Daiichi Sankyo Co. v. Mylan Pharmaceuticals

• Decision Date: 30 July 2009
• Docket Number: Civ. No. 07-3039.,Civ. No. 06-3462.,Civ. No. 08-2752.
• Citation: 670 F.Supp.2d 359
• Parties: DAIICHI SANKYO COMPANY, LIMITED and Daiichi Sankyo, Inc., Plaintiffs and Counterclaim Defendants, v. MYLAN PHARMACEUTICals inc., Mylan Laboratories Inc., Matrix Laboratories, Ltd., and Mylan, Inc., Defendants and Counterclaim Plaintiffs.
• Court: U.S. District Court — District of New Jersey

Page 359

670 F.Supp.2d 359

DAIICHI SANKYO COMPANY, LIMITED and Daiichi Sankyo, Inc., Plaintiffs and Counterclaim Defendants, v. MYLAN PHARMACEUTICals inc., Mylan Laboratories Inc., Matrix Laboratories, Ltd., and Mylan, Inc., Defendants and Counterclaim Plaintiffs.

Civ. No. 06-3462.

Civ. No. 07-3039.

Civ. No. 08-2752.

United States District Court, D. New Jersey.

July 30, 2009.

COPYRIGHT MATERIAL OMITTED

William J. Heller, Jonathan M.H. Short, Mark H. Anania, Nicole A. Corona, McCarter & English, LLP, Newark, NJ, for Plaintiffs and Counterclaim Defendants.

Arnold B. Calmann, Jeffrey S. Soos, Katherine Ann Escanlar, Saiber LLC, Newark, NJ, for Defendants and Counterclaim Plaintiffs.

OPINION

MARTINI, District Judge.

Plaintiffs Daiichi Sankyo Company, Limited and Daiichi Sankyo, Inc. (collectively "Daiichi Sankyo") are the inventors and producers of olmesartan medoxomil, the active ingredient in the hypertension medications Benicar, Benicar HCT, and Azor. Defendants Mylan Pharmaceuticals Inc., Mylan Laboratories Inc., Matrix Laboratories, LTD., and Mylan, Inc. (collectively "Mylan") are drug manufacturers seeking to market a generic version of olmesartan medoxomil. Daiichi Sankyo filed this suit claiming infringement of its United States Patent No. 5,616,599 ("the '599 patent"). Mylan concedes infringement of the '599 patent, but counters that the '599 is invalid due to obviousness. Claim 13 of the '599 patent is the only claim at issue.¹

The parties tried this case before the Court on various days from March 31, 2009 to April 20, 2009. Thereafter, they submitted proposed findings of fact and conclusions of law. The Court carefully considered the parties' submission and the record evidence. For the reasons set forth below,² the Court finds that Mylan has failed to prove by clear and convincing evidence that the '599 patent is obvious under 35 U.S.C. § 103(a). As a result, the '599 patent is neither invalid nor unenforceable. Mylan has infringed on the '599 patent under 35 U.S.C. § 271(e)(2).

I. BACKGROUND

Olmesartan medoxomil is the active ingredient in several medications produced by Daiichi Sankyo used for the treatment of hypertension. (Stipulation of Fact ("SF") ¶ 13.) Hypertension, or high blood pressure, is one of the world's leading causes of death. (Brown 4/2/09 Tr. JA 282:20-22.) Approximately seventy-three million people in the United States age twenty and older suffer from high blood pressure, with roughly sixty-two percent of this group receiving treatment. (Boghigian 4/8/09 Tr. JA 873:9-18; JA 5275.) Hypertension contributes to stroke, myocardial infarction, and other life-threatening conditions. (Brown 4/2/09 Tr. JA 282:6-10; Carey 4/14/09 Tr. JA 1009:5-9.)

A. The Renin-Angiotensin System and Early Angiotensin Receptor Blockers

Starting in the 1970s, scientists began to understand the role of the reninangiotensin system ("RAS" in controlling hypertension.) (Brown 4/2/09 Tr. JA 279:1-JA 281:21; DTX 356-B, at JA 5175-81, 5171 & 5197-200.) Angiotensin II, a peptide produced by the RAS, binds to AT₁ receptors, which are found on the surfaces of a variety of cell types including blood vessels and renal tubules. (Id.) The constriction caused by the binding of the angiotensin II to the AT₁ receptors leads to increased blood pressure. (Id.)

By the late 1970s, scientists developed angiotensin converting enzyme inhibitors ("ACE" inhibitors), which directly interfered with the production of angiotensin II. (Brown 4/2/09 Tr. JA 282:22-284:5.) While ACE inhibitors proved effective, these compounds resulted in certain unwanted side-effects. (Cohn 4/7/09 Tr. JA 784:11-JA 785:23.)

In 1982, a Japanese pharmaceutical company, Takeda Chemical Industries Ltd. ("Takeda"), developed the first non-peptide compounds, which blocked the binding of angiotensin II to AT₁ receptors. (Brown 4/2/09 Tr. JA 284:10-285:16; Weinstock 3/31/09 Tr. JA 96:14-97:10.) Termed angiotensin II receptor blockers ("ARBs"), these Takeda compounds contained an imidazole ring—a five membered ring having two nitrogen atoms. (Weinstock 3/31/09 Tr. JA 101:4-102:7; DTX 125, at JA 4164.) One early Takeda compound, known as S-8307, employed a single six-membered phenyl ring through a methylene linkage (CH₂) at the 1-position of the imidazole ring, a butyl group at the 2-position, a chlorine atom (Cl) at the 4-position, and an acetic acid (CH₂COOH) at the 5-position. (Weinstock 3/31/09 Tr. JA 102:10-20, 104:10-106:3; DTX 356-A, at JA 5127, 5130-32.)

