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Novartis Pharms. Corp. v. Breckenridge Pharm., Inc.

Case Name:  Novartis Pharms. Corp. v. Breckenridge Pharm., Inc., Civ. Nos. 14-1043-RGA, 14-1196-RGA, 14-1289-RGA, 2017 U.S. Dist. LEXIS 46595 (D. Del. Mar. 28, 2017) (Andrews, J.) 

Drug Product and Patent(s)-in-Suit: Zortress® (everolimus); U.S. Patents Nos. 5,665,772 (“the ’772 patent”), 6,239,124 (“the ’124 patent”), and 6,455,518 (“the ’518 patent”)

Nature of the Case and Issue(s) Presented: Plaintiffs brought patent infringement actions against multiple defendants for filing ANDAs seeking from the FDA to market generic Zortress. Plaintiffs alleged that all of the ANDAs infringe the ’772 patent, that Roxane and Breckenridge induced infringement of the ’124 patent, and that Breckenridge, Roxane, and Par induced infringement of the ’518 patent.

Everolimus is a derivative of the compound rapamycin and is claimed in the ’772 patent. The only difference between rapamycin and everolimus is that the hydroxyl group at the C-40 position in rapamycin is replaced with a 2-hydroxyethyl group in everolimus. Rapamycin has long been known to have beneficial medicinal properties, such as antifungal activity, anticancer activity, and immunosuppressive activity. Rapamycin is recognized as having limited utility in pharmaceutical applications as it has low bioavailability, high toxicity, and poor solubility. Rapamycin derivatives such as everolimus, however, have been shown to have better stability and bioavailability, making them more desirable for pharmaceutical preparations.

The ’124 patent claims the use of synergistically effective amounts of cyclosporin A and everolimus in weight ratios from 2:1 to 180:1. The proposed labels for both Roxane’s and Breckenridge’s generic products include instructions for co-administration of cyclosporin A and everolimus for the prevention and treatment of transplant rejection in kidney transplant patients. The ’518 patent claims the use of synergistically effective amounts of an IL-2 transcription inhibitor and everolimus in weight ratios from 2:1 to 180:1. The proposed labels for both Roxane’s and Par’s generic products include instruction for co-administration of the IL-2 transcription inhibitor FK506, also known as tacrolimus, and everolimus for the prevention and treatment of transplant rejection in liver transplant patients.

After a bench trial, Defendants conceded infringement of the ’772 patent, but argued that Plaintiffs have not proven by a preponderance of evidence that Defendants induced infringement of the ’124 and ’518 patents. Defendants further argued that all of the patents-in-suit were invalid as obvious and for obviousness-type double patenting. The court found that Defendants proved that the asserted claims of the ’772 patent were invalid for obviousness-type double patenting, that Defendants failed to prove that the asserted claims of the ’124 and ’518 patents were invalid, and that Defendants infringed the ’124 and ’518 patents.

Why Plaintiffs Prevailed:  The court first addressed the ’772 patent. Prior to trial, the parties stipulated that another patent, the ’990 patent, disclosed all limitations of claims 1- 3, 7, and 10 of the ’772 patent, and that the two patents are assigned to the same entity and share named inventors. Therefore, the only issue to be decided was whether the ’990 patent was a proper double-patenting reference.Through the operation of the Uruguay Round Agreements Act, the ’772 patent, which issued from an earlier filed application, has a later expiration date than the later-filed ’990 patent. Relying on Federal Circuit caselaw addressing the issue of whether a later-filed but earlier expiring patent can serve as a double-patenting reference for an earlier-filed but later-expiring patent, the court found that what matters in a double patenting analysis, at least for post-URAA patents, is the expiration dates of the patents. The court found that the ’990 patent was a proper double patenting reference thereby invalidating the ’772 patent.

The court next addressed the validity of the ’124 and ’518 patents. The essence of Defendants’ obviousness argument is that the prior art teaches that rapamycin could be safely co-administered with cyclosporin A or tacrolimus with synergistic effectiveness and that everolimus would have been an obvious substitute for rapamycin.

The prior art disclosed everolimus as a preferred compound for immunosuppressive use, including treatment and prevention of transplant rejection. But Defendants acknowledged that none of the references they rely on explicitly taught co-administration of everolimus and cyclosporin A. Instead, Defendants argued that the prior art disclosed co-administration of rapamycin and cyclosporin A, and that everolimus is an obvious substitute for rapamycin. Defendants’ obviousness theory relied on a combination of three references: Tu, which taught co-administration of rapamycin and cyclosporin A in mice; Murgia, which taught combination therapy with rapamycin and cyclosporin A in humans, but was silent on timing; and Kahan, which taught a theoretical basis for synergy when rapamycin and cyclosporin A are administered as a combination therapy, but is also silent on timing.

The court was not persuaded that patient compliance would be sufficient motivation for a physician to co-administer the two drugs, in the absence of evidence that it would be safe for humans, in light of the known toxicity of each of those drugs. The court further found that Defendants presented no direct evidence that co-administration of everolimus and cyclosporin A or tacrolimus was known to be safe in humans in 1996. On the contrary, there was evidence in 1996 that co-administration of rapamycin and cyclosporin A was not safe. Thus, the co-administration of rapamycin and cyclosporin A in humans would not have been obvious to a skilled artisan in view of the prior art. The Tu reference was the only piece of prior art that expressly disclosed co-administration. But the court was not persuaded that a single reference disclosing co-administration in an experimental study in mice would cause a skilled artisan to conclude that co-administration of those two drugs in humans would be safe. The court likewise dismissed all of Defendants’ remaining obviousness arguments.

Defendants also argued that claim 7 of each of the ’124 and ’518 patents were invalid for obviousness-type double patenting over the ’990 patent in view of the same prior art references cited in their obviousness argument. Plaintiffs did not contest that the ’990 patent was a proper double patenting reference. But the court found that the ’990 patent did not disclose co-administration, synergistically effective amounts, or the weight ratios claimed in the ’124 and ’518 patents. Therefore obviousness-type double patenting was not applicable.

Finally, concerning infringement of the ’124 and ’518 patents, Defendants conceded that their proposed labels taught all elements of claim 7 with the exception of the synergistic effectiveness element. Specifically, Defendants argued that Plaintiffs have not proven that co-administration of everolimus with cyclosporin A (for kidney transplant indication) or tacrolimus (for liver transplant indication), as indicated on the label instructions, would result in synergistic effectiveness. The court disagreed, finding that Plaintiffs presented substantial evidence that co-administration of these drugs results in synergistic effectiveness, including examples from the patents themselves, peer-reviewed journal articles, results of a clinical trial, and testimony of an expert with years of experience treating transplant recipients using these and other drugs. 

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