Intra Cellular Therapies Inc v. Hetero USA Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Intra-Cellular Therapies, Inc. (Delaware)
  • Defendant: Hetero USA, Inc. (Delaware/New Jersey); Hetero Labs Ltd. Unit-V (India); Hetero Labs Ltd. (India)
  • Plaintiff’s Counsel: Walsh Pizzi O'Reilly Falanga LLP; Williams & Connolly LLP
• Case Identification: 3:24-cv-04317, D.N.J., 03/28/2024
• Venue Allegations: Venue is alleged to be proper in the District of New Jersey based on Defendant Hetero USA, Inc. having its principal place of business in the state, and the other foreign defendants being subject to personal jurisdiction within the district.
• Core Dispute: Plaintiff alleges that Defendants' submission of an Abbreviated New Drug Application (ANDA) seeking to market a generic version of Plaintiff's CAPLYTA® (lumateperone) capsules infringes ten U.S. patents covering the drug's composition, formulation, and methods of use.
• Technical Context: The technology relates to pharmaceutical compositions and methods for treating central nervous system disorders, such as schizophrenia and bipolar depression, using the active ingredient lumateperone.
• Key Procedural History: This action arises under the Hatch-Waxman Act, triggered by a Notice Letter dated February 20, 2024, in which Defendants informed Plaintiff of their ANDA filing containing Paragraph IV certifications that the asserted patents are invalid, unenforceable, and/or not infringed. The complaint was filed within the statutory 45-day window.

Case Timeline

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

U.S. Reissue Patent No. RE48,839 - Methods and Compositions for Sleep Disorders and Other Disorders

The Invention Explained

• Problem Addressed: The patent background describes the need for treatments for disorders associated with the serotonin 5-HT2A receptor, such as anxiety, depression, psychosis, schizophrenia, and sleep disorders (RE ’839 Patent, col. 1:28-39).
• The Patented Solution: The invention claims a method for treating these disorders by administering a specific class of compounds (defined by Formula I) that selectively block the 5-HT2A receptor (RE ’839 Patent, Abstract; col. 10:45-53). This selective action is presented as the core therapeutic mechanism for the claimed methods (RE ’839 Patent, col. 10:66-67).
• Technical Importance: Targeting the 5-HT2A receptor was a key therapeutic strategy for treating a range of neuropsychiatric disorders by modulating serotonin pathways in the central nervous system (RE ’839 Patent, col. 1:28-39).

Key Claims at a Glance

• The complaint asserts independent claim 1 (Compl. ¶44).
• Claim 1 requires the following essential elements:
  • A method for treating one or more 5-HT2A-related disorders.
  • The method comprises administering a compound of a specific chemical structure (Formula I).
  • The compound is administered in a free or pharmaceutically acceptable salt form.
  • The administration is at a dose that "selectively blocks the 5-HT2A receptor."
• The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 8,648,077 - 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone Toluenesulfonic Acid Addition Salt and Salt Crystals

The Invention Explained

• Problem Addressed: The patent addresses the need for stable, solid forms of certain heterocycle fused gamma-carboline compounds, noting that as a free base, these compounds can be unstable and undesirable for pharmaceutical products (US 8,648,077 Patent, col. 1:59-62).
• The Patented Solution: The invention is a specific toluenesulfonic acid addition salt crystal of the lumateperone compound. This crystalline salt form is described as being especially stable and advantageous for pharmaceutical formulations (US 8,648,077 Patent, col. 2:23-40). The patent defines this specific crystalline form (termed "Crystal Form A") by its characteristic X-ray powder diffraction (XRPD) pattern (US 8,648,077 Patent, FIG. 7; col. 13:1-2).
• Technical Importance: Creating a stable, well-characterized crystalline form of an active pharmaceutical ingredient is a critical step in drug development, essential for ensuring product consistency, shelf-life, and reliable manufacturing (US 8,648,077 Patent, Abstract).

