DCT

1:24-cv-00432

Horizon Therap US Holding LLC v. Teva Pharma Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:24-cv-00432, D. Del., 04/05/2024
  • Venue Allegations: Plaintiff alleges venue is proper because Defendant is a Delaware corporation that conducts business in the state and has previously been sued in the district without challenging personal jurisdiction.
  • Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application (ANDA) for a generic version of Plaintiff’s RAVICTI® product constitutes an act of infringement of fourteen patents related to methods of treating and monitoring urea cycle disorders.
  • Technical Context: The technology involves nitrogen-scavenging drugs used for the chronic management of urea cycle disorders (UCDs), rare and life-threatening genetic diseases that impair the body's ability to remove ammonia from the blood.
  • Key Procedural History: This case was initiated under the Hatch-Waxman Act following Defendant’s notification to Plaintiff of its ANDA submission. This ANDA included a "Paragraph IV Certification," asserting that the patents-in-suit are invalid, unenforceable, or will not be infringed by the proposed generic product.

Case Timeline

Date Event
2011-09-30 Earliest Priority Date for patents-in-suit
2014-02-04 U.S. Patent No. 8,642,012 Issued
2016-02-09 U.S. Patent No. 9,254,278 Issued
2016-05-03 U.S. Patent No. 9,326,966 Issued
2017-02-07 U.S. Patent No. 9,561,197 Issued
2018-05-08 U.S. Patent No. 9,962,359 Issued
2018-06-19 U.S. Patent No. 9,999,608 Issued
2018-08-14 U.S. Patent No. 10,045,958 Issued
2018-08-14 U.S. Patent No. 10,045,959 Issued
2019-01-22 U.S. Patent No. 10,183,002 Issued
2019-01-22 U.S. Patent No. 10,183,003 Issued
2019-01-22 U.S. Patent No. 10,183,004 Issued
2019-01-22 U.S. Patent No. 10,183,005 Issued
2019-01-22 U.S. Patent No. 10,183,006 Issued
2020-06-02 U.S. Patent No. 10,668,040 Issued
2024-02-20 Defendant notifies Plaintiff of ANDA filing
2024-04-05 Complaint Filing Date

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

U.S. Patent No. 8,642,012 - "Methods of Treatment Using Ammonia-Scavenging Drugs"

  • Issued: February 4, 2014

The Invention Explained

  • Problem Addressed: The patent addresses the challenge of accurately dosing ammonia-scavenging drugs for patients with nitrogen retention disorders like UCDs. It notes that relying on plasma levels of the drug or its metabolites is unreliable for assessing treatment efficacy (’012 Patent, col. 2:48-52, col. 3:1-6).
  • The Patented Solution: The invention provides methods for determining or adjusting drug dosages by measuring the urinary excretion of phenylacetylglutamine (PAGN), the metabolite responsible for removing waste nitrogen. This method directly quantifies the drug's therapeutic effect, allowing dosages to be calculated based on factors like a patient's dietary protein intake and residual urea synthesis capacity (’012 Patent, Abstract; col. 7:45-56).
  • Technical Importance: This approach allows for more precise and individualized dosing of a life-sustaining therapy, moving beyond less reliable plasma-level monitoring to a method based on the drug's actual waste-removal activity.

Key Claims at a Glance

  • The complaint asserts infringement of one or more claims of the ’012 Patent (Compl. ¶ 76). Independent claim 1 is representative:
  • A method for determining or adjusting the dose of an ammonia scavenging drug administered to a patient with a urea cycle disorder, comprising:
    • determining the patient's dietary protein intake;
    • determining the patient's residual urea synthetic capacity, if any;
    • calculating a target urinary PAGN output based on protein intake and residual urea synthetic capacity;
    • calculating an effective dosage of the PAA prodrug that results in the target urinary PAGN output based on a mean conversion of PAA prodrug to urinary PAGN of 60-75%; and
    • administering the calculated effective dosage to the patient.

