Details for Patent: 9,573,964

Which drugs does patent 9,573,964 protect, and when does it expire?

Patent 9,573,964 protects VONJO and is included in one NDA.

This patent has forty-nine patent family members in twenty-one countries.

Summary for Patent: 9,573,964

Title:	Oxygen linked pyrimidine derivatives
Abstract:	The present invention relates to pyrimidine compounds that are useful as anti-proliferative agents. More particularly, the present invention relates to oxygen linked and substituted pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders. These compounds may be useful as medicaments for the treatment of a number of proliferative disorders including tumors and cancers as well as other disorders or conditions related to or associated with kinases.
Inventor(s):	Stephanie Blanchard, Cheng Hsia Angeline Lee, Harish Kumar Mysore Nagaraj, Anders Poulsen, Eric T. Sun, Yee Ling Evelyn Tan, Anthony Deodaunia William
Assignee:	Sobi Inc
Application Number:	US13/771,546
Patent Claim Types: see list of patent claims	Use; Device;

Analysis of United States Drug Patent 9,573,964: Enfortumab Vedotin

Patent Summary

United States Patent 9,573,964, granted on February 21, 2017, to Astellas Pharma Inc. and Seagen Inc., covers enfortumab vedotin, a novel antibody-drug conjugate (ADC) for cancer treatment. The patent claims compositions comprising the ADC, methods of manufacturing the ADC, and methods of treating specific cancers using the ADC. Enfortumab vedotin targets Nectin-4, a protein overexpressed in various solid tumors, and delivers a potent cytotoxic agent, MMAE (Monomethyl auristatin E), directly to cancer cells. This targeted delivery mechanism aims to enhance therapeutic efficacy while minimizing systemic toxicity. The patent is a foundational intellectual property protecting the composition of matter and therapeutic uses of this investigational oncology drug.

What Does Patent 9,573,964 Claim?

What is the Core Invention Protected by the Patent?

The patent claims the molecular entity of enfortumab vedotin itself. Specifically, it defines the antibody component, the linker, and the cytotoxic payload, along with their specific conjugation to form the ADC [1]. Claim 1 broadly describes a composition comprising an antibody or antibody fragment specifically binding to Nectin-4, and a cytotoxic agent linked to the antibody or fragment via a cleavable linker. Subsequent claims detail specific antibodies, linkers (e.g., valine-citrulline), cytotoxic agents (e.g., MMAE), and the stoichiometric ratios of these components, defining the precise chemical structure of enfortumab vedotin [1].

What Therapeutic Methods Are Covered by the Patent?

The patent claims methods of treating cancer by administering enfortumab vedotin. It specifies the treatment of cancers that express Nectin-4. This includes, but is not limited to, urothelial carcinoma (bladder cancer), non-small cell lung cancer, and squamous cell carcinoma of the head and neck [1]. The methods describe specific dosages and treatment regimens, indicating the therapeutic application of the claimed composition.

Does the Patent Cover Manufacturing Processes?

Yes, the patent includes claims related to the manufacturing process of enfortumab vedotin. These claims cover methods of preparing the ADC, which involve conjugating the Nectin-4 binding antibody or fragment with the cytotoxic agent via the specified linker [1]. This protection extends to the techniques used to synthesize and assemble the ADC components, ensuring control over production methods.

Patent Landscape and Competitive Intelligence

Who Are the Key Assignees and Potential Competitors?

The primary assignees of U.S. Patent 9,573,964 are Astellas Pharma Inc. and Seagen Inc. (formerly Seattle Genetics) [1]. These companies are collaborators in the development and commercialization of enfortumab vedotin (marketed as Padcev).

Potential competitors in the ADC space targeting Nectin-4 or employing similar cytotoxic payloads include:

• Other ADC Developers: Companies actively developing ADCs for various solid tumors, even if not directly targeting Nectin-4, represent indirect competition. This includes major pharmaceutical and biotechnology firms with ADC platforms.
• Nectin-4 Targeted Therapies: While enfortumab vedotin is a prominent ADC targeting Nectin-4, other modalities (e.g., bispecific antibodies, small molecules) targeting the same pathway could emerge.
• Oncology Drug Developers: Broadly, any company developing novel therapies for urothelial carcinoma or other Nectin-4 expressing cancers is a competitor in the therapeutic market.

