DCT
2:25-cv-02861
Fresenius Kabi USA LLC v. Endo Operations Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Fresenius Kabi USA, LLC (Delaware)
- Defendant: Endo Operations Limited (Ireland), Endo USA, Inc. (Delaware), and Endo International PLC (Ireland)
- Plaintiff’s Counsel: Arentfox Schiff LLP
- Case Identification: 2:25-cv-02861, D.N.J., 04/18/2025
- Venue Allegations: Venue is alleged to be proper in the District of New Jersey because Defendant Endo USA, Inc. is registered to do business in the state and Defendants operate and maintain regular and established places of business in the district.
- Core Dispute: Plaintiff alleges that Defendants' submission of a New Drug Application to the FDA for generic levothyroxine sodium injections constitutes an act of infringement of three patents covering stable, ready-to-use liquid formulations of the drug.
- Technical Context: The technology concerns aqueous formulations of levothyroxine, a thyroid hormone, designed to be stable for long-term storage, thereby avoiding the need for reconstitution of a lyophilized powder prior to injection.
- Key Procedural History: This is a Hatch-Waxman action initiated under 35 U.S.C. § 271(e)(2) following Defendants’ submission of New Drug Application (NDA) No. 217130. The complaint states Defendants submitted a Paragraph IV Certification asserting that their proposed generic products would not infringe the patents-in-suit, and subsequently sent a notice letter to the Plaintiff.
Case Timeline
| Date | Event |
|---|---|
| 2016-12-01 | Earliest Priority Date for ’376, ’669, and ’190 Patents |
| 2017-10-10 | U.S. Patent No. 9,782,376 Issues |
| 2019-09-03 | U.S. Patent No. 10,398,669 Issues |
| 2021-10-05 | U.S. Patent No. 11,135,190 Issues |
| 2024-01-16 | Endo USA, Inc. registered with NJ Department of Treasury |
| 2025-03-06 | Endo sends Paragraph IV Notice Letter to Fresenius Kabi |
| 2025-04-18 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 9,782,376, "Levothyroxine Liquid Formulations," Issued October 10, 2017
The Invention Explained
- Problem Addressed: The patent describes that conventional levothyroxine sodium for injection is a preservative-free lyophilized (freeze-dried) powder that must be reconstituted with a diluent before administration. This process introduces risks of contamination, and the resulting solution has a limited stability of only a few hours. (’376 Patent, col. 1:39-54).
- The Patented Solution: The invention provides a ready-to-use, stable liquid formulation of levothyroxine that does not require reconstitution. The solution is achieved by combining levothyroxine with specific stabilizing agents, including tromethamine and sodium iodide, in water and adjusting the formulation to a basic pH range of about 9.0 to 11.5, which enhances long-term stability. (’376 Patent, col. 2:12-25; Abstract).
- Technical Importance: This approach creates a commercially viable, ready-to-use injectable product, which improves convenience for healthcare providers and enhances patient safety by eliminating reconstitution steps. (’376 Patent, col. 1:47-54).
Key Claims at a Glance
- The complaint asserts at least independent claim 1. (Compl. ¶51).
- The essential elements of independent claim 1 are:
- A liquid formulation comprising levothyroxine or a pharmaceutically acceptable salt thereof;
- about 1 mg/mL to about 50 mg/mL of tromethamine;
- about 10 mcg/mL to about 500 mcg/mL of sodium iodide;
- and water;
- wherein the formulation has a pH of about 9.0 to about 11.5,
- and wherein the formulation is stable for at least 12 months at 25±2°C.
- The complaint alleges infringement of "one or more claims" and states the accused products are "covered by each claim," reserving the right to assert other claims. (Compl. ¶47-48).
U.S. Patent No. 10,398,669, "Levothyroxine Liquid Formulations," Issued September 3, 2019
The Invention Explained
- Problem Addressed: This patent, part of the same family, also addresses the degradation of levothyroxine in aqueous solutions. It specifically notes that a major degradation product is 3,3',5-triiodothyronine, also known as liothyronine or T3, which is a significant impurity. (’669 Patent, col. 1:55-63).
- The Patented Solution: The invention is a liquid levothyroxine formulation that not only maintains its potency but also controls the formation of impurities. The claims require the formulation to contain levothyroxine, a stabilizing agent comprising tromethamine, and water, while also meeting two distinct stability criteria: retaining at least 95% of the initial drug concentration after 12 months at room temperature and after 2 months at an accelerated temperature of 40°C. The formulation must also contain "not more than 2% liothyronine (T3)." (’669 Patent, col. 15:46 - col. 16:8; Abstract).
- Technical Importance: By claiming specific, low levels of the T3 degradant and demonstrating stability under both normal and accelerated conditions, the invention provides a formulation with a well-defined and controlled purity profile suitable for a regulated pharmaceutical product. (’669 Patent, col. 1:60-63).
Key Claims at a Glance
- The complaint asserts at least independent claim 1. (Compl. ¶65).
