DCT
3:22-cv-06220
Fresenius Kabi USA LLC v. Xiromed Pharma Espana SL
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Fresenius Kabi USA, LLC (Delaware)
- Defendant: Xiromed Pharma Espana, S.L. (Spain); Xiromed, LLC (New Jersey)
- Plaintiff’s Counsel: ROBINSON MILLER LLC
- Case Identification: 3:22-cv-06220, D.N.J., 10/21/2022
- Venue Allegations: Venue is alleged to be proper as to Xiromed Pharma Espana, S.L. because it is a foreign entity. Venue is alleged to be proper as to Xiromed, LLC because it is incorporated in New Jersey and prepared and filed the Abbreviated New Drug Application (ANDA) at issue from its office in Florham Park, New Jersey.
- Core Dispute: Plaintiff alleges that Defendants' filing of an ANDA to market a generic version of Plaintiff's levothyroxine sodium for injection constitutes an act of infringement of three patents covering stable pharmaceutical formulations.
- Technical Context: The technology concerns lyophilized (freeze-dried) formulations of levothyroxine, a synthetic thyroid hormone used for parenteral (injectable) treatment of conditions such as myxedema coma.
- Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendants' submission of ANDA No. 217495 seeking FDA approval to market a generic levothyroxine product. Defendants' ANDA included a Paragraph IV certification, asserting that Plaintiff's patents-in-suit are invalid, unenforceable, and/or will not be infringed by the proposed generic product. The patents are listed in the FDA's "Orange Book" for Plaintiff's approved New Drug Application (NDA) No. 202231.
Case Timeline
| Date | Event |
|---|---|
| 2011-06-24 | Plaintiff's NDA No. 202231 approved |
| 2011-08-30 | Earliest Priority Date for all patents-in-suit |
| 2015-04-14 | ’289 Patent Issued |
| 2015-10-27 | ’238 Patent Issued |
| 2015-10-27 | ’239 Patent Issued |
| 2022-09-09 | Plaintiff received Defendant's Notice Letter |
| 2022-10-21 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 9,006,289 - "Levothyroxine Formulations"
- Patent Identification: U.S. Patent No. 9,006,289, "Levothyroxine Formulations", issued April 14, 2015 (’289 Patent). (Compl. ¶16).
The Invention Explained
- Problem Addressed: The patent addresses the instability of conventional injectable levothyroxine sodium formulations. It notes the desirability of a new formulation that can "further improve the stability of the levothyroxine," particularly for extended periods above room temperature. (’289 Patent, col. 2:17-23).
- The Patented Solution: The invention is a lyophilized solid composition of levothyroxine sodium that uses a significantly lower amount of mannitol, a bulking agent, compared to conventional formulations. The specification explains that improved stability can be achieved by lowering the mass ratio of mannitol to levothyroxine sodium (M:L) to a level below that of conventional compositions, which had M:L ratios of 50:1 and 20:1. (’289 Patent, col. 6:50-65). This reduction in mannitol is shown to decrease the degradation of levothyroxine into its impurity, liothyronine (T3), over time. (’289 Patent, col. 7, Table 1).
- Technical Importance: Achieving greater stability for an injectable drug like levothyroxine allows for longer shelf-life and less stringent storage requirements, which is critical for a product used in urgent care settings like myxedema coma. (’289 Patent, col. 2:1-3).
Key Claims at a Glance
- The complaint asserts independent claim 1. (Compl. ¶42).
- The essential elements of claim 1 are:
- A composition, comprising:
- about 100 or about 200 micrograms of levothyroxine sodium;
- a phosphate buffer; and
- from 2 to 4 milligrams of mannitol,
- where the composition is a lyophilized solid.
- The complaint reserves the right to assert "one or more additional claims." (Compl. ¶43).
U.S. Patent No. 9,168,238 - "Levothyroxine Formulations"
- Patent Identification: U.S. Patent No. 9,168,238, "Levothyroxine Formulations", issued October 27, 2015 (’238 Patent). (Compl. ¶20).
The Invention Explained
- Problem Addressed: Like the ’289 Patent, the ’238 Patent addresses the need for levothyroxine sodium formulations with improved chemical stability compared to existing products. (’238 Patent, col. 2:17-20).
