DCT

1:20-cv-00985

Acadia Pharma Inc v. Aurobindo Pharma Ltd

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Key Events
Amended Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:20-cv-00985, D. Del., 06/02/2022
  • Venue Allegations: Plaintiff alleges venue is proper in the District of Delaware because Defendants market, distribute, and sell generic pharmaceutical products in the state, have committed acts of patent infringement that will cause foreseeable harm to Plaintiff (a Delaware corporation), and have previously been sued in the district without challenging jurisdiction or venue.
  • Core Dispute: Plaintiff alleges that Defendants' filing of Abbreviated New Drug Applications (ANDAs) with the FDA for generic versions of Plaintiff’s drug NUPLAZID® constitutes an act of infringement of seven U.S. patents relating to the active ingredient pimavanserin, its formulations, and its methods of use.
  • Technical Context: The technology pertains to pimavanserin, a selective serotonin inverse agonist used for treating hallucinations and delusions associated with Parkinson's disease psychosis.
  • Key Procedural History: The complaint notes that on May 18, 2022, the parties stipulated that under the Court’s current claim construction of certain dosage-related terms, Defendants’ 34 mg generic product does not infringe U.S. Patent Nos. 10,449,185, 10,646,480, and 10,849,891. Plaintiff states it includes these patents in the complaint solely to preserve its right to appeal the Court's claim construction.

Case Timeline

Date Event
2004-01-16 Priority Date for U.S. Patent No. 7,601,740
2006-05-03 Priority Date for U.S. Patent No. 7,659,285
2009-10-13 U.S. Patent No. 7,601,740 Issued
2010-02-09 U.S. Patent No. 7,659,285 Issued
2016-03-25 Priority Date for U.S. Patent Nos. 10,517,860 & 10,953,000
2017-08-30 Priority Date for U.S. Patent Nos. 10,449,185, 10,646,480 & 10,849,891
2019-10-22 U.S. Patent No. 10,449,185 Issued
2019-12-31 U.S. Patent No. 10,517,860 Issued
2020-05-12 U.S. Patent No. 10,646,480 Issued
2020-06-22 ACADIA receives notice of Zydus' ANDA filings
2020-12-01 U.S. Patent No. 10,849,891 Issued
2021-02-12 ACADIA receives second notice letter for ANDA No. 214493
2021-03-23 U.S. Patent No. 10,953,000 Issued
2021-07-19 ACADIA receives second notice letter for ANDA No. 214502
2022-05-18 Parties enter Non-infringement Stipulation regarding '185, '480, and '891 patents
2022-06-02 Third Amended Complaint Filed

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) such as Parkinson's disease often suffer from neuropsychiatric symptoms like psychosis, but available antipsychotic treatments are poorly tolerated and can worsen motor function (e.g., dyskinesias) due to their interaction with dopamine receptors (’740 Patent, col. 2:1-14).
  • The Patented Solution: The invention is a method for treating psychosis in patients by administering a compound, such as pimavanserin, that acts as a "selective inverse agonist" for the serotonin 2A receptor (’740 Patent, col. 3:4-9; col. 4:1-15). This mechanism aims to reduce psychotic symptoms without the motor side effects associated with dopamine receptor antagonism, thereby offering a better-tolerated therapy for this specific patient population (’740 Patent, Abstract).
  • Technical Importance: This approach provided a therapeutic pathway for treating psychosis in ND patients that was decoupled from the dopamine system, which is central to the motor symptoms of the underlying disease (’740 Patent, col. 14:8-14).

Key Claims at a Glance

  • The complaint implicitly asserts a range of claims, including dependent claims 2-10, 18-21, and 24-25, by alleging Zydus's notice letters failed to provide a basis for invalidity (Compl. ¶¶59, 69). The parent independent claim for these is Claim 1.
  • Independent Claim 1 of the ’740 Patent includes the following essential elements:
    • A method of treating Parkinson's Disease psychosis in a patient,
    • comprising administrating to a patient having Parkinson's Disease a therapeutically effective amount of N-(1-methylpiperidin-4-yl)-N-(4-flourophenylmethyl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide [pimavanserin],
    • or a pharmaceutically acceptable salt thereof.
  • The complaint does not explicitly reserve the right to assert other dependent claims but references a range of them.

