Eurand, Inc. v. Mylan Pharms. Inc. (In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig.)

• Citation: 676 F.3d 1063,102 U.S.P.Q.2d 1760
• Decision Date: 16 April 2012
• Docket Number: Nos. 2011–1399,2011–1409.,s. 2011–1399
• Parties: In re CYCLOBENZAPRINE HYDROCHLORIDE EXTENDED–RELEASE CAPSULE PATENT LITIGATION.Eurand, Inc. (Now Known as Aptalis Pharmatech, Inc.), Cephalon, Inc., and Anesta AG, Plaintiffs–Cross Appellants, v. Mylan Pharmaceuticals Inc. and Mylan Inc., Defendants–Appellants,andPar Pharmaceutical, Inc., Defendant–Appellee.
• Court: United States Courts of Appeals. United States Court of Appeals for the Federal Circuit

102 U.S.P.Q.2d 1760

676 F.3d 1063

In re CYCLOBENZAPRINE HYDROCHLORIDE EXTENDED–RELEASE CAPSULE PATENT LITIGATION.Eurand, Inc. (Now Known as Aptalis Pharmatech, Inc.), Cephalon, Inc., and Anesta AG, Plaintiffs–Cross Appellants,

v.Mylan Pharmaceuticals Inc. and Mylan Inc., Defendants–Appellants,andPar Pharmaceutical, Inc., Defendant–Appellee.

Nos. 2011–1399

2011–1409.

United States Court of Appeals, Federal Circuit.

April 16, 2012.

Jonathan E. Singer Fish & Richardson, P.C., of Wilmington, DE, argued for plaintiff-cross appellant. With him on the brief were William J. Marsden, Jr. of Minneapolis, MN, Juanita R. Brooks, of San Diego, CA, and Cherylyn Esoy Mizzo, Tryn T. Stimart, Cooley Godward Kronish, LLP, of Washington, DC.

Robert L. Byer, Duane Morris LLP, of Pittsburg, Pennsylvania, for amici curiae Gregory Dolin and Robert C. Kahrl. With him on the brief were Kristina Caggiano and Elese Hanson.

James H. Wallace, Jr., Wiley Rein LLP, of Washington, DC, argued defendants-appellants. With him on the brief were Mark A. Pacella, Robert J. Scheffel, Matthew J. Dowd, Kevin P. Anderson and Brian H. Pandya.

Before NEWMAN, O'MALLEY, and REYNA, Circuit Judges.

O'MALLEY, Circuit Judge.

After a bench trial, the U.S. District Court for the District of Delaware found U.S. Patent Nos. 7,387,793 and 7,544,372 invalid as obvious. Case No.2011–1409 is an appeal from that judgment. We reverse and vacate the district court's judgment of invalidity because the district court erred when it declared the patents in suit invalid as obvious. Specifically, by failing to consider the lack of a known pharmacokinetic/pharmacodynamic relationship for the claimed drug formulation, the trial court erred when it assessed the importance of the teachings of the prior art to the obviousness analysis.

As an alternative ground in support of the district court's judgment invalidating the '793 and '372 patents, the defendants argue that the district court erred when it found that the patents satisfy the best mode disclosure requirement. We affirm the district court's best mode ruling. The evidence supports a finding that the patents in suit enable one of ordinary skill in the art to practice the inventor's preferred dew points.

After invalidating the '793 and '372 patents as obvious, the district court enjoined the defendants—the parties who prevailed at trial—from launching their generic product pending appeal to this court. That order is challenged in Case No.2011–1399. We dismiss that appeal as premature because several outstanding issues in the district court leave uncertain whether the defendants could recover on their appeal bond.

I.

Plaintiff Aptalis Pharmatech, Inc. is the owner of the '793 and '372 patents. Plaintiff Anesta AG, a wholly owned subsidiary of plaintiff Cephalon, Inc., is the exclusive licensee of the patents. We refer to the plaintiffs collectively as Cephalon.

The '793 patent covers a modified-release dosage form of skeletal muscle relaxants. The '372 patent covers a method of relieving muscle spasms with the formulation disclosed in the '793 patent. Cephalon markets a drug covered by the patents under the brand name Amrix. The active pharmaceutical ingredient in Amrix is cyclobenzaprine hydrochloride. A single dose of Amrix releases cyclobenzaprine hydrochloride in the body during a twenty-four-hour period. Immediate-release formulations, by contrast, release the drug in a shorter amount of time and require multiple daily doses.

The '793 and '372 patents share the same specification and, as relevant to this appeal, have the same limitations in claims 1–3. Claim 1 recites a dosage form of a skeletal muscle relaxant (in the '793 patent) and a method of relieving muscle spasms (in the '372 patent), which, in relevant part, “provides [a] therapeutically effective plasma concentration over a period of 24 hours to treat muscle spasm associated with painful musculoskeletal conditions....” '793 patent col.10 ll.23, 43–46 (filed Nov. 14, 2003); ' 372 patent col.10 ll.21, 43–46 (filed Feb. 6, 2008). Claim 2 depends on claim 1 and specifies the claimed skeletal muscle relaxant as cyclobenzaprine hydrochloride. '793 patent col.10 ll.62–64; '372 patent col.10 ll.61–62. Claim 3 depends on claim 2 and specifies the following pharmacokinetic values:

[A] maximum blood plasma concentration (Cmax) within the range of about 80% to 125% of about 20 ng/mL of cyclobenzaprine HC1 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.... '793 patent col.10 l.65–col.11 l.5; '372 patent col.10 l.63–col.11 l.3.

Pharmacokinetics is the study of what a person's body does to a drug after administration. The pharmacokinetic (“PK”) values recited in claim 3 measure various characteristics about the drug's behavior in a patient's blood plasma. Cmax, as claim 3 alludes, represents the maximum concentration of the drug in a person's blood plasma. AUC0–168 represents the area under the blood plasma concentration curve, or, in other words, the body's total exposure to the drug. Tmax represents the time after administration when the maximum concentration of the drug in the blood plasma (Cmax) occurs.

To formulate a therapeutically effective, extended-release version of cyclobenzaprine hydrochloride, the inventors had to ascertain the correct pharmacokinetic/pharmacodynamic (“PK/PD”) profile. The PK side of the relationship—what a person's body does to the drug—includes the Cmax, AUC, and Tmax, as identified in claim 3. The PD side of the relationship describes the effect that a drug renders on a person's body. The PD of cyclobenzaprine hydrochloride is the relief of muscle spasms.

The determination of a PK profile is a quantitative exercise. The determination of PD, or therapeutic effectiveness, however, is a qualitative exercise. As one of Cephalon's experts, Dr. Stanley Davis, explained, a therapeutically effective plasma concentration is “a concentration that the formulation provides when the formulation works.” The district court, likewise, construed the claim limitation “therapeutically effective plasma concentration” to mean “the amount of a drug required to produce the therapeutic result.”

One of the patents' inventors, Dr. Gopi Venkatesh, testified at trial about how he and his co-inventor, Dr. James Clevenger, ascertained the correct PK/PD profile for the patented formulation. First, they estimated PK values with computer models. They started by creating PK profiles for the immediate-release formulation. The immediate-release formulation is dosed at 10 mg. Using immediate-release PK data, the inventors created models for twice-a-day dosing and three-times-a-day dosing at 10 mg per dose. Then, they drew on that data to create a model for a single, 30 mg dose. The inventors then created an in vitro dissolution profile, which modeled how much drug would be released over time if the formulation with the model PK values were placed in a solution such as water. Finally, the inventors tested a formulation with the model PK values and dissolution profile in a clinic. Clinical test results confirmed that the formulation was therapeutically effective.

II.

The defendants, Mylan Pharmaceuticals Inc. and Mylan Inc. (collectively, “Mylan”), and Par Pharmaceutical, Inc. (“Par”), filed abbreviated new drug applications (“ANDAs”) for generic versions of extended-release cyclobenzaprine hydrochloride. In support of their ANDAs, Mylan and Par filed “Paragraph IV” certifications, in which they alleged that their generic products would not infringe the '793 patent, or that the patent was invalid or unenforceable. See 21 U.S.C. § 355(j)(2)(A)(vii)(IV) (2006). The U.S. Food and Drug Administration (“FDA”) approved both defendants' applications. Because Mylan was the first party to file a Paragraph IV certification, the FDA granted Mylan a 180–day exclusive marketing period for its generic product.

Cephalon sued Mylan and Par for patent infringement, claiming that the defendants' filing of their ANDAs infringed the '793 patent. See 35 U.S.C. § 271(e)(2) (2006 & Supp. IV 2010). The FDA stayed Mylan's exclusive marketing period for thirty months because of the litigation. The district court conducted a bench trial in September and October 2010. Rather than ruling from the bench, the district court took the matter under advisement to prepare a written opinion. The end of the FDA's thirty-month stay approached as the parties waited for the district court's opinion. On April 8, 2011, the district court, sua sponte, temporarily enjoined Mylan from launching its generic product pending the issuance of an opinion. The thirty-month stay expired on April 17, 2011.

The district court issued its written opinion on May 12, 2011. It ruled that Mylan's and Par's products infringed the '793 and '372 patents, but that Cephalon's asserted patent claims were invalid as obvious. The district court entered judgment of invalidity in favor of Mylan and Par. The district court's sua sponte injunction expired by its own terms upon entry of judgment.

On May 13, 2011, the day after the district court entered judgment, Mylan launched its generic product. On May 15, 2011, Cephalon moved for an injunction to bar Mylan's launch pending appeal and to recapture product already released. Cephalon argued that it was likely to prevail on appeal because it believed the district court had made a number of errors in its obviousness analysis. In response, the district court conceded certain errors and modified some of its findings, but reaffirmed its obviousness ruling. Notwithstanding that it affirmed Mylan's victory, the district court granted Cephalon's motion for injunctive relief and issued an injunction pending appeal to this court. The district court expressed uncertainty about whether this court would affirm its invalidity ruling and found that Cephalon was “just as likely as...