DCT
1:23-cv-00150
Actelion Pharma US Inc v. Lupin Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Actelion Pharmaceuticals US, Inc. (Delaware); Actelion Pharmaceuticals Ltd (Switzerland); Nippon Shinyaku Co., Ltd. (Japan)
- Defendant: Lupin Ltd. (India); Lupin Pharmaceuticals, Inc. (Delaware)
- Plaintiff’s Counsel: Ashby & Geddes LLP; Paul Hastings LLP
- Case Identification: 1:23-cv-00150, D. Del., 02/09/2023
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Lupin Inc. is a Delaware corporation and because Defendant Lupin Ltd., as a foreign corporation, may be sued in any judicial district where it is subject to personal jurisdiction. The complaint asserts personal jurisdiction based on the defendants' business activities in Delaware, including deriving substantial revenue from sales in the state, and consent to jurisdiction through prior litigation conduct.
- Core Dispute: Plaintiffs allege that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA for a generic version of UPTRAVI® (selexipag) constitutes an act of infringement of two patents covering a specific crystalline form of selexipag and its use in treating pulmonary arterial hypertension.
- Technical Context: The technology relates to pharmaceutical polymorphism—specifically, a stable crystalline form ("Form-I") of the active pharmaceutical ingredient selexipag, which is critical for ensuring consistent quality, efficacy, and manufacturability of the drug product.
- Key Procedural History: This lawsuit was triggered by a Paragraph IV Certification Notice Letter sent by Lupin Ltd. to the Plaintiffs, a standard procedure in Hatch-Waxman litigation where a generic applicant challenges the validity or infringement of patents listed in the FDA's Orange Book. The complaint notes the patents-in-suit are listed in the Orange Book as covering UPTRAVI® for injection. The complaint also alleges that U.S. Patent No. 8,791,122 was reissued on September 15, 2017.
Case Timeline
| Date | Event |
|---|---|
| 2009-06-26 | Earliest 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 Alleged Reissue Date |
| 2021-07-29 | FDA Approval for Intravenous UPTRAVI® (NDA No. 214275) |
| 2022-12-28 | Date of Lupin Ltd.'s Paragraph IV Certification Notice Letter |
| 2023-02-09 | 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
- Patent Identification: U.S. Patent No. 8,791,122, titled “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 on July 29, 2014.
The Invention Explained
- Problem Addressed: The patent addresses the challenge of developing a viable pharmaceutical product from a known active compound, selexipag (referred to as "compound A"). The background section states that while the therapeutic usefulness of compound A was known, "no reference describes or suggests the possibility of existence of crystals of compound A" (’122 Patent, col. 2:45-48). The unstated problem is that non-crystalline (amorphous) forms of a drug can have poor stability and handling properties, making consistent manufacturing difficult.
- The Patented Solution: The invention provides a novel, stable crystalline form of selexipag, designated "Form-I." This specific polymorph is defined by its unique powder X-ray diffraction (PXRD) pattern, which serves as a structural fingerprint. The patent's detailed description provides methods for producing this crystal, which is intended to be a "thing of a high quality for which constant effect can be always shown and of a form which is handled easily industrially" (’122 Patent, Abstract; col. 2:57-61; col. 5:35-col. 6:34).
- Technical Importance: Identifying a stable crystalline polymorph is a crucial step in drug development, as it directly impacts the drug's shelf-life, dissolution rate, bioavailability, and manufacturability.
Key Claims at a Glance
- The complaint asserts infringement of one or more claims without specification (Compl. ¶36). The patent contains one independent claim, Claim 1.
- Independent Claim 1 requires:
- A crystal of the specific chemical compound 2-{-4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide.
- The crystal must show diffraction peaks in its PXRD spectrum at least at the 2θ angles of 9.4°, 9.8°, 17.2°, and 19.4°.
- The PXRD measurement must be obtained using Cu Kα radiation.
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
- Patent Identification: U.S. Patent No. 9,284,280, titled “Use of Form-I Crystal of 2-{4-[N-(5,6-Diphenylpyrazin-2-yl)-N-Isopropyl-Amino]Butyloxy}-N-(Methyl-Sulfonyl)Acetamide,” issued on March 15, 2016. This patent is a continuation of the application that led to the ’122 Patent.
The Invention Explained
- Problem Addressed: The patent addresses the need for effective treatments for a range of medical conditions, including pulmonary hypertension, for which selexipag is a useful therapeutic agent (’280 Patent, col. 2:50-col. 3:4).
- The Patented Solution: The invention is not the compound itself, but a method of using the specific Form-I crystal of selexipag (as claimed in the ’122 patent) to treat a long list of diseases, including pulmonary hypertension (’280 Patent, Abstract; col. 17:48-col. 18:14). It directly links the stable crystalline form to a therapeutic application.
- Technical Importance: Method-of-use patents are a common and important tool for extending patent protection for a drug product by claiming the specific act of administering it for a particular medical indication.
Key Claims at a Glance
- The complaint asserts infringement of one or more claims without specification (Compl. ¶36). The patent contains multiple independent method claims. Claim 1 is representative.
- Independent Claim 1 requires:
- A method for treating a list of specified diseases, which includes pulmonary hypertension.
- The method comprises the step of administering to a subject the specific Form-I crystal of selexipag.
- The Form-I crystal is defined by the same PXRD peaks (9.4°, 9.8°, 17.2°, and 19.4°) as in the ’122 patent.
