DCT

1:24-cv-00095

Advanced Accelerator Applications USA Inc v. Lantheus Medical Imaging Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:24-cv-00095, D. Del., 02/03/2025
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware based on Defendants’ incorporation in the state.
  • Core Dispute: Plaintiff alleges that Defendant's filing of an Abbreviated New Drug Application (ANDA) for a generic version of the cancer therapy LUTATHERA® constitutes an act of infringement of five patents related to stable, concentrated radiopharmaceutical solutions.
  • Technical Context: The technology concerns formulations for radiopharmaceuticals used in targeted radioligand therapy, a treatment for certain types of cancer such as neuroendocrine tumors.
  • Key Procedural History: The action was triggered by Defendant’s submission of ANDA No. 217060 to the U.S. Food and Drug Administration. As required under the Hatch-Waxman Act, Defendant sent Plaintiff notice letters with Paragraph IV certifications, asserting that the patents-in-suit are invalid, unenforceable, or will not be infringed by the proposed generic product.

Case Timeline

Date Event
2018-07-25 Earliest Priority Date for all Patents-in-Suit
2020-03-24 U.S. Patent No. 10,596,276 Issued
2023-12-12 Defendant provides Paragraph IV notice for the ’276 Patent
2024-11-19 U.S. Patent No. 12,144,873 Issued
2024-11-26 U.S. Patent No. 12,151,003 Issued
2024-12-10 U.S. Patent No. 12,161,732 Issued
2024-12-16 Defendant provides Paragraph IV notice for the ’873 and ’003 Patents
2024-12-17 U.S. Patent No. 12,168,063 Issued
2024-12-20 Defendant provides Paragraph IV notice for the ’732 and ’063 Patents
2025-02-03 Complaint Filed

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

U.S. Patent No. 10,596,276 - “Stable, Concentrated Radionuclide Complex Solutions” (Issued Mar. 24, 2020)

The Invention Explained

  • Problem Addressed: The patent addresses the problem of "radiolysis," or the degradation of radiopharmaceutical drug products caused by the energy released from the radionuclide itself. This instability has historically required such drugs to be produced in high dilution, which is inconvenient for patients, or stabilized with high concentrations of ethanol, which can cause tolerability issues. (Compl. Ex. A, ’276 Patent, col. 3:9-50).
  • The Patented Solution: The invention is a highly concentrated, ready-to-use radiopharmaceutical solution that achieves chemical and radiochemical stability through the use of specific stabilizers that protect the drug molecules from radiolytic degradation. The patent describes using a combination of two different stabilizers, such as gentisic acid and ascorbic acid, noting a sequential application process (one stabilizer during complex formation, another added later) as particularly advantageous for protecting the drug during manufacturing and ensuring a longer shelf-life. (’276 Patent, col. 4:1-15, col. 5:1-6).
  • Technical Importance: This technical approach allows for the centralized, commercial-scale production of a ready-to-use radiopharmaceutical that can be shipped to clinical centers, obviating the need for on-site preparation and reconstitution from "cold" kits immediately before administration. (’276 Patent, col. 4:30-47).

Key Claims at a Glance

  • The complaint asserts infringement of one or more claims without specification. Independent claim 23 is a representative composition claim.
  • Essential elements of Independent Claim 23 include:
    • A pharmaceutical aqueous solution comprising a complex formed by the radionuclide ¹⁷⁷Lutetium and a chelating agent linked to a somatostatin receptor binding moiety (DOTA-TATE or DOTA-TOC).
    • The radionuclide is present in a concentration providing a volumetric radioactivity of 250 to 500 MBq/mL.
    • A first stabilizer, gentisic acid, present in a concentration of 0.5 to 1 mg/mL.
    • A second stabilizer, ascorbic acid, present in a concentration of 2.0 to 5.0 mg/mL.

U.S. Patent No. 12,144,873 - “Stable, Concentrated Radionuclide Complex Solutions” (Issued Nov. 19, 2024)

The Invention Explained

  • Problem Addressed: As with the related ’276 Patent, this patent addresses the challenge of creating a stable, concentrated radiopharmaceutical solution that is resistant to radiolytic degradation. (Compl. Ex. B, ’873 Patent, col. 1:15-2:51).
  • The Patented Solution: The patent claims methods of treating tumors by administering a specific volume (10 mL to 50 mL) of a pharmaceutical aqueous solution containing the ¹⁷⁷Lutetium-DOTA complex. The solution's stability is ensured by the presence of at least one stabilizer at a specified total concentration and a low concentration (less than 2%) of ethanol, enabling the administration of a high radioactive dose in a small, well-tolerated volume. (’873 Patent, col. 3:1-4:65).
  • Technical Importance: The claimed method provides a specific therapeutic regimen that leverages the stable, concentrated formulation to deliver an effective dose to a patient within a convenient and clinically practical infusion volume and time frame. (’873 Patent, col. 4:50-56).

