Cephalon Inc. v. Watson Pharmaceuticals Inc.

• Decision Date: 11 March 2011
• Docket Number: Civ. No. 08–330–SLR.
• Citation: 2011 Markman 845376,769 F.Supp.2d 729
• Parties: CEPHALON, INC., and Cima Labs, Inc., Plaintiffs,v.WATSON PHARMACEUTICALS, INC., Watson Laboratories, Inc., and Watson Pharma, Inc., Defendants.
• Court: U.S. District Court — District of Delaware

769 F.Supp.2d 729

2011 Markman 845376

CEPHALON, INC., and Cima Labs, Inc., Plaintiffs,

v.WATSON PHARMACEUTICALS, INC., Watson Laboratories, Inc., and Watson Pharma, Inc., Defendants.

Civ. No. 08–330–SLR.

United States District Court, D. Delaware.

March 11, 2011.

William J. Marsden, Jr., Esquire and Douglas E. McCann, Esquire of Fish & Richardson, P.C., Wilmington, DE, Of Counsel: Juanita R. Brooks, Esquire of Fish & Richardson, P.C., San Diego, CA; Jonathan E. Singer, Esquire of Fish & Richardson, P.C., Minneapolis, MN; and Michael A. Siem, Esquire of Fish & Richardson, P.C., New York, NY, for Plaintiffs.Frederick L. Cottrell, III, Esquire, Steven J. Fineman, Esquire, and Laura D. Hatcher, Esquire of Richards, Layton & Finger P.A., Wilmington, DE, Of Counsel: Barry S. White, Esquire, James K. Stronski, Esquire, John G. Taylor, Esquire and Chiemi D. Suzuki, Esquire of Frommer Lawrence & Haug LLP, New York, NY; and Rami Bardenstein, Esquire and Bryan J. Braunel, Esquire of Frommer Lawrence & Haug LLP, Washington, D.C., for Defendants.

OPINION

SUE L. ROBINSON, District Judge.I. INTRODUCTION

This action arises out of the filing of an Abbreviated New Drug Application (“ANDA”) ¹ by defendants Watson Pharmaceuticals, Inc., Watson Laboratories, Inc., and Watson Pharma, Inc. (collectively, “Watson”) in 2008 for a generic version of Fentora® (fentanyl buccal tablets), used to treat breakthrough pain in cancer patients. Plaintiff CIMA Labs, Inc. (“CIMA”) is the assignee of U.S. Patent Nos. 6,200,604 (“the '604 patent”) and 6,974,590 (“the '590 patent”), directed to a sublingual buccal effervescent pharmaceutical dosage form. Plaintiff Cephalon, Inc. (“Cephalon”) is the exclusive licensee of the '604 and ' 590 patents (hereinafter, collectively the “Khankari patents”) and is also the owner of U.S. Patent No. 6,264,981 (“the '981 patent”).² Cephalon is the holder of an approved New Drug Application (“NDA”) ³ for the manufacture and sale of fentanyl buccal tablets for the treatment of breakthrough cancer pain. Cephalon listed with the Food and Drug Administration (“FDA”) the '604 and ' 590 patents in the Orange Book in connection with its NDA. In response to Watson's ANDA filing, which contained a paragraph IV certification as to the '604 and ' 590 patents,⁴ plaintiffs filed a patent infringement suit on June 2, 2008.⁵ (Civ. No. 08–330, D.I. 1) The court denied defendants' (renewed) motion to dismiss certain counts of the complaint on April 3, 2009, 629 F.Supp.2d 338 (D.Del.2009).

On September 25, 2009, plaintiffs filed a second complaint of patent infringement against defendants seeking a declaratory judgment of infringement of U.S. Patent No. 6,264,981 (“the '981 patent”), directed to a method for oral transmucosal drug delivery. (Civ. No. 09–724, D.I. 1) In both cases, defendants asserted defenses and counterclaims of noninfringement and invalidity. The two actions were consolidated for purposes of discovery and tried together in a bench trial held between May 10 and 17, 2010. (Civ. No. 09–724, D.I. 23) The issues of infringement and invalidity have been fully briefed post-trial. Having been advised that the 30–month stay on the FDA's approval of defendants' ANDA (triggered by plaintiffs' first suit) expired, ⁶ the court recently enjoined defendants' launch of generic fentanyl buccal tablets pending the issuance of its decision. (Civ. No. 08–330, D.I. 157) ⁷ The court has jurisdiction pursuant to 28 U.S.C. §§ 1331, 1338(a) and 1400(b). 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 Technology at Issue

1. Drug delivery across the oral mucosa

1. There are several methods by which a drug may be delivered to the human bloodstream. In traditional oral administration, a dosage form is swallowed and drug absorption occurs across the gastrointestinal mucosa (the stomach or intestines). (D.I. 282 at 108:22–109:10) By contrast, when a drug is administered by an oral transmucosal route, the drug is absorbed across the mucous membranes of the mouth and directly into the blood stream. ( Id. at 116:2–21)

2. The inventions at bar relate to oral transmucosal drug delivery. The oral mucosa are the mucous membranes lining the mouth, and include the buccal, sublingual, and gingival mucosa. ( Id. at 109:17–110:10) The buccal mucosa is along the inside of the cheek; the sublingual mucosa is under the tongue; and the gingival mucosa is between the upper lip and gum. ( Id.)

