Bristol-Myers Squibb Co. v. Teva Pharma. USA, Inc.

Composition claim is invalid when the patented molecule was an obvious modification of a lead compound that existed in the prior art.

April 17, 2013

GENERICally Speaking

Case Name: Bristol-Myers Squibb Co. v. Teva Pharma. USA, Inc. , Civ. No. 10-805-CJB, 2013 U.S. Dist. LEXIS 18176 (D. Del., Feb. 11, 2013) (Burke, J.)

Drug Product and Patent(s)-in-Suit: Baraclude® (entecavir); U.S. Pat. No. 5,206,244 (“the ’244 patent”)

Nature of the Case and Issue(s) Presented: Plaintiff BMS manufactures and sells Baraclude, which is used in the treatment of patients with chronic hepatitis B viral infections and according to BMS is covered by the claims of the ’244 patent. Teva filed an ANDA including a Paragraph IV certification challenging the validity of the ’244 patent. BMS filed suit, and Teva asserted counterclaims alleging that the ’244 patent was invalid and unenforceable due to inequitable conduct. After a three-day bench trial, the court found that claim 8 of the ‘244 patent was invalid due to obviousness, but rejected Teva’s argument that the ‘244 patent was unenforceable due to inequitable conduct.

Why Teva Prevailed: Claim 8 is a composition claim that describes the structure of entecavir, the active ingredient in Baraclude. The issue before the court was whether the patented entecavir molecule was an obvious modification of a lead compound that existed in the prior art, known as 2’-CDG. The court first found that a person of ordinary skill in the art would have selected 2’-CDG over other compounds. As evidence, the court pointed to the fact that researchers in the late 1980’s expressed great excitement regarding the antiviral activities of carbocyclic analogs (a group that included the 2’-CDG lead molecule). BMS argued that a skilled artisan would have been more likely to have selected an acyclic or a furanose lead compound. But the court rebutted this argument by citing to BMS’s own internal documents, which indicated that BMS itself was touting the promise of carbocyclic analogs. In fact, BMS had praised lobucavir (a carbocyclic precursor to entecavir) as superior to acyclovir, and indicated that carbocyclics were “a natural choice for further development.” The court also pointed to evidence that researchers outside of BMS had recognized the antiviral promise of carbocyclic analogs. In fact, medicinal chemists were already treating and using 2’-CDG as a lead compound prior to the date that entecavir was conceived of by BMS inventors. The court next analyzed the similarities between 2’-CDG and entecavir. Again, BMS attempted to highlight the major differences between the two molecules, but the court was not convinced they were radically different. The court pointed to an article co-authored by one of the inventors of the ’244 patent that emphasized the structural similarity between the two molecules.

Turning to the chemical properties of 2’-CDG, the court found that the prior art compounds exhibited the highest potency and/or activity were most likely to be chosen as lead compounds. Evidence submitted at trial established that 2’-CDG’s promising properties were being widely reported in the literature prior to the conception of entecavir. BMS tried to rebut this evidence with studies showing that 2’-CDG had higher than expected toxicity. The court rejected this argument because the toxicity studies cited by BMS postdated the conception date of the ’244 patent.

After finding that Teva had successfully established that a person of ordinary skill in the art would have selected 2’-CDG as a lead compound, the court determined whether there was a reason or motivation to convert 2’-CDG to entecavir with a reasonable expectation of success. The court held that there was because a person or ordinary skill , motivated by the teachings in the prior art, would modify at the 2-prime and 5-prime positions of 2’-CDG in order to synthesize entecavir. Those modifications would have been well-understood by a chemist with a basic understanding of the periodic table. The court concluded that the substitution of a methylene group to 2’-CDG to arrive at entecavir was an obvious modification of that molecule, and that there was a reasonable expectation of success that such a modification would work.

Turning to the evidence of secondary considerations of non-obviousness, the court placed little emphasis on copying, finding that in the context of the Hatch-Waxman Act, a defendant was essentially required to copy the patented compound. With respect to commercial success, the court concluded that Baraclude had been commercially successful, but not as successful as BMS had asserted at trial. Specifically, the court cited evidence that in all the years that Baraclude had been on the market, over half the prescriptions written to treat hepatitis B during that time were written for some other drug. The court next considered BMS’s evidence regarding the failure of others in the field of the invention, and found BMS’s evidence unpersuasive. There were several other antiviral drugs on the market that were effective in treating hepatitis B infections. Because of those other drugs, the court did not find that there existed a long felt, but un-met need. Last, the court reviewed BMS’s evidence of unexpected results, and found that some of the evidence favored BMS, including the fact that entecavir was shown to be much more potent in treating hepatitis B virus than had been expected. The drug also was found to have a much higher barrier to genetic resistance than would have been expected. However, the court found that the fact that entecavir would be effective as an antiviral was expected, as was the drug’s low toxicity profile. Ultimately, BMS’s evidence of objective considerations of non-obviousness was not persuasive enough to rebut Teva’s prima faciecase that the entecavir molecule was obvious in light of prior art.

Finally, the court addressed Teva’s inequitable conduct counterclaim. Teva argued that three BMS employees had withheld a number of material prior art references during the course of prosecution with intent to deceive the USPTO. The court rejected Teva’s evidence of inequitable conduct, finding that each employee had logical reasons for not submitting the prior art identified by Teva as improperly withheld. The court noted that the individuals identified by Teva did not submit the references because the inventors failed to bring the reference to their attention, and they would have had little reason to identify the prior art as relevant on their own.

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