U.S. Patent No. 9,254,278 - "Methods of Therapeutic Monitoring of Nitrogen Scavenging Drugs"

  • Issued: February 9, 2016

The Invention Explained

  • Problem Addressed: The patent identifies the clinical impracticality of using multiple daily blood draws to accurately assess a patient's daily ammonia burden, which can fluctuate significantly. It notes that a single random ammonia measurement may lead to over- or under-treatment (’278 Patent, col. 3:1-9, col. 5:4-11).
  • The Patented Solution: The invention provides a method for determining whether to increase a drug dosage by measuring a single fasting blood ammonia level. The patent discloses a strong correlation between fasting ammonia and total daily ammonia exposure, establishing that a fasting level greater than half the upper limit of normal (ULN) indicates a need for a dosage increase (’278 Patent, Abstract; col. 4:10-21).
  • Technical Importance: This invention provides a clinically practical tool—a single fasting blood draw—to predict a patient's overall daily ammonia control, simplifying dose adjustment and reducing the need for more burdensome monitoring procedures.

Key Claims at a Glance

  • The complaint asserts infringement of one or more claims of the ’278 Patent (Compl. ¶ 93). Independent claim 1 is representative:
  • A method for determining whether to increase a dosage of a nitrogen scavenging drug in a subject with a nitrogen retention disorder, comprising:
    • measuring a fasting blood ammonia level of the subject; and
    • comparing the fasting blood ammonia level to the upper limit of normal (ULN) for blood ammonia,
    • wherein a fasting blood ammonia level that is greater than half the ULN for blood ammonia indicates that the dosage is to be increased.

Multi-Patent Capsule: U.S. Patent No. 9,326,966

  • Patent Identification: U.S. Patent No. 9,326,966, "Methods of Therapeutic Monitoring of Nitrogen Scavenging Drugs", issued May 3, 2016 (Compl. ¶ 22).
  • Technology Synopsis: This patent, related to the ’278 Patent, also describes methods for monitoring and adjusting dosages of nitrogen-scavenging drugs. The claimed methods similarly rely on comparing a patient's fasting blood ammonia level to the upper limit of normal (ULN) to determine if a dosage adjustment is needed.
  • Asserted Claims: The complaint asserts infringement of one or more claims (Compl. ¶ 110). Representative independent claims include 1 and 12.
  • Accused Features: The complaint alleges that the use of Teva’s ANDA Product according to its proposed label for managing UCDs will infringe the claimed methods (Compl. ¶ 110).

Multi-Patent Capsule: U.S. Patent No. 9,561,197

  • Patent Identification: U.S. Patent No. 9,561,197, "Methods of Therapeutic Monitoring of Phenylacetic Acid Prodrugs", issued February 7, 2017 (Compl. ¶ 25).
  • Technology Synopsis: This patent describes methods for adjusting PAA prodrug dosages by measuring the plasma ratio of PAA to its metabolite PAGN. The ratio serves as an indicator of whether the patient's metabolic capacity to convert PAA to PAGN is saturated, allowing for dose optimization to maximize efficacy while minimizing the risk of toxicity from PAA accumulation.
  • Asserted Claims: The complaint asserts infringement of one or more claims (Compl. ¶ 127). Representative independent claims include 1 and 2.
  • Accused Features: The complaint alleges that the use of Teva’s ANDA Product according to its proposed label for managing UCDs will infringe the claimed methods (Compl. ¶ 127).

Multi-Patent Capsule: U.S. Patent No. 9,962,359

  • Patent Identification: U.S. Patent No. 9,962,359, "Methods of Therapeutic Monitoring of Nitrogen Scavenging Drugs", issued May 8, 2018 (Compl. ¶ 28).
  • Technology Synopsis: This patent, related to the '278 and '966 patents, claims methods of treating UCDs by administering a nitrogen-scavenging drug and adjusting the dosage if a single fasting plasma ammonia level is greater than half the ULN. It directly links the monitoring step to the treatment action.
  • Asserted Claims: The complaint asserts infringement of one or more claims (Compl. ¶ 144). Representative independent claim is claim 1.
  • Accused Features: The complaint alleges that the use of Teva’s ANDA Product according to its proposed label for managing UCDs will infringe the claimed methods (Compl. ¶ 144).

