DCT
2:16-cv-04992
Merck Sharp & Dohme Corp v. Genentech Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Merck Sharp & Dohme Corp. (New Jersey)
- Defendant: Genentech, Inc. (Delaware); City of Hope (California)
- Plaintiff’s Counsel: Quinn Emanuel Urquhart & Sullivan, LLP
- Case Identification: 2:16-cv-04992, C.D. Cal., 07/07/2016
- Venue Allegations: Venue is alleged to be proper in the Central District of California because both Defendants reside in the district and a substantial part of the events giving rise to the claims occurred there.
- Core Dispute: Plaintiff seeks a declaratory judgment that its antibody products, KEYTRUDA® and bezlotoxumab, do not infringe Defendant’s patent related to methods of making recombinant antibodies, and that the patent is invalid and/or unenforceable.
- Technical Context: The lawsuit concerns foundational methods for producing therapeutic monoclonal antibodies by using recombinant DNA techniques to co-express separate antibody heavy and light chains in a single host cell.
- Key Procedural History: The complaint details a complex, multi-decade prosecution history for the patent-in-suit and its family. This history includes a patent interference proceeding against a rival patent (the "Boss patent"), where priority was initially awarded to Boss but later reversed following a private settlement agreement between the parties. Plaintiff alleges this history, resulting in a patent term extending more than 35 years from the original application, gives rise to an unenforceability defense based on prosecution laches.
Case Timeline
| Date | Event |
|---|---|
| 1983-04-08 | Priority date of U.S. Patent No. 7,923,221 (’221 Patent) based on Cabilly I application filing |
| 1989-03-28 | U.S. Patent No. 4,816,567 ("Cabilly I patent") issues |
| 1995-04-13 | Application for the '221 Patent ("Cabilly III") filed |
| 2001-12-18 | U.S. Patent No. 6,331,415 ("Cabilly II patent") issues |
| 2006-03-28 | Cabilly I patent expires |
| 2011-04-12 | U.S. Patent No. 7923221 ("Cabilly III patent") issues |
| 2016-07-07 | Complaint for Declaratory Judgment filed |
| 2016-07-23 | PDUFA action date for bezlotoxumab |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 7,923,221 - Methods of Making Antibody Heavy and Light Chains Having Specificity for a Desired Antigen
- Patent Identification: U.S. Patent No. 7,923,221, "Methods of Making Antibody Heavy and Light Chains Having Specificity for a Desired Antigen," issued April 12, 2011.
The Invention Explained
- Problem Addressed: The patent's background describes the technical and commercial limitations of producing monoclonal antibodies using hybridoma technology. These limitations included the instability of hybridoma cell lines, potential for contamination with other proteins and nucleic acids, high cost, and the inability to genetically manipulate the antibody sequence to create novel forms like chimeric antibodies. (’221 Patent, col. 2:42-67).
- The Patented Solution: The invention provides methods for producing immunoglobulins (antibodies) and their fragments using recombinant DNA technology. The core of the solution is to introduce the genetic sequences for both the antibody heavy chain and light chain into a single host cell, allowing for the co-expression of the separate chains, which can then assemble into a functional antibody. (’221 Patent, Abstract; col. 4:51-67). This approach overcomes the purity and stability issues of hybridomas and enables the creation of "chimeric" antibodies, where parts of the antibody (e.g., the variable region) can be derived from one species (like a mouse) and other parts (e.g., the constant region) from another (like a human). (’221 Patent, col. 6:36-50).
- Technical Importance: This recombinant approach was foundational for the modern biopharmaceutical industry, enabling the large-scale production of highly pure, consistent, and therapeutically optimized monoclonal antibodies. (Compl. ¶¶ 12, 38).
Key Claims at a Glance
- The complaint seeks a declaration of invalidity for claims 1-47 and non-infringement of all valid and enforceable claims. (Compl. ¶¶ 52, 59). Independent claims 1, 15, and 21 appear to be central to the dispute.
- Independent Claim 1: A method for making antibody chains, comprising the steps of:
- Culturing a recombinant host cell comprising DNA encoding an antibody heavy chain and an antibody light chain.
- The heavy chain comprises a human constant region sequence and a variable region comprising non-human mammalian variable region sequences.
- Recovering the heavy and light chains from the host cell culture.
III. The Accused Instrumentality
Product Identification
- Plaintiff's KEYTRUDA® (pembrolizumab) and bezlotoxumab products. (Compl. ¶1).
Functionality and Market Context
- KEYTRUDA® (pembrolizumab) is described as a recombinantly-engineered monoclonal antibody used in cancer therapy that targets the programmed death receptor-1 ("PD-1"). (Compl. ¶15). It is identified as the first anti-PD-1 therapy approved in the United States. (Compl. ¶16).