- The Patented Solution: The patented solution is a specific lyophilized solid composition of levothyroxine sodium. As with the related ’289 Patent, the key is a formulation with a reduced amount of the excipient mannitol, which leads to improved stability and a lower rate of degradation into the T3 impurity. (’238 Patent, Abstract; col. 6:56-65).
- Technical Importance: The invention provides a more stable injectable levothyroxine product, enhancing its reliability and shelf-life for treating hypothyroid conditions. (’238 Patent, col. 2:20-23).
Key Claims at a Glance
- The complaint asserts independent claim 1. (Compl. ¶55).
- The essential elements of claim 1 are:
- A lyophilized solid composition, comprising:
- about 100 micrograms of levothyroxine sodium;
- a buffer; and
- between 2 to 4 milligrams of mannitol.
- The complaint also reserves the right to assert additional claims, including dependent method claims. (Compl. ¶¶56-57).
U.S. Patent No. 9,168,239 - "Levothyroxine Formulations"
- Patent Identification: U.S. Patent No. 9,168,239, "Levothyroxine Formulations", issued October 27, 2015 (’239 Patent). (Compl. ¶24).
- Technology Synopsis: Belonging to the same patent family, the ’239 Patent also seeks to solve the problem of levothyroxine instability in injectable formulations. The patented invention is a lyophilized solid composition comprising a salt of levothyroxine, a buffer, and a specific low-range quantity of mannitol, which is taught to provide superior stability compared to conventional formulations with higher mannitol content. (’239 Patent, col. 6:50-65).
- Asserted Claims: The complaint asserts independent claim 1. (Compl. ¶69).
- Accused Features: The complaint alleges that Xiromed's proposed generic levothyroxine sodium for injection, as described in its ANDA, is a lyophilized solid that will contain the claimed elements: a salt of levothyroxine, a buffer, and between 2 to 4 milligrams of mannitol. (Compl. ¶¶34, 69-70).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is Defendants' "generic levothyroxine products," specifically the "lyophilized levothyroxine sodium for powder for injection, 100 mcg/vial" for which Defendants seek FDA approval via ANDA No. 217495. (Compl. ¶¶1, 34).
Functionality and Market Context
The product is a generic version of Plaintiff's approved NDA product, intended for injection after reconstitution. (Compl. ¶¶34-35). It is intended for the treatment of myxedema coma. (Compl. ¶31). The complaint alleges that, to gain FDA approval, the generic product must be bioequivalent to Plaintiff's product and that Defendants intend to begin manufacturing and selling it in the United States upon approval. (Compl. ¶¶32, 36). No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
'289 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A composition, comprising: about 100 or about 200 micrograms of levothyroxine sodium; | Defendants' ANDA Notice Letter states the proposed product's active ingredient is lyophilized levothyroxine sodium at a strength of 100 mcg/vial. | ¶34, ¶43 | col. 4:11-12 |
| a phosphate buffer; and | The complaint alleges on information and belief that the generic product contains each element of the claim, including a phosphate buffer. | ¶43 | col. 6:45-49 |
| from 2 to 4 milligrams of mannitol, | The complaint alleges on information and belief that the generic product contains mannitol within the claimed range. | ¶43 | col. 5:2-4 |
| where the composition is a lyophilized solid. | The Notice Letter allegedly identified the product as "lyophilized levothyroxine sodium." | ¶34, ¶43 | col. 2:4-5 |
'238 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A lyophilized solid composition, comprising: about 100 micrograms of levothyroxine sodium; | Defendants' ANDA Notice Letter indicates the product is a lyophilized solid with a strength of 100 mcg/vial of levothyroxine sodium. | ¶34, ¶56 | col. 4:11-12 |
| a buffer; and | The complaint alleges on information and belief that the generic product contains each claimed element, including a buffer. | ¶56 | col. 6:45-49 |
| between 2 to 4 milligrams of mannitol. | The complaint alleges on information and belief that the generic product's formulation includes mannitol in the claimed amount. | ¶56 | col. 5:2-4 |
Identified Points of Contention
- Evidentiary Questions: The complaint's infringement allegations for the excipients (the buffer and mannitol) are made "on information and belief." A central issue for the court will be an evidentiary one: does the formulation described in Defendants' confidential ANDA submission in fact contain "a phosphate buffer" (as required by the ’289 Patent) or "a buffer" (as required by the ’238 Patent) and an amount of mannitol that falls "from 2 to 4 milligrams"? The case will likely turn on the precise composition revealed in discovery.
