1:23-cv-00655
Merck KGaA v. Apotex Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Merck KGaA (Germany), Merck Serono SA (Switzerland), and Ares Trading SA (Switzerland)
- Defendant: Apotex Inc. (Canada) and Apotex Corp. (Delaware)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP; Wilmer Cutler Pickering Hale and Dorr LLP
- Case Identification: 1:23-cv-00655, D. Del., 06/15/2023
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Apotex Corp. is a Delaware corporation, and Defendant Apotex Inc. is a foreign corporation that may be sued in any judicial district.
- Core Dispute: Plaintiff alleges that Defendant’s submission of an Abbreviated New Drug Application (ANDA) to the FDA seeking to market a generic version of Plaintiff's MAVENCLAD® multiple sclerosis treatment constitutes an act of infringement of three patents covering specific cladribine treatment regimens.
- Technical Context: The technology concerns specific oral dosing regimens for the drug cladribine, used to treat various forms of multiple sclerosis, a chronic inflammatory disease of the central nervous system.
- Key Procedural History: This action was filed under the Hatch-Waxman Act following Plaintiff’s receipt of a May 19, 2023 Notice Letter from Defendant. The letter stated that Defendant had filed an ANDA containing Paragraph IV certifications alleging that U.S. Patent Nos. 7,713,947 and 8,377,903 are invalid and/or will not be infringed by its proposed generic product. The complaint also alleges Defendant knew of U.S. Patent No. 10,849,919 no later than its listing in the FDA’s Orange Book on September 12, 2022.
Case Timeline
| Date | Event |
|---|---|
| 2004-12-22 | ’947 and ’903 Patent Priority Date |
| 2010-05-11 | ’947 Patent Issue Date |
| 2013-02-19 | ’903 Patent Issue Date |
| 2017-11-24 | ’919 Patent Priority Date |
| 2019-03-29 | MAVENCLAD® FDA Approval Date |
| 2020-12-01 | ’919 Patent Issue Date |
| 2022-09-12 | ’919 Patent listed in Orange Book for MAVENCLAD® |
| 2023-05-19 | Apotex sends Notice Letter to Merck |
| 2023-06-15 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 7,713,947 - “Cladribine Regimen for Treating Multiple Sclerosis”
The Invention Explained
- Problem Addressed: The patent describes a need for a multiple sclerosis treatment that provides a therapeutic effect on MS lesions while decreasing the occurrence and severity of adverse events associated with the drug cladribine (’947 Patent, col. 3:21-26). Prior clinical trials had led practitioners to exclude the oral route for cladribine in treating MS due to an unfavorable balance of efficacy and side effects (’947 Patent, col. 3:45-52).
- The Patented Solution: The invention is a specific oral dosing regimen for cladribine that separates treatment into distinct periods: an initial "induction period" with a specified total dose, followed by a "Cladribine-free period," and then a subsequent "maintenance period" with a lower total dose (’947 Patent, Abstract; col. 4:46-64). This structured, intermittent oral dosing schedule is designed to achieve sustained therapeutic benefit while managing toxicity.
- Technical Importance: The claimed regimen provided a viable path for oral administration of cladribine, a route previously considered unsuitable for MS treatment due to safety concerns.
Key Claims at a Glance
- The complaint asserts at least claim 36, which depends on independent claim 20 (Compl. ¶31). The essential elements of independent claim 20 are:
- A method of treating multiple sclerosis comprising the oral administration of a formulation comprising cladribine.
- The administration follows sequential steps including:
- An "induction period" of about 2 to 4 months with a total cladribine dose of about 1.7 mg/kg to 3.5 mg/kg.
- A "cladribine-free period" of about 8 to 10 months.
- A "maintenance period" of about 2 to 4 months where the total cladribine dose is lower than the induction period dose.
- A subsequent "cladribine-free period."
- The complaint does not explicitly reserve the right to assert additional dependent claims.
U.S. Patent No. 8,377,903 - “Cladribine Regimen for Treating Multiple Sclerosis”
The Invention Explained
- Problem Addressed: As a continuation of the application leading to the ’947 Patent, the ’903 Patent addresses the same technical problem: the need for an effective and safe oral treatment regimen for multiple sclerosis, particularly relapsing-remitting MS (RRMS) or early secondary progressive MS (SPMS) (’903 Patent, col. 3:21-30).
- The Patented Solution: The patent claims a method of treatment using a specific, structured oral dosing schedule for cladribine. This regimen involves an "induction period" and a subsequent "maintenance period," separated by a "cladribine-free period," with specific total doses defined for each treatment phase (’903 Patent, Abstract; col. 4:50-65). This patent further refines the dosing parameters for specific types of MS.
- Technical Importance: This patent provides continued and more specific protection for the structured oral cladribine regimen that enabled its use as a viable MS therapy.
