DCT
1:24-cv-00700
Merck KGaA v. TWi Pharma Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Merck KGaA (Germany), Merck Serono SA (Switzerland), and Ares Trading SA (Switzerland)
- Defendant: TWi Pharmaceuticals, Inc. (Taiwan) and TWi Pharmaceuticals USA, Inc. (Delaware)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP; Wilmer Cutler Pickering Hale and Dorr LLP
- Case Identification: 1:24-cv-00700, D. Del., 06/14/2024
- Venue Allegations: Venue is alleged based on Defendant TWi Pharmaceuticals USA, Inc.'s incorporation in Delaware, and on both Defendants' purposeful availment of the forum through business activities within the state.
- Core Dispute: Plaintiff alleges that Defendant’s Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's MAVENCLAD® product infringes patents related to a specific oral dosing regimen for cladribine.
- Technical Context: The technology concerns a method-of-use for the drug cladribine, a purine antimetabolite, for the long-term treatment of relapsing forms of multiple sclerosis.
- Key Procedural History: The lawsuit was filed under the Hatch-Waxman Act following Plaintiff’s receipt of a May 6, 2024 notice letter from Defendant concerning its ANDA submission. The notice included a Paragraph IV certification alleging that the patents-in-suit are invalid and/or will not be infringed by the proposed generic product. The patents are listed in the FDA's Orange Book as covering MAVENCLAD®.
Case Timeline
| Date | Event |
|---|---|
| 2004-12-22 | Priority Date for '947 and '903 Patents |
| 2010-05-11 | '947 Patent Issue Date |
| 2013-02-19 | '903 Patent Issue Date |
| 2019-03-29 | MAVENCLAD® NDA Approval Date |
| 2024-05-06 | TWi Sends Paragraph IV Notice Letter |
| 2024-06-14 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 7,713,947 - Cladribine Regimen for Treating Multiple Sclerosis
(Issued May 11, 2010)
The Invention Explained
- Problem Addressed: The patent describes the challenge of treating multiple sclerosis (MS) with cladribine, noting that prior administration methods (intravenous or subcutaneous) had a "narrow margin of safety" between the effective dose and doses causing significant adverse effects, such as myelosuppression (’947 Patent, col. 3:60-64). The patent suggests that a new method was needed to improve the drug's therapeutic effect while decreasing adverse events, particularly for a chronic disease requiring long-term treatment (’947 Patent, col. 3:12-21).
- The Patented Solution: The invention is a specific, long-term oral dosing regimen for cladribine. It consists of sequential phases: an initial "induction period" with a total dose of 1.7 to 3.5 mg/kg, followed by a long "Cladribine-free period" of 8-10 months, and then at least one "maintenance period" with a lower total dose of about 1.7 mg/kg (’947 Patent, col. 4:49-64; Abstract). This structured, multi-year oral regimen is designed to provide a sustained benefit while managing safety.
- Technical Importance: The claimed regimen proposed a way to administer cladribine orally over extended periods, potentially making treatment for a chronic condition like MS more manageable for patients and safer by structuring the dosage to mitigate cumulative toxicity (’947 Patent, col. 3:12-21).
Key Claims at a Glance
- The complaint asserts infringement of at least independent claim 36 (Compl. ¶34).
- The essential elements of independent claim 36 are:
- A method of treating multiple sclerosis comprising orally administering a cladribine formulation according to the following sequential steps:
- (i) an "induction period" lasting from about 2 to 4 months, achieving a total cladribine dose of about 1.7 mg/kg to about 3.5 mg/kg;
- (ii) a "cladribine-free period" lasting from about 8 to 10 months with no cladribine administered;
- (iii) a "maintenance period" lasting from about 2 to 4 months, achieving a total cladribine dose of about 1.7 mg/kg; and
- (iv) a second "cladribine-free period" with no cladribine administered.
- The complaint notes that the infringed claims "include at least claim 36," reserving the right to assert other claims (Compl. ¶34).
U.S. Patent No. 8,377,903 - Cladribine Regimen for Treating Multiple Sclerosis
(Issued February 19, 2013)
The Invention Explained
- Problem Addressed: As a continuation of the application leading to the ’947 Patent, this patent addresses the same technical problem: the need for a safe and effective oral cladribine regimen for MS that minimizes adverse events associated with prior administration methods (’903 Patent, col. 3:1-21).
- The Patented Solution: The invention claims a structured oral dosing method for cladribine characterized by distinct induction, cladribine-free, and maintenance periods over multiple years (’903 Patent, col. 4:50-65). It specifies the treatment is for "relapsing-remitting multiple sclerosis or early secondary progressive multiple sclerosis" (’903 Patent, col. 17:5-8).