- The essential elements of independent claim 1 are:
- A liquid formulation comprising levothyroxine or a pharmaceutically acceptable salt thereof;
- a stabilizing agent comprising tromethamine;
- not more than 2% liothyronine (T3);
- and water;
- wherein the formulation retains at least about 95% of the initial concentration of levothyroxine... after storage for 12 months at 25±2 °C.,
- and retains at least about 95% of the initial concentration of levothyroxine... after storage for 2 months at 40±2 °C.
- The complaint reserves the right to assert other claims. (Compl. ¶61-62).
Multi-Patent Capsule: U.S. Patent No. 11,135,190
- Patent Identification: U.S. Patent No. 11,135,190, "Levothyroxine Liquid Formulations," issued October 5, 2021.
- Technology Synopsis: This patent continues the same theme of creating stable liquid levothyroxine formulations. It claims a pharmaceutical product comprising a liquid formulation with levothyroxine, water, and a stabilizing agent selected from a specific Markush group of amines, which includes tromethamine. The claims require the formulation to retain at least 95% of its initial concentration after two months at 40°C and after at least 12 months at room temperature. (’190 Patent, col. 15:46 - col. 16:1).
- Asserted Claims: The complaint asserts at least independent claim 1. (Compl. ¶79).
- Accused Features: The complaint alleges that Defendants' proposed generic levothyroxine injection products, as described in their NDA, meet the compositional and functional stability requirements of the claims. (Compl. ¶75-76, 80).
III. The Accused Instrumentality
Product Identification
The accused instrumentalities are Defendants' proposed generic levothyroxine sodium injection products ("Endo's NDA Products") for which NDA No. 217130 was filed. (Compl. ¶2, ¶36).
Functionality and Market Context
The products are proposed as intravenous solutions at strengths of 100 mcg/5 mL, 200 mcg/5 mL, and 500 mcg/5 mL. (Compl. ¶42). The complaint alleges these are generic versions of Plaintiff's own FDA-approved drug and are intended for the same therapeutic use of thyroid replacement. (Compl. ¶39, ¶43). The filing of the NDA is an attempt to enter the U.S. market with a competing product prior to the expiration of the patents-in-suit. (Compl. ¶44).
- No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
U.S. Patent No. 9,782,376 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A liquid formulation comprising levothyroxine or a pharmaceutically acceptable salt thereof; | Endo’s NDA Products are described as an intravenous solution containing the active ingredient levothyroxine sodium. | ¶42 | col. 3:13-19 |
| about 1 mg/mL to about 50 mg/mL of tromethamine; | The complaint alleges, based on a confidential review of Endo’s NDA, that the accused products contain tromethamine within the claimed concentration range. | ¶52 | col. 4:15-34 |
| about 10 mcg/mL to about 500 mcg/mL of sodium iodide; | The complaint alleges, based on a confidential review of Endo’s NDA, that the accused products contain sodium iodide within the claimed concentration range. | ¶52 | col. 4:38-56 |
| and water; | Endo’s NDA Products are described as an intravenous solution, which is an aqueous formulation. | ¶42 | col. 2:21-25 |
| wherein the formulation has a pH of about 9.0 to about 11.5, | The complaint alleges, based on a confidential review of Endo’s NDA, that the accused products have a pH value that falls within the claimed range. | ¶52 | col. 5:12-27 |
| and wherein the formulation is stable for at least 12 months at 25±2°C. | The complaint alleges that information in Endo's NDA confirms its products meet this stability requirement. This is a functional limitation that would be proven by stability testing data submitted to the FDA. | ¶52 | col. 3:1-4 |
Identified Points of Contention
- Evidentiary Question: The complaint's allegations rely entirely on a confidential review of Endo's NDA. (Compl. ¶52). The central dispute will be factual: does the data within the NDA actually demonstrate the presence of all claimed components at the claimed concentrations and, critically, prove that the formulation meets the functional stability requirement of being "stable for at least 12 months at 25±2°C"?
- Scope Questions: The term "stable" is defined by a functional outcome. A potential point of contention is whether Endo's stability data, even if showing a high degree of stability, precisely meets the 12-month threshold as defined and measured according to the methods contemplated by the patent.
U.S. Patent No. 10,398,669 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A liquid formulation comprising levothyroxine or a pharmaceutically acceptable salt thereof; | Endo’s NDA Products are intravenous solutions containing levothyroxine sodium. | ¶42, ¶66 | col. 3:13-19 |
| a stabilizing agent comprising tromethamine; | The complaint alleges, based on a confidential review of Endo’s NDA, that the accused products contain tromethamine as a stabilizing agent. | ¶66 | col. 4:7-14 |
| not more than 2% liothyronine (T3); | The complaint alleges the accused product formulation meets this impurity limit, which would be confirmed by purity analysis data in the NDA. | ¶66 | col. 6:45-54 |
| and water; | Endo’s NDA Products are described as an intravenous solution. | ¶42, ¶66 | col. 2:21-25 |
| wherein the formulation retains at least about 95% of the initial concentration... after storage for 12 months at 25±2 °C., | The complaint alleges that confidential stability data in Endo's NDA confirms its products meet this first functional stability requirement. | ¶66 | col. 16:1-5 |
| and retains at least about 95% of the initial concentration... after storage for 2 months at 40±2 °C. | The complaint alleges that confidential stability data in Endo's NDA confirms its products meet this second, separate functional stability requirement under accelerated conditions. | ¶66 | col. 16:5-8 |
Identified Points of Contention
- Technical Questions: The claim requires meeting two separate and distinct functional stability tests (one at 25°C, one at 40°C). A key technical question is whether Endo's NDA data demonstrates satisfaction of both limitations. A failure to meet either one would provide a basis for a non-infringement defense.
