Post-filing recognition of a drug compound’s unexpected property may not be sufficient to establish the compound’s nonobviousness.

Cindy Chen | July 24, 2014

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

June 12, 2014

Summary

The Federal Circuit found that a patent claim directed to a drug compound for treating hepatitis B was invalid as an obvious modification to a structurally similar lead compound. In so finding, the Federal Circuit dismissed evidence of later discovery, after the time of invention, that the lead compound was highly toxic and therapeutically useless. The Federal Circuit then determined that evidence of the drug compound’s later-discovered unexpected lack of toxicity was insufficient to prove nonobviousness, despite additional evidence demonstrating the drug compound’s unexpectedly high potency and unexpectedly high barrier to resistance. The Federal Circuit’s decision may have taken some bite out of the court’s precedents that an invention’s properties and advantagesneed not be fully known as of the filing date of the patent application to be relevant to nonobviousness.

Details

In 2010, Bristol-Myers Squibb Co. (“Bristol-Myers”) sued Teva Pharmaceuticals

USA, Inc. (“Teva”) for infringing U.S. Patent No. 5,206,244 (“’244 patent”). The ’244 patent issued on April 27, 1993, and is directed to nucleoside analog compounds with antiviral activities. Bristol-Myers asserted only claim 8 of the ’244 patent against Teva. Claim 8 recites the compound known as entecavir, which has the following chemical structure:

Entecavir - chemical structure

 

 

 

 

 

 

Entecavir is the active ingredient in Baraclude®,which is a highly potent and popular treatment for hepatitis B. The popularity of Baraclude® makes it a hugely profitable commodity for Bristol-Myers. In 2013 alone, the drug generated $240 million in U.S. sales and $1.5 billion in worldwide sales.

Teva manufactures a generic version of entecavir. Teva countered Bristol-Myers’ infringement allegations with the assertion that claim 8 is invalid as obvious. Teva’s obviousness arguments began with the selection of 2’-CDG as the lead compound. Like entecavir, 2’-CDG is an antiviral nucleoside analog. 2’CDG and entecavir are also structurally similar. The structure of 2’-CDG, reproduced below, differs from that of entecavir only in the absence of a double bond at the circled position:

2'CDG Chemical structure - pic 2

 

 

 

 

 

 

Evidence from Teva showed that in the late 80’s, at the time of entecavir’s invention, 2’-CDG was garnering interest from various drug makers in the search for new antiviral drugs, and as such, was a natural choice as a lead compound for further modification. Evidence of Teva also showed that the modification to 2’-CDG necessary to create entecavir—that is, to include a double bond at the circled position—had not only been done to other structurally similar compounds, but had also led to the improved antiviral properties of those compounds. Such modification would therefore have been small and conservative, and entirely within the routine experimentation of a chemist endeavoring to formulate a drug with better antiviral activity.

That the necessary modification to 2’-CDG would have been routine was undisputed. What Bristol-Myers disagreed with was that 2’-CDG, if modified, would have been expected to exhibit similar antiviral potency as entecavir. Bristol-Myers’ reasoning was that in the 90’s, not long after entecavir’s invention, 2’-CDG was found to be highly toxic, and therefore therapeutically useless.

The district court sided with Teva, as did the Federal Circuit panel. The Federal Circuit dismissed Bristol-Myers’ argument, because the question of whether one skilled in the art would have expected 2’-CDG, once modified, to exhibit improved antiviral activity is determined from the perspective of one skilled in the art at the time of entecavir’s invention. The Federal Circuit agreed with the district court that, at the time of entecavir’s invention, 2’-CDG was thought to be nontoxic and was used frequently as the starting point in drug development. And as 2’-CDG is structurally similar to entecavir, the modified 2’-CDG was presumed to be equally potent against hepatitis B as entecavir.

Bristol-Myers then presented evidence of unexpected results. These evidence sought to demonstrate that entecavir possesses unexpectedly the combination of: (1) high potency (a daily dose of 0.5 mg of entecavir has at least similar efficacy against hepatitis B as a daily dose of 20-600 mg of other hepatitis B drugs); (2) broad therapeutic window (entecavir was effective against hepatitis B without known toxicity), and (3) high genetic barrier to resistance (very few recipients of entecavir develop biological resistance to the drug).

The district court, and then the Federal Circuit, found that on balance, Bristol-Myers’ evidence of unexpected results were insufficient for patentability. This despite having found that the degree of entecavir’s potency was unexpected, and that entecavir’s high barrier to resistance was an unexpected difference in kind (Op., pp. 17-18). That entecavir’s lack of toxicity was not unexpected in view of the structurally similar 2’-CDG seemed to have trumped the other evidence of unexpected results.

