Docket No. 2011-1399, -1409
NEWMAN, O’MALLEY, REYNA
April 16, 2012
Subject matter: ANDA/generics, obviousness
Brief summary: Bioequivalence parameters are not necessarily obvious, and “therapeutically effective” claims may prove very valuable. Best mode may not be found where there is enablement.
Summary: The FC panel reversed the DC judgment of invalidity for obviousness and affirmed the best mode judgment regarding Cephalon’s US 7,387,793 and 7,544,372 relating to the product Amrix (cyclobenzaprine hydrochloride) and affirmed the best mode judgment. The obviousness issues related to whether bioequivalence alone was sufficient to render the claims (“therapeutically effective plasma concentration”, “maximum blood plasma concentration (Cmax) within the range of about 80% to 125% of about 20 ng/mL of cyclobenzaprine HCl and an AUC0–168 within the range of about 80% to 125% of about 740 ng·hr/mL and a Tmax within the range of 80% to 125% of about 7 hours following oral administration”) obvious. The DC reasoned that “it would have been obvious to a person having ordinary skill in the art to target extended-release PK values ‘mirroring’-in other words, bioequivalent to-those of the immediate-release cyclobenzaprine formulation” but the panel pointed out that the DC should have considered the therapeutic effectiveness limitations. As such, the panel wrote, the DC would not be able to “find obviousness without finding that the prior art would have taught or suggested a therapeutically effective formulation to one of ordinary skill in the art” (“[w]hile it may have been obvious to experiment with the use of the same PK profile when contemplating an extended-release formulation, there is nothing to indicate that a skilled artisan would have had a reasonable expectation that such an experiment would succeed in being therapeutically effective”, citing Proctor & Gamble, FC 2009). Citing In re Kubin (FC 2009), the panel distinguished between the pursuit of “known options” from “a finite number of identified, predictable solutions” (KSR, US 2007; obviousness) and “‘merely throw[ing] metaphorical darts at a board’ in hopes of arriving at a successful result, [where] ‘the prior art gave either no indication of which parameters were critical or no direction as to which of many possible choices is likely to be successful'” (Kubin). In the second situation, it concluded, “courts should reject ‘hindsight claims of obviousness.'” The DC “found that a skilled artisan could calculate the claimed AUC and Tmax by conducting what it called ‘routine experimentation’” but the FC found the expert testimony insufficient to support that conclusion (“The fact that a skilled artisan could have predicted a particular blood plasma concentration, however, does not mean that such knowledge would have provided a skilled artisan a reasonable expectation of success in calculating a blood plasma concentration that was therapeutically effective…While it might appear to a layperson that 129.5% is ‘about’ 125%, expert testimony is necessary to establish how a person having ordinary skill in the art would perceive those figures. We have no way of knowing the importance of even small differences in these percentages in the absence of some evidence in the record addressing that point.” (citing Ortho-McNeil, FC 2007)) Regarding “obvious-to-try” evidence, the panel wrote that it must show “that the possible options skilled artisans would have encountered were ‘finite,’ ‘small,’ or ‘easily traversed,’ and that skilled artisans would have had a reason to select the route that produced the claimed invention” (citing Ortho-McNeil, FC 2008); “knowledge of the goal does not render its achievement obvious” (Abbott, FC 2009; Cardiac Pacemakers, FC 2004)). Cases relating to the consideration of secondary consideration evidence were also reviewed, the panel concluding that those should be considered “before reaching an obviousness determination” (Stratoflex, FC 1983) (as opposed to being considered as rebuttal evidence after the conclusion is reached). It also found that the DC conclusion that there was no best mode violation was correct because “the disclosure is adequate to enable a person of ordinary skill in the art to practice the invention”.