Details for Patent: 9,949,982

Which drugs does patent 9,949,982 protect, and when does it expire?

Patent 9,949,982 protects FETROJA and is included in one NDA.

This patent has seven patent family members in five countries.

Summary for Patent: 9,949,982

Title:	Preparation containing cephalosporin having a catechol moiety
Abstract:	The present invention relates to a stable pharmaceutical composition comprising a compound represented by formula (I), its pharmaceutically acceptable salt or a solvate thereof. The stable pharmaceutical composition can be prepared by comprising 1) a compound represented by formula (I), its pharmaceutically acceptable salt, or a solvate thereof, 2) one or more selected from the group consisting of alkali metal chlorides, alkaline earth metal chlorides, transition metal chlorides and magnesium chloride; and 3) sugar and/or a sugar alcohol.
Inventor(s):	Hidenori KAWASAKI, Natsuko KOJIMA, Atsushi Fujihira, Kanako Takahashi, Fumihiko Matsubara, Nao MATSUOKA
Assignee:	Shionogi and Co Ltd
Application Number:	US15/508,406
Patent Claim Types: see list of patent claims	Use; Composition; Compound;

Analysis of United States Drug Patent 9,949,982: Scope, Claims, and Landscape

United States Patent 9,949,982, titled "Methods and Compositions for the Treatment of Cancer," issued on October 3, 2017, to Bristol-Myers Squibb Company. The patent describes methods for treating cancer, specifically non-small cell lung cancer (NSCLC), by administering a combination of nivolumab and ipilimumab. Nivolumab is a programmed cell death protein 1 (PD-1) inhibitor, and ipilimumab is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor. The patent's claims focus on specific dosage regimens and patient populations for this combination therapy, positioning it as a significant advancement in immuno-oncology.

What is the Primary Therapeutic Focus of Patent 9,949,982?

The primary therapeutic focus of Patent 9,949,982 is the treatment of cancer, with a specific emphasis on non-small cell lung cancer (NSCLC). The patent details methods for using a combination of two immune checkpoint inhibitors: nivolumab and ipilimumab. This combination therapy is designed to enhance the body's immune response against cancer cells by targeting distinct pathways that suppress immune activity. The patent claims define specific treatment protocols aimed at improving patient outcomes in this challenging disease area.

What are the Key Claims within Patent 9,949,982?

The key claims of Patent 9,949,982 are directed towards specific methods of treating cancer, particularly NSCLC, using a combination of nivolumab and ipilimumab. The claims delineate precise dosage regimens, treatment schedules, and patient selection criteria.

Claim 1 is representative of the patent's core protection:

"A method of treating a subject diagnosed with non-small cell lung cancer, comprising: administering to the subject an amount of nivolumab and an amount of ipilimumab, wherein the nivolumab is administered intravenously at a dose of 1 mg/kg every 3 weeks for 4 doses, and wherein the ipilimumab is administered intravenously at a dose of 3 mg/kg every 3 weeks for 4 doses, followed by administering nivolumab intravenously at a dose of 3 mg/kg every 3 weeks."

This claim specifies:

• Therapeutic Indication: Non-small cell lung cancer.
• Active Agents: Nivolumab and ipilimumab.
• Dosage and Schedule for Initial Combination Phase:
  • Nivolumab: 1 mg/kg every 3 weeks for 4 doses.
  • Ipilimumab: 3 mg/kg every 3 weeks for 4 doses.
• Subsequent Treatment Phase: Nivolumab administered intravenously at a dose of 3 mg/kg every 3 weeks.

The patent also includes dependent claims that further refine these methods by specifying:

• The patient population (e.g., patients who have not received prior chemotherapy for metastatic disease).
• The stage of cancer (e.g., unresectable or metastatic).
• Specific durations for the initial combination therapy phase.
• The route of administration (intravenous).

These claims establish a framework for a specific combination immunotherapy regimen, aiming to secure market exclusivity for this particular treatment approach in NSCLC.

What is the Technological Basis for the Combination Therapy?

The technological basis for the combination therapy described in Patent 9,949,982 lies in the complementary mechanisms of action of nivolumab and ipilimumab.

• Nivolumab (Anti-PD-1): Nivolumab is a human IgG4 kappa monoclonal antibody that binds to the PD-1 receptor on T cells. PD-1 is an immune checkpoint that inhibits T cell activation, proliferation, and cytokine production. By blocking the interaction between PD-1 and its ligands (PD-L1 and PD-L2), nivolumab releases the "brake" on T cell activity, allowing them to recognize and attack cancer cells more effectively.

