DCT

1:22-cv-01269

Otsuka Pharmaceutical Co Ltd v. Zenara Pharma Private Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:22-cv-01269, D. Del., 09/27/2022
  • Venue Allegations: Venue is alleged to be proper because Defendants are incorporated in India and may be sued in any U.S. judicial district.
  • Core Dispute: Plaintiffs allege that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market generic versions of Plaintiffs' REXULTI® (brexpiprazole) tablets constitutes an act of infringement of six patents covering the active pharmaceutical ingredient, tablet formulations, and methods of treating schizophrenia and depression.
  • Technical Context: The technology concerns piperazine-substituted benzothiophene compounds used as antipsychotic medications for treating mental disorders, particularly schizophrenia and major depressive disorder.
  • Key Procedural History: This action arises under the Hatch-Waxman Act, triggered by Defendants’ submission of ANDA No. 213477 with Paragraph IV certifications alleging non-infringement, invalidity, or unenforceability of the patents-in-suit. The complaint notes this is the third lawsuit between the parties concerning this ANDA, following prior actions filed in 2019 and 2020. The original patent covering the brexpiprazole compound, U.S. Patent No. 7,888,362, was reissued as RE48,059, which subsequently received a patent term extension. Several of the asserted patents are subject to terminal disclaimers, potentially affecting their expiration dates.

Case Timeline

Date Event
2005-04-14 Priority Date for RE’059, ’840, ’109, and ’637 Patents
2011-02-15 U.S. Patent No. 7,888,362 Issues
2011-10-14 Priority Date for ’419 Patent
2013-01-08 U.S. Patent No. 8,349,840 Issues
2013-12-31 U.S. Patent No. 8,618,109 Issues
2015-07-10 FDA Approves REXULTI® (brexpiprazole) NDA No. 205422
2017-12-12 U.S. Patent No. 9,839,637 Issues
2019-06-04 U.S. Patent No. 10,307,419 Issues
2019-08-30 Defendants send First Notice of Paragraph IV Certification
2020-06-23 U.S. Reissue Patent No. RE 48,059 Issues
2020-10-13 Defendants send Second Notice of Paragraph IV Certification
2022-08-18 Defendants send Third Notice of Paragraph IV Certification
2022-09-27 Complaint Filed

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

U.S. Reissue Patent No. RE 48,059 (reissue of U.S. Patent No. 7,888,362)

  • Patent Identification: RE 48,059, Piperazine-Substituted Benzothiophenes for Treatment of Mental Disorders, reissued June 23, 2020. (Compl. ¶ 22).

The Invention Explained

  • Problem Addressed: The patent's background describes a need for antipsychotic drugs with a wider treatment spectrum, fewer side effects, and better safety profiles than existing therapies, noting that the heterogeneous causes of disorders like schizophrenia make multi-faceted drugs desirable. (’362 Patent, col. 1:12-19).
  • The Patented Solution: The invention is a novel heterocyclic compound, 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (brexpiprazole), designed to possess a unique combination of pharmacological activities. It acts as a dopamine D2 receptor partial agonist, a serotonin 5-HT2A receptor antagonist, and an adrenalin α1 receptor antagonist, while also inhibiting serotonin uptake. (’362 Patent, col. 2:11-23). This multi-receptor profile is intended to provide a broad therapeutic effect for central nervous system disorders. (’362 Patent, col. 2:11-23).
  • Technical Importance: This multi-receptor profile established a "dopamine system stabilizer" approach, intended to modulate dopaminergic neurotransmission to treat both positive and negative symptoms of schizophrenia with a reduced risk of side effects compared to earlier antipsychotics. (’362 Patent, col. 17:30-41).

Key Claims at a Glance

  • The complaint asserts infringement of claims 1-9. (Compl. ¶ 56). Claim 1 is the sole independent claim.
  • Independent Claim 1:
    • 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof. (’362 Patent, col. 47:45-47).

U.S. Patent No. 8,349,840

  • Patent Identification: 8349840, Piperazine-Substituted Benzothiophenes for Treatment of Mental Disorders, issued January 8, 2013. (Compl. ¶ 27).

The Invention Explained

  • Problem Addressed: As with the parent ’362 patent, the '840 Patent addresses the need for improved treatments for mental disorders like schizophrenia. (’840 Patent, col. 1:12-19).
  • The Patented Solution: The patent claims a method for treating schizophrenia by administering the brexpiprazole compound (or a salt thereof) to a human or animal. (’840 Patent, Claim 1). The solution is thus the specific therapeutic application of the compound to manage the clinical symptoms of schizophrenia. (’840 Patent, col. 5:44-50).
  • Technical Importance: This patent protects the specific use of the brexpiprazole compound for schizophrenia, a primary approved indication for the REXULTI® drug, thereby protecting a key commercial market for the product. (’840 Patent, col. 5:44-46).

