DCT

4:24-cv-01392

Advanced Accelerator Applications USA Inc v. Curium US LLC

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 4:24-cv-01392, E.D. Mo., 10/18/2024
  • Venue Allegations: Venue is asserted based on Defendants Curium US LLC and Curium US Holdings LLC having their principal places of business in St. Louis, Missouri, within the judicial district.
  • Core Dispute: Plaintiff alleges that Defendant’s filing of a New Drug Application for a generic version of Plaintiff's LUTATHERA® cancer therapy constitutes an act of infringement of three patents related to stable, concentrated radiopharmaceutical formulations.
  • Technical Context: The technology concerns formulations for targeted radioligand therapies, which use radioactive isotopes attached to cell-targeting molecules to deliver radiation directly to cancer cells.
  • Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following a September 5, 2024 notification letter from Defendant. In that letter, Defendant informed Plaintiff of its New Drug Application No. 218525 and made a "Paragraph IV certification," asserting that the patents-in-suit are invalid, unenforceable, and/or will not be infringed by its proposed product.

Case Timeline

Date Event
2018-07-25 Earliest Patent Priority Date for ’276, ’278, and ’027 Patents
2020-03-24 U.S. Patent No. 10,596,276 Issued
2020-03-24 U.S. Patent No. 10,596,278 Issued
2024-02-20 U.S. Patent No. 11,904,027 Issued
2024-09-05 Defendant Notifies Plaintiff of New Drug Application Filing
2024-10-18 Complaint Filed

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

No probative visual evidence provided in complaint.

U.S. Patent No. 10,596,276, Stable, Concentrated Radionuclide Complex Solutions, issued March 24, 2020

The Invention Explained

  • Problem Addressed: Radiopharmaceutical drug products are inherently unstable due to "radiolysis," where the radioactive decay of the isotope releases high-energy emissions that degrade the drug molecules, limiting shelf-life and efficacy (Compl. ¶27; ’276 Patent, col. 3:45-54). This instability has historically required such drugs to be prepared in hospitals for immediate patient use, rather than being manufactured at a commercial scale ('276 Patent, col. 3:55-61).
  • The Patented Solution: The patent describes a highly concentrated, ready-to-use aqueous solution of a radionuclide complex that is stabilized against radiolytic degradation through the use of specific stabilizers ('276 Patent, Abstract; col. 3:51-57). The invention discloses using a combination of stabilizers, such as gentisic acid and ascorbic acid, to protect the cell-targeting drug moiety, thereby enabling a longer shelf-life and facilitating centralized, commercial-scale manufacturing ('276 Patent, col. 4:20-28, 4:30-39).
  • Technical Importance: This approach allows a sensitive, targeted cancer therapy to be produced as a standardized, stable, ready-to-use product, potentially improving quality, consistency, and accessibility compared to traditional on-site preparations ('276 Patent, col. 4:30-47).

Key Claims at a Glance

The complaint alleges infringement of one or more claims without specification (Compl. ¶41). Independent claim 23 is representative of the patented composition.

  • Independent Claim 23: A pharmaceutical aqueous solution comprising:
    • a complex formed by the radionuclide ¹⁷⁷Lutetium (Lu-177) in a concentration providing a volumetric radioactivity of from 250 to 500 MBq/mL, and the chelating agent linked somatostatin receptor binging organic moiety DOTA-TATE or DOTA-TOC;
    • gentisic acid or a salt thereof as a first stabilizer in a concentration of from 0.5 to 1 mg/mL; and
    • ascorbic acid or a salt thereof as the second stabilizer in a concentration of from 2.0 to 5.0 mg/mL.

U.S. Patent No. 10,596,278, Stable, Concentrated Radionuclide Complex Solutions, issued March 24, 2020

The Invention Explained

  • Problem Addressed: The '278 Patent addresses the same technical challenge as the '276 Patent: the radiolytic instability of concentrated radiopharmaceutical solutions, which limits their shelf-life and prevents large-scale commercial production (Compl. ¶29; ’278 Patent, col. 3:45-50). The background also notes that prior art stabilization strategies, such as using ethanol, can be problematic for patient tolerability ('278 Patent, col. 3:18-24).
  • The Patented Solution: The '278 Patent claims a stable, concentrated, and ready-to-use aqueous solution of a radionuclide complex that uses at least two different stabilizers, specifically identifying gentisic acid and ascorbic acid ('278 Patent, Abstract; col. 10:55-65). The invention achieves high stability (≥95% radiochemical purity for at least 72 hours) while containing less than 1% ethanol, addressing the tolerability issue ('278 Patent, col. 11:3-11).
  • Technical Importance: The invention provides a formulation that is not only stable enough for commercial distribution but is also designed for high physiological tolerability by strictly limiting the ethanol content ('278 Patent, col. 4:25-28).