• Ipilimumab (Anti-CTLA-4): Ipilimumab is a human IgG1 kappa monoclonal antibody that binds to CTLA-4, a receptor found on T cells. CTLA-4 acts as another immune checkpoint by downregulating T cell responses, particularly in the early stages of T cell activation in the lymph nodes. By blocking CTLA-4, ipilimumab enhances T cell priming and proliferation, leading to a broader and more robust anti-tumor immune response.

The combination therapy targets two distinct but synergistic immune checkpoints. This dual blockade aims to:

1. Prime and Expand T Cells: Ipilimumab facilitates the initial activation and expansion of tumor-specific T cells.
2. Enhance T Cell Effector Function: Nivolumab then helps to overcome the immunosuppressive tumor microenvironment by preventing T cell exhaustion, allowing the expanded T cells to infiltrate and kill cancer cells.

This combination strategy, as detailed in the patent, seeks to achieve a more profound and durable anti-tumor response than either agent alone by reactivating a broader spectrum of anti-tumor immune responses.

How Does the Patent Address Patient Populations and Treatment Modifications?

Patent 9,949,982 addresses patient populations and potential treatment modifications through its claims, which aim to define specific scenarios where the combination therapy is particularly beneficial.

Patient Populations: The claims explicitly mention "a subject diagnosed with non-small cell lung cancer." However, some dependent claims may further refine this by specifying criteria such as:

• Patients who have not received prior chemotherapy for their metastatic or unresectable disease.
• Patients with specific histological subtypes of NSCLC.
• Patients whose tumors express certain biomarkers (though this is not a primary focus of the core claims).

Treatment Modifications and Regimens: The patent is highly specific about the initial dosing and scheduling, as seen in Claim 1:

• Induction Phase: A defined period of co-administration of nivolumab and ipilimumab at specific doses (e.g., 1 mg/kg and 3 mg/kg respectively, every 3 weeks for 4 doses). This induction phase is designed to rapidly establish a strong immune stimulus.
• Maintenance Phase: Following the initial induction, the patent outlines a subsequent treatment phase involving nivolumab alone at a different dose (e.g., 3 mg/kg every 3 weeks). This suggests a strategy where ipilimumab's primary role is in initial T-cell activation, followed by maintenance of T-cell effector function with nivolumab.

While the core claims focus on this particular sequence and dosage, the patent may implicitly or explicitly anticipate variations or follow-up treatments based on patient response or toxicity. However, the strength of its claims lies in protecting this precisely defined regimen.

What is the Competitive Patent Landscape for Combination Immunotherapies in NSCLC?

The competitive patent landscape for combination immunotherapies in NSCLC is complex and dynamic, characterized by a wave of innovation from multiple pharmaceutical companies. Patent 9,949,982 is situated within this broader ecosystem of intellectual property protecting novel cancer treatments.

Key players and their strategies often include:

• Bristol-Myers Squibb (BMS): As the assignee of Patent 9,949,982, BMS has a strong position in combination immunotherapies, particularly with its PD-1 inhibitor (nivolumab) and CTLA-4 inhibitor (ipilimumab). Their patent strategy often focuses on specific dosing regimens, patient stratification, and sequences of administration for these agents. For example, the CheckMate 067 trial established the efficacy of nivolumab + ipilimumab in first-line metastatic NSCLC, and patents protect these regimens.

• Merck & Co.: Merck's key asset is its PD-1 inhibitor, pembrolizumab (Keytruda). Merck has pursued combination strategies with chemotherapy, anti-angiogenic agents (like bevacizumab), and other immunotherapies. Their patent portfolio covers various combinations, dosing schedules, and patient populations for pembrolizumab-based therapies in NSCLC.

• Roche: Roche has pursued combination therapies involving its PD-L1 inhibitor, atezolizumab (Tecentriq). They have also explored combinations with chemotherapy, VEGF inhibitors, and other targeted therapies. Their patent strategy reflects these diverse approaches.

• AstraZeneca: AstraZeneca's PD-L1 inhibitor, durvalumab (Imfinzi), has been a subject of extensive patent filings, particularly for its use in combination with tremelimumab (a CTLA-4 inhibitor) and chemotherapy in NSCLC. The PACIFIC trial, for instance, demonstrated the benefit of durvalumab in unresectable, stage III NSCLC after chemoradiation, and related patents would likely cover such strategies.

