DCT
2:17-cv-05900
Horizon Therap LLC v. Lupin Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Horizon Therapeutics, LLC (Delaware)
- Defendant: Lupin Ltd. (India) and Lupin Pharmaceuticals, Inc. (Virginia)
- Plaintiff’s Counsel: McCarter & English LLP
- Case Identification: Horizon Therapeutics, LLC v. Lupin Ltd., et al., 2:17-cv-05900, D.N.J., 08/08/2017
- Venue Allegations: Plaintiff alleges venue is proper in the District of New Jersey based on Defendants' business contacts, prior submission to jurisdiction in other cases, and intent to market and sell the accused generic product in the district.
- Core Dispute: Plaintiff alleges that Defendants' Abbreviated New Drug Application (ANDA) seeking FDA approval to market a generic version of Plaintiff's RAVICTI® pharmaceutical product constitutes an act of infringement of a patent covering methods of therapeutically monitoring the drug.
- Technical Context: The technology relates to personalized medicine for patients with rare metabolic conditions known as urea cycle disorders, focusing on optimizing drug dosage by monitoring specific metabolites to balance efficacy and toxicity.
- Key Procedural History: This is a patent infringement action filed under the Hatch-Waxman Act. The complaint notes that Defendants previously filed a Paragraph IV certification concerning a different patent ('012) related to RAVICTI®, but Plaintiff had not, as of the filing date, received a certification for the patent-in-suit. Plaintiff also certified that the patent-in-suit is the subject of another pending action against a different generic manufacturer.
Case Timeline
| Date | Event |
|---|---|
| 2012-04-20 | Priority Date for U.S. Patent No. 9,561,197 |
| 2015-09-04 | Date of letter regarding Paragraph IV Certification for '012 Patent |
| 2017-02-07 | Issue Date for U.S. Patent No. 9,561,197 |
| 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"
- Patent Identification: 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 addresses the challenge of safely dosing patients who take phenylacetic acid (PAA) prodrugs to treat nitrogen retention disorders like urea cycle disorders (UCDs) (Compl. ¶22; ’197 Patent, col. 1:11-17). While these drugs are effective, their active metabolite, PAA, can be toxic at high concentrations. The patent notes that simply measuring PAA levels is insufficient for dose adjustment, as there is no single target PAA level and no correlation with blood ammonia, creating a risk of either under-treatment or toxicity (’197 Patent, col. 9:40-50).
- The Patented Solution: The invention provides a method for adjusting the dosage of a PAA prodrug by measuring the plasma levels of both the active metabolite (PAA) and its downstream, non-toxic conjugate, phenylacetylglutamine (PAGN). By calculating the ratio of PAA to PAGN, a clinician can determine if the metabolic pathway that clears PAA is saturated. The dosage is then adjusted to bring this ratio into a specific target range, thereby optimizing the drug's therapeutic effect while minimizing toxicity risk (’197 Patent, Abstract; col. 4:50-54). Figure 1 illustrates the relevant metabolic pathways involved.
- Technical Importance: This ratio-based monitoring provides a clinically useful tool to personalize and guide therapy for complex metabolic diseases, moving beyond simple measurement of a single active metabolite to a more sophisticated assessment of metabolic efficiency (’197 Patent, col. 9:45-56).
Key Claims at a Glance
- The complaint asserts infringement of "one or more claims" of the '197 patent (Compl. ¶38). The patent contains two independent claims.
- Independent Claim 1: 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: 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 2.5,
- 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 2.5.
III. The Accused Instrumentality
Product Identification
- Defendants' proposed generic glycerol phenylbutyrate oral liquid, for which they filed ANDA No. 207694 (Compl. ¶12).
Functionality and Market Context
- The accused product is a generic version of Plaintiff's FDA-approved drug, RAVICTI® (Compl. ¶1, ¶29). The complaint alleges that Lupin seeks approval to market its product for the same use as RAVICTI®: the chronic management of patients with certain urea cycle disorders (Compl. ¶27). It further alleges that the conditions of use set forth in the proposed labeling for the Lupin Product are the same as those in the FDA-approved labeling for RAVICTI® (Compl. ¶28). The infringement allegation is based on the premise that use of the Lupin Product in accordance with its proposed labeling would practice the patented method (Compl. ¶38).
