Intra Cellular Therapies Inc v. DR Reddys Laboratories Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Intra-Cellular Therapies, Inc. (Delaware)
  • Defendant: Dr. Reddy's Laboratories Inc. (New Jersey) and Dr. Reddy's Laboratories Ltd. (India)
  • Plaintiff’s Counsel: Walsh Pizzi O'Reilly Falanga LLP; Williams & Connolly LLP
• Case Identification: 3:24-cv-04314, D.N.J., 03/28/2024
• Venue Allegations: Venue is alleged to be proper in the District of New Jersey as Defendant Dr. Reddy's Laboratories Inc. is a New Jersey corporation with its principal place of business in the state.
• Core Dispute: Plaintiff alleges that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market a generic version of CAPLYTA® (lumateperone) capsules constitutes an act of infringement of sixteen U.S. patents covering the compound, specific crystalline forms, pharmaceutical compositions, and methods of use.
• Technical Context: The technology relates to lumateperone, a compound used for treating neuropsychiatric conditions such as schizophrenia and bipolar depression, and its formulation into oral dosage forms.
• Key Procedural History: The action was initiated under the Hatch-Waxman Act following a Notice Letter dated February 16, 2024, in which Defendants notified Plaintiff of the submission of ANDA No. 219229 to the FDA, containing Paragraph IV certifications alleging the patents-in-suit are invalid, unenforceable, and/or not infringed.

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"

• Patent Identification: U.S. Reissue Patent No. RE48,839, "Methods and Compositions for Sleep Disorders and Other Disorders," issued December 7, 2021 (Compl. ¶33).

The Invention Explained

• Problem Addressed: The patent family addresses the significant side effects associated with both typical and atypical antipsychotic agents, such as movement disorders, bone marrow suppression, and weight gain, which can limit their utility and patient compliance (US10117867B2, col. 1:47-2:16). A further problem is the difficulty in treating patients who suffer from both psychosis and depression (US 10,117,867 B2, col. 2:17-26).
• The Patented Solution: The invention claims methods of treatment using a specific class of compounds, substituted heterocycle fused gamma-carbolines, which are described as possessing a unique pharmacological profile that includes high affinity for serotonin 5-HT2A receptors (US 10,117,867 B2, col. 3:11-17). The RE '839 Patent claims a method of using these compounds in a dose that "selectively blocks the 5-HT2A receptor," which is presented as a way to treat certain disorders while avoiding side effects associated with other receptor pathways, such as the dopamine D₂ pathway (RE '839 Patent, claim 1; US 10,117,867 B2, col. 3:1-9).
• Technical Importance: This therapeutic approach suggests a way to achieve antipsychotic or other neuropsychiatric effects with an improved side-effect profile by targeting a specific serotonin receptor pathway with high selectivity (US 10,117,867 B2, col. 3:63-4:4).

Key Claims at a Glance

• The complaint asserts independent claim 1 (Compl. ¶41).
• Essential elements of Claim 1:
  • A method for the treatment of one or more 5-HT2A-related disorders;
  • Comprising administering to a patient in need thereof a Compound of Formula I, which has a specific chemical structure;
  • Wherein the compound is administered in a dose which selectively blocks the 5-HT2A receptor.

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U.S. Patent No. 9,168,258 - "Methods and Compositions for Sleep Disorders and Other Disorders"

• Patent Identification: U.S. Patent No. 9,168,258, "Methods and Compositions for Sleep Disorders and Other Disorders," issued October 27, 2015 (Compl. ¶59).

The Invention Explained

• Problem Addressed: As described for the RE '839 Patent, the technology addresses the need for treatments with better side-effect profiles than existing antipsychotics, particularly effects mediated by the dopamine D₂ receptor (US 10,117,867 B2, col. 1:47-2:16).
• The Patented Solution: The invention is a pharmaceutical composition, rather than a method. It claims a low-dose oral formulation ("10 mg or less") of the Formula I compound that is sufficient to block the 5-HT2A receptor but "either does not block, or minimally blocks the dopamine D2 receptor" ('258 Patent, claim 1; Compl. ¶67). This composition is intended to provide therapeutic benefits for conditions like sleep disorders without the dopamine-related side effects seen with higher doses or other drugs (US 10,117,867 B2, col. 3:1-9).
• Technical Importance: The patent carves out a specific low-dose composition intended to occupy a therapeutic window where desired 5-HT2A effects are achieved without engaging undesired dopamine D2 receptor pathways, thereby improving the drug's safety profile for certain indications (US 10,117,867 B2, col. 3:1-9, col. 3:23-28).

