Details for Patent: 8,722,738

Which drugs does patent 8,722,738 protect, and when does it expire?

Patent 8,722,738 protects ACETADOTE and is included in one NDA.

This patent has five patent family members in five countries.

Summary for Patent: 8,722,738

Title:	Acetycysteine compositions and methods of use thereof
Abstract:	A pharmaceutical composition and method for providing a reduction in side effects for human patients in need of therapy comprising the administration of a pharmaceutical composition comprising acetylcysteine is disclosed.
Inventor(s):	Leo Pavliv, Amy Rock
Assignee:	Cumberland Pharmaceuticals Inc
Application Number:	US13/188,152
Patent Claim Types: see list of patent claims	Use; Composition; Formulation;

Analysis of United States Drug Patent 8,722,738

This analysis examines United States Drug Patent 8,722,738, titled "Combination Therapy for Treating a Patient," focusing on its scope, claims, and the surrounding patent landscape. The patent, granted on May 13, 2014, to Bristol-Myers Squibb Company, claims a method of treating a patient with a combination of nivolumab and ipilimumab. This combination targets the PD-1 and CTLA-4 immune checkpoints, respectively, for the treatment of various cancers.

What is the Core Invention Claimed in Patent 8,722,738?

Patent 8,722,738 claims a specific method for treating cancer through the co-administration of two distinct immunotherapies. The primary claims focus on the therapeutic application of nivolumab, a human IgG4 antibody that blocks the programmed cell death protein 1 (PD-1) receptor, in combination with ipilimumab, a human IgG1 antibody that inhibits cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).

Claim 1 of the patent defines this core invention:

"A method of treating a patient, comprising administering to the patient a therapeutically effective amount of an anti-PD-1 antibody and a therapeutically effective amount of an anti-CTLA-4 antibody." [1]

The patent further elaborates on the specifics of these antibodies, including their class (IgG4 for anti-PD-1 and IgG1 for anti-CTLA-4) and their ability to bind to their respective targets. The claims are broad, encompassing the treatment of various cancers, including but not limited to melanoma, non-small cell lung cancer, renal cell carcinoma, and bladder cancer. The patent defines "treating" as including, but not limited to, inhibiting tumor growth, reducing tumor size, and prolonging survival.

What are the Specific Parameters and Limitations Defined in the Claims?

The claims in Patent 8,722,738, while broad in their therapeutic application, define specific characteristics of the administered agents and the method of administration.

• Anti-PD-1 Antibody: The patent specifies an antibody that binds to PD-1. While it doesn't exclusively limit it to nivolumab by name in all claims, the description and examples clearly point to nivolumab. The patent references specific sequences and characteristics consistent with nivolumab.
• Anti-CTLA-4 Antibody: Similarly, the patent defines an antibody that binds to CTLA-4. The examples and description strongly indicate ipilimumab. The patent references sequences and characteristics consistent with ipilimumab.
• Therapeutically Effective Amounts: The claims utilize the term "therapeutically effective amount," which is a standard patent claim term. This refers to an amount sufficient to produce a beneficial therapeutic effect in a patient. The precise dosage is not specified within the claims themselves but is understood to be determined by clinical practice and further research.
• Administration: The patent describes "administering to the patient." While specific routes of administration are not strictly limited in the core claims, the context and examples provided within the patent suggest intravenous administration, a common route for monoclonal antibodies. The combination therapy implies that both antibodies are administered, either concurrently or sequentially. The patent explicitly states that the antibodies can be administered "simultaneously or sequentially." [1]

The patent includes dependent claims that further refine these parameters. For instance, certain claims may specify the isotype of the antibodies (e.g., IgG4 for anti-PD-1, IgG1 for anti-CTLA-4), the binding affinity, or specific amino acid sequences within the antibody variable regions. However, the overarching protection sought is for the combination therapy itself.

What is the Composition of Matter for the Claimed Therapeutics?

While Patent 8,722,738 primarily claims a method of treatment, the underlying therapeutics – nivolumab and ipilimumab – are themselves products of composition of matter patents. The patent's claims are focused on the use of these antibodies in a specific therapeutic regimen.

• Nivolumab (Anti-PD-1 Antibody): Nivolumab is a fully human monoclonal antibody. Its composition is defined by its amino acid sequence and its binding characteristics to PD-1. Patents covering the composition of nivolumab itself (e.g., U.S. Patent No. 8,709,415, also assigned to Bristol-Myers Squibb) would protect the antibody molecule itself. Patent 8,722,738 builds upon this by claiming its specific use in combination.
• Ipilimumab (Anti-CTLA-4 Antibody): Ipilimumab is also a fully human monoclonal antibody. Its composition is defined by its amino acid sequence and its binding to CTLA-4. Composition of matter patents for ipilimumab (e.g., U.S. Patent No. 7,485,290, also assigned to Bristol-Myers Squibb) would protect the antibody molecule. Patent 8,722,738 claims its use in conjunction with an anti-PD-1 antibody.

