In September 2010, plaintiff Bristol-Myers Squibb Company (“BMS”) commenced this ANDA litigation against defendant Teva Pharmaceuticals in response to Teva’s filing of Abbreviated New Drug Application No. 202122, which sought “approval to market a generic version of Baraclude.” BMS markets Baraclude to treat adults with certain types of “chronic hepatitis B virus infections.” The Orange Book lists U.S. Patent No. 5,206,244 (the “’244 Patent”) “in connection with BMS’s Baraclude Product,” and BMS sought to enforce claim 8 of that patent, which “covers the chemical compound entecavir.” However, in a recent post-trial opinion, Magistrate Judge Christopher J. Burke held that claim 8 of the ‘244 Patent is invalid as obvious under 35 U.S.C. § 103. Bristol-Myers Squibb Company v. Teva Pharmaceuticals USA, Inc., C.A. No. 10-805-CJB, at 1-4 (D. Del. Feb. 11, 2013).
In reaching his obviousness determination, Judge Burke first relied on a two-prong test specific to chemical compounds and found that Teva met its burden in proving a prima facie case of obviousness. See id. at 88, 131. Addressing the test’s first prong, Judge Burke concluded that Teva proved by clear and convincing evidence that a “chemist” of ordinary skill in the art would have selected 2′-CDG—a compound similar to entecavir—as a “lead compound” at the alleged time of invention. Id. at 112. Judge Burke explained that a “lead compound” is a prior art compound that “would be most promising to modify in order to improve upon [that compound’s activity] and obtain a compound with better activity.” Id. at 91 (quoting Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1357 (Fed. Cir. 2007)) (internal quotation marks omitted). Judge Burke’s conclusion that a chemist of ordinary skill in the art would have chosen 2′-CDG as a lead compound was supported by the following findings: (1) By the late 1980s, carbocyclic analogs, a class of compounds to which 2′-CDG belongs, had “generated excitement” among researchers, including researchers from BMS; (2) 2′-CDG and entecavir were structurally similar; (3) 2′-CDG had demonstrated “positive attributes,” including high potency and good activity in certain applications; (4) Researchers during the relevant time period “were actually treating and using 2′-CDG as a lead compound.” See id. at 94-112.
Turning to the second prong of the prima facie obviousness test, Judge Burke concluded that Teva demonstrated by clear and convincing evidence that the “ordinary medicinal chemist, having selected 2′-CDG as a lead compound, would have had reason to and been motivated” to alter 2′-CDG to create entecavir, and that chemist would have “reasonably expect[ed] to be successful in synthesizing [that] new compound.” Id. at 126, 131. Addressing the “reason” or “motivation” to create entecavir, Judge Burke explained that the chemist of ordinary skill in the art would have been motivated to make “small, conservative changes” to the “2 prime or 5 prime positions” of 2′-CDG, and one of the most conservative changes would have been the “addition of a carbon.” Id. at 119. Such changes were reflected in entecavir’s structure, which was essentially 2′-CDG with a “carbon” added to the “5 prime position.” See id. at 98. With respect to the “reasonable expectation of success,” Judge Burke found the structural similarity between 2′-CDG and entecavir significant, as it is “well-settled that structurally similar compounds ‘often have similar properties.’” Id. at 127 (quoting Takeda, 492 F.3d at 1356). Judge Burke also cited expert testimony that explained that all the “tools” necessary to synthesize entecavir were “in the literature.” Id. at 130.
After concluding that Teva established a prima facie case of obviousness, Judge Burke considered “objective indicia of nonobviousness.” Id. at 131. The evidence with respect to objective considerations, as Judge Burke explained, “was mixed.” Id. at 152-53. However, as Judge Burke’s decision reflects, secondary objective indicia of nonobviousness do not necessarily control the obviousness conclusion. See id. Judge Burke ultimately concluded that “in light of the significant force of Teva’s prima facie case” in addition to the fact that the “PTO was not able to consider certain material prior art references regarding 2′-CDG during prosecution of the patent,” Teva had “demonstrated by clear and convincing evidence that claim 8 of the ‘244 Patent is invalid as obvious under Section 103.” Id. at 153.
Teva also claimed inequitable conduct, arguing that a named inventor on the ‘244 Patent and two prosecuting attorneys intentionally failed to disclose 2′-CDG to the PTO despite their awareness of the similarity between entecavir and 2′-CDG. Id. at 155. Judge Burke held, however, that Teva failed to demonstrate this claim by clear and convincing evidence. Id. at 171. Judge Burke explained that it was “reasonable, if not more reasonable, to infer that these men had made a determination that the most important feature of entecavir was the addition of an exocyclic methylene group . . . and that because they were focused on that feature, they went on to cite prior art to the PTO that referred to compounds containing that type of substitution.” Id. at 170. Judge Burke further explained that with regard to at least the two prosecuting attorneys, it was “just as reasonable, if not more reasonable, to infer that another reason why they did not cite these references was because the references had not been brought to their attention by the inventors, and these men would have had little reason to have identified the prior art as relevant on their own.” Id.