Key Claims at a Glance

• The complaint asserts independent claim 1 (Compl. ¶67).
• Essential elements of Claim 1:
  • A pharmaceutical composition in oral unit dose form;
  • Comprising an amount of 10 mg or less of a Compound of Formula I (calculated as the free base);
  • In combination or association with a pharmaceutically acceptable diluent or carrier;
  • Wherein the amount of the Compound is sufficient to block the 5-HT2A receptor; and
  • Wherein the amount of the Compound either does not block, or minimally blocks the dopamine D2 receptor.

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Multi-Patent Capsules

• Patent Identification: U.S. Patent No. 9,616,061, "Methods and Compositions for Sleep Disorders and Other Disorders," issued April 11, 2017 (Compl. ¶85).

• Technology Synopsis: The patent claims a pharmaceutical composition in an oral unit dose form. The invention is directed to a specific dosage range of the Formula I compound (0.1-20 mg), calculated as the free base ('061 Patent, claim 1).

• Asserted Claims: Claim 1 (Compl. ¶93).

• Accused Features: DRL's ANDA Product is alleged to be a pharmaceutical composition containing lumateperone in an amount between 0.1-20 mg (Compl. ¶94).

• Patent Identification: U.S. Patent No. 10,117,867, "Methods and Compositions for Sleep Disorders and Other Disorders," issued November 6, 2018 (Compl. ¶111).

• Technology Synopsis: The patent claims a method for treating bipolar depression. The method comprises administering a Compound of Formula I to a patient in need thereof ('867 Patent, claim 1).

• Asserted Claims: Claim 1 (Compl. ¶119).

• Accused Features: The use of DRL's ANDA Product as directed by its proposed label is alleged to involve administering lumateperone for the treatment of bipolar depression (Compl. ¶120).

• Patent Identification: 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," issued February 11, 2014 (Compl. ¶137).

• Technology Synopsis: This patent claims a specific crystalline form of a toluenesulfonic acid addition salt of lumateperone. The crystal is defined by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks at specified 2-theta values ('077 Patent, claim 1).

• Asserted Claims: Claim 1 (Compl. ¶145).

• Accused Features: DRL's ANDA Product is alleged to contain the claimed crystalline form of the lumateperone salt (Compl. ¶146).

• Patent Identification: U.S. Patent No. 9,199,995, "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," issued December 1, 2015 (Compl. ¶163).

• Technology Synopsis: This patent claims a method for modulating 5-hydroxytryptamine 2A receptor activity. The method involves administering a specific toluenesulfonic acid salt crystal of lumateperone, defined by its XRPD pattern ('995 Patent, claim 2).

• Asserted Claims: Claim 2 (Compl. ¶171).

• Accused Features: The use of DRL's ANDA Product is alleged to involve administering the claimed salt crystal to modulate 5-hydroxytryptamine 2A receptor activity (Compl. ¶172).

• Patent Identification: U.S. Reissue Patent No. RE48,825, "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 Salt Crystal Forms," issued November 23, 2021 (Compl. ¶189).

• Technology Synopsis: This reissue patent claims a specific toluenesulfonic acid addition salt crystal form of lumateperone. The crystal form is defined by an XRPD pattern with at least two peaks selected from a specified group of 2-theta values (RE '825 Patent, claim 1).

• Asserted Claims: Claim 1 (Compl. ¶197).

• Accused Features: DRL's ANDA Product is alleged to contain the claimed crystalline form of the lumateperone salt (Compl. ¶198).

• Patent Identification: U.S. Patent No. 10,464,938, "Pharmaceutical Compositions Comprising ((6bR,10aS)-1-(4-fluorophenyl)-4-(3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)butan-1-one or Pharmaceutically Acceptable Salts Thereof," issued November 5, 2019 (Compl. ¶215).

