DCT

1:20-cv-01021

Acadia Pharma Inc v. Zydus Pharma USA Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:20-cv-01021, D. Del., 07/30/2020
  • Venue Allegations: Plaintiff alleges venue is proper in the District of Delaware based on Defendants' business contacts with the state, including the marketing and sale of generic pharmaceutical products, and their stated intent to commercially manufacture and sell the accused generic products throughout the United States, including in Delaware. The complaint also notes that Defendants have been sued in this district previously and have not challenged jurisdiction.
  • Core Dispute: Plaintiff alleges that Defendants' submission of Abbreviated New Drug Applications (ANDAs) to the U.S. Food and Drug Administration (FDA) seeking approval to market generic versions of Plaintiff's NUPLAZID® drug product constitutes an act of patent infringement.
  • Technical Context: The patents relate to the compound pimavanserin, specific formulations and crystalline forms thereof, and methods of its use for treating psychosis associated with neurodegenerative disorders such as Parkinson's disease.
  • Key Procedural History: The lawsuit was filed under the Hatch-Waxman Act following Plaintiff's receipt of Defendants' Paragraph IV Notice Letters, which certified that the patents-in-suit are invalid or would not be infringed by Defendants' proposed generic products. The filing of the complaint within 45 days of receiving this notice triggers an automatic 30-month stay on FDA approval of the Defendants' ANDAs.

Case Timeline

Date Event
2003-01-16 ’740 Patent Priority Date
2004-09-27 ’615 Patent Priority Date
2009-10-13 ’740 Patent Issue Date
2010-06-08 ’615 Patent Issue Date
2016-03-25 ’860 Patent Priority Date
2017-08-30 ’185 & ’480 Patents Priority Date
2019-10-22 ’185 Patent Issue Date
2019-12-31 ’860 Patent Issue Date
2020-05-12 ’480 Patent Issue Date
2020-06-22 Zydus ANDA Notice Letter Date
2020-07-30 Complaint Filing Date

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

U.S. Patent No. 7,601,740, "Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases", issued October 13, 2009

The Invention Explained

  • Problem Addressed: The patent describes that patients with neurodegenerative disorders (NDs) like Parkinson's disease often suffer from psychosis and dyskinesias (abnormal movements) (’740 Patent, col. 2:3-9). Existing antipsychotic therapies are poorly tolerated in these patients because they can worsen motor function, a significant concern in diseases already characterized by motor impairment (’740 Patent, col. 2:46-51).
  • The Patented Solution: The invention is a method of treating these symptoms by administering a compound that is a selective inverse agonist of the serotonin 5-HT2A receptor (’740 Patent, Abstract). This mechanism is intended to provide antipsychotic and anti-dyskinetic effects without the motor side effects associated with drugs that act on dopamine receptors, which are the traditional targets for such therapies (’740 Patent, col. 2:51-67).
  • Technical Importance: This approach provided a therapeutic pathway for treating psychosis in ND patients that was distinct from the dopamine-antagonism mechanism, suggesting the possibility of managing psychiatric symptoms without compromising motor control.

Key Claims at a Glance

  • The complaint asserts independent claims 1 and 17, among others (Compl. ¶53).
  • Independent Claim 17 recites the essential elements:
    • A method for treating a neurodegenerative disease,
    • comprising administering to a patient an effective amount of a compound of Formula (I),
    • or a pharmaceutically acceptable salt thereof.

U.S. Patent No. 7,732,615, "N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms", issued June 8, 2010

The Invention Explained

  • Problem Addressed: Pharmaceutical development requires active ingredients to be in a form that is stable, pure, and has consistent physical properties to ensure reliable manufacturing and bioavailability (’615 Patent, col. 1:21-25). The patent addresses the need for such well-defined forms of the pimavanserin compound.
  • The Patented Solution: The invention provides specific crystalline forms of pimavanserin and its tartrate salt (’615 Patent, Abstract). These crystalline forms, such as "Form C," are defined by unique X-ray powder diffraction (XRPD) patterns, which correspond to a specific, ordered arrangement of molecules. This consistency is critical for producing a safe and effective drug product (’615 Patent, col. 4:45-51).
  • Technical Importance: The creation of stable, characterizable crystalline forms of an active pharmaceutical ingredient is a critical step in moving a drug from a laboratory chemical to a manufacturable and clinically viable product.

