DCT
1:20-cv-00333
Vytacera Bio LLC v. Cytomx Therap Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Vytacera Bio, LLC (Delaware)
- Defendant: CytomX Therapeutics, Inc. (Delaware)
- Plaintiff’s Counsel: Stamoulis & Weinblatt LLC; Goldberg Segalla LLP
- Case Identification: 1:20-cv-00333, D. Del., 03/04/2020
- Venue Allegations: Venue is alleged to be proper in the District of Delaware as Defendant is a Delaware corporation that has purposefully availed itself of the privileges of conducting business in the state.
- Core Dispute: Plaintiff alleges that Defendant’s Probody™ technology platform for creating conditionally activated antibody therapeutics infringes patents related to inhibitor molecules that are deactivated by reagents produced by target cells.
- Technical Context: The technology concerns targeted drug delivery, specifically creating prodrugs that remain inactive in the body until they reach a specific disease site, such as a tumor, where they are activated, thereby reducing systemic toxicity.
- Key Procedural History: The complaint alleges that the inventor contacted Defendant as early as 2014 to offer a license to the ’504 patent and the application that later issued as the ’913 patent, and that Defendant refused to negotiate. This allegation may form the basis for a claim of willful infringement.
Case Timeline
| Date | Event |
|---|---|
| 2002-09-03 | Priority Date for ’504 and ’913 Patents |
| 2008-XX-XX | Defendant CytomX Therapeutics, Inc. Founded |
| 2014-XX-XX | Alleged Pre-Suit Notice of Infringement to Defendant |
| 2014-08-19 | U.S. Patent No. 8,809,504 Issues |
| 2017-10-03 | U.S. Patent No. 9,775,913 Issues |
| 2020-03-04 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 8,809,504 - "Inhibitor which is deactivatable by a reagent produced by a target cell"
The Invention Explained
- Problem Addressed: The patent addresses the challenge of administering biologically active agents, such as therapeutics for cancer, at concentrations high enough to be effective at a disease site without causing severe systemic toxicity and side effects throughout the body (’504 Patent, col. 1:30-58).
- The Patented Solution: The invention is an "inhibitor" molecule designed to temporarily suppress the activity of a therapeutic agent. This inhibitor is a chimeric molecule comprising a "first moiety" that binds to and neutralizes the active agent, and a "second moiety" containing a cleavage site. This second moiety is specifically designed to be cleaved by a reagent, such as a protease, that is uniquely produced by target cells (e.g., tumor cells). Upon reaching the target site, the reagent cleaves the second moiety, which in turn deactivates the inhibitor and releases the therapeutic agent in its fully active form precisely where it is needed (’504 Patent, Abstract; col. 3:51-64).
- Technical Importance: This technology provides a platform for creating conditionally activated therapeutics, or prodrugs, that can be targeted to specific cellular microenvironments, a key goal in reducing the toxicity of potent biologic drugs (’504 Patent, col. 2:1-12).
Key Claims at a Glance
- The complaint asserts independent claim 1 (Compl. ¶77).
- Essential elements of claim 1:
- An inhibitor which is deactivatable by a reagent produced by a target cell, comprising:
- (a) a first moiety that binds, inhibits, suppresses, neutralizes, or decreases activity of a biologically active agent, operably linked to;
- (b) a second moiety specifically cleavable by a protease produced by a target cell;
- wherein the first and second moieties are not attached in nature;
- and wherein specific cleavage of the second moiety causes reduction of binding activity of the inhibitor.
- The complaint reserves the right to assert additional claims (Compl. ¶116).
U.S. Patent No. 9,775,913 - "Method of site-specific activation of an antibody by a protease"
The Invention Explained
- Problem Addressed: As a divisional of the application leading to the ’504 patent, the ’913 patent addresses the same technical problem of delivering potent biologics to a target site without causing systemic toxicity (’913 Patent, col. 2:1-53).
- The Patented Solution: The invention claims a method for achieving site-specific activation of an antibody. The method comprises administering an inhibitor molecule, as described in the ’504 patent, that is capable of neutralizing an antibody. The inhibitor's activity is suppressed upon cleavage by a protease found at the target cell. This process ensures the antibody's activity is reduced systemically but is restored at the disease site where the inhibitor is cleaved (’913 Patent, Abstract; col. 4:26-41).
