Senju Pharm. Co. Ltd. v. Apotex Inc.

• Decision Date: 14 June 2010
• Docket Number: No. Civ. No. 07-779-SLR,Civ. No. 07-779-SLR
• Citation: 717 F.Supp.2d 404
• Parties: SENJU PHARMACEUTICAL CO. LTD., Kyorin Pharmaceutical Co. Ltd. and Allergan, Inc., Plaintiffs, v. APOTEX INC. and Apotex Corp., Defendants.
• Court: U.S. District Court — District of Delaware

717 F.Supp.2d 404

SENJU PHARMACEUTICAL CO. LTD., Kyorin Pharmaceutical Co. Ltd. and Allergan, Inc., Plaintiffs,

v.APOTEX INC. and Apotex Corp., Defendants.

No. Civ. No. 07-779-SLR.

United States District Court,

D. Delaware.

June 14, 2010.

Jack B. Blumenfeld, Esquire and Maryellen Noreika, Esquire of Morris, Nichols, Arsht & Tunnell LLP, Wilmington, Delaware. Counsel for Plaintiffs. Of Counsel: Richard D. Kelly, Esquire, Stephen G. Baxter, Esquire and Frank J. West, Esquireof Oblon, Spivak, McClelland, Maier & Neustadt, P.C., Alexandria, Virginia.

Francis J. Murphy, Esquire of Murphy & Landon, Wilmington, Delaware. Counsel for Defendants. Of Counsel: David G. Greene, Esquire and Alan B. Clement of Locke Lord Bissell & Liddell LLP, New York, New York, Keith D. Parr, Esquire, Scott B. Feder, Esquire, David B. Abramowitz, Esquire, Patrick C. Gallagher, Esquire and Kevin M. Nelson, Esquire of Locke Lord Bissell & Liddell LLP, Chicago, Illinois.

MEMORANDUM OPINION

SUE L. ROBINSON, District Judge.

I. INTRODUCTION

Senju Pharmaceutical Co., Ltd. ("Senju") and Kyorin Pharmaceutical Co., Ltd. ("Kyorin") are co-owners of U.S. Patent No. 6,333,045 ("the '045 patent"). (D.I. 100, ex. 1 at ¶ 1) The '045 patent is directed to aqueous liquid pharmaceutical compositions comprising gatifloxacin and disodium edetate, as well as various methods utilizing these compositions. Allergan, Inc. ("Allergan") holds a New Drug Application ("the NDA"),¹ approved by the United States Food and Drug Administration ("FDA"), which describes a 0.3% gatifloxacin ophthalmic solution containing disodium edetate, sold under the trade name ZYMAR®. ( Id. at ¶¶ 9, 10) ZYMAR® is indicated for the treatment of bacterial conjunctivitis. ( Id.) The FDA's Approved Drug Products With Therapeutic Equivalence Evaluations ("the Orange Book") lists, inter alia, the ' 045 patent and U.S. Patent No. 4,980,470 ("the ' 470 patent") ² in connection with ZYMAR®. ( Id. at ¶¶ 12, 31)

On July 18, 2007, Apotex Inc. filed an Abbreviated New Drug Application ("the ANDA") ³ with the FDA, seeking approval, prior to the expiry of the ' 045 patent, to manufacture, market and sell a generic version of the 0.3% gatifloxacin ophthalmic solution described in the NDA ("the ANDA product"). ( Id. at ¶ 13) Apotex Inc. subsequently assigned its rights in the ANDA to Apotex Corp. (collectively, "Apotex" or "defendants"). ( Id. at ¶ 16) On October 17, 2007, defendants sent Senju, Kyorin and Allergan (collectively, "plaintiffs") a notification letter, informing plaintiffs that the ANDA contained a Paragraph IV certification ⁴ for the ' 045 patent. ( Id. at ¶ 17) In the Paragraph IV certification, defendants contend that the ANDA product will not infringe claims 4, 5, 10 and 11 of the ' 045 patent and that all the claims of the ' 045 patent are invalid. ( Id. at ¶ 18)

Plaintiffs brought this infringement action on November 29, 2007 pursuant to 35 U.S.C. § 271(e)(2)(A), alleging that the ANDA product will infringe claims 1-3, 6, 7 and 9 of the '045 patent. ( Id. at ¶ 19) Defendants responded with affirmative defenses and counterclaims seeking declaratory judgment of noninfringement, invalidity ⁵ and unenforceability of the ' 045 patent. ( See D.I. 63) While defendants maintain that claims 6 and 7 willnot be infringed, the parties stipulate that, if valid, the ANDA product will infringe claims 1-3 and 9 of the ' 045 patent. (D.I. 100, ex. 1 at ¶ 8) The court held a claim construction hearing on December 4, 2009. A bench trial was conducted from January 12-14, 2010, principally to resolve these issues, which have been fully briefed post-trial. (D.I. 110; D.I. 112; D.I. 115; D.I. 116) The court has jurisdiction pursuant to 28 U.S.C. §§ 1331, 1338(a) and 1400(b). Having considered the documentary evidence and testimony, the court makes the following findings of fact and conclusions of law pursuant to Fed.R.Civ.P. 52(a).