Key Claims at a Glance

  • The complaint asserts infringement of one or more claims without specification. Independent claim 1 is a representative method of treatment claim.
  • Essential elements of Independent Claim 1 include:
    • A method of treating a tumor by administering 10 mL to 50 mL of a pharmaceutical aqueous solution.
    • The solution comprises a complex of the radionuclide ¹⁷⁷Lu and a somatostatin receptor binding peptide linked to the chelating agent DOTA.
    • The solution contains at least one stabilizer against radiolytic degradation at a total concentration of 0.5 mg/mL to 10.0 mg/mL.
    • The radionuclide provides a volumetric radioactivity of 250 to 500 MBq/mL.
    • The solution comprises less than 2% ethanol.

U.S. Patent No. 12,151,003 - “Stable, Concentrated Radionuclide Complex Solutions” (Issued Nov. 26, 2024)

  • Technology Synopsis: This patent, from the same family as the lead patents, claims pharmaceutical compositions for stable radionuclide solutions. The claims specify concentrations for the active complex, two distinct stabilizers (gentisic acid and ascorbic acid), and further require the presence of a sequestering agent and an acetate buffer. (Compl. Ex. C, ’003 Patent, Abstract; Claim 1).
  • Asserted Claims: The complaint asserts one or more unspecified claims; independent claims include claim 1 (a composition claim). (Compl. ¶¶ 75-76).
  • Accused Features: The formulation of Defendants' ANDA Product is accused of infringing the claimed composition. (Compl. ¶ 79).

U.S. Patent No. 12,161,732 - “Stable, Concentrated Radionuclide Complex Solutions” (Issued Dec. 10, 2024)

  • Technology Synopsis: This patent claims methods for manufacturing a pharmaceutical aqueous solution. The claimed process involves forming a radionuclide complex in the presence of a first stabilizer, and then diluting that complex with a solution containing a second, different stabilizer to achieve the final stable product. (Compl. Ex. D, ’732 Patent, Abstract; Claim 1).
  • Asserted Claims: The complaint asserts one or more unspecified claims; independent claims include claim 1 (a process claim). (Compl. ¶¶ 95-96).
  • Accused Features: Defendants' process for manufacturing their ANDA Product is accused of infringing the claimed method. (Compl. ¶ 99).

U.S. Patent No. 12,168,063 - “Stable, Concentrated Radionuclide Complex Solutions” (Issued Dec. 17, 2024)

  • Technology Synopsis: This patent claims pharmaceutical compositions for stable radionuclide solutions, similar to the ’003 patent. The claims specify concentrations for the active complex, at least one stabilizer, and require the solution to have a low ethanol content (less than 1%) and a radiochemical purity of at least 95% for 72 hours. (Compl. Ex. E, ’063 Patent, Abstract; Claim 1).
  • Asserted Claims: The complaint asserts one or more unspecified claims; independent claims include claim 1 (a composition claim). (Compl. ¶¶ 115-116).
  • Accused Features: The formulation of Defendants' ANDA Product is accused of infringing the claimed composition. (Compl. ¶ 119).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is "Defendants' ANDA Product," a generic version of LUTATHERA® (lutetium Lu 177 dotatate) injection solution, for which Defendants filed ANDA No. 217060 seeking FDA approval. (Compl. ¶ 9).

Functionality and Market Context

The complaint alleges that, by virtue of the ANDA filing process, the Defendants' ANDA Product will necessarily have the same active ingredient, method of administration, dosage form, and strength as the branded LUTATHERA® product. (Compl. ¶ 35). LUTATHERA® is a radiolabeled therapy indicated for the treatment of certain neuroendocrine tumors in adults. (Compl. ¶ 31). The complaint alleges that Defendants' product, upon approval, will be bioequivalent to LUTATHERA® and will be sold for the same therapeutic uses. (Compl. ¶ 35).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

’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 The complaint alleges Defendants' ANDA Product is a pharmaceutical solution for infusion that, being bioequivalent to LUTATHERA®, will contain ¹⁷⁷Lu at a concentration providing the claimed radioactivity. ¶35, ¶39 col. 3:5-10
(aii) the chelating agent linked somatostatin receptor binging organic moiety DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide); The active ingredient is alleged to be the same as LUTATHERA®, which is a lutetium Lu 177 dotatate complex. ¶35 col. 5:40-48
(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 ANDA Product, as a generic equivalent, is alleged to contain the necessary stabilizers, including gentisic acid, within the claimed concentration range to achieve stability. ¶35, ¶39 col. 3:11-14
(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 ANDA Product is alleged to contain ascorbic acid as a second stabilizer within the claimed concentration range. ¶35, ¶39 col. 3:14-17

’873 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of treating a tumor in a patient in need thereof, the method comprising administering to the patient 10 mL to 50 ml of a pharmaceutical aqueous solution The complaint alleges that Defendants' proposed product labeling will instruct medical professionals to administer the generic drug in a volume that meets this limitation to treat tumors. ¶58, ¶61 col. 4:50-56
comprising: (a) a complex comprising: (ai) the radionuclide ¹⁷⁷Lu, and (aii) a somatostatin receptor binding peptide linked to the chelating agent DOTA; The ANDA Product is alleged to contain the same active ¹⁷⁷Lu-DOTA complex as the branded product. ¶55 col. 6:1-6
and (b) at least one stabilizer(s) against radiolytic degradation; wherein: the at least one stabilizer(s) against radiolytic degradation is/are present in a total concentration of 0.5 mg/mL to 10.0 mg/mL; The ANDA Product's formulation is alleged to contain stabilizers within the claimed total concentration range to ensure product stability, consistent with its status as a generic equivalent. ¶55, ¶59 col. 3:11-14
the radionuclide is present in the pharmaceutical aqueous solution in a concentration that provides a volumetric radioactivity of 250 to 500 MBq/mL; The ANDA Product is alleged to match the strength and dosage form of LUTATHERA®, thereby meeting the claimed radioactivity concentration. ¶55 col. 3:3-5
and the pharmaceutical aqueous solution comprises less than 2% ethanol. The ANDA Product is alleged to be a formulation with low or no ethanol, consistent with the patent's teachings and the branded product's characteristics. ¶59 col. 5:7-16

Identified Points of Contention

  • Factual Questions: A primary point of contention will be factual: does the precise formulation of the Defendants' ANDA Product, including the identity and concentration of its stabilizers, fall within the ranges recited in the asserted composition claims (e.g., of the ’276 and ’003 Patents)? The complaint relies on the ANDA's bioequivalence representation, but the actual excipient composition will be a key area of discovery.
  • Scope Questions: The infringement theory for method claims (e.g., in the ’873 Patent) and process claims (in the ’732 Patent) will depend on the content of the Defendants' proposed product label and their manufacturing process. A key question for the court will be whether the label's instructions will induce infringement of the method claims and whether the manufacturing process meets all limitations of the process claims.

V. Key Claim Terms for Construction

The Term: "stabilizer against radiolytic degradation" (appears in asserted patents)

  • Context and Importance: This term is the technological core of the invention, as the patents are directed to achieving stability through the use of such agents. The scope of this term is critical because it defines which chemical compounds can be used to meet this claim limitation. Practitioners may focus on this term because the specific choice and combination of stabilizers are central to the patent's novelty and non-obviousness arguments.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification provides a functional definition, describing stabilizers as agents that protect against radiolytic degradation, and provides a list of examples including "gentisic acid... ascorbic acid... methionine, histidine, melatonin, ethanol, and Se-methionine" (’276 Patent, col. 5:1-6). This list could support an interpretation that the term covers any of these specified compounds or others with similar function.
    • Evidence for a Narrower Interpretation: The preferred embodiments, working examples, and many of the claims focus specifically on the combination of gentisic acid and ascorbic acid. A party might argue that the invention's true scope, when read in context, is limited to this specific, highly effective combination rather than the broader class of potential stabilizers.

The Term: "pharmaceutical aqueous solution" (appears in asserted patents)

  • Context and Importance: While seemingly straightforward, the nature of this solution is a key feature of the invention. The patents distinguish the invention from prior art "kits" that require reconstitution. The definition of this term will be important for determining whether a product that requires any form of mixing or dilution at the point of care could infringe.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: A party could argue for the plain and ordinary meaning: a solution suitable for pharmaceutical administration in which water is the solvent.
    • Evidence for a Narrower Interpretation: The specification repeatedly emphasizes that a key advantage of the invention is providing a "ready-to-use" product that avoids the reconstitution steps required by prior art kits (’276 Patent, col. 3:4-8; col. 4:44-47). This context may support an argument that the term "pharmaceutical aqueous solution" as used in the patents implicitly requires the solution to be in a final, stable, pre-mixed form suitable for direct administration.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges active inducement of infringement, stating that Defendants intend for their ANDA Product to be used in an infringing manner upon approval, as will be instructed by the product's proposed labeling (Compl. ¶¶ 41, 61, 81, 101, 121). The complaint also pleads contributory infringement, alleging the ANDA Product is especially made or adapted for infringing uses and is not suitable for substantial non-infringing use (Compl. ¶¶ 42, 62, 82, 102, 122).
  • Willful Infringement: The complaint does not contain an explicit count for willful infringement. However, it establishes a basis for potential future willfulness allegations by pleading that Defendants have had actual knowledge of each patent-in-suit since the dates they provided their Paragraph IV notice letters (Compl. ¶¶ 37, 57, 77, 97, 117).

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

  • A core issue will be one of factual correspondence: does the specific formulation of the Defendants' ANDA Product—particularly the identity, concentration, and combination of its stabilizers—fall within the precise numerical ranges defined by the asserted composition claims, or does it represent a non-infringing "design around"?
  • A second central question will be one of induced infringement: will the instructions for use on the Defendants’ proposed product label direct medical professionals to administer the generic drug in a manner that satisfies every step of the asserted method of treatment claims?
  • Finally, the case will likely involve a significant validity dispute: although not detailed in the complaint, the Defendants' Paragraph IV notice letters assert invalidity, raising the question of whether the claimed inventions are obvious or otherwise unpatentable in light of prior art related to stabilizing radiopharmaceuticals.