Multi-Patent Capsule: U.S. Patent No. 9,999,608

  • Patent Identification: U.S. Patent No. 9,999,608, "Methods of Therapeutic Monitoring of Nitrogen Scavenging Drugs", issued June 19, 2018 (Compl. ¶ 31).
  • Technology Synopsis: This patent claims methods of treating a UCD subject by orally administering glyceryl tri-[4-phenylbutyrate] and subsequently adjusting the dosage. The adjustment is based on a measured fasting plasma ammonia level, aiming to achieve a level at or below half the ULN.
  • Asserted Claims: The complaint asserts infringement of one or more claims (Compl. ¶ 161). Representative independent claim is claim 1.
  • Accused Features: The complaint alleges that the use of Teva’s ANDA Product, a generic version of glyceryl tri-[4-phenylbutyrate], according to its proposed label will infringe the claimed methods (Compl. ¶ 161).

Multi-Patent Capsule: U.S. Patent No. 10,045,958

  • Patent Identification: U.S. Patent No. 10,045,958, "Methods of Therapeutic Monitoring of Nitrogen Scavenging Drugs", issued August 14, 2018 (Compl. ¶ 34).
  • Technology Synopsis: This patent claims a method of treating a subject with a UCD by administering an initial dosage of glyceryl tri-[4-phenylbutyrate] and later administering an adjusted, higher dosage if a single fasting plasma ammonia level is measured to be greater than half the ULN.
  • Asserted Claims: The complaint asserts infringement of one or more claims (Compl. ¶ 178). Representative independent claim is claim 1.
  • Accused Features: The complaint alleges that the use of Teva’s ANDA Product according to its proposed label for managing UCDs will infringe the claimed methods (Compl. ¶ 178).

Multi-Patent Capsule: U.S. Patent No. 10,045,959

  • Patent Identification: U.S. Patent No. 10,045,959, "Methods of Therapeutic Monitoring of Nitrogen Scavenging Drugs", issued August 14, 2018 (Compl. ¶ 37).
  • Technology Synopsis: This patent claims a method of treating certain specified UCDs (OTC deficiency, CPS1 deficiency, etc.) by orally administering glyceryl tri-[4-phenylbutyrate] and increasing the dosage if a single fasting plasma ammonia measurement exceeds half the ULN, where the patient is not experiencing a hyperammonemic crisis.
  • Asserted Claims: The complaint asserts infringement of one or more claims (Compl. ¶ 195). Representative independent claim is claim 1.
  • Accused Features: The complaint alleges that the use of Teva’s ANDA Product according to its proposed label for managing UCDs will infringe the claimed methods (Compl. ¶ 195).

Multi-Patent Capsule: U.S. Patent Nos. 10,183,002, 10,183,003, 10,183,004, 10,183,005, and 10,183,006

  • Patent Identification: This family of five patents, all titled "Methods of Therapeutic Monitoring of Nitrogen Scavenging Drugs" and issued January 22, 2019, are continuations of the application leading to the '959 Patent (Compl. ¶¶ 40, 43, 46, 49, 52).
  • Technology Synopsis: These patents claim variations on the method of treating specific UCDs by orally administering glyceryl tri-[4-phenylbutyrate]. They specify different time periods for reaching a steady state (e.g., 48 hours, 48-72 hours) before measuring the fasting ammonia level and adjusting the dose if it exceeds half the ULN.
  • Asserted Claims: The complaint asserts infringement of one or more claims of each patent (Compl. ¶¶ 212, 229, 246, 263, 280).
  • Accused Features: The complaint alleges that the use of Teva’s ANDA Product according to its proposed label for managing UCDs will infringe the claimed methods (Compl. ¶¶ 212, 229, 246, 263, 280).

Multi-Patent Capsule: U.S. Patent No. 10,668,040

  • Patent Identification: U.S. Patent No. 10,668,040, "Treatment of Urea Cycle Disorders in Neonates and Infants", issued June 2, 2020 (Compl. ¶ 55).
  • Technology Synopsis: This patent claims methods for treating UCDs specifically in neonates and infants (patients under 2 years of age) by administering glyceryl phenylbutyrate. Dosing adjustments are guided by measuring urinary PAGN and/or the plasma PAA:PAGN ratio to ensure safety and efficacy in this vulnerable patient population.
  • Asserted Claims: The complaint asserts infringement of one or more claims (Compl. ¶ 297). Representative independent claim is claim 1.
  • Accused Features: The complaint alleges that the use of Teva’s ANDA Product according to its proposed label, which includes instructions for use in pediatric patients, will infringe the claimed methods (Compl. ¶¶ 69-70, 297).