Key Claims at a Glance

The complaint asserts one or more claims without specification (Compl. ¶61). Independent claim 1 is representative of the patented composition.

  • Independent Claim 1: A pharmaceutical aqueous solution comprising:
    • a complex formed by the radionuclide ¹⁷⁷Lu and a somatostatin receptor binding peptide linked to the chelating agent DOTA;
    • at least two different stabilizers against radiolytic degradation comprising gentisic acid and ascorbic acid;
    • wherein the radionuclide provides a volumetric radioactivity of from 250 to 500 MBq/mL;
    • the stabilizers are present in a total concentration of from 1.0 to 5.0 mg/mL;
    • the solution has less than 1% ethanol; and
    • the radiochemical purity is maintained at ≥95% for at least 72 hours when stored at 25° C.

Multi-Patent Capsule: U.S. Patent No. 11,904,027, Stable, Concentrated Radionuclide Complex Solutions, issued February 20, 2024

  • Technology Synopsis: The '027 Patent is in the same family as the '276 and '278 patents and addresses the same technical problem of stabilizing concentrated radiopharmaceutical solutions against radiolytic degradation (Compl. ¶31). The patented solution involves specific formulations containing the radionuclide complex and at least two stabilizers to achieve high stability and enable a commercially viable, ready-to-use drug product ('027 Patent, Abstract).
  • Asserted Claims: The complaint asserts infringement of one or more claims of the patent (Compl. ¶81).
  • Accused Features: The accused features are the overall composition and stability characteristics of Defendant's proposed Lutetium Lu-177 Dotatate injection solution (Compl. ¶¶ 77, 81).

III. The Accused Instrumentality

  • Product Identification: Defendant's Lutetium Lu-177 Dotatate injection solution, for which New Drug Application (NDA) No. 218525 was submitted to the FDA (Compl. ¶15).
  • Functionality and Market Context: The complaint alleges that Defendant's product is a version of Plaintiff’s LUTATHERA® product, a radiolabeled somatostatin analog for treating certain neuroendocrine tumors in adults (Compl. ¶¶ 15, 33). By filing its NDA, Defendant has represented to the FDA that its product will have the same active ingredient, dosage form, strength, and method of administration as LUTATHERA® and will be bioequivalent to it (Compl. ¶37). The product is therefore positioned to compete directly with Plaintiff's branded cancer therapy upon receiving FDA approval.

IV. Analysis of Infringement Allegations

The complaint does not provide specific technical details of the accused product's formulation. The infringement theory is predicated on the allegation that because Defendant's product is a bioequivalent version of LUTATHERA®, it will necessarily meet the limitations of the asserted patent claims covering the LUTATHERA® formulation (Compl. ¶¶ 37, 57).

’276 Patent Infringement Allegations

Claim Element (from Independent Claim 23) Alleged Infringing Functionality Complaint Citation Patent Citation
A pharmaceutical aqueous solution, comprising (a) a complex formed by (ai) the radionuclide ¹⁷⁷Lutetium (Lu-177), present in a concentration that it provides a volumetric radioactivity of from 250 to 500 MBq/mL, and (aii) the chelating agent linked somatostatin receptor binging organic moiety DOTA-TATE... or DOTA-TOC... The accused product is a Lutetium Lu-177 Dotatate injection solution alleged to have the same active ingredient and strength as LUTATHERA®. ¶¶ 15, 37 col. 5:40-44, col. 5:61-67
(bi) gentisic acid or a salt thereof as the first stabilizer against radiolytic degradation present in a concentration of from 0.5 to 1 mg/mL; The accused product, being bioequivalent to LUTATHERA®, is alleged to contain the claimed stabilizers in the claimed concentration range. ¶37 col. 7:25-29
(bii) ascorbic acid or a salt thereof as the second stabilizer against radiolytic degradation present in a concentration of from 2.0 to 5.0 mg/mL. The accused product, being bioequivalent to LUTATHERA®, is alleged to contain the claimed stabilizers in the claimed concentration range. ¶37 col. 7:30-34

