DCT
1:18-cv-00088
H Lundbeck As v. Lupin Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: H. Lundbeck A/S (Denmark), Takeda Pharmaceutical Company Ltd. (Japan), et al.
- Defendant: Unichem Laboratories, Limited (India)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
- Case Identification: 1:18-cv-00088, D. Del., 08/16/2018
- Venue Allegations: Defendant is an Indian corporation, and Plaintiffs allege venue is proper because Defendant is subject to personal jurisdiction in the District of Delaware and intends to sell its accused products there.
- Core Dispute: Plaintiffs allege that Defendant’s submission of an Abbreviated New Drug Application (ANDA) to the FDA seeking approval to market a generic version of the antidepressant drug Trintellix® constitutes an act of patent infringement.
- Technical Context: The technology involves the pharmaceutical compound vortioxetine, used for treating Major Depressive Disorder, and specific crystalline forms of its hydrobromide salt which are asserted to possess advantageous properties for formulation.
- Key Procedural History: This is a Hatch-Waxman action initiated after Defendant sent Plaintiffs notice letters dated November 29, 2017, and July 6, 2018, containing Paragraph IV certifications asserting that Plaintiffs’ patents are invalid, unenforceable, or will not be infringed by its proposed generic product. The complaint was filed within the statutory 45-day window, triggering an automatic 30-month stay on FDA approval of Defendant's ANDA.
Case Timeline
| Date | Event |
|---|---|
| 2006-06-16 | Earliest Patent Priority Date ('684, '355, '946, '630 Patents) |
| 2013-09-30 | FDA approves Trintellix® (NDA No. 204447) |
| 2014-05-13 | '684 Patent Issued |
| 2015-03-03 | '355 Patent Issued |
| 2016-01-05 | '946 Patent Issued |
| 2017-11-29 | Defendant's First Notice Letter Sent |
| 2018-01-09 | '630 Patent Issued |
| 2018-07-06 | Defendant's Second Notice Letter Sent |
| 2018-08-16 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 8,722,684 - "1-[2-(2,4-DIMETHYLPHENYLSULFANYL)-PHENYL] PIPERAZINE AS A COMPOUND WITH COMBINED SEROTONIN REUPTAKE, 5-HT3 AND 5-HT1A ACTIVITY FOR THE TREATMENT OF COGNITIVE IMPAIRMENT"
The Invention Explained
- Problem Addressed: The patent background describes shortcomings of Selective Serotonin Reuptake Inhibitors (SSRIs), the first-choice therapeutics for depression, including a slow onset of effect and a significant fraction of patients who do not respond to treatment (’684 Patent, col. 1:31-45). The patent also notes that CNS disorders like depression are often co-morbid with cognitive impairment (’684 Patent, col. 2:1-6).
- The Patented Solution: The inventors claim to have "surprisingly found" that the compound 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine (vortioxetine) exerts a combination of serotonin transporter (SERT) inhibition, 5-HT3 antagonism, and 5-HT1A partial agonism (’684 Patent, col. 2:28-31). The patent claims the compound itself, or a pharmaceutically acceptable salt thereof, in various crystalline forms, which are characterized by X-ray powder diffraction (XRPD) patterns shown in Figures 1-17 (’684 Patent, col. 2:46-48; Claim 1). This multi-modal activity profile is asserted to be useful for treating CNS diseases, particularly cognitive impairment in depressed patients (’684 Patent, col. 2:18-25).
- Technical Importance: The development of a single molecule with this specific multi-modal activity profile was presented as a potential advance over standard SSRIs, suggesting the possibility of a faster onset of antidepressant effect and a targeted treatment for associated cognitive deficits (’684 Patent, col. 2:20-25).
Key Claims at a Glance
- The complaint alleges infringement of one or more claims, noting that Defendant does not contest infringement of claims 2 and 5 in its notice letter (Compl. ¶42-43). The analysis focuses on independent claim 1.
- Independent Claim 1:
- The compound 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] piperazine or a pharmaceutically acceptable salt thereof
- in a crystalline form
- characterized by an XRPD pattern as shown in any of FIGS. 1-17.
- The complaint does not explicitly reserve the right to assert dependent claims but alleges infringement of "one or more claims" (Compl. ¶42).
U.S. Patent No. 8,969,355 - "1-[2-(2,4 DIMETHYLPHENYLSULFANYL)-PHENYL]PIPERAZINE AS A COMPOUND WITH COMBINED SEROTONIN REUPTAKE, 5-HT3 AND 5-HT1A ACTIVITY FOR THE TREATMENT OF COGNITIVE IMPAIRMENT"
The Invention Explained
- Problem Addressed: The ’355 Patent, which is part of the same family as the '684 Patent, addresses the same technical problems: the limitations of existing SSRI treatments for depression and the co-morbidity of depression with cognitive impairment (’355 Patent, col. 1:40-45, col. 2:5-9).
