DCT
1:23-cv-00389
Actelion Pharma US Inc v. Cipla Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Actelion Pharmaceuticals US, Inc. (Delaware), Actelion Pharmaceuticals Ltd (Switzerland), and Nippon Shinyaku Co., Ltd. (Japan)
- Defendant: Cipla Limited (India) and Cipla USA Inc. (Delaware)
- Plaintiff’s Counsel: Paul Hastings LLP
- Case Identification: 1:23-cv-00389, D. Del., 04/06/2023
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Cipla USA Inc. is a Delaware corporation and because Defendant Cipla Ltd., a foreign corporation, is subject to personal jurisdiction in the district through its own and its subsidiary's business activities, including deriving substantial revenue from sales in Delaware and intending to market the accused product in the state.
- Core Dispute: Plaintiffs allege that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA for a generic version of Plaintiffs' UPTRAVI® (selexipag) drug product infringes two patents covering a specific crystalline form of selexipag and its therapeutic use.
- Technical Context: The technology concerns pharmaceutical polymorphism—specifically, a stable crystalline form of the active pharmaceutical ingredient selexipag, which is used for the treatment of pulmonary arterial hypertension.
- Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiffs' receipt of a Paragraph IV Certification Notice Letter from Cipla, asserting that its generic product would not infringe the patents-in-suit or that the patents are invalid. The patents are listed in the FDA's "Orange Book" as covering the branded drug UPTRAVI®. U.S. Patent No. 8,791,122 was the subject of an ex parte reexamination, with a certificate issuing on September 15, 2017, that cancelled claim 3 and confirmed the patentability of claims 1 and 2.
Case Timeline
| Date | Event |
|---|---|
| 2009-06-26 | Priority Date for '122 and '280 Patents |
| 2014-07-29 | '122 Patent Issue Date |
| 2016-03-15 | '280 Patent Issue Date |
| 2017-09-15 | '122 Patent Reexamination Certificate Issued |
| 2021-07-29 | FDA Approval for UPTRAVI® (NDA No. 214275) |
| 2023-03-09 | Date of Cipla's Paragraph IV Notice Letter |
| 2023-04-06 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 8,791,122, “Form-I Crystal of 2-{4-[N-(5,6-Diphenylpyrazin-2-yl)-N-Isopropylamino]Butyloxy}-N-(Methylsulfonyl)Acetamide and Method for Producing the Same,” issued July 29, 2014
- The Invention Explained:
- Problem Addressed: The patent's background section notes that while the therapeutic utility of the chemical compound selexipag (referred to as "compound A") was known, "no reference describes or suggests the possibility of existence of crystals of compound A" ('122 Patent, col. 2:44-48). For a compound to be developed into a viable drug product, it must be produced in a stable, pure, and consistent form that is suitable for industrial handling ('122 Patent, col. 2:57-59).
- The Patented Solution: The patent discloses a novel, stable crystalline form of selexipag, which the inventors designated "Form-I" ('122 Patent, Abstract). This specific polymorph is distinguished from other potential solid forms by a unique fingerprint, specifically a set of characteristic peaks observed in its powder X-ray diffraction (PXRD) spectrum ('122 Patent, col. 2:64-col. 3:4). The specification provides methods for reliably producing this Form-I crystal, such as dissolving the compound in an alcoholic solvent and then gradually cooling the solution to induce crystallization ('122 Patent, col. 6:35-51).
- Technical Importance: The discovery and characterization of a specific, stable crystalline polymorph is a critical step in pharmaceutical development, as it helps ensure batch-to-batch consistency in the drug's physical properties, which can directly impact its manufacturing, stability, and bioavailability.
- Key Claims at a Glance:
- The complaint asserts infringement of "one or more claims" of the patent (Compl. ¶38). Independent claim 1 is central to the '122 patent.
- Independent Claim 1:
- A crystal of 2-{-4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide,
- 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,
- wherein the X-ray powder diffraction diagram is obtained by using Cu Kα radiation.
- The complaint does not specify assertion of 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
- The Invention Explained:
- Problem Addressed: The patent background explains that selexipag ("compound A") has an excellent PGI2 agonistic effect and is useful as a therapeutic agent for a wide range of conditions, including pulmonary hypertension, thrombosis, and diabetic neuropathy ('280 Patent, col. 1:44-col. 2:43). The technical challenge is to effectively use this compound to treat patients suffering from these disorders.
- The Patented Solution: The invention claims methods of treating various enumerated medical conditions by administering the specific "Form-I crystal" of selexipag, as identified in the '122 patent, to a subject ('280 Patent, Abstract; col. 10:48-65). The patent directly links the therapeutic method to the specific, well-defined crystalline form of the active ingredient.
- Technical Importance: By claiming a method of treatment using a specific polymorph, the patent seeks to ensure that the therapeutic benefit is derived from a well-characterized and consistent form of the drug, which is a key principle of pharmaceutical science for delivering predictable clinical outcomes ('280 Patent, col. 1:56-62).
- Key Claims at a Glance:
- The complaint asserts infringement of "one or more claims" of the patent (Compl. ¶38). Independent claim 1 is the sole independent claim.
- Independent Claim 1:
- A method for treating diabetic neuropathy, diabetic gangrene, peripheral circulatory disturbance, chronic arterial occlusion, intermittent claudication, scleroderma, thrombosis, pulmonary hypertension, myocardial infarction, angina, glomerulonephritis, diabetic nephropathy, chronic renal failure, bronchial asthma, interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease, inflammatory bowel disease, or symptoms associated with spinal canal stenosis,
- comprising the step of administering, as an active ingredient to a subject, a crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide
- 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,
- wherein the X-ray powder diffraction diagram is obtained by using Cu Kα radiation.
