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Forest Laboratories, LLC v. Sigmapharm Laboratories, LLC

United States District Court, D. Delaware

November 15, 2018


          Jack B. Blumenfeld, Esquire and Jeremy A. Tigan, 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, Mindy L. Ehrenfried, Esquire, and Jorge F. Gonzalez, Esquire of Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, New York, New York.

          John C. Phillips, Jr., Esquire and Megan C. Haney, Esquire of Phillips, Goldman, McLaughlin & Hall, P.A., Wilmington, Delaware. Counsel for Defendant Sigmapharm Laboratories, LLC. Of Counsel: Anthony G. Simon, Esquire and Anthony R. Friedman, Esquire of The Simon Law Firm, P.C., St. Louis, Missouri.




         This Hatch-Waxman patent infringement action revolves around an Abbreviated New Drug Application (“ANDA”) filed by Sigmapharm Laboratories, LLC (“Sigmapharm”) seeking approval to market a generic version of Saphris®, a sublingual asenapine maleate tablet commonly used to treat schizophrenia and bipolar related disorders. Plaintiffs Forest Laboratories LLC, Forest Laboratories Holdings, Ltd., and Allergan Pharmaceuticals International Ltd. (collectively, “Forest”) are the assignee of U.S. Patent Nos. 5, 763, 476 (“the '476 patent”), 7, 741, 358 (“the '358 patent”), and 8, 022, 228 (“the '228 patent”), which are listed in the Food and Drug Administration's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations (the “Orange Book”) as covering Saphris®. (PTX 563).

         From June 18-20, 2018, I held a three-day bench trial on the only remaining issue in this matter: Sigmapharm's alleged infringement of claim 1 of the '476 patent.[1] After review of the evidence and briefing submitted by the parties, I find that Forest has proven by a preponderance of the evidence that Sigmapharm's ANDA infringes claim 1 of the '476 patent. Pursuant to Fed.R.Civ.P. 52(a)(1), the facts and conclusions supporting this decision are set forth below.


         A. Consolidation and Stay

         On August 7, 2014, Sigmapharm notified Forest that it had submitted an ANDA to the FDA seeking approval of a generic version of sublingual asenapine maleate tablets with a Paragraph IV certification, pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV), stating that the patents-in-suit are invalid and/or will not be infringed. (PTX 118). On September 3, 2014, Forest sued Sigmapharm for infringement of two of the three patents covering Saphris®-the '476 patent and '358 patent. (D.I. 1, C.A. No. 14-1119). Forest brought similar suits against Hikma Pharmaceuticals, LLC, Hikma Pharmaceuticals, PLC, and West-Ward Pharmaceutical Corp. (collectively, “Hikma”) (see D.I. 1, C.A. No. 14-1266); Breckenridge Pharmaceutical, Inc. (“Breckenridge”) (see D.I. 1, C.A. No. 14-1504); Alembic Pharmaceuticals Ltd., Alembic Global Holding S.A., and Alembic Pharmaceuticals, Inc. (collectively, “Alembic”) (see D.I. 1, C.A. No. 15-0158); and Amneal Pharmaceuticals, LLC, Amneal Pharmaceuticals of New York, LLC, and Amneal Pharmaceuticals Co. India PVT., Ltd. (collectively, “Amneal”) (see D.I. 1, C.A. No. 15-0430). These cases were initially overseen by the Honorable Sue L. Robinson, now retired, and consolidated under Civil Action No. 14-1119. (D.I. 21; D.I. 35; D.I. 70).

         On June 10, 2015, Sigmapharm filed counterclaims seeking a declaratory judgment of invalidity and non-infringement for all three patents covering Saphris®-i.e., the '476 patent, the '358 patent, and the '228 patent. (D.I. 43). On April 15, 2016, Judge Robinson entered the following judgments pursuant to a stipulation by the parties: (i) in favor of Sigmapharm for Forest's claim of infringement of the '358 patent; (ii) in favor of Sigmapharm for Sigmapharm's counterclaim of non-infringement of the '358 patent; and (iii) in favor of Sigmapharm for Sigmapharm's counterclaim of non-infringement of the '228 patent. (D.I. 181 at ¶ 1(a-c)). Also by stipulation of the parties, Judge Robinson dismissed without prejudice, Sigmapharm's counterclaims seeking a declaration that the '358 patent and '228 patent were invalid. (Id.). As a result, the only remaining claim and counterclaim between Forest and Sigmapharm related to the infringement and validity of the '476 patent.

         On October 13, 2016, Judge Robinson ordered that all issues relating to Sigmapharm's infringement of the '476 patent be stayed and that the 30-month stay of FDA approval of Sigmapharm's ANDA be tolled until the stay was lifted. (D.I. 278). Judge Robinson further ordered that she would proceed to trial with the remaining four defendants (Hikma, Breckenridge, Alembic, and Amneal) to determine, among other things, the validity of the '476 patent. (Id.). Pursuant to that order, Sigmapharm would be bound by any final judgment concerning the validity of the '476 patent. (Id.).