- Technical Importance: The invention provides a specific, long-term protocol for oral cladribine, aiming to optimize the balance between efficacy and safety for patients with specific forms of relapsing MS (’903 Patent, col. 3:12-21).
Key Claims at a Glance
- The complaint asserts infringement of at least independent claim 17 (Compl. ¶45).
- The essential elements of independent claim 17 are:
- A method of treating relapsing-remitting MS or early secondary progressive MS by orally administering a cladribine formulation according to the following sequential steps:
- (i) an "induction period" lasting from about 2 to 4 months, achieving a total cladribine dose of about 1.7 mg/kg to about 3.5 mg/kg;
- (ii) a "cladribine-free period" lasting from about 8 to 10 months with no cladribine administered;
- (iii) a "maintenance period" lasting from about 2 to 4 months, achieving a total cladribine dose of about 1.7 mg/kg; and
- (iv) a second "cladribine-free period" with no cladribine administered.
- The complaint reserves the right to assert other claims beyond claim 17 (Compl. ¶45).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is Defendant's proposed generic cladribine 10 mg tablets, for which it submitted ANDA No. 217530 to the FDA (Compl. ¶¶ 1, 9). The infringement allegation is directed at the use of this product in accordance with its proposed labeling (Compl. ¶¶ 36, 47).
Functionality and Market Context
The TWi ANDA Product is represented as being a generic version of Merck’s MAVENCLAD® product, with the same active ingredient, dosage form, and strength (Compl. ¶28). The complaint alleges that TWi is seeking approval to market its product for the same indication as MAVENCLAD®, which is the treatment of relapsing forms of MS in adults (Compl. ¶¶ 25, 29). The act of infringement arises from the instructions for use in the proposed product labeling, which Plaintiff alleges will direct users to follow the patented method (Compl. ¶¶ 36-38). No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
The complaint alleges that the use of Defendant's ANDA product, as directed by its proposed labeling, will infringe the patents-in-suit. The specific content of the proposed label is not provided in the complaint.
’947 Patent Infringement Allegations
| Claim Element (from Independent Claim 36) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of treating multiple sclerosis comprising the oral administration of a formulation comprising cladribine | Defendant's proposed product is an oral cladribine tablet for which approval is sought for the same indication as MAVENCLAD®, the treatment of relapsing MS. | ¶¶9, 29 | col. 2:13-18 |
| (i) an induction period lasting from about 2 months to about 4 months wherein said formulation is orally administered and wherein the total dose of cladribine reached at the end of the induction period is from about 1.7 mg/kg to about 3.5 mg/kg; | The proposed labeling for Defendant’s product will allegedly instruct an initial treatment course that meets these duration and cumulative dosage parameters. | ¶36 | col. 8:28-32 |
| (ii) a cladribine-free period lasting from about 8 months to about 10 months, wherein no cladribine is administered; | The proposed labeling will allegedly instruct a subsequent period of non-administration that meets this duration requirement. | ¶36 | col. 9:1-7 |
| (iii) a maintenance period lasting from about 2 months to about 4 months, wherein said formulation is orally administered and wherein the total dose of cladribine reached at the end of the maintenance period is about 1.7 mg/kg; | The proposed labeling will allegedly instruct a second treatment course that meets these duration and lower cumulative dosage parameters. | ¶36 | col. 8:37-43 |
| (iv) a cladribine-free period wherein no cladribine is administered. | The proposed labeling will allegedly instruct a second period of non-administration following the maintenance period. | ¶36 | col. 8:44-45 |
- Identified Points of Contention:
- Evidentiary Question: The central dispute will depend on evidence not included in the complaint: the exact text of TWi's proposed product labeling. The case will turn on whether that text instructs a regimen that meets every claimed parameter for dosage and timing.
- Scope Question: A key question will be whether the instructions on the proposed label fall squarely within the claimed numerical ranges. For example, does the label's instruction for the second course of treatment result in a "total dose" of "about 1.7 mg/kg," or does it specify a different dose or a range that might fall outside a reasonable interpretation of "about"?
