DCT

1:23-cv-00079

Bristol Myers Squibb Co v. AstraZeneca Pharma LP

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:23-cv-00079, D. Del., 01/23/2023
  • Venue Allegations: Plaintiff alleges venue is proper in the District of Delaware because Defendant AstraZeneca Pharmaceuticals LP is a Delaware entity and Defendant AstraZeneca AB conducts business in the district through its subsidiary and has consented to jurisdiction in prior cases.
  • Core Dispute: Plaintiff alleges that Defendant’s cancer immunotherapy drug, IMJUDO®, when used in certain combination therapies, infringes two patents related to methods of treating cancer by combining checkpoint inhibitor antibodies with other therapeutic agents.
  • Technical Context: The lawsuit concerns cancer immunotherapy, a field focused on using a patient's own immune system to fight cancer, specifically through the use of "checkpoint inhibitors" that block signals used by cancer cells to evade immune attack.
  • Key Procedural History: The complaint alleges that the parties engaged in licensing discussions regarding Plaintiff's CTLA-4 patent portfolio, including one of the patents-in-suit, beginning in December 2021. The complaint also references prior patent litigation between the parties involving Defendant's related immunotherapy product, IMFINZI®, as a basis for Defendant's knowledge of Plaintiff's patent portfolio.

Case Timeline

Date Event
2005-07-01 U.S. Patent No. 9,273,135 Priority Date
2008-08-01 U.S. Patent No. 9,320,811 Priority Date
2016-03-01 U.S. Patent No. 9,273,135 Issues
2016-04-26 U.S. Patent No. 9,320,811 Issues
2021-12-01 Alleged licensing discussions begin between parties (approximate)
2022-10-21 FDA approves IMJUDO® for use in treating unresectable hepatocellular carcinoma (uHCC)
2022-11-10 FDA approves IMJUDO® for use in treating metastatic non-small cell lung cancer (NSCLC)
2023-01-23 Complaint Filed

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

U.S. Patent No. 9,320,811 - "Combination of Anti-CTLA4 Antibody with Diverse Therapeutic Regimens for the Synergistic Treatment of Proliferative Diseases"

  • Issued: April 26, 2016

The Invention Explained

  • Problem Addressed: The patent addresses the general need for improved anticancer regimens to treat the wide variety of existing cancers (’811 Patent, col. 1:27-33). It notes that combining chemotherapy with immunotherapy is a novel approach that could enhance the effects of both treatments ('811 Patent, col. 2:51-63).
  • The Patented Solution: The invention is a method for treating cancer that combines two different types of therapies to achieve a synergistic, or greater-than-additive, effect. It specifically claims the concurrent administration of an anti-CTLA-4 antibody (an immunotherapy agent that blocks an immune checkpoint) with a nucleoside analogue like gemcitabine (a chemotherapy agent) ('811 Patent, Abstract; col. 3:1-9). This combination is intended to both directly attack cancer cells with chemotherapy and stimulate a more robust anti-tumor immune response.
  • Technical Importance: The invention provided a framework for combining two major pillars of cancer therapy—chemotherapy and immunotherapy—to create a more powerful, synergistic treatment than either could provide alone ('811 Patent, col. 2:45-63).

Key Claims at a Glance

  • The complaint asserts independent claim 1, among other claims (Compl. ¶39).
  • The essential elements of independent claim 1 are:
    • A method for the treatment of cancer,
    • comprising the concurrent administration to a mammal in need thereof
    • a synergistic, therapeutically effective amount of
    • an anti-CTLA-4 antibody with
    • 2'-deoxy-2',2'-difluorocytidine monohydrochloride (β-isomer) [gemcitabine hydrochloride], or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • The complaint also asserts dependent claims 2, 4-5, 7-9, and 13-16 (Compl. ¶39).

U.S. Patent No. 9,273,135 - "Human Monoclonal Antibodies to Programmed Death Ligand 1 (PD-L1)"

  • Issued: March 1, 2016

The Invention Explained

  • Problem Addressed: The patent background describes how tumors can express the PD-L1 ligand to interact with the PD-1 receptor on T-cells, which suppresses T-cell activation and allows the tumor to evade the immune system (’135 Patent, col. 1:50-59). This highlights the need for therapies that can block this immunosuppressive pathway.
  • The Patented Solution: The invention is a method for enhancing a patient's immune response to cancer by administering two different types of checkpoint inhibitors together: an anti-CTLA-4 antibody and an anti-PD-L1 antibody ('135 Patent, col. 8:60-67). The patent does not claim any specific anti-PD-L1 antibody by name, but rather defines it functionally as one that "cross-competes" for binding to PD-L1 with a set of ten specific reference antibodies defined by their amino acid sequences ('135 Patent, col. 139:15-55).
  • Technical Importance: This patent covers the concept of dual checkpoint blockade, targeting both the CTLA-4 and PD-1/PD-L1 pathways simultaneously, which has become a foundational and highly effective strategy in modern cancer immunotherapy.

