Forest Labs., LLC v. Sigmapharm Labs., LLC

• Decision Date: 30 June 2017
• Docket Number: Civ. No. 14-1119-SLR.
• Citation: 257 F.Supp.3d 664
• Parties: FOREST LABORATORIES, LLC and Forest Laboratories Holdings, Ltd., Plaintiffs, v. SIGMAPHARM LABORATORIES, LLC, et al., Defendants.
• Court: U.S. District Court — District of Delaware

257 F.Supp.3d 664

FOREST LABORATORIES, LLC and Forest Laboratories Holdings, Ltd., Plaintiffs,

v.SIGMAPHARM LABORATORIES, LLC, et al., Defendants.

Civ. No. 14-1119-SLR.

United States District Court, D. Delaware.

Signed June 30, 2017

Jack B. Blumenfeld, Esquire and Maryellen Noreika, Esquire of Morris, Nichols, Arsht & Tunnell LLP, Wilmington, Delaware. Counsel for Plaintiffs. Of Counsel: Howard W. Levine, Esquire, Sanya Sukduang, Esquire, Jonathan R. Davies, Esquire, Courtney B. Casp, Esquire, and Charles E. Lipsey, Esquire of Finnegan, Henderson, Farabow, Garrett & Dunner LLP.

John C. Phillips, Esquire, David A. Bilson, Esquire and Megan C. Haney of Phillips, Goldman, McLaughlin & Hall, P.A., Wilmington, Delaware. Counsel for Defendant Sigmapharm Laboratories, LLC. Of Counsel: Anthony G. Simon, Esquire, Anthony R. Friedman, Esquire, Benjamin R. Askew, Esquire, and Michael P. Kella, Esquire of The Simon Law Firm, P.C.

Karen Elizabeth Keller, Esquire and Jeffrey Thomas Castellano, Esquire of Shaw Keller, LLP, Wilmington, Delaware. Counsel for Defendants Hikma Pharmaceuticals LLC, Hikma Pharmaceuticals PLC, and West–Ward Pharmaceutical Corp. Of Counsel: Imron T. Aly, Esquire, Joel M. Wallace, Esquire, and Helen H. Ji, Esquire of Schiff Hardin LLP.

Richard D. Kirk, Esquire, Stephen B. Brauerman, Esquire and Sara E. Bussiere, Esquire of Bayard, P.A., Wilmington, Delaware. Counsel for Defendant Breckenridge Pharmaceutical, Inc. Of Counsel: Beth D. Jacob, Esquire, Clifford Katz, Esquire, and Malavika A. Rao, Esquire of Kelley, Drye & Warren LLP.

Karen Pascale, Esquire and Pilar G. Kraman, Esquire of Young, Conaway, Stargatt & Taylor, LLP, Wilmington, Delaware. Counsel for Defendants Alembic Pharmaceuticals Ltd., Alembic Global Holding SA and Alembic Pharmaceuticals, Inc. Of Counsel: Steven J. Lee, Esquire, Michael K. Levy, Esquire, Paul M. Richter, Jr., Esquire and Ksenia Takhistova, Esquire of Andrews Kurth Kenyon LLP.

Neal C. Belgam, Esquire and Eve H. Ormerod, Esquire of Smith, Katzenstein & Jenkins, LLP, Wilmington, Delaware. Counsel for Defendants Amneal Pharmaceuticals LLC. Amneal Pharmaceuticals of New York, LLC and Amneal Pharmaceuticals Co. India Pvt. Ltd. Of Counsel: Michael R. Dzwonczyk, Esquire, Azy S. Kokabi, Esquire, and Aiyda Ghahramani, Esquire of Sughrue Mion, PLLC.

OPINION

Sue L. Robinson, Senior District Judge

I. INTRODUCTION

This consolidated case arises out of the filing of Abbreviated New Drug Applications ("ANDAs") by defendants Sigmapharm Laboratories, LLC ("Sigmapharm"); Breckenridge Pharmaceutical, Inc. ("Breckenridge"); Hikma Pharmaceuticals, LLC, Hikma Pharmaceuticals, PLC, and West–Ward Pharmaceutical Corporation (collectively, "Hikma"); Alembic Pharmaceuticals Ltd., Alembic Global Holding S.A., and Alembic Pharmaceuticals, Inc. (collectively, "Alembic"); and Amneal Pharmaceuticals, LLC, Amneal Pharmaceuticals of New York, LLC, and Amneal Pharmaceuticals Co. India PVT.LTD (collectively, "Amneal"). All defendants may be collectively referred to as "defendants." Each of the defendants has submitted an ANDA in an attempt to market generic versions of asenapine before the expiration of U.S. Patent No. 5,763,476 ("the '476 patent"), which claims sublingual or buccal compositions of asenapine and methods of using such compositions to treat mental disorders, including schizophrenia

. Plaintiffs Forest Laboratories, LLC and Forest Laboratories Holdings, Ltd. (collectively, "Forest" or "plaintiffs") brought patent infringement suits against each of the defendants, which suits were consolidated into the above captioned suit. In the case tried before the court, each of the defendants conceded infringement of claim 1 of the '476 patent and two of the four defendants (Amneal and Hikma) conceded infringement of claim 4.¹ Therefore, the focus of the trial (conducted in the fall of 2016) was infringement of claim 4 and the validity of the '476 patent. The court has jurisdiction over this matter pursuant to 28 U.S.C. §§ 1331 and 1338(a). Venue is appropriate pursuant to 28 U.S.C. § 1400(b). Having considered the documentary evidence and testimony, the court makes the following findings of fact and conclusions of law, pursuant to Federal Rule of Civil Procedure 52(a).