U.S. Patent No. 7,659,285 - "Selective Serotonin 2A/2C Receptor Inverse Agonists as Therapeutics for Neurodegenerative Diseases," Issued February 9, 2010

The Invention Explained

  • Problem Addressed: The patent addresses the need for treatments for neuropsychiatric diseases, such as schizophrenia and related psychoses, which are associated with the dysfunction of monoamine receptors like the serotonin receptor (’285 Patent, col. 6:35-43). Existing treatments often have a broad range of side effects due to their lack of receptor selectivity (’285 Patent, col. 13:45-51).
  • The Patented Solution: The invention provides a method of treating neuropsychiatric diseases by administering a compound, pimavanserin, that is a selective inverse agonist for the 5-HT2A receptor (’285 Patent, col. 18:8-23). This selectivity allows the compound to provide a therapeutic effect while avoiding the side effects caused by interaction with other receptors, particularly dopamine receptors (’285 Patent, Abstract; col. 14:1-14).
  • Technical Importance: The invention claims a method of use for a compound with a specific pharmacological profile—inverse agonism at a selective serotonin receptor—to treat a broad class of neuropsychiatric diseases beyond Parkinson's disease psychosis (’285 Patent, col. 11:1-5).

Key Claims at a Glance

  • The complaint implicitly asserts dependent claims 3-5, 10, and 11, which depend from independent claim 1 (Compl. ¶¶59, 69).
  • Independent Claim 1 of the ’285 Patent includes the following essential elements:
    • A method for treating a neuropsychiatric disease,
    • comprising: identifying a patient suffering from a neuropsychiatric disease; and
    • administering to the patient an effective amount of an inverse agonist selective for a serotonin receptor.
  • The complaint does not explicitly reserve the right to assert other dependent claims.

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

  • Patent Identification: 10,449,185, "Formulations of pimavanserin," Issued October 22, 2019 (Compl. ¶30).
  • Technology Synopsis: The patent addresses the manufacturing challenges of pimavanserin, such as low bulk density and poor flowability, which make it difficult to produce small, single-unit oral doses (’185 Patent, col. 1:53-62). The solution is a specific granulation process, using a controlled amount of water without a binder, to create a granulated form of pimavanserin with improved physical properties suitable for encapsulation in small capsules (’185 Patent, col. 10:29-45).
  • Asserted Claims: The complaint mentions claims of the '185 patent generally (Compl. ¶59). Claim 1 is independent.
  • Accused Features: The Zydus 34 mg Generic Product, which is the subject of ANDA No. 214493 (Compl. ¶57).

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

  • Patent Identification: 10,517,860, "Combination of pimavanserin and cytochrome P450 modulators," Issued December 31, 2019 (Compl. ¶32).
  • Technology Synopsis: The patent addresses the need for adjusted dosing of pimavanserin when a patient is concurrently taking a drug that inhibits cytochrome P450 (CYP450) enzymes, which are responsible for metabolizing pimavanserin (’860 Patent, col. 1:47-51; col. 2:6-14). The solution is a method of treatment where the dose of pimavanserin is reduced by at least 20% when co-administered with a CYP450 inhibitor to avoid potential toxicity from increased drug exposure (’860 Patent, Abstract; col. 2:1-5).
  • Asserted Claims: The complaint mentions claims of the '860 patent generally (Compl. ¶¶67, 70). Claim 1 is independent.
  • Accused Features: The Zydus 10 mg Generic Product, which is the subject of ANDA No. 214502 (Compl. ¶67).

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

  • Patent Identification: 10,646,480, "Formulations of pimavanserin," Issued May 12, 2020 (Compl. ¶34).
  • Technology Synopsis: Similar to the '185 patent, this patent discloses specific pharmaceutical capsules containing granulated pimavanserin tartrate with particular bulk density and particle size distribution properties (’480 Patent, Abstract). These formulations are designed to enable the reliable manufacturing of small, single-dose capsules for patient administration (’480 Patent, col. 1:40-52).
  • Asserted Claims: The complaint mentions claims of the '480 patent generally (Compl. ¶59). Claim 1 is independent.
  • Accused Features: The Zydus 34 mg Generic Product, which is the subject of ANDA No. 214493 (Compl. ¶57).