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Although the first of its kind, the Takeda compounds exhibited limited therapeutic value due to a lack of oral activity. (Weinstock 3/31/09 Tr. JA 100:7-8.)

B. Losartan

Using Takeda's work as lead, E.I. du Pont de Nemours Company, Inc. ("DuPont") embarked on its own ARB development program in 1982. (Id. at JA 95:23-96:1.) Several years later, in 1989, DuPont announced that it had selected one of its compounds, DuP 753, also known as losartan, for clinical trials. (Id. at JA 111:5-9.)

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Losartan resembled Takeda S-8307 in the sense that it retained the imidazole ring and the chlorine atom at the 4-position of the imidazole ring. The compound, however, differed through the addition of a biphenyl tetrazole—a six membered phenyl and a tetrazole—at the 1-position of the imidazole ring, as well as a hydroxymethyl at the 5-position. (DTX 356-A, at JA 5132, 5138.)

As a result of these changes, losartan exhibited a ten-fold greater binding affinity³ and twenty-fold greater oral activity over the Takeda compounds. (Weinstock 03/31/09 Tr. JA 112:19-JA 113:8.) Losartan represented a "milestone," becoming the first non-peptide ARB clinical candidate. (Id. at JA 111:5-9; PTX 190, at JA 10028.) DuPont disclosed losartan and several hundred structurally related ARB compounds in United States Patent No. 5,138,069 ("the '069 patent"). (Weinstock 3/31/09 Tr. JA 119:11-23; DTX 195, at JA 3602-746.)

C. Development of Olmesartan Medoxomil

Following DuPont's success with losartan, more than twenty pharmaceutical companies established ARB research programs. (Lipinski 4/20/09 Tr. JA 1558:19-20.) Daiichi Sankyo started its own program, in late 1989, using losartan as a reference. (Yanagisawa 4/17/09 Tr. JA 1424:10-12, 1457:1-5.) The company employed a team of scientists lead by Dr. Hiroaki Yanagisawa "to come up with a drug that had ten times the activity of losartan" with "long enough duration so as to be dosed once-a-day." (Id. at JA 1422:10-20.)

After testing several hundred compounds, Daiichi Sankyo discovered the chemical compound olmesartan. (Id. at JA 1447:5-6; PTX 202-A, at JA 10499, 10256-498.) Dissatisfied with the compound's oral absorption, Daiichi Sankyo attempted to improve olmesartan's properties by attaching various ester promoieties to the chemical, converting olmesartan into the prodrug olmesartan medoxomil. (Yanagisawa 4/17/09 Tr. JA 1442:25-1446:1; PTX 26, at JA 9548-63.) The company discovered that a medoxomil ester at the 5-position of the imidazole ring led to a compound with 100 times the potency of losartan on oral administration. The medoxomil ester also crystallized, an "important factor in [a drug's] manufacturing, its formulation and in quality assurance." (Yanagisawa 4/17/09 Tr. JA 1445:20-23.)

Based on this research, on April 26, 1991, Daiichi Sankyo filed a patent application in Japan, and subsequently in the United States, claiming olmesartan and olmesartan medoxomil. (SF ¶ 8; PTX 1, at JA 5611.) This led to the issuance the '599 patent by the United States Patent and Trademark Office ("PTO") on April 1, 1997, with Claim 13 specifically covering olmesartan medoxomil.⁴ (SF ¶¶ 6, 11; PTX 1, at JA 5610.)

Like losartan and the early Takeda compounds, olmesartan medoxomil retained an imidazole backbone and possessed a biphenyl tetrazole at the 1-position of the imidazole ring. (PTX 1, JA 5610-11.)

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However, olmesartan medoxomil differed from losartan in two major respects. First, at the 4-position of the imidazole ring, olmesartan medoxomil employed a hydroxyisopropyl (C(CH₃)₂OH) instead of a chlorine atom. (Weinstock 3/31/09 Tr. JA 121:11-17, 125:6-127:1 & 129:3-5; DTX 356-A, at JA 5143, 5146.) Second, the compound contained a medoxomil ester linked to a carboxylic acid at the 5-position.⁵ (Weinstock 3/31/09 Tr. JA 121:1-10; DTX 356-A, at JA 5143, 5146.)

D. DuPont's '902 Patent Compounds and DuP 532

DuPont itself continued to look for improvements to losartan prior to Daiichi Sankyo's April 26, 1991 patent application in Japan. (Hieble 4/7/09 Tr. JA 711:17-23.) This additional research led to the disclosure of the '902 patent compounds, as well as DuP 532.

Following the disclosure of the '069 patent compounds, DuPont revealed six additional compounds in United States Patent No. 5,137,902 ("the '902 patent") with a February 4, 1991 priority date. (DTX 96, at JA 3747-52.) A "culmination of DuPont's ARB research," the '902 patent compounds utilized losartan's biphenyl-tetrazoleimidazole structure and contained a straight-chain propyl at the 2-position of the imidazole ring. (Weinstock 3/31/09 Tr. JA 119:24-120:12; DTX 96, at JA 3748.) Examples 1, 2, and 6 of the '902 patent compounds use a carboxylic acid at the 5-position, while Examples 3, 4, and 5 employ an aldehyde (CHO). (Lipinski 4/20/09 Tr. JA 1616:1-2.) At the 4-position of the imidazole ring, the '902 patent compounds contain various branched alkyls, including an ethyl, methyl, t-butyl, and isopropyl. (DTX 356-A, at JA 5143.)

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Although DuPont ultimately chose not to commercialize the '902 patent compounds, the most preferred '902 patent compounds exhibited oral activity "approximately 2 to 4 fold higher than most active compound specifically disclosed [in the '069...