Key Claims at a Glance

  • The complaint asserts infringement of one or more claims. (Compl. ¶ 67). Claim 1 is the sole independent claim.
  • Independent Claim 1:
    • A method for treating schizophrenia
    • comprising administering a heterocyclic compound which is 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one, or a salt thereof
    • to a human or animal. (’840 Patent, Claim 1).

U.S. Patent No. 8,618,109

  • Patent Identification: 8618109, Piperazine-Substituted Benzothiophenes for Treatment of Mental Disorders, issued December 31, 2013. (Compl. ¶ 31).
  • Technology Synopsis: This patent addresses the need for improved treatments for mental disorders and claims a method for treating depression by administering the brexpiprazole compound. (’109 Patent, Abstract, Claim 1).
  • Asserted Claims: The complaint alleges infringement of one or more claims; Claim 1 is the sole independent claim. (Compl. ¶ 81).
  • Accused Features: The accused instrumentality is a generic version of REXULTI®, which is approved for the adjunctive treatment of major depressive disorder, and Defendants' ANDA filing seeks approval for that use. (Compl. ¶¶ 20, 43, 83).

U.S. Patent No. 9,839,637

  • Patent Identification: 9839637, Piperazine-Substituted Benzothiophenes for Treatment of Mental Disorders, issued December 12, 2017. (Compl. ¶ 35).
  • Technology Synopsis: This patent covers a method of treating schizophrenia by administering a specific daily dose of brexpiprazole, namely 2 mg or 4 mg. (’637 Patent, Abstract, Claims 1, 10).
  • Asserted Claims: The complaint alleges infringement of one or more claims; Claims 1 and 10 are independent claims covering the specific dosages. (Compl. ¶ 95).
  • Accused Features: Defendants' ANDA filing seeks approval for tablets in dosages of 2 mg, 3 mg, and 4 mg, which overlap with the claimed dosages for treating schizophrenia. (Compl. ¶¶ 20, 43, 97).

U.S. Patent No. 10,307,419

  • Patent Identification: 10307419, Tablet Comprising 7-[4-(4-benzo[b]thiopen-4-yl-piperazine-1-yl)butoxy]-1H-quinolin-2-one or a Salt Thereof, issued June 4, 2019. (Compl. ¶ 39).
  • Technology Synopsis: The patent addresses the technical challenge of creating a stable oral dosage form of brexpiprazole with good disintegration ability and photostability. The claimed solution is a coated tablet comprising specific categories of excipients (e.g., lactose, corn starch), binders (hydroxypropyl cellulose), and disintegrants, with a coating layer that includes an iron oxide colorant to enhance photostability. (’419 Patent, col. 1:42-47, Claim 1).
  • Asserted Claims: The complaint alleges infringement of one or more claims; Claim 1 is a key independent claim. (Compl. ¶ 109).
  • Accused Features: Defendants' proposed generic product is a tablet formulation of brexpiprazole alleged to be pharmaceutically equivalent to Plaintiffs' REXULTI® tablets. (Compl. ¶¶ 43, 107).

III. The Accused Instrumentality

  • Product Identification: The accused products are Defendants’ generic brexpiprazole tablets in 0.25, 0.5, 1, 2, 3, and 4 mg dosage forms, as described in ANDA No. 213477 submitted to the FDA. (Compl. ¶ 43).
  • Functionality and Market Context: The complaint alleges that Defendants' proposed products are generic versions of Plaintiffs’ REXULTI® tablets, containing brexpiprazole as the active pharmaceutical ingredient. (Compl. ¶¶ 13, 43). The products are alleged to be "pharmaceutically and therapeutically equivalent" to REXULTI®, which is approved for the adjunctive treatment of major depressive disorder and the treatment of schizophrenia. (Compl. ¶¶ 20, 54). The act of infringement under 35 U.S.C. § 271(e)(2) is the submission of the ANDA seeking approval to market these generic products before the expiration of the patents-in-suit. (Compl. ¶ 1).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide detailed infringement allegations or claim charts. The infringement theory is based on 35 U.S.C. § 271(e)(2)(A), where the filing of an ANDA for a drug claimed in a patent is a technical act of infringement. The following summaries are based on this statutory framework and the general allegations in the complaint.