- Scope Questions: Should the evidence show a formulation at the edge of the claimed ranges, the construction of the term "about" could become a key dispute. Furthermore, if Defendants' product uses a non-phosphate buffering agent, the infringement analysis for the ’289 Patent would fail, raising the question of whether the broader term "a buffer" in the ’238 Patent covers the agent used.
V. Key Claim Terms for Construction
The Term: "a phosphate buffer" (’289 Patent, Claim 1)
- Context and Importance: This term is a specific limitation distinguishing the ’289 Patent's claim from the broader claims of the other patents. Infringement hinges on whether the accused product contains this specific class of buffer. Practitioners may focus on this term because if the accused product uses a different type of buffer (e.g., a citrate buffer) or a substance that provides pH control but is not technically a "buffer," there would be no literal infringement of this claim.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification provides non-limiting examples, stating the buffer can be "dibasic sodium phosphate (Na2HPO4) or monobasic sodium phosphate (NaH2PO4)." (’289 Patent, col. 6:47-48). A party could argue this demonstrates an intent to cover the general class of phosphate-based buffering agents.
- Evidence for a Narrower Interpretation: A party could argue the term should be limited by the context of the invention, which seeks to improve upon prior art that used "tribasic sodium phosphate." (’289 Patent, col. 2:6-8). This could be used to argue the term requires a specific function or excludes certain phosphate compounds.
The Term: "about" (’289 and ’238 Patents, Claim 1)
- Context and Importance: This term modifies the numerical ranges for both the active ingredient and mannitol. Its scope is critical for determining infringement if the accused product's formulation is close but not identical to the recited values. Practitioners may focus on this term because its construction often determines the outcome of infringement for chemical composition claims.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The term itself suggests the patentee did not intend to be limited to the exact numbers recited. A party could argue it encompasses a range of values that achieve the same result (improved stability) and accounts for normal manufacturing variances.
- Evidence for a Narrower Interpretation: The patent includes tables and figures with stability data corresponding to specific amounts (e.g., "3 mg" or "10 mg" of mannitol). (’289 Patent, Tables 1-3). A party could argue that these examples define the term's boundaries, suggesting that values outside this demonstrated range would not possess the claimed stability and thus fall outside the scope of "about."
VI. Other Allegations
- Indirect Infringement: The complaint alleges that Defendants will induce and contribute to the infringement of dependent method claims in the ’238 and ’239 patents. This is based on the allegation that Defendants will distribute the generic product with a label instructing medical professionals on its reconstitution and use, which would constitute performance of the claimed methods. (Compl. ¶¶57, 71).
- Willful Infringement: The complaint alleges willful infringement based on Defendants' knowledge of the patents-in-suit at the time of their ANDA submission, as evidenced by their Paragraph IV certification. (Compl. ¶¶46, 60, 74). The complaint further alleges that Defendants have "no reasonable basis" for their non-infringement and invalidity positions, which forms the basis for a request for enhanced damages and attorneys' fees for an "exceptional case." (Compl. ¶¶47-48, 61-62, 75-76).
VII. Analyst’s Conclusion: Key Questions for the Case
- A primary issue for the court will be one of factual correspondence: does the specific chemical composition detailed in Defendants' confidential ANDA filing meet every limitation of the asserted claims? The complaint's pleading "on information and belief" regarding the formulation's excipients underscores that the central dispute will be an evidentiary one, dependent on facts produced during discovery.
- A second core issue will be the validity of the patents. Defendants' Paragraph IV certification signals an intent to challenge the patents, likely on grounds of obviousness. The key question for validity will be whether it was obvious to a person of ordinary skill at the time to achieve improved levothyroxine stability by reducing the amount of a standard excipient like mannitol, a finding the patentee presents as a surprising and unexpected result.
- Finally, a key legal question may be one of claim scope: how broadly should the term "about" be interpreted in the context of the patent's stability data, and does the term "a phosphate buffer" in the '289 Patent encompass any buffering agent used in the accused product, or is it more narrowly defined?