Case Name: Fresenius Kabi USA, LLC v. Dr. Reddy’s Labs., Ltd., Civ. Nos. 13-925-RGA, 13-1015-RGA, 2014 U.S. Dist. LEXIS 117924 (D. Del. Aug. 25, 2014) (Andrews, J.)
Drug Product and Patent(s)-in-Suit: Diprivan® (propofol); 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”)
Nature of the Case and Issue(s) Presented: Plaintiff filed suit alleging infringement of claims 1, 16, 36, and 37 of each of the patents-in-suit. The patents-in-suit all claim pharmaceutical compositions containing propofol and edetate. All of the asserted claims contain “edetate” as a limitation. Before trial, the parties stipulated that the proposed ANDA products did not literally infringe the “edetate” limitation, and agreed that the sole remaining issue for trial would be whether those ANDA products infringed under the doctrine of equivalents. The court held that there was no infringement.
Why Defendants Prevailed: Prior-art propofol emulsions were susceptible to microbial contamination and growth, and therefore required the inclusion of an antimicrobial compound. The patents-in-suit claimed the use of edetate as a broad spectrum antimicrobial that could be added to propofol emulsions. The inventors experimented with a variety of other antimicrobials before identifying edetate as the best candidate.
Defendants formulated generic propofol emulsions that resembled those of Plaintiff’s reference listed drug in all other respects, save for the type of antimicrobial compound added to the product. Dr. Reddy’s formulation incorporated benzyl alcohol as an antimicrobial; Watson used sodium benzoate. Plaintiff’s primary argument was that benzyl alcohol and sodium benzoate are not known to be effective antimicrobials and that the dipropofol in the generic versions was the true source of antimicrobial activity in the Defendants’ products. Neither proposed ANDA product listed dipropofol as a preservative, but did indicate that the compound may exist as a degradation product of propofol, at a concentration of less than 0.005 mg/ml. Additionally, each of the Defendants’ proposed ANDA products had been tested for the presence of dipropofol, but none was detected.
The court addressed Plaintiff’s argument that Defendants’ preservatives could not provide antimicrobial activity because both compounds (sodium benzoate and benzyl alcohol) were known to be ineffective at the pH ranges present in the Defendants’ ANDA formulations. The court noted that Plaintiff’s argument had support in the scientific literature. But testing had established that the sodium benzoate and benzyl alcohol did exhibit some antimicrobial activity in pH ranges found in the Defendants’ ANDA formulations. The court noted that the antimicrobials did not need to exhibit optimal efficiency; some antimicrobial activity was sufficient. The court also noted that Plaintiff did not perform any tests establishing the presence of dipropofol in the Defendants’ ANDA products. Additionally, the court found that Plaintiff failed to explain why dipropofol would act as an antimicrobial in the Defendants’ ANDA formulations when it did not exhibit antimicrobial properties in prior-art formulations.
The court then noted that even assuming that the Plaintiff had been able to establish that dipropofol was present in the ANDA formulations, and actually was acting as a preservative, it still did not function in substantially the same manner as edetate did. The court pointed out various differences in the compounds: dipropofol was a phenol while edetate was a polyaminocarboxylate; and dipropofol is highly lipophilic while edetate tended to dissolve in the aqueous phase of a solution. The court also took issue with Plaintiff’s claim that edetate functioned in the same manner as dipropofol, namely, via metal-ion chelation as well as membrane insertion. After reviewing the evidence produced by Plaintiff, the court found that the Plaintiff failed to establish that edetate acted by membrane insertion, or that dipropofol acted by metal-ion chelation or membrane insertion.
