06/13/2014

Bristol-Myers Squibb v. Teva Pharma.: Industry Practice of making Incremental Modifications to Compound is Probative in 103 Analysis


Category: 103 
 
 
 
 By: Jesus Hernandez, Blog Editor/Contributor
 
TitleBristol-Myers Squibb Co. v. Teva Pharma. USA, Inc., No. 2013-1306 (Fed. Cir. June 12, 2014).
IssueBMS attacks the lower court’s obviousness determination by contending that a skilled artisan would have had to make too many decisions to arrive at entecavir. Those decisions include selecting (1) the class of nucleoside analog compounds, (2) 2′-CDG as a lead compound from the class of carbocyclics, (3) the carbocyclic ring or guanine base of 2′-CDG for modification, (4) the 2’ or 5’ position on the carbocyclic ring, (5) the specific chemical element on the 5’ position (carbon), and (6) the type of carbon to carbon bond (single or double).
Bristol-Myers Squibb Co. at *9.
HoldingBased on (1) the structural similarity between entecavir and 2′-CDG, (2) the teachings of the Madhavan reference [teaching that adding an exocyclic methylene group to a carbocyclic nucleoside analog can result in a lead compound with improved antiviral activity], (3) the finding that the exocyclic methylene substitution would be a “small, conservative change[]”and (4) the “totality of the prior art” on 2′-CDG [teaching that 2′-CDG was a promising compound and subject to a multitude of modifications], the district court found [and the CAFC affirms] that a skilled artisan would have been motivated to substitute an exocyclic methylene group at the 5’ position of 2′-CDG, with a reasonable expectation of success of creating a compound with beneficial antiviral properties.
Id. at *7 (text added, no direct correspondence between issue and holding  numbering).
 
 
Procedural HistoryThis patent infringement case concerns a drug for the treatment of hepatitis B. After a four-day bench trial, the United States District Court for the District of Delaware found claim 8 of U.S. Patent No. 5,206,244 (’244 patent) invalid as obvious.
Bristol-Myers Squibb Co. at *2.
 
 
 