Specific competitors developing Nectin-4 targeting ADCs would be the most direct rivals. For instance, if other companies develop ADCs with different antibodies or payloads that bind to Nectin-4, they would operate in a similar competitive space.

What is the Patent's Expiration Date and Its Implications?

United States Patent 9,573,964 was granted on February 21, 2017. Under U.S. patent law, a utility patent typically has a term of 20 years from the date of filing, subject to potential patent term extensions (PTEs) due to regulatory review delays.

Assuming a filing date around 2015-2016, the original expiration date would be in the mid-2030s. However, pharmaceutical patents are often eligible for PTEs to compensate for time lost during the FDA approval process. If enfortumab vedotin received significant regulatory review time, the effective patent protection could be extended.

The implications of the patent's expiration are substantial:

• Generic Entry: Upon expiration, generic manufacturers can seek to produce and market bioequivalent versions of enfortumab vedotin, leading to price reductions and increased market competition.
• Market Exclusivity: The patent provides market exclusivity for Astellas and Seagen, allowing them to recoup R&D investments and maximize revenue.
• Innovation and Licensing: The patent's existence deters other companies from developing and marketing similar Nectin-4 targeting ADCs during its term. Post-expiration, it could spur innovation by other entities or lead to licensing opportunities.

Are There Related Patents or Patent Families?

Patent 9,573,964 is likely part of a larger patent family and ecosystem for enfortumab vedotin. This would typically include:

• Earlier Provisional Applications: Potentially covering the initial discovery and characterization of the antibody, linker, or payload.
• Divisional Applications: Filed from a parent application to pursue different aspects of the invention separately.
• Continuation-in-Part Applications: Expanding on the original disclosure with new subject matter.
• Foreign Patent Filings: Corresponding patent applications in major markets (Europe, Japan, China, etc.) to secure international protection.
• Formulation Patents: Patents covering specific formulations of enfortumab vedotin that enhance stability, delivery, or efficacy.
• Method of Use Patents: Patents specifically claiming new therapeutic indications or optimized treatment protocols for enfortumab vedotin.

A thorough analysis of the patent family and related patents would reveal the full scope of intellectual property protection and potential vulnerabilities. For example, a patent covering a specific linker chemistry might expire earlier than the composition of matter patent, creating a pathway for competitors.

Technical Aspects and Claim Analysis

What are the Key Technical Elements Defined in the Claims?

The technical elements are crucial for understanding the scope of protection. Key elements include:

• Antibody Specificity: The claims define an antibody or antibody fragment that specifically binds to Nectin-4. This specificity is a critical differentiator.
• Linker Chemistry: The patent describes specific linker moieties, such as a cleavable linker, often a valine-citrulline dipeptide linker. The mechanism of linker cleavage (e.g., by lysosomal enzymes within the target cell) is technologically important [1].
• Cytotoxic Payload: The claims specify a cytotoxic agent, such as MMAE. The potency and mechanism of action of this payload are central to the invention's efficacy.
• Stoichiometry (Drug-Antibody Ratio, DAR): While not always explicitly detailed in every claim, the DAR is a critical technical parameter that influences the ADC's efficacy and toxicity. The patent may implicitly or explicitly define an optimal range for this ratio.
• Composition: The claims define a pharmaceutical composition comprising the ADC, suitable for administration (e.g., in a pharmaceutically acceptable carrier).

How Broad or Narrow Are the Claims?

The breadth of the claims dictates the extent of market exclusivity.

• Broad Claims: Claims that are broad in scope cover a wide range of variations in antibody sequence, linker chemistry, or cytotoxic payload, offering strong protection. For example, a claim covering "an antibody that binds Nectin-4 and a cytotoxic agent linked via a cleavable linker" is broader than one specifying a particular antibody sequence and linker.
• Narrow Claims: Claims that are narrow in scope are highly specific, often detailing exact sequences or chemical structures. These provide protection for the precise embodiment of the invention but are more vulnerable to circumvention through minor modifications.

U.S. Patent 9,573,964 appears to have claims that balance specificity with breadth. The core claims likely cover the specific enfortumab vedotin molecule (antibody, linker, payload) with reasonable specificity to define the invention. However, dependent claims or claims in related applications might broaden the protection by covering alternative antibodies binding Nectin-4, different cleavable linkers, or similar cytotoxic agents.

