DCT
1:22-cv-03059
Merck Sharp & Dohme LLC v. Johns Hopkins University
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Merck Sharp & Dohme LLC (New Jersey)
- Defendant: The Johns Hopkins University (Maryland)
- Plaintiff’s Counsel: Paul Hastings LLP
- Case Identification: 1:22-cv-03059, D. Md., 11/29/2022
- Venue Allegations: Venue is alleged to be proper in the District of Maryland because Defendant The Johns Hopkins University is a Maryland corporation and resides in the district.
- Core Dispute: Plaintiff seeks declaratory judgment of noninfringement of four patents obtained by Defendant following a joint research collaboration, alleging that Defendant breached the collaboration contract and that Plaintiff's cancer drug Keytruda does not practice the patented methods.
- Technical Context: The dispute centers on cancer immunotherapy, specifically the use of anti-PD-1 antibodies to treat tumors identified by a genetic biomarker known as microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR).
- Key Procedural History: The complaint alleges that the patents-in-suit arose from a joint research collaboration between Merck and The Johns Hopkins University (JHU). JHU is alleged to have filed and prosecuted the patents without Merck's involvement, overcoming Patent Office rejections by submitting declarations that emphasized the criticality of data from the joint study. Merck alleges that JHU's subsequent licensing of the patents and demands for payment from Merck constitute a breach of the parties' collaboration agreement.
Case Timeline
| Date | Event |
|---|---|
| 2012-Late | JHU contacts Merck regarding a clinical study for pembrolizumab |
| 2013-02-25 | JHU sends Merck a draft protocol for the clinical study |
| 2013-04-30 | Merck scientists suggest revised dosage and scanning schedule for the study |
| 2013-06-10 | The revised clinical study protocol is published |
| 2013-August | Merck and JHU enter into a formal written collaboration contract |
| 2013-September | The joint research study begins |
| 2014-11-13 | Earliest Priority Date for ’356, ’974, ’975, and ’219 Patents |
| 2020-02-04 | JHU submits sworn declaration of Dr. Pardoll to the PTO |
| 2020-06-08 | JHU submits sworn declaration of Dr. Kuchroo to the PTO |
| 2020-12-14 | PTO issues its first notice of allowance for the patent family |
| 2021-03-02 | U.S. Patent No. 10,934,356 Issues |
| 2021-March | JHU notifies Merck of the ’356 Patent issuance and requests Merck take a license |
| 2021-05-14 | JHU requests that Merck pay hundreds of millions of dollars tied to Keytruda sales |
| 2022-05-10 | U.S. Patent Nos. 11,325,974 and 11,325,975 Issue |
| 2022-05-24 | U.S. Patent No. 11,339,219 Issues |
| 2022-11-29 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 10,934,356 - "Checkpoint Blockade and Microsatellite Instability"
The Invention Explained
- Problem Addressed: The patent describes a challenge in cancer therapy where immune checkpoint blockade drugs, such as anti-PD-1 antibodies, are effective in some cancers (e.g., melanoma, lung cancer) but show limited success in others, such as colorectal cancer (CRC). A key problem was identifying which patients were likely to respond to this form of immunotherapy (’356 Patent, col. 1:59-col. 2:14).
- The Patented Solution: The invention provides a method of treating cancer by first identifying patients whose tumors have a specific genetic profile—high microsatellite instability (MSI-H) or mismatch repair (MMR) deficiency—and then administering an anti-PD-1 antibody, pembrolizumab. The patent is based on the discovery that MMR-deficient tumors are significantly more responsive to PD-1 blockade than MMR-proficient tumors, providing a predictive biomarker for treatment efficacy (’356 Patent, Abstract; col. 3:9-24).
- Technical Importance: This approach established a method for treating cancer based on a genetic biomarker rather than the cancer's tissue of origin, expanding the applicability of checkpoint inhibitors to a genetically-defined subset of patients across various tumor types (Compl. ¶1, 33).
Key Claims at a Glance
- The complaint asserts noninfringement of claims 1, 11, 19, and 23 of the ’356 Patent (Compl. ¶¶57-59). Independent claim 1 is representative.
- Essential elements of independent claim 1 include:
- A method for treating cancer in a patient who has received a prior cancer therapy drug.
- Step 1: "determining that the patient has a tumor that exhibits a high microsatellite instability (MSI-high) or a mismatch repair (MMR) deficiency status".
- Step 2: "administering an effective amount of pembrolizumab to the patient".
- Step 3: "determining that the patient exhibits an outcome that is improved as compared to a corresponding outcome that would be observed in a reference patient that has been administered pembrolizumab, wherein the reference patient has a tumor that does not exhibit a MSI-high or a MMR deficiency status".