’903 Patent Infringement Allegations
| Claim Element (from Independent Claim 17) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of treating relapsing-remitting multiple sclerosis or early secondary progressive multiple sclerosis comprising the oral administration of a formulation comprising cladribine | Defendant seeks approval for its oral cladribine product for the same indication as MAVENCLAD®, which is for treating relapsing forms of MS. | ¶¶25, 29, 47 | col. 2:19-22 |
| (i) an induction period lasting from about 2 months to about 4 months...total dose...is from about 1.7 mg/kg to about 3.5 mg/kg; | The proposed labeling for Defendant’s product will allegedly instruct an initial treatment course that meets these duration and cumulative dosage parameters. | ¶47 | col. 6:35-39 |
| (ii) a cladribine-free period lasting from about 8 months to about 10 months, wherein no cladribine is administered; | The proposed labeling will allegedly instruct a subsequent period of non-administration that meets this duration requirement. | ¶47 | col. 6:59-62 |
| (iii) a maintenance period lasting from about 2 months to about 4 months...total dose...is about 1.7 mg/kg; | The proposed labeling will allegedly instruct a second treatment course that meets these duration and lower cumulative dosage parameters. | ¶47 | col. 17:15-18 |
| (iv) a cladribine-free period wherein no cladribine is administered. | The proposed labeling will allegedly instruct a second period of non-administration following the maintenance period. | ¶47 | col. 17:19-20 |
- Identified Points of Contention:
- Congruence Question: As with the ’947 Patent, the primary issue will be whether the specific instructions in TWi's proposed label are congruent with every limitation of claim 17. Any mismatch between the labeled instructions and the claimed parameters for dose, duration, or rest periods could support a non-infringement defense.
- Specificity Question: Claim 17 is directed specifically to "relapsing-remitting" or "early secondary progressive" MS. The infringement analysis will require showing that the indication for use on TWi's label corresponds to these specific patient populations.
V. Key Claim Terms for Construction
The Term: "about"
- Context and Importance: This term qualifies every numerical limitation for dose and duration in the asserted claims. The scope of "about" is critical; a narrow construction would provide Defendant more opportunity to argue its labeled regimen is different, while a broad construction would favor Plaintiff's infringement case. Practitioners may focus on this term because its construction will directly define the boundaries of literal infringement for the entire claimed method.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification uses the term "about" repeatedly when describing the invention's parameters, suggesting the inventors intended to claim a range of values and not be limited to the exact numbers stated (’947 Patent, col. 4:56, col. 8:56). This suggests the numbers are approximations.
- Evidence for a Narrower Interpretation: The specification includes detailed tables with specific, calculated doses for different patient weight ranges (’947 Patent, Tables 3 & 4, col. 15-16). A party could argue that "about" should be interpreted narrowly in light of these highly specific examples, potentially limiting its scope to standard rounding or the variation shown in the examples.
The Term: "total dose ... reached at the end of the ... period"
- Context and Importance: This phrase dictates how the cumulative dosage limitations are to be met. Its construction is important for determining whether a prescribed regimen, which may involve multiple administrations over weeks or months, satisfies the claimed cumulative dose. A dispute could arise over the precise method of calculation, especially if a label provides for dose adjustments.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent defines "total dose" as "the total dose of Cladribine administered during the treatment, i.e. the dose reached at the end of the treatment that is calculated by adding the daily doses" (’947 Patent, col. 4:21-24). This definition appears straightforward and could support a simple summation of prescribed daily doses.
- Evidence for a Narrower Interpretation: The patent's examples calculate the total dose based on a specific number of 10 mg tablets administered to patients in certain weight brackets over a set number of months (’947 Patent, Tables 3 & 4). A party could argue that this phrase should be construed in light of these specific embodiments, requiring a calculation method consistent with the examples.
VI. Other Allegations
- Indirect Infringement: The complaint alleges active inducement of infringement under 35 U.S.C. § 271(b). The factual basis for this claim is that Defendant's proposed product labeling will allegedly instruct and encourage physicians and patients to use the generic drug in a manner that directly practices the steps of the claimed methods (Compl. ¶¶ 37-38, 48-49).
- Willful Infringement: The complaint alleges that Defendant "acted without a reasonable basis for believing that it would not be liable for infringing" the patents (Compl. ¶¶ 41, 52). This allegation is based on alleged pre-suit knowledge of the patents, as demonstrated by Defendant's submission of a Paragraph IV certification to the FDA, which is a statutory requirement that acknowledges the existence of the patents-in-suit (Compl. ¶¶ 35, 46).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue will be one of instructional congruence: will the specific text of Defendant's proposed product label direct a course of treatment that maps precisely onto the claimed multi-step regimen, including the cumulative dosages and durations for both the "induction" and "maintenance" periods? The outcome will likely depend on a detailed, side-by-side comparison of the label and the claims.
- The case may also turn on a question of definitional breadth: how will the court construe the term "about"? The degree of numerical flexibility this term affords will be a dispositive factor in determining whether the dosing regimen on Defendant's label falls within the literal scope of the claims.
- Finally, while not detailed in the complaint, a core part of the litigation will involve the question of patent validity: can Defendant prove by clear and convincing evidence, as it alleged in its Paragraph IV notice, that the claimed dosing regimen was obvious or anticipated by the prior art at the time of the invention?