With the ‘244 patent scheduled to expire in February of 2015, Bristol-Myers sought to keep Teva’s generic hepatitis B drugs out of the market until then,1 and strategically petitioned for an en banc rehearing of the panel decision. Bristol-Myers’ petition is interesting for its reliance on the recent Federal Circuit decision in Sanofi-Aventis Deutschland GMBH v. Glenmark Pharmaceuticals Inc., 748 F.3d 1354 (April 21, 2014). More particularly, Bristol-Myers cited Sanofi-Aventis for its proposition that “patentability may consider all of the characteristics possessed by the claimed invention, whenever those characteristics become manifest.” Later-discovered benefits of the claimed invention are perfectly acceptable as evidence of nonobviousness.

Bristol-Myers then attacked the Federal Circuit panel’s determination that one of ordinary skill in the art would have expected 2’-CDG, once modified, to exhibit similar potency against hepatitis B as entecavir. That the structurally similar 2’-CDG was found to be highly toxic should in fact be the strongest proof of entecavir’s nonobviousness, even if the toxicity of 2’-CDG was not discovered until after entecavir’s invention. Bristol-Myers argued that the Federal Circuit panel erroneously limited its consideration of nonobviousness to only those differences not known at the time of the invention.

As Bristol-Myers wrote, “[b]y rigidly applying the presumption that structurally similar compounds will have similar properties without taking into account the later-discovered difference in toxicity, the panel effectively constructed ‘a selective version of the facts relating to the objective considerations so as to confirm its hunch that the asserted claims were obvious’” (citing In re Cyclobenzoprine, 676 F.3d 1063 (Fed. Cir. 2012)) (Petition, p. 11, line 16 – p. 17, line 1).

Bristol-Myers’ petition for rehearing also argued that the Federal Circuit panel incorrectly analyzed Bristol-Myers’ evidence of unexpected results. Rather than separating the evidence into individual categories and characterizing each category as either “difference in degree” or “difference in kind”, the Federal Circuit should have considered the evidence holistically, that is, in terms of entecavir’s combination of unique and unexpected properties. Bristol-Myers argued that entecavir’s nonobviousness rests not in one property of high potency, high genetic barrier to resistance, or lacked toxicity, but in its unique combination of all three properties.

Takeaway

Bristol-Myers’ argument in its petition pertaining to the unexpected lack of toxicity of entecavir seems to make sense in light of Federal Circuit precedents, including Sanofi-Aventis; Genetics Institute, LLC v. Novartis Vaccines and Diagnostics, Inc., 655 F.3d 1291 (Fed. Cir. 2011) (holding that “every property of a claimed compound need not be fully recognized as of the filing date of the patent application to be relevant to nonobviousness”, and that unexpected property discovered after the patent’s filing or issue date may be relied upon for patentability)(Case Summary by Lee Wright); and Knoll Pharm. Co. v. Teva Pharm. USA, Inc., 367 F.3d 1381 (Fed. Cir. 2004) (holding that “[t]here is no requirement that an invention’s properties and advantageswere fully known before the patent application was filed, or that the patent application contains all of the work done in studying the invention, in order for that work to be introduced into evidence in response to litigation attack.”). It would be interesting to see how Bristol-Myers’ petition for rehearing plays out.

That said, as the Federal Circuit appears to be curbing somewhat the reach of Sanofi-Aventis, Genetics Institute, and Knoll Pharm., an argument of nonobviousness would do well by continuing to focus on what one of ordinary skill in the art would not have known at the time of invention.

The Federal Circuit also seems to be increasingly rigid in its application of the proposition that “‘difference in degree’ of a known and expected property are not as persuasive in rebutting obviousness as differences in ‘kind’—i.e., a new property dissimilar to the known property” (Op., p. 16). This attitude seems to be consistent with the Federal Circuit’s recent decision in Galderma Labs. v. Tolmar, Inc., 737 F.3d 731 (Fed. Cir. 2011)(Case Summary by Lee Wright), where the court held, almost as a per se rule, that “no unexpected results [exist] where improved yields over the prior art, measured by percentages, reflect a difference in degree, not in kind”. This line of reasoning does not seem logical, as in some art, a small improvement in “percentages” may nevertheless make a large difference in the properties of the invention.


1 Claim 8 of the ‘244 patent remains valid while Bristol-Myers’ request for rehearing is pending.

Full Opinion

U.S. Patent 5,206,244

 

 

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