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Actelion Pharmaceuticals Ltd. v. Sun Pharmaceutical Industries, Inc.

United States District Court, D. New Jersey

February 15, 2019

Actelion Pharmaceuticals, Ltd., Plaintiff,
v.
Sun Pharmaceutical Industries, Inc., et al, Defendants.

          MEMORANDUM

          SHERIDAN, U.S.D.J.

         This matter comes before the Court on joint claim construction submitted by plaintiff Actelion Pharmaceuticals, Ltd., and defendants Sun Pharmaceutical Industries, Inc., and Sun Pharmaceutical Industries, Ltd., concerning United States Patent No. 8, 598, 227 ('"227 patent"). The '227 patent is listed to market and sell the drug Veletri, ® a treatment which improves exercise capacity for individuals suffering from pulmonary arterial hypertension (PAH). The parties dispute the meaning of "alkalinizing agent," as used in the '227 patent. The Court held a Markman hearing on November 13 and 14, 2018. The sole claim construction issue is whether Actelion disclaimed glycine from its definition of "alkalinizing agent" in statements it made to distinguish prior art during the prosecution of a divisional patent.

         Background

         PAH is a disease characterized by high blood pressure in the lungs, which causes shortness of breath, fatigue, and chest pain in those afflicted, and ultimately results in death from ventricular failure. (Declaration of Preston K. Ratliff II ("Ratliff Decl."), Ex. 2, Humbert et al., Treatment of Pulmonary Arterial Hypertension, N. Engl. J. Med. 351;14 (Sept. 30, 2014) ("Humbert"), at 1425-26). Epoprostenol, also known as prostacyclin, is a naturally occurring prostaglandin which dilates blood vessels and inhibits platelet aggregation. (Ratliff Decl., Ex. 5, Flolan Product Information, at 1).

         On August 28, 1980, two inventors filed an application for a United States Patent, which ultimately issued as U.S. Patent No. 4, 335, 139 ("the Watts Patent"). (See Declaration of Paul N. Harold (Harold Decl.), Ex. I, United States Patent No. 4, 335, 139). The Watts patent claims:

A pharmaceutical formulation comprising an active compound selected from prostacyclin, 15-methyl-prostacyclin, 16, 16-dimethylprostacyclin or a pharmaceutically acceptable salt of any one of those in association with a pharmaceutically acceptable buffer having a pH of at least 9 and based on a pharmaceutically acceptable amino acid as a buffering acid as a buffering acid in the buffer and, optionally, a further pharmaceutically acceptable carrier.

(Id. at 8:35 to 43). The invention claimed by the Watts Patent had an "antiaggregatory effect on blood platelets" and was "useful, for example, in preventing or mitigating the formation of thrombi or emboli during extra corporeal circulation of blood." (Id. at 1:16 to 19).

         Although "[i]ntravenous prostacyclin (epoprostenol) was first used to treat primary pulmonary hypertension in the early 1980s," it was first approved by the FDA for treatment of PAH in 1995, and subsequently marketed by GlaxoSmithKline as Flolan. (Ratliff Decl., Ex. 2, Humbert, et al., Treatment of Pulmonary Arterial Hypertension, N. Engl. J. Med. 2004: 351:1425-36 (Sept. 30, 2004); Ex. 1, U.S. Patent Number 8, 598, 227 ('"227 Patent")). Flolan consists of "epoprostenol sodium equivalent to either 0.5 mg... or 1.5 mg... epoprostenol, 3.76 mg glycine, 2.93 mg sodium chloride, and 50 mg mannitol." (Id.). Clinical studies have shown that epoprostenol improves exercise tolerance, hemodynamics, and long-term survival, and can render lung transplants unnecessary in patients with severe forms of PAH. (Id. at 6-7; Ratliff Decl., Ex. 2, Humbert et al., at 1430).

         However, some considered Flolan-brand epoprostenol, with a half-life of just several minutes, to be highly unstable; it was administered by continuous infusion via a portable pump connected to a catheter permanently tunneled into the patient's subclavian vein. (Ratliff Decl., Ex. 2, Humbert et al., at 1430). Flolan is a freeze-dried product, which is reconstituted using a proprietary sterile diluent prior to its infusion. (Ratliff Decl., Ex. 5, Flolan Product Information, at 7, 20-21, 28). The sterile diluent for Flolan "is supplied in 50-mL glass vials containing 94 mg glycine, 73.5 mg sodium chloride, sodium hydroxide (added to adjust pH), and Water for Injection, USP." (Id. at 1). One reservoir of reconstituted Flolan could be stored in refrigerated conditions for no more than forty hours and administered at room temperature for only eight hours. (Id. at 27-28).

         Nagesh Palepu, an inventor, later discovered "that epoprostenol in the presence of an alkalinizing agent, and high pH ... is very stable compared to Flolan." (Ratliff Decl.), Ex. 1, '227 Patent, at 4:15 to 18). The new formulation, marketed as Veletri®, allows epoprostenol to be stored in refrigerated conditions for up to eight days and remains stable at room temperature for forty-eight to seventy-two hours. (Ratliff Decl., Ex. 4, Veletri Highlights of Prescribing Information, at 4-5).

         In 2006, Palepu filed a provisional application with the Patent and Trademark Office (PTO) titled "Novel Epoprostenol Formulation and Method of Making Thereof." (Declaration of Paul N. Harold (Harold Decl.), Ex. C, Provisional Patent Application Nos. 60/783, 429, 60/772, 563, and 60/764, 769). The '227 patent, a division of the 2006 application, names Actelion as assignee. (See '227 Patent, at cover (60)). The patent examiner restricted that prior application because it contained three "groups of inventions": (1) "a method of making a composition"; (2) "a composition"; and (3) "a method of treating a patient." (Harold Decl., Ex. F, May 7, 2010 Office Action Summary, at 2). The examiner required Actelion "to elect a single invention to which the claims must be restricted." (Id.).

         '802 Patent

         Actelion elected to prosecute the "composition" claims in a divisional application that would result in United States Patent Number 8, 318, 802 (the '802 patent). (Harold Decl., Ex. G, Response to Restriction Requirement). By way of background, Actelion's initial application sought to claim:

Claim 16 (Previously Presented): A pharmaceutical composition comprising:
(a) epoprostenol or a salt thereof; and
(b) an alkalinizing agent, wherein when the composition is reconstituted, the pH of the reconstituted solution is greater than 11.
Claim 19 (Original): The composition of claim 16, wherein the alkalinizing agent is selected from the group consisting of arginine, lysine, meglumine, N-methyl glucosomine, an amino acid with a pKa of 9.0 and above, trisodium phosphates, sodium carbonates, and tetrasodium-EDTA.

(Id. at 4-5 (emphasis added)). The examiner rejected that initial application noting that prior art "teaches stabilized formulations of prostacyclin (which is also known as epoprostenol) with an amino acid and a base . . . and they further specify glycine and arginine as amino acids to be used as buffers." (Harold Decl., Ex. H, August 17, 2010 Office Action Summary, at 4). The examiner found the claims "fail[ed] to particularly point out and distinctly claim the subject matter which applicant regards as the invention" because, as to claim 19, "[a]rginine is claimed as an alkalinizing agent . . . and glycine is an amino acid with a pKa above 9 and thus they teach compositions comprising both prostacyclin/epoprostenol and an alkalinizing agent." (Id. at 4-5). The examiner also noted that claim 16 "would not require any specific pH in the composition." (Id. at 4). In other words, she concluded the claimed invention was insufficiently distinct from the prior art.

         Actelion submitted another response with, in pertinent part, the following amendments:

Claim 16 (Currently amended): A pharmaceutical composition that is capable of being reconstituted with a conventional intravenous fluid to a pH greater than 12 comprising:
(a) epoprostenol or a salt thereof; and
(b) an alkalinizing agent arginine; and
(c) an inorganic base selected from the group consisting of sodium hydroxide and ...

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