In re Cyclobenzaprine Hydrochloride Extended–release Capsule Patent Litig..

• Decision Date: 12 May 2011
• Docket Number: Civ. No. 09–2118–SLR.
• Citation: 794 F.Supp.2d 517,2011 Markman 1827348
• Parties: In re CYCLOBENZAPRINE HYDROCHLORIDE EXTENDED–RELEASE CAPSULE PATENT LITIGATION.
• Court: U.S. District Court — District of Delaware

794 F.Supp.2d 517

2011 Markman 1827348

In re CYCLOBENZAPRINE HYDROCHLORIDE EXTENDED–RELEASE CAPSULE PATENT LITIGATION.

Civ. No. 09–2118–SLR.

United States District Court, D. Delaware.

May 12, 2011.

William J. Marsden, Jr., Esquire, Susan M. Coletti, Esquire, and Jennifer L. Hall, Esquire, of Fish & Richardson P.C., Wilmington, DE, of Counsel: John D. Garretson, Esquire, and John S. Goetz, Esquire of Fish & Richardson P.C., New York, NY, Jonathan E. Singer, Esquire and Geoff D. Biegler, Esquire of Fish & Richardson P.C., Minneapolis, MN, Juanita Brooks, Esquire of Fish & Richardson P.C., San Diego, CA, for Plaintiffs Eurand, Inc., Cephalon, Inc., and Anesta AG.Tryn T. Stimart, Esquire of Cooley LLP, Washington, D.C., Jon Graves, Esquire, of Cooley LLP, Reston, VA, Of Counsel for plaintiff Eurand, Inc.John C. Phillips, Jr., Esquire of Phillips Goldman & Spence, P.A., Wilmington, DE, of Counsel: George C. Lombardi, Esquire, Maureen L. Ruka, Esquire, Lynn M. Ulrich, Esquire, and Julia M. Johnson, Esquire of Winston & Strawn LLP, Chicago, IL, Megan C. Haney, Esquire of Phillips, Goldman & Spence, P.A., Wilmington, DE, for Defendants Barr Laboratories, Inc., Teva Pharmaceuticals USA, Inc. and Teva Pharmaceutical Industries Ltd.Richard L. Horwitz, Esquire and David E. Moore, Esquire, of Potter, Anderson and Corroon LLP, Wilmington, DE, of Counsel: James H. Wallace Jr., Esquire, Mark A. Pacella, Esquire, Robert J. Scheffel, Esquire, Brian H. Pandya, Esquire, and Matthew J. Dowd, Esquire of Wiley Rein LLP, Washington, D.C., for Defendants Mylan Inc. and Mylan Pharmaceuticals, Inc.

OPINION

SUE L. ROBINSON, District Judge.I. INTRODUCTION

This action arises out of the filing of an Abbreviated New Drug Application (“ANDA”) ¹ by Mylan Pharmaceuticals, Inc. (“Mylan”), Barr Laboratories, Inc. (“Barr”), Impax Laboratories, Inc. (“Impax”) and Anchen Pharmaceuticals, Inc. (“Anchen”) to market a generic version of the pain drug AMRIX® proprietary to Eurand, Inc. (“Eurand”) and exclusive licensee Anesta AG (“Anesta”) (collectively “plaintiffs”). The active ingredient in AMRIX® is cyclobenzaprine hydrochloride (“cyclobenzaprine”) in an extended release formulation, which is protected by, inter alia, U.S. Patent Nos. 7,387, 793 (“the '793 patent”) and 7,544,372 (“the '372 patent”). Upon receiving notification of the filing of Mylan's ANDA, plaintiffs brought this suit for infringement of the '793 and '321 patents pursuant to 35 U.S.C. § 271(e)(2)(A).² (D.I. 234 at 3–4) Plaintiffs filed similar suits against Barr, Impax and Anchen. ( Id.) On December 2, 2009, the cases were consolidated by order of the United States Judicial Panel on Multi–District Litigation. (D.I. 1) Mylan concedes that its generic drug infringes the asserted claims of the patents-in-suit. (D.I. 201) Barr concedes that its generic drug infringes all asserted claims of the patents-in-suit under its claim construction, but not claims 3 and 4 of either patent under plaintiffs' construction. (D.I. 219 at 58:10–13) The parties previously submitted their memoranda on claim construction to the court. From September 29 to October 7, 2010, a bench trial was held on plaintiffs' claims that defendants infringe the patents-in-suit, and defendants' defenses and counterclaims that the patents-in-suit are invalid and/or unenforceable due to obviousness, indefiniteness, failure to specify the best mode, and/or inequitable conduct.³ The issues have been fully briefed post-trial. On October 11, 2010, plaintiffs and Impax jointly moved to dismiss Impax, which the court granted on October 13, 2010. ( C.A. No. 09–018, D.I. 105) The court has jurisdiction pursuant to 28 U.S.C. §§ 1331, 1338(a), 2201 and 2202. Having considered the documentary evidence and testimony, the court makes the following findings of fact and conclusions of law pursuant to Fed.R.Civ.P. 52(a).

II. FINDINGS OF FACT AND CONCLUSIONS OF LAWA. The Parties

1. Eurand is a Nevada corporation with its principal place of business in Vandalia, Ohio. Anesta AG is a Swiss corporation with its principal place of business in Zug, Switzerland. Both companies are involved in research, development and marketing of pharmaceutical drugs.

2. Mylan is a Pennsylvania corporation with its principal place of business in Canonsburg, Pennsylvania. Mylan Pharmaceuticals is a West Virginia corporation with a principal place of business in Morgantown, West Virginia. Mylan Inc. is the parent company of Mylan Pharmaceuticals. Barr Pharmaceuticals is a Delaware corporation with its principal place of business in Pomona, New York. Anchen Pharmaceuticals, Inc. is a California corporation with its principal place of business in Irvine, California. Amchen Inc., is a Delaware corporation with its principal place of business in Irvine, California. Mylan, Barr and Amchen are involved in research, development and marketing of pharmaceutical drugs.

B. The Patents and Technology at Issue

3. This case involves an extended release formulation of cyclobenzaprine, a skeletal muscle relaxant which has been available in immediate-release form for over 30 years.

4. Despite existing in immediate release form for over 30 years, plaintiffs were the first to formulate a viable extended relief version of the drug with a pharmacodynamic (“PD”) profile that matched its immediate release form.

5. AMRIX® is plaintiff's commercial extended release cyclobenzaprine product.

6. The '793 patent issued June 17, 2008, and is entitled “Modified Release Dosage Forms of Skeletal Muscle Relaxants.” The '372 patent issued June 9, 2009 and is also entitled “Modified Release Dosage Forms of Skeletal Muscle Relaxants.” The '793 patent discloses an extended release dosage form of cyclopenzaprine, and the '372 patent claims a method for its use. The ' 372 patent is a divisional patent of the '793 patent, and shares both its specification and much of the structure of its claims.⁴ (' 372 patent, [52] )

7. Claim 1 of the '793 patent reads as follows:

1. A multi-particulate pharmaceutical dosage form of a skeletal muscle relaxant providing a modified release profile comprising a population of extended release beads,

wherein said extended release beads comprise an active-containing core particle comprising a skeletal muscle relaxant selected from the group consisting of cyclobenzaprine, pharmaceutically acceptable salts or derivatives thereof and mixtures thereof; and

an extended release coating comprising a water insoluble polymer membrane surrounding said core,

wherein said dosage form when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm) in 900 mL of 0.1 N HCI at 37° C exhibits a drug release profile substantially corresponding to the following pattern:

after 2 hours, no more than about 40% of the total active is released;

after 4 hours, from about 40–65% of the total active is released;

after 8 hours, from about 60–85% of the total active is released;

wherein said dosage form provides therapeutically effective plasma concentration over a period of 24 hours to treat muscle spasm associated with painful musculoskeletal conditions when administered to a patient in need thereof; and

wherein said water insoluble polymer membrane comprises a water insoluble polymer selected from the group consisting of ethers of cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based on ethylacrylate and methylmethacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, pH-insensitive ammonio methacrylic acid copolymers, and mixtures thereof; and a plasticizer selected from the group consisting of triacetin, tributyl citrate, tri-ethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil, acetylated mono- and di-glycerides and mixtures thereof.

('793 patent, col. 10:22–61)

8. Claim 2 depends from claim 1, and reads:

2. The pharmaceutical dosage form of claim 1, wherein said skeletal muscle relaxant comprises cyclobenzaprine hydrochloride.

( Id., col. 10:62–64)

Claim 3 depends from claim 2, and reads:

3. The pharmaceutical dosage form of claim 2 wherein said pharmaceutical dosage form provides a maximum blood plasma concentration (Cmax) within the range of about 80% to 125% of about 20 ng/mL of cyclobenzaprine HCL and an AUG0–168 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 of a single 30 mg cyclobenzaprine HCL MR Capsule.

( Id., col. 10:65–11:5)

9. Claim 4 depends from claim 3, and reads:

4. The pharmaceutical dosage form of claim 3 wherein the adjusted mean ratio of CMR 30 mg/CMR 15 mg is greater than about 2 for each of AUC0–168 (p< 0.001), AUC0–8 (p<0.001), and Cmax (p<0.001).

( Id., col. 11:6–9)

10. Claims 3 and 4 of the '372 patent essentially mirror claims 3 and 4 of the '793 patent. The primary difference between the claims is the substitution of “[t]he pharmaceutical dosage form of claim” for “[t]he method of claim.” ⁵

11. Barr's proposed generic drug product is a capsule containing multilayer beads. These beads are made of three layers applied atop a sugar core. (PTX–9F BARR_CYC000376–77) Like plaintiffs' product, all beads are manufactured using a fluid bed system with a bottom spray Wurster insert. (JTX–6I, CEPH–AMRIX–00000385) The first layer contains cyclobenzaprine, dissolved in a mixture of 50/50 acetone and purified water which is then sprayed onto sugar spheres. ( Id.) The second layer is created by spraying a mixture of Opadry Clear YS–1–7006 and purified water into the drug-layered beads, ( Id.; PTX–009B at BARR_CYC001822) The beads are then passed through 14–mesh and 24–mesh screens to remove oversized and undersized beads. ( Id.) This forms an immediate release product. ( Id.) To form the extended release version, the immediate release beads are further coated with...