DCT

1:20-cv-03859

Actelion Pharma Ltd v. MSN Pharma Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:20-cv-03859, D.N.J., 04/09/2020
  • Venue Allegations: Plaintiffs allege venue is proper in the District of New Jersey because several U.S.-based Defendant entities maintain their principal places of business in the state, and the foreign-based parent companies have purposely availed themselves of the jurisdiction through the activities of their U.S. agents and subsidiaries.
  • Core Dispute: Plaintiffs allege that Defendants' submissions of Abbreviated New Drug Applications (ANDAs) to seek FDA approval for generic versions of Plaintiffs' UPTRAVI® (selexipag) drug product constitute an act of infringement of three U.S. patents.
  • Technical Context: The technology relates to pharmaceutical compounds, specifically heterocyclic derivatives that act as PGI₂ receptor agonists for the treatment of pulmonary arterial hypertension, and to a specific crystalline form of the active ingredient selexipag.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiffs' receipt of Paragraph IV Certification Notice Letters from each of the Defendant groups. These letters notified Plaintiffs that the Defendants were seeking FDA approval to market generic selexipag prior to the expiration of the patents-in-suit. The patents are listed in the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (the "Orange Book") as covering UPTRAVI®.

Case Timeline

Date Event
2001-04-26 ’302 Patent Priority Date
2007-04-17 ’302 Patent Issue Date
2009-06-26 ’122 and ’280 Patents Priority Date
2014-07-29 ’122 Patent Issue Date
2015-12-21 FDA grants approval for UPTRAVI® (selexipag)
2016-03-15 ’280 Patent Issue Date
2017-09-15 ’122 Patent Reissue Date mentioned in complaint
2020-02-25 Aizant sends Paragraph IV Notice Letter
2020-02-27 MSN Ltd. sends Paragraph IV Notice Letter
2020-02-28 Alembic Ltd. sends Paragraph IV Notice Letter
2020-03-02 Zydus sends Paragraph IV Notice Letter
2020-04-09 Complaint Filing Date

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

U.S. Patent No. 7,205,302 - "Heterocyclic Compound Derivatives and Medicines", issued April 17, 2007 (’302 Patent)

The Invention Explained

  • Problem Addressed: The patent’s background section describes the therapeutic potential of Prostaglandin I₂ (PGI₂), which has potent pharmacological effects such as inhibiting platelet aggregation and promoting vasodilation. However, PGI₂ itself is not suitable for use as a medicine because it is chemically unstable and has a very short biological half-life, making sustained therapeutic effect difficult to achieve (’302 Patent, col. 1:15-39).
  • The Patented Solution: The invention discloses a new class of heterocyclic derivative compounds that function as PGI₂ receptor agonists but are chemically stable and non-prostanoid in structure (’302 Patent, col. 1:41-47). These compounds, represented by a general formula, are designed to mimic the therapeutic effects of PGI₂ while being suitable for pharmaceutical formulation and administration (’302 Patent, col. 2:5-11).
  • Technical Importance: The development of stable, long-acting PGI₂ receptor agonists represented a significant advancement for treating conditions like peripheral vascular diseases and hypertension, for which PGI₂’s biological activity is beneficial (’302 Patent, col. 1:20-29).

Key Claims at a Glance

  • The complaint alleges infringement of "one or more claims" of the ’302 Patent against Defendant Zydus without specifying which claims (Compl. ¶ 150). Independent claim 1 is representative of the invention's composition claims.
  • Independent Claim 1:
    • A pharmaceutical composition comprising a heterocyclic compound represented by a specific general chemical formula [1], or a salt thereof, as an active ingredient.
    • The formula comprises a central heterocyclic core (defined by Y and Z), substituted by two optionally substituted aryl groups (R¹ and R²).
    • A linker chain (A-D-E-G) connects the core to a terminal functional group (Q).
    • The functional group Q is defined as a carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl, or N-(alkylsulfonyl)carbamoyl group.
    • The composition further comprises a pharmaceutically acceptable carrier.

