DCT

2:16-cv-00179

Roxane Laboratories Inc v. Vanda Pharma Inc

Log In

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:16-cv-00179, S.D. Ohio, 02/26/2016
  • Venue Allegations: Plaintiff alleges venue is proper in the Southern District of Ohio based on Defendant’s contract manufacturing of a pharmaceutical product in Cincinnati, as well as foreseeable harm caused in Ohio by Defendant’s listing of the patents-in-suit in the FDA’s Orange Book.
  • Core Dispute: Plaintiff, a generic drug manufacturer, seeks a declaratory judgment that its generic iloperidone product does not infringe, and that Defendant's patents related to pharmacogenomic methods for administering the drug are invalid.
  • Technical Context: The patents relate to personalized medicine, specifically using a patient's genetic markers (genotype) to predict the risk of QT prolongation (a heart rhythm abnormality) when treated with the antipsychotic drug iloperidone.
  • Key Procedural History: The complaint states that Plaintiff submitted an Abbreviated New Drug Application (ANDA) to the FDA for its generic iloperidone product, including a Paragraph IV certification that Defendant's patents were invalid or not infringed. After receiving notice, Defendant did not initiate a patent infringement suit within the 45-day statutory period provided by the Hatch-Waxman Act, prompting Plaintiff to file this declaratory judgment action to resolve the uncertainty over its right to commercialize its product.

Case Timeline

Date Event
2007-03-29 U.S. Patent 9,074,254 Priority Date
2007-09-10 U.S. Patent 8,652,776 Priority Date
2009-04-06 U.S. Patents 8,999,638, 9,072,742, 9,074,255, 9,074,256, 9,157,121 Priority Date
2014-02-18 U.S. Patent 8,652,776 Issued
2015-04-07 U.S. Patent 8,999,638 Issued
2015-07-07 U.S. Patents 9,072,742, 9,074,254, 9,074,255, 9,074,256 Issued
2015-10-13 U.S. Patent 9,157,121 Issued
2015-XX-XX Plaintiff provides notice to Defendant of its ANDA filing and Paragraph IV certification (month/day not specified)
2016-02-26 Complaint for Declaratory Judgment Filed

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

U.S. Patent No. 8,652,776 - “Prediction of QT Prolongation Based on SNP Genotype,” Issued February 18, 2014

The Invention Explained

  • Problem Addressed: The patent describes that many drugs, including antipsychotics like iloperidone, have the potential to prolong the QT interval of the heart's electrical cycle, which can lead to life-threatening arrhythmias (U.S. Patent 8,652,776, col. 1:19-28). However, there is a poor correlation between the extent of QT prolongation and the occurrence of these dangerous events, and it is difficult to predict which patients are genetically predisposed to this adverse effect (U.S. Patent 8,652,776, col. 1:28-34).
  • The Patented Solution: The invention provides a method for predicting a patient's risk of QT prolongation by first determining the patient's genotype at a specific single nucleotide polymorphism (SNP) locus ('776 Patent, Abstract). Based on this genetic information, the method allows for a prediction of whether the patient will experience above-average or below-average QT prolongation, enabling tailored treatment strategies, such as adjusting drug dosage or selecting an alternative therapy ('776 Patent, col. 2:6-15, col. 9:10-31).
  • Technical Importance: This approach represents a move toward personalized medicine, aiming to improve the safety profile of certain pharmaceuticals by using genetic markers to stratify patient risk before treatment begins ('776 Patent, col. 1:31-34).

Key Claims at a Glance

  • The complaint asserts independent claim 1 ('776 Patent, col. 16:60-18:4; Compl. ¶29).
  • Essential Elements of Claim 1:
    • A method of treating a human patient for a psychotic disorder.
    • Determining, from a biological sample, the patient's genotype at the SNP locus rs3924426.
    • Treating the patient based on whether the genotype is associated with increased QT prolongation, which includes:
      • If the patient has a TT genotype (associated with increased risk), administering an amount of iloperidone that is less than would be given to a patient without that genotype.
      • If the patient does not have a TT genotype, administering an increased amount of iloperidone.
  • The complaint notes that all other asserted claims are dependent on claim 1 (Compl. ¶29).

