DCT
1:22-cv-00035
Lindis Biotech GmbH v. Amgen Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Lindis Biotech, GMBH (Germany)
- Defendant: Amgen Inc. (Delaware)
- Plaintiff’s Counsel: Saul Ewing LLP
- Case Identification: 1:22-cv-00035, D. Del., 04/04/2024
- Venue Allegations: Venue is alleged to be proper as Defendant Amgen Inc. is a Delaware corporation and is deemed to reside in the district.
- Core Dispute: Plaintiff alleges that Defendant’s immunotherapy drug Blincyto, and the method of its administration, infringes patents related to a cancer treatment regimen that uses a glucocorticoid premedication to reduce the non-specific cytokine release associated with bispecific antibody therapy.
- Technical Context: The technology addresses a significant challenge in cancer immunotherapy: managing Cytokine Release Syndrome, a potentially dangerous side effect of treatments that use bispecific antibodies to engage the patient's T-cells to attack tumor cells.
- Key Procedural History: The complaint alleges that Defendant Amgen had pre-suit knowledge of the patented technology due to its opposition to the European counterpart of the ’421 Patent, filed in January 2014, and through direct communications and licensing negotiations with Plaintiff Lindis between November 2013 and September 2014. The patents-in-suit also underwent extensive examination at the U.S. Patent and Trademark Office.
Case Timeline
| Date | Event |
|---|---|
| 2004-09-15 | Earliest Priority Date for ’421 and ’158 Patents |
| 2005-04-26 | First U.S. patent application in family filed |
| 2009-07-30 | U.S. Patent Publication No. 2009/0191201 published |
| 2013-11-25 | Confidentiality agreement executed between Amgen and Lindis |
| 2014-01-17 | Amgen affiliate files opposition to Lindis European Patent |
| 2014-04-29 | U.S. Patent No. 8,709,421 issues |
| 2014-12-03 | Accused Product (Blincyto) first approved by FDA |
| 2017-11-01 | Blincyto prescribing information revised to instruct premedication with dexamethasone |
| 2018-09-11 | U.S. Patent No. 10,071,158 issues |
| 2019-04-01 | Blincyto prescribing information revised to instruct premedication with prednisone or dexamethasone |
| 2023-06-01 | Blincyto prescribing information revised |
| 2024-04-04 | Complaint filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 8,709,421 - “Combination of the Application of Antibodies for Immunostimulation Together with Glucocorticoids”
- Issued: April 29, 2014
The Invention Explained
- Problem Addressed: The patent addresses the severe side effects caused by immunostimulating antibody therapies, which are often correlated with a "non-specific release of cytokine" (a "cytokine storm") that can lead to severe adverse events and limits the clinically compatible dose of the antibody treatment (Compl. ¶¶ 8, 12; ’421 Patent, col. 1:41-59).
- The Patented Solution: The invention is a method that combines an immunostimulating antibody with a glucocorticoid, administered "immediately before or immediately after" the antibody. This combination surprisingly reduces the non-specific, systemic cytokine release without impairing the targeted, therapeutic immune response against cancer cells, thereby allowing for higher and more effective antibody dosages (Compl. ¶15; ’421 Patent, col. 3:36-44).
- Technical Importance: This method provided a potential solution to manage the dose-limiting toxicity of a promising class of cancer therapies, improving the safety profile and enabling dose escalation to potentially increase efficacy (Compl. ¶15).
Key Claims at a Glance
- The complaint asserts at least claim 1 and claim 3 of the ’421 Patent (Compl. ¶¶ 30, 42).
- Independent Claim 1 recites:
- A method for reducing the non-specific release of a cytokine associated with cancer or tumor treatment;
- The method comprises administering at least one glucocorticoid "immediately before or immediately after" administering at least one "trifunctional, bispecific immunostimulating antibody";
- The antibody is directed against a tumor antigen and a CD marker;
- The glucocorticoid reduces the non-specific release of the cytokine; and
- The CD marker is selected from a group that includes CD3.
U.S. Patent No. 10,071,158 - “Combination of the Application of Antibodies for Immunostimulation Together with Glucocorticoids”
- Issued: September 11, 2018
The Invention Explained
- Problem Addressed: The ’158 Patent addresses the same technical problem as its parent ’421 Patent: mitigating the severe side effects from non-specific cytokine release during immunotherapy ('158 Patent, col. 1:35-52).
- The Patented Solution: The invention claimed in the ’158 Patent is a more specific method for reducing cytokine release. It requires administering the glucocorticoid as "premedication on the same day and prior in time" relative to the antibody. The claim further specifies the components: the glucocorticoid must be dexamethasone, the tumor antigen must be CD19, and the T-cell marker must be CD3 ('158 Patent, col. 28:13-33).
- Technical Importance: This patent claims a specific, clinically defined regimen for a particular combination of therapeutic agents, potentially reflecting developments in clinical practice and providing more targeted protection for a specific treatment protocol (Compl. ¶23).
Key Claims at a Glance
- The complaint asserts at least claim 1 of the ’158 Patent (Compl. ¶43).
- Independent Claim 1 recites:
- A method for reducing non-specific cytokine release during cancer treatment with a bispecific immunostimulating antibody;
- The method comprises administering an effective amount of a glucocorticoid "by way of premedication on the same day and prior in time relative to" the antibody administration;
- The glucocorticoid must reduce cytokine release caused by the antibody;
- The glucocorticoid must comprise dexamethasone;
- The antibody must be directed against tumor antigen CD19; and
- The antibody must be directed against CD marker CD3.
III. The Accused Instrumentality
Product Identification
- The accused instrumentality is the immunotherapy drug blinatumomab, which is marketed and sold by Amgen under the name Blincyto (Compl. ¶25).
Functionality and Market Context
- Blincyto is a "bispecific CD19-directed CD3 T-cell engager" antibody approved for treating certain types of Acute Lymphoblastic Leukemia ("ALL") (Compl. ¶¶ 25, 31). It functions by linking CD19-positive cancer cells to the patient’s own CD3-positive T-cells, thereby directing the T-cells to attack the cancer (Compl. ¶26).
- The complaint alleges that Blincyto's prescribing information instructs physicians to premedicate patients with glucocorticoids, including dexamethasone and prednisone, to "help reduce infusion reactions" and control the risk of "CYTOKINE RELEASE SYNDROME," which is listed as a potential life-threatening or fatal side effect (Compl. ¶¶ 27, 29, 32).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
’421 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method for reducing the non-specific release of a cytokine in a subject which is associated with a treatment of a cancer or tumor with an antibody... | The administration of Blincyto as instructed by Amgen is a method for treating ALL. The prescribing information warns of "Cytokine Release Syndrome" and instructs premedication to control it. | ¶¶31, 32 | col. 3:36-44 |
| ...administering to the subject at least one glucocorticoid immediately before or immediately after administering at least one trifunctional, bispecific immunostimulating antibody... | The Blincyto prescribing information instructs premedication with glucocorticoids (dexamethasone, prednisone). Blincyto is alleged to be a bispecific immunostimulating antibody. | ¶¶29, 33, 34 | col. 4:55-64 |
| ...directed against a tumor antigen and a CD marker... | Blincyto is a bispecific antibody directed against the tumor antigen CD19 and the T-cell marker CD3. | ¶34 | col. 5:44-55 |
| ...which glucocorticoid reduces the non-specific release of the cytokine associated with the treatment of the cancer or tumor... | The prescribing information states that the corticosteroid is given to "help reduce infusion reactions," which include inflammatory cytokine release. | ¶32 | col. 3:54-59 |
| ...wherein the CD marker is selected from the group consisting of CD2, CD3, CD4, CD5, CD6, CD8, CD28, and CD44. | The CD marker targeted by Blincyto is CD3, which is a member of the claimed group. | ¶34 | col. 5:35-39 |
Identified Points of Contention
- Scope Questions: Claim 1 of the ’421 Patent requires a "trifunctional" antibody. The complaint describes Blincyto as a "bispecific" antibody (Compl. ¶26). A central dispute may be whether Blincyto meets the "trifunctional" limitation, which the patent specification links to a specific mechanism involving a "tri-cell complex" formed by the antibody's Fc portion binding to accessory immune cells (’421 Patent, col. 5:25-66).
- Technical Questions: The temporal scope of "immediately before or immediately after" may be contested. The parties may dispute whether the timing of glucocorticoid administration as instructed for Blincyto falls within the proper construction of this phrase.