III. The Accused Instrumentality

Product Identification

  • Teva's ANDA No. 218738 Product, a generic version of RAVICTI®, identified as "glycerol phenylbutyrate oral liquid, 1.1 gm/ml" (Compl. ¶¶ 1, 8).

Functionality and Market Context

  • The complaint alleges that Teva's ANDA Product is intended for use as a nitrogen-binding agent for the chronic management of patients with UCDs who cannot be managed by dietary restrictions alone (Compl. ¶ 70). It is alleged that Teva's product will have the same active ingredient, method of administration, dosage form, and dosage amount as the branded RAVICTI® product and will be bioequivalent (Compl. ¶ 68). The complaint further alleges that the proposed labeling for Teva's ANDA Product copies the FDA-approved label for RAVICTI® (Compl. ¶ 69). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not contain a claim chart. The infringement theory is that Teva's proposed product label will instruct and encourage physicians and patients to perform the methods protected by the patents-in-suit.

’012 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for determining or adjusting the dose of an ammonia scavenging drug... comprising: Teva's proposed product label allegedly instructs medical practitioners on how to dose and adjust its generic glycerol phenylbutyrate product for treating UCDs. ¶¶ 69, 70, 76 col. 7:45-48
calculating a target urinary PAGN output based on protein intake and residual urea synthetic capacity; The instructions on the FDA-approved RAVICTI® label, which Teva's label allegedly copies, direct physicians to consider factors such as protein intake when determining the appropriate dose. ¶¶ 69, 70, 78 col. 8:39-44
calculating an effective dosage of the PAA prodrug that results in the target urinary PAGN output based on a mean conversion... of 60-75%; and The dosing instructions in the copied label will allegedly lead practitioners to prescribe an effective dosage that inherently relies on the claimed conversion principles to achieve therapeutic control. ¶¶ 69, 70, 79 col. 8:45-51
administering the calculated effective dosage to the patient. Teva's product is intended to be administered to patients by or under the direction of a physician following the dosing instructions on the proposed label. ¶¶ 70, 71, 76 col. 8:52-53
  • Identified Points of Contention:
    • Scope Questions: A central question will be whether the general dosing guidance on the RAVICTI® label, allegedly copied by Teva, instructs the specific, multi-step calculation recited in claim 1, particularly the step of calculating a dosage "based on a mean conversion of PAA prodrug to urinary PAGN of 60-75%."
    • Technical Questions: What evidence will be presented to show that a physician following the label's instructions would necessarily perform all the claimed steps? The dispute may focus on whether the label merely provides general guidelines or actively "instructs" the performance of the patented method.

’278 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for determining whether to increase a dosage of a nitrogen scavenging drug... comprising: Teva's proposed label allegedly instructs physicians on monitoring and adjusting the dosage of its generic product to manage UCDs in patients. ¶¶ 69, 70, 93 col. 3:9-14
measuring a fasting blood ammonia level of the subject; and The label for RAVICTI®, allegedly copied by Teva, contains instructions for patient monitoring, which necessarily includes blood tests to assess ammonia control. ¶¶ 69, 70, 95 col. 4:65-67
comparing the fasting blood ammonia level to the upper limit of normal (ULN) for blood ammonia, A physician following the standard of care and the label's guidance would allegedly compare a patient's ammonia test results to a normal range to assess treatment efficacy. ¶¶ 69, 70, 96 col. 4:10-14
wherein a fasting blood ammonia level that is greater than half the ULN for blood ammonia indicates that the dosage is to be increased. The complaint alleges that following the instructions on the proposed label to manage the patient's condition will lead physicians to increase the drug dosage if ammonia levels are not adequately controlled, which would be indicated by a test result greater than half the ULN. ¶¶ 70, 93, 95 col. 4:14-17
  • Identified Points of Contention:
    • Scope Questions: Does the term "measuring a fasting blood ammonia level" require a specific instruction on the label for the blood draw to occur after a fast, or can this be inferred from the standard of care that the label encourages?
    • Technical Questions: The dispute will likely focus on whether the instructions on Teva's proposed label are sufficient to meet the legal standard for inducement—specifically, whether Teva's label will lead physicians to inevitably perform the claimed method of comparing a fasting ammonia level to half the ULN as the specific trigger for a dosage increase.