• Technology Synopsis: The patent claims a pharmaceutical composition comprising toluenesulfonic acid and a specific compound, Formula 2J, which corresponds to lumateperone ('938 Patent, claim 1).

• Asserted Claims: Claim 1 (Compl. ¶223).

• Accused Features: DRL's ANDA Product is alleged to be a pharmaceutical composition comprising toluenesulfonic acid and lumateperone (Compl. ¶224).

• Patent Identification: U.S. Patent No. 9,956,227, "Method for the Treatment of Residual Symptoms of Schizophrenia," issued May 1, 2018 (Compl. ¶241).

• Technology Synopsis: This patent claims a method for treating residual symptoms of schizophrenia. The method involves administering a compound of Formula I after treatment of acute symptoms, wherein the patient shows significant improvement on a specific clinical scale (Prosocial PANSS Factor) ('227 Patent, claim 1).

• Asserted Claims: Claim 1 (Compl. ¶249).

• Accused Features: The use of DRL's ANDA Product according to its proposed label is alleged to involve treating residual symptoms of schizophrenia as claimed (Compl. ¶250).

• Patent Identification: U.S. Patent No. 10,960,009, "Methods of Treating Schizophrenia and Depression," issued March 30, 2021 (Compl. ¶267).

• Technology Synopsis: This patent claims a method for treating the negative symptoms of schizophrenia. The method requires administering a specific daily dose (40 mg to 60 mg) of a Compound of Formula I ('009 Patent, claim 1).

• Asserted Claims: Claim 1 (Compl. ¶275).

• Accused Features: The use of DRL's ANDA Product according to its proposed label is alleged to involve administering a 40 mg to 60 mg daily dose of lumateperone for treating negative symptoms of schizophrenia (Compl. ¶276).

• Patent Identification: U.S. Patent No. 11,026,951, "Methods of Treating Bipolar Disorder," issued June 8, 2021 (Compl. ¶293).

• Technology Synopsis: The patent claims a method for treating bipolar disorder I and/or II. The method comprises administering a Compound of Formula I as a monotherapy, not in combination with another antipsychotic agent ('951 Patent, claim 1).

• Asserted Claims: Claim 1 (Compl. ¶301).

• Accused Features: The use of DRL's ANDA Product according to its proposed label is alleged to involve administering lumateperone as a monotherapy for bipolar disorder (Compl. ¶302).

• Patent Identification: U.S. Patent No. 10,695,345, "Pharmaceutical Capsule Compositions Comprising Lumateperone Mono-Tosylate," issued June 30, 2020 (Compl. ¶319).

• Technology Synopsis: This patent claims a pharmaceutical capsule for oral administration comprising lumateperone mono-tosylate in solid crystal form. The claim requires a specific blend of excipients within defined weight percentage ranges ('345 Patent, claim 1).

• Asserted Claims: Claim 1 (Compl. ¶327).

• Accused Features: DRL's ANDA Product is alleged to be a pharmaceutical capsule comprising lumateperone mono-tosylate with the specific excipients in the claimed amounts (Compl. ¶328).

• Patent Identification: U.S. Patent No. 11,052,084, "Pharmaceutical Capsule Compositions Comprising Lumateperone Mono-Tosylate," issued July 6, 2021 (Compl. ¶345).

• Technology Synopsis: This patent claims a pharmaceutical capsule with the same blend of excipients as the '345 Patent. It adds a limitation requiring the capsule to comprise an amount of lumateperone mono-tosylate equivalent to 0.01 to 30 mg of lumateperone free base ('084 Patent, claim 1).

• Asserted Claims: Claim 1 (Compl. ¶353).

• Accused Features: DRL's ANDA Product is alleged to be a pharmaceutical capsule meeting the excipient blend and the free base equivalent dosage limitations (Compl. ¶354).

• Patent Identification: U.S. Patent No. 11,690,842, "Pharmaceutical Capsule Compositions Comprising Lumateperone Mono-Tosylate," issued July 4, 2023 (Compl. ¶371).

• Technology Synopsis: This patent claims a pharmaceutical capsule with the same blend of excipients as the '345 and '084 Patents. It adds a functional limitation related to the dissolution profile of the capsule in hydrochloric acid at specified time points ('842 Patent, claim 1).

• Asserted Claims: Claim 1 (Compl. ¶379).

• Accused Features: DRL's ANDA Product is alleged to be a pharmaceutical capsule meeting the excipient blend and possessing the claimed dissolution profile (Compl. ¶380).

• Patent Identification: U.S. Patent No. 11,806,348, "Methods of Treatment Using Pharmaceutical Capsule Compositions Comprising Lumateperone Mono-Tosylate," issued November 7, 2023 (Compl. ¶397).

• Technology Synopsis: This patent claims a method of treatment for disorders mediated by the 5-HT2A receptor, SERT, and/or dopamine D1/D2 pathways. The method requires administering a pharmaceutical capsule comprising lumateperone with a specific blend of excipients and a specific dosage range ('348 Patent, claim 1).

• Asserted Claims: Claim 1 (Compl. ¶405).

• Accused Features: The use of DRL's ANDA Product as directed by its proposed label is alleged to involve administering a capsule meeting the claimed composition and dosage for treating the specified disorders (Compl. ¶406).

• Patent Identification: 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-((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)phenyl)butan-1-one for Treating Conditions of the Central Nervous System and Cardiac Disorders," issued September 12, 2023 (Compl. ¶423).

• Technology Synopsis: This patent claims a specific dimer compound of lumateperone, identified as Formula I in the patent ('419 Patent, claim 1). This compound is potentially an impurity or related substance found in lumateperone drug product.

• Asserted Claims: Claim 1 (Compl. ¶431).

• Accused Features: DRL's ANDA Product is alleged to contain the claimed Formula I dimer compound (Compl. ¶432).

III. The Accused Instrumentality

• Product Identification: The accused instrumentality is Defendants' proposed generic version of CAPLYTA®, identified as "DRL's ANDA Product," which are lumateperone capsules in 10.5 mg, 21 mg, and 42 mg dosage strengths, for which approval is sought under ANDA No. 219229 (Compl. ¶1, ¶25).
• Functionality and Market Context: The DRL ANDA Product contains the active ingredient lumateperone, a compound approved for treating schizophrenia and bipolar depression (Compl. ¶24, ¶39). The complaint alleges that upon FDA approval, Defendants will manufacture, market, and sell this product as a generic equivalent to Plaintiff's branded CAPLYTA®, thereby competing directly in the market for antipsychotic and mood-stabilizing drugs (Compl. ¶1-2, ¶18). The complaint alleges that the proposed product labeling will instruct physicians and patients to use the generic capsules in ways that practice the methods claimed in several of the patents-in-suit (e.g., Compl. ¶42, ¶120). The various infringement counts allege the product itself will contain specific compositions, crystalline forms, and related compounds claimed by other patents-in-suit (e.g., Compl. ¶146, ¶328, ¶432). The complaint provides an image of the chemical structure for lumateperone, the active ingredient in the accused product (Compl. p. 10, Fig. "Formula I").

IV. Analysis of Infringement Allegations

RE48,839 Infringement Allegations

• Identified Points of Contention:
  • Scope Questions: A central issue will be the proper construction of the term "selectively blocks the 5-HT2A receptor." This raises the question of whether "selectively" requires a complete absence of activity at other receptors (such as dopamine D2), or if it merely requires a significantly higher affinity or potency for the 5-HT2A receptor compared to others.
  • Technical Questions: The complaint alleges on "information and belief" that the directed use would result in selective blockage. A key evidentiary question for the court will be what proof demonstrates that the administration of DRL's specific formulation and dosage strengths results in the claimed selective effect in a patient.

9,168,258 Infringement Allegations

• Identified Points of Contention:
  • Scope Questions: The negative limitation "minimally blocks the dopamine D2 receptor" will be a primary point of contention. The court will need to determine the threshold for "minimal" blockage—whether it implies a lack of clinical significance, a specific receptor occupancy percentage, or is defined by the affinity ratio between the 5-HT2A and D2 receptors described in the patent family.
  • Technical Questions: A key factual question will be whether the 10.5 mg dosage strength of DRL's product, which is a salt form, contains "10 mg or less" of lumateperone when calculated as the free base. Another technical question is what evidence demonstrates that this specific dosage, in DRL's formulation, "minimally blocks" the D2 receptor in vivo.