3. Cells in the intestinal tract, an area naturally designed for absorption, are present in a single layer lining the intestinal wall. ( Id. at 114:8–115:11) Between these cells are “tight junctions,” or certain proteins that act as a gate controlling what substances may pass through the intestine into the body. ( Id.) Tight junctions are generally not present in the oral mucosa, ⁸ however, the oral mucosa lining comprises multiple, staggered layers of cells such that a “molecule has to take a tortuous path to get to the other end.” ( Id.) The surface area for absorption of the oral mucosa is also small. ( Id.) Despite these disadvantages, drug delivery across the oral mucosa offers the advantage of a faster onset of action. This is because the drug need not travel through the gastrointestinal tract and the liver prior to blood absorption, and the “first-pass effect”—a percentage of drug lost to metabolization in the liver—is avoided. ( Id. at 115:14–116:21) Consequently, the same therapeutic effect can be achieved with a lower dose of drug administered across the oral mucosa. ( Id.) Rapid entry of the drug into the bloodstream benefits the treatment of conditions requiring fast relief, such as breakthrough cancer pain.

4. For both the traditional oral and transmucosal routes of administration, the drug traverses the relevant mucosa and can reach the bloodstream primarily by two pathways: paracellular or transcellular. ( Id. at 110:11–15.) With paracellular absorption, the drug moves between cells to reach the bloodstream. ( Id. at 110:16–23) With transcellular absorption, the drug moves across the mucosa by passing through cells until reaching the bloodstream. ( Id. at 110:24–111:8; 112:23–113:7) In doing so, the drug must breach the cell membrane wall. ( Id. at 113:5–7)

5. Fentanyl is a lipophilic drug, meaning that it dissolves much more readily in lipid (fats and oils) than in water. ( Id. at 113:13–17) Highly lipophilic compounds like fentanyl are absorbed primarily through the transcellular route. ( Id. at 120:9–20; 154:10–20) Lipophilicity and, thus, the ability to absorb via the transcellular route, is increased by increasing the pH. At a higher pH, unionized (lipophilic) species of the drug are favored. ( Id. at 122:2–124:7)

6. A high starting pH level is impracticable, however, because a high pH hinders the dissolution of the drug. ( Id. at 124:8–16) Herein lies the formulator's quandary; while a high pH is favored for absorption, a low pH is favored for solubility. Put in terms of ionization, when a weakly acidic or basic drug dissolves, it becomes ionized. The ionized form is hydrophilic while the dissolved, unionized form is favored for transcellular absorption. ( Id. at 123:9–13; 124:4–7) Therefore, the “holy grail” is to provide a drug designed for oral mucosal delivery having both improved solubility and absorption.

2. The Khankari patents: overview

7. A method for achieving this result is claimed by Drs. Sathasivan Indiran Pather (“Dr. Pather”), Rajentra K. Khankari (“Dr. Khankari”), Jonathan D. Eichman (“Dr. Eichman”), Joseph R. Robinson (“Dr. Robinson”), and John Hontz (“Dr. Hontz”): using an effervescent agent to enhance the penetration of the medicament across the buccal, sublingual and gingival mucosa. ('590 patent, col. 2:13–15)

8. Dr. Khankari testified that the inventors achieved a dynamic change in pH—a low starting pH, promoting dissolution, followed by an increase in pH, favoring absorption—by incorporating effervescent agents that react to form carbon dioxide (CO2). (D.I. 282 at 120:9–23) When CO2 dissolves in saliva, it forms a weak acid (carbonic acid) that reduces the salival pH. ( Id. at 121:1–11) The carbonic acid thereafter dissociates into CO2 and water; CO2 is released as gas, causing the pH to slowly rise. ( Id. at 121:13–20) In this manner, a balance between dissolution and absorption is achieved. The inventors believed that effervescence increases the rate and extent of absorption of an active drug by “one or all of the following mechanisms: (1) reducing the mucosal layer thickness and/or viscosity; (2) tight junction alteration; (3) inducing a change in the cell membrane structure; and (4) increasing the hydrophobic environment within the cellular membrane.” ('590 patent, col. 2:23–31)

9. The Khankari patents characterize the invention as the use of “an effervescent agent effective to aid penetration of the drug across the oral mucosa.” ( Id., col. 2:32–34) To this end, specific quantities of an effervescent agent (between 5% and 95% by weight and, preferably, 30% to 80% by weight) are provided for formulation purposes. ( Id., col. 2:34–38) This quantity, in turn, should be sufficient to provide “about 5 cm ³ to but less than about 30 cm ³ [of evolved gas] upon exposure of the tablet to an aqueous environment.” ( Id., col. 2:38–41) While most often a soluble acid source and a carbonate source (such as potassium bicarbonate) will be used, which reaction produces CO2 gas, reactants may also be used which evolve other gases. ( Id., col. 2:48–col. 3:3)

10. Other pharmaceutical ingredients are preferably incorporated into the dosage form of the invention for a variety of purposes, including aiding disintegration. “Disintegrants may comprise up to about 20 weight percent” of the composition and, preferably, between 2% and 10% of the composition. ( Id.,...