 
Legal Reasoning (Prost, Plager, Chen)
Background
Shealy ReferenceThe earliest priority date for the ’244 patent is the date that BMS filed the application, October 18, 1990. 2′- CDG’s synthesis was first published in the Journal of Medicinal Chemistry in 1984 by Dr. Y. Fulmer Shealy (the Shealy reference) of the Southern Research Institute (the SRI). The Shealy reference taught that 2′-CDG exhibited better in vitro antiviral activity against the herpes virus than the FDA-approved best-selling drug at the time, Ara-A.
Bristol-Myers Squibb Co. at *4-5.
Madhavan Reference[T]he Madhavan reference demonstrated that adding an exocyclic methylene group to a carbocyclic nucleoside analog can result in a lead compound with improved antiviral activity. Specifically, it teaches that aristeromycin and Madhavan 30 were two compounds that differed only in the presence of an exocyclic methylene substitution at the 5’ position; that modification resulted in the formation of a much more potent antiviral.
Id. at *12.
Legal Standard: Obviousness of Chemical Compounds
GenerallyTo establish obviousness in cases involving new chemical compounds, the accused infringer must identify some reason that would have led a chemist to modify a known compound. [...]. Generally, an obviousness inquiry concerning such “known compounds” focuses on the identity of a “lead compound.” [...].
Id. at *8 (internal citations omitted).
Identifying the Lead CompoundA lead compound is a compound in the prior art that would be “a natural choice for further development efforts.” Altana Pharma AG v. Teva Pharms. USA, Inc., 566 F.3d 999, 1008 (Fed. Cir. 2009). The motivation to modify that lead compound can come from any number of sources and need not necessarily be explicit in the art. “[I]t is sufficient to show that the claimed and prior art compounds possess 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. Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280, 1293 (Fed. Cir. 2012) [...]
Id. at *8-9 (some internal citations omitted).
I. Obviousness Analysis
(1) A person of ordinary skill in art would have studied nucleoside analog compoundsDuring the relevant time period in the late 1980s, carbocyclic analogs were generating a great deal of interest among researchers searching for compounds with antiviral activity. Both parties’ experts agree on that point. Several research institutions—including Glaxo, Syntex, Abbott Laboratories, and SRI— investigated and published on antiviral activity of carbocyclic nucleosides. Thus, the district court had sufficient evidence to conclude that one of ordinary skill in the art during the relevant time period would have studied carbocyclic analogs “as a promising area” for antiviral drug discovery. J.A. 97.
Bristol-Myers Squibb Co. at *9-10.
(2) A person of ordinary skill in art would have picked 2′-CDG as lead compound[A]t the time of entecavir’s invention, the Price reference showed that 2′-CDG was generally understood to be safe and nontoxic, and other researchers were already using it as a lead compound. As the district court points out, in “October 1990, 2′-CDG was not yet known to have high toxicity,” and BMS’s expert, Dr. Schneller, agreed that researchers at the time treated 2′-CDG as a “promising compound.” […]. Therefore, we see no error in the selection of 2′-CDG as the lead compound here. […]
Id. at *10 (internal citations omitted).
(3) One of ordinary skill in the art would have had a motivation to modify 2′-CDG’s carbocyclic ringIn choosing whether to modify 2′-CDG’s carbocyclic ring or its guanine base, BMS’s expert, Dr. Schneller, initially testified that he would “retain the [carbocyclic] portion,” J.A. 114, but he acknowledged on cross-examination that other chemists were making changes to the carbocyclic portion. JA 1307-08. Teva’s expert, Dr. Heathcock, also testified that changing the carbocyclic portion resulted in greater activity than changes to the guanine ring. Accordingly, this was a natural decision because the goal was to develop antivirals with improved activity.
Id. at *12.
(4) obvious choice for modification would have been either the 2’ or 5’ position on the carbocyclic ringUnrefuted expert testimony also explained how the next obvious choice for modification would have been either the 2’ or 5’ position on the carbocyclic ring, because only at these locations could small changes easily be made to the molecule. Both experts agreed that a skilled artisan would focus on the smallest elements on the top row of the periodic table, including carbon and fluorine. For a specific element, BMS’s expert, Dr. Schneller, testified in his deposition that he would “rule out everything but the carbon” and that carbon was “the only one that sticks out.” […] Teva’s expert, Dr. Heathcock, also explained that the choice to have an exocyclic methylene (carbon-to-carbon double bond) over a methyl group (carbon-to-carbon single bond) would be a more conservative choice, because a methyl group is bigger and longer than an exocyclic methylene group, and the easiest way to synthesize a methyl group would be to make methylene first. […]
Id. at *12.
(5) Prior Art showed specific chemical element on the 5’ position[T]he Madhavan reference demonstrated that adding an exocyclic methylene group to a carbocyclic nucleoside analog can result in a lead compound with improved antiviral activity. Specifically, it teaches that aristeromycin and Madhavan […] were two compounds that differed only in the presence of an exocyclic meth- ylene substitution at the 5’ position; that modification resulted in the formation of a much more potent antiviral.
Id. at *12.
(6) the type of carbon to carbon bond (single or double)Based on the record, we see no clear error in the district court’s finding that the modification required to transform 2′-CDG into the structurally similar entecavir is a minor one: the addition of a single carbon atom to form an exocyclic methylene with the already-present carbon atom at the 5’ position of the carbocyclic ring of 2′- CDG to create entecavir. See supra at 6. Upon selecting 2′-CDG as the lead compound, the steps of deciding which bond to modify and how to modify that bond “equate to a small, finite number of changes to try to [arrive at] the lead compound.”
Id. at *13.
II. Secondary Considerations
Unexpected PropertiesThe antiviral activity of entecavir, however, was not entirely unexpected because, as the district court found, it was already known in the prior art that 2′-CDG was effective against hepatitis B. J.A. 150. Specifically, the Price reference suggested that the structurally similar entecavir would likely have excellent antiviral activity against hepatitis B because 2′-CDG already demonstrated “excellent activity” against the virus. J.A. 2086. Moreover, the Price reference also suggested—and Teva’s expert, Dr. Heathcock, testified—that 2′-CDG was known to have a good therapeutic window. Thus, while the district court found that entecavir’s degree of effectiveness was unexpected, it also noted that entecavir’s “effectiveness against hepatitis B without known toxicity issues” was “not unexpected” in light of the structurally similar 2′-CDG. J.A. 150 (emphasis added). As for the high genetic barrier to resistance, the district court properly credited this attribute as an unexpected property. All taken together, the district court found that the proffered evidence of unexpected properties provided “some support to BMS’s argument as to nonobviousness,” but did not find it sufficient. J.A. 151-53.
Bristol-Myers Squibb Co. at *17-18.
Commercial SuccessThe district court found that Baraclude® achieved commercial success based on sales and market share, but it was “less dynamic” than BMS represented. J.A. 138. Baraclude®’s market share built up gradually over four years and it ultimately held onto the top spot for less than a year. Evidence also showed that two other competitors were able to gain market share more quickly at launch than Baraclude®. J.A. 54, 137. Even BMS’s internal documents viewed Baraclude®’s market performance as “sub optimal.” J.A. 136-38.
Id. at *19.
Conclusion
After considering all of the findings for and against obviousness, as well as Teva’s burden of proof, we see no basis to disturb the district court’s ultimate legal conclusion, and we affirm the judgment that claim 8 of the ’244 patent is invalid as obvious.
Bristol-Myers Squibb Co.  at *20.

 
 
  Image Attribution Statement: Bristol-Myers Squibb Co. at *3 and *4.
 
 
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