- The Patented Solution: The patent claims methods of treating certain CNS disorders, including major depressive disorder, by administering the compound vortioxetine or its salts in specific crystalline forms (’355 Patent, col. 2:32-40, Claim 1). The underlying technical solution is the same multi-modal activity profile (SERT inhibition, 5-HT3 antagonism, 5-HT1A partial agonism) as described in the '684 patent.
- Technical Importance: This patent extends protection from the compound itself to methods of using it to treat specific diseases, providing a different layer of coverage for the commercial use of the Trintellix® product.
Key Claims at a Glance
- The complaint alleges infringement of one or more claims, noting that Defendant does not contest infringement of claims 1 and 4 in its notice letter (Compl. ¶54, 56). The analysis focuses on independent claim 1.
- Independent Claim 1:
- A method of treating a disease selected from a group including affective disorders, depression, and major depressive disorder
- comprising administering a therapeutically effective amount of Compound I (1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine) or a pharmaceutically acceptable salt thereof
- wherein the Compound I or salt is in a crystalline form characterized by an XRPD pattern as shown in any of FIGS. 1-17.
- The complaint does not explicitly reserve the right to assert dependent claims but alleges infringement of "one or more claims" (Compl. ¶54).
Multi-Patent Capsule: U.S. Patent No. 9,227,946
- Patent Identification: U.S. Patent No. 9,227,946, issued January 5, 2016, with a title similar to the lead patents.
- Technology Synopsis: This patent claims specific crystalline forms (polymorphs) of the hydrobromide salt of vortioxetine. It specifically claims the "beta form," which is described as being more stable and having low hygroscopicity, properties that make it particularly suitable for pharmaceutical tablet formulations (’946 Patent, col. 5:1-15).
- Asserted Claims: The complaint alleges infringement of claims 1, 2, 4, and 5, which Defendant allegedly does not contest (Compl. ¶69). Claim 1 is independent.
- Accused Features: The accused features are the Defendant’s ANDA Products, which are vortioxetine hydrobromide tablets intended for the treatment of major depressive disorder (Compl. ¶67-68).
Multi-Patent Capsule: U.S. Patent No. 9,861,630
- Patent Identification: U.S. Patent No. 9,861,630, issued January 9, 2018, with a title similar to the lead patents.
- Technology Synopsis: This patent claims methods of treating depression or major depressive disorder by administering specific crystalline forms of vortioxetine hydrobromide. The claims cover methods of using various specific polymorphs, including the alpha, beta, and gamma forms, as well as the hemihydrate and ethyl acetate solvate forms (’630 Patent, Abstract; Claim 1).
- Asserted Claims: The complaint alleges indirect infringement of claims 1, 5, 6, and 7, which Defendant allegedly does not contest (Compl. ¶83). Claim 1 is independent.
- Accused Features: The accused features involve the use of Defendant's ANDA Products in accordance with their proposed labeling for treating major depressive disorder, which allegedly will induce infringement of the patented methods (Compl. ¶82, 86).
III. The Accused Instrumentality
Product Identification
- The accused products are the vortioxetine hydrobromide tablets for which Defendant Unichem Laboratories, Limited has sought FDA approval via Abbreviated New Drug Application (ANDA) No. 211131 (Compl. ¶1, 28).
Functionality and Market Context
- The complaint alleges that the Defendant’s "ANDA Products" are purported generic versions of Plaintiffs' Trintellix® tablets, an oral antidepressant (Compl. ¶22, 28). The active ingredient in Trintellix® is vortioxetine hydrobromide (Compl. ¶21). The complaint further alleges that the proposed labeling for the ANDA Products sets forth the same indication as Trintellix®: the treatment of major depressive disorder (MDD) (Compl. ¶35). The filing of the ANDA itself, seeking approval to market this product prior to the expiration of the patents-in-suit, constitutes the statutory act of infringement under 35 U.S.C. § 271(e)(2)(A) (Compl. ¶44).