  • RE 48,059 Infringement Allegations
Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof Defendants’ ANDA product is alleged to contain brexpiprazole, which is the chemical compound identified in the claim, or a salt thereof. ¶¶13, 43, 54 ’362 Patent, col. 29:14-57

  • Identified Points of Contention:

    • Factual Question: The central question will be whether the active pharmaceutical ingredient in Defendants' ANDA product, including its specific salt form and any polymorphs, falls within the asserted claim's scope. The complaint does not provide sufficient detail for analysis of potential disputes regarding the specific form of the compound.

  • U.S. Patent No. 8,349,840 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for treating schizophrenia Defendants are alleged to seek FDA approval for their generic product for indications that include the treatment of schizophrenia, and their proposed product label will allegedly instruct healthcare professionals to prescribe the drug for this purpose. ¶¶20, 69, 71 ’840 Patent, col. 5:44-46
comprising administering a heterocyclic compound which is 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one, or a salt thereof The active ingredient in Defendants' ANDA product is alleged to be the claimed compound. ¶¶13, 43 ’840 Patent, col. 51:48-67
  • Identified Points of Contention:
    • Scope Questions: A central issue may be whether Defendants' proposed product label will induce infringement. This raises the question of whether Defendants will attempt to market their product under a "skinny label" that carves out the patented indication of treating schizophrenia, which could potentially avoid infringement of this method patent. The complaint does not provide the proposed label for analysis.

V. Key Claim Terms for Construction

  • The Term: "a salt thereof" (’059, Claim 1)

  • Context and Importance: The definition of this term is critical for determining the scope of the compound patent. Infringement will depend on whether the specific salt form of brexpiprazole used in Defendants' ANDA product is encompassed by this term. Practitioners may focus on this term because different salt forms can have different properties and may or may not have been contemplated by the patent.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The specification provides a non-exhaustive list of "pharmacologically acceptable salts," including salts of inorganic acids (e.g., hydrochloride, sulfate) and organic acids (e.g., fumarate, maleate), indicating an intent to cover a wide range of conventional salt forms. (’362 Patent, col. 15:28-67).
    • Evidence for a Narrower Interpretation: An argument for a narrower scope could focus on the specific salts synthesized and tested in the patent's examples, suggesting that only those forms are covered. The patent describes making a hydrochloride salt, sulfate, fumarate, maleate, and citrate, among others. (’362 Patent, col. 43:43-46:13).

  • The Term: "treating schizophrenia" (’840 Patent, Claim 1)

  • Context and Importance: This term is central to the induced infringement allegation for the method-of-use patent. The dispute will likely turn on whether the instructions and indications on Defendants' proposed product label encourage, recommend, or promote the administration of the generic drug for the purpose of "treating schizophrenia."

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The specification describes the compound as being effective for a wide range of central nervous system disorders, explicitly including schizophrenia. (’840 Patent, col. 5:44-46). The patent also includes data from pharmacological tests relevant to antipsychotic activity, supporting a conventional medical understanding of "treating." (’840 Patent, col. 49:18-67).
    • Evidence for a Narrower Interpretation: The complaint does not provide a basis to anticipate arguments for a narrower interpretation beyond the standard medical definition.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement under 35 U.S.C. § 271(b) for the method-of-use patents (’840, ’109, ’637). The allegations are based on the assertion that Defendants know their proposed package insert will instruct and encourage healthcare professionals to prescribe the generic product for the patented methods of treating schizophrenia and depression. (Compl. ¶¶ 70-71, 84-85, 98-99).
  • Willful Infringement: The complaint does not include a formal count for willful infringement. However, it alleges that Defendants have "actual knowledge" of each of the patents-in-suit, citing the Paragraph IV certification letters sent in 2019, 2020, and 2022 as evidence. (Compl. ¶¶ 55, 66, 80, 94, 108). These allegations may form the basis for a future claim of willful infringement based on post-suit conduct.

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

  • A core issue will be one of validity: can the Defendants demonstrate, by clear and convincing evidence, that any of the asserted claims across the six patents are invalid for reasons such as obviousness or lack of enablement? The Paragraph IV certifications suggest this will be a central part of the defense strategy.
  • A key question for the method-of-use patents will be one of inducement: does the language of Defendants’ proposed product label actively encourage or instruct physicians to prescribe the generic product for the patented methods of treating schizophrenia and depression, or have Defendants successfully carved out these patented indications to avoid liability for induced infringement?
  • A central evidentiary question for the formulation patent (’419 Patent) will be one of technical identity: does the Defendants’ proposed tablet formulation, as detailed in their ANDA, contain the specific combination of excipients, binder, disintegrant, and coating layer required by the asserted claims, or is there a material difference in the composition that avoids infringement?