Key Claims at a Glance

• The complaint asserts independent claim 1 (Compl. ¶70).
• Claim 1 requires the following essential elements:
  • A toluenesulfonic acid addition salt crystal of the lumateperone chemical structure.
  • The salt crystal must exhibit an X-ray powder diffraction pattern with at least two peaks selected from a specific list of ten 2-theta values.
  • The XRPD data must be collected using a diffractometer with a copper anode and a nickel filter.
• The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 9,956,227 - Method for the Treatment of Residual Symptoms of Schizophrenia

• Technology Synopsis: The patent claims a method for treating the residual symptoms of schizophrenia, as defined by the Positive and Negative Syndrome Scale (PANSS). The method requires administering an effective amount of a compound of Formula I to a patient after they have already been treated for acute symptoms with an antipsychotic agent, targeting a later phase of the illness (Compl. ¶96). The complaint provides a chemical structure diagram representing the compound of Formula I as recited in claim 1 of the ’227 Patent (Compl. ¶96).
• Asserted Claims: Independent claim 1 is asserted (Compl. ¶96).
• Accused Features: The complaint alleges that Defendants' proposed product labeling will instruct for the use of its lumateperone product to treat residual symptoms of schizophrenia after initial treatment of acute symptoms, thereby inducing infringement (Compl. ¶97).

U.S. Patent No. 10,960,009 - Methods of Treating Schizophrenia and Depression

• Technology Synopsis: This patent claims a method for treating the negative symptoms of schizophrenia. The method requires administering a specific daily dose of a particular Formula I compound, between 40 mg and 60 mg, measured as the free base (Compl. ¶122). The complaint includes a visual of the compound of Formula I from claim 1 of the ’009 Patent (Compl. p. 23).
• Asserted Claims: Independent claim 1 is asserted (Compl. ¶122).
• Accused Features: The complaint alleges that Defendants' 42 mg dosage form of its lumateperone product falls within the claimed 40-60 mg range and that its proposed label will instruct use for treating negative symptoms of schizophrenia (Compl. ¶28, ¶123).

U.S. Patent No. 11,026,951 - Methods of Treating Bipolar Disorder

• Technology Synopsis: The patent claims a method for treating bipolar disorder I and/or II. The method comprises administering an effective amount of a specific Formula I compound, with the key negative limitation that the compound is "not used in combination with another antipsychotic agent," claiming a monotherapy use (Compl. ¶148). The complaint supplies a diagram of the claimed compound (Compl. p. 27).
• Asserted Claims: Independent claim 1 is asserted (Compl. ¶148).
• Accused Features: The complaint alleges that Defendants' proposed label will instruct the use of their lumateperone product as a standalone therapy for bipolar disorder, without combination with other antipsychotics (Compl. ¶149).

U.S. Patent No. 10,695,345 - Pharmaceutical Capsule Compositions Comprising Lumateperone Mono-Tosylate

• Technology Synopsis: The patent claims a physical composition: a pharmaceutical capsule for oral administration. The capsule must comprise lumateperone mono-tosylate in solid crystal form, blended with a specific list of excipients (mannitol, croscarmellose sodium, talc, and magnesium stearate) within defined weight percentage ranges (Compl. ¶174). A chemical structure of lumateperone is depicted in the complaint's recitation of claim 1 (Compl. p. 31).
• Asserted Claims: Independent claim 1 is asserted (Compl. ¶174).
• Accused Features: The complaint alleges that Defendants' ANDA product is a pharmaceutical capsule that contains the same active ingredient and the same blend of excipients in the same specified amounts as recited in the claim (Compl. ¶175).

U.S. Patent No. 11,052,084 - Pharmaceutical Capsule Compositions Comprising Lumateperone Mono-Tosylate

• Technology Synopsis: This patent claims a pharmaceutical capsule composition similar to the '345 patent, specifying a blend of lumateperone mono-tosylate with certain excipients. It adds a dosage limitation, requiring the capsule to comprise the active ingredient in an amount equivalent to 0.01 to 30 mg of lumateperone free base (Compl. ¶200).
• Asserted Claims: Independent claim 1 is asserted (Compl. ¶200).
• Accused Features: The complaint alleges that Defendants' 10.5 mg and 21 mg capsule products meet the claimed compositional elements and fall within the claimed dosage range (Compl. ¶28, ¶201).