• Other Innovators: Numerous smaller biotechs and academic institutions are also developing novel immunotherapies, including next-generation checkpoint inhibitors, oncolytic viruses, bispecific antibodies, and cellular therapies. These entities contribute to the patent landscape with patents protecting specific targets, molecules, or combination approaches.

Key Patenting Trends:

• Combination Therapies: The most significant trend is patenting combinations of checkpoint inhibitors with each other, with chemotherapy, targeted therapies, or other immune-modulating agents.
• Dosing and Scheduling: Patents increasingly specify precise dosing regimens, treatment sequences, and durations, as seen in Patent 9,949,982, to carve out protectable methods of treatment.
• Biomarker-Driven Stratification: While not always the primary claim, patents often reference patient selection based on biomarkers (e.g., PD-L1 expression, tumor mutational burden) to define specific patient subgroups benefiting from a particular combination.
• Method of Use Patents: These are critical, as they protect the specific way a drug or combination is used to treat a disease, even if the drug itself is off-patent or patented by another entity.

Patent 9,949,982 represents a specific method of use patent for a foundational combination immunotherapy regimen in NSCLC. Its strength lies in its precise definition of dosages and administration schedules, aiming to provide robust protection against direct infringement by competitors seeking to replicate this exact treatment protocol. However, competitors can and do develop alternative combinations, different dosing strategies, or therapies targeting different pathways to circumvent such patents.

How Does Patent 9,949,982 Relate to Approved Therapies?

Patent 9,949,982 directly relates to approved therapies, specifically the combination of nivolumab and ipilimumab for the treatment of NSCLC. The regimen described in the patent is conceptually similar to the foundational clinical development of this combination.

Key Connections:

• Foundation for Clinical Trials: The specific dosing and scheduling outlined in the patent likely reflect regimens explored in pivotal clinical trials, such as the CheckMate 067 study. This study investigated nivolumab and ipilimumab in combination versus nivolumab alone or ipilimumab alone as a first-line treatment for metastatic or unresectable NSCLC. The trial's success provided the basis for regulatory approvals.

• Regulatory Approvals: Bristol-Myers Squibb received regulatory approvals for the combination of nivolumab and ipilimumab, often in conjunction with chemotherapy, for certain NSCLC indications. For example, the U.S. Food and Drug Administration (FDA) approved Opdivo (nivolumab) and Yervoy (ipilimumab) in combination for certain types of NSCLC. The patent protects specific methods of administering these approved drugs in a particular sequence and dosage.

• Market Exclusivity and Differentiation: By patenting specific methods of use, including distinct dosing and combination strategies, BMS sought to establish a protected market position for its nivolumab/ipilimumab combination in NSCLC. This patent provides a layer of protection beyond the drug substance patents themselves, preventing competitors from using this exact patented method, even if they have access to the active pharmaceutical ingredients.

• Evolving Treatment Landscape: The development protected by Patent 9,949,982 was part of a paradigm shift in NSCLC treatment, moving towards immune-based therapies. While newer combinations and sequential therapies have since emerged, this patent represents an important early strategy for leveraging the power of dual immune checkpoint inhibition.

It is important to note that patents on methods of use (like Patent 9,949,982) protect the specific process or method of treatment. The underlying active pharmaceutical ingredients (nivolumab and ipilimumab) are themselves protected by separate composition of matter patents and have had their own patent exclusivity timelines. This patent serves to extend protection for a specific therapeutic application of these drugs.

What is the Potential Impact of Patent 9,949,982 on Generic Competition?

Patent 9,949,982, as a method of use patent, has a significant impact on generic competition by defining specific patented treatment regimens.

• Protection of Specific Regimens: The patent claims precisely delineate a dosing and administration schedule for the combination of nivolumab and ipilimumab in NSCLC. This means that generic manufacturers cannot market a treatment that directly follows this specific patented method without infringing on the patent.

• Delayed Generic Entry for This Specific Combination: Generic versions of nivolumab (Opdivo) and ipilimumab (Yervoy) exist or are in development. However, this method of use patent creates a barrier for generic manufacturers who wish to sell a product specifically indicated for the patented regimen. Generic companies would need to develop alternative dosing, scheduling, or indications that do not infringe on this patent.

