DCT

2:17-cv-05901

Horizon Therap LLC v. Par Pharmaceutical Inc

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:17-cv-05901, D.N.J., 08/08/2017
  • Venue Allegations: Plaintiff alleges venue is proper based on Defendant's systematic and continuous contacts with New Jersey, its receipt of revenue from marketing and sales of generic drugs within the district, and its intent to market and sell the accused product to residents of the district.
  • Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff’s drug RAVICTI® constitutes an act of infringement of a patent directed to methods for therapeutically monitoring patients.
  • Technical Context: The technology involves methods for optimizing the dosage of drugs used to treat urea cycle disorders by measuring and analyzing the plasma ratio of a drug metabolite (PAA) to its conjugated form (PAGN).
  • Key Procedural History: This is a Hatch-Waxman action triggered by Defendant’s submission of an ANDA with a Paragraph IV certification, asserting that U.S. Patent No. 9,561,197 is invalid, unenforceable, and/or will not be infringed. Plaintiff also notes a separate, pending action against a different defendant concerning the same patent.

Case Timeline

Date Event
2012-04-20 U.S. Patent No. 9,561,197 Priority Date
2017-02-07 U.S. Patent No. 9,561,197 Issue Date
2017-08-02 Plaintiff received Defendant's Paragraph IV Certification letter
2017-08-08 Complaint Filing Date

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

U.S. Patent No. 9,561,197 - Methods of Therapeutic Monitoring of Phenylacetic Acid Prodrugs

Issued: February 7, 2017

The Invention Explained

  • Problem Addressed: The patent describes the challenge of dosing PAA prodrugs, such as glyceryl tri-[4-phenylbutyrate] (the active ingredient in RAVICTI®), for patients with nitrogen retention disorders like urea cycle disorders (UCDs) (’197 Patent, col. 2:10-14). The prodrug is metabolized into phenylacetic acid (PAA), which is then conjugated with glutamine to form phenylacetylglutamine (PAGN) and excreted (’197 Patent, col. 2:31-36). If this conjugation process becomes saturated or is compromised (e.g., due to liver dysfunction), PAA can accumulate to toxic levels (’197 Patent, col. 3:20-43). Basing dose adjustments solely on PAA levels is insufficient because those levels fluctuate widely and do not fully reflect the body's ability to clear the compound (’197 Patent, col. 9:1-14).
  • The Patented Solution: The invention is a method of treatment that involves measuring plasma concentrations of both PAA and PAGN, then calculating the ratio between them (’197 Patent, col. 4:51-54). This PAA:PAGN ratio is used to determine if the patient's metabolic pathway is saturated. The dosage of the prodrug is then adjusted to bring this ratio into a specific, therapeutically optimal target range, thereby maximizing the drug's nitrogen-scavenging effect while minimizing the risk of PAA toxicity (’197 Patent, Abstract; col. 12:40-58). Figure 2A of the patent graphically illustrates the relationship between the PAA:PAGN ratio and plasma PAA levels, showing a sharp increase in PAA as the ratio rises, which supports the method's rationale (’197 Patent, Fig. 2A).
  • Technical Importance: The use of the PAA:PAGN ratio provides a more stable and reliable indicator of metabolic capacity than measuring either PAA or PAGN levels alone, offering a "clinically useful surrogate for evaluating the efficiency of PAA to PAGN conversion" (’197 Patent, col. 10:41-47).

Key Claims at a Glance

  • The complaint asserts "one or more claims" of the ’197 patent (Compl. ¶28). The patent contains two independent claims, Claim 1 and Claim 2.
  • Independent Claim 1 recites a method with the following essential elements:
    • A method of treating a urea cycle disorder in a subject
    • comprising administering to a subject having a plasma PAA to PAGN ratio outside the target range of 1 to 2,
    • a dosage of glyceryl tri-[4-phenylbutyrate] (HPN-100),
    • effective to achieve a plasma PAA to PAGN ratio within the target range of 1 to 2.
  • Independent Claim 2 is identical to Claim 1, except it recites a target range of 1 to 2.5.

III. The Accused Instrumentality

Product Identification

The accused instrumentality is Defendant Par Pharmaceutical’s filing of ANDA No. 205742 for a generic version of Plaintiff’s RAVICTI® (glycerol phenylbutyrate oral liquid), referred to as "the Par Product" (Compl. ¶1, ¶7).

Functionality and Market Context

The Par Product is intended to be a bioequivalent generic version of RAVICTI® (Compl. ¶22). It is intended for use as a "nitrogen-binding agent for chronic management of patients two (2) months of age and older with urea cycle disorders" (Compl. ¶20). The complaint alleges that the conditions of use for which Par seeks approval are the same as those in the FDA-approved labeling for RAVICTI® (Compl. ¶21).