- The complaint does not explicitly reserve the right to assert dependent claims but seeks a declaratory judgment of noninfringement for all claims (Prayer for Relief ¶D).
U.S. Patent No. 11,325,974 - "Checkpoint Blockade and Microsatellite Instability"
The Invention Explained
- Problem Addressed: As with the ’356 Patent, this patent addresses the need to identify which cancer patients will respond favorably to anti-PD-1 immunotherapy, which had previously shown inconsistent results in certain cancer types (’974 Patent, col. 1:59-col. 2:14).
- The Patented Solution: The invention is a method of treating cancer by administering pembrolizumab to patients whose tumors exhibit instability in microsatellite markers or deficiency in mismatch repair markers. A central element of the claimed method is the improved outcome observed in these patients compared to a reference patient whose tumor lacks these genetic markers (’974 Patent, Abstract; col. 3:9-24).
- Technical Importance: The invention provides a biomarker-driven treatment paradigm that allows for the targeted application of a powerful immunotherapy agent to a responsive patient population, irrespective of the cancer's anatomical location (Compl. ¶1, 33).
Key Claims at a Glance
- The complaint asserts noninfringement of claim 1 of the ’974 Patent (Compl. ¶64).
- Essential elements of independent claim 1 include:
- A method for treating cancer in a patient who has received a prior cancer therapy drug.
- Step 1: "administering an effective amount of pembrolizumab to the patient, wherein the patient has a tumor that exhibits an instability of one or more microsatellite markers or a deficiency of one or more mismatch repair markers".
- Step 2: A "wherein" clause specifying that "the patient exhibits an outcome that is improved as compared to a corresponding outcome that would be observed in a reference patient that has been administered pembrolizumab," where the reference patient's tumor does not have the specified genetic markers.
- The complaint seeks a declaratory judgment of noninfringement for all claims of the patent (Prayer for Relief ¶D).
U.S. Patent No. 11,325,975 - "Checkpoint Blockade and Microsatellite Instability"
- Patent Identification: U.S. Patent No. 11,325,975, "Checkpoint Blockade and Microsatellite Instability," issued May 10, 2022.
- Technology Synopsis: This patent, part of the same family, claims methods of treating cancer by administering an anti-PD-1 antibody to patients with MSI-high or dMMR tumors. The claims, like others in the family, rely on the concept of an improved outcome in the treated patient when compared to a reference patient lacking the MSI-H/dMMR biomarker (’975 Patent, Abstract).
- Asserted Claims: The complaint cites claim 1 for its noninfringement argument (Compl. ¶69).
- Accused Features: Merck's use of Keytruda is the subject of the dispute. Merck alleges noninfringement by stating it does not perform, nor induce others to perform, the claimed step of comparing a patient's outcome to that of a reference patient (Compl. ¶69).
U.S. Patent No. 11,339,219 - "Checkpoint Blockade and Microsatellite Instability"
- Patent Identification: U.S. Patent No. 11,339,219, "Checkpoint Blockade and Microsatellite Instability," issued May 24, 2022.
- Technology Synopsis: This patent also covers methods of cancer treatment using pembrolizumab in patients selected for having MSI-H or dMMR tumors. The claims require that the treated patient exhibits an improved outcome relative to a hypothetical reference patient whose tumor does not possess these genetic markers (’219 Patent, Abstract).
- Asserted Claims: The complaint cites claim 1 in its request for a declaratory judgment of noninfringement (Compl. ¶75).
- Accused Features: At issue is the use of Keytruda. Merck’s noninfringement position is based on the argument that the prescribed use of its drug does not involve the comparative determination step required by the patent claims (Compl. ¶75).
III. The Accused Instrumentality
- Product Identification: The accused instrumentality is the manufacture, use, and sale of Merck's cancer drug Keytruda® (pembrolizumab) (Compl. ¶1).
- Functionality and Market Context:
- Keytruda is described as a "breakthrough cancer drug" and an "anti-PD-1 antibody" that functions by "aiding the immune system to identify and destroy cancer cells" (Compl. ¶1, 10). The complaint highlights that Keytruda has received FDA approval for treating adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors (Compl. ¶13).
- The approved labeling for these indications specifies dosing regimens such as "200 mg every 3 weeks or 400 mg every 6 weeks for adults" (Compl. ¶14). Crucially, the complaint alleges that "The Keytruda labeling does not instruct anyone to perform any sort of comparison of the treatment outcome of a given patient to another reference patient" (Compl. ¶16).
- No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
Merck's complaint seeks a declaratory judgment of noninfringement. Its core theory is that the administration and use of Keytruda, even in the specified patient population, does not meet all the limitations of the asserted claims because it does not involve the required comparative step.