- Technical Importance: This patent protects the therapeutic application and method of use for the conditionally activatable inhibitor technology, extending protection from the molecule itself to its practical implementation in treatment (’913 Patent, col. 2:1-5).
Key Claims at a Glance
- The complaint asserts independent claims 1 and 22 (Compl. ¶123, 143-144).
- Essential elements of claim 1:
- A method of site specific activation of an antibody comprising administering an inhibitor deactivatable by a protease from a target cell. The inhibitor comprises:
- (a) a first moiety that binds or inhibits the antibody, operably linked to;
- (b) a second moiety comprising a polypeptide specifically cleavable by the protease;
- wherein the moieties are not attached in nature;
- and wherein cleavage of the second moiety reduces the inhibitor's activity and restores the antibody's activity;
- The method includes administering the inhibitor such that the antibody's activity is reduced until it reaches the target cell, where cleavage restores its activity.
- The complaint reserves the right to assert additional claims (Compl. ¶190).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is Defendant’s "Probody™ technology platform" and the methods associated with it (Compl. ¶3, 36). The complaint identifies several therapeutic candidates developed using this platform, including CX-072 and CX-2009 (Compl. ¶90, n.16).
Functionality and Market Context
The Probody™ platform is used to develop masked antibody prodrugs designed for selective activation in a tumor microenvironment (Compl. ¶40). According to the complaint, a "masking peptide" is attached to an antibody via a "protease cleavable linker." This mask sterically blocks the antibody's binding site, rendering it inactive in healthy tissue. In the tumor microenvironment, tumor-associated proteases cleave the linker, causing the mask to dissociate and thereby activating the antibody to bind to its target on cancer cells (Compl. ¶90-94). The complaint includes a diagram from Defendant's materials illustrating this mechanism of action (Compl. ¶94, p. 20). CytomX's business is allegedly built on this platform, which it uses to provide drug discovery services and products to major pharmaceutical companies, including Bristol-Meyers Squibb, Pfizer, and Amgen (Compl. ¶42, 54).
IV. Analysis of Infringement Allegations
’504 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| An inhibitor which is deactivatable by a reagent produced by a target cell comprising: | The Probody™ platform creates inhibitors (masked antibodies) that are deactivatable by proteases produced by target tumor cells. | ¶90 | col. 3:51-54 |
| (a) a first moiety that binds, inhibits, suppresses, neutralizes, or decreases activity of a biologically active agent wherein said first moiety is operably linked to; | A "masking peptide" (the first moiety) binds to and inhibits the activity of an anti-cancer antibody (the biologically active agent). | ¶91 | col. 4:55-58 |
| (b) a second moiety specifically cleavable by a protease produced by a target cell... | The masking peptide is attached via a "protease substrate" or linker (the second moiety) that is specifically cleavable by proteases in the tumor microenvironment. | ¶92 | col. 6:35-39 |
| ...wherein said first and second moieties are not attached in nature... | The complaint alleges that the engineered construct of a masking peptide and cleavable linker is not found in nature. | ¶93 | col. 6:49-50 |
| ...and wherein specific cleavage of said second moiety causes reduction of binding activity of said inhibitor. | Cleavage of the linker (second moiety) causes the masking peptide (the inhibitor) to dissociate, thereby reducing its ability to bind to and inhibit the antibody. A diagram in the complaint illustrates this mechanism. | ¶94 | col. 8:34-37 |
’913 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of site specific activation of an antibody comprising administration of an inhibitor... | The Probody™ platform allegedly involves methods for site-specific activation of antibodies through the administration of inhibitors. | ¶145 | col. 4:26-29 |
| (a) a first moiety that binds, inhibits...activity of said antibody...operably linked to (b) a second moiety comprising a polypeptide specifically cleavable by said protease... | The accused inhibitors contain a "masking peptide" (first moiety) connected to a cleavable linker (second moiety) to neutralize antibody activity until cleaved by proteases at the target cell. | ¶146-147 | col. 5:1-14 |
| ...wherein specific cleavage of said second moiety causes reduction of...activity of said inhibitor and restoration of activity of said antibody; | The complaint alleges that cleavage of the linker restores the antibody's activity. A visual shows the mask falling away and the antibody binding its target. | ¶148-149; Fig. p. 32 | col. 4:34-38 |
| ...said inhibitor is administered...such that the activity of said antibody is reduced until it reaches said target cell...wherein the inhibitor is cleaved...and activity of said antibody is restored. | The complaint alleges the Probody™ method involves reducing antibody activity systemically until the inhibitor is cleaved at the target cells, restoring antibody function. | ¶149 | col. 4:38-41 |
Identified Points of Contention
- Scope Questions: A central question may be whether the term "inhibitor" as claimed reads on the "masking peptide" portion of Defendant's integrated Probody™ therapeutic. The patent's abstract describes administering the "inhibitor alone or together with the active agent," which could suggest two separate molecules, whereas the accused product is a single recombinant protein. However, other patent language, such as "fusion protein" and "covalent" linkage, may support a broader construction covering the accused single-molecule prodrug design (’504 Patent, col. 4:57; col. 6:42).