U.S. Patent No. 11,690,842 - Pharmaceutical Capsule Compositions Comprising Lumateperone Mono-Tosylate

• Technology Synopsis: This patent claims a pharmaceutical capsule composition with specific excipient ranges, similar to the '345 and '084 patents. It further adds a functional limitation related to the capsule's performance, requiring that it dissolves in 500 mL of 0.1N aqueous hydrochloric acid to an extent of at least 85% after 15 minutes (Compl. ¶226).
• Asserted Claims: Independent claim 1 is asserted (Compl. ¶226).
• Accused Features: The complaint alleges that Defendants' ANDA product meets the claimed compositional requirements and possesses the claimed dissolution profile, which is a required characteristic for establishing bioequivalence with the branded product (Compl. ¶227).

U.S. Patent No. 11,806,348 - Methods of Treatment Using Pharmaceutical Capsule Compositions Comprising Lumateperone Mono-Tosylate

• Technology Synopsis: The patent claims a method of treating disorders mediated by the 5-HT2A receptor, SERT, and/or dopamine receptors. The method requires administering a specific pharmaceutical capsule that contains lumateperone mono-tosylate in a defined dose range (0.01 to 30 mg or 35 to 45 mg) and blended with specified excipients (Compl. ¶252).
• Asserted Claims: Independent claim 1 is asserted (Compl. ¶252).
• Accused Features: The complaint alleges Defendants' proposed labeling will direct administration of their capsule products (including 10.5 mg, 21 mg, and 42 mg doses) for the claimed indications, thereby infringing the method claim (Compl. ¶253).

U.S. Patent No. 11,753,419 - [4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)butyl] [4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)butan-1-one] Dimer

• Technology Synopsis: This patent claims a specific chemical compound, a dimer of the lumateperone structure, identified as Formula I in the patent's claim 1. This compound may be present as an impurity in the manufacturing of lumateperone (Compl. ¶278). The complaint includes a figure showing the structure of this dimer compound (Compl. ¶278).
• Asserted Claims: Independent claim 1 is asserted (Compl. ¶278).
• Accused Features: The complaint alleges that Defendants' ANDA product itself contains the claimed Formula I compound, in free base or pharmaceutically acceptable salt form (Compl. ¶279).

III. The Accused Instrumentality

Product Identification

• The accused instrumentality is "Hetero's ANDA Product," which is a generic version of Plaintiff's CAPLYTA® drug product (Compl. ¶1).

Functionality and Market Context

• The accused product contains the active ingredient lumateperone and is formulated as capsules for oral administration in dosages of 10.5 mg, 21 mg, and 42 mg (Compl. ¶2). The product is intended for the treatment of schizophrenia and bipolar depression, the same indications for which CAPLYTA® is approved (Compl. ¶27). The complaint alleges that Hetero's ANDA filing was for the purpose of obtaining FDA approval to commercially manufacture and sell this generic product in the United States prior to the expiration of the patents-in-suit (Compl. ¶30). The filing of the ANDA itself constitutes the act of infringement under the Hatch-Waxman Act (Compl. ¶47, ¶73). The complaint includes a diagram of the chemical structure of lumateperone as part of its recitation of claim 1 of the RE '839 patent (Compl. ¶44).

IV. Analysis of Infringement Allegations

RE48,839 Infringement Allegations

• Identified Points of Contention:
  • Scope Questions: A central issue may be the construction of the term "selectively blocks the 5-HT2A receptor." The dispute could focus on the degree of selectivity required, particularly since lumateperone is known to have activity at other receptors, such as dopamine and SERT.
  • Technical Questions: A key evidentiary question will be whether the dosages described in Defendants' proposed label result in a biological effect that can be characterized as "selective" blockage of the 5-HT2A receptor, as opposed to a multi-receptor mechanism of action that falls outside the claim's scope.

