DCT

1:24-cv-01025

Ingenus Pharma LLC v. Hetero USA Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:24-cv-01025, D. Del., 09/11/2024
  • Venue Allegations: Venue is alleged based on Defendant Hetero USA, Inc. being a Delaware corporation and all Defendants conducting substantial business in the district, including the anticipated sale and distribution of the accused generic drug products.
  • Core Dispute: Plaintiff alleges that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA for a generic cyclophosphamide solution constitutes an act of patent infringement.
  • Technical Context: The technology concerns stable, ready-to-use liquid formulations for cyclophosphamide, a chemotherapy drug, designed to avoid the need for on-site reconstitution of lyophilized powders.
  • Key Procedural History: The lawsuit was triggered by Defendants’ submission of ANDA No. 219271 with a Paragraph IV certification, asserting that U.S. Patent No. 10,993,952 is invalid, unenforceable, or will not be infringed. Plaintiff received a notice letter regarding this filing on July 31, 2024. The complaint notes the patent-in-suit is listed in the FDA's Orange Book for Plaintiff's corresponding approved drug product. Plaintiff also discloses a license agreement with Dr. Reddy's Laboratories, Inc. related to its approved New Drug Application (NDA).

Case Timeline

Date Event
2015-02-16 '952 Patent Priority Date
2020-07-30 FDA approves Plaintiff's initial NDA No. 212501
2021-05-04 U.S. Patent No. 10,993,952 issues
2021-11-19 FDA approves supplemental dosage form for Plaintiff's NDA
2024-06-11 Plaintiff enters license agreement with Dr. Reddy's Laboratories
2024-07-04 '952 Patent assigned to Plaintiff Ingenus Pharmaceuticals
2024-07-31 Date of Defendant's Paragraph IV Notice Letter to Plaintiff
2024-09-11 Complaint filed

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

U.S. Patent No. 10,993,952 - "Stable Ready to Use Cyclophosphamide Liquid Formulations"

The Invention Explained

  • Problem Addressed: The patent background describes that prior cyclophosphamide formulations were typically supplied as a lyophilized (dry) powder that required reconstitution with a diluent before administration (’952 Patent, col. 1:52-64). This process is described as decreasing the "ease of administration," and the resulting reconstituted solutions have a limited storage life, compromising product quality if not used promptly (’952 Patent, col. 1:59-64).
  • The Patented Solution: The invention is a "stable ready to use, liquid parenteral formulation" that contains cyclophosphamide pre-dissolved in a specific solvent system, eliminating the need for reconstitution (’952 Patent, Abstract). The solution uses a combination of solvents—specifically ethanol, polyethylene glycol (PEG), and propylene glycol—and an antioxidant to maintain chemical stability and limit the formation of degradation impurities (’952 Patent, col. 3:26-49; col. 2:4-6).
  • Technical Importance: The development of a stable, liquid, ready-to-use formulation of this drug simplifies the administration process for healthcare providers, potentially reducing preparation time and the risk of dosing errors associated with reconstitution (’952 Patent, col. 1:59-64).

Key Claims at a Glance

The complaint asserts infringement of "one or more claims" of the ’952 Patent without specifying which ones (Compl. ¶47). The patent contains two independent claims, 1 and 4.

  • Independent Claim 1:
    • A stable liquid parenteral formulation of cyclophosphamide comprising:
    • cyclophosphamide at a concentration of about 12% to about 23% by total formulation weight;
    • an ethanol content of about 70% to about 75% by total formulation weight;
    • both polyethylene glycol and propylene glycol, where their mass ratio is between approximately 1.0:1.0 to approximately 2.0:1.0;
    • about 3.4% to about 8.8% polyethylene glycol by total formulation weight;
    • about 3.4% to about 4.4% propylene glycol by total formulation weight; and
    • wherein after storage for 7 days at 40° C./75% RH, decomposition to three specific impurities is less than 0.5% each.
  • Independent Claim 4:
    • A stable liquid parenteral formulation of cyclophosphamide comprising:
    • cyclophosphamide at a concentration of about 23% by total formulation weight;
    • an ethanol content of about 70% by total formulation weight;
    • both polyethylene glycol and propylene glycol, where their mass ratio is about 1.0:1.0;
    • about 3.4% to about 8.8% polyethylene glycol by total formulation weight;
    • about 3.4% to about 4.4% propylene glycol by total formulation weight; and
    • about 0.02% monothioglycerol by total formulation weight.
  • The complaint does not explicitly reserve the right to assert dependent claims, but the general allegation of infringing "one or more claims" preserves this option.

III. The Accused Instrumentality

Product Identification

  • The accused instrumentalities are Defendants' proposed generic "Cyclophosphamide Solution; 500mg/2.5ml (200mg/ml), 1gm/5ml (200mg/ml), and 2gm/10ml (200mg/ml)" products, for which Defendants submitted Abbreviated New Drug Application (ANDA) No. 219271 to the FDA (Compl. ¶1, 20).