- Scope Questions: The limitation "not more than 2% liothyronine (T3)" is not explicitly tied to a point in time (e.g., at release or end of shelf-life). This raises a potential claim construction dispute over when this impurity level must be measured to determine infringement.
V. Key Claim Terms for Construction
For U.S. Patent No. 9,782,376:
The Term
"stable"
Context and Importance
This term is defined functionally in claim 1 as being "stable for at least 12 months at 25±2°C." Its construction is dispositive for infringement, as the analysis will turn on whether stability data in Endo's NDA meets this requirement. Practitioners may focus on this term because proving a negative (i.e., that the product is not stable for the full duration) can be a viable defense strategy if the NDA data is ambiguous or incomplete.
Intrinsic Evidence for Interpretation
- Evidence for a Broader Interpretation: The specification describes stability more generally as retaining "at least about 90%, or about least about 95%... of the labeled concentration of levothyroxine." (’376 Patent, col. 2:46-51). Plaintiff may argue this general description informs the meaning of "stable," allowing for some flexibility in measurement and outcome.
- Evidence for a Narrower Interpretation: Defendant may argue that the claim explicitly defines the term by its outcome ("stable for at least 12 months at 25±2°C"), and this specific definition overrides any general descriptions in the specification. Therefore, any product that does not provably meet this exact durational requirement does not infringe.
For U.S. Patent No. 10,398,669:
The Term
"a stabilizing agent comprising tromethamine"
Context and Importance
The construction of this term is critical to determining whether an accused product with a complex mixture of excipients infringes. The dispute would center on whether the open-ended term "comprising" reads on a formulation where tromethamine may not be the sole or even primary stabilizing component.
Intrinsic Evidence for Interpretation
- Evidence for a Broader Interpretation: Plaintiff will argue that "comprising" is a well-established term of art meaning "including but not limited to." Therefore, as long as tromethamine is present as a stabilizing agent, the presence of other stabilizers is irrelevant to the infringement analysis. The specification lists other possible amines, suggesting the inventors contemplated combinations. (’669 Patent, col. 4:7-14).
- Evidence for a Narrower Interpretation: Defendant could argue that the patent repeatedly emphasizes the novel stabilizing effect of the claimed components in combination. If their product achieves stability primarily through a different, un-claimed agent, and tromethamine is present for a different purpose (e.g., as a pH buffer in a different range) or in a functionally insignificant amount, they may argue it is not "a stabilizing agent" in the context of their specific formulation.
VI. Other Allegations
Indirect Infringement
The complaint's primary focus is on direct infringement under 35 U.S.C. § 271(a) and the statutory act of infringement from the NDA submission under § 271(e)(2). (Compl. ¶47, 61, 75). While it references Defendants' "proposed labeling" in the context of future infringement (Compl. ¶53, 67, 81), it does not plead the specific elements of knowledge and intent required for induced infringement.
Willful Infringement
The complaint alleges that Defendants' infringement has been and will be willful. This allegation is based on Defendants having knowledge of the patents-in-suit prior to submitting their NDA, as evidenced by their Paragraph IV Certification. (Compl. ¶55, 69, 83). The complaint further claims that Defendants have "no reasonable basis" for their non-infringement or invalidity positions. (Compl. ¶56, 70, 84).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue will be one of evidentiary proof: The infringement allegations hinge on confidential data in Endo's NDA. The case will likely turn on whether the chemical composition and, more importantly, the long-term and accelerated stability data contained in that regulatory filing, conclusively demonstrate that Endo's products meet the specific quantitative and functional limitations of the asserted claims.
- A key legal battle will be over claim construction of functional limitations. The claims are defined not just by what they contain, but by how they perform over time (e.g., "retains at least about 95%... after storage for 12 months... and... after storage for 2 months"). The court's interpretation of whether both conditions must be strictly and independently met, and how those stability outcomes must be proven, will be critical to the infringement analysis.
- Finally, the case raises a question of infringement under the doctrine of equivalents. The complaint pleads infringement literally or, in the alternative, under the doctrine of equivalents for all three patents. (Compl. ¶52, 66, 80). This preserves the question of whether any differences between the patented formulation and Endo's product are insubstantial, an issue that will become central if literal infringement is not found.