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Daiichi SANKYO Co, Limited v. Mylan Pharmaceuticals Inc.

July 30, 2009

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.



The opinion of the court was delivered by: Hon. William J. Martini

OPINION

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.*fn1

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,*fn2 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.)

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.)

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 affinity*fn3 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.*fn4 (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.)

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.*fn5

(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.)

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 patent] which have been tested." (Brown 4/2/09 Tr. JA 405:14-16; DTX 96, at JA 3748.)

In mid-April 1991, DuPont also reported DuP 532, as part of its "new series of 4-perfluoro-alkylimidazole." (PTX 244, at JA 10761-762; PTX 246, at JA 10765-766; Weinstock 4/6/09 Tr. JA 517:3-22; Timmermans 4/16/09 Tr. JA 1383:13-1384:16; Lipinski 4/20/09 Tr. JA 1573:24-1575:3, 1576:24-1577:15.) DuPont used losartan's biphenyl-tetrazole-imidazole structure for DuP 532, but changed the 4-position of losartan from a chlorine atom to a substituent containing multiple fluorine atoms (CF2CF3). (Weinstock 4/1/09 Tr. JA 213:3-6; 4/6/09 Tr. JA 517:19-22.) Unlike losartan's hydroxymethyl at the 5-position, DuP 532 employed a carboxylic acid (COOH). (Weinstock 3/31/09 Tr. JA 115:2-14; DTX 356-A at JA 5138, 5140.)

Through these changes, DuPont improved upon the oral activity of losartan. DuP 532 exhibited a three-fold increase in oral activity when compared to the company's breakthrough drug. (Timmermans 4/16/09 Tr. JA 1391:12-16; Lipinski 4/20/09 Tr. JA 1577:11-15.)

E. Other "Second Generation" ARBs

Daiichi Sankyo and DuPont were not alone in their respective quests to develop compounds superior to losartan. By April 1991, several other large pharmaceutical companies contemporaneously developed their own "second generation" ARBs. Merck & Co. ("Merck") revealed L-158,809. Ciba-Geigy, Ltd. ("Ciba-Geigy") developed valsartan. Eisai Co. Ltd. ("Eisai") released information about a series of compounds, including E-4177 and Takeda disclosed candesartan cilexetil. (Weinstock 3/31/09 Tr. JA 48:6-9, 50:21-51:10, 62:2-5 & 63:1.)

The structure of these "second generation" ARBs differed from the early Takeda compounds, losartan, and olmesartan medoxomil. Several of these drugs did not utilize an imidazole ring: L-158,809 and E-4177 used an imidazopyridine ring, candesartan cilexetil employed a benzimidazole ring, and valsartan lacked any ring whatsoever. (PTX 248, at JA 10769-770, PTX 250, at JA 10773-813.) These compounds also differed at the position corresponding to the 2-position of the imidazole ring: E-4177 utilized a hydrocarbon ring, while cyclopropyl and candesartan cilexetil contained a nonhydrocarbon carbon chain ethyoxy. (DTX 99, at JA 3753-94; PTX 250, at JA 10773-813.)

F. Commercialization of Olmesartan Medoxomil and Other ARBs

As a result of this extensive pharmaceutical research, seven ARBs have been released for public consumption. (Boghigian 4/8/09 Tr. JA 873:25-874:2.) Daiichi Sankyo commercialized olmesartan medoxomil in three products, specifically Benicar and two combination drugs Benicar HCT and Azor.*fn6 (SF ¶¶ 17-19.) At the time of Benicar's launch in 2002, six other ARBs in the drug's class had hit the market. (Boghigian 04/8/09 Tr. JA 874:11-12.) The oldest drug, Cozaar (losartan), manufactured by DuPont and then Merck, had been available for seven years, while the newest drug Teveten, manufactured by Abbott Laboratories, had been on the market for roughly two years. (PTX 584, at JA 25089.)

In its first year, Benicar enjoyed $22.5 million in gross sales. (PTX 590-1, at JA 25092.) By 2008, the combined gross sales of Benicar, Benicar HCT, and Azor reached $1.3 billion. (Id.) During the same time, Benicar's market share grew to 16.6%, making it the third largest ARB on the market. (PTX 583, at JA 25088.)

G. Mylan's Abbreviated New Drug Applications and the Current Litigation

Following Daiichi Sankyo's success with Benicar and the combination drugs, Mylan submitted several Abbreviated New Drug Applications ("ANDA"), seeking approval to manufacture and sell generic versions of Benicar, Benicar HCT, and Azor. (SF ¶¶ 21-23.) In conjunction with each ANDA, Mylan filed a certification under 21 U.S.C. § 355(j)(2)(A)(vii)(IV), commonly referred to as a "Paragraph IV certification." (Id. ¶ 24.) These certifications stated that, in Mylan's "opinion and to the best of [their] knowledge, [the '599 patent is] invalid, unenforceable or will not be infringed by the manufacture, use, sale, offer for sale, or importation of [Mylan's ANDA products]." (Id.)

After filing each Paragraph IV certification, Mylan sent a Paragraph IV Notice Letter to Daiichi Sankyo alleging that Mylan's ANDA products will not infringe any valid claim of the '599 patent. (Id. ¶ 25.) Each Notice Letter affirmed that Mylan provided the factual and legal bases, known by the company at that time, that no valid claim of the '599 patent would be infringed, either literally or under the doctrine of equivalents, by the commercial manufacture, use, or sale of Mylan's ANDA products prior to the expiration of the '599 patent. (Id.)

After receiving Notice Letters for Benicar, Benicar HCT, and Azor, Daiichi Sankyo filed three separate actions against Mylan, each within the relevant 45-day statutory time period. (Id. ¶ 25.) These actions have been consolidated for all purposes under the present matter. (Id. ¶ 26.)

II. JURISDICTION, VENUE, AND APPLICABLE LAW

This Court has subject matter jurisdiction over Daiichi Sankyo's patent infringement claims and Mylan's counterclaims pursuant to 28 U.S.C. §§ 1331 and 1338(a). Since this action arises under the patent laws of the United States, the Court must apply the precedents of the United States Court of Appeals for the Federal Circuit, which has jurisdiction over any appeal of this judgment. See 28 U.S.C. § 1295(a).

III. CONCLUSIONS OF LAW

A. Standard for Obviousness

Under the United States Patent Act, an invention cannot be patented if "the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains." 35 U.S.C. §103(a). Since patents are presumed to be valid, Kao Corp. v. Unilever U.S., Inc., 441 F.3d 963, 968 (Fed. Cir. 2006), the party seeking to invalidate a patent based on obviousness must demonstrate "by clear and convincing evidence that a skilled artisan would have been motivated to combine the teachings of the prior art references to achieve the claimed invention, and that the skilled artisan would have had a reasonable expectation of success in doing so." Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1361 (Fed. Cir. 2007). Clear and ...


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