         Judge Robinson held a bench trial with the remaining four defendants between October 24, 2016 and November 3, 2016 and issued an opinion and order on June 30, 2017. (D.I. 322; D.I. 323). A final judgment was entered on July 11, 2017. (D.I. 325). All four trial defendants stipulated to infringement of claims 1, 2, 5, and 6 of the '476 patent. (D.I. 323). Two of the four defendants (Hikma and Amneal) also stipulated to infringement of claims 4, 9, and 10 of the '476 patent. (Id.). The other two defendants (Alembic and Breckenridge) were found not to infringe claims 4, 9, and 10 of the '476 patent. (Id.). Finally, Judge Robinson held that the '476 patent was valid and entered judgment on that issue in favor of Forest and against all defendants, including Sigmapharm. (D.I. 325).

         The four trial defendants have appealed Judge Robinson's decision finding the asserted claims of the '476 patent valid, and Forest has cross-appealed Judge Robinson's decision that Alembic and Breckenridge did not infringe claims 4, 9, and 10 of the '476 patent. (D.I. 326; D.I. 327; D.I. 328; D.I. 329; D.I. 334). That appeal is pending before the Court of Appeals for the Federal Circuit. (See Lead No. 17-2369; Cross Appeal Nos. 17-2436, 17-2441).

         On July 25, 2017, the case was reassigned to my docket. On February 9, 2018, I lifted Judge Robinson's stay on Sigmapharm. (D.I. 358). On June 21, 2018, the 30-month stay of FDA approval of Sigmapharm's ANDA expired. (D.I. 362 at 2). Effective July 17, 2018, the FDA approved Sigmapharm's ANDA No. 206107, for Asenapine Sublingual Tablets, 5 mg and 10 mg. (D.I. 398 at 1 n. 1).

         B. Issues and Asserted Claims for Trial

         Forest asserts that Sigmapharm infringes claims 1-2, 4-6, and 9-10 of the '476 patent. (D.I. 384-1, Ex. 4). The parties agree that Sigmapharm's infringement of claims 2, 5, and 6 rises and falls with infringement of claim 1. (D.I. 362 at ¶ 3). The parties further agree that Sigmapharm's infringement of claims 4, 9, and 10 will depend on the outcome of the appeal pending before the Federal Circuit, because any finding as to infringement of those claims by Alembic and Breckenridge will apply with equal force to Sigmapharm. (Id. at ¶ 4). Given these agreements, the sole issue before me is whether Sigmapharm infringes claim 1 of the '476 patent either literally or under the doctrine of equivalents. (Id. at ¶ 3).


         A. The '476 Patent

         The '476 patent, entitled “Sublingual or Buccal Pharmaceutical Composition, ” was issued from the United States Patent and Trademark Office on June 9, 1998. (D.I. 384, Ex. 1 at ¶ 5). Claim 1 of the '476 patent is a composition claim and recites:

A pharmaceutical composition comprising as a medically active compound: trans-5-chloro-2-methyl-2, 3, 3a, 12b-tetrahydro-1H-dibenz[2, 3:6, 7]oxepino-[4, 5-c] pyrrole or a pharmaceutically acceptable salt thereof;[2] wherein the composition is a solid composition and disintegrates within 30 seconds in water at 37° C.

(Id. at ¶ 15). No. terms from claim 1 were construed in the only claim construction order issued in this case. (See D.I. 133). Judge Robinson did, however, construe claim 1 in her June 2017 trial opinion. She found claim 1 “limited to sublingual or buccal compositions.” (D.I. 322 at 18). For sublingual tablets, the patient places the formulation under the tongue and waits for it to dissolve. (Id. at 2). For buccal tablets, the formulation is placed in the pouch of the cheek. (Id. at 12).

         B. The Experts

         Four experts testified at trial. Forest presented the expert testimony of Dr. Adam Myers (“Dr. Myers”) and Dr. Lisbeth Illum (“Dr. Illum”) and Sigmapharm stipulated to their qualification as experts. (D.I. 386 at 82:8-22; D.I. 388 at 29:10-21). Dr. Myers is a PhD organic chemist. (D.I. 386 at 36:4-7, 85:1-8). He performed testing on samples of Sigmapharm's product and was generally offered as an expert in disintegration testing, pharmaceutical analysis, and U.S. Pharmacopeia, Chapter <701> (“USP <701>”). (D.I. 386 at 89:23-90:2). Dr. Illum has a PhD and DSc in pharmacy. (D.I. 388 at 28:1-25). She was generally offered as an expert in drug delivery systems, transmucosal drug delivery, and disintegration testing. (D.I. 388 at 34:22-25). Sigmapharm presented the expert testimony of Dr. Thomas Kupiec (“Dr. Kupiec”) and Dr. Harry Brittain (“Dr. Brittain”). Dr. Kupiec has a PhD in pharmaceutical sciences. He performed testing on samples of Sigmapharm's product and was generally offered as an expert on disintegration testing and USP <701>. (D.I. 390 at 4:25-5:3). Dr. Kupiec was found to be qualified as an expert. (Id. at 39:24-25). Dr. Brittain is a pharmaceutical scientist with a PhD in physical chemistry. (D.I. 391 at 4:22-25). He was generally offered as an expert on USP <701> and Forest stipulated to his qualification as an expert. (Id. at 4:22-5:22). Finally, Sigmapharm offered the testimony of Dr. Spiridon Spireas (“Dr. Spireas”), the CEO of Sigmapharm, but did not seek to have him qualified as an expert. (D.I. 386 at 9:18-14:1).