IV. Analysis of Infringement Allegations

The complaint does not provide sufficient detail for a full claim-chart analysis, as it does not include Par's proposed product label or specify which language in the label is alleged to infringe. The infringement theory is based on 35 U.S.C. § 271(e)(2)(A), which defines the submission of an ANDA to obtain approval for a drug or a method of use claimed in a patent as an act of infringement (Compl. ¶26). The central allegation is that the use of the Par Product "in accordance with the proposed labeling submitted in the Par ANDA would infringe one or more of the claims of the '197 patent" (Compl. ¶28). This suggests a theory of induced infringement, where the proposed label would instruct or encourage medical professionals to perform the steps of the patented method.

No probative visual evidence provided in complaint.

  • Identified Points of Contention:
    • Scope Questions: The primary dispute will likely concern whether the instructions in Par's proposed product label will cause physicians to practice every element of the claimed method. A key question is whether the label directs physicians to administer the drug specifically to achieve a plasma PAA:PAGN ratio within the claimed numerical ranges ("1 to 2" or "1 to 2.5"), or if it provides more general dosing guidance.
    • Technical Questions: A factual question for the court will be whether following the proposed label's instructions would make infringement of the method claims inevitable. This analysis will depend entirely on the specific language of the proposed label, which is not included in the complaint.

V. Key Claim Terms for Construction

  • The Term: "a dosage... effective to achieve a plasma PAA to PAGN ratio within the target range of [1 to 2 or 1 to 2.5]"

    • Context and Importance: This limitation defines the therapeutic goal of the claimed method. Practitioners may focus on this term because the infringement analysis will hinge on whether Par's proposed label instructs titrating the dose to achieve this specific, numerically-defined ratio, as opposed to achieving a more general clinical outcome like ammonia control.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification describes the overall goal as optimizing treatment, stating that the methods are for adjusting dosage "in order to minimize the risk of toxicities and maximize drug effectiveness" (’197 Patent, col. 4:46-49). This could support an interpretation where any dosing that results in the target ratio meets the limitation, even if not an explicit goal.
      • Evidence for a Narrower Interpretation: The claims explicitly link the "effective" dosage to achieving a PAA:PAGN ratio "within the target range" of "1 to 2" or "1 to 2.5." This language may support a construction requiring that achieving this specific numerical ratio is the intended purpose of the administration step, not merely an incidental result of general dose titration.

  • The Term: "administering to a subject having a plasma PAA to PAGN ratio outside the target range"

    • Context and Importance: This phrase appears to set a condition precedent for the administration step. Its interpretation is critical because it could limit the scope of infringement to only those situations where a patient's PAA:PAGN ratio is already known to be out of range before a dose is given.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The patent provides methods for subjects who have "not previously been administered a PAA prodrug," which implies that the method can be initiated on patients whose baseline ratio is unknown but is being optimized for the first time (’197 Patent, col. 13:30-45). This could support construing the term to cover the entire therapeutic process of dose optimization.
      • Evidence for a Narrower Interpretation: A literal reading suggests the claim step only covers the act of giving a dose after a patient's ratio has been measured and confirmed to be "outside the target range." This could support an argument that an initial administration to a treatment-naive patient, whose ratio is unknown, would not meet this limitation.

VI. Other Allegations

  • Indirect Infringement: Plaintiff alleges that upon FDA approval, Defendant will "actively induce and/or contribute to infringement" of the ’197 patent (Compl. ¶29). This allegation is based on the assertion that the proposed labeling for the Par Product will instruct or encourage medical professionals to use the product in a manner that infringes the patent's method claims (Compl. ¶28).
  • Willful Infringement: The complaint alleges that Defendant had "actual and constructive notice" of the ’197 patent as of its issue date and that its infringement is therefore willful (Compl. ¶30). This is supported by Defendant's Paragraph IV certification letter, which demonstrates actual knowledge of the patent (Compl. ¶23).

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

  1. A core issue will be one of label-induced infringement: Does the specific language of Defendant’s proposed product label—which is not yet public—actively instruct or encourage physicians to perform all steps of the patented method, particularly the step of adjusting dosage with the explicit goal of achieving a plasma PAA:PAGN ratio within the specific numerical ranges recited in the claims?
  2. A second key question will relate to claim scope and inevitability: To prove infringement, must Plaintiff show that the proposed label makes practicing the patented method the only reasonable or intended way to use the drug, or is it sufficient to show that the label's guidance will foreseeably result in physicians performing the claimed steps, even if other dosing strategies are also possible?
  3. Finally, the case may turn on a definitional question of claim construction: Does the claim limitation "administering to a subject having a plasma PAA to PAGN ratio outside the target range" require pre-existing knowledge of the patient's out-of-range ratio before the administration step, or can it be read more broadly to cover the entire process of therapeutic dose optimization?