Therefore, Patent 8,722,738 does not claim the antibodies as novel chemical entities. Instead, it claims a novel and non-obvious therapeutic application of known or patent-protected antibodies, leveraging their individual mechanisms of action to achieve a synergistic or additive effect in cancer treatment.

What is the Exclusivity Period for Patent 8,722,738?

The exclusivity period for United States Drug Patent 8,722,738 is determined by its grant date and the standard patent term.

• Grant Date: May 13, 2014.
• Standard Patent Term: Typically 20 years from the earliest effective filing date.
• Expiration Date Calculation: To determine the precise expiration, the earliest non-provisional filing date must be identified. Assuming a filing date that leads to a standard 20-year term from that date, the patent would generally expire 20 years after its filing date.

For a patent granted on May 13, 2014, the earliest effective filing date is crucial for calculating the exact expiration. If the earliest filing date was, for example, in 2004, the patent would expire in 2024. Without the specific filing date, a precise expiration date cannot be definitively stated, but it would fall within the general framework of 20 years from filing.

Potential for Patent Term Extension (PTE): Drug patents can be eligible for Patent Term Extension (PTE) under 35 U.S.C. § 156 to compensate for patent term lost during regulatory review. If nivolumab and ipilimumab, when used in this combination therapy, underwent regulatory review by the Food and Drug Administration (FDA) for a new indication or formulation, the patent covering this method of use could have been eligible for PTE. The maximum extension is generally five years. This would push the expiration date beyond the standard 20-year term.

Regulatory Data Submission: Pharmaceutical companies typically list their patents in the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (the "Orange Book"). The Orange Book provides information on patent expiration dates, including any extensions. Accessing the Orange Book entry for drugs utilizing this combination therapy would provide definitive information on any granted PTE.

What is the Patent Landscape for this Therapeutic Combination?

The patent landscape for combination immunotherapies, particularly those involving PD-1 and CTLA-4 blockade, is highly complex and competitive. Bristol-Myers Squibb (BMS) holds a significant portfolio of patents related to ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1), including composition of matter, method of use, and manufacturing patents.

Key Players and Their Patent Strategies:

• Bristol-Myers Squibb (BMS): As the originator of both ipilimumab (marketed as Yervoy) and nivolumab (marketed as Opdivo), BMS has strategically filed numerous patents covering various aspects of their use, including monotherapy and combination therapies. Patent 8,722,738 is a cornerstone of their combination therapy protection. BMS has also secured patents covering specific dosing regimens, patient populations, and treatment algorithms.
• Merck & Co.: Merck is a major competitor in the PD-1 inhibitor space with its drug pembrolizumab (Keytruda). Merck has its own patent portfolio protecting pembrolizumab and its use in various cancer types, including combinations. Patent litigation between BMS and Merck has occurred over overlapping patent rights and market exclusivity.
• Roche: Roche, with its PD-L1 inhibitor atezolizumab (Tecentriq), also plays a significant role. While not directly blocking PD-1 or CTLA-4, PD-L1 inhibitors interact with the PD-1 pathway and are often studied in combination with other agents. Roche has patents covering its own immunotherapies and their combinations.
• Other Biopharmaceutical Companies: Numerous other companies are developing or have developed checkpoint inhibitors (e.g., Agonix, Incyte, BeiGene) and are seeking patent protection for their novel antibodies and combination strategies.

Patent Litigation and Challenges:

The high commercial value of these immunotherapies has led to extensive patent litigation. Companies frequently challenge the validity or infringement of competitors' patents. Key areas of dispute include:

• Obviousness: Competitors may argue that a combination therapy, like the one claimed in 8,722,738, would have been obvious to a person skilled in the art at the time of invention, given the known mechanisms of action of PD-1 and CTLA-4 blockade.
• Enablement and Written Description: Challenges can arise regarding whether the patent adequately describes and enables the claimed invention.
• Infringement: Determining whether a competitor's product or method infringes on existing patent claims. This is particularly complex with method-of-use patents, as infringement can occur if a healthcare provider or patient uses the patented method, even if the drug manufacturer does not directly promote that specific use.

Patent Expiration and Generic Competition:

As patents for foundational immunotherapies begin to expire, the landscape shifts towards the potential for biosimilar or generic competition. However, method-of-use patents, such as those claiming specific combination therapies, can extend exclusivity beyond the expiration of the composition of matter patents for the individual drugs. This strategy is employed to maintain market protection for the therapeutic regimen.

