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In Re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litigation

Case Name: In Re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litigation, 676 F.3d 1063 (Fed. Cir. April 16, 2012) (Circuit Judges Newman, O'Malley and Reyna presiding; Opinion by O'Malley) (Appeal from D. Del., Robinson, J.)

Drug Product and Patent(s)-in-Suit: Amrix® (cyclobenzaprine hydrochloride); U.S. Pat. Nos. 7,387,793 ("the '793 patent") and 7,544,372 ("the '372 patent")

Nature of the Case and Issue(s) Presented: Plaintiffs Aptalis Pharmatech, Cephalon, Inc. and Anesta AG (a wholly owned subsidiary of Cephalon) appealed the district court's finding that the patents-in-suit were invalid as obvious. Defendants Mylan Pharmaceuticals, Inc., Mylan Inc., and Par Pharmaceutical, Inc. appealed the district court's finding that the patents-in-suit met the best mode requirement and the district court's entry of a preliminary injunction pending the outcome of the appeal. On appeal, the Federal Circuit considered: (i) whether the patents where obvious; (ii) whether the patents satisfied the best mode requirement and (iii) whether defendants should be enjoined from launching their generic products. The Federal Circuit found that the district court failed to consider the lack of a known pharmacokinetic (PK) / pharmacodynamic (PD) relationship for the claimed drug formulation in its obviousness analysis. The claims contain a limitation that the dosage form "provides [a] therapeutically effective plasma concentration." The Federal Circuit determined that to formulate a therapeutically effective, extended-release version of the product, one of ordinary skill in the art would need to know the PK/PD relationship for, at least, the immediate-release version. Without such knowledge, the prior art of record could not render the claims obvious. With respect to the best mode requirement, the Court affirmed the district court's finding, despite its finding that the district court applied the incorrect test for a best model disclosure violation. Finally, the Federal Circuit determined that defendants' appeal regarding the injunction was premature.

Why Plaintiffs Prevailed: At the outset, the Federal Circuit stated that "the district court's legal conclusion that bio equivalence alone was sufficient to render the claims at issue obvious was in error." The district court found that the claimed extended-release PK profile is bio equivalent to the immediate-release PK profile. The district court also found that cyclobenzaprine lacked a known PK/PD relationship at the time of the invention, but found that a person skilled in the art would have expected an extended-release's PD profile to be the same as an immediate-release formulation if the extended-release and immediate-release both have the same PK profile. The Federal Circuit disagreed with the district court's conclusions and found that the prior art failed to disclose the claim limitation of "therapeutically effective" reversing the finding of obviousness. The Federal Circuit stated that the district court reached its obviousness finding by assuming that a known PK/PD relationship for the immediate-release formulation existed and that one of ordinary skill in the art would assume that the PK profiles of the immediate and extended release formulations would produce the same PD effect. But all the experts and parties agreed that skilled artisans did not know the PK/PD relationship of even the immediate-release formulation. The Federal Circuit determined that a finding of obviousness could not be supported since there was no way to match the dosage for the extended-release formulation to achieve a known therapeutic amount. The Federal Circuit stated that while it may have been obvious to experiment with the immediate-release formulation, there was no reasonable expectation of success. The Court found that the FDA's guidance on extended-release formulations and the prior art's disclosure of the structure of the drug delivery system and dissolution profile were insufficient evidence to demonstrate the therapeutically effective limitation, since the references reveal nothing about the critical limitation-a therapeutically effective PK profile. Importantly, the Federal Circuit clarified its precedent regarding the procedural structure for considering secondary indicia of nonobviousness. Prior decisions might suggest that secondary indicia of nonobviousness are considered only after a prima facie case of obviousness has been shown, and that the burden is on the patentee to rebut the prima facie case with evidence of secondary considerations of nonobviousness. This is incorrect. The Federal Circuit found that the district court misapplied the objective considerations to obviousness and misplaced the burden of proof. The lower court failed to consider the objective evidence in its entirety before making an obviousness determination. The Federal Circuit made clear that there is no two-step approach; all evidence of obviousness and nonobviousness should be considered before deciding whether a claimed invention is obvious or nonobvious. Further, the Federal Circuit stated that the burden of establishing the invalidity of a patent rests with the patent challenger and the burden of persuasion never shifts to the patentee to prove nonobviousness.

Next, the Federal Circuit addressed the Defendants' best mode defense. The Federal Circuit stated that the district court applied the incorrect test for best mode. The district court found that dew points used during the formulation process did not need to be disclosed because they amounted to routine details. According to the Federal Circuit, the district court should have made a more fundamental finding; namely, that the specification need not disclose optimal dew points to enable one of ordinary skill to practice the best mode. After reviewing the evidence, the Federal Circuit found that defendants could not meet their burden because the evidence showed that skilled artisans could readily obtain the optimal dew point using a common fluid bed.

Finally, the Federal Circuit concluded that defendants challenge to the injunction was premature given its findings on obviousness and defendants remaining claims in the suit. The Federal Circuit allowed the injunction to remain in place forty-five days after the mandate or such other order from the district court.

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