DCT

1:18-cv-00089

H Lundbeck As v. Alkem Laboratories Ltd

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:18-cv-00089, D. Del., 01/12/2018
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant S&B Pharma, Inc. is a Delaware corporation, and Defendant Alkem Laboratories Limited is a foreign corporation subject to personal jurisdiction in the district.
  • Core Dispute: Plaintiffs allege that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA, seeking to market a generic version of the antidepressant drug TRINTELLIX®, constitutes an act of infringement of three U.S. patents covering the drug's active ingredient and its method of use.
  • Technical Context: The technology is in the field of pharmaceutical compounds for treating Major Depressive Disorder, specifically concerning the compound vortioxetine, which exhibits a multi-modal mechanism of action targeting multiple serotonin receptors.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiffs' receipt of a Notice Letter from Alkem, dated November 30, 2017, which included a Paragraph IV certification against the patents-in-suit. The complaint states it was filed within the 45-day statutory window, which triggers an automatic 30-month stay of FDA approval for the Defendants' ANDA. The complaint notes that the Notice Letter did not contain allegations that the patents-in-suit are invalid or unenforceable.

Case Timeline

Date Event
2006-06-16 Earliest Priority Date for ’684, ’355, and ’946 Patents
2013-09-30 FDA approves Plaintiffs' New Drug Application for TRINTELLIX®
2014-05-13 U.S. Patent No. 8,722,684 issues
2015-03-03 U.S. Patent No. 8,969,355 issues
2016-01-05 U.S. Patent No. 9,227,946 issues
2017-11-30 Defendants send Paragraph IV Notice Letter to Plaintiffs
2018-01-12 Complaint for Patent Infringement 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"

  • Issued: May 13, 2014.

The Invention Explained

  • Problem Addressed: The patent's background section describes the shortcomings of then-existing Selective Serotonin Reuptake Inhibitors (SSRIs) used to treat depression, including that a significant fraction of patients do not respond and that the drugs typically have a slow onset of therapeutic effect (’684 Patent, col. 1:36-44). It also notes that CNS diseases like depression are often co-morbid with cognitive impairment (’684 Patent, col. 2:1-6).
  • The Patented Solution: The invention is the compound 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine and its pharmaceutically acceptable salts, which combine serotonin reuptake inhibition with activity at the serotonin 1A (5-HT1A) and serotonin 3 (5-HT3) receptors (’684 Patent, col. 2:29-34). This multi-modal mechanism of action is described as being useful not only for depression but also for treating associated cognitive deficits by affecting the cholinergic system (’684 Patent, col. 2:8-16). The patent specifically claims crystalline forms of the compound's hydrobromide salt (’684 Patent, Claims 1-4).
  • Technical Importance: The invention provided a novel chemical entity with a multi-modal pharmacological profile intended to offer improved efficacy, a faster onset of action, and benefits for cognitive symptoms compared to traditional SSRIs (Compl. ¶30).

Key Claims at a Glance

  • The complaint asserts infringement of "one or more claims" of the ’684 Patent (Compl. ¶48). Claim 2 is a representative independent claim directed to a specific crystalline product.
  • Claim 2 requires:
    • Compound 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt
    • in a crystalline form which is characterized by XRPD reflections at 6.89, 9.73, 13.78 and 14.62+/-0.10° 2θ.
  • The complaint does not explicitly reserve the right to assert dependent claims.

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"

  • Issued: March 3, 2015.

The Invention Explained

  • Problem Addressed: The patent addresses the same technical problems as the ’684 Patent: the limitations of existing SSRI treatments for depression and the co-morbidity of depression with cognitive impairment (’355 Patent, col. 1:36-44, col. 2:1-6).
  • The Patented Solution: The patent claims a method of treating certain CNS disorders, including major depressive disorder, by administering a therapeutically effective amount of the compound 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a pharmaceutically acceptable salt thereof (’355 Patent, col. 1:1-8). The therapeutic benefit is attributed to the compound's combined effect on serotonin reuptake and multiple serotonin receptors (’355 Patent, col. 2:28-34).
  • Technical Importance: This patent claims the specific therapeutic use of the active ingredient in TRINTELLIX® for treating depression, providing a layer of intellectual property protection tied directly to the drug's approved medical indication (Compl. ¶30, ¶41).

Key Claims at a Glance

  • The complaint asserts infringement of "one or more claims" of the ’355 Patent (Compl. ¶60). Claim 1 is the sole independent claim.
  • Claim 1 requires:
    • A method of treating a disease selected from a group including affective disorders, depression, and major depressive disorder
    • The method comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need thereof
    • Wherein Compound I is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine.
  • The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 9,227,946 - "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"

  • Issued: January 5, 2016. (Compl. ¶34).

Technology Synopsis

  • The patent addresses the same technical problems as the parent ’684 Patent, namely the limitations of existing antidepressants and the need to treat cognitive deficits associated with CNS disorders (’946 Patent, col. 1:36-44, col. 2:1-6). The invention claimed is the "beta" crystalline form of the hydrobromide salt of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine, defined by a specific set of X-ray powder diffraction (XRPD) peaks, which is described in the specification as being a particularly stable polymorph suitable for pharmaceutical formulations (’946 Patent, Claim 1; ’684 Patent, col. 5:4-10).

Asserted Claims

  • The complaint alleges infringement of "one or more claims" (Compl. ¶73). Claim 1 is the sole independent claim.