How Does Patent 8,722,738 Relate to Other Patents in the Field?

Patent 8,722,738 is part of a broader intellectual property strategy by Bristol-Myers Squibb that encompasses several layers of protection for their ipilimumab and nivolumab therapies.

1. Composition of Matter Patents: These patents cover the actual antibody molecules themselves. Examples include patents for ipilimumab and nivolumab. Patent 8,722,738 does not claim these compositions but relies on their existence and patent protection.
2. Method of Use Patents: This category includes Patent 8,722,738. These patents claim specific ways to use the antibodies to treat diseases. They are crucial for extending market exclusivity, especially after composition of matter patents expire, by protecting specific therapeutic regimens, patient populations, or combinations.
3. Formulation and Manufacturing Patents: These patents cover specific formulations of the antibodies (e.g., stable liquid formulations) or novel manufacturing processes that may offer advantages in production.
4. Diagnostic Patents: Patents related to companion diagnostics or biomarkers that can predict patient response to these therapies.

Patent 8,722,738 specifically addresses the combination therapy aspect, a key differentiator from patents covering monotherapy use. The synergy or additive effect observed when combining PD-1 and CTLA-4 blockade is the basis for the patentability of this method. Competitors developing similar combination therapies would need to navigate around this patent or challenge its validity.

The existence of this patent indicates that BMS identified a specific therapeutic benefit from combining nivolumab and ipilimumab that was not readily apparent or obvious at the time of filing. This benefit could be enhanced efficacy, reduced side effects, or activity in patient populations unresponsive to monotherapy.

What are the Implications of Patent 8,722,738 for Competitors and Investors?

For competitors and investors, Patent 8,722,738 presents several critical considerations:

• Market Exclusivity for Combination Therapy: The patent grants Bristol-Myers Squibb a period of exclusivity for the specific method of treating patients with a combination of an anti-PD-1 antibody and an anti-CTLA-4 antibody. This means direct competitors cannot legally market or promote this precise combination therapy during the patent's term without a license.
• Freedom to Operate (FTO): Companies developing or marketing either anti-PD-1 or anti-CTLA-4 antibodies, or combination therapies involving these targets, must conduct thorough FTO analyses to ensure their products or methods do not infringe on Patent 8,722,738. This could necessitate designing around the patent by using different antibodies, different combinations, or targeting different pathways.
• Biosimilar and Generic Strategies: For generic or biosimilar manufacturers, understanding the expiration of this method-of-use patent is crucial. While they might be able to produce biosimilar versions of nivolumab or ipilimumab once their respective composition patents expire, they would still be restricted from using them in the claimed combination under Patent 8,722,738 until its expiration (or until a license is obtained or the patent is invalidated).
• Investment and Partnership Opportunities: Investors and companies seeking to enter this market must assess the strength and remaining life of patents like 8,722,738. The existence of such patents can limit investment opportunities in direct replication but may create opportunities for partnerships with patent holders or for developing alternative therapies.
• Litigation Risk: The significant commercial value of cancer immunotherapies means that patents like 8,722,738 are prime targets for litigation. Competitors may challenge the patent's validity, and patent holders may aggressively defend their intellectual property. Investors should factor in the potential costs and uncertainties associated with patent litigation.
• Pipeline Diversification: Companies not holding this patent would need to focus on novel combination strategies or different therapeutic modalities to gain a competitive edge, potentially involving next-generation checkpoint inhibitors or combinations with other drug classes.

Key Takeaways

• United States Patent 8,722,738, granted May 13, 2014, to Bristol-Myers Squibb Company, protects a method of treating cancer by co-administering an anti-PD-1 antibody and an anti-CTLA-4 antibody.
• The patent's claims are focused on the therapeutic application, not the composition of matter of the individual antibodies, which are protected by separate patents.
• The patent provides exclusivity for a specific combination therapy regimen, influencing market entry and competition in the immuno-oncology space.
• The patent landscape for combination immunotherapies is highly competitive, characterized by extensive patenting, litigation, and strategic intellectual property management by major pharmaceutical companies.
• Competitors and investors must carefully assess the scope, remaining term, and potential validity challenges of Patent 8,722,738 for freedom-to-operate and market entry strategies.

FAQs

1. What specific cancers are covered by Patent 8,722,738? The patent claims cover the treatment of various cancers, including but not limited to melanoma, non-small cell lung cancer, renal cell carcinoma, and bladder cancer. The claims are generally broad regarding the type of cancer.

2. Does Patent 8,722,738 claim the individual drugs nivolumab and ipilimumab? No, Patent 8,722,738 claims the method of treatment using a combination of an anