Medicines Co. v. Mylan Inc.

• Decision Date: 27 October 2014
• Docket Number: No. 11–cv–1285,11–cv–1285
• Court: U.S. District Court — Northern District of Illinois
• Parties: The Medicines Company, Plaintiff, v. Mylan Inc., Mylan Pharmaceuticals Inc., and Bioniche Pharma USA, LLC, Defendants.

72 F.Supp.3d 837

The Medicines Company, Plaintiff

v.Mylan Inc., Mylan Pharmaceuticals Inc., and Bioniche Pharma USA, LLC, Defendants.

No. 11–cv–1285

United States District Court, N.D. Illinois, Eastern Division.

Signed October 27, 2014

Porter F. Fleming, Angus Chen, Jason A. Lief, Laura Krawczyk, Jason Kanter, Sam Desai, Erika Selli, Jonathan Herstoff, Frommer Lawrence & Haug LLP, New York, NY, John Bostjancich, Patricia Susan Smart, Smart & Bostjancich, Chicago, IL, for Plaintiff.

Anne M. Readel, David E. Jones, Autumn N. Nero, David J. Harth, Emily J. Greb, William W. Adolfsen, Perkins Coie LLP, Madison, WI, James B. Coughlan, Perkins Coie LLP, Chicago, IL, Scott D. Eads, Perkins Coie LLP, Portland, OR, Shannon M. Bloodworth, Perkins Coie LLP, Washington, DC, for Defendants.

MEMORANDUM OPINION AND ORDER

AMY J. ST. EVE, District Court Judge:

In this patent infringement action, The Medicines Company (“TMC”) asserts that Defendants' proposed generic bivalirudin drug product infringes United States Patent No. 7,582,727 (the “ '727 patent”). Specifically, TMC claims that Defendants Mylan, Inc., Mylan Pharmaceuticals Inc. and Bioniche Pharma USA, LLC (collectively, “Mylan”) proposed generic bivalirudin drug infringes claims 1–3, 7–10, and 17 of the '727 patent. (See R.1, Compl.; PTX 397, Parties' Statement of Uncontested Facts, ¶ 38.) Mylan disputes that its proposed drug infringes the '727 patent and asserts that the '727 patent is invalid on grounds of anticipation, obviousness, and non-enablement and unenforceable for inequitable conduct. The Court held a bench trial on TMC's infringement claim and Mylan's counterclaims regarding the '727 patent.¹ Having considered the evidence and the parties' arguments, the Court finds as follows: (1) Mylan failed to prove by clear and convincing evidence that claims 1–3, 7–10, and 17 of the '727 patent are invalid or unenforceable; and (2) Mylan's proposed bivalirudin drug product infringes claims 1–3, 7–10, and 17 of the '727 patent.

BACKGROUND

I. The '727 Patent

The '727 patent was filed with the United States Patent and Trademark Office (“PTO”) as U.S. Application No. 12/180,553 on July 27, 2008 and issued as the '727 patent on September 1, 2009. (PTX 1, '727 patent ; see PTX 397, ¶ 6.) The '727 patent is entitled “Pharmaceutical Formulations of Bivalirudin and Processes of Making the Same.” (Id. ) Dr. Gary Musso and Dr. Gopal Krishna are the named inventors of the '727 patent, but TMC owns all rights, title, and interest to the '727 patent.² (PTX 397, ¶¶ 8, 9.)

The '727 patent generally pertains to pharmaceutical formulations of bivalirudin, a reversible thrombin inhibitor used to temporarily prevent blood clotting during catherization procedures. (See id., at col. 1:21–56; PTX 397, ¶ 6.) The section of the '727 patent entitled “Background of the Invention” states: “[o]ne class of anticoagulants is direct thrombin inhibitors that disrupt the activity of thrombin, an important protein in the coagulation cascade.” (Id., col. 1:49–51.) The '727 further states: “[i]n particular, bivalirudin (ANGIOMAX ®), which directly inhibits thrombin by specifically binding to both its catalytic site and to the anion-binding exosite, is regarded as a highly effective anticoagulant for use during catherization [sic] procedures.” (Id., col. 1:52–56.) The medical and therapeutic applications of bivalirudin, make it “essential that the bivalirudin formulation maintains a high level of purity.” (Id., col. 2:1–3.) The compounding process for the bivalirudin formulation may generate impurities, such as Asp⁹ –bivalirudin (from deamidation of asparagine at position 9 of bivalirudin to aspartic acid) and D–Phe¹² impurities (from isomerization of L-phenylalanine at position 12 of bivalirudin to the D-isomer). (Id. at col. 2:1–13.) The '727 patent also relates to development of processes for synthesizing bivalirudin that minimize the generation of impurities and pharmaceutical batches produced by such processes. (Id. at col. 2:19–22.) By way of background, this compounding process involves three basic steps. (See DTX 1080, Compounding Instructions–Bivalirudin Formulation, at MEDMYL4509463, MEDMYL450971.) First, the active pharmaceutical ingredient (“API”), bivalirudin, is dissolved into a mannitol solution to form a bivalirudin solution. Second, the resulting bivalirudin solution is mixed with a pH-adjusting solution, such as sodium hydroxide, to raise the pH of the bivalirudin API to an acceptable level. Third, the mannitol solution and the pH-adjusting solution are removed from the mixture to form the final drug product.³

The asserted claims describe pharmaceutical batches of bivalirudin. Specifically, claim 1 of the '727 patent teaches “pharmaceutical batches” of bivalirudin having a maximum Asp⁹ impurity level of 0.6%. (PTX 1, col. 25:56–64.) Dependent claims 2 and 3 contain even stricter limitations on Asp⁹ impurities, reducing the maximum allowable level of Asp⁹ impurities to 0.4% and 0.3%, respectively. (See id. at col. 25:65–26:56.) Dependent claims 7–10 and 17 contain all the limitations of claim 1 and additional limitations regarding the maximum level of D–Phe¹² –bivalirudin impurities (claim 7), the type of pharmaceutically acceptable carrier contained in the final drug product (claims 8–10), and the base used to adjust the pH of the final drug product (claim 17). (See id. at col. 27–28.)

The asserted claims of the '727 patent read as follows:

1. Pharmaceutical batches of a drug product comprising bivalirudin (SEQ ID No: 1) and a pharmaceutically acceptable carrier for use as an anticoagulant in a subject in need thereof, wherein the batches have a pH adjusted by a base, said pH is about 5–6 when reconstituted in an aqueous solution for injection, and wherein the batches have a maximum impurity level of Asp⁹ –bivliarudin of about 0.6% as measured by HPLC [high-performance liquid chromatography ].

2. The pharmaceutical batches of claim 1, wherein the maximum impurity level of Asp⁹ –bivalirudin does not exceed about 0.4% as measured by HPLC.

3. The pharmaceutical batches of claim 2, wherein the maximum impurity level of Asp⁹ –bivalirudin does not exceed about 0.3% as measured by HPLC.

7. The pharmaceutical batches of claim 1, wherein the batches have a maximum level of D–Phe¹² –bivalirudin that does not exceed about 2.5% as measured by HPLC.

8. The pharmaceutical batches of claim 1, wherein the pharmaceutically acceptable carrier comprises one or more of a bulking agent or a stabilizing agent.

9. The pharmaceutical batches of claim 8, wherein the bulking agent is a sugar.

10. The pharmaceutical batches of claim 9, wherein the sugar is mannitol.

17. The pharmaceutical batches of claim 1, wherein the base is sodium hydroxide.

(PTX 1, col. 25:55–28:9.) During claim construction, the Court construed the term “pharmaceutical batches” as follows:

“Pharmaceutical batches” may include a single batch, wherein the single batch is representative of all commercial batches (see generally, Manual of Policies and Procedures, Center for Drug Evaluation and Research, MAPP 5225.1, Guidance on the Packaging of Test Batches at 1) made by a compounding process, and wherein the levels of, for example, Asp⁹ –bivalirudin, total impurities, and largest unknown impurity, and the reconstitution time represent levels for all potential batches made by said process. “Batches” may also include all batches prepared by a same compounding process.

(See R.119, Claim Construction Order.)

The '727 patent specification describes several experiments Dr. Musso and Dr. Krishna ran and provides the resulting Asp⁹ impurity levels for the batches produced in each experiment. Examples 4 and 5 in the specification provide a comparison of an old “inefficient” mixing process (Example 4) and a new “efficient” mixing process (Example 5), and Tables 6 and 7 report the impurity levels and reconstitution times for Original Angiomax ® batches produced using inefficient mixing (Table 6) and Improved Angiomax ® batches produced using efficient mixing (Table 7). (See PTX 397, ¶¶ 13–17.)

Comparison of the results in Table 6 (“inefficient mixing”) and Table 7 (“efficient mixing”) reveals that the percentage of Asp⁹ –bivalirudin impurities in the 24 reported batches of Improved Angiomax ® (shown in Table 7, recreated below) has a lower mean, standard deviation, and a lower maximum level when compared to the 87 reported batches of Original Angiomax ® (shown in Table 6, recreated below):

TABLE 6

Characteristics of the batches generated by the compounding process that features rapid addition of a pH-adjusting solution and inefficient mixing rates.
No. of batches	Mean ± SD	Maximum
Asp9 –bivalirudin (%)	87	0.5 ± 0.4	3.6
Total Impurities (%)	63	1.4 ± 0.5	3.0
Largest unknown impurity (%)	86	0.3 ± 0.1	0.5
Reconstitution Time (seconds)	85	30 ± 12	72

(See PTX 1, col. 22:10–20.)

TABLE 7

Characteristics of the batches generated by the compounding process that features addition of a pH-adjusting solution at a constant rate with efficient mixing.
No. of batches	Mean ± SD	Maximum
Asp9 –bivalirudin (%)	24	0.3 ± 0.1	0.6
Total Impurities (%)	24	1.0 ± 0.4	2.0
Largest unknown impurity (%)	24	0.2 ± 0.1	0.3
Reconstitution Time (seconds)	24	18 ± 6	42

(See id. at col. 23:1–13.) In addition to the 24 reported batches of Improved Angiomax ®, the patent specification discloses that Table 7 did not include the results for one batch because “the method used to generate the batch was not compliant with the protocol established for this study.” (See id. at col. 23:14–16.)

II. The Present Litigation

TMC is the owner of New Drug Application (“NDA”) No. 20–873, which was approved by the U.S. Food and Drug Administration (“FDA”), on December 15, 2000, for the manufacture and sale of a bivalirudin drug product for intravenous injection. (PTX 397, ¶ 19.) TMC's bivalirudin dug product is marketed in the United States under the tradename Angiomax®. (Id., ¶ 20.) Bivalirudin is the active ingredient in TMC's Angiomax ® drug, which is indicated for use as...