8,648,077 Infringement Allegations

• Identified Points of Contention:
  • Technical Questions: The primary dispute will likely be factual: what is the precise crystalline form of lumateperone tosylate in the accused ANDA product? Defendants may contend that their product contains a different, non-infringing polymorph, an amorphous form, or a form that otherwise does not exhibit the claimed XRPD pattern.
  • Scope Questions: While the claim requires "at least two peaks" from a list, which may seem broad, the dispute will likely center on whether the accused product's crystal form is the same as the one characterized in the patent, raising the question of whether matching a small subset of peaks is sufficient to prove infringement if the overall pattern differs.

V. Key Claim Terms for Construction

• The Term: "selectively blocks the 5-HT2A receptor" (from RE ’839 Patent, Claim 1)

• Context and Importance: This term defines the functional mechanism of the claimed method. The definition of "selectively" is critical to the scope of the claim. Practitioners may focus on this term because lumateperone's known activity at other receptors (e.g., dopamine, SERT) raises the question of how much greater its effect on the 5-HT2A receptor must be to qualify as "selective."

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The patent does not provide an explicit numerical definition for "selectively," which may support an argument that the term should be given its plain and ordinary meaning as understood by a person of ordinary skill in the art, potentially encompassing any preferential activity at the 5-HT2A receptor.
  • Evidence for a Narrower Interpretation: The patent's background describes the compound class as serotonin receptor, dopamine receptor, and SERT ligands (RE ’839 Patent, col. 1:28-35). This context could be used to argue that "selectively" implies a clinically meaningful distinction in activity between the 5-HT2A receptor and these other known targets at the claimed "dose."

• The Term: "exhibits an X-ray powder diffraction pattern comprising at least two peaks having 2-theta values selected from the group consisting of..." (from '077 Patent, Claim 1)

• Context and Importance: This term defines the specific crystalline polymorph of the lumateperone tosylate salt. Proving infringement requires showing that the accused product contains a crystal that produces this specific analytical signature. The dispute will likely focus on whether minor variations in peak position or the presence of other peaks can defeat a claim of literal infringement.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The claim language only requires "at least two peaks," which on its face suggests that matching any two peaks from the list is sufficient for infringement, regardless of other differences in the full XRPD pattern.
  • Evidence for a Narrower Interpretation: The specification consistently refers to a specific crystalline form, "Crystal Form A," and provides a full diffractogram (US 8,648,077 Patent, FIG. 7) and a detailed list of peaks (US 8,648,077 Patent, Table 4). This could support an argument that the claim, read in light of the specification, is intended to cover only Crystal Form A, and infringement requires more than a coincidental match of two peaks.

VI. Other Allegations

• Indirect Infringement: The complaint alleges active inducement of infringement for the method claims, asserting that Defendants' proposed product labeling will instruct physicians and patients to administer the accused product in a manner that directly infringes (Compl. ¶51, ¶77, ¶103). The complaint also alleges contributory infringement, stating that the accused product is not a staple article of commerce and is especially made or adapted for an infringing use (Compl. ¶52, ¶78, ¶104).
• Willful Infringement: The complaint alleges that Defendants have acted with full knowledge of the patents-in-suit. This allegation is based on Defendants' Paragraph IV certification, which demonstrates awareness of the patents listed in the FDA's Orange Book for CAPLYTA® (Compl. ¶55, ¶81, ¶107).

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

• A core issue will be one of induced infringement: For the multiple method-of-use patents, will the specific language in Defendants' proposed product label be found to instruct or encourage physicians and patients to perform each and every step of the asserted claims, thereby creating liability for indirect infringement?
• A key evidentiary question will be one of physical and compositional identity: For the patents claiming specific crystalline forms and formulations, does the accused generic product in fact contain the precise polymorph defined by the claimed X-ray diffraction peaks and the exact blend of excipients within the claimed weight percentage ranges, or have Defendants designed a non-infringing alternative?
• A central question for the '419 patent will be one of presence and legal significance: Does the accused product contain the claimed dimer compound, which may be an impurity, and if so, does the mere, potentially unintended, presence of this compound in a drug product constitute infringement of a composition of matter claim?