DCT

3:17-cv-05015

Actelion Pharma Ltd v. Sun Pharmaceutical Industries Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 3:17-cv-05015, D.N.J., 07/07/2017
  • Venue Allegations: Venue is alleged to be proper because Defendant Sun has committed acts of infringement and maintains a regular and established place of business in the District of New Jersey.
  • Core Dispute: Plaintiff alleges that Defendants’ filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's VELETRI® product constitutes an act of infringement of a patent covering a stable formulation of the drug epoprostenol.
  • Technical Context: The technology concerns pharmaceutical formulations designed to improve the chemical stability of epoprostenol, a prostacyclin vasodilator used to treat pulmonary arterial hypertension.
  • Key Procedural History: This action was filed under the Hatch-Waxman Act following Plaintiff's receipt of a Paragraph IV Certification Notice Letter from Defendants. The letter advised of Defendants' filing of ANDA No. 210473, which seeks FDA approval to market a generic epoprostenol product prior to the expiration of Plaintiff's U.S. Patent No. 8,598,227, which is listed in the FDA's "Orange Book" for VELETRI®.

Case Timeline

Date Event
2006-02-03 ’227 Patent Earliest Priority Date
2008-06-27 FDA approval for VELETRI® (1.5 mg/vial)
2012-06-28 FDA approval for VELETRI® (0.5 mg/vial)
2013-12-03 ’227 Patent Issue Date
2017-05-26 Defendants send Paragraph IV Notice Letter to Plaintiff
2017-07-07 Complaint Filing Date

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 8,598,227 - Epoprostenol Formulation and Method of Making Thereof

  • Patent Identification: U.S. Patent No. 8,598,227, "Epoprostenol Formulation and Method of Making Thereof," issued December 3, 2013.

The Invention Explained

  • Problem Addressed: The patent describes the drug epoprostenol as being chemically unstable, particularly in solution, where it rapidly hydrolyzes and loses potency, especially at a neutral or slightly basic pH (’227 Patent, col. 3:36-43). Existing commercial formulations, such as Flolan, required reconstitution with a specific sterile diluent, had to be refrigerated if not used immediately, and possessed a very limited shelf-life even when chilled, creating significant inconvenience for patients requiring continuous infusion (’227 Patent, col. 4:1-12).
  • The Patented Solution: The invention is a pharmaceutical formulation and method that significantly enhances the stability of epoprostenol. This is achieved by creating a highly alkaline environment, specifically by formulating a lyophilized (freeze-dried) powder from a bulk solution with a pH greater than 11, and preferably greater than 13, using an alkalinizing agent like arginine and a base like sodium hydroxide (’227 Patent, Abstract; col. 4:15-27). This high-pH formulation allows the reconstituted drug to remain stable for over 24 hours at ambient temperatures and to be compatible with standard, commercially available intravenous fluids (’227 Patent, col. 4:15-27).
  • Technical Importance: This improved stability simplifies drug administration for patients with chronic conditions like pulmonary arterial hypertension, reducing the need for constant refrigeration and frequent drug preparation (’227 Patent, col. 4:36-39).

Key Claims at a Glance

  • The complaint alleges infringement of "one or more claims" without specifying them (Compl. ¶26). Independent method-of-treatment claim 16 is representative:
  • Independent Claim 16:
    • A method for treating a patient suffering from a disease selected from a group including cardiovascular disease and hypertension.
    • The method comprises combining an intravenous fluid with an effective amount of a lyophilized pharmaceutical composition.
    • The composition comprises: (a) a unit dose of 0.5 mg or 1.5 mg of epoprostenol or a salt thereof; (b) arginine; and (c) sodium hydroxide.
    • The lyophilized composition is "formed from a bulk solution having a pH of 13 or higher."
    • The method concludes with administering the resulting intravenous fluid to a patient in need thereof.
  • The complaint does not foreclose the assertion of other independent or dependent claims.

III. The Accused Instrumentality

Product Identification

  • The accused instrumentalities are Defendants’ proposed generic drug products, identified as "Epoprostenol Sodium Injection, Eq. 0.5 mg Base/Vial and Eq. 1.5 mg Base/Vial" (the "ANDA Products") (Compl. ¶16, ¶22).

Functionality and Market Context

  • The ANDA Products are generic versions of Actelion's VELETRI®, a drug indicated for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity (Compl. ¶19). The infringement alleged in the complaint is not based on current commercial activity, but is a statutory act of infringement under 35 U.S.C. § 271(e)(2)(A), which arises from Defendants' submission of ANDA No. 210473 to the FDA seeking approval to market these generic products prior to the expiration of the ’227 Patent (Compl. ¶26). The specific formulation of the ANDA Products is not detailed in the complaint, as it is contained within the confidential ANDA submission to the FDA.