No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
'684 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| Compound 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] piperazine or a pharmaceutically acceptable salt thereof | Defendant’s ANDA Products are tablets containing vortioxetine hydrobromide, which is a pharmaceutically acceptable salt of the claimed compound. | ¶10, 28 | col. 2:28-34 |
| in a crystalline form characterized by an XRPD pattern as shown in any of FIGS. 1-17. | The complaint alleges that the ANDA Products fall within one or more claims of the patent and that Defendant’s notice letter does not contest infringement of claims covering specific crystalline forms, implying the product contains a claimed crystalline form. | ¶42, 43 | col. 4:45-48 |
'355 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of treating a disease selected from the group consisting of ... major depressive disorder... | The proposed labeling for Defendant’s ANDA Products is for the treatment of major depressive disorder (MDD). | ¶35, 55 | col. 7:1-50 |
| comprising administering a therapeutically effective amount of Compound I ... or a pharmaceutically acceptable salt thereof | The ANDA Products are tablets containing vortioxetine hydrobromide which are intended for administration to patients for the treatment of MDD. | ¶10, 58 | col. 2:28-34 |
| wherein the Compound I or salt is in a crystalline form characterized by an XRPD pattern as shown in any of FIGS. 1-17. | The complaint alleges that use of the ANDA Products will directly infringe and that Defendant’s notice letter does not contest infringement, implying the product contains a crystalline form covered by the patent for the claimed use. | ¶56, 58 | col. 4:45-48 |
- Identified Points of Contention: The primary dispute in a Hatch-Waxman case often revolves around patent validity rather than infringement, particularly where, as alleged here, the ANDA filer does not contest infringement in its notice letter. However, should infringement become a contested issue, the analysis may raise the following question:
- Technical Question: A central question would be one of polymorphic identity: What is the specific crystalline form (or mixture of forms) of vortioxetine hydrobromide in Defendant's ANDA product, and does its XRPD pattern correspond to one of the specific forms claimed in the patents? The complaint alleges infringement based on the ANDA submission but does not provide direct comparative evidence, such as an analysis of Defendant's actual product samples.
V. Key Claim Terms for Construction
- The Term: "crystalline form"
- Context and Importance: The patents claim specific crystalline forms (polymorphs) of vortioxetine or its salts, distinguishing them from non-crystalline (amorphous) forms and from each other. Infringement hinges on whether the Defendant’s product contains one of the claimed crystalline forms. Practitioners may focus on this term because the scope of protection depends on whether minor impurities or the presence of multiple polymorphs in the accused product removes it from the definition of the claimed "crystalline form."
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification suggests an intent to cover various forms, stating that the invention "is intended to encompass all such polymorphic forms, either as pure compounds or as mixtures thereof" (’684 Patent, col. 4:38-40). This language may support an interpretation where the presence of the claimed crystalline form, even in a mixture, is sufficient for infringement.
- Evidence for a Narrower Interpretation: The claims require the form to be "characterized by an XRPD pattern as shown in any of FIGS. 1-17" (’684 Patent, Claim 1). Furthermore, the specification provides tables of specific 2-theta peak positions for each polymorph (’684 Patent, col. 4:51-65). A party could argue that this detailed characterization limits the claims to forms that closely match the specific XRPD peaks and patterns depicted, excluding forms with significant variations.
VI. Other Allegations
- Indirect Infringement: The complaint alleges both induced and contributory infringement for all asserted patents. The inducement theory is based on the allegation that Defendant’s proposed product labeling will instruct physicians and patients to use the generic drug for the treatment of MDD, thereby encouraging infringement of the method-of-use claims (Compl. ¶46, 59, 72, 86). The contributory infringement theory is based on the allegation that the ANDA product is especially made for an infringing use and has no substantial non-infringing uses (Compl. ¶47, 60, 73, 87).
- Willful Infringement: The complaint does not use the term "willful infringement" but does allege that Defendant's conduct renders the case "exceptional" under 35 U.S.C. § 285, entitling Plaintiffs to attorneys' fees (Compl. ¶49, 62, 75, 89). This is based on the allegation that Defendant had actual and constructive notice of the patents and filed its ANDA "without adequate justification" (Compl. ¶48-49).
VII. Analyst’s Conclusion: Key Questions for the Case
This action presents a standard Hatch-Waxman challenge to a portfolio of patents covering a branded drug. While the complaint alleges that infringement of certain claims is not contested, the ultimate resolution will likely depend on the following core questions:
- A central issue will be one of polymorphic identity: What is the precise crystalline structure of the vortioxetine hydrobromide in Unichem’s proposed generic product? An evidentiary dispute may arise over whether this structure, as revealed by techniques like XRPD, falls within the scope of one of the specific polymorphs claimed in the patents-in-suit.
- For the method-of-use patents, a key question will be one of induced infringement: Assuming the underlying patents are valid, does the language in Unichem’s proposed product label actively encourage or instruct medical professionals to prescribe, and patients to use, the drug in a manner that directly practices the steps of the patented treatment methods?
- A dispositive issue for the case, though not the focus of the infringement complaint, will be patent validity. The central dispute will likely focus on whether the claims to specific crystalline forms and treatment methods are valid over the prior art, an issue that will be resolved through subsequent proceedings.