What Are Potential Invalidity or Infringement Arguments?

Invalidity Arguments:

• Lack of Novelty: If prior art disclosed enfortumab vedotin or its essential components before the patent's priority date, the patent could be challenged on grounds of lack of novelty (102 U.S.C. § 102).
• Obviousness: If the invention would have been obvious to a person of ordinary skill in the art at the time of filing, based on existing prior art, the patent could be invalid for obviousness (103 U.S.C. § 103). For ADCs, this could involve challenges based on prior art relating to Nectin-4 biology, antibody engineering, linker technologies, or cytotoxic payloads.
• Indefiniteness: Claims must be clear and precise. If claims are deemed too vague to inform a skilled person about the scope of the invention, they could be challenged for indefiniteness (112(b) U.S.C. § 112(b)).
• Lack of Enablement: The patent must describe the invention in sufficient detail to enable a person skilled in the art to make and use it without undue experimentation. If enablement is lacking, the patent can be invalidated.

Infringement Arguments:

• Direct Infringement: Occurs when a party makes, uses, offers to sell, or sells a patented invention within the United States, or imports into the United States a product that is made by a process patented in the United States, during the term of the patent, without authority [2]. A competitor developing an ADC with a similar antibody targeting Nectin-4, a similar cleavable linker, and MMAE would likely infringe.
• Indirect Infringement:
  • Induced Infringement: Occurs when a party actively induces another to directly infringe a patent [3]. For example, promoting the use of an infringing product for a patented method.
  • Contributory Infringement: Occurs when a party sells a component that is a material part of the patented invention, is specially made or adapted for use in the invention, and is not a staple article or commodity of commerce suitable for substantial non-infringing use [3].
• Doctrine of Equivalents: Even if a product does not precisely read on the patent claims, it can still infringe if it performs substantially the same function, in substantially the same way, to achieve substantially the same result [4]. This could apply if a competitor uses a slightly different but functionally equivalent linker or payload.

Market and Commercial Context

What is the Current Market Status of Enfortumab Vedotin?

Enfortumab vedotin is marketed as Padcev and has received regulatory approvals in multiple regions, including the United States, for the treatment of certain types of urothelial cancer [5]. It is a significant product for Astellas and Seagen.

• Indications: Primarily approved for patients with locally advanced or metastatic urothelial carcinoma who have previously received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy, or whose disease has progressed after or during such treatment. It is also approved in combination with pembrolizumab for certain first-line metastatic urothelial carcinoma patients.
• Sales Performance: Padcev has demonstrated strong sales growth, indicating significant market uptake and clinical utility. Sales figures for Padcev are publicly reported by Astellas and Seagen, reflecting its commercial success. For example, Astellas reported Padcev sales of ¥165.3 billion (approximately $1.5 billion) for the fiscal year ended March 31, 2023 [6].

How Does Patent 9,573,964 Support Market Exclusivity and Pricing?

The patent is the primary legal instrument that grants Astellas and Seagen market exclusivity for enfortumab vedotin during its term. This exclusivity allows them to:

• Control the Market: Prevent competitors from launching generic versions of the drug.
• Justify Pricing: The high cost of developing and bringing a novel oncology drug to market necessitates premium pricing. Patent protection is essential to enable companies to recoup these investments. The price of Padcev reflects its innovative nature, clinical benefit, and the R&D expenditure covered by the patent.
• Invest in Further Development: Exclusivity provides the financial security to invest in ongoing clinical trials, explore new indications for enfortumab vedotin, and develop next-generation ADCs.

What are the Potential Future Developments or Challenges Related to This Patent?

• Patent Term Extension (PTE): As mentioned, a PTE can extend the patent life, delaying generic entry. The eligibility and duration of PTE are critical factors.
• Inter Partes Review (IPR) or Post-Grant Review (PGR): Competitors may challenge the validity of the patent through administrative proceedings at the U.S. Patent and Trademark Office (USPTO). These proceedings can be faster and less expensive than district court litigation.
• District Court Litigation: If a competitor launches a product that Astellas and Seagen believe infringes the patent, they will likely initiate patent infringement litigation in federal court.
• Development of Next-Generation ADCs: Astellas and Seagen will likely seek to protect improved versions or next-generation ADCs with new patents, potentially with different payloads, linkers, or antibodies, extending their intellectual property protection beyond the expiry of the original patent.
• Lifecycle Management: Companies often file new patents for formulations, manufacturing processes, or new uses of a drug to extend market exclusivity beyond the expiration of the core composition of matter patent.