U.S. Patent No. 8,999,638 - “Method of Treatment Based on Polymorphisms of the KCNQ1 Gene,” Issued April 7, 2015

The Invention Explained

  • Problem Addressed: The patent addresses the risk of drug-induced Long QT Syndrome (LQTS), a cardiac repolarization abnormality, associated with both typical and atypical antipsychotics (U.S. Patent 8,999,638, col. 1:24-27, col. 2:3-11). The patent background notes that DNA variants in certain potassium channels, such as KCNQ1, are known to predispose patients to this condition ('638 Patent, col. 1:43-52).
  • The Patented Solution: The invention provides a method of treatment that involves genotyping a patient to identify specific polymorphisms within the KCNQ1 gene, which is required for the repolarization phase of the cardiac action potential ('638 Patent, col. 1:53-64). The treatment quantity of a QT-prolonging compound like iloperidone is then adjusted based on whether the patient's KCNQ1 genotype is associated with an increased risk of QT prolongation ('638 Patent, Abstract; col. 3:65-col. 4:5).
  • Technical Importance: This method further refines personalized drug administration by focusing on genetic variations in a specific gene (KCNQ1) known to be functionally critical to cardiac rhythm ('638 Patent, col. 1:53-57).

Key Claims at a Glance

  • The complaint asserts independent claims 1, 6, and 8 (Compl. ¶38).
  • Essential Elements of Claim 1:
    • A method of administering iloperidone to a human individual.
    • Determining the individual's KCNQ1 genotype at position 79764 of SEQ. ID. 1.
    • If the genotype is GG (associated with increased risk), administering a "first quantity" of iloperidone.
    • If the genotype is non-GG, administering a "second quantity" of iloperidone, where the first quantity is less than the second.
  • Essential Elements of Claim 6: A method of treating an individual with iloperidone by first "characterizing an expression product of the individual's KCNQ1 gene" and then administering a smaller or larger quantity of the drug based on whether the expression product corresponds to a GG or non-GG genotype.
  • Essential Elements of Claim 8: A method of administering iloperidone to a human individual suffering from LQTS, which comprises determining the KCNQ1 genotype at position 79764 and administering a quantity of the drug based on that genotype.
  • The complaint states that all other claims of the '638 Patent depend on these independent claims (Compl. ¶38).

U.S. Patent No. 9,072,742 - “Method of Predicting a Predisposition to QT Prolongation,” Issued July 7, 2015

  • Technology Synopsis: This patent describes methods for administering QT-prolonging compounds, such as iloperidone, based on an individual's genetic sequence. The claimed method specifically involves determining the sequence of the BAI3 gene at the rs1083338 locus to assess the risk of QT prolongation and adjust treatment accordingly.
  • Asserted Claims: Independent claims 1 and 5 (Compl. ¶47).
  • Accused Features: Roxane's generic iloperidone product is accused in the context of a method claim requiring genotyping, which Roxane alleges its product label will not induce (Compl. ¶49).

U.S. Patent No. 9,074,254 - “Method of Predicting a Predisposition to QT Prolongation,” Issued July 7, 2015

  • Technology Synopsis: This patent claims a method for predicting QT prolongation based on a patient's genotype at the rs993648 locus within the CERKL gene. The method involves administering adjusted amounts of a QT-prolonging compound based on whether the patient's genotype is associated with an increased risk.
  • Asserted Claims: Independent claims 1 and 3 (Compl. ¶56).
  • Accused Features: Roxane's generic iloperidone product is accused in the context of a method claim requiring genotyping at the rs993648 locus, which Roxane alleges its product label will not induce (Compl. ¶58).