- Technical Questions: The infringement theory relies on the allegation that cleavage of the "second moiety" (the linker) causes "reduction of binding activity of said inhibitor" (the mask). The complaint's theory, supported by Defendant's marketing materials, is that cleavage leads to the mask's dissociation. The case may turn on factual evidence demonstrating that this dissociation is the direct cause of the reduction in the mask's inhibitory binding activity as required by the claim.
V. Key Claim Terms for Construction
- The Term: "inhibitor"
- Context and Importance: The definition of this term is critical to determining infringement. The dispute may focus on whether an "inhibitor" must be a distinct molecule that interacts with a separate active agent, or if it can be a component (the mask) of a single, integrated prodrug molecule that also contains the active agent (the antibody).
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent defines an inhibitor broadly to include a "fusion protein" or "hybrid molecule" (’504 Patent, col. 4:57-58). The specification also states that association between components can be "covalent" and that "operably linked means any link that makes the inhibitor functional" (’504 Patent, col. 6:41-43, 49-50). This language may support reading the claim onto a single-molecule construct where the masking domain functions as the inhibitor.
- Evidence for a Narrower Interpretation: The abstract states that the "inhibitor [can be administered] alone or together with the active agent," which may suggest two separate entities (’504 Patent, Abstract). The specification also discusses an "inhibitor-ligand pair," a term that can imply a non-covalent association between two distinct molecules (’504 Patent, col. 5:36).
VI. Other Allegations
Indirect Infringement
The complaint alleges that Defendant induces infringement of the ’913 method patent by providing its Probody™ platform to partners and collaborators with instructions on how to use it in an infringing manner (Compl. ¶184-185). It also alleges contributory infringement, stating the platform is not a staple article of commerce and is especially adapted for infringing uses (Compl. ¶187).
Willful Infringement
Willfulness is alleged based on pre-suit knowledge dating back to 2014. The complaint asserts that the inventor, Dr. Lauermann, directly contacted Defendant, provided a copy of the issued ’504 patent, notified Defendant of the patent application that would become the ’913 patent, and supplied a "detailed claim analysis showing that the ’504 patent covered CytomX’s activities" (Compl. ¶68-69). The complaint alleges Defendant "refused to continue negotiations" and proceeded with its infringing activities with "reckless disregard" for Plaintiff's patent rights (Compl. ¶70, 73).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of definitional scope: can the term "inhibitor," which the patent at times describes as a separate entity administered "together with" an active agent, be construed to cover the integrated "masking peptide" of the accused Probody™ prodrug, which exists as a single recombinant molecule with the antibody it inhibits?
- A dispositive threshold question will be the applicability of the 35 U.S.C. § 271(e)(1) safe harbor: are Defendant's activities in developing and providing its Probody™ platform to pharmaceutical partners commercial "research tool" sales that fall outside the safe harbor, as Plaintiff alleges, or are they activities "solely for uses reasonably related" to seeking FDA approval, which would exempt them from infringement?
- A key question for damages will be willfulness: do the allegations of direct pre-suit notice to Defendant in 2014, including the provision of a claim analysis, establish that any subsequent infringement was willful, potentially justifying an award of enhanced damages?