IV. Analysis of Infringement Allegations

The complaint does not provide a detailed, element-by-element infringement analysis or an appended claim chart. The infringement allegation is statutory, based on the act of filing an ANDA for a drug claimed in a patent (Compl. ¶26). The core of the dispute will depend on the specific formulation and manufacturing process for the ANDA Products as described in Defendants' confidential FDA submission.

  • Identified Points of Contention:
    • Technical Questions: A central question for the court will be factual: does the formulation described in Sun's ANDA No. 210473 meet every limitation of an asserted claim? Specifically, this will involve determining if Sun's proposed product (1) contains "arginine" and "sodium hydroxide" in combination with epoprostenol, and (2) is manufactured from a "bulk solution having a pH of 13 or higher," as required by claim 16. The details of Sun's manufacturing process and formulation are confidential but will be subject to discovery.
    • Scope Questions: The dispute may also raise questions of claim scope. For instance, if Sun’s formulation uses an excipient other than arginine, a dispute could arise over whether that excipient functions as an "alkalinizing agent" as that term is defined in the ’227 Patent (col. 5:3-12). The interpretation of the process step "formed from" could also be contested, focusing on precisely when and for how long the bulk solution must be maintained at the claimed pH level.

No probative visual evidence provided in complaint.

V. Key Claim Terms for Construction

  • The Term: "alkalinizing agent"

  • Context and Importance: This term is central to the patented solution for stabilizing epoprostenol. Whether Sun’s formulation contains an excipient that falls within the scope of this term will be critical to the infringement analysis, especially if Sun attempts to design around the patent by using an alternative to arginine.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The specification provides a functional definition, stating an alkalinizing agent is one that "provides an alkaline environment (pH>7)" and "may contain at least one functional group that accepts a proton from water" (’227 Patent, col. 5:3-8). It then provides a non-exhaustive list of examples, including "arginine, lysine, meglumine,...alkaline phosphates...inorganic carbonates...or combinations thereof," which may support a construction not limited to the specific examples (’227 Patent, col. 5:12-19).
    • Evidence for a Narrower Interpretation: The patent repeatedly identifies arginine as "most preferred" and uses it in nearly all disclosed embodiments and examples (’227 Patent, col. 5:19-20; col. 14:60-65). A party might argue that the invention is effectively centered on arginine and that the term should be construed in light of these specific disclosures, potentially limiting its scope.

  • The Term: "formed from a bulk solution having a pH of 13 or higher"

  • Context and Importance: This process limitation defines how the claimed lyophilized composition must be made. Infringement will depend on the actual pH used in Sun's confidential manufacturing process. Practitioners may focus on this term because it shifts the infringement inquiry from the final product's composition alone to the specific steps used to create it.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The patent consistently links superior stability to a pH of 13 or higher. The summary of the invention states a key object is to provide compositions with a pH>11, and the detailed description specifies a preferred pH of 12.5-13.5, and "most preferably 13" (’227 Patent, col. 4:20-22; col. 5:51-53). Extensive data tables show that formulations prepared at pH 13 are significantly more stable than those prepared at pH 12 (’227 Patent, Tables 10-18).
    • Evidence for a Narrower Interpretation: A defendant could argue that the term "formed from" requires the bulk solution to be maintained at pH 13+ for a specific duration or at a critical stage immediately preceding lyophilization. They might argue that a transient or intermediate pH reading of 13 is insufficient to meet this limitation if their process differs from the embodiments described in the patent.

VI. Other Allegations

  • Indirect Infringement: The complaint includes a request for a declaration that future commercial activity by Sun would constitute infringement, including inducement (Compl. ¶33). This is premised on the allegation that Sun's product labeling will inevitably instruct medical professionals and patients to reconstitute and administer the drug, thereby directly infringing the asserted method-of-use claims.
  • Willful Infringement: The complaint does not contain a specific count for willful infringement or a request for enhanced damages. However, it alleges facts that would support a finding of knowledge, stating that Sun was aware of the ’227 patent through its listing in the FDA's Orange Book and through the Paragraph IV certification process (Compl. ¶21, ¶23).

VII. Analyst’s Conclusion: Key Questions for the Case

The resolution of this case will likely depend on the answers to two central questions:

  1. A key question will be one of factual identity: Does the confidential manufacturing process and chemical composition detailed in Sun's ANDA submission for its generic epoprostenol fall within the boundaries of the asserted claims of the ’227 patent, specifically regarding the use of arginine and the manufacturing of the formulation from a bulk solution with a pH of 13 or higher?
  2. Should the factual record show that Sun's formulation deviates from the patent's preferred embodiments, the case may turn on a question of claim construction: Can the term "alkalinizing agent" be construed broadly enough to read on a different excipient used by Sun, or is its meaning effectively limited by the patent's repeated emphasis on arginine?