Key Claims at a Glance
- The complaint asserts at least independent claim 17 (Compl. ¶42). Its essential elements are:
- A method of treating relapsing-remitting multiple sclerosis or early secondary progressive multiple sclerosis by orally administering cladribine.
- The administration follows sequential steps including:
- An "induction period" of about 2 to 4 months with a total cladribine dose of about 1.7 mg/kg to 3.5 mg/kg.
- A "cladribine-free period" of about 8 to 10 months.
- A "maintenance period" of about 2 to 4 months with a total cladribine dose of about 1.7 mg/kg.
- A subsequent "cladribine-free period."
- The complaint does not explicitly reserve the right to assert additional dependent claims.
U.S. Patent No. 10,849,919 - “Cladribine Regimen for Treating Progressive Forms of Multiple Sclerosis”
Technology Synopsis
This patent addresses the high unmet medical need for therapeutics effective against progressive forms of MS, such as Primary Progressive Multiple Sclerosis (PPMS) and Secondary Progressive Multiple Sclerosis (SPMS) (’919 Patent, col. 3:21-25). The invention is based on the discovery that a specific oral cladribine dosing regimen (e.g., a cumulative dose of 3.5 mg/kg over two years) is surprisingly and significantly more effective in treating these progressive forms of MS compared to relapsing-remitting forms (’919 Patent, col. 3:36-54).
Asserted Claims
Independent claims 1, 14, and 27 (Compl. ¶53).
Accused Features
The complaint alleges that the use of Apotex's ANDA Product, as directed by its proposed labeling, will infringe the claims covering methods of treating progressive forms of MS (Compl. ¶55).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is Defendant Apotex's proposed generic cladribine 10 mg tablets, identified as the "Apotex ANDA Product" associated with ANDA No. 218425 (Compl. ¶¶1, 9).
Functionality and Market Context
The complaint alleges that the Apotex ANDA Product has the same active ingredient (cladribine), dosage form, and strength as Plaintiff’s MAVENCLAD® product and is bioequivalent to it (Compl. ¶26). The infringement theory is based on the future commercial manufacture, use, and sale of this generic product, which would be prescribed and used according to a product label that allegedly directs infringing uses (Compl. ¶33). MAVENCLAD® is an FDA-approved treatment for relapsing forms of multiple sclerosis (Compl. ¶23).
IV. Analysis of Infringement Allegations
The complaint alleges that Apotex's submission of its ANDA is an act of infringement and that the future, post-approval use of the Apotex ANDA Product in accordance with its proposed labeling will induce infringement of the asserted method claims (Compl. ¶¶30, 33, 41, 44, 52, 55). The complaint does not provide specific details or a claim chart mapping the proposed product label to the claim elements. The following summary is based on the infringement theory implied in the complaint.
No probative visual evidence provided in complaint.
7,713,947 Patent Infringement Allegations
| Claim Element (from Independent Claim 20) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of treating multiple sclerosis comprising the oral administration of a formulation comprising cladribine... | Apotex’s proposed product is an oral formulation of cladribine for treating MS, and its label allegedly instructs administration for that purpose. | ¶¶26, 33 | col. 8:16-17 |
| (i) an induction period lasting from about 2 months to about 4 months wherein...the total dose...is from about 1.7 mg/kg to about 3.5 mg/kg; | Apotex's proposed label allegedly instructs administering cladribine according to this specific induction period dosing regimen. | ¶¶26, 33 | col. 8:55-58 |
| (ii) a cladribine-free period lasting from about 8 months to about 10 months, wherein no cladribine is administered; | Apotex's proposed label allegedly instructs a period with no cladribine administration that meets this temporal requirement. | ¶¶26, 33 | col. 8:62-65 |
| (iii) a maintenance period lasting from about 2 months to about 4 months...wherein the total dose...is lower than the total dose of cladribine reached at the end of the induction period (i); | Apotex's proposed label allegedly instructs administering a subsequent course of cladribine that meets the claimed maintenance period requirements. | ¶¶26, 33 | col. 8:46-50 |
| (iv) a cladribine-free period wherein no cladribine is administered. | Apotex's proposed label allegedly instructs a second period with no cladribine administration following the maintenance period. | ¶¶26, 33 | col. 8:62-65 |
8,377,903 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... | Apotex’s proposed product is an oral formulation of cladribine, and its label allegedly instructs administration for treating these forms of MS. | ¶¶26, 44 | col. 1:15-20 |
| (i) an induction period lasting from about 2 months to about 4 months wherein...the total dose...is from about 1.7 mg/kg to about 3.5 mg/kg; | Apotex's proposed label allegedly instructs administering cladribine according to this specific induction period dosing regimen. | ¶¶26, 44 | col. 4:55-58 |
| (ii) a cladribine-free period lasting from about 8 months to about 10 months, wherein no cladribine is administered; | Apotex's proposed label allegedly instructs a period with no cladribine administration that meets this temporal requirement. | ¶¶26, 44 | col. 4:65-67 |
| (iii) a maintenance period lasting from about 2 months to about 4 months, wherein the total dose...is about 1.7 mg/kg; | Apotex's proposed label allegedly instructs administering a subsequent course of cladribine that meets the claimed maintenance period dose. | ¶¶26, 44 | col. 4:50-54 |
| (iv) a cladribine-free period wherein no cladribine is administered. | Apotex's proposed label allegedly instructs a second period with no cladribine administration following the maintenance period. | ¶¶26, 44 | col. 4:65-67 |
Identified Points of Contention
- Scope Questions: The complaint does not specify which instructions in the Apotex proposed label are alleged to map to the claimed steps. A central question will be whether the proposed label requires or merely permits a dosing regimen that falls within the scope of the claims.