II. FINDINGS OF FACT

A. Development of Saphris®

Saphris®² is an atypical antipsychotic containing asenapine maleate approved for the treatment of schizophrenia

and manic or mixed episodes associated with bipolar I disorder. (PTX 54 at 1, 3) Saphris is the only antipsychotic³ that is administered sublingually. (D.I. 311 at 85:9–12; D.I. 315 at 1039:5–13) Sublingual administration requires patients to put the formulation under the tongue and wait for the formulation to dissolve. Patients taking Saphris sublingually also cannot eat or drink for ten minutes following administration. (PTX 54 at 1, 3, 37)

Asenapine was not initially developed as a sublingual tablet but, instead, as a standard conventional tablet given orally. This is shown in a series of publications by Organon, the company that first developed asenapine for use in humans. (PTX 33; PTX 37; PTX 53) One of the first publications concerning asenapine is Sitsen, J. M. Ad., et al., Org 5222: Preliminary Clinical Results 15–18 (Raven Press, Ltd., 1992) ("Sitsen 1992"). (PTX 37) Sitsen 1992 explains that while there were drugs then available for the treatment of schizophrenia

, they were not satisfactory due to their debilitating side effects. (Id. at 15) In particular, the available first generation antipsychotics caused serious movement disorders, referred to as "extrapyramidal" side effects ("EPS"), including Parkinsonism and tardyskinesia—side effects that persisted even when the patients stopped taking the medicines. (D.I. 311 at 71:12–25, 85:20–86:5; D.I. 313 at 612:18–613:2, 618:18–619:20)

At the time of the publication of Sitsen 1992, there were two second generation or "atypical" antipsychotics available, clozapine

and risperidone. Although clozapine caused fewer movement disorders, it caused other serious side effects including a rare white blood cell condition, termed "agranulocytosis

," that was potentially fatal and had to be closely monitored. (D.I. 313 at 730:4–12; D.I. 315 at 1059:9–1061:23) For this reason, clozapine was used sparingly and was only approved for the most treatment-resistant of schizophrenia patients. Risperidone caused an increase in prolactin, which resulted in the serious side effect of breast growth and lactation, even in men. (DTX 63, 955 at figure 4D, 960; D.I. 311 at 70:25–71:11; D.I. 313 at 672:3–673:18, 674:10–24; D.I. 315 at 1057:1–1058:12)

Sitsen 1992 explained that there was a need for an effective second generation atypical antipsychotic that could be widely used for schizophrenic patients. (PTX 37 at 3) Sitsen 1992 declared that asenapine (referred to by its internal Organon designation "Org 5222"), an atypical antipsychotic, satisfied that need. Org 5222 was described as "a new antipsychotic drug with high in vitro affinity for dopamine

D1 and D2 receptors and for several types of serotonin (5–HT) receptors." (Id. at 3) "Its behavioral pharmacology suggests antipsychotic properties with a relatively low propensity to induce movement disorders." (Id. ) "Org 5222 is a novel antipsychotic drug with a pharmacological profile that is different from that of the classical antipsychotics haloperidol⁴ and chlorpromazine." (Id. at 5)

Sitsen 1992 also discussed early clinical studies with asenapine that provided promising results. The article explained that healthy male volunteers received oral doses of Org 5222 up to 30 mg, and reported that "[a]t the highest dose levels some volunteers experienced mild drowsiness and/or moderate fatigue. No other clinically significant or dose-related changes in biochemical, hematological, or urinary parameters were found." (PTX 37 at 4) When the article referred to "oral doses," it referred to a conventional tablet that is swallowed, passes through the digestive system, and is subject to "first-pass metabolism," where the drug is metabolized by the liver before it enters the blood. (D.I. 314 at 939:25–940:11) Similarly, Sitsen 1992 reported that, in a different clinical trial using multi-dosing of asenapine, there was a slight elevation of liver enzymes that were reversible after discontinuation of treatment. (PTX 37 at 4) The article reported that this side effect was considered safe, and skilled artisans understood that this sort of side effect was not considered serious, particularly for a drug that was being used to treat schizophrenia

. (D.I. 314 at 845:3–847:23, 944:1–15) Sitsen 1992 concluded that "[p]reliminary results of a pilot trial comparing the effects of Org 5222 ... suggest [it] is an effective antipsychotic drug that lacks sedative properties and extrapyramidal side effects," and that "Org 5222 is well tolerated by healthy persons and schizophrenic patients." (PTX 37 at 5)

In terms of efficacy, the article discussed an early clinical trial comparing the effects of Org 5222 and haloperidol

in schizophrenia patients. The clinical study showed "that Org 5222 is an effective antipsychotic drug that lacks sedative properties and extrapyramidal side effects." (PTX 37 at 5) Although more patients dropped out of the trial who were on asenapine than who were on haloperidol, the patients who dropped out on asenapine did so because of lack of treatment effect. (Id. ) As explained by "De Boer 1993,"⁵ "[t]he main reason for patient dropout was inadequate treatment effect occurring more frequently in the Org 5222 group," but that the asenapine arm of the study was "significantly more ill than other patients in the study." (PTX 33 at 6) That is, the higher dropout rate observed in the asenapine group was likely due to the fact that the patients were more difficult to treat than the patients in the haloperidol

group, not that asenapine was ineffective. (D.I. 314 at 946:2–22, 947:24–948:19)

Organon published an abstract in 1993,...