DCT
1:21-cv-00164
Fresenius Kabi USA LLC v. Custopharm Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Fresenius Kabi USA, LLC (Delaware)
- Defendant: Custopharm, Inc. (Colorado/Texas)
- Plaintiff’s Counsel: Sherman & Howard L.L.C.
- Case Identification: 1:21-cv-00164, D. Colo., 10/30/2020
- Venue Allegations: Venue is alleged to be proper in the District of Colorado because Defendant Custopharm is organized under the laws of Colorado and therefore resides in the district for venue purposes.
- Core Dispute: Plaintiff alleges that Defendant’s submission of a New Drug Application to the FDA for a generic levothyroxine solution constitutes an act of infringement of two patents covering stable, ready-to-use liquid formulations of the drug.
- Technical Context: The lawsuit concerns sterile, injectable formulations of levothyroxine, a synthetic thyroid hormone used for thyroid replacement therapy, particularly in urgent clinical settings.
- Key Procedural History: The complaint alleges that this action arises under the Hatch-Waxman Act, triggered by Defendant’s filing of New Drug Application (NDA) No. 214253. Plaintiff alleges Defendant improperly referenced a prior "powder" formulation NDA to avoid making a required Paragraph IV certification against the patents-in-suit, which are listed in the FDA Orange Book for Plaintiff's own liquid "solution" NDA. This procedural step, Plaintiff alleges, was an attempt to deprive Plaintiff of a statutory 30-month stay of FDA approval for Defendant's product.
Case Timeline
| Date | Event |
|---|---|
| 2016-12-01 | Priority Date for ’376 and ’669 Patents |
| 2017-10-10 | ’376 Patent Issued |
| 2019-04-11 | FDA Approved Plaintiff's NDA No. 210632 |
| 2019-09-03 | ’669 Patent Issued |
| 2019-09-16 | Plaintiff Received Defendant's Notice Letter |
| 2020-10-30 | 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: Conventional levothyroxine sodium for injection was supplied as a preservative-free lyophilized (freeze-dried) powder that required reconstitution by healthcare practitioners before use (’376 Patent, col. 1:29-41). These reconstituted solutions have limited stability and must be used within hours, and the reconstitution process itself introduces risks of contamination (’376 Patent, col. 1:42-49).
- The Patented Solution: The invention provides a stable, "ready-to-use" liquid formulation of levothyroxine that does not require reconstitution (’376 Patent, col. 2:19-24). The formulation achieves stability through a combination of specific excipients, including tromethamine and sodium iodide, and by maintaining the solution's pH within a basic range of about 9.0 to 11.5 (’376 Patent, Abstract; col. 2:13-18).
- Technical Importance: The creation of a commercially stable, ready-to-use liquid injectable avoids the labor, potential for error, and contamination risks associated with reconstituting lyophilized powders in a clinical setting (’376 Patent, col. 1:42-49).
Key Claims at a Glance
- The complaint asserts independent claim 1 and dependent claims 2-30 (Compl. ¶45).
- Independent Claim 1 requires:
- 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.
U.S. Patent No. 10,398,669 - Levothyroxine Liquid Formulations, Issued September 3, 2019
The Invention Explained
- Problem Addressed: As with the parent ’376 Patent, the ’669 Patent addresses the instability of levothyroxine in aqueous solutions, which leads to degradation and the formation of impurities, such as liothyronine (T3) (’669 Patent, col. 1:50-65).
- The Patented Solution: The invention discloses a ready-to-use liquid formulation that limits degradation and maintains potency over long-term storage (’669 Patent, col. 2:21-30). It achieves this using a "stabilizing agent comprising tromethamine" and limits the amount of the T3 degradant to "not more than 2%" while defining stability through specific functional requirements for retaining the initial concentration of levothyroxine after storage under defined conditions (’669 Patent, Claim 1).
- Technical Importance: This invention provides specific, quantifiable metrics for the stability of a liquid levothyroxine formulation, offering a solution that maintains a high degree of purity and potency over its shelf-life, which is critical for drug safety and efficacy (’669 Patent, col. 2:43-52).
Key Claims at a Glance
- The complaint asserts independent claim 1 and dependent claims 2-17 (Compl. ¶61).
- Independent Claim 1 requires:
- 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.
III. The Accused Instrumentality
- Product Identification: Custopharm's NDA Product, identified as a "liquid levothyroxine sodium injection, 100 mcg/mL" for which Defendant seeks FDA approval via NDA No. 214253 (Compl. ¶24).