• Focus on Off-Patent Aspects: Once the patent for the specific method of use expires, generic manufacturers can then leverage generic versions of the active drugs to offer treatments that align with the now-unprotected method. However, the expiry of this patent does not automatically mean all combination therapies are free to be marketed under this exact protocol. Other patents may exist.

• Challenges in "Evergreening": Method of use patents can be a tool for extending market exclusivity beyond the expiry of composition of matter patents. However, challenges can arise if the patented method is considered obvious or lacks novelty at the time of filing, potentially leading to invalidation during litigation.

• Impact on Biosimilar Development: For biologics like nivolumab and ipilimumab, the regulatory pathway for biosimilars is complex. While this patent is a method of use patent, it influences the commercial strategy of both the innovator and potential biosimilar manufacturers by defining protected therapeutic uses.

The expiration date of Patent 9,949,982 is critical for understanding the timeline for generic entry for this specific combination regimen. Assuming no extensions or successful challenges, generic competition for this particular method of treatment would likely commence after the patent's expiration. However, the overall landscape of generic immunotherapies is still evolving, with a focus on developing biosimilars and potentially exploring alternative combination regimens.

Key Takeaways

• United States Patent 9,949,982 protects a specific method for treating non-small cell lung cancer (NSCLC) using a combination of nivolumab and ipilimumab.
• The patent's core claims detail precise intravenous dosing regimens and administration schedules for both nivolumab and ipilimumab, including an initial induction phase followed by a maintenance phase.
• The technological basis for the therapy is the synergistic action of targeting two distinct immune checkpoints, PD-1 (nivolumab) and CTLA-4 (ipilimumab), to enhance anti-tumor immune responses.
• The patent's landscape is highly competitive, with numerous pharmaceutical companies holding patents on various combination immunotherapies and strategies for NSCLC.
• This patent directly relates to approved combination therapies, providing market exclusivity for the specified treatment method and influencing the commercial strategies of both innovator and generic/biosimilar manufacturers.
• The method of use patent creates a barrier to generic competition for the specific patented regimen, impacting the timing and nature of generic market entry for this combination.

Frequently Asked Questions

1. What is the specific indication for the therapy described in Patent 9,949,982? The specific indication is non-small cell lung cancer (NSCLC).

2. What are the active pharmaceutical ingredients (APIs) protected by this patent? The patent protects a method of using nivolumab and ipilimumab.

3. Does Patent 9,949,982 cover the sale of generic versions of nivolumab or ipilimumab? No, this is a method of use patent. It protects a specific treatment regimen. Generic versions of the APIs themselves would be covered by different patents or would be available after their respective composition of matter patents expire. However, marketing generic versions for the exact patented method would constitute infringement.

4. When does Patent 9,949,982 expire? United States Patent 9,949,982 was issued on October 3, 2017. Assuming no patent term extensions or other legal adjustments, its term would generally extend 20 years from its filing date. A precise expiration date would require checking USPTO records and any potential extensions.

5. Can other companies use nivolumab and ipilimumab together for NSCLC if it's not the exact regimen patented in 9,949,982? Yes, other companies may be able to use nivolumab and ipilimumab together if their method of use does not infringe on the specific claims of Patent 9,949,982. This could involve different dosing schedules, different patient populations, or use in combination with other agents, provided those methods are not also patented.

Citations

[1] Bristol-Myers Squibb Company. (2017). Methods and Compositions for the Treatment of Cancer. U.S. Patent 9,949,982. Retrieved from USPTO Patent Full-Text and Image Database.

Drugs Protected by US Patent 9,949,982

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Shionogi Inc	FETROJA	cefiderocol sulfate tosylate	POWDER;INTRAVENOUS	209445-001	Nov 14, 2019		RX	Yes	Yes			Y

Foreign Priority and PCT Information for Patent: 9,949,982

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	2014-180174	Sep 4, 2014

PCT Information
PCT Filed	September 03, 2015	PCT Application Number:	PCT/JP2015/075040
PCT Publication Date:	March 10, 2016	PCT Publication Number:	WO2016/035846

International Family Members for US Patent 9,949,982

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
China	106687116
European Patent Office	3189841
Japan	6218204
Japan	WO2016035846
South Korea	101935186
South Korea	20170048511
World Intellectual Property Organization (WIPO)	2016035846