’278 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A pharmaceutical aqueous solution comprising: (a) a complex formed by (ai) the radionuclide ¹⁷⁷Lu... and (aii) a somatostatin receptor binding peptide linked to the chelating agent DOTA; The accused product is a Lutetium Lu-177 Dotatate injection solution alleged to have the same active ingredient as LUTATHERA®. ¶¶ 15, 57 col. 10:55-59
(b) at least two different stabilizers against radiolytic degradation comprising (bi) gentisic acid... and (bii) ascorbic acid... The accused product, being bioequivalent to LUTATHERA®, is alleged to contain at least these two specified stabilizers. ¶57 col. 10:60-63
wherein said radionuclide is present in a concentration that it provides a volumetric radioactivity of from 250 to 500 MBq/mL; The accused product is alleged to have the same strength as LUTATHERA® and thus meet the claimed radioactivity concentration. ¶57 col. 10:66-67
said stabilizers are present in a total concentration of from 1.0 to 5.0 mg/mL; The accused product is alleged to contain stabilizers meeting this total concentration range. ¶57 col. 11:1-3
and the pharmaceutical aqueous solution has less than 1% ethanol... The accused product is alleged to meet this negative limitation on ethanol content. ¶57 col. 11:3-5
and the radiochemical purity... is maintained at ≥95% for at least 72 h when stored at 25° C. The accused product, as a stable commercial formulation, is alleged to meet this functional stability requirement. ¶57 col. 11:5-11

Identified Points of Contention:

  • Factual Questions: The central dispute will be factual and dependent on discovery. What is the precise qualitative and quantitative composition of the Defendant's proposed product? Does it contain both gentisic acid and ascorbic acid, and if so, are they present in concentrations that fall within the ranges specified by the claims?
  • Scope Questions: Can Defendant design a formulation that is "bioequivalent" for FDA purposes but avoids the specific compositional or functional limitations of the claims? For instance, a key question may be whether Defendant's product achieves the required stability (e.g., ≥95% purity for 72 hours) as claimed in the ’278 Patent, or if it has a different stability profile that falls outside the claim scope.

V. Key Claim Terms for Construction

  • The Term: "stabilizer against radiolytic degradation" (’276 Patent, cl. 23; ’278 Patent, cl. 1)

    • Context and Importance: This functional term is central to the invention. A defendant may argue that certain excipients in its formulation, even if they are gentisic or ascorbic acid, are present for a different primary purpose (e.g., as a general antioxidant or pH buffer) and do not function as a "stabilizer against radiolytic degradation" in the manner required by the patent. The question is whether the mere presence of the substance is sufficient, or if it must be present for the stated purpose.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification provides a list of compounds that can be used as stabilizers, including gentisic acid and ascorbic acid, and refers to them with alternative terms such as "radical scavengers" or "quenchers," suggesting the term covers compounds that perform this general function ('276 Patent, col. 5:1-6; col. 29:13-24).
      • Evidence for a Narrower Interpretation: The background section specifically ties the problem of "radiolytic degradation" to the "cleavage of the chemical bonds of the molecules which form part of the drug product," particularly the receptor binding moiety ('276 Patent, col. 3:45-54). A party could argue the term should be limited to substances that are shown to specifically protect the active drug moiety from this particular degradation pathway.

  • The Term: "radiochemical purity... is maintained at ≥95% for at least 72 h when stored at 25° C." (’278 Patent, cl. 1)

    • Context and Importance: This functional limitation defines a required performance characteristic of the claimed solution. Infringement will depend on whether the accused product actually meets this stability threshold. Practitioners may focus on the precise test method for determining "radiochemical purity" (e.g., the patent mentions HPLC) and whether the accused product satisfies the "at least 72 h" duration ('278 Patent, cl. 1; col. 15:33-36).
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The patent frames this stability as a key advantage enabling a 3-day shelf-life required for a commercially viable, centrally manufactured drug product ('278 Patent, col. 4:29-39). This suggests the term should be understood in the practical context of commercial drug stability.
      • Evidence for a Narrower Interpretation: A party might argue that any deviation from the specific testing conditions and methodologies implicitly or explicitly disclosed in the patent's examples for measuring purity would place a product outside the scope of the claim.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges Defendants "plan and intend to... actively induce infringement" upon approval of their product (Compl. ¶¶ 43, 63, 83). The alleged basis for inducement is the future marketing, distribution, and labeling of the product, which will instruct users on its infringing use.
  • Willful Infringement: The complaint does not contain an explicit count for willful infringement. However, it alleges that Defendants have had "actual and constructive knowledge" of the patents-in-suit since at least September 5, 2024, the date of their notification letter (Compl. ¶¶ 39, 59, 79). This allegation establishes pre-suit knowledge of the patents and the alleged infringement, a predicate for any future claim of willfulness.

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

  • A core issue will be one of factual composition: What is the precise quantitative and qualitative formulation of the Defendants' proposed product as described in its confidential NDA? The outcome of the case will depend heavily on whether that formulation includes gentisic acid and ascorbic acid within the specific concentration ranges required by the asserted claims.
  • A key evidentiary question will be one of functional performance: Does the accused formulation demonstrate the specific, quantified stability recited in claims like Claim 1 of the ’278 patent—namely, maintaining ≥95% radiochemical purity for at least 72 hours at 25°C? Proving or disproving this functional limitation will be a central technical battleground.