'356 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Non-Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| determining that the patient has a tumor that exhibits a high microsatellite instability (MSI-high) or a mismatch repair (MMR) deficiency status | While physicians test for MSI-H/dMMR status to identify candidates for Keytruda, this step alone does not constitute infringement of the full method claim. | ¶13 | col. 5:51-54 |
| administering an effective amount of pembrolizumab to the patient | Keytruda is administered according to FDA-approved labeling. | ¶14 | col. 8:50-51 |
| determining that the patient exhibits an outcome that is improved as compared to a corresponding outcome that would be observed in a reference patient... | Merck alleges that neither it, nor physicians prescribing Keytruda, nor patients receiving it, performs this comparative step. The drug is administered based on the MSI-H/dMMR biomarker status, and the labeling does not instruct any such comparison. | ¶16, 57 | col. 3:9-24 |
'974 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Non-Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| administering an effective amount of pembrolizumab to the patient, wherein the patient has a tumor that exhibits an instability of one or more microsatellite markers... | Keytruda is administered to patients with this biomarker status per its FDA approval. | ¶13, 14 | col. 8:50-51 |
| wherein the patient exhibits an outcome that is improved as compared to a corresponding outcome that would be observed in a reference patient... | Merck alleges this comparative step is not performed in practice. The complaint states, "Merck does not perform this step, nor does Merck induce or have the intent to induce any others to perform this step." | ¶16, 64 | col. 3:9-24 |
- Identified Points of Contention:
- Scope Questions: A central question for the court will be whether the act of prescribing and administering Keytruda to an MSI-H patient—with the a priori knowledge that such patients are expected to respond better than non-MSI-H patients—satisfies the claim limitation of "determining that the patient exhibits an outcome that is improved as compared to a... reference patient."
- Technical Questions: The dispute raises the question of what actions constitute "determining" in the context of a method of treatment claim. Does this require an active, post-treatment comparison for each patient, or can it be satisfied by the physician's initial decision to treat, which is based on clinical trial data showing such a comparative improvement for the patient population? The complaint suggests JHU argued during prosecution that this very limitation was necessary to distinguish the invention from simply administering the drug, an argument Merck may now use to support a narrower interpretation requiring an active comparison (Compl. ¶33).
V. Key Claim Terms for Construction
- The Term: "determining that the patient exhibits an outcome that is improved as compared to a corresponding outcome that would be observed in a reference patient" (and functionally similar clauses in the other patents).
- Context and Importance: The construction of this term is dispositive for the noninfringement analysis. If construed to require an active, discrete step of comparison performed by a medical professional for each patient, Merck's noninfringement argument may be strengthened. If construed more broadly to encompass a physician's reliance on general clinical knowledge when deciding to prescribe the drug, JHU's position may be supported.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: JHU may argue that the specification's extensive discussion of the clinical trial that established the superior efficacy in MSI-H patients provides the context for this "determining" step (’356 Patent, col. 8:9-col. 9:39; Figs. 1A-B). A practitioner, by selecting a patient with the biomarker and prescribing the drug, may be seen as implicitly making the determination based on this foundational knowledge.
- Evidence for a Narrower Interpretation: The plain language of the claim suggests an active verb ("determining") performed as part of the method. The complaint alleges that JHU, during prosecution, distinguished the claims from prior art by arguing this comparative clause was a necessary limitation to avoid claiming simply "giving an effective amount of pembrolizumab to a patient" (Compl. ¶33). This prosecution history may be used to argue that the term requires a specific, post-administration comparative act that is not taught or encouraged by Merck (Compl. ¶16, 57).
VI. Other Allegations
- Indirect Infringement: This is a declaratory judgment action where Merck is the plaintiff. Merck proactively pleads that it does not induce infringement of the asserted patents. The basis for this allegation is that its product labeling and instructions for Keytruda do not teach or encourage users (e.g., physicians) to perform the claimed step of comparing a patient's outcome to that of a hypothetical reference patient (Compl. ¶16, 57, 64, 69, 75).
VII. Analyst’s Conclusion: Key Questions for the Case
This case presents a complex interplay between patent law and contract law arising from a university-industry research collaboration. The outcome will likely depend on the resolution of two central questions for the court:
- A core issue will be one of infringement and claim scope: Does the act of prescribing an FDA-approved drug for a biomarker-positive population inherently satisfy a method claim limitation requiring a "determination" of an improved outcome relative to a biomarker-negative "reference patient," or must that determination be a distinct, affirmative step performed as part of the treatment?
- A foundational issue is one of contractual rights and ownership: Do the patents-in-suit constitute "Joint Inventions" under the terms of the Merck-JHU collaboration agreement, as Merck's contributions to the clinical trial design might suggest? An affirmative answer could give Merck co-ownership or license rights that would render the infringement question moot.