V. Key Claim Terms for Construction

  • The Term: "fasting blood ammonia level" (from the ’278 Patent family)

    • Context and Importance: The infringement case for a large family of the asserted patents depends on whether Teva's label induces the measurement of a "fasting" blood ammonia level. The definition will be critical to determining if standard patient monitoring, as encouraged by the label, meets this claim limitation. Practitioners may focus on this term because if "fasting" is given a strict definition that is not explicitly required by the product label, the infringement case could be weakened.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification discusses that "a random ammonia value obtained during an outpatient visit may fail to provide a reliable measure" and that a fasting level is a better predictor, suggesting "fasting" is used in contrast to "random" and could encompass any non-postprandial measurement intended to establish a baseline (’278 Patent, col. 4:57-64).
      • Evidence for a Narrower Interpretation: The patent's examples and detailed figures often refer to a "Pre-Dose" or "0 hr" sample taken before breakfast, which could support a narrower construction requiring a measurement after a specific period of overnight fasting (’278 Patent, FIG. 3A).

  • The Term: "calculating an effective dosage... based on a mean conversion of PAA prodrug to urinary PAGN of 60-75%" (from the '012 Patent)

    • Context and Importance: This term recites a specific technical basis for the dosage calculation. Infringement of the '012 Patent hinges on whether Teva's label instructs this specific calculation. Practitioners may focus on this term because it appears to require a quantitative step that may not be explicitly stated on a product label, potentially creating a point of non-infringement.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification broadly describes that the methods "may be combined with urinary PAGN measurements" and that "urinary PAGN is simply used to calculate the initial or adjusted dosage," which may support an interpretation where any dose adjustment informed by PAGN levels meets the limitation, even if the 60-75% range is not explicitly used in the calculation (’012 Patent, col. 14:15-17, 50-52).
      • Evidence for a Narrower Interpretation: The patent repeatedly states that its method is based on the discovery that "PBA prodrugs are converted to urinary PAGN with a mean efficiency of 60-75%," and describes this as a basis for the claimed methods. This could support a narrower construction requiring an explicit or implicit use of this specific conversion range in the dosage calculation (’012 Patent, col. 14:20-24).

VI. Other Allegations

  • Indirect Infringement: The complaint is centered on indirect infringement. It alleges that Teva, with actual knowledge of the patents, will induce infringement by physicians and patients who use the generic product according to the instructions on its proposed label (Compl. ¶¶ 77-79, 94-96). It also alleges contributory infringement, stating the ANDA product is a material part of the patented methods and is not a staple article of commerce suitable for substantial noninfringing uses (Compl. ¶¶ 80, 97).
  • Willful Infringement: The complaint does not explicitly use the term "willful infringement" or request enhanced damages. However, it alleges that Teva has and will have "actual knowledge" of the patents-in-suit, citing Teva's Notice Letter and its Paragraph IV Certification as evidence (Compl. ¶¶ 75, 92). These allegations could form the basis for a later claim of willfulness.

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

  • A core issue will be one of instructional specificity: Does the language on Teva's proposed label—which is alleged to be a copy of the branded RAVICTI® label—rise to the level of actively instructing or encouraging physicians to perform the specific, multi-step methods of the asserted claims? Or, does the label provide only general guidance that falls short of inducing infringement of every claimed element?
  • A central question will be one of claim construction: The dispute will likely focus on whether key claim terms, such as "fasting blood ammonia level" and "calculating an effective dosage... based on a mean conversion of... 60-75%," can be interpreted broadly enough to read on the general standard of care that the product label encourages, or if they require specific actions not explicitly detailed on the label.
  • A key defense question will be one of validity: Though not detailed in the complaint, Teva's Paragraph IV certification alleges that the patents-in-suit are invalid. A significant portion of the case will therefore involve Teva's attempt to prove, by clear and convincing evidence, that the asserted claims are invalid as obvious or otherwise unpatentable over the prior art.