U.S. Patent No. 10,849,891 - "Formulations of Pimavanserin," Issued December 1, 2020

  • Patent Identification: 10,849,891, "Formulations of Pimavanserin," Issued December 1, 2020 (Compl. ¶36).
  • Technology Synopsis: Similar to the '185 and '480 patents, this patent discloses capsules containing granulated pimavanserin and specific excipients, characterized by particular physical properties like bulk density (’891 Patent, Abstract). The invention aims to solve manufacturing problems associated with pimavanserin to facilitate the creation of a single daily therapeutic dose in a small capsule (’891 Patent, col. 1:53-62).
  • Asserted Claims: The complaint mentions claims of the '891 patent generally (Compl. ¶59). Claim 1 is independent.
  • Accused Features: The Zydus 34 mg Generic Product, which is the subject of ANDA No. 214493 (Compl. ¶57).

U.S. Patent No. 10,953,000 - "Combination of pimavanserin and cytochrome P450 modulators," Issued March 23, 2021

  • Patent Identification: 10,953,000, "Combination of pimavanserin and cytochrome P450 modulators," Issued March 23, 2021 (Compl. ¶38).
  • Technology Synopsis: Similar to the '860 patent, this patent discloses a method for treating psychosis by administering a reduced dose of pimavanserin (specifically 10 mg) to a patient who is concurrently being treated with a strong CYP3A4 inhibitor (’000 Patent, Abstract). This dose reduction is intended to compensate for the inhibitor's effect on pimavanserin metabolism (’000 Patent, col. 31:35-43).
  • Asserted Claims: The complaint mentions claims of the '000 patent generally (Compl. ¶70). Claim 1 is independent.
  • Accused Features: The Zydus 10 mg Generic Product, which is the subject of ANDA No. 214502 (Compl. ¶67).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are the "Zydus 34 mg Generic Product" and the "Zydus 10 mg Generic Product," which are the subjects of Abbreviated New Drug Applications (ANDA) No. 214493 and No. 214502, respectively (Compl. ¶7).

Functionality and Market Context

The complaint alleges that these generic products are pimavanserin capsules (34 mg) and tablets (10 mg) intended as generic equivalents to Plaintiff’s branded drug, NUPLAZID® (Compl. ¶7). The filing of the ANDAs certifies that the generic products have the same active ingredient and same or substantially the same proposed labeling as NUPLAZID®, which is approved for treating hallucinations and delusions associated with Parkinson’s disease psychosis (Compl. ¶¶24, 43, 48). The alleged act of infringement is the submission of these ANDAs to the FDA seeking approval to manufacture, use, and sell the products in the United States before the expiration of the patents-in-suit (Compl. ¶¶42, 47, 57, 67). Zydus is alleged to be a major generic pharmaceutical corporation intending to commercialize these products throughout the United States (Compl. ¶¶7, 16).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint alleges that the filing of the ANDAs under 21 U.S.C. § 355(j) is a technical act of infringement under 35 U.S.C. § 271(e)(2)(A) (Compl. ¶¶57, 67). For the method of use patents, infringement is predicated on the allegation that the proposed labeling for the Zydus Generic Products will instruct and encourage physicians and patients to use the drug in a manner covered by the patent claims (Compl. ¶¶64, 72). For the formulation patents, infringement is based on the allegation that the generic products themselves will contain the claimed formulations (Compl. ¶57).

U.S. Patent No. 7,601,740 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of treating Parkinson's Disease psychosis in a patient, The Zydus Generic Products, via their proposed labeling, will be indicated for treating hallucinations and delusions associated with Parkinson's disease psychosis, which is the same indication as NUPLAZID®. ¶¶43, 48, 57, 67 col. 2:1-5
comprising administrating to a patient having Parkinson's Disease a therapeutically effective amount of N-(1-methylpiperidin-4-yl)-N-(4-flourophenylmethyl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide or a pharmaceutically acceptable salt thereof. The Zydus Generic Products contain pimavanserin tartrate, which is a pharmaceutically acceptable salt of the claimed compound, and the proposed labeling will instruct its administration to patients. ¶¶7, 43, 48 col. 3:9-15