Accused Features

  • The accused features are the vortioxetine hydrobromide tablets described in Defendants' ANDA, which Plaintiffs allege will contain the claimed "beta" crystalline form of the active pharmaceutical ingredient (Compl. ¶35, ¶73).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentalities are the "vortioxetine hydrobromide tablets" described in Defendants' ANDA No. 211089 (the "ANDA Products") (Compl. ¶15, ¶35).

Functionality and Market Context

  • The ANDA Products are purported generic versions of Plaintiffs' TRINTELLIX® tablets, an oral antidepressant approved for the treatment of Major Depressive Disorder (MDD) (Compl. ¶1, ¶30). The active ingredient is vortioxetine hydrobromide (Compl. ¶29). The complaint alleges that the proposed labeling for the ANDA Products sets forth the same indication as TRINTELLIX®, namely the treatment of MDD (Compl. ¶41). Defendants allegedly seek to commercially manufacture, market, and sell these products in the United States prior to the expiration of the patents-in-suit (Compl. ¶1, ¶15, ¶38). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

’684 Patent Infringement Allegations

Claim Element (from Independent Claim 2) Alleged Infringing Functionality Complaint Citation Patent Citation
Compound 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt Defendants' ANDA Products are described as "vortioxetine hydrobromide tablets." Vortioxetine is the nonproprietary name for the claimed compound. ¶15, ¶30, ¶35 col. 2:29-34
in a crystalline form which is characterized by XRPD reflections at 6.89, 9.73, 13.78 and 14.62+/-0.10° 2θ. The complaint alleges that the ANDA Products "fall within one or more claims of the '684 patent," which suggests the active ingredient in the proposed generic product is the claimed crystalline "beta" form. ¶48 col. 3:56-61
  • Identified Points of Contention:
    • Scope Questions: A primary question for the court will be one of polymorphic identity: does the active pharmaceutical ingredient described in Defendants' ANDA possess the specific crystalline structure defined by the X-ray powder diffraction peaks recited in Claim 2? The complaint makes a conclusory allegation of infringement without providing specific data from the ANDA to support it.

’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 complaint alleges that the proposed labeling for the ANDA Products will indicate the product for the treatment of major depressive disorder (MDD). ¶41, ¶61 col. 7:4-9
the method comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need thereof, The ANDA Products are tablets intended for oral administration to patients. The proposed labeling will instruct physicians and patients on this administration for treating MDD. ¶15, ¶41, ¶65 col. 7:4-9
wherein Compound I is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine. The active ingredient of the ANDA Products is vortioxetine, which is the chemical name for the claimed compound. ¶15, ¶29, ¶30 col. 2:29-34
  • Identified Points of Contention:
    • Technical Questions: The infringement analysis will focus on the contents of the proposed product label submitted with the ANDA. A key question will be whether the language of that label instructs, encourages, or recommends that medical professionals and patients use the generic drug in a manner that directly practices the steps of the claimed method.

V. Key Claim Terms for Construction

  • The Term: "a crystalline form which is characterized by XRPD reflections at 6.89, 9.73, 13.78 and 14.62+/-0.10° 2θ" (’684 Patent, Claim 2).
  • Context and Importance: The definition of this term is dispositive for infringement of the asserted composition of matter patents (’684 and ’946 Patents). This language defines a specific polymorph of the drug substance, known as the "beta form." The dispute will turn on whether the Defendants' proposed product contains this exact crystalline form. Practitioners may focus on this term because the existence of other non-infringing polymorphs is a common design-around strategy in generic drug development.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification refers to the values in the associated table as the "major XRPD reflections," which may suggest that the presence of these peaks is sufficient to characterize the form, even if other minor peaks differ or are absent (’684 Patent, col. 3:49-50). The use of the phrase "characterized by" could be argued as less restrictive than language like "consisting of" the recited peaks.
    • Evidence for a Narrower Interpretation: The specification explicitly describes multiple distinct polymorphs (alpha, beta, gamma, hydrate), each with its own XRPD figure, suggesting the inventors viewed them as patentably distinct entities (’684 Patent, Figs. 2-5). The patent also highlights specific physical properties of the beta form, such as its superior stability and lower solubility compared to the alpha form, which may support a narrow and precise definition to distinguish it from other known forms (’684 Patent, col. 5:4-10).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that if the ANDA is approved, Defendants will actively induce infringement by marketing the ANDA Products with a label that instructs physicians and patients to use the drug for the patented method of treating major depressive disorder (Compl. ¶52, ¶65, ¶78). The complaint also alleges contributory infringement, stating the ANDA Products have no substantial non-infringing uses and are especially made for an infringing use (Compl. ¶53, ¶66, ¶79).
  • Willful Infringement: Willfulness is alleged for all three patents based on Defendants having "actual and constructive notice" of the patents prior to filing their ANDA (Compl. ¶54, ¶67, ¶80). The complaint further alleges that Defendants' Paragraph IV certification was made "without adequate justification" (Compl. ¶55, ¶68, ¶81).

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

  • A central factual issue will be one of polymorphic identity: does the active pharmaceutical ingredient in Defendants' proposed generic product meet the specific X-ray powder diffraction fingerprint of the patented "beta form" crystalline structure as claimed in the ’684 and ’946 Patents, or does it utilize a different, non-infringing polymorph or an amorphous form?
  • A key legal and factual issue will be one of induced infringement: does the proposed product labeling submitted with Defendants' ANDA contain language that will actively encourage or instruct medical professionals to prescribe, and patients to use, the generic product for the treatment of major depressive disorder in a manner that infringes the method claims of the ’355 Patent?