Functionality and Market Context

  • The complaint alleges that the accused ANDA Products are generic versions of Plaintiff's approved NDA Product (Compl. ¶34). It further alleges that, upon approval, the ANDA Products will share the same indication as Plaintiff's product, which is the treatment of various malignant diseases (Compl. ¶29, 40). The complaint asserts that Defendants intend to sell their product nationwide, including in Delaware, and that it will directly compete with and displace sales of Plaintiff's product (Compl. ¶24). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide a claim chart or specific, element-by-element infringement allegations. The infringement theory is based on the statutory act of filing the ANDA under 35 U.S.C. § 271(e)(2) for a product that allegedly "falls within one or more claims of the ’952 Patent" (Compl. ¶47, 49). The complaint states that Defendants did not contest infringement in their Paragraph IV notice letter, which Plaintiff suggests is a failure to comply with federal regulations that require such a basis to be stated (Compl. ¶48).

Given the lack of specific allegations, a claim chart table cannot be constructed. The central infringement allegation is that the formulation detailed in Defendants' confidential ANDA filing meets all the compositional and concentration limitations of at least one of the asserted claims of the ’952 Patent.

  • Identified Points of Contention:
    • Compositional Questions: The primary question will be factual: Does the formulation described in ANDA No. 219271 contain cyclophosphamide, ethanol, polyethylene glycol, and propylene glycol within the specific weight percentages and component ratios required by the independent claims? This will be a battle of experts analyzing the ANDA's contents.
    • Scope Questions: A likely point of dispute will be the interpretation of the term "approximately" as used in Claim 1. The degree of variance permitted by this term in the context of the claimed mass ratio will be critical to the infringement analysis.

V. Key Claim Terms for Construction

  • The Term: "a polyethylene glycol to propylene glycol mass ratio is between approximately 1.0:1.0 to approximately 2.0:1.0" (from Claim 1)

  • Context and Importance: The precise numerical range of this ratio is a core limitation of Claim 1. Infringement will depend on whether the ratio in Defendants' product falls within the scope of "approximately" the claimed range. Practitioners may focus on this term because its indefiniteness creates a clear boundary dispute for infringement.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The patent's repeated use of "approximately" and "about" in the claims could suggest that the inventors did not intend for the numerical ranges to be exact and unforgiving. A party might argue this language was intended to cover minor, functionally insignificant variations.
    • Evidence for a Narrower Interpretation: A party could argue that the provided numerical examples in the patent (e.g., Example 1-8) establish the intended metes and bounds of the invention. Further, Claim 4 recites a specific ratio of "about 1.0:1.0" without the "approximately" modifier, suggesting that when the patentees wanted to be more precise, they were. This doctrine of claim differentiation may be used to argue for a narrower construction of "approximately" in Claim 1.

  • The Term: "stable liquid parenteral formulation" (preamble of Claims 1 and 4)

  • Context and Importance: While "stable" is in the preamble, Claim 1 explicitly defines a performance-based aspect of stability: having less than 0.5% of three specific impurities after storage under accelerated conditions. This links the term "stable" to a measurable outcome. Whether Defendants' product meets this stability requirement could become a point of contention.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: A party could argue "stable" should be given its plain meaning in the pharmaceutical arts and that the specific impurity limitation in Claim 1 is just one way of defining stability, not the only way.
    • Evidence for a Narrower Interpretation: A party would argue that the term "stable" is expressly defined by the functional limitation within the body of Claim 1 ("wherein, after storage for 7 days...decomposition...is less than 0.5%"). They would contend that to infringe, an accused product must not only have the right ingredients but must also demonstrate this claimed level of stability.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that upon FDA approval, Defendants will induce infringement by marketing the ANDA product with labeling that instructs medical professionals to use it in an infringing manner (Compl. ¶51). It also alleges contributory infringement, asserting that the ANDA Product is especially made for an infringing use and lacks substantial non-infringing uses (Compl. ¶52).
  • Willful Infringement: Willfulness is alleged based on Defendants having actual knowledge of the ’952 Patent, as evidenced by their filing of a Paragraph IV certification against it (Compl. ¶53). The complaint further alleges that Defendants lack a reasonable basis for their assertions of invalidity or non-infringement, rendering their conduct willful and the case "exceptional" under 35 U.S.C. § 285 (Compl. ¶54).

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

  1. A central compositional question will be dispositive: Does the formulation described in Defendants' confidential ANDA No. 219271 contain the exact combination of excipients (ethanol, polyethylene glycol, propylene glycol) within the specific concentration ranges and mass ratios recited in the independent claims of the ’952 Patent?
  2. The primary legal question will be one of claim scope: How broadly will the court construe the term "approximately" as it applies to the glycol mass ratio in Claim 1? The outcome of this construction could determine infringement if the accused product's ratio is close to, but not strictly within, the 1.0:1.0 to 2.0:1.0 range.
  3. A key evidentiary issue will revolve around performance: What evidence will be presented to determine if Defendants' product meets the functional stability limitation required by Claim 1—specifically, that decomposition into named impurities remains below 0.5% after accelerated storage?