IV. Analysis of Infringement Allegations
The complaint does not contain a claim chart. The infringement theory is one of induced infringement under 35 U.S.C. § 271(e)(2)(A), where the act of filing an ANDA for a drug with a proposed label that instructs users to perform a patented method constitutes infringement. No probative visual evidence provided in complaint.
'197 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of treating a urea cycle disorder in a subject | Lupin’s ANDA seeks approval to market its product for the treatment of urea cycle disorders. | ¶27 | col. 32:6-7 |
| comprising administering to a subject having a plasma PAA to PAGN ratio outside the target range of 1 to 2, | The complaint alleges that use of Lupin's product in accordance with its proposed label would infringe the claims, implying the label will instruct physicians to administer the drug to patients, including those whose PAA:PAGN ratio is outside the target range. | ¶38 | col. 32:8-10 |
| 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. | The complaint alleges that the proposed labeling for the Lupin Product will instruct physicians to administer the drug in a manner that results in achieving the claimed therapeutic outcome. | ¶38 | col. 32:10-14 |
Identified Points of Contention
- Scope Questions: The central issue will be whether Lupin's proposed product label, as submitted in its ANDA, will actively induce physicians to infringe the method claims. A key question for the court will be whether the label's instructions for dosage and monitoring direct physicians to perform the specific steps of measuring PAA and PAGN and titrating the dose to achieve a PAA:PAGN ratio within the specific numerical ranges recited in the claims.
- Technical Questions: Since the complaint does not include the proposed label, a primary factual question is what the label actually says. The dispute will turn on whether the label's guidance on dose adjustment constitutes an instruction to practice the patented method, or if it provides more general guidance that does not meet every limitation of the asserted claims.
V. Key Claim Terms for Construction
The complaint does not provide sufficient detail for a deep analysis of claim construction, but the following term is likely to be central.
- The Term: "a dosage ... effective to achieve a plasma PAA to PAGN ratio within the target range"
- Context and Importance: This limitation defines the functional outcome of the claimed method. The entire infringement case may depend on how this phrase is construed. Practitioners may focus on this term because it links the act of administering the drug to a specific, numerically defined metabolic state. The dispute will likely question whether this requires the physician to have the specific intent to reach the claimed ratio, or if the limitation is met as long as the ratio is, in fact, achieved as a result of the administration.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification describes the general principle of adjusting dosage based on the ratio. For example, it states that "a PAA:PAGN ratio above the target range indicates that the dosage of the PAA prodrug needs to be decreased" (’197 Patent, col. 4:55-58). This could support an interpretation where any dose adjustment informed by the ratio meets the limitation.
- Evidence for a Narrower Interpretation: The claims themselves and specific examples could support a more stringent interpretation. The claims require administration of a dosage "effective to achieve" the ratio, and Example 3 describes a specific instance of a physician decreasing a dose in response to a calculated ratio of ">2.5" (’197 Patent, col. 27:45-col. 28:22). This might suggest that the method requires a deliberate calculation and targeting of the specific numerical range.
VI. Other Allegations
- Indirect Infringement: The complaint alleges that upon FDA approval, Defendants will actively induce infringement of the '197 patent (Compl. ¶39). The basis for this allegation is that the proposed labeling for the Lupin Product will instruct medical professionals and patients on an infringing use of the drug (Compl. ¶38).
- Willful Infringement: The complaint alleges that Defendants had actual and constructive notice of the ’197 patent as of its issue date and that their infringement is willful (Compl. ¶40).
VII. Analyst’s Conclusion: Key Questions for the Case
This case appears to turn on the content of documents not yet in the public record—namely, the proposed labeling from Lupin's ANDA. The central questions for the court will likely be:
- A core issue will be one of induced infringement: Does the language in Lupin's proposed product label instruct, direct, or encourage physicians to monitor both PAA and PAGN levels and subsequently adjust the dosage of glycerol phenylbutyrate with the specific goal of achieving a PAA:PAGN ratio within the numerically defined ranges of 1-2 or 1-2.5?
- A key legal question will be one of claim scope: What actions satisfy the "effective to achieve" limitation in the claims? Must a physician consciously calculate the PAA:PAGN ratio and target the claimed numerical range, or is the claim infringed if a physician’s standard dose titration, informed by metabolite levels, results in a patient's ratio falling within that range? The answer will define the evidence required for Plaintiff to prove infringement.