Novartis Pharms. Corp. v. Par Pharm., Inc. (D. Del.)

Asserted claims found infringed based on presence of antioxidant and free radical generators creating an oxidative environment susceptible to degradation, and not obvious because a lack of motivation to combine prior art references.

Summer 2014

GENERICally Speaking

Case Name: Novartis Pharms. Corp. v. Par Pharm., Inc., Case No. 11-cv-1077, 2014 U.S. Dist. LEXIS 82780 (D. Del. June 18, 2014) (Andrews, J.)

Drug Product and Patent(s)-in-Suit: Exelon® (rivastigmine); U.S. Patent Nos. 6,335,031 (“the ’031 patent”) and 6,316,023 (“the ’023 patent”)

Nature of the Case and Issue(s) Presented: Novartis sued Watson and Par alleging infringement of the patents-in-suit. Both patents share the same specification. The ’031 and ’023 patents claim pharmaceutical compositions, transdermal devices, and methods of stabilizing compositions comprising the drug rivastigmine, which is an acetylcholinesterase inhibitor, and an antioxidant. On the eve of trial, Novartis and Par entered into a settlement agreement (which ultimately fell through), therefore, the court’s instant opinion only concerns infringement claims against Watson’s proposed ANDA product. Novartis asserted that Watson’s ANDA product infringed claims 3, 7, 13, 16, and 18 of the ’031 patent and claims 2 and 7 of the ’023 patent. Watson countered that the asserted claims were obvious and not infringed. The court held a four-day bench trial and found that Watson’s ANDA product infringed by a preponderance of the evidence, and that Watson did not prove by clear and convincing evidence that the asserted claims were invalid as obvious.

Why Novartis Prevailed: The claims asserted by Novartis can be broken down into two groups: the “presence” claims and the “function” claims. Claims 3 and 7 of the ’031 patent, as well as claims 2 and 7 of the ’023 patent constitute the presence claims. These claims require proof that Compound A and an antioxidant are present. Claims 13, 16, and 18 of the ’031 patent are referred to as the function claims. All three claims require “an amount of antioxidant effective to stabilize compound A from degradation.” The function claims, therefore, have an additional requirement that the antioxidant interact with Compound A to reduce degradation.

The three limitations of the presence claims are: Compound A, a certain weight percent of antioxidant, and a diluent or carrier. The parties agree that Watson’s ANDA product contains Compound A and a diluent/carrier. Only the second limitation requiring “0.01 to 0.5 weight percent” of an antioxidant is in dispute. Butylhydroxytoluene, or BHT, is well known in the art as an antioxidant. The patents-in-suit identify BHT as an antioxidant in the specification and claim BHT as an antioxidant in the asserted claims. Novartis’s infringement expert, Dr. Davies, performed tests on Watson’s ANDA product that identified the presence of BHT. Watson's expert, Dr. Sessler, admitted that Watson’s ANDA products contain BHT, and Watson itself conceded that BHT may have been introduced into its product by an upstream supplier. This evidence proves that BHT is present in Watson’s ANDA products. Moreover, in view of Dr. Davis’s tests, the court found that BHT was present in Watson's ANDA products within the claimed ranges. Therefore, Watson’s ANDA product infringes the presence claims of the patents-in-suit.

Concerning the function claims, the court found that Novartis has proven that free radical generators created an oxidative environment, that Watson’s ANDA product contains three known free radical generators, and that rivastigmine was susceptible to oxidative degradation in the presence of those free radical generators. Despite this oxidative environment, the rivastigmine in Watson’s ANDA product undergoes only minimal oxidative degradation over a prolonged period of time. “The most logical conclusion is that the BHT in Watson’s ANDA product acts as an antioxidant by scavenging free radicals, thereby protecting rivastigmine from oxidative degradation.” The court rejected Watson’s argument that free radicals were not present in the ANDA product. Novartis set forth evidence that the manufacturing process of the ANDA product was done in ambient air, thus exposed to oxygen. Relying on Federal Circuit precedent, the court held that it was not material to infringement that Novartis did not show which free radical was present or the amount of free radicals in the product. Infringement only required evidence that free radicals were likely present, which Novartis had shown by a preponderance of the evidence.

Turning to Watson’s obviousness defense, Watson argued that a skilled artisan would have been motivated to develop a rivastigmine transdermal patch based on the teachings of GB ’040, the closest piece of prior art to the patents in suit. GB ’040 discloses rivastigmine’s efficacy in the treatment of Alzheimer’s disease, and discloses therapeutic benefits that can be obtained through the use of a transdermal formulation. Watson contended that a skilled artisan seeking to improve on the rivastigmine transdermal device of GB ’040, or any other rivastigmine formulation, would have conducted routine stability testing and would have been motivated to add an antioxidant if any oxidative degradation were identified. The court disagreed. GB ’040 and the other references relied on by Watson do not teach that rivastigmine was susceptible to oxygen degradation. There are many types of degradation, and one of skill in the art would not use any excipient to address all known degradation possibilities. The court concluded, “[T]he obviousness determination in this case turns on whether a PHOSITA in January 1998, looking at all of the prior art, would have known rivastigmine was susceptible to oxidative degradation. If the answer is yes, the asserted claims of the ’023 and ’031 patents are invalid because the addition of an antioxidant to a pharmaceutical composition that oxidatively degrades is one of several known, obvious solutions. If the answer is no, then the discovery that rivastigmine oxidatively degrades and the solution to that problem are an inventive contribution worthy of patent protection. There can be no motivation to combine prior art references to solve a problem that no one knows exists. Because I find that a PHOSITA would not have appreciated rivastigmine’s susceptibility to oxidative degradation in January 1998, Watson has not proven obviousness by clear and convincing evidence.”


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