’158 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method for reducing the non-specific release of at least one cytokine in a subject, which is associated with a treatment of a cancer with at least one bispecific immunostimulating antibody... | The instructed use of Blincyto is a method for treating ALL that includes premedication to reduce the risk of "Cytokine Release Syndrome." | ¶¶44, 46 | col. 28:13-17 |
| ...administering an effective amount of at least one glucocorticoid to the subject by way of premedication on the same day and prior in time... | The Blincyto prescribing information explicitly instructs physicians to "[p]remedicate with... dexamethasone... 1 hour prior to the first dose of BLINCYTO," satisfying the "premedication," "same day," and "prior in time" limitations. | ¶45 | col. 28:20-24 |
| ...such that said effective amount of said at least one glucocorticoid reduces cytokine release caused by the administration of the... antibody... | The purpose of the premedication is to "help reduce infusion reactions," and the Blincyto label warns of cytokine release as a major risk. | ¶46 | col. 28:25-29 |
| ...wherein the at least one glucocorticoid comprises dexamethasone... | The Blincyto prescribing information specifically instructs premedication with dexamethasone. | ¶¶45, 47 | col. 28:30-31 |
| ...the tumor antigen is CD19... | Blincyto is a "bispecific CD19-directed CD3 T-cell engager." | ¶48 | col. 28:32 |
| ...and the CD marker is CD3. | Blincyto is a "bispecific CD19-directed CD3 T-cell engager." | ¶48 | col. 28:33 |
Identified Points of Contention
- Scope Questions: The complaint notes that the prescribing information instructs to "premedicate with prednisone or equivalent dexamethasone" (Compl. ¶45). A question may arise as to whether administration of prednisone alone, which is permitted by the instructions, would fall outside the scope of Claim 1, which requires the glucocorticoid to comprise dexamethasone.
V. Key Claim Terms for Construction
The Term: "trifunctional" (’421 Patent, Claim 1)
- Context and Importance: This term is a primary potential point of non-infringement for the ’421 patent. The complaint identifies Blincyto as "bispecific" but the claim requires a "trifunctional" antibody. The construction of this term may be outcome-determinative for the ’421 patent allegations.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent does not appear to provide an explicit definition that would broaden the term beyond its structural and functional context. A party arguing for a broader scope might focus on the general purpose of engaging multiple cell types to achieve a therapeutic effect.
- Evidence for a Narrower Interpretation: The specification describes a "trifunctional bispecific antibody" as a molecule that, via its Fc portion, binds to "accessory immune cells" (e.g., monocytes, macrophages) to form a "tri-cell complex," thereby triggering phagocytosis (’421 Patent, col. 5:25-66). This detailed description of a specific structure and mechanism may support a narrower construction limited to antibodies possessing this third functional capability.
The Term: "immediately before or immediately after" (’421 Patent, Claim 1)
- Context and Importance: The temporal scope of this phrase is critical to determining whether the instructed administration of Blincyto meets the claim limitation. Practitioners may focus on this term because its plain meaning could be subject to differing interpretations in a clinical setting.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification mentions administration can be "simultaneously, separately or in temporally staggered manner" (’421 Patent, col. 7:22-24), which could support a flexible interpretation covering administration within the same clinical visit or day.
- Evidence for a Narrower Interpretation: The use of the word "immediately" could be argued to imply a very close temporal proximity, such as within minutes of the antibody infusion. The existence of the related ’158 Patent, which uses the more specific phrase "on the same day and prior in time," could be cited as evidence that "immediately" was intended to mean something more constrained.
VI. Other Allegations
Indirect Infringement
- The complaint's primary theory is indirect infringement. It alleges Amgen induces infringement by instructing physicians, via Blincyto's prescribing information and product labels, to perform the patented methods (Compl. ¶¶ 35, 49). It further alleges contributory infringement, asserting that Blincyto is a material component of the invention, is not a staple article of commerce, and is specially adapted for an infringing use (Compl. ¶¶ 41, 53).
Willful Infringement
- The complaint alleges willful infringement based on pre-suit knowledge. The basis for this allegation includes Amgen's 2014 opposition to the European counterpart of the ’421 Patent and direct licensing negotiations with Lindis in 2013-2014, which allegedly made Amgen "keenly aware" that Blincyto would infringe (Compl. ¶¶ 38-40, 50-52). Knowledge is alleged to have continued post-issuance of both patents.
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of definitional scope: does the accused drug Blincyto, described as a "bispecific" antibody, meet the "trifunctional" limitation of the ’421 Patent, which the specification appears to define as an antibody capable of forming a "tri-cell complex" with accessory immune cells?
- A second central question will be one of intent and knowledge: given the allegations regarding Amgen’s European patent opposition and prior licensing discussions, the case will likely examine not just whether infringement occurred, but whether Amgen acted willfully and egregiously, which could expose it to enhanced damages.
- A key evidentiary question for this indirect infringement case will be the causal link between instruction and action: what evidence, beyond the drug's label, will demonstrate that Amgen's instructions actually caused prescribing physicians to perform all steps of the claimed methods?