisdiction over this matter is proper pursuant to 28 U.S.C. §§ 1331, 1338, and 2201.

         2. “The presumption that all patents are valid is the starting point for any obviousness determination.” Impax Labs., Inc. v. Lannett Holdings Inc., 246 F.Supp.3d 1024, 1035-36 (D. Del. 2017) (citing 35 U.S.C § 282).

         3. A party challenging a patent based on obviousness bears the burden of demonstrating by clear and convincing evidence that “the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious to a person having ordinary skill in the art.” Bayer Pharma AG v. Watson Laboratories, Inc., 183 F.Supp.3d 579, 584 (D. Del. 2016) (quoting 35 U.S.C. § 103(a)); see Impax Labs., Inc., 246 F.Supp.3d at 584-85.

         4. The standard requires “a reasonable expectation of success.” Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006) (quoting In re ...

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