III. The Accused Instrumentality
Product Identification
- Lupin's Abbreviated New Drug Application ("ANDA") No. 217991, which seeks FDA approval for a generic version of "Selexipag for Injection, 1800 mcg/vial" (Compl. ¶13).
Functionality and Market Context
- The accused product is a generic drug intended to be a therapeutic equivalent to Plaintiffs' branded UPTRAVI®, which is approved for the treatment of pulmonary arterial hypertension (PAH) (Compl. ¶¶13, 25). The complaint alleges that upon approval, Lupin will manufacture and sell this generic product in the United States, creating a lower-cost competitor to UPTRAVI® (Compl. ¶¶23, 38).
IV. Analysis of Infringement Allegations
The complaint alleges infringement under 35 U.S.C. § 271(e)(2), where the filing of an ANDA for a drug claimed in a patent is a statutory act of infringement. The complaint does not contain a claim chart or detailed infringement contentions, stating that Lupin's failure to provide requested information and samples has "impaired Plaintiffs' ability to evaluate" infringement (Compl. ¶32). The analysis below is based on the inferred infringement theory for the representative independent claims.
No probative visual evidence provided in complaint.
'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, | Lupin's ANDA Product is described as a generic version of "Selexipag for Injection," which is the common name for the claimed chemical compound. | ¶13 | col. 2:21-30 |
| 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, | Based on information and belief, the complaint alleges that the selexipag active pharmaceutical ingredient in Lupin's ANDA product will be the claimed Form-I crystal, thereby exhibiting the required diffraction peaks. | ¶37 | col. 3:1-4 |
| wherein the X-ray powder diffraction diagram is obtained by using Cu Kα radiation. | This is a standard condition for the measurement required by the claim. The complaint's general allegation that Lupin's product meets all claim elements covers this limitation. | ¶37 | col. 3:1-4 |
'280 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method for treating diabetic neuropathy...pulmonary hypertension... | Lupin's ANDA seeks approval for a generic version of UPTRAVI®, which is indicated for the treatment of pulmonary arterial hypertension (PAH), one of the diseases listed in the claim. The proposed label for Lupin's product would instruct for this use. | ¶¶13, 25 | col. 17:48-col. 18:14 |
| 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 | The purpose of Lupin's ANDA product is for it to be administered to patients as an active ingredient for the treatment of PAH. | ¶¶13, 23 | col. 18:5-9 |
| 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... | As with the ’122 patent, the core allegation is that the active ingredient in Lupin's product is the claimed Form-I crystal. | ¶37 | col. 18:9-13 |
- Identified Points of Contention:
- Factual Question: The central dispute will be factual: does the active pharmaceutical ingredient (API) in the product described in Lupin's ANDA No. 217991 consist of the claimed "Form-I" crystal? The complaint relies on "information and belief" and notes Lupin's refusal to provide samples, positioning this as a key issue for discovery (Compl. ¶¶32, 37).
- Technical Question: Can a bioequivalent and stable generic selexipag product be made using a different polymorph (such as the Form-II or Form-III crystals also described in the patents) or an amorphous form? If an alternative form is used in Lupin's product, it may fall outside the scope of the asserted claims.
V. Key Claim Terms for Construction
- The Term: "diffraction peaks...at...9.4 degrees, 9.8 degrees, 17.2 degrees and 19.4 degrees"
- Context and Importance: In polymorph litigation, the precise values and allowable variance of instrumental measurements like PXRD peaks are often dispositive. A defendant may argue that its product's measured peaks are sufficiently different from the claimed values to be non-infringing. Practitioners may focus on this term because the entire infringement case for the composition-of-matter patent rests on matching these numerical "fingerprints."
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent specification provides an explicit definition that favors a broader reading: "When specifying an angle of diffraction 2 theta (2θ) for a peak...it should be understood that 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. 3:24-29). Plaintiffs may argue this language builds a specific margin of error directly into the claim's scope.
- Evidence for a Narrower Interpretation: A defendant could argue that the explicit +/- 0.2° range is the absolute limit and that its product's peaks, accounting for standard experimental error, fall outside this range. Alternatively, they might argue that the specific PXRD chart shown in Figure 1 of the patents represents the true invention, and any significant deviation from that pattern, even if some peaks fall within the +/- 0.2° range, indicates a different crystal form.
VI. Other Allegations
- Indirect Infringement: The complaint alleges that if Lupin commercializes its ANDA product, it will induce infringement of the ’280 patent (Compl. ¶42). This allegation is based on the premise that Lupin's product label will instruct physicians and patients to administer the drug for the treatment of PAH, thereby directing them to perform the steps of the claimed method.
- Willful Infringement: While the complaint does not use the word "willful," it requests a declaration of an "exceptional case" and an award of attorneys' fees (Compl. p. 11, ¶E). The factual basis for this is the allegation that Lupin had "actual and constructive notice" of the patents prior to filing its ANDA, as the patents are listed in the FDA's Orange Book and were the subject of Lupin's Paragraph IV Certification (Compl. ¶¶29, 30, 40).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of factual evidence: can Plaintiffs demonstrate through discovery and expert testing that the selexipag API specified in Lupin’s ANDA is, in fact, the claimed Form-I crystal? The outcome will likely depend on the PXRD data and other characterization evidence obtained from Lupin's product samples.
- A secondary issue will be one of claim scope: if Lupin's product exhibits PXRD peaks that are close but not identical to the claimed values, the case may turn on claim construction. The central question for the court will be interpreting the meaning of "at" a certain degree in light of the patent's explicit "+/- 0.2°" language and principles of measurement uncertainty.