- Functionality and Market Context: The complaint alleges the accused product is a liquid solution levothyroxine formulation intended for injection (Compl. ¶¶33-34). The filing of the NDA itself indicates an intent to market a generic version of a drug for which Plaintiff holds an approved NDA, suggesting the product is intended to be a therapeutic equivalent to Plaintiff's commercial product (Compl. ¶¶1, 24). The complaint does not provide further technical detail on the accused product's operation or formulation, noting that Defendant has refused to provide its NDA to Plaintiff under what Plaintiff considers reasonable terms (Compl. ¶38). No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
’376 Patent 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; | Defendant's NDA Product is alleged to be a "liquid formulation containing levothyroxine." | ¶47 | col. 2:13-14 |
| about 1 mg/mL to about 50 mg/mL of tromethamine; | The NDA Product is alleged on information and belief to contain each element of claim 1. | ¶48 | col. 4:15-34 |
| about 10 mcg/mL to about 500 mcg/mL of sodium iodide; and water; | The NDA Product is alleged on information and belief to contain each element of claim 1. | ¶48 | col. 4:35-56 |
| wherein the formulation has a pH of about 9.0 to about 11.5, and | The NDA Product is alleged on information and belief to contain each element of claim 1. | ¶48 | col. 5:11-28 |
| wherein the formulation is stable for at least 12 months at 25±2° C. | The NDA Product is alleged on information and belief to meet this stability requirement. | ¶48 | col. 2:43-52 |
’669 Patent 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; | Defendant's NDA Product is alleged to be a "liquid formulation containing levothyroxine." | ¶64 | col. 2:25-26 |
| a stabilizing agent comprising tromethamine; | The NDA Product is alleged on information and belief to contain each element of claim 1. | ¶65 | col. 4:8-13 |
| not more than 2% liothyronine (T3); and water; | The NDA Product is alleged on information and belief to contain each element of claim 1. | ¶65 | col. 5:42-57 |
| wherein the formulation retains at least about 95% of the initial concentration of levothyroxine... after storage for 12 months at 25±2° C., and | The NDA Product is alleged on information and belief to meet this stability requirement. | ¶65 | col. 16:1-6 |
| retains at least about 95% of the initial concentration of levothyroxine... after storage for 2 months at 40±2° C. | The NDA Product is alleged on information and belief to meet this stability requirement. | ¶65 | col. 16:1-6 |
- Identified Points of Contention:
- Factual Questions: The primary dispute will be factual and contingent on the actual, undisclosed composition of the Defendant's NDA Product. The complaint relies on "information and belief" for the presence and concentration of specific excipients (tromethamine, sodium iodide) and for the satisfaction of the functional pH and stability limitations (Compl. ¶¶48, 65). The case will turn on whether the formulation detailed in NDA No. 214253 falls within the claimed parameters.
- Scope Questions: A potential question for the court is whether the functional stability limitations (e.g., "stable for at least 12 months") are met by the Defendant's product. This raises an evidentiary question of what test data from the NDA demonstrates and how that data aligns with the methods for assessing stability described in the patent specifications (’376 Patent, col. 2:52-64).
V. Key Claim Terms for Construction
The Term: "stable for at least 12 months at 25±2° C." (’376 Patent, Claim 1)
Context and Importance: This functional limitation is central to distinguishing the invention from prior art reconstituted solutions with short-term stability. Infringement will depend on whether the Defendant's product is proven to possess this characteristic. Practitioners may focus on this term because its definition is not merely temporal but is tied to multiple chemical characteristics.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The plain language of the claim does not specify a particular metric for stability, which could support an argument that meeting any reasonable industry measure of stability suffices.
- Evidence for a Narrower Interpretation: The specification defines "stable" and "stability" as encompassing characteristics including, but "without limitation, potency, total impurities, levothyroxine degradation products, specific optical rotation, optical purity, water content, appearance, viscosity, sterility, and color and clarity" (’376 Patent, col. 2:37-43). A party could argue the term requires the formulation to remain within acceptable limits for several or all of these specified characteristics over the 12-month period.
The Term: "stabilizing agent comprising tromethamine" (’669 Patent, Claim 1)
Context and Importance: This term defines a key ingredient of the formulation. The dispute could center on whether tromethamine must be the sole or primary stabilizing agent, or if the term permits the presence of other, unlisted stabilizing agents in the accused product.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The open-ended term "comprising" suggests that other components, including other potential stabilizers, may be present without departing from the claim scope (’669 Patent, col. 15:10-14).
- Evidence for a Narrower Interpretation: The specification identifies tromethamine as a preferred example of an "amine" stabilizing agent and lists other specific amines (’669 Patent, col. 4:5-13). A party might argue that "stabilizing agent" should be construed in light of these examples, potentially limiting its scope or how it functions in the overall composition.
VI. Other Allegations
- Indirect Infringement: The complaint does not plead separate counts for indirect infringement. The primary allegation is a statutory act of infringement under 35 U.S.C. § 271(e)(2) based on the submission of the NDA (Compl. ¶¶42, 58). The complaint also alleges that subsequent commercial manufacture, use, or sale would constitute direct infringement under § 271(a) (Compl. ¶¶44, 60).
- Willful Infringement: The complaint alleges that Defendant was aware of the applications that led to the patents-in-suit "since before the submission of NDA No. 214253" (Compl. ¶¶52, 69). Plaintiff also alleges that Defendant has "no reasonable basis for believing" its product will not infringe or that the claims are invalid (Compl. ¶¶53, 70). These allegations form the basis for a claim of an "exceptional" case under 35 U.S.C. § 285 (Compl. ¶¶54, 71).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central procedural issue revolves around regulatory strategy: does Defendant’s alleged choice to reference a "powder" NDA rather than Plaintiff’s "solution" NDA, for which the patents-in-suit are listed, have legal consequences for the infringement analysis or the availability of a 30-month stay of approval?
- The core substantive issue is one of factual correspondence: once the composition of Defendant's NDA product is revealed through discovery, will its specific formulation—including the identity and concentration of its excipients, its pH, and its demonstrated shelf-life under various conditions—fall within the specific numerical and functional limitations of the asserted claims?
- A key evidentiary question will be one of functional performance: does the stability data contained within Defendant's NDA demonstrate that its product actually meets the functional requirements of the claims, such as retaining "at least about 95%" of its initial levothyroxine concentration after 12 months at room temperature, as mandated by Claim 1 of the ’669 patent?