DCT

1:23-cv-00266

Neurocrine Biosciences Inc v. Zydus Pharma USA Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:23-cv-00266, D. Del., 03/10/2023
  • Venue Allegations: Plaintiff alleges venue is proper in the District of Delaware because certain defendants are foreign corporations that may be sued in any judicial district, another defendant is incorporated in Delaware, and another defendant purposefully conducts business in the district.
  • Core Dispute: Plaintiff alleges that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market generic valbenazine capsules constitutes an act of infringement of two patents covering the valbenazine compound and its methods of use.
  • Technical Context: The technology involves specific stereoisomers of tetrabenazine analogs, developed as prodrugs to treat hyperkinetic neurological disorders like tardive dysk...
  • Key Procedural History: This action arises under the Hatch-Waxman Act, triggered by Defendants' submission of ANDA No. 216137 with a Paragraph IV certification. The complaint notes that this is the fifth in a series of lawsuits filed by the Plaintiff against the same Defendants concerning the same ANDA, with the prior suits involving different patents. The complaint also states that the term of U.S. Patent No. 8,039,627 was extended by 552 days pursuant to 35 U.S.C. § 156.

Case Timeline

Date Event
2006-11-08 Priority Date for ’627 and ’697 Patents
2011-10-18 U.S. Patent No. 8039627 Issues
2013-01-22 U.S. Patent No. 8,357,697 Issues
2017-04-11 FDA Approves NDA for INGREZZA® (valbenazine)
2023-03-10 Complaint Filed

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

U.S. Patent No. 8,039,627 - "Substituted 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol Compounds and Methods Relating Thereto," issued October 18, 2011

The Invention Explained

  • Problem Addressed: The patent describes the drug tetrabenazine (TBZ), used to treat hyperkinetic movement disorders, as having known side effects and a "fairly low and variable bioavailability" due to extensive first-pass metabolism ('627 Patent, col. 6:31-54).
  • The Patented Solution: The invention discloses specific prodrugs of tetrabenazine analogs. These compounds are designed to be metabolized in the body into a single, specific stereoisomer of dihydrotetrabenazine, which is the active therapeutic agent ('627 Patent, col. 6:55-65). This approach seeks to improve the pharmacokinetic profile and potentially reduce side effects by controlling which metabolic products are formed ('627 Patent, col. 6:15-25, 6:55-65).
  • Technical Importance: The use of prodrugs to deliver a specific, active stereoisomer of a known drug is a key strategy in pharmaceutical development for enhancing therapeutic efficacy, improving bioavailability, and minimizing off-target effects ('627 Patent, col. 6:55-65).

Key Claims at a Glance

  • The complaint alleges infringement of at least one claim without specifying which one (Compl. ¶69). The patent contains one independent claim.
  • Independent Claim 1:
    • A compound that is (S)-2-Amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester;
    • or a pharmaceutically acceptable salt thereof.

U.S. Patent No. 8,357,697 - "Substituted 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol Compounds and Methods Relating Thereto," issued January 22, 2013

The Invention Explained

  • Problem Addressed: As a divisional of the application leading to the ’627 patent, this patent addresses the same problem: the undesirable side effects and variable pharmacokinetics associated with the administration of tetrabenazine ('697 Patent, col. 6:30-55).
  • The Patented Solution: The invention claims methods of using the specific prodrug compound disclosed in the ’627 patent. The method involves administering this compound to treat hyperkinetic disorders by inhibiting the VMAT2 transporter, thereby delivering the desired active metabolite in a controlled manner ('697 Patent, col. 6:56-col. 7:2).
  • Technical Importance: Claiming a specific method of use for a novel compound is crucial for protecting the commercial application of a new drug in treating specific medical conditions ('697 Patent, col. 9:1-12).

Key Claims at a Glance

  • The complaint alleges infringement of at least one claim without specifying which one (Compl. ¶81). The patent contains two independent claims.
  • Independent Claim 1:
    • A method of treating a hyperkinetic disorder;
    • comprising administering to a subject a pharmaceutically effective amount of a composition;
    • wherein the composition comprises the compound (S)-2-Amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, or a salt or solvate thereof.
  • Independent Claim 7 recites a similar method for "inhibiting monoamine transporter isoform 2 (VMAT2)" using the same compound.

III. The Accused Instrumentality

  • Product Identification: Defendants’ proposed "Valbenazine Capsules" in 40 mg, 60 mg, and 80 mg dosage strengths, for which they filed ANDA No. 216137 (Compl. ¶60).
  • Functionality and Market Context: The complaint alleges that the accused products are generic versions of Plaintiff's INGREZZA® Capsules and are "pharmaceutically and therapeutically equivalent" (Compl. ¶¶60, 67, 79). INGREZZA®'s active ingredient is valbenazine, and it is approved for the treatment of tardive dyskinesia (Compl. ¶50). The lawsuit was triggered by Defendants' filing of the ANDA, which represents a request for FDA approval to market the generic drug before the expiration of the patents-in-suit (Compl. ¶¶1, 60).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not contain a detailed infringement analysis or claim chart. The infringement allegations are based on the act of filing the ANDA under 35 U.S.C. § 271(e)(2) and the assertion that the proposed generic product is equivalent to the patented INGREZZA® product.