U.S. Patent No. 8,791,122 - "Form-I Crystal of 2-{4-[N-(5,6-Diphenylpyrazin-2-yl)-N-Isopropylamino]Butyloxy}-N-(Methylsulfonyl)Actemide", issued July 29, 2014 (’122 Patent)

The Invention Explained

  • Problem Addressed: The patent addresses the need for a high-quality, industrially manageable form of the active pharmaceutical ingredient ("compound A," or selexipag). The background suggests that not all physical forms of a drug compound are suitable for large-scale manufacturing and consistent therapeutic performance (’122 Patent, col. 2:55-59).
  • The Patented Solution: The invention identifies and claims a specific crystalline polymorph of selexipag, designated "Form-I." This crystalline form is defined by its unique powder X-ray diffraction (PXRD) spectrum, which exhibits characteristic peaks at specific angles of diffraction, distinguishing it from other potential solid forms of the compound (’122 Patent, Abstract; col. 2:65-col. 3:4).
  • Technical Importance: Identifying a stable, pure, and reproducible crystalline form of an active pharmaceutical ingredient is a critical step in drug development. It ensures consistent manufacturability, stability, dissolution rates, and bioavailability, which are essential for a safe and effective drug product.

Key Claims at a Glance

  • The complaint alleges infringement of "one or more claims" of the ’122 patent without further specification (Compl. ¶¶ 117-118, 128-129, 139-140). Independent claim 1 is the sole independent claim.
  • Independent Claim 1:
    • A crystal of 2-{-4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide.
    • The crystal must show diffraction peaks in its X-ray powder diffraction spectrum at least at the following angles of diffraction 2θ: 9.4 degrees, 9.8 degrees, 17.2 degrees, and 19.4 degrees.
    • The spectrum is defined as being obtained using Cu Kα radiation.
  • The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 9,284,280 - "Use of Form-I Crystal of 2-{4-[N-(5,6-Diphenylpyrazin-2-yl)-N-Isopropyl-Amino]Butyloxy}-N-(Methyl-Sulfonyl)Acetamide", issued March 15, 2016 (’280 Patent)

Technology Synopsis

This patent claims methods of treating various medical conditions by administering the specific "Form-I" crystal of selexipag that is the subject of the ’122 Patent. The claimed uses include treatment of diabetic neuropathy, peripheral circulatory disturbance, and pulmonary hypertension, thereby protecting the specific medical application of this particular crystalline form (’280 Patent, Abstract; col. 1:45-51).

Asserted Claims

The complaint asserts "one or more claims," and the patent contains one independent claim (Claim 1) (’280 Patent, col. 16:48-67).

Accused Features

The accused features are the Defendants' acts of seeking FDA approval to market generic selexipag for the treatment of pulmonary arterial hypertension, an indication covered by the ’280 Patent's claims. The infringement allegation is based on the proposed labeling for the generic products, which will instruct physicians and patients on the patented method of use (Compl. ¶¶ 83, 117, 128, 139).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are the generic selexipag oral tablets for which Defendants Alembic, MSN, VGYAAN/Aizant, and Zydus have each submitted an ANDA to the FDA (Compl. ¶¶ 90, 95, 101, 109).

Functionality and Market Context

The Defendants' products are intended to be bioequivalent generic versions of Plaintiffs' branded drug, UPTRAVI®. UPTRAVI® is approved and prescribed for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression and reduce the risk of hospitalization (Compl. ¶ 83). The Defendants seek to market their generic tablets in various strengths (e.g., 200 mcg, 400 mcg, 600 mcg, etc.) for this same indication prior to the expiration of the patents-in-suit (Compl. ¶¶ 44, 57, 64, 81). The filing of the ANDAs represents a commercial effort to enter the market for selexipag upon receiving FDA approval.
No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide sufficient detail for a claim-chart analysis. The allegations are made "upon information and belief" and assert that the Defendants' ANDA products, if approved, will meet all the elements of one or more claims of each of the patents-in-suit (Compl. ¶¶ 118, 129, 140, 151). The complaint notes that Defendants' failure to provide product samples has "impaired Plaintiffs' ability to evaluate infringement" of the polymorph-related patents (Compl. ¶¶ 93, 98, 106).

