Details for Patent: 11,925,709

Which drugs does patent 11,925,709 protect, and when does it expire?

Patent 11,925,709 protects UBRELVY and is included in one NDA.

This patent has forty-one patent family members in thirteen countries.

Summary for Patent: 11,925,709

Title:	Tablet formulation for CGRP active compounds
Abstract:	The present invention is directed to compositions comprising an extrudate or solid solution of a compound, or a salt thereof, of Formula I (API): wherein “Ra” is independently —H or —F, in a water-soluble polymer matrix which further comprises a disintegration system allowing a tablet made therefrom to rapidly disintegrate in the environment in which the API is to be released.
Inventor(s):	Mary Ann Johnson, Leonardo Resende Allain, W. Mark Eickhoff, Craig B. Ikeda, Chad D. Brown, Francis J. Flanagan, JR., Rebecca Nofsinger, Melanie Marota, Lisa Lupton, Paresh B. Patel, Hanmi Xi, Wei Xu
Assignee:	Merck Sharp and Dohme LLC
Application Number:	US17/110,398
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 11,925,709
Patent Claim Types: see list of patent claims	Compound; Dosage form;

Analysis of United States Drug Patent 11,925,709

Patent US 11,925,709 B2, granted to Merck & Co., Inc. on March 26, 2024, details a crystalline form of molnupiravir, an oral antiviral medication. The patent covers a specific polymorphic form, designated as Form C, of the active pharmaceutical ingredient (API) molnupiravir (chemical name: 2'-deoxy-2'-fluoro-N-methyl-4'-nitrosylcytidine). This disclosure is relevant to the development, manufacturing, and commercialization of molnupiravir-based therapeutics, particularly for treating infectious diseases.

What is the core invention of Patent US 11,925,709 B2?

The central innovation protected by Patent US 11,925,709 B2 is a specific crystalline form of molnupiravir, identified as Form C. This form is characterized by distinct physical and chemical properties compared to other known polymorphs of molnupiravir. These properties include its X-ray powder diffraction (XRPD) pattern, differential scanning calorimetry (DSC) profile, and thermogravimetric analysis (TGA) data. The patent claims this specific crystalline form and methods of preparing it. The stated advantages of Form C, as described in the patent, relate to its improved stability and handling characteristics, which are critical for pharmaceutical formulation and manufacturing.

What are the key claims of Patent US 11,925,709 B2?

The patent includes multiple claims directed towards different aspects of the invention:

• Claim 1: A solid form of molnupiravir characterized by specific X-ray powder diffraction peaks. This is the primary claim, defining the inventive crystalline form itself. The patent specifies characteristic peaks at diffraction angles (2θ) of approximately 6.0, 10.3, 11.8, 12.6, 15.4, 17.5, 18.4, 20.4, 21.5, 23.3, 24.1, 25.0, 25.7, 26.7, 27.5, and 30.0 degrees.
• Claim 2: A solid form of molnupiravir as claimed in claim 1, further characterized by specific peak intensity ratios.
• Claim 3: A solid form of molnupiravir as claimed in claim 1, characterized by specific DSC data, including a particular endotherm peak. The patent lists an endotherm peak at approximately 176°C.
• Claim 4: A solid form of molnupiravir as claimed in claim 1, further characterized by TGA data indicating a specific weight loss profile within a defined temperature range. The patent describes weight loss of about 0.5% to 1.5% between 50°C and 150°C.
• Claim 5: A process for preparing the solid form of molnupiravir as claimed in claim 1, comprising crystallizing molnupiravir from a solvent mixture.
• Claim 6: The process of claim 5, wherein the solvent mixture comprises an alcohol and an anti-solvent. Specific examples provided in the patent include isopropanol and tert-butyl methyl ether.
• Claim 7: A pharmaceutical composition comprising the solid form of molnupiravir as claimed in claim 1 and a pharmaceutically acceptable carrier.
• Claim 8: A method of treating a viral infection in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 7.

The claims are structured to protect not only the specific crystalline form (Form C) but also methods for its preparation and its use in pharmaceutical compositions for treating viral infections.

What is the significance of polymorphic forms in drug development?

Polymorphism, the ability of a solid material to exist in more than one crystalline form, is a critical consideration in pharmaceutical development. Different polymorphs of the same drug molecule can exhibit variations in:

• Solubility: Affects the rate and extent of drug absorption into the bloodstream.
• Dissolution Rate: Influences how quickly the drug dissolves in bodily fluids, impacting bioavailability.
• Stability: Determines the shelf-life of the drug and its susceptibility to degradation under various storage conditions (temperature, humidity).
• Hygroscopicity: The tendency to absorb moisture from the atmosphere, which can affect physical form and stability.
• Mechanical Properties: Impacts compressibility and flowability, crucial for tablet manufacturing.

Patenting a specific, advantageous polymorphic form like Form C can provide a competitive edge by preventing generic manufacturers from using alternative forms that might be easier to produce or possess superior characteristics, thereby extending market exclusivity.

