DCT
2:23-cv-01369
Neurocrine Biosciences Inc v. Zydus Pharma USA Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Neurocrine Biosciences, Inc. (Delaware)
- Defendant: Zydus Pharmaceuticals (USA) Inc. (New Jersey); Zydus Worldwide DMCC (United Arab Emirates); Zydus Healthcare (USA) LLC (Delaware); Zydus Lifesciences Limited (Republic of India)
- Plaintiff’s Counsel: McCarter & English, LLP
- Case Identification: 2:23-cv-01369, D.N.J., 03/10/2023
- Venue Allegations: Plaintiff alleges venue is proper in the District of New Jersey because Defendant Zydus Pharmaceuticals is incorporated in New Jersey, Defendant Zydus Healthcare’s principal place of business is in New Jersey, and Defendants Zydus Worldwide and Zydus Lifesciences are foreign corporations that may be sued in any judicial 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 compound and its method of use.
- Technical Context: The technology concerns specific pharmaceutical compounds and their use in treating hyperkinetic movement disorders, such as tardive dyskinesia, which is characterized by involuntary, repetitive body movements.
- Key Procedural History: The complaint describes an extensive litigation history between the parties concerning the same ANDA (No. 216137). This filing represents the fifth wave of litigation, following four prior sets of lawsuits over different patents listed in the FDA's Orange Book for Plaintiff's drug, INGREZZA®. The prior suits, initially filed in both New Jersey and Delaware, were consolidated in the District of Delaware. The complaint also notes that U.S. Patent No. 8,039,627 received a 552-day patent term extension from the PTO.
Case Timeline
| Date | Event |
|---|---|
| 2006-11-08 | Priority Date for ’627 and ’697 Patents |
| 2011-10-18 | U.S. Patent No. 8,039,627 Issued |
| 2013-01-22 | U.S. Patent No. 8,357,697 Issued |
| 2017-04-11 | FDA Approves NDA for INGREZZA® (valbenazine) Capsules |
| 2021-06-15 | Zydus sends First Notice Letter regarding ANDA No. 216137 |
| 2021-07-30 | Neurocrine files "First Suits" against Zydus |
| 2021-09-16 | Zydus sends Second Notice Letter |
| 2021-10-29 | Neurocrine files "Second Suits" against Zydus |
| 2022-02-18 | Zydus sends Third Notice Letter |
| 2022-04-01 | Neurocrine files "Third Suits" against Zydus |
| 2022-08-17 | Zydus sends Fourth Notice Letter |
| 2022-09-30 | Neurocrine files "Fourth Suits" against Zydus |
| 2023-01-25 | Zydus sends Fifth Notice Letter |
| 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 disorders, as having significant side effects and "low and variable bioavailability" due to rapid and extensive metabolism in the body (’627 Patent, col. 6:46-53).
- The Patented Solution: The invention is a specific prodrug of dihydrotetrabenazine (HTBZ), the active metabolite of TBZ. It chemically links a single, specific stereoisomer of HTBZ to an amino acid (L-valine) to form a new compound, valbenazine (’627 Patent, Abstract; col. 6:60-65). This design is intended to improve upon TBZ by providing a longer duration of action, greater selectivity for the VMAT2 transporter target, and potentially fewer side effects (’627 Patent, col. 9:57-65).
- Technical Importance: This prodrug strategy aimed to create a "best-in-class" VMAT2 inhibitor by optimizing the pharmacokinetic profile of an existing drug's active metabolite, potentially leading to a more effective therapy with a more convenient once-daily dosing regimen (’627 Patent, col. 9:1-5).
Key Claims at a Glance
- The complaint alleges infringement of "at least one claim" without specifying which one (Compl. ¶60). The patent contains one independent claim.
- Independent Claim 1:
- (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: The patent, which shares its specification with the ’627 patent, identifies the clinical limitations of tetrabenazine, including off-target side effects and poor, variable bioavailability, as problems to be solved (’697 Patent, col. 6:30-55).
- The Patented Solution: The patent claims methods of using the specific valbenazine compound described in the ’627 patent to treat neurological conditions (’697 Patent, col. 9:5-12). By administering this specific prodrug, the method aims to deliver the therapeutic benefits of VMAT2 inhibition more effectively and with a better safety profile than prior treatments (’697 Patent, col. 6:54-65).
- Technical Importance: The claimed methods provide a new therapeutic option for patients with hyperkinetic disorders, leveraging the improved properties of the valbenazine compound to achieve a clinical benefit (’697 Patent, col. 9:5-12).
Key Claims at a Glance
- The complaint alleges infringement of "at least one claim" without specification (Compl. ¶72). The patent contains one independent claim.
- Independent Claim 1:
- A method of treating a hyperkinetic disorder,
- said method comprising administering to a subject a pharmaceutically effective amount of a pharmaceutical composition,
- the composition comprising a pharmaceutically acceptable carrier or diluent, and
- 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 (valbenazine) or a pharmaceutically acceptable salt or solvate thereof.
III. The Accused Instrumentality
Product Identification
The accused products are Defendants’ proposed "Valbenazine Capsules, 40 mg, 60 mg and 80 mg," for which Defendants submitted ANDA No. 216137 to the FDA (Compl. ¶¶1, 51).