- The complaint does not specify assertion of dependent claims.
III. The Accused Instrumentality
- Product Identification: The accused instrumentality is "Cipla's ANDA Product," identified as a generic version of "Selexipag for Injection, 1.8 mg/vial," for which Cipla Ltd. submitted ANDA No. 216607 to the FDA (Compl. ¶13).
- Functionality and Market Context: The ANDA product is a proposed generic equivalent to Plaintiffs' branded drug, UPTRAVI®, which is a lyophilized powder for injection indicated for the treatment of pulmonary arterial hypertension (PAH) (Compl. ¶13, ¶26-27). As a generic, Cipla's product is required to have the same active ingredient, dosage form, strength, and route of administration as UPTRAVI®. The complaint alleges that Cipla seeks to market this product prior to the expiration of the patents-in-suit (Compl. ¶13).
- No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
The complaint alleges infringement under 35 U.S.C. § 271(e)(2)(A), where the filing of the ANDA is the statutorily defined act of infringement (Compl. ¶38). The specific factual allegations are made on "information and belief," noting that Cipla has not provided its ANDA or product samples for analysis (Compl. ¶34, ¶39).
'122 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A crystal of 2-{-4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, | Cipla’s ANDA product is a generic version of UPTRAVI® and therefore contains selexipag as its active pharmaceutical ingredient. The complaint alleges this ingredient exists in a crystalline form. | ¶13, ¶39 | col. 2:64-65 |
| 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, | Plaintiffs allege on information and belief that the crystalline selexipag in Cipla’s ANDA product, if analyzed via PXRD, would exhibit the characteristic diffraction peaks of the claimed Form-I crystal. | ¶39 | col. 3:1-4 |
| wherein the X-ray powder diffraction diagram is obtained by using Cu Kα radiation. | This recites a standard condition for the PXRD measurement which Plaintiffs allege would confirm the presence of the claimed crystal form in Cipla's product. | ¶39 | col. 3:4-5 |
'280 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method for treating... pulmonary hypertension... | Cipla's ANDA product is a generic of UPTRAVI® and its proposed label will instruct for its use in treating pulmonary arterial hypertension, one of the diseases enumerated in the claim. | ¶13, ¶27 | col. 10:48-56 |
| comprising the step of administering, as an active ingredient to a subject, a crystal of ... acetamide | The proposed label for Cipla's ANDA product will instruct physicians and patients to administer the selexipag-containing drug product. | ¶13, ¶39 | col. 10:56-60 |
| showing diffraction peaks in its X-ray powder diffraction spectrum at least at the following angles ... | As with the '122 Patent, Plaintiffs allege on information and belief that the crystal being administered is the claimed Form-I crystal, characterized by these specific diffraction peaks. | ¶39 | col. 10:60-64 |
- Identified Points of Contention:
- Factual Question: The central dispute will be factual: does the selexipag in Cipla's ANDA product exist as the claimed Form-I crystal, or does it utilize an alternative, non-infringing solid form (e.g., a different polymorph or an amorphous solid)? Cipla's Paragraph IV certification implies a belief that its product does not infringe.
- Scope Questions: The interpretation of the phrase "showing diffraction peaks...at least at the following angles" will be critical. The court will need to determine the acceptable margin of error for the peak positions. This raises the question of whether any measured peaks in Cipla's product fall within the claimed ranges.
V. Key Claim Terms for Construction
- The Term: "showing diffraction peaks...at...9.4 degrees, 9.8 degrees, 17.2 degrees and 19.4 degrees"
- Context and Importance: This phrase defines the patented crystalline form. The entire infringement analysis for both patents rests on whether the PXRD pattern of Cipla's product meets this definition. Practitioners may focus on this term because even minor variations in PXRD data between the accused product and the claim language can form the basis of a non-infringement defense.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The use of "at least" suggests that the presence of additional peaks in a PXRD spectrum would not necessarily preclude a finding of infringement, as long as the four recited peaks are present.
- Evidence for a Narrower Interpretation: The specification provides an explicit definition that will likely control the scope, stating that for a given peak, "the value given is to be understood as an interval from said value minus 0.2° to said value plus 0.2°" ('122 Patent, col. 3:25-30). This provides a specific, narrow window for each peak location and will be central to comparing any experimental data with the claim language.
VI. Other Allegations
- Indirect Infringement: The complaint alleges that if Cipla commercially manufactures and sells its ANDA product post-approval, it will induce infringement of the '280 Patent (Compl. ¶41, ¶46). The basis for this allegation is that Cipla's product label will necessarily instruct medical professionals and patients to administer the drug for the treatment of pulmonary hypertension, thereby directing them to perform the steps of the patented method.
- Willful Infringement: The complaint does not use the term "willful" but does request a declaration that the case is "exceptional" and an award of attorneys' fees pursuant to 35 U.S.C. § 285 (Compl., Prayer for Relief ¶E). The factual basis for this is the allegation that Cipla had "actual and constructive notice of the patents-in-suit" before filing its ANDA (Compl. ¶44).
VII. Analyst’s Conclusion: Key Questions for the Case
A central question will be one of factual identity: Does the active ingredient in Cipla's ANDA product consist of the specific "Form-I" crystal of selexipag, as defined by the four characteristic PXRD peaks in the patent claims, or has Cipla designed its product around the patents by using a different, non-infringing polymorph or an amorphous solid form?
A key issue of claim construction will be the application of the patent’s explicit definition that each recited diffraction peak encompasses a range of ±0.2 degrees. The resolution of the case will depend on how experimental evidence from Cipla's product is measured against these precisely defined boundaries.