         C. U.S. Pharmacopeia, Chapter <701>

         A determination of whether Sigmapharm's accused product infringes claim 1 of the '476 patent depends on one issue: does the accused product “disintegrate[] within 30 seconds in water at 37° C.” The parties agree that USP <701> is the proper method for measuring disintegration. (D.I. 386 at 33:16-22, 59:17-60:11; D.I. 388 at 46:15-47:16; D.I. 398 at 3; D.I. 400 at 3). Because Forest relies on USP <701> to prove infringement and the parties criticize how the opposing experts conducted their tests, it is useful to first understand the purpose of the test, the testing procedures prescribed by USP <701>, and the possible test outcomes.

         1. The Purpose of the USP <701> Test

         USP<701> is a standardized test used in the United States to determine whether tablets disintegrate within the time prescribed. (D.I. 384, Ex. 1 at ¶ 39). USP<701> is most commonly used by manufacturers to test whether a batch of tablets is in compliance with a disintegration specification before a product is released for use or sale. (D.I. 387 at 59:13-22; D.I. 390 at 13:24-14:3). For example, if a disintegration specification requires the tablets to disintegrate in 30 seconds in water at 37° C, then USP <701> is used to confirm that a batch of tablets will perform as required before being released. The test is conducted on a representative sample of tablets from a drug product batch. (D.I. 391 at 15:12-16). Then, the results of a single USP <701> disintegration test are imputed to the entire batch. (D.I. 387 at 73:10-19; D.I. 389 at 40:12-19). Thus, in the case of Sigmapharm, the characteristics of anywhere between 6 and 18 sample tablets are imputed onto a batch of 150, 000 tablets. (PTX 679 at 1).

         2. Test Procedures

         USP <701> requires a basket-rack assembly with six open-ended transparent tubes held in a vertical position.[3] (PTX 631 at 3; PTX 592). The bottom of each tube is a stainless-steel wire screen. (PTX 631 at 3; DTX 29 at SIGMA111656, SIGMA112023-SIGMA112024). An apparatus is used to raise and lower the basket in an immersion fluid, such as water, at a constant frequency rate. (PTX 631 at 3; PTX 594; DTX 29 at SIGMA111806; D.I. 386 at 110:23-24). “Dips per minute” refers to the rate at which the apparatus moves the basket up and down in the water, which the experts here set at 30 per minute. (D.I. 386 at 109:6-7). To conduct the test, one tablet is placed in each of the six tubes and a plastic cylindrical disk is added above the tablet. (PTX 631 at 4). After loading the tablets into the tubes, the apparatus is operated for the time specified. (Id.). Here, the time specified by the '476 patent is 30 seconds. (PTX 1 at 6:2-3).

         After operating the apparatus for the time specified, one must determine if “complete disintegration” has occurred. Under USP <701>, complete disintegration “does not imply complete solution of the [tablet] or even of its active constituent.” (PTX 631 at 3). Instead, “complete disintegration” is defined as “that state in which any residue of the [tablet], except fragments of insoluble coating or capsule shell, remaining on the screen of the [basket-rack assembly] or adhering to the lower surface of the disk is a soft mass having no palpably firm core.” (Id.). Therefore, a tablet is considered to have completely disintegrated under USP <701> even if some part of the tablet remains at the end of the time specified, as long as the remaining pieces are “fragments of insoluble coating or capsule shell” or “a soft mass having no palpably firm core.” (D.I. 386 at 102:8-24). The experts agree “palpably firm core” means that any remaining mass should be probed or palpated, typically with a spatula, to determine if it is soft or hard. (Id.; D.I. 391 at 64:1-4).

         3. Possible Test Outcomes

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;USP<701> has two stages of testing. In stage one, a run of 6 tablets is tested. (PTX 631 at 4). If all 6 tablets (written by the parties as 6/6) completely disintegrate within 30 seconds, testing stops because the results are conclusive: The batch from which the sample tablets were taken will disintegrate within 30 seconds. (Id.; D.I. 386 at 106:4-11). If 3 or fewer tablets (1/6, 2/6, or 3/6) completely disintegrate within 30 seconds, then testing stops and the product cannot be released because the batch is not “in control, ” meaning the tablets are not uniformly performing within the required specifications. (D.I. 386 at 105:18-106:3; D.I. 390 at 13:24-14:3; D.I. 391 ...

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