Identified Points of Contention

  • For the ’302 Patent (Compound): The threshold question will be whether the active pharmaceutical ingredient in the Defendants' ANDA products is a compound falling within the scope of the asserted claims. In a generic drug case, this is often stipulated, but remains a required element of proof.
  • For the ’122 Patent (Crystal Form): A central technical question will be one of polymorphic identity. Does the crystalline form of selexipag in the Defendants' ANDA products exhibit the specific powder X-ray diffraction peaks required by Claim 1 of the ’122 Patent? Generic manufacturers may attempt to design around such patents by using a different, non-infringing crystalline form or an amorphous version of the drug substance. The resolution of this issue will depend on expert analysis of the Defendants' product samples, once they are produced in discovery.

V. Key Claim Terms for Construction

The Term

"a crystal of ... showing diffraction peaks in its X-ray powder diffraction spectrum at least at the following angles of diffraction 2θ: 9.4 degrees, 9.8 degrees, 17.2 degrees and 19.4 degrees" (from ’122 Patent, Claim 1).

Context and Importance

This term is the central limitation defining the patented invention of the ’122 Patent. The infringement analysis will depend entirely on whether the Defendants' products contain a crystal form that meets this definition. Practitioners may focus on this term because the existence of other polymorphs is common for complex organic molecules, and any variation in the Defendants' crystal structure from that claimed could be a basis for a non-infringement defense.

Intrinsic Evidence for Interpretation

  • Evidence for a Broader Interpretation: The claim uses the phrase "at least at," which may suggest that the presence of these four peaks is the dispositive factor, even if other peaks are present or absent compared to the patent's exemplary diffractogram (’122 Patent, FIG. 1). The specification notes that PXRD peak positions "may contain some errors depending on the measuring device, measuring conditions, etc.," which could support an argument that the claimed angles should not be read with absolute precision (’122 Patent, col. 3:1-4).
  • Evidence for a Narrower Interpretation: The claim language recites the angles to a tenth of a degree without using qualifying language such as "about" or "approximately." A party could argue that this precision requires a strict, literal reading and that any measurable deviation from these exact values falls outside the claim scope. Further, a defendant might argue that the term should be construed to mean a crystal that is substantially pure Form-I, as characterized by the full set of representative peaks disclosed in the specification, not just the four recited in the claim.

VI. Other Allegations

Indirect Infringement

The complaint alleges direct infringement under 35 U.S.C. § 271(e)(2) based on the filing of the ANDAs. It also seeks a declaration that commercial launch of the generic products would constitute direct infringement under § 271(a) and indirect infringement under §§ 271(b) and (c) (Compl. ¶ 124). The basis for induced infringement of the ’280 method of use patent is the allegation that the Defendants’ proposed product labeling will instruct physicians and patients to administer the drug for the patented indication of treating pulmonary arterial hypertension.

Willful Infringement

The complaint does not include an explicit allegation of willful infringement. However, it does allege that each Defendant had "actual and constructive notice" of the patents-in-suit prior to filing their respective ANDAs, which is a factual predicate for any future claim of willfulness (Compl. ¶¶ 122, 133, 144, 155, 166).

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

  • A core issue will be one of polymorphic identity: does the active pharmaceutical ingredient in the Defendants’ generic products exist in the specific "Form-I" crystalline state, as defined by the characteristic X-ray diffraction peaks recited in Claim 1 of the ’122 patent? The case will likely hinge on detailed factual evidence and expert testimony comparing the physical form of the drug in the accused products to the patent’s claims.
  • A second key question will be one of claim scope for the method of use: assuming the Defendants' products contain the claimed crystal form, does the language of their proposed product labeling for the treatment of pulmonary arterial hypertension fall within the scope of the method claims of the ’280 patent? This will involve a comparison of the clinical instructions in the proposed label against the specific steps and patient populations defined in the patent claims.