Functionality and Market Context
The complaint alleges that the accused products are generic versions of Plaintiff’s INGREZZA® Capsules (Compl. ¶51). INGREZZA® is a prescription drug approved for the treatment of tardive dyskinesia, with its active ingredient being valbenazine, present as a tosylate salt (Compl. ¶41). The complaint further alleges that Defendants have represented to the FDA that their generic products are "pharmaceutically and therapeutically equivalent" to INGREZZA® (Compl. ¶¶58, 70).
IV. Analysis of Infringement Allegations
The complaint does not contain a detailed infringement analysis or claim chart. Instead, it alleges that Defendants have admitted infringement of at least one claim of each patent-in-suit because their Paragraph IV notice letter "did not provide any non-infringement allegation" (Compl. ¶¶57, 69). The infringement theory is based on the submission of ANDA No. 216137, which seeks approval to market a generic version of Plaintiff's patented drug prior to patent expiration.
’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 | The accused ANDA products are identified as "Valbenazine Capsules" and are alleged to be generic versions of INGREZZA®, whose active ingredient is valbenazine. | ¶1, ¶41, ¶51, ¶58 | 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... | The accused ANDA products are alleged to be therapeutically equivalent to INGREZZA®, which is approved for treating tardive dyskinesia, a hyperkinetic disorder. | ¶41, ¶70, ¶77 | col. 19:12-20 |
| ...comprising administering to a subject a pharmaceutically effective amount of a pharmaceutical composition comprising... [valbenazine] or a pharmaceutically acceptable salt or solvate thereof | The complaint alleges Defendants' proposed package insert will instruct physicians and patients to administer the accused Valbenazine Capsules for the treatment of tardive dyskinesia. | ¶75, ¶77 | col. 20:2-7 |
Identified Points of Contention
- Validity vs. Infringement: The complaint states that Defendants’ Paragraph IV certification alleges the patents-in-suit are "invalid, unenforceable and/or will not be infringed" (Compl. ¶52). However, the pleading focuses on an alleged admission of infringement, suggesting the primary battleground in this litigation may be over the validity of the patents, rather than infringement. The basis for Defendants' invalidity contentions is not detailed in the complaint.
- Scope Questions: A potential issue for the court could be the construction of "pharmaceutically acceptable salt" in the ’627 patent. The infringement case rests on this term being construed to cover the specific tosylate salt form of valbenazine used in INGREZZA® and presumably in the proposed generic product (Compl. ¶41).
No probative visual evidence provided in complaint.
V. Key Claim Terms for Construction
"pharmaceutically acceptable salt" (’627 Patent, Claim 1)
- Context and Importance: This term is critical because the branded drug, INGREZZA®, contains valbenazine as a "tosylate salt" (Compl. ¶41). For a finding of literal infringement, the scope of "pharmaceutically acceptable salt" must encompass this specific salt form. Practitioners may focus on this term to confirm the accused product falls squarely within the claim's scope.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification provides a non-exhaustive list of acids suitable for forming salts, including "methanesulfonic" and "benzenesulfonic acids" (’627 Patent, col. 9:39-44). As p-toluenesulfonic acid (tosylic acid) is a derivative of benzenesulfonic acid, this language may support a construction that includes the tosylate salt.
- Evidence for a Narrower Interpretation: The specification does not explicitly name "tosylate" or "p-toluenesulfonate" in its list of exemplary salts. A party could argue that the absence of this specific, commercially important salt form from the examples implies its exclusion, although this is generally a difficult argument to sustain for a non-exhaustive list.
"hyperkinetic disorder" (’697 Patent, Claim 1)
- Context and Importance: Infringement of this method claim is contingent on the accused product being intended for the treatment of a condition that falls within the definition of "hyperkinetic disorder." The defendants' proposed label will be the key evidence.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification explicitly lists "tardive dyskinesia" as an example of a hyperkinetic disorder that can be treated by the invention (’697 Patent, col. 10:9-10). Since INGREZZA® is approved for tardive dyskinesia (Compl. ¶41), and the generic is alleged to be equivalent, this evidence strongly supports a construction that covers the intended use.
- Evidence for a Narrower Interpretation: The complaint does not provide a basis for a narrower interpretation that would exclude tardive dyskinesia. A defendant would have to argue that the specific etiology or patient population for its product falls outside the patent's intended scope, which appears challenging based on the provided documents.
VI. Other Allegations
Indirect Infringement
The complaint alleges induced infringement of the ’697 patent. The basis for this allegation is that Defendants' "proposed package insert will recommend, suggest, encourage and/or instruct" healthcare professionals and patients on how to use the generic product in a way that directly infringes the method claim (Compl. ¶77). This allegation is intended to establish the requisite knowledge and specific intent for inducement.
Willful Infringement
The complaint does not explicitly allege "willful infringement." However, it requests a declaration that the case is "exceptional" and seeks an award of attorney fees pursuant to 35 U.S.C. § 285 (Compl., Request for Relief ¶K). The factual basis for this is Defendants' alleged actual knowledge of the patents-in-suit, as evidenced by the "Fifth Notice Letter" (Compl. ¶¶59, 71).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue will be one of patent validity: Since the complaint frames infringement as effectively conceded, the case will likely turn on whether Defendants can prove by clear and convincing evidence that the asserted claims of the ’627 and ’697 patents are invalid on grounds such as obviousness or lack of adequate written description, which are common defenses in ANDA litigation.
- A key question for the method patent will be one of induced infringement: Assuming the ’697 patent is found valid, the court will examine whether the language in Defendants’ proposed product label is sufficient to establish that Defendants specifically intended to encourage or instruct physicians and patients to perform the patented method of treating a "hyperkinetic disorder."