Key Claims at a Glance

  • The complaint asserts independent claim 1, among other claims (Compl. ¶73).
  • The essential elements of independent claim 1 are:
    • A method for enhancing an immune response in a subject
    • comprising administering a combination of an anti-PD-L1 monoclonal antibody and an anti-CTLA-4 monoclonal antibody,
    • wherein the anti-PD-L1 monoclonal antibody cross-competes for binding to PD-L1 with a reference antibody comprising one of ten specific heavy and light chain variable region amino acid sequences, and
    • wherein enhancing the immune response results in inhibition of tumor cell growth.
  • The complaint also asserts dependent claims 2-3, 6-9, 11, 13-16, 17, 20, 24, 26-27, and 30 (Compl. ¶73).

III. The Accused Instrumentality

  • Product Identification: The accused product is IMJUDO® (tremelimumab-actl) (Compl. ¶8).
  • Functionality and Market Context: IMJUDO® is a human monoclonal IgG2 anti-CTLA-4 antibody, a type of checkpoint inhibitor used to treat cancer (Compl. ¶¶28, 33). The complaint alleges infringement based on IMJUDO®'s FDA-approved use in specific combination regimens:
    • For metastatic non-small cell lung cancer (NSCLC), it is approved for use in combination with durvalumab (an anti-PD-L1 antibody) and platinum-based chemotherapy. The complaint alleges that this chemotherapy regimen includes gemcitabine for patients with squamous NSCLC (Compl. ¶¶31, 35).
    • For unresectable hepatocellular carcinoma (uHCC), it is approved for use in combination with durvalumab (Compl. ¶29).
    • The complaint positions IMJUDO® as a direct competitor to Plaintiff's own anti-CTLA-4 antibody, YERVOY® (Compl. ¶41).
  • No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

U.S. Patent No. 9,320,811 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for the treatment of cancer, comprising... Defendants market and sell IMJUDO® for the treatment of cancer, specifically including NSCLC, and provide instructions for this use (Compl. ¶¶34, 35). ¶35 col. 3:1-2
...the concurrent administration to a mammal in need thereof a synergistic, therapeutically effective amount of... The prescribing information for IMJUDO® allegedly instructs administration in combination with durvalumab plus platinum and gemcitabine chemotherapy on the same day for patients with squamous NSCLC (Compl. ¶37). ¶37, ¶38 col. 3:2-3
...an anti-CTLA-4 antibody... The active ingredient in IMJUDO® is tremelimumab-actl, which is an anti-CTLA-4 antibody (Compl. ¶33, 35). ¶33 col. 3:6-7
...with 2'-deoxy-2',2'-difluorocytidine monohydrochloride (β-isomer), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. According to the complaint, IMJUDO®’s prescribing information indicates its use in combination with a chemotherapy regimen for squamous NSCLC that includes carboplatin and gemcitabine or cisplatin and gemcitabine. Gemcitabine is 2'-deoxy-2',2'-difluorocytidine (Compl. ¶¶24, 35, 37). ¶35 col. 3:7-9, col. 6:23-26

U.S. Patent No. 9,273,135 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for enhancing an immune response in a subject... wherein enhancing the immune response results in inhibition of growth of tumor cells in the subject. Administering IMJUDO® to a human patient allegedly enhances an immune response and inhibits the growth of tumor cells (Compl. ¶50). ¶50 col. 139:9, col. 139:56-58
...comprising administering to the subject a combination of an anti-PD-L1 monoclonal antibody or an antigen-binding portion thereof and an anti-CTLA-4 monoclonal antibody or an antigen-binding portion thereof... IMJUDO® (an anti-CTLA-4 antibody) is administered in combination with durvalumab (an anti-PD-L1 antibody) for the treatment of uHCC and NSCLC, with both drugs administered on the same day (Compl. ¶¶50, 56). ¶56 col. 139:10-14
...wherein the anti-PD-L1 monoclonal antibody or antigen-binding portion thereof cross-competes for binding to PD-L1 with a reference antibody comprising: (b) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:2 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO:12... The complaint alleges that durvalumab is a human, monoclonal anti-PD-L1 antibody that cross-competes for binding to human PD-L1 with the reference antibody defined by the amino acid sequences set forth in SEQ ID NO:2 and SEQ ID NO:12, which are recited in claim 1(b) (Compl. ¶53). ¶53 col. 139:15-22
  • Identified Points of Contention:
    • Scope Questions ('811 Patent): A potential dispute may arise over the term "concurrent administration". While the complaint alleges same-day administration (Compl. ¶37), the precise timing required by the claim will be a matter for claim construction. Further, the infringement allegation relies on a chemotherapy regimen that includes gemcitabine (Compl. ¶35), raising the question of whether infringement occurs only when gemcitabine is actually chosen and administered from the available options.
    • Technical Questions ('135 Patent): The infringement allegation hinges on the functional limitation that durvalumab "cross-competes" with a specific reference antibody. The complaint asserts this as a fact (Compl. ¶53), but this will be a central technical question requiring factual evidence, such as data from binding assays, to be proven in court.