- Technical Questions: The dispute will likely focus on the contents of the proposed label for the Apotex ANDA Product. The court will need to determine if the instructions in that label direct physicians and patients to follow the specific sequence of dosing periods, total dose calculations, and drug-free intervals required by the asserted claims.
V. Key Claim Terms for Construction
The complaint does not provide sufficient detail for analysis of specific claim term disputes. However, based on the structure of the asserted claims, the following terms may be central to the litigation.
The Term: "total dose of cladribine" (e.g., ’947 Patent, claim 20; ’903 Patent, claim 17)
Context and Importance: This quantitative limitation is the cornerstone of the claimed regimen. Its definition is critical for determining whether a prescribed or administered amount of the accused product meets the claimed thresholds. Practitioners may focus on this term because its calculation (e.g., per kilogram of body weight, over a specific time period) must be precisely met for infringement to occur.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification defines "total dose" as "the dose reached at the end of the treatment that is calculated by adding the daily doses," which could be interpreted to encompass the prescribed amount irrespective of minor patient compliance deviations (’947 Patent, col. 4:21-25).
- Evidence for a Narrower Interpretation: The claims tie the "total dose" to specific treatment periods (e.g., "reached at the end of the induction period"), suggesting the calculation is strictly confined to the drug administered within that defined window, potentially excluding any doses taken outside of it (’947 Patent, col. 18:24-27).
The Term: "cladribine-free period" (e.g., ’947 Patent, claim 20; ’903 Patent, claim 17)
Context and Importance: This term defines the mandatory "drug holiday" that is a key feature of the patented method. The duration and nature of this period are essential limitations. The dispute may turn on whether any de minimis or inadvertent administration of cladribine during this period would defeat an infringement allegation.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification simply states it is "a period wherein no Cladribine is administered to the patient," which could be read to mean no prescribed administration, allowing for accidental or non-compliant doses (’947 Patent, col. 4:65-67).
- Evidence for a Narrower Interpretation: The term "no cladribine" is absolute. A defendant may argue that this requires a complete absence of the drug, and any evidence of administration during the specified timeframe would place a user outside the claim scope. The patent does not appear to provide explicit definitions that would soften this absolute language.
VI. Other Allegations
Indirect Infringement
The complaint alleges that Apotex will actively induce infringement by physicians and patients (Compl. ¶¶35, 46, 57). This allegation is based on the assertion that Apotex's proposed product labeling will instruct users to administer the generic product in a manner that practices the steps of the patented methods (Compl. ¶¶33, 44, 55).
Willful Infringement
Willfulness is alleged based on Apotex’s pre-suit knowledge of the patents-in-suit. For the ’947 and ’903 patents, knowledge is alleged based on Apotex's submission of Paragraph IV certifications as part of its ANDA filing (Compl. ¶¶32, 43). For the ’919 patent, knowledge is alleged to have occurred no later than the date the patent was listed in the FDA's Orange Book for MAVENCLAD® (Compl. ¶54). The complaint alleges Apotex acted without a reasonable basis for believing it would not be liable for infringement (Compl. ¶¶38, 49, 60).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of induced infringement: does the language of Apotex's proposed product label direct, encourage, or recommend that a substantial number of physicians or patients will administer the generic product in a way that practices every step of the claimed multi-stage dosing regimens?
- A second key issue will be claim construction: how will the court interpret the temporal and quantitative boundaries of the claims, such as the meaning of "about" in the context of treatment period durations (e.g., "about 2 months to about 4 months") and the precise method for calculating the "total dose" per kilogram of body weight?
- A final dispositive question, although not detailed in the complaint, will be validity: will Apotex be able to prove by clear and convincing evidence that the asserted claims, which rely on specific dosing schedules, are invalid as obvious over prior art studies involving cladribine for the treatment of MS?