- Bezlotoxumab is described as a recombinantly-engineered monoclonal antibody that targets and neutralizes "Clostridium difficile" toxin B to prevent infection recurrence. (Compl. ¶18).
- The complaint alleges that both products are made by "recombinant DNA techniques." (Compl. ¶42).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
The complaint does not provide a claim chart but presents a narrative non-infringement theory. The summary below is based on that theory as applied to the elements of a representative independent claim.
- Claim Chart Summary: ’221 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method for making an antibody heavy chain or fragment thereof and an antibody light chain or fragment thereof... | The complaint states that Plaintiff's products are manufactured using recombinant methods. (Compl. ¶¶15, 18, 42). | ¶42 | col. 4:51-54 |
| ...the method comprising culturing a recombinant host cell comprising DNA encoding the heavy chain or fragment thereof and the light chain or fragment thereof... | The complaint alleges Plaintiff's products are made using recombinant DNA techniques, which implies the use of recombinant host cells. (Compl. ¶42). | ¶42 | col. 4:55-61 |
| ...wherein the heavy chain or fragment thereof comprises a human constant region sequence and a variable region comprising non human mammalian variable region sequences... | The complaint alleges that Plaintiff's KEYTRUDA® and bezlotoxumab products do not infringe because they do not contain this feature. | ¶60 | col. 6:36-41 |
| ...and recovering the heavy chain or fragment thereof and light chain or fragment thereof from the host cell culture. | The complaint does not provide sufficient detail for analysis of this element. | col. 4:62-64 |
- Identified Points of Contention:
- Scope Questions: The central infringement dispute appears to turn on claim construction. A primary question is whether the claim term "variable region comprising non human mammalian variable region sequences" can be interpreted to read on Plaintiff's products. The complaint's targeted denial suggests its products may be humanized or fully human antibodies that, in Plaintiff's view, fall outside this limitation. (Compl. ¶60).
- Technical Questions: A key factual question will be the precise amino acid sequence and origin of the variable regions in KEYTRUDA® and bezlotoxumab. The court will need to determine if any portion of these variable regions constitutes "non human mammalian variable region sequences" as defined by the patent.
V. Key Claim Terms for Construction
- The Term: "variable region comprising non human mammalian variable region sequences"
- Context and Importance: This term appears to be the dispositive limitation for Plaintiff's non-infringement argument. (Compl. ¶60). The definition of this phrase—specifically, whether it covers "humanized" antibodies where only the complementarity-determining regions (CDRs) are of non-human origin, versus requiring the entire variable region framework to be non-human—will likely determine the outcome of the infringement analysis.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The plain language "comprising" suggests that the variable region must include, but is not limited to, non-human sequences. The patent’s general discussion of creating "altered antibodies" by changing "one or a few amino acids" or performing a "complete redesign" could support an interpretation that any inclusion of non-human sequences in the variable region meets the limitation. (’221 Patent, col. 7:1-12).
- Evidence for a Narrower Interpretation: The specification's primary embodiment for this concept is a "chimeric antibody," which it describes as one where "the variable region of both light and heavy chains mimics the variable regions of antibodies derived from one species of mammals, while the constant portions are homologous to the sequences in antibodies derived from another." (’221 Patent, col. 6:36-41). This language may support an argument that the claim requires the entire variable region, not just a portion of it, to be of non-human mammalian origin.
VI. Other Allegations
- Patent Invalidity: The complaint alleges that claims 1-47 of the ’221 Patent are invalid on several grounds, including obviousness-type double patenting over the expired "Cabilly I" patent, failure to meet the written description requirement of 35 U.S.C. § 112, and failure to meet the enablement requirement of § 112. (Compl. ¶¶ 52-55).
- Unenforceability (Prosecution Laches): The complaint alleges that the ’221 Patent is unenforceable under the doctrine of prosecution laches. (Compl. ¶65). The basis for this allegation is the 28-year period between the patent's priority date (April 8, 1983) and its issue date (April 12, 2011), which Plaintiff characterizes as a "purposeful delay" that caused actual harm to Plaintiff and the public. (Compl. ¶¶ 66-67).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of definitional scope: How will the court construe the term "variable region comprising non human mammalian variable region sequences"? The case may turn on whether this language is broad enough to cover modern humanized antibodies, which often incorporate only small, non-human-derived CDRs into a human framework, or if it is limited to traditional chimeric antibodies where the entire variable region is of non-human origin.
- A second central issue will be the equitable defense of unenforceability: Did the 28-year prosecution history, which involved multiple patent interferences and a private settlement that reversed a PTO priority decision, constitute an unreasonable and prejudicial delay sufficient to render the patent unenforceable under the doctrine of prosecution laches?