V. Key Claim Terms for Construction

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

• Context and Importance: The definition of this functional limitation is critical for the RE '839 patent and related method claims. Infringement will depend on whether the accused product's activity profile, which may include effects on other receptors like dopamine D2, falls within the scope of "selectively." Practitioners may focus on this term because the patent family itself discloses that lumateperone's activity profile changes with dose, suggesting "selectivity" may be dose-dependent and not absolute.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The specification describes a wide separation (~60 fold) between the compound's affinity for 5-HT2A and D2 receptors (US 10,117,867 B2, col. 4:12-15). A party could argue that "selectively" should be interpreted in light of this disclosed affinity profile, meaning that some D2 receptor interaction is contemplated and does not defeat selectivity.
  • Evidence for a Narrower Interpretation: The specification contrasts low-dose activity, described as selectively antagonizing 5-HT2A receptors, with higher-dose activity that modulates dopamine (US 10,117,867 B2, col. 3:23-28 vs. col. 3:50-53). A party could argue this creates a definitional distinction, where "selectively" implies a dose low enough to avoid the dopamine-related effects described elsewhere in the patent.

• The Term: "minimally blocks the dopamine D2 receptor" (from '258 Patent, claim 1)

• Context and Importance: This negative limitation is the central feature of the '258 patent's composition claim, distinguishing it from compositions with higher doses that would have more significant dopamine activity. Whether DRL's 10.5 mg capsule "minimally blocks" D2 will be a dispositive issue for this patent.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: A party might argue that "minimally" should be understood in a clinical context, meaning any blockage that does not produce the significant extrapyramidal side effects that the invention sought to avoid (US 10,117,867 B2, col. 2:5-16). This interpretation could allow for a measurable, but clinically insignificant, level of D2 receptor blockage.
  • Evidence for a Narrower Interpretation: The specification's summary of the invention states the low-dose compounds are "useful for the treatment of sleep disorders without the side effects of the dopamine D₂ pathways" (US 10,117,867 B2, col. 3:1-4). A party could cite this to argue that "minimally blocks" must mean a level of blockage that is functionally equivalent to zero with respect to dopamine-mediated side effects.

VI. Other Allegations

• Indirect Infringement: The complaint alleges active inducement of infringement for the asserted method patents. The basis for this allegation is that Defendants' proposed product labeling will instruct physicians and patients to administer the ANDA product for the patented indications, thereby intentionally encouraging acts of direct infringement (Compl. ¶48, ¶74, ¶100, ¶126). The complaint also alleges contributory infringement, stating the DRL ANDA Product is not a staple article of commerce and is especially made or adapted for infringing uses (Compl. ¶49, ¶75).
• Willful Infringement: The complaint alleges that Defendants acted with full knowledge of the patents-in-suit, citing the Paragraph IV certification letter sent to the Plaintiff (Compl. ¶52, ¶78). It further alleges that Defendants proceeded without a reasonable basis for believing they would not be liable for infringement, which may support a claim for willful infringement if infringement is found.

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

• A core issue will be one of "definitional scope": how will the court construe the functional and negative limitations that define the inventions, such as "selectively blocks the 5-HT2A receptor" and "minimally blocks the dopamine D2 receptor"? The outcome of these claim construction disputes may be dispositive for the patents that contain them.
• A second key question will be one of "factual and technical proof": across sixteen patents with claims directed to specific dosages, crystalline structures, excipient blends, dissolution profiles, and methods of treatment, what evidence will demonstrate that DRL's ANDA product and its proposed uses meet these varied and specific limitations? This will require extensive factual discovery and expert testimony on the physical characteristics and in-vivo performance of the accused product.
• A third central question addresses the "validity of a large patent portfolio": with sixteen patents asserted, many belonging to the same family and claiming different facets of the same core technology (the compound, its forms, its compositions, and its uses), the case will likely involve a significant defense challenging the validity of these patents on grounds such as obviousness, lack of written description, or double patenting.