Key Claims at a Glance

  • The complaint asserts infringement of the ’615 Patent generally (Compl. ¶¶50, 61). Independent claim 1 is representative.
  • Independent Claim 1 recites the essential elements:
    • A crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate,
    • that exhibits an X-ray powder diffraction pattern with characteristic peaks at specific d-values (e.g., about 12.0, 10.7, 5.86, 4.84, 4.70, 4.57, and 3.77 angstroms).

U.S. Patent No. 10,449,185, "Formulations of pimavanserin", issued October 22, 2019

Technology Synopsis

The patent addresses manufacturing challenges associated with pimavanserin, which in its native state has low bulk density and poor flowability, making it difficult to fill into capsules accurately at high speed (’185 Patent, col. 1:53-61). The invention is a granulation process, using a small amount of water but no binder, that increases the bulk density and improves the flow properties of pimavanserin tartrate, enabling the manufacture of smaller, single-dose capsules (’185 Patent, col. 9:30-45).

Asserted Claims

The complaint asserts the ’185 Patent generally (Compl. ¶50). Independent claim 1 is representative.

Accused Features

The "Zydus 34 mg Generic Product" is accused of infringement (Compl. ¶50).

U.S. Patent No. 10,517,860, "Combination of pimavanserin and cytochrome P450 modulators", issued December 31, 2019

Technology Synopsis

This patent addresses a drug-drug interaction. It describes that when pimavanserin is co-administered with a strong inhibitor of the CYP3A4 enzyme, the patient's exposure to pimavanserin increases significantly (’860 Patent, col. 18:6-14; col. 29:1-15). The invention is a method for safely treating psychosis in such patients by administering a reduced dose of pimavanserin (e.g., 10 mg) to compensate for this metabolic interaction (’860 Patent, col. 31:45-55).

Asserted Claims

The complaint asserts the ’860 Patent generally (Compl. ¶61). Independent claim 1 is representative.

Accused Features

The "Zydus 10 mg Generic Product" is accused of infringement (Compl. ¶61).

U.S. Patent No. 10,646,480, "Formulations of pimavanserin", issued May 12, 2020

Technology Synopsis

Similar to the ’185 patent, this patent addresses the manufacturing challenges of pimavanserin due to its poor physical properties (’480 Patent, col. 1:53-61). The patented solution is a granulation process that improves bulk density and flow, allowing for the reliable manufacture of single-dose capsules containing a therapeutic quantity of the drug (’480 Patent, col. 9:30-45).

Asserted Claims

The complaint asserts the ’480 Patent generally (Compl. ¶50). Independent claim 1 is representative.

Accused Features

The "Zydus 34 mg Generic Product" is accused of infringement (Compl. ¶50).

III. The Accused Instrumentality

  • Product Identification: The accused instrumentalities are Defendants’ proposed generic drug products: "the Zydus 34 mg Generic Product" (subject of ANDA No. 214493) and "the Zydus 10 mg Generic Product" (subject of ANDA No. 214502) (Compl. ¶7).
  • Functionality and Market Context: The complaint alleges that these products are generic versions of Plaintiff's NUPLAZID® capsules and tablets (Compl. ¶¶21-22). The products contain pimavanserin as the active pharmaceutical ingredient (Compl. ¶¶36, 40). By filing ANDAs under the Hatch-Waxman Act, Defendants seek FDA approval to market these products as bioequivalent to NUPLAZID® for its approved uses prior to the expiration of the patents-in-suit (Compl. ¶¶35, 39). The complaint alleges that Zydus's proposed labels are the same or substantially the same as the FDA-approved labeling for NUPLAZID® (Compl. ¶¶36, 40). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide a detailed, element-by-element analysis of infringement for any of the asserted patents. Instead, it asserts infringement under 35 U.S.C. § 271(e)(2)(A), which defines the submission of an ANDA seeking approval to market a generic drug before the expiration of a patent as a statutory act of infringement (Compl. ¶¶50, 61). The substantive infringement analysis will depend on the confidential technical details of Defendants' ANDA submissions, which are not public.

