United States District Court, D. Delaware
For Plaintiff: Brian E. Farnan, Esq., Farnan LLP, Wilmington, DE; Daryl L. Wiesen, Esq., Goodwin Proctor LLP, Boston, MA; John T. Bennet, Esq., Goodwin Proctor LLP, Boston, MA; Sundar Subramanyam, Esq., Goodwin Proctor LLP, Boston, MA; Samuel Sherry, Esq., Goodwin Proctor LLP, Boston, MA; Todd Marabella, Esq., Goodwin Proctor LLP, Boston, MA; Jennifer L. Ford, Esq., Goodwin Proctor LLP, Boston, MA.
For Watson Laboratories, Inc. and Actavis, Inc., Defendants: Collins J. Seitz, Jr., Esq., Seitz Ross Aronstam & Moritz LLP, Wilmington, DE; Benjamin J. Schladweiler, Esq., Seitz Ross Aronstam & Moritz LLP, Wilmington, DE; Steven A. Maddox, Esq., Knobbe, Martens, Olson & Bear, LLP, Washington, D.C.; Jeremy J. Edwards, Esq., Knobbe, Martens, Olson & Bear, LLP, Washington, D.C.; Daniel Kazhdan, Esq., Knobbe, Martens, Olson & Bear, LLP, Washington, D.C.
For Dr. Reddy's Laboratories, Ltd. and Dr. Reddy's Laboratories, Inc., Defendants: Neal C. Belgam, Esq., Smith Katzenstein & Jenkins LLP, Wilmington, DE; Alan H. Pollack, Esq., Budd Lamer, P.C., Short Hills, NJ; Frank D. Rodriguez, Esq., Budd Lamer, P.C., Short Hills, NJ; Dmitry Shelhoff, Esq., Budd Lamer, P.C., Short Hills, NJ.
RICHARD G. ANDREWS, United States District Judge.
Plaintiff, Fresenius Kabi USA, LLC, brought this suit against Dr. Reddy's Laboratories, Ltd., Dr. Reddy's Laboratories, Inc. (collectively " Dr. Reddy" ), Watson Laboratories, Inc., and Actavis, Inc. (collectively " Watson" ), for infringement of four U.S. Patents: Nos. 5,714,520 (" the '520 patent" ), 5,731,355 (" the '355 patent), 5,731,356 (" the '356 patent" ) and 5,908,869 (" the '869 patent" ) (collectively, " the patents in suit" ). Fresenius sells a propofol injectable emulsion product, under the trade name Diprivan, and listed the patents in suit in the Food and Drug Administration's " Approved Drug Products with Therapeutic Equivalence Evaluations" (commonly referred to as the " Orange
Book" ) as covering Diprivan. Defendants' Abbreviated New Drug Applications (" ANDAs" ) seek approval to engage in the commercial manufacture, importation, use, or sale of a propofol injectable emulsion product before the expiration of the patents in suit.
Fresenius asserts that the Defendants' generic products would infringe claims 1, 16, 36, and 37 of each of the patents in suit. The patents in suit all concern pharmaceutical compositions containing propofol and edetate. All asserted claims contain " edetate" as a limitation. The Court has adopted the construction of " edetate," set forth in Abraxis Bioscience, Inc. v. Mayne Pharma (USA), Inc., 467 F.3d 1370, 1378 (Fed. Cir. 2006), as " EDTA and derivatives of EDTA, such as salts, but not including structural analogs." Fresenius concedes that Defendants' ANDA products do not literally infringe the " edetate" limitation. In order to expedite trial, the parties stipulated that the only issue for trial was whether Defendants infringe the " edetate" limitation under the doctrine of equivalents. (D.I. 21 in 13-925). The Court held a two day bench trial on June 2-3, 2014. As explained below, Fresenius did not prove infringement by a preponderance of the evidence.
Because prior propofol emulsion formulations were susceptible to microbial contamination and growth, the formulations required the addition of an antimicrobial. The specification makes clear that the critical part of the invention was the discovery that edetate is a broad-spectrum antimicrobial that can be added to propofol emulsions. '520 patent at Col. 4:22-37. The inventors studied at least ten known preservatives besides edetate. None of the others met the inventor's requirements. '520 patent at Col. 4:22-37.
The inventors explained that there were numerous difficulties in finding a preservative that could be added to the propofol emulsion. Specifically, the inventors had to find a hydrophilic additive, because it was believed that the antimicrobial properties were exerted in the aqueous phase. '520 patent at Col. 3:55-60. The inventors believed that a lipophilic preservative would not be effective because there would be insufficient amounts in the aqueous phase and too much in the lipid layer, leading to toxicity problems. '520 patent at Col. 3:60-67. During the inventors' investigation they considered or tested phenylmercuric acetate, phenylmercuric nitrate, benzyl alcohol, chlorobutanol, chlorocresol, phenol, sodium metabisulphite, sodium sulphite, sodium methyl hydroxybenzoate and sodium propyl hydroxybenzoate. '520 patent at Col. 4:22-28.
The inventors' discovery that edetate could be added to propofol as an antimicrobial resulted in the issuance of the patents in suit. The following claims of the '520 patent are representative:
1. A sterile pharmaceutical composition for parenteral administration which comprises an oil-in-water emulsion in which propofol dissolved in a water-immiscible solvent, is emulsified with water and stabilized by means of a surfactant, and which further comprises an amount of edetate sufficient to prevent a no more than 10-fold increase in growth of each of Staphylococcus aureus ATCC 6438, Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 9027 and Candida albicans ATCC 10231 for at least 24 hours as measured by a test wherein a washed suspension of each said organism is added to a separate
aliquot of said composition at approximately 50 colony forming units per ml. at a temperature in the range 20° -25° C, whereafter said aliquots are incubated at 20° -25° C. and are tested for viable counts of said organism after 24 hours, said amount of edetate being no more than 0.1% by weight of said composition.
16. A sterile pharmaceutical composition for parenteral administration which comprises an oil-in-water emulsion in which propofol dissolved in a water-immiscible solvent, is emulsified with water and stabilized by means of a surfactant, and which further comprises an amount of edetate wherein the amount of edetate is a molar concentration in the range 3x10(##RefNum=-5 FootnoteNum=2##) to 9x10(##RefNum=-4 FootnoteNum=3##).
'520 patent claims 1 and 16.
Defendants' ANDA products are oil-in-water emulsions. PTX-013; PTX-021; Tr. at 241:9-242:7. Propofol is dissolved in soybean oil along with egg phospholipids, which is then mixed with an aqueous solution. Tr. at 270:20-28, 280:11-24; PTX-013; PTX-021. After homogenization, the egg phospholipids act as emulsifiers, allowing the oil phase to be evenly distributed in tiny droplets throughout the continuous aqueous phase. Tr. at 247:21-249:7, 252:22-253:10, ...