SENJU PHARMACEUTICAL CO., LTD., KYORIN PHARMACEUTICAL CO., LTD., AND ALLERGAN, INC., Plaintiffs,
LUPIN LIMITED AND LUPIN PHARMACEUTICALS, INC., Defendants. SENJU PHARMACEUTICAL CO., LTD., KYORIN PHARMACEUTICAL CO., LTD., AND ALLERGAN, INC., Plaintiffs,
HI-TECH PHARMACAL CO., INC., Defendants.
Jack B. Blumenfeld, Esquire and Maryellen Noreika of Morris, Nichols, Arsht & Tunnell LLP, Wilmington, Delaware. Counsel for Plaintiffs. Of Counsel: Richard D. Kelly, Esquire, Stephen G. Baxter, Esquire, Frank J. West, Esquire, Akihiro Yamazaki, Esquire, and Tia D. Fenton, Esquire of Obion, Spivak, McClelland, Maier & Neustadt, P.C.
John C. Phillips, Jr., Esquire and Megan C. Haney, Esquire of Phillips, Goldman & Spence, P.A., Wilmington, Delaware. Counsel for Defendants Lupin Ltd. and Lupin Pharmaceuticals, Inc. Of Counsel: William A. Rakoczy, Esquire, Paul J. Molino, Esquire, Deanne M. Mazzochi, Esquire, Anuj K. Wadhwa, Esquire, John D. Polivick, Esquire, and Brian P. Murray, Esquire of Rakoczy Molino Mazzochi Siwik LLP.
Karen E. Keller, Esquire and Jeffrey T. Castellano, Esquire of Shaw Keller LLP, Wilmington, Delaware. Counsel for Defendant Hi-Tech Pharmacal Co. Inc.
This patent infringement litigation is a consolidation of four separate actions by Senju Pharmaceutical Co., Ltd. ("Senju"), Kyorin Pharmaceutical Co., Ltd. ("Kyorin"), and Allergan Inc. ("Allergan") (collectively, "plaintiffs") asserting infringement of reexamined claims 6 and 12-16 of U.S. Patent No. 6, 333, 045 ("the '045 patent")against Lupin Limited and Lupin Pharmaceuticals, Inc. ("LPI") (collectively, "Lupin"), and Hi-Tech Pharmacal Co. Inc. ("Hi-Tech") (all three collectively "defendants"). (D.I. 33, 35; 11-439 D.I. 8; 11-926 D.I. 11; 11-1059 D.I. 9) Defendants answered and Lupin counterclaimed seeking a declaratory judgment of non-infringement and invalidity. (D.I. 138, 139, 143, 144) Plaintiffs answered the counterclaims. (D.I. 146, 147)
On October 8, 2012, Lupin moved for judgment on the pleadings alleging that the narrower reexamined claims of the '045 patent were invalid for obviousness and plaintiffs should be collaterally estopped from relitigating these claims based on the court's finding in Apotex II. (D.I. 105) The court found that, although Lupin might later succeed in showing that the reexamined claims were invalid, plaintiffs did not fully litigate a claim with a limitation of 0.01 w/v% disodium edetate ("EDTA") and, therefore, collateral estoppel could not apply. (D.I. 135)
The '045 patent is directed to aqueous liquid pharmaceutical compositions comprising gatifloxacin and disodium edetate, as well as various methods utilizing these compositions. (D.I. 33 at ex. A) Plaintiffs allege infringement by Lupin's Abbreviated New Drug Application ("ANDA") Nos. 202-653, 0.5 w/v% gatifloxacin ("Lupin 0.5%") and 202-709, 0.3 w/v% gatifloxacin ("Lupin 0.3%"), as well as Hi-Tech's ANDA Nos. 203189, 0.5 w/v% gatifloxacin ("Hi-Tech 0.5%") and 203190, 0.3 w/v% gatifloxacin ("Hi-Tech 0.3%"),  which seek FDA approval to market and sell generic copies of plaintiffs' FDA approved 0.3 w/v % gatifloxacin ophthalmic solution (sold under the trademark "Zymar®") and/or 0.5 w/v % gatifloxacin ophthalmic solution (sold under the trademark "Zymaxid®"), which are the commercial embodiments of reexamined claims 6 and 12-16 of the '045 patent. (See JTX 4 (Lupin 0.5%); JTX 5 (Lupin 0.3%); JTX 6 (Hi-Tech 0.5%); JTX 7 (Hi-Tech 0.3%))
The court held a claim construction hearing on December 19, 2012. A bench trial was conducted from January 14-17, 2012, principally to resolve the issues of infringement and invalidity, which have been fully briefed post-trial. (D.I. 163, 172, 178, 179, 182, 183) 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 and Kyorin are corporations organized under the laws of Japan with principal places of business in Osaka and Tokyo, Japan, respectively. (D.I. 33 at ¶2, 3) Senju develops pharmaceutical products that have applications regarding the eye, ear, nose, throat and skin. Kyorin engages in the development of pharmaceuticals directed to infectious, immunological, allergic and metabolic diseases. Allergan is a Delaware corporation, having its principal place of business in Irvine, California. (Id. at ¶ 4) The business of Allergan is directed to the development and sale of pharmaceuticals, biologies and medical devices.