  • Identified Points of Contention:
    • Scope Questions: A central question for the method-of-use patents (’740 Patent, ’860 Patent) will be whether the proposed product labels for the Zydus Generic Products instruct or encourage physicians and patients to use the products in a manner that falls within the scope of the asserted claims. For the ’860 Patent, this may involve whether the label directs a 10 mg dose for patients concurrently taking a CYP3A4 inhibitor.
    • Technical Questions: For the composition and formulation patents (’615 Patent, ’185 Patent, ’480 Patent), the dispute will center on whether the Zydus Generic Products, as formulated and described in the confidential ANDAs, possess the specific physical and chemical properties required by the claims. This includes questions such as: does the pimavanserin tartrate in the Zydus products have the specific crystalline structure claimed in the ’615 Patent, and are the granulated particles within the claimed ranges for bulk density and particle size distribution as required by the ’185 and ’480 patents?

V. Key Claim Terms for Construction

  • For the ’740 Patent:

    • The Term: "treating a neurodegenerative disease" (from Claim 17).
    • Context and Importance: The scope of this term will define the patented method. Practitioners may focus on whether "treating" requires halting or reversing the disease, or if it can be construed more broadly to include the management of symptoms, such as the psychosis that the invention is aimed at.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The patent's detailed description focuses on treating symptoms associated with NDs, such as psychosis and dyskinesia, which may support a construction that "treating" includes symptomatic relief (’740 Patent, col. 2:3-9).
      • Evidence for a Narrower Interpretation: A defendant could argue that the plain meaning of "treating a... disease" implies an effect on the underlying disease pathology itself, not just its symptoms.

  • For the ’615 Patent:

    • The Term: "crystalline form" (from Claim 1).
    • Context and Importance: This term's definition is critical, as infringement hinges on whether Zydus's product contains this exact solid state form of pimavanserin tartrate. The dispute will be a direct scientific comparison.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The claim language uses "about" when listing the d-values for the XRPD peaks, which suggests the peaks do not have to match with absolute precision, allowing for some experimental variability (’615 Patent, col. 51:40-45).
      • Evidence for a Narrower Interpretation: The patent explicitly defines Form C by a specific set of XRPD peaks and provides a corresponding figure (FIG. 4). This may support a narrow construction where any significant deviation from this pattern falls outside the claim scope.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that Defendants "actively and knowingly caused to be submitted, assisted with, participated in, contributed to, and/or directed the submission" of the ANDAs (Compl. ¶¶54, 65). This supports a claim for induced infringement under § 271(b). The infringement theories for the method-of-use patents (’740, ’860) will likely rely on inducement through the proposed product labeling.
  • Willful Infringement: The complaint alleges that Defendants were "aware of the existence of the patents-in-suit" and knew that filing their ANDAs constituted an act of infringement (Compl. ¶¶55, 67). This knowledge is based on the patents being listed in the FDA's Orange Book and the statutory requirement for Defendants to provide a Paragraph IV certification regarding those patents.

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

  • A core issue will be one of technical identity: will discovery reveal that the Zydus generic products, as described in the confidential ANDA submissions, contain pimavanserin tartrate with the exact crystalline structure, particle size, and bulk density characteristics required by the asserted claims of the ’615, ’185, and ’480 patents?
  • A key evidentiary question will be one of induced infringement: does the proposed product labeling for the Zydus 10 mg and 34 mg products instruct or encourage medical professionals to prescribe the drugs in a manner that directly reads on the methods claimed in the ’740 and ’860 patents, particularly concerning the treatment of specific neurodegenerative diseases and dose adjustments for patients on CYP450 modulators?
  • The case will also turn on patent validity: as indicated by their Paragraph IV certifications, Defendants will argue that the asserted patent claims are invalid (Compl. ¶¶38, 42). A central question will be whether Defendants can prove by clear and convincing evidence that the patented inventions were obvious or anticipated by the prior art at the time of their filing.