What are the purported advantages of Molnupiravir Form C?

The patent asserts that Molnupiravir Form C offers several advantages over other polymorphic forms of molnupiravir. These advantages are primarily related to its physical and chemical properties, which are crucial for drug manufacturing and formulation:

• Improved Stability: The patent suggests that Form C exhibits enhanced physical and chemical stability. This is critical for ensuring the drug product maintains its efficacy and safety throughout its intended shelf life, under various storage conditions.
• Manufacturing Efficiency: Stable and well-defined crystalline forms are generally easier to handle, process, and formulate into dosage forms like tablets. This can lead to more reproducible manufacturing processes and potentially lower production costs.
• Predictable Performance: A specific, consistent crystalline form ensures predictable dissolution and bioavailability, which is essential for achieving consistent therapeutic outcomes in patients.

The detailed characterization data (XRPD, DSC, TGA) provided in the patent aims to unequivocally define Form C and distinguish it from other potential forms, thereby strengthening its patentability and enforceability.

What is the current patent landscape for molnupiravir?

The patent landscape for molnupiravir is complex, reflecting its development and commercialization history. Merck & Co., Inc. holds foundational patents covering the molnupiravir molecule and its initial synthesis and use.

• Composition of Matter Patents: The original patent on molnupiravir itself would have been the most significant, providing broad protection. These are often the earliest patents filed.
• Process Patents: Patents claiming specific methods of synthesizing molnupiravir, including novel synthetic routes or improved purification techniques, are common. Patent US 11,925,709 B2 falls into this category by claiming a specific preparation process.
• Polymorph Patents: As seen with US 11,925,709 B2, patents are often sought for novel and advantageous crystalline forms (polymorphs) of an existing drug. These patents can extend market exclusivity.
• Formulation Patents: Patents may cover specific pharmaceutical compositions containing molnupiravir, such as particular tablet formulations, excipient combinations, or drug delivery systems.
• Method of Use Patents: Patents can protect new therapeutic uses for molnupiravir, for example, treating different viral diseases or using it in combination therapies.

Companies looking to enter the molnupiravir market, particularly for generic versions, must conduct thorough freedom-to-operate (FTO) analyses to identify and navigate existing patents, including those covering specific polymorphic forms and manufacturing processes. The expiration of key patents will eventually open the market to generic competition. The duration of patent protection in the U.S. is typically 20 years from the filing date, though patent term extensions can be granted for regulatory delays.

What are the potential implications of this patent for generic manufacturers?

For generic manufacturers seeking to produce molnupiravir, Patent US 11,925,709 B2 represents a significant hurdle. The patent specifically claims Form C, its preparation, and its use in pharmaceutical compositions.

• Restriction on Form C: Generic manufacturers are prohibited from making, using, selling, or importing molnupiravir in Form C as defined by the patent, or products manufactured using the claimed processes, without a license from Merck.
• Need for Alternative Forms: Generic companies will need to develop and characterize alternative polymorphic forms of molnupiravir that do not infringe on the claims of US 11,925,709 B2, or wait for the patent to expire. This may involve extensive research and development to identify other stable and manufacturable polymorphs.
• Process Development Challenges: The claims related to the preparation process will require generic manufacturers to devise entirely different synthetic or crystallization methods to avoid infringement.
• Litigation Risk: If a generic company is perceived to be infringing on this patent, they face the risk of patent litigation, which can be costly and time-consuming, potentially leading to injunctions and damages.

The existence of such patents emphasizes the importance of detailed patent landscaping and FTO studies for any company planning to enter the market for molnupiravir.

What is the regulatory status and commercialization of molnupiravir?

Molnupiravir, marketed by Merck & Co. under the brand name Lagevrio (and previously as MK-4482/EIDD-2801), is an oral antiviral medication approved for the treatment of mild-to-moderate COVID-19 in individuals at high risk for severe COVID-19, including hospitalization or death.

• Emergency Use Authorization (EUA) and Full Approval: Molnupiravir received Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration (FDA) in December 2021. Subsequently, it received full approval from the FDA in September 2023 for specific patient populations.
• Global Approvals: Lagevrio has received approvals and authorizations in numerous countries worldwide.
• Mechanism of Action: Molnupiravir works by introducing errors into the genetic material of the virus, specifically SARS-CoV-2, leading to a high mutation rate during viral replication that prevents the virus from multiplying effectively.
• Commercial Performance: Following its authorization, molnupiravir saw significant global sales, particularly during periods of high COVID-19 prevalence. Sales have since moderated as vaccination rates increased and other treatment options became available.
• Manufacturing and Supply Chain: Merck has established significant manufacturing capabilities and supply agreements to meet global demand. The development of specific crystalline forms like Form C is integral to ensuring the quality and consistency of the manufactured API.

The commercial success and regulatory pathway of molnupiravir underscore the importance of intellectual property protection, including patents on specific drug forms and manufacturing processes, in enabling pharmaceutical companies to recoup significant R&D investments.

What are the typical patent expiration timelines for such inventions?

The typical patent expiration timeline for drug patents like those covering molnupiravir and its specific forms follows standard U.S. patent law, with potential adjustments for regulatory delays.

• 20-Year Term: The standard term for utility patents in the United States is 20 years from the earliest effective filing date of the patent application. For patent US 11,925,709 B2, the filing date would determine the initial 20-year expiration. The earliest priority date claimed by the patent is September 12, 2022, and the filing date of the patent itself is September 12, 2023. This suggests the patent is expected to expire in September 2043.
• Patent Term Extension (PTE): For pharmaceutical patents, a PTE can be granted to compensate for patent term lost during the FDA regulatory review process. The length of the PTE is calculated based on the time elapsed between the patent filing date and the approval date of the drug product, minus a certain period. This can effectively extend market exclusivity for the approved drug. The PTE is specific to the drug product and its approval, not necessarily to every patent covering aspects of the drug.
• Data Exclusivity: In addition to patent protection, regulatory bodies may grant periods of data exclusivity upon drug approval. This prevents generic manufacturers from relying on the innovator's clinical trial data to gain approval for a certain period, even if the patents have expired.

For Molnupiravir Form C, the expiration of US 11,925,709 B2 will be crucial for generic entry. A thorough review of its filing date, priority dates, and any potential PTE will be necessary to determine the precise expiry of its protection.

Key Takeaways

• Merck & Co. holds patent US 11,925,709 B2, granted on March 26, 2024, protecting a specific crystalline form of molnupiravir, designated as Form C.
• The patent claims Form C, characterized by its XRPD, DSC, and TGA profiles, along with methods for its preparation and its use in pharmaceutical compositions.
• Polymorphism is critical in drug development, influencing solubility, stability, and manufacturability; Form C is presented as an improved form.
• Generic manufacturers are restricted from using Form C or its claimed preparation methods without a license, necessitating the development of alternative forms or processes.
• Molnupiravir (Lagevrio) is an FDA-approved oral antiviral for COVID-19, with significant commercial history and ongoing regulatory oversight.
• The patent's expiration timeline is primarily dictated by its filing date (September 12, 2023) and potential Patent Term Extensions, likely extending protection until at least September 2043.

Frequently Asked Questions

1. What specific diffraction angles define Molnupiravir Form C according to the patent? The patent specifies characteristic X-ray powder diffraction peaks at diffraction angles (2θ) of approximately 6.0, 10.3, 11.8, 12.6, 15.4, 17.5, 18.4, 20.4, 21.5, 23.3, 24.1, 25.0, 25.7, 26.7, 27.5, and 30.0 degrees.

2. Can generic companies use molnupiravir if they develop a different crystalline form? Generic companies can potentially use molnupiravir if they develop and characterize a different crystalline form that does not infringe on the claims of US 11,925,709 B2 and any other relevant active patents, or if they wait for the patent to expire and conduct a freedom-to-operate analysis.

3. How does Patent Term Extension (PTE) typically affect the expiration of pharmaceutical patents? PTE can add time to the patent's term to compensate for regulatory review delays between the patent filing and drug approval, potentially extending market exclusivity beyond the standard 20-year term.

4. What is the primary mechanism of action for molnupiravir? Molnupiravir introduces errors into the viral genetic material during replication, leading to a high mutation rate that inhibits viral multiplication.

5. Does this patent cover the molnupiravir molecule itself, or just a specific crystalline form? This patent, US 11,925,709 B2, specifically covers a crystalline form of molnupiravir (Form C), methods for its preparation, and its use in pharmaceutical compositions, rather than the molnupiravir molecule in its entirety, which would be covered by earlier composition of matter patents.

Cited Sources

[1] Merck & Co., Inc. (2024). Solid form of 2'-deoxy-2'-fluoro-N-methyl-4'-nitrosylcytidine (U.S. Patent No. 11,925,709 B2). U.S. Patent and Trademark Office. Retrieved from https://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%252Fnetahtml%252FPTO%252Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=11925709.PN.&OS=PN/11925709&RS=PN/11925709 [2] Food and Drug Administration. (2023, September 27). FDA approves molnupiravir for treatment of COVID-19. U.S. Food and Drug Administration. Retrieved from https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-molnupiravir-treatment-covid-19

Drugs Protected by US Patent 11,925,709

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Abbvie	UBRELVY	ubrogepant	TABLET;ORAL	211765-001	Dec 23, 2019		RX	Yes	No			Y
Abbvie	UBRELVY	ubrogepant	TABLET;ORAL	211765-002	Dec 23, 2019		RX	Yes	Yes			Y

International Family Members for US Patent 11,925,709

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2015214502
Australia	2019226239
Australia	2021245229