V. Key Claim Terms for Construction

  • The Term: "concurrent administration" ('811 Patent, Claim 1)

  • Context and Importance: This term dictates the required timing relationship between the administration of the anti-CTLA-4 antibody and gemcitabine. The infringement case against the IMJUDO® regimen depends on whether the instructions for "same-day" administration (Compl. ¶37, 38) fall within the scope of "concurrent."

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The patent uses the general term "in combination" throughout the specification, which may support a construction that is not strictly simultaneous but covers administration within the same overall treatment protocol ('811 Patent, col. 2:45-63).
    • Evidence for a Narrower Interpretation: The patent includes figures that explicitly distinguish between "Concurrent Administration" and "Sequential Administration," showing the former involves overlapping treatment periods starting on the same or adjacent days ('811 Patent, Fig. 10). A party could argue this graphical depiction defines "concurrent" as requiring administration close in time, rather than merely within the same extended treatment plan.

  • The Term: "cross-competes" ('135 Patent, Claim 1)

  • Context and Importance: This functional language is the primary definition of the required anti-PD-L1 antibody. The infringement determination will depend entirely on whether the accused product, durvalumab, is proven to exhibit this competitive binding behavior with one of the patent's ten specified reference antibodies.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The patent specification describes standard, well-known laboratory methods for determining cross-competition, such as Biacore analysis, ELISA assays, or flow cytometry, without specifying a required quantitative threshold of competition ('135 Patent, col. 27:3-13). This could support an argument that any scientifically recognized level of competition meets the claim limitation.
    • Evidence for a Narrower Interpretation: While no explicit threshold is stated, a party might argue that the term implies a significant or meaningful level of competition, potentially referencing the specific binding characteristics of the antibodies described in the patent's examples as the standard that must be met ('135 Patent, col. 67:43-67).

VI. Other Allegations

  • Indirect Infringement: The complaint is founded on theories of indirect infringement. It alleges that Defendants induce infringement by providing prescribing information, marketing materials, and instructions that "recommend and encourage healthcare providers to infringe" by using IMJUDO® in the patented combination methods (Compl. ¶¶48, 66). It also alleges contributory infringement, asserting that IMJUDO® is especially made for these infringing uses and is not a staple article of commerce with substantial non-infringing uses (Compl. ¶¶47, 65).
  • Willful Infringement: The complaint alleges willful infringement based on both pre-suit and post-suit knowledge. It claims Defendants had actual knowledge of the '811 patent since at least December 2021 due to licensing discussions between the parties (Compl. ¶41-42) and knowledge of the '135 patent family through related litigation over their IMFINZI® product (Compl. ¶61). The complaint also alleges knowledge based on citations to Plaintiff's patents made during the prosecution of Defendants' own patent applications (Compl. ¶¶40, 58). In the alternative, the complaint alleges willful blindness (Compl. ¶¶43, 61).

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

  • A central issue will be one of claim construction and infringement: For the '811 patent, does the "same day" administration detailed in IMJUDO®'s prescribing information meet the legal definition of "concurrent administration" as required by the claim?
  • A key evidentiary question will be one of functional proof: For the '135 patent, can Plaintiff provide sufficient technical evidence to prove that AstraZeneca's durvalumab "cross-competes" for binding to PD-L1 with the specific reference antibodies recited in the claim, thereby satisfying a core functional limitation?
  • Finally, a critical question for damages will be scienter: Given the extensive allegations of prior licensing discussions, related litigation, and citations in patent prosecution, did AstraZeneca act with the knowledge and intent required to support a finding of willful infringement, which could expose it to enhanced damages?