U.S. Patent No. 7,659,285 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for treating a neuropsychiatric disease, The Zydus Generic Products, via their proposed labeling, will be indicated for treating a neuropsychiatric disease (hallucinations and delusions associated with Parkinson's disease psychosis). ¶¶43, 48, 57, 67 col. 6:35-40
comprising: identifying a patient suffering from a neuropsychiatric disease; and administering to the patient an effective amount of an inverse agonist selective for a serotonin receptor. The proposed labels for the Zydus Generic Products will instruct physicians to identify such patients and administer the drug, which contains pimavanserin, an inverse agonist selective for a serotonin receptor. ¶¶43, 48, 57, 67 col. 18:8-14
  • Identified Points of Contention:
    • Scope Questions: A central issue for the method patents ('740, '285, '860, '000) will be one of induced infringement: does the specific language in Zydus’s proposed product labels actively instruct or encourage medical professionals and patients to perform all steps of the claimed methods?
    • Technical Questions: For the formulation patents ('185, '480, '891), a primary question, highlighted by the parties' prior stipulation, is one of claim construction: does Zydus’s 34 mg formulation meet the specific quantitative limitations of the claims, such as "40 mg granulated pimavanserin tartrate," as construed by the court? The case may turn on whether the appellate court upholds or reverses the district court's construction of these terms (Compl. ¶9).

V. Key Claim Terms for Construction

The complaint does not provide sufficient detail for analysis of specific claim terms that are likely to be disputed, other than the dosage-related terms in the formulation patents that were the subject of the Non-infringement Stipulation. However, based on the technology, practitioners may focus on the following terms from the method of use patents:

  • The Term: "inverse agonist" (from Claim 1 of '740 and '285 Patents)
  • Context and Importance: This term defines the specific pharmacological mechanism of action required by the claims. Its construction is critical because if Zydus could argue that pimavanserin does not meet the technical definition of an "inverse agonist" (as opposed to a "neutral antagonist," for example), it could present a non-infringement defense.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification provides a general definition: "An 'inverse agonist' is defined as a compound, which reduces, or suppresses the basal activity of a receptor, such that the compound is not technically an antagonist but, rather, is an agonist with negative intrinsic activity" ('285 Patent, col. 4:33-37).
    • Evidence for a Narrower Interpretation: The specification distinguishes an inverse agonist from a neutral antagonist, which "has no effect on constitutive receptor activity" ('285 Patent, col. 7:47-50). A defendant could argue this distinction requires a specific, measurable level of reduction in basal activity that its product does not achieve or that is not proven for pimavanserin.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that should Zydus commercially launch its products, it would induce infringement under 35 U.S.C. § 271(b) (Compl. ¶¶64, 72). The basis for this allegation is that Zydus’s proposed product labeling will instruct medical professionals and patients to administer the generic drugs for indications and in a manner that is covered by the asserted method claims (Compl. ¶¶43, 48).
  • Willful Infringement: The complaint alleges that Zydus was aware of the patents-in-suit and knew that filing its ANDAs constituted an act of infringement (Compl. ¶¶62, 73). It further alleges that Zydus filed its ANDAs "without adequate justification for asserting that the patents-in-suit are invalid, unenforceable, and/or not infringed" (Compl. ¶¶63, 74).

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

  1. A core issue will be one of claim construction: For the three formulation patents subject to the non-infringement stipulation ('185, '480, '891), the viability of the infringement claim depends entirely on whether Plaintiff can successfully appeal and overturn the district court's construction of key dosage and formulation terms.
  2. A second central question will be one of induced infringement: For the four asserted method-of-use patents ('740, '285, '860, '000), the dispute will likely focus on whether the specific language of Zydus's proposed product labels meets the legal standard for encouraging, recommending, or promoting an infringing use by physicians and patients.
  3. A final key question will be one of validity: While not detailed in the complaint, Zydus’s ANDA certifications assert that the patents-in-suit are invalid (Compl. ¶¶45, 50). The case will therefore also depend on whether Zydus can successfully prove by clear and convincing evidence that the asserted claims are invalid under grounds such as anticipation or obviousness.