May 2012
Federal Circuit Reaffirms Broad and Expansive Obviousness Inquiry, Rejecting a Formal Burden-Shifting Framework
| Judges: Newman, O’Malley (author), Reyna |
| [Appealed from D. Del., Judge Robinson] |
In In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litigation, Nos. 11-1399,
-1409 (Fed. Cir. Apr. 16, 2012), the Federal Circuit reversed the district court’s obviousness finding, holding that it failed to consider the lack of a known pharmokinetic/pharmodynamic (“PK/PD”) relationship for the claimed drug formulation, thereby erring in assessing the importance of the teachings of the prior art. The Court also affirmed the rejection of the defendants’ alternate argument that the asserted patents were invalid for failure to disclose the best mode, stating that the evidence supported a finding that the patents enable one of ordinary skill in the art to practice the inventor’s preferred dew points.
The plaintiffs, Aptalis Pharmatech, Inc. (formerly Eurand, Inc.), Anesta AG, and Cephalon, Inc. (collectively “Cephalon”), are the owners and exclusive licensees, respectively, of U.S. Patent Nos. 7,387,793 (“the ’793 patent”) and 7,544,372 (“the ’372 patent”). The ’793 patent covers an
extended-release dosage form of skeletal-muscle relaxants; the ’372 patent covers a method of relieving muscle spasms with the formulation. Cephalon markets a drug covered by the ’793 and ’372 patents with cyclobenzaprine hydrochloride as the active pharmaceutical ingredient under the brand name Amrix. To formulate a therapeutically effective extended-release version of the drug, the inventors had to determine the correct PK/PD profile. The PK value indicates what a person’s body does to the drug, and the PD value describes the effect the drug renders on a person’s body.
The defendants, Mylan Pharmaceuticals Inc. and Mylan Inc. (collectively “Mylan”), and Par Pharmaceutical, Inc. (“Par”), filed ANDAs for generic versions of extended-release cyclobenzaprine hydrochloride. The defendants filed Paragraph IV certifications in support of their ANDAs, alleging that their generic products would not infringe the ’793 patent, or that the patent was invalid or unenforceable. Because Mylan was the first party to file a Paragraph IV certification, the FDA granted it a 180-day exclusive marketing period for its generic product.
Cephalon sued Mylan and Par for patent infringement based on their ANDA filings. The district court ruled that the defendants’ products infringed the ’793 and ’372 patents, but that Cephalon’s asserted patent claims were invalid as obvious, finding the claimed extended-release PK profile was bioequivalent to the immediate-release PK profile. Mylan launched its generic product the day after this order, and Cephalon moved to enjoin Mylan’s launch pending appeal. The district court granted Cephalon’s motion for injunctive relief, holding that the potential harm to Cephalon and lack of corresponding harm to Mylan weighed in favor of an injunction.
“[O]n the facts of this case—in which therapeutic effectiveness is a claimed limitation and the parties do not dispute that cyclobenzaprine lacked a known PK/PD relationship—[the defendants] cannot rely on bioequivalence as the sole basis for an obviousness finding, particularly given the heavy burden of proof imposed on them in this context.” Slip op. at 38.
On appeal, the Court held that the district court should have gone beyond bioequivalence and also considered the asserted claims’ limitation requiring therapeutic effectiveness. Further, the district court should have determined whether it would have been obvious to a skilled artisan at the time of the invention that a bioequivalent PK value would satisfy that limitation. Because cyclobenzaprine lacked a known PK/PD relationship at the time of the invention, skilled artisans could not predict whether any particular PK profile, including a bioequivalent one, would produce a therapeutically effective formulation. The Court determined that while the prior art references may teach the claimed physical drug delivery system or dissolution profile, they did not reveal anything about the therapeutically effective PK profile. Accordingly, the Court held that because therapeutic effectiveness is a claimed limitation and the parties did not dispute that cyclobenzaprine lacked a known PK/PD relationship, the defendants could not rely on bioequivalence as the only basis for an obviousness finding.
The Court further clarified the proper framework for making an obviousness determination generally. According to the Court, the district court erred by making its finding that the patents-in-suit were obvious before considering the objective (or “secondary”) considerations and by shifting the burden of persuasion to Cephalon. The Court reiterated the “expansive and flexible” nature of the obviousness inquiry, affirming that the fact-finder must consider all objective evidence before reaching an obviousness conclusion. This approach, the Court noted, guards against the hindsight bias by requiring the fact-finder to withhold judgment on an obviousness challenge until it considers all relevant evidence. In doing so, the Court rejected the formal burden-shifting approach taken by the district court, where secondary considerations are only considered to rebut a “prima facie” case of obviousness. The Court found the secondary considerations of nonobviousness particularly helpful in this case, determining that a long-felt need for an extended-release formulation and the failure of others to formulate one strongly support a conclusion of nonobviousness.
The defendants also argued that the asserted claims were invalid for failure to meet the best mode requirement because the specification failed to disclose the best mode by omitting a particular range of dew points. The Court, however, rejected this argument, determining that the specification need not disclose the optimal dew points to enable skilled artisans to practice the best mode.
Finally, the Court considered Mylan’s appeal of the district court’s order enjoining their launch of a generic version of Amrix. Because Mylan was no longer a prevailing party and several issues had not yet been litigated between the parties, the Court declined to consider the arguments relating to when an injunction pending appeal may be imposed on a prevailing party in an ANDA action.
