Cyclobenzaprine hydrochloride – USA

On Jan 04, 2018, the Federal Circuit vacated & remanded district court’s infringement decision in Amrix (Cyclobenzaprine hydrochloride) ANDA case.

In this Hatch-Waxman case, Apotex Inc. and Apotex Corp. appeal from the district court’s claim construction of “extended release coating” and its finding that Apotex’s product infringes U.S. Patent Nos. 7,790,199 and 7,829,121. Aptalis Pharmatech, Inc. and Ivax International GmbH own the ’199 and ’121 patents which relate generally to extended release dosage forms of cyclobenzaprine hydrochloride, a skeletal muscle relaxant. Instead of requiring three daily doses of cyclobenzaprine, as in the prior art, the asserted patents disclose an extended release cyclobenzaprine formulation that provides twenty-four hour relief from muscle spasms with a single dose.

The asserted patents teach two different formulations that use a water insoluble polymer coating to achieve an extended release profile. The parties refer to these alternatives as membrane systems and matrix systems. In a membrane system, a water insoluble polymer coating is applied onto an active-containing core. In a matrix system, the water insoluble polymer is mixed together with the drug and compacted into a tablet. Although the specification discloses two different extended release formulations, the claims are not expressly limited to a specific formulation by name (i.e., “membrane system” or “matrix system”). Claim 1 reads:

1. A pharmaceutical dosage form comprising a population of extended release beads, wherein said extended release beads comprise: an active-containing core particle comprising cyclobenzaprine hydrochloride as the active; and an extended release coating comprising a water insoluble polymer membrane surrounding said core, wherein said water insoluble polymer membrane comprises a polymer selected from the group consisting of ethers of cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, pH-insensitive ammoniomethacrylic acid copolymers, and mixtures thereof; wherein the total amount of cyclobenzaprine hydrochloride in the pharmaceutical dosage form is 30 mg; wherein following a single oral administration of the pharmaceutical dosage form, the pharmaceutical dosage form provides a maximum blood plasma concentration (Cmax) of 19.851±5.8765 ng/mL of cyclobenzaprine HCl and an AUC0-168 of 736.60±259.414 ng·hr/mL.

Apotex argued that it does not infringe because its products contain a matrix-style formulation. Parties stipulated to a construction for part of the disputed term that “a water insoluble polymer membrane surrounding said core” means “a water insoluble polymer covering that surrounds the active core.” The district court subsequently construed “extended release coating,” the remainder of the disputed claim term, as “[a] layer of any substance that is applied onto the surface of another, the purpose of which is to delay the release of a drug in order to maintain the drug at therapeutically effective concentrations over an extended period of time.” Applying this claim construction, the district court found that Apotex’s ANDA product contained an extended release coating and infringed the asserted claims of the ’199 and ’121 patents.

Apotex appealed the district court’s claim construction and its infringement finding. During appeal Apotex contended that the intrinsic evidence would have taught an ordinarily skilled artisan at the time of the invention that an “extended release coating” is limited to a continuous outer film, not simply “[a] layer of any substance that is applied onto the surface of another.” Federal circuit said that a coating that surrounds the core or encloses it on all sides connotes a continuous coating, i.e., one that covers the entire surface of the core. And, because the extended release coating must surround the core, the plain claim language suggests that the coating must be located outside of the core. In other words, the water insoluble polymer membrane is an outer coating relative to the core. This construction reflects these limitations by requiring a “continuous outer film applied onto the surface of the active-containing core.” The specification also bolsters the conclusion that the extended release coating must be a continuous outer film. And the specification’s frequent references to applying the extended release coating “onto” the active-containing core comports with court’s understanding of the spatial orientation required by the claims.

Federal circuit was not persuaded by Aptalis’ arguments in defense of the district court’s contrary construction. Aptalis first argued that the “applied onto the surface of the active-containing core” and “outer” requirements would exclude preferred embodiments. In Example 2, for instance, a seal coat is applied onto the active-containing core before the extended release coating, and an additional coating layer is added after the extended release coating. Because there is a seal coat between the extended release coating and the active-containing core, Aptalis argued that the extended release coating was applied onto the seal coat, not “onto the surface of the active-containing core.” Similarly, Aptalis interpreted “outer” to mean “outermost” and points out that there is a coating layer applied onto the extended release coating in Example 2. Aptalis next asserted that the word “continuous” does not appear in the asserted patents and that a “continuous” extended release coating would not be functional because the coating must be permeable to gastrointestinal fluids. Federal circuit denied all Aptalis arguments & finally held that district court erred in construing the claims. Thus it vacated and remanded the district court’s infringement finding for further proceedings consistent with court’s claim construction.