II. FINDINGS OF FACT

A. The Parties

Senju is a Japanese corporation with its principal place of business in Osaka, Japan. (D.I. 100, ex. 1 at 11) Senju develops pharmaceutical products that have applications regarding the eye, ear, nose, throat and skin. Kyorin is a corporation organized and existing under the laws of the Nation of Japan, and having its principal place of business in Tokyo, Japan. ( Id. at ¶ 2) Kyorin engages in the development of pharmaceuticals directed to infectious, immunological, allergic and metabolic diseases. Allergan is a corporation formed under the laws of the State of Delaware, having its principal place of business in Irvine, California. ( Id. at ¶ 3) The business of Allergan is directed to the development and sale of pharmaceuticals, biologies and medical devices.

Apotex Corp. is a corporation formed under the laws of the State of Delaware, having its principal place of business in Weston, Florida. ( Id. at ¶ 4) Apotex Inc. is a corporation formed under the laws of the Nation of Canada, having its principal place of business in Ontario, Canada. ( Id. at ¶ 5) Apotex primarily develops, manufactures and commercializes generic pharmaceutical products.

B. The Asserted Prior Art

1. Gatifloxacin

Fluoroquinolones, otherwise known as quinolone carboxylic acids or simply "quinolones," are a class of broad spectrum antibacterial compounds ⁶ that share a common core chemical structure. ( See DTX 37 at col. 1:7-10; D.I. 107 at 326-28) A carboxylic acid, along with a nitrogen-containing carbon ring and a double-bonded oxygen, are fundamental and common aspects of all quinolone antibiotics. (D.I. 107 at 327-28)

The '470 patent,⁷ which was before the examiner during the prosecution of the ' 045 patent, claims gatifloxacin ⁸ and its acid derivatives. The properties of this fourth generation quinolone are revealed following a discussion of previously discovered quinolones, to wit, norfloxacin, ofloxacin and ciprofloxacin.⁹ ( Id., col. 1:32-61) The ' 470 patent teaches that gatifloxacin represents an improvement over the prior art quinolones in that it exhibits a broader antibacterial activity, higher selective toxicity and safe oral and parenteral administration. (col. 1:62-2:7)

In a passing reference to chemical structure, the '470 patent explains that each of the disclosed quinolones have "similar substituents." (col. 1:41-43) Defendants' expert, Dr. Paul Myrdal ("Dr. Myrdal"), testified that, in this manner, the '470 patent recognizes the structural similarity between gatifloxacin and these prior art quinolones. (D.I. 107 at 326-27) This structural similarity is emphasized in a slide prepared by Dr. Myrdal, wherein the blue portion of the molecules represents a chemical backbone common to all four quinolones and the black portions represent functional group variations:

Image 1 (4.88" X 2.63") Available for Offline Print

(DTX 194 at 44) Dr. Myrdal further testified that gatifloxacin is a polar compound due to its ability to readily ionize and because it contains several polar moieties. (D.I. 107 at 343)

2. Disodium edetate

Disodium edetate is the disodium salt of ethylenediamine tetraacetic acid (commonly known as "EDTA").¹⁰ (D.I. 100, ex. 1 at ¶ 40) EDTA, a multi-purpose excipient,¹¹ is widely known as a chelating agent. ¹² (D.I. 107 at 332-33; DTX 166 at 109-110) EDTA has four carboxylic acid groups. (D.I. 107 at 354; D.I. 108 at 669) In a September 1967 article by D.E. Griffith ("the Griffith reference"), the author reported that EDTA, by "sequestering" metal ions through a chelating mechanism, prevents coloration in a variety of active pharmaceutical ingredients. (JTX 56 at 1197-98) The Griffith reference teachesthat disodium edetate, in concentrations of between 0.005 and 0.02 w/v%, prevented coloration of papaverine hydrochloride and that, in concentrations between 0.005 and 0.04 w/v%, it similarly prevented coloration in other pharmaceutical agents. ( Id.)

EDTA is also known to increase the corneal permeability of certain polar compounds. ( See JTX 12) A layer of epithelial cells, bound tightly together by calcium ions, forms a protective barrier that prevents foreign molecules from entering the eye. ( Id. at 111) In a 1985 publication by Grass et al. ("the Grass reference"), considered during the prosecution of the '045 patent, the authors sought to determine the effect of EDTA on the permeability of organic and inorganic compounds with respect to the corneal epithelia.¹³ ( Id. at 110) The Grass reference teaches that EDTA can reduce the number of calcium ions through chelation, thus creating small channels between corneal epithelial cells. ( See id.) These channels allow polar molecules to penetrate through the cornea into the aqueous humor of the eye. ( See id.) In reporting the results of this study, the Grass reference describes how the addition of 0.5 w/v% disodium edetate to separate solutions of glycerol and cromolyn resulted in increased corneal permeability in both solutions. ( Id. at 112) A lower unspecified concentration of EDTA was also shown to function in this manner, albeit to a lesser extent.¹⁴ ( Id.) The authors of the Grass reference conclude that the propensity of EDTA to increase the corneal permeability of polar compounds has a "direct bearing upon ophthalmic solutions currently in use." ¹⁵ (D.I. 107 at 341; see also JTX 12 at 112-13)

3. Aqueous quinolone ophthalmic compositions comprising disodium edetate

Dr. Myrdal testified at trial that, in the context of quinolone solution chemistry, the variations in functional groups among the quinolones named by the '470 patent, shown in black, supra, are "really not from a physical/chemical standpoint huge differences." (D.I. 107 at 326-27) Generally, he contends that, while different functional groups may result in some differences in solubility ( id. at 399-402), one of skill in the art can expect a relatively predictable pH-dependent solubility profile for these quinolones. ( Id. at 329-30, 350-53) In support of this opinion, Dr. Myrdal relies upon a 1989 article by Riley et al. ("the Riley...