Counterclaim v. Laboratories

• Decision Date: 09 September 2010
• Docket Number: No. 2009-1511.,2009-1511.
• Citation: 619 F.3d 1346
• Parties: DAIICHI SANKYO COMPANY, LTD., and Daiichi Sankyo, Inc., Plaintiffs/Counterclaim Defendant-Appellees, v. MATRIX LABORATORIES, LTD., Mylan Inc., Mylan Laboratories, Inc., and Mylan Pharmaceuticals, Inc., Defendants-Counterclaimant-Appellants.
• Court: U.S. Court of Appeals — Federal Circuit

619 F.3d 1346

DAIICHI SANKYO COMPANY, LTD., and Daiichi Sankyo, Inc., Plaintiffs/Counterclaim Defendant-Appellees,

v.MATRIX LABORATORIES, LTD., Mylan Inc., Mylan Laboratories, Inc., and Mylan Pharmaceuticals, Inc., Defendants-Counterclaimant-Appellants.

No. 2009-1511.

United States Court of Appeals,Federal Circuit.

Sept. 9, 2010.

Dominick A. Conde, Fitzpatrick, Cella, Harper & Scinto, of New York, NY, argued for plaintiffs/counterclaim defendant-appellees. With him on the brief were Lisa B. Pensabene and Joshua I. Rothman. Of counsel on the brief were Henry B. Gutman, Robert A. Bourque and Noah M. Leibowitz, Simpson Thacher & Bartlett LLP, of New York, NY.

Robert L. Byer, Duane Morris LLP, of Pittsburgh, PA, argued for defendants/counterclaimant-appellants. Of counsel on the brief were Shannon M. Bloodworth, Perkins Coie LLP, of Washington, DC, and David J. Harth, The Law Office of David J. Harth, of Madison, WI. Of counsel was Dan L. Bagatell, Perkins Coie Brown & Bain P.A., of Phoenix, AZ.

Before LOURIE, FRIEDMAN, and LINN, Circuit Judges.

LOURIE, Circuit Judge.

Matrix Laboratories, Ltd., Mylan Inc., Mylan Laboratories, Inc., and Mylan Pharmaceuticals, Inc. (collectively, “Mylan”) appeal from the final decision of the United States District Court for the District of New Jersey sustaining the validity of U.S. Patent 5,616,599 (“the '599 patent”) under 35 U.S.C. § 103. We affirm.

Background

I.

Daiichi Sankyo Company, Ltd. and Daiichi Sankyo, Inc. (collectively, “Daiichi”) own the '599 patent, which claims 1-biphenylmethylimidazole compounds and their use as angiotensin receptor blockers (“ARBs”) for the treatment of high blood pressure. Claim 13 of the '599 patent covers the chemical compound olmesartan medoxomil, an ARB approved by the Food and Drug Administration (“FDA”) and commercialized by Daiichi as the active ingredient in Benicar®, Benicar HCT®, and Azor®.

The invention of olmesartan medoxomil as an effective ARB built on years of research beginning in the 1970s, when scientists first came to appreciate the role of the angiotensin protein in controlling blood pressure. The first non-protein, small molecule ARBs were developed in the late 1970s and early 1980s by the Japanese pharmaceutical company Takeda Pharmaceutical Co. Ltd. (“Takeda”). These compounds each comprised an imidazole ring-a five-membered ring of the formula C₃H₄N₂-to which other chemical moieties were bonded at the 1-5-positions of the ring. One Takeda compound, S-8307, possessed a chlorophenyl group bonded through a methylene group at the 1-position, a butyl group (-C₄H₉) at the 2-position, a chlorine atom (-Cl) at the 4-position, and an acetic acid moiety (-CH₂COOH) at the 5-position. The chemical structure of S-8307 is pictured below with the ring's 1-position nitrogen positioned at the bottom of the ring.

Image 1 (3" X 2.13") Available for Offline Print

The Takeda compounds, however, bound only weakly to the angiotensin receptor and thus were of little therapeutic value. Nevertheless, using Takeda's compounds as leads, scientists at E.I. du Pont de Nemours and Company (“DuPont”) embarked on their own ARB research program with the aim of developing new compounds with increased receptor-binding activity. DuPont's research led to the discovery of the first orally active ARB, known as losartan, which exhibited ten-fold greater binding affinity than the Takeda compounds. To obtain losartan, DuPont modified Takeda's S-8307 at the 1- and 5-positions of the imidazole ring: At the 1-position, DuPont added a second phenyl group with a tetrazole group attached, generating a biphenyltetrazole substituent. At the 5-position, DuPont replaced the acetic acid group with a hydroxymethyl group (-CH₂OH), which is metabolized to a carboxylic acid (-COOH) in the body. The chemical structure of losartan is depicted below.

Image 2 (2.77" X 2.1") Available for Offline Print

DuPont disclosed losartan in U.S. Patent 5,138,069 (“the '069 patent”) along with more than four hundred structurally related ARBs. The '069 patent also discloses binding affinity data, measured as IC₅₀ values, ¹ for over two hundred compounds, including forty-two in losartan's biphenyltetrazole series. Chemists were able to use the data disclosed in the ' 069 patent to uncover correlations between the compounds' structures and their binding affinities, called “structural-activity relationships” (“SARs”), which they could then use to guide the development of even more potent ARBs. For example, if the presence of a certain chemical moiety or type of chemical moiety at a given position correlates with an increase in binding affinity, chemists could attempt to use that chemical moiety or type of moiety in the next generation of ARBs, and they did.