’627 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
(S)-2-Amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester or a pharmaceutically acceptable salt thereof Defendants' ANDA is for "Valbenazine Capsules," which are alleged to be generic versions of INGREZZA®, whose active ingredient is valbenazine. The complaint alleges that this valbenazine product is therapeutically equivalent to INGREZZA®. ¶¶50, 60, 67 col. 20:1-5

’697 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of treating a hyperkinetic disorder Defendants are seeking FDA approval for a generic version of INGREZZA®, a drug approved for treating tardive dyskinesia, which is a hyperkinetic disorder. The proposed package insert for the generic product would instruct for this infringing use. ¶¶50, 84, 86 col. 20:20-21
...comprising administering...a pharmaceutical composition comprising...(b) (S)-2-Amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy...ester, or a pharmaceutically acceptable salt or solvate thereof The proposed generic product is Valbenazine Capsules, which contain the compound recited in the claim as the active pharmaceutical ingredient. ¶¶60, 79 col. 20:23-31
  • Identified Points of Contention:
    • Infringement vs. Validity: In a Hatch-Waxman case where the generic product must be bioequivalent to the branded drug, the primary legal battle is typically over the patent's validity rather than infringement. The complaint notes Defendants' Paragraph IV certification alleges the patents are "invalid, unenforceable and/or will not be infringed" (Compl. ¶61). However, the complaint also asserts that Defendants "admit[] infringement" because their notice letter allegedly "did not provide any non-infringement allegation" for at least one claim of each patent (Compl. ¶¶66, 78). This suggests the core dispute will center on the validity and enforceability of the asserted patents.
    • Scope Questions: A threshold question is whether the active pharmaceutical ingredient in Zydus's proposed generic product, identified as valbenazine, is the same chemical entity described in claim 1 of the ’627 Patent. Given that "valbenazine" is the international nonproprietary name for the patented compound, this may not be a primary point of dispute.

V. Key Claim Terms for Construction

The complaint does not provide sufficient detail to identify specific claim construction disputes. However, based on the claim language, the following term may be relevant.

  • The Term: "pharmaceutically acceptable salt thereof" (’627 Patent, cl. 1; ’697 Patent, cl. 1)
  • Context and Importance: This term defines the scope of protection beyond the specific ester compound to include its various salt forms. Practitioners may focus on this term because the specific salt form of an active ingredient can affect its physical properties and bioavailability. Its construction is critical to determining whether different salt forms developed by a competitor would fall within the scope of the claims.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification provides a broad, functional definition, stating the term "is intended to encompass any and all acceptable salt forms" and provides a non-exhaustive list of suitable organic and inorganic acids and bases that can form such salts ('627 Patent, col. 9:35-54).
    • Evidence for a Narrower Interpretation: A party could argue that the term should be limited by the examples provided in the specification or by what was understood to be "pharmaceutically acceptable" by a person of ordinary skill in the art at the time of the invention.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that Defendants will induce infringement of the ’697 patent's method claims. The basis for this allegation is that Defendants' proposed package insert for their generic valbenazine product will instruct physicians and patients to use the drug to treat tardive dyskinesia, thereby directing them to perform the steps of the patented method (Compl. ¶¶84-86). The complaint also makes a general allegation of contributory infringement (Compl. ¶¶71, 83).
  • Willful Infringement: The complaint does not explicitly allege willful infringement. It does allege that Defendants have "actual knowledge" of the patents-in-suit based on their notice letter (Compl. ¶¶68, 80). In its prayer for relief, Plaintiff requests a declaration that this is an "exceptional case" and an award of attorneys' fees under 35 U.S.C. § 285 (Compl., p. 20, ¶K).

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

  • Patent Validity: A central issue for the court will be one of patent validity: Because the accused generic product must be bioequivalent to the patented branded drug to gain FDA approval, the litigation will likely focus not on whether the product infringes, but on whether the asserted claims of the ’627 and ’697 patents are valid and enforceable against Defendants' challenges of, for example, obviousness or lack of written description.
  • Admitted Infringement: A related question will be one of admitted infringement: The court may need to address the legal effect of Plaintiff's allegation that Defendants "admitted" infringement by failing to provide a detailed non-infringement statement for certain claims in their notice letter. This procedural point could shape the scope of the infringement portion of the case.