U.S. Patent No. 9,074,255 - “Method of Predicting a Predisposition to QT Prolongation,” Issued July 7, 2015

  • Technology Synopsis: This patent claims a method for administering QT-prolonging compounds based on an individual's gene sequence at the rs3775378 locus within the FAM13A1 gene. The method involves tailoring the quantity of the compound based on the patient's genetic predisposition to QT prolongation.
  • Asserted Claims: Independent claims 1 and 5 (Compl. ¶65).
  • Accused Features: Roxane's generic iloperidone product is accused in the context of a method claim requiring genotyping of the FAM13A1 gene, which Roxane alleges its product label will not induce (Compl. ¶67).

U.S. Patent No. 9,074,256 - “Method of Predicting a Predisposition to QT Prolongation,” Issued July 7, 2015

  • Technology Synopsis: This patent describes a method of treatment that involves determining an individual's gene sequence at the rs7067971 locus within the ABCC2 gene. Based on this genetic information, the dose of a QT-prolonging compound is adjusted to manage the risk of QT prolongation.
  • Asserted Claims: Independent claims 1 and 5 (Compl. ¶74).
  • Accused Features: Roxane's generic iloperidone product is accused in the context of a method claim requiring genotyping of the ABCC2 gene, which Roxane alleges its product label will not induce (Compl. ¶76).

U.S. Patent No. 9,157,121 - “Method of Treatment Based on Polymorphism of the KCNQ1 Gene,” Issued October 13, 2015

  • Technology Synopsis: Similar to the '638 Patent, this patent claims a method of treatment based on polymorphisms in the KCNQ1 gene. The claimed method involves determining an individual's genotype at a different position (78927 of SEQ. ID. 1) to guide the administration of iloperidone.
  • Asserted Claims: Independent claims 1, 8, and 12 (Compl. ¶83).
  • Accused Features: Roxane's generic iloperidone product is accused in the context of a method claim requiring genotyping of the KCNQ1 gene at a specific locus, which Roxane alleges its product label will not induce (Compl. ¶85).

III. The Accused Instrumentality

Product Identification

  • The subject of the declaratory judgment action is Plaintiff's "Roxane iloperidone product," described as generic oral iloperidone tablets in dosages of 1, 2, 4, 6, 8, 10, and 12 mg (Compl. ¶21).

Functionality and Market Context

  • The complaint states that the product is bioequivalent to Vanda's FANAPT® product, containing the same active ingredient, strength, dosage form, and route of administration (Compl. ¶21). The central functionality relevant to the infringement analysis is the product's proposed label. The complaint alleges that this label, which will "largely track" the FANAPT® label, will contain "no mention" of the specific patient genotypes required by the patents-in-suit (Compl. ¶31, 40, 49, 58, 67, 76, 85).

IV. Analysis of Infringement Allegations

As this is a complaint for declaratory judgment of non-infringement, the following tables summarize Plaintiff's alleged basis for why its product does not meet the claim limitations.

[8,652,776 Patent] Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Non-Infringing Functionality Complaint Citation Patent Citation
A method of treating a human patient for one or more symptoms of a psychotic disorder... Plaintiff Roxane, as a manufacturer, will not be administering iloperidone for any purpose and therefore does not directly perform the claimed treatment method. ¶30 col. 16:60-62
determining, from a biological sample of the patient, the patient's genotype in both copies of the single nucleotide polymorphism (SNP) locus rs3924426... The proposed label for Plaintiff's product will not contain any mention of a patient's genotype at the rs3924426 locus. ¶31 col. 16:63-67
treating the patient based upon whether the patient's genotype...is associated with increased QT prolongation... Plaintiff's product label will not recommend, promote, or encourage physicians to perform the claimed genotype-based dosing steps, and therefore Plaintiff does not indirectly infringe the claim. ¶31 col. 17:1-18:4

[8,999,638 Patent] Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Non-Infringing Functionality Complaint Citation Patent Citation
A method of administering iloperidone or a metabolite thereof to a human individual... Plaintiff Roxane will not be administering iloperidone for any purpose and therefore does not directly perform the claimed method. ¶39 col. 14:1-3
determining or having determined the individual's KCNQ1 genotype at position 79764 of SEQ. ID. 1... The proposed label for Plaintiff's product will contain no mention of a patient's KCNQ1 genotype. ¶40 col. 14:4-6
administering to the individual a first quantity...[or]...a second quantity of iloperidone...wherein the first quantity is less than the second quantity... Plaintiff's label will not recommend, promote, or encourage physicians to perform the claimed genotype-based dosing steps, and therefore Plaintiff lacks the specific intent to induce infringement. ¶40 col. 14:7-23
  • Identified Points of Contention:
    • Direct Infringement: The asserted claims across all patents are method-of-treatment claims. A primary legal question will be whether a pharmaceutical manufacturer, which sells a drug but does not itself perform the diagnostic and administration steps on a patient, can be held to directly infringe such a claim.
    • Indirect (Induced) Infringement: The central dispute appears to be one of intent. The complaint alleges that the proposed product label will not instruct, suggest, or encourage physicians to perform the claimed genotyping steps. This raises the question of what evidence Defendant could present to demonstrate that Plaintiff, by commercializing its generic drug, possessed the specific intent to encourage physicians to perform the patented methods.
    • Patent Eligibility: The complaint raises a fundamental challenge to the validity of all patents-in-suit under 35 U.S.C. § 101, alleging they are directed to a natural law (the correlation between a gene and a drug response) without adding an inventive concept (Compl. ¶33, 42, 51, 60, 69, 78, 87). This poses the legal question of whether the "administering" or "treating" steps are sufficient to transform the claim into a patent-eligible application of the natural law.

No probative visual evidence provided in complaint.

V. Key Claim Terms for Construction

  • The Term: "determining... the patient's genotype" (and variants like "characterizing an individual's KCNQ1 genotype").
  • Context and Importance: This term is the lynchpin of the infringement analysis. It defines the diagnostic act that Plaintiff alleges it neither performs directly nor encourages indirectly. The scope of this term is critical because if it is construed narrowly to require an active, specific test that is not standard medical practice and is not mentioned on the product label, it may strengthen Plaintiff's argument against inducement.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification discusses identifying genetic markers generally, and practitioners may argue that "determining" could encompass not just active testing but also accessing a patient's pre-existing genetic record ('776 Patent, col. 2:6-9).
    • Evidence for a Narrower Interpretation: The language of Claim 1 of the '776 Patent specifies "determining, from a biological sample of the patient," which suggests an active step of obtaining and analyzing a physical sample, not merely accessing a record ('776 Patent, col. 16:63-65). Similarly, the specification describes processes like DNA sequencing and PCR amplification as methods for determination ('776 Patent, col. 9:4-6).

VI. Other Allegations

  • Indirect Infringement: The complaint's primary non-infringement argument is a rebuttal of anticipated indirect infringement allegations. For each patent, Plaintiff alleges that its product label will not recommend, promote, or encourage physicians to perform the claimed genotyping step, and therefore Plaintiff will not "evidence a specific intent and/or action to induce" infringement (Compl. ¶31, 40, 49, 58, 67, 76, 85).
  • Willful Infringement: Willful infringement is not alleged in this declaratory judgment complaint.

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

This declaratory judgment action appears to center on two fundamental questions of patent law as applied to personalized medicine claims.

  • A core issue will be one of induced infringement: In the context of a method-of-treatment claim requiring a specific genetic test, can a generic drug manufacturer be found to have induced infringement by selling a bioequivalent product with a label that is silent on the claimed testing and dosing regimen?
  • A second key issue will be one of patent eligibility: Do the asserted claims, which link a patient's natural genetic makeup to a tailored administration of a known drug, represent a patent-eligible application of a natural law, or are they an impermissible attempt to monopolize the natural law itself with only routine and conventional activity appended?