Following losartan's success, over twenty different pharmaceutical companies, including Daiichi, established research programs to develop the next generation of ARBs. Daiichi's program resulted in the synthesis of olmesartan, the active metabolite of olmesartan medoxomil. Like losartan, olmesartan consists of an imidazole ring containing a biphenyltetrazole substituent at the 1-position and an alkyl group (propyl rather than butyl) at the 2-position. At the 4-position, however, olmesartan replaced losartan's lipophilic, or fat-loving, chlorine atom with its opposite, a hydrophilic, or water-loving, hydroxyisopropyl group (-C(CH₃)₂OH). ² Of the compounds disclosed in DuPont's ' 069 patent, the vast majority contain a lipophilic group at the ring's 4-position. One compound with a hydrophilic group is losartan's regioisomer, ³ Example 118, in which the 4- and 5-positions on the imidazole ring are reversed. The transposition results in a compound with a chlorine atom at the 5-position and a hydrophilic hydroxymethyl group (-CH₂OH) at the 4-position, as shown below.

Image 3 (1.96" X 1.67") Available for Offline Print

Image 4 (1.92" X 1.66") Available for Offline Print

Olmesartan medoxomil also differs from losartan at the 5-position. Daiichi replaced losartan's hydroxymethyl group with a carboxy group masked by a medoxomil prodrug substituent to improve oral absorption. Like the hydroxymethyl group, the medoxomil moiety is metabolized to the carboxylic acid in the body. The structures of olmesartan medoxomil and olmesartan are depicted below.

Image 5 (4.87" X 3.11") Available for Offline Print

Other second-generation ARBs, all prior art to olmesartan medoxomil, include DuPont's DuP 532, in which losartan's chlorine at the 4-position is replaced with multiple lipophilic fluorine atoms (-C₂F₅), and six compounds disclosed in DuPont's U.S. Patent 5,137,902 (“the '902 patent”), each of which has a more lipophilic alkyl group at the 4-position. The ARBs disclosed in DuPont's '902 patent (“the '902 compounds” or “the '902 ARBs”) are the closest structurally to olmesartan, with Example 6 differing from olmesartan by only a single oxygen atom at the 4-position, as depicted below

Image 6 (1.77" X 2.02") Available for Offline Print

Image 7 (1.74" X 1.93") Available for Offline Print

Other second-generation ARBs differ more significantly from losartan by not containing an imidazole ring, including Merck & Co., Inc.'s L-158,809 compound, Ciba-Geigy Corp.'s valsartan, and Eisai Inc.'s E-4177 compound.

II.

Mylan filed multiple Abbreviated New Drug Applications (“ANDAs”) with Paragraph IV certifications under the Hatch-Waxman Act, 21 U.S.C. § 355, challenging the '599 patent and seeking FDA approval to manufacture generic olmesartan medoxomil in various dosages and combinations. Daiichi responded by filing suit against Mylan for patent infringement in the United States District Court for the District of New Jersey. The parties stipulated to infringement of claim 13, leaving only Mylan's counterclaim that claim 13 would have been obvious in light of (1) the second-generation ARBs in DuPont's '902 patent, which Mylan alleged one of skill in the art would have been motivated to select as lead compounds; (2) Example 118, losartan's regioisomer, in DuPont's ' 069 patent, which Mylan alleged would have motivated one of skill in the art to modify the '902 compounds' lipophilic alkyl groups at the 4-position with olmesartan's hydrophilic hydroxyalkyl group; and (3) the well-known use of medoxomil as a prodrug.

After a ten-day bench trial, the district court held, in a comprehensive and well-reasoned opinion, that claim 13 of the '599 patent was not invalid as obvious. Daiichi Sankyo Co., Ltd. v. Mylan Pharms. Inc., 670 F.Supp.2d 359 (D.N.J.2009). The court determined that Mylan had failed to show by clear and convincing evidence that one skilled in the art would have chosen the '902 ARBs as lead compounds over other better-studied ARBs with greater potency and thus had failed to establish a prima facie case of obviousness. Id. at 376-77. The district court went on to find that, even assuming that Mylan had shown the '902 ARBs to be leads, the structure of the '902 compounds differed significantly from olmesartan medoxomil, id. at 377-78, and that, even assuming structural similarity, Mylan had failed to prove that one of skill in the art would have been motivated to modify the 4- and 5-positions of the '902 ARBs to obtain olmesartan medoxomil, id. at 378-81. Regarding the 4-position, the court found that the emphasis on lipophilicity in both the ' 069 patent and the second-generation ARBs taught away from the use of a hydrophilic group at the 4-position and from any expectation that the use of a hydrophilic group would generate an ARB with significantly improved biological properties. Id. at 370-75, 378-80. Regarding the 5-position, the court found that converting olmesartan into a prodrug was a disfavored and unpredictable approach and that medoxomil was a disfavored prodrug. Id. at 380.

Finally, the district court concluded that even if Mylan had established a prima facie

case of obviousness, secondary considerations counseled against a...