Lupin Limited is an Indian corporation with a place of business in Mumbai, India. (D.I. 37 at ¶ 5) Lupin develops and manufactures pharmaceutical products, including generic drug products. LPI is a Virginia corporation, having a place of business in Baltimore, Maryland. (Id. at ¶7) LPI distributes and sells pharmaceutical products. Hi-Tech Pharmacal, Inc is a Delaware corporation with a place of business at 369 Bayview Avenue, Amityville, NY 11701. (11-926 D.I. 1 ¶ 5; 11-926 D.I. 14 ¶ 5) Hi-Tech manufactures, sells and/or offers to sell generic products in the United States.
B. The Patent
On December 25, 2001, the original '045 patent, entitled "Aqueous Liquid Pharmaceutical Composition Comprised of Gatifloxacin, " was issued listing Shinichi Yasueda and Katsuhiro Inada as inventors and Senju and Kyorin as assignees. (D.I. 33, ex. A) On February 25, 2011, plaintiffs filed a request for reexamination of claims 1-3, 6, 8 and 9 of the '045 patent and on October 25, 2011, the examiner allowed the following reexamined claims, each of which is at issue:
6. A method for raising corneal permeability of an aqueous pharmaceutical Gatifloxacin eye drop solution comprising Gatifloxacin or its salt, having a pH of from above 5 to about 6 containing from about 0.3 to about 0.8 w/v% Gatifloxacin or its salt, which comprises incorporating about 0.01 w/v% disodium edetate into [eye drops containing Gatifloxacin or its salt] said Gatifloxacin eye drop solution.
12. An aqueous liquid pharmaceutical eye drop composition which comprises from about 0.3 to about 0.8 w/v% Gatifloxacin or its salt, about 0.01 w/v% disodium edetate, and wherein the aqueous liquid pharmaceutical composition has a pH of from about 5 to about 6.
13. The aqueous liquid pharmaceutical eye drop composition according to claim 12, comprising about 0.3 w/v% Gatifloxacin or its salt.
14. The aqueous liquid pharmaceutical eye drop composition according to claim 12, comprising about 0.5 w/v% Gatifloxacin or its salt.
15. The aqueous liquid pharmaceutical eye drop composition according to claim 12, comprising at least one isotonic agent selected from the group consisting of sodium chloride, potassium chloride, glycerin, mannitol and glucose.
16. The aqueous liquid pharmaceutical eye drop composition according to claim 14, wherein the at least one isotonic agent is sodium chloride.
'045 patent, 1:25-2:24.
C. The Asserted Prior Art
Fluoroquinolones, otherwise known as quinolone carboxylic acids or simply "quinolones, " are a class of broad spectrum antibacterial compounds that share a common core chemical structure. (See U.S. Patent No. 4, 980, 470 ("the '470 patent"), abstract; D.1. 166 at 595:22-596:15) The '470 patent,  which was before the examiner during the prosecution of the '045 patent, claims gatifloxacin 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. ('470 patent, 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. (1:62-2:7) In a passing reference to chemical structure, the '470 patent explains that each of the disclosed quinolones have "similar substituents." (1:41-43) Defendants' expert, Dr. Sherman, testified that the prior art quinolones and gatifloxacin are structurally similar. (D.I. 166 at 595:22-596:15) Dr. Sherman further testified that gatifloxacin is a polar compound due to its ability to readily ionize and because it contains several polar moieties. (Id. at 596:16-597:2)
2. Disodium edetate
Disodium edetate is the disodium salt of ethylenediamine tetraacetic acid (commonly known as "EDTA"). (D.I. 166 at 600:25-601:4) EDTA, a multi-purpose excipient,  is widely known as a chelating agent. (Id. at 589:10-590:12) In Griffith,  a September 1967 article, EDTA was found to prevent coloration in a variety of active pharmaceutical ingredients by "sequestering" metal ions through a chelating mechanism. (DTX-981; D.I. 166 at 610-612) Griffith teaches that 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. (DTX-981)
EDTA is also known to increase corneal permeability of certain polar compounds. (See JTX 9) 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 Grass (1985),  considered during the prosecution and reexamination 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. (Id. at 110) Grass (1985) 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, Grass (1985) 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. (Id.) The authors of Grass (1985) conclude that the propensity of EDTA to increase corneal permeability of polar compounds has a "direct bearing upon ophthalmic solutions currently in use." (JTX 12 at 112-13)
After building on this work, Dr. Grass authored two additional papers in 1988.These papers tested lower concentrations of 0.1, 0.05 and 0.01 w/v% EDTA, finding increased corneal permeability at these lower concentrations. (JTX 50; JTX 53) Rojanasakul built further on these teachings by testing EDTA concentrations as low as 0.00037 w/v% EDTA, and finding that even ...