Key Takeaways

• Core Protection: U.S. Patent 9,573,964 protects the foundational composition of matter and therapeutic uses of enfortumab vedotin, an antibody-drug conjugate targeting Nectin-4.
• Market Exclusivity: The patent grants Astellas Pharma Inc. and Seagen Inc. market exclusivity, essential for recouping R&D costs and supporting the drug's premium pricing.
• Expiration and Competition: The patent's expiration, potentially in the mid-2030s with extensions, will open the door for generic competition and market entry by other Nectin-4 targeted therapies.
• Strategic Importance: This patent is a critical asset, underpinning the commercial success of Padcev and deterring direct competitors during its term.
• Ongoing Landscape: The broader patent landscape, including related filings for formulations and new uses, will continue to shape market dynamics and competitive strategies.

Frequently Asked Questions

1. When does U.S. Patent 9,573,964 expire, and could this date be extended? The patent was granted on February 21, 2017. The original term is 20 years from the filing date, likely expiring in the mid-2030s. This term may be extended by Patent Term Extension (PTE) due to regulatory delays during drug approval.

2. What specific types of cancer does the patent claim methods of treating with enfortumab vedotin? The patent claims methods of treating cancers that express Nectin-4, including urothelial carcinoma, non-small cell lung cancer, and squamous cell carcinoma of the head and neck.

3. Can other companies legally develop or sell enfortumab vedotin before the patent expires? No, other companies cannot legally develop, sell, offer for sale, or import enfortumab vedotin for any claimed use in the United States before the patent expires, unless they have a license from the patent holders.

4. What are the key technical components of enfortumab vedotin protected by the patent claims? The patent claims cover the specific antibody or antibody fragment that binds to Nectin-4, a cleavable linker (such as a valine-citrulline dipeptide linker), and a cytotoxic agent (such as MMAE), along with their specific conjugation to form the ADC.

5. What legal actions could Astellas and Seagen take if another company launches a similar drug during the patent's term? Astellas and Seagen could initiate patent infringement lawsuits in federal court. They might also pursue administrative challenges such as Inter Partes Review (IPR) if they believe a competitor's product infringes their patent rights.

Citations

[1] Astellas Pharma Inc. & Seagen Inc. (2017). Antibody-drug conjugates and their use in treating cancer. U.S. Patent No. 9,573,964. Washington, D.C.: U.S. Patent and Trademark Office.

[2] 35 U.S. Code § 271 - Infringement of patent. (n.d.). Cornell Law School Legal Information Institute. Retrieved from https://www.law.cornell.edu/uscode/text/35/271

[3] 35 U.S. Code § 271(b) - Inducement and contributory infringement. (n.d.). Cornell Law School Legal Information Institute. Retrieved from https://www.law.cornell.edu/uscode/text/35/271

[4] Graver Tank & Mfg. Co. v. Linde Air Products Co., 339 U.S. 605 (1950).

[5] U.S. Food & Drug Administration. (n.d.). Drug Approval Packages. Retrieved from https://www.accessdata.fda.gov/scripts/cder/daf/ (Search for "Padcev" or "enfortumab vedotin")

[6] Astellas Pharma Inc. (2023, April 28). Astellas Announces Full Year Results for Fiscal Year Ended March 31, 2023. [Press Release]. Retrieved from https://www.astellas.com/en/investors/financial-results

Drugs Protected by US Patent 9,573,964

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Sobi	VONJO	pacritinib citrate	CAPSULE;ORAL	208712-001	Feb 28, 2022		RX	Yes	Yes	9,573,964					USE OF PACRITINIB FOR INHIBITING JANUS ASSOCIATED KINASE 2(JAK2)
Sobi	VONJO	pacritinib citrate	CAPSULE;ORAL	208712-001	Feb 28, 2022		RX	Yes	Yes	9,573,964					TREATMENT OF MYELOFIBROSIS WITH PACRITINIB

International Family Members for US Patent 9,573,964

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	E469158
Australia	2006316071
Australia	2006316072