Bristol-Myers Squibb Company v. Teva Pharmaceuticals USA, Inc.

Docket Nos. 2013-1306

June 12, 2014

Brief Summary: DC decision that claim encompassing BMS’s hepatitis B drug entecavir, (marketed as Baraclude®) would have been obvious because modification of lead compound to replace an oxygen with a carbon-carbon double bond was a “small, conservative change[]” affirmed.

Summary: Bristol-Myers Squibb (BMS) appealed DC decision that claim 8 of US 5,206,244 directed a nucleoside analog having a carbocyclic ring and a guanine base for treatment of hepatitis B (entecavir, marketed as Baraclude®) is invalid for obviousness. The opinion explains that entecavir is structurally identical to deoxyguanosine (DG) except that entecavir has a carbon-carbon double bond where DG has an oxygen atom. Teva filed an ANDA and focused its paragraph IV invalidity argument on the selection of the prior art compound 2’-CDG (an antiviral carbocyclic nucleoside analog differing from DG in that it replaces the oxygen atom with a carbon atom) as a lead compound. One prior art reference (Madhaven) showed substitution the corresponding oxygen atom with a carbon-carbon double bond in a structurally similar antiviral nucleoside analog led to “significantly superior antiviral properties”. BMS’s inventor acknowledged being aware of that reference before conceiving of entecavir and submitted that art to the USPTO as the “most relevant” prior art. The DC found claim 8 obvious based on the structural similarity between 2’-CDG and entecavir, the Madhaven reference, the finding that the substitution “would be a ‘small, conservative change[]”, and that the “totality of the prior art” indicated that a skilled artisan would have been motivated to make the substitution with a reasonable expectation of success of creating an antiviral compound. Secondary considerations of commercial success, long-felt need and unexpected properties were considered but, even though some “cut in favor of nonobviousness”, were not persuasive. The opinion explained that under Takeda (FC 2007), “the accused infringer must identify some reason that would have led a chemist to modify a known compound”. That compound must be a “lead compound…that would be a ‘natural choice for further development efforts” (Eisai, FC 2008 and Altana Pharma AG, FC 2009). And the motivation to modify the lead compound need not be explicity in the prior art but may come from the showing of “a ‘sufficiently close relationship…to create an expectation,’ in light of the totality of the prior art, that the new compound will have ‘similar properties’ to the old” (Otsuka Pharm., FC 2012; Daiichi Sankyo, FC 2010). BMS argued that the skilled artisan “would have had to make too many decisions to arrive at entecavir” but the FC concluded the DC analysis was “well supported” given the evidence “at the time of invention” (Velander, FC 2003; Amgen, FC 2009). BMS’s arguments regarding toxicity were dismissed because as of the priority date, “2’-CDG was not yet known to have high toxicity” (not recognized until after the priority date). And expert testimony showed that “a chemist in drug development would seek to make small, conservative changes” to a lead compound such as those made to create entecavir (In re Cyclobenzaprine, FC 2012). The proferred evidence of unexpected properties was found similarly unconvincing as unexpected “results [per se] do not per se defeat, or prevent, the finding that a modification will yield expected, beneficial properties” (Dillon, FC 1990; In re Papesch, CCPA 1963; In re Hoch, CCPA 1970; In re Merck, FC 1986; In re Albrecht, CCPA 1975 (“marked superiority” or difference in “kind” persuasive vs. “mere difference in degree”)). Evidence of commercial success was also unpersuasive since “share grew up gradually over four years and it ultimately held the top spot for less than a year” and “[e]ven BMS’s internal documents viewed Baraclude®’s market performance as ‘sub optimal’”. Thus, the DC decision that claim 8 was obvious was affirmed.

This entry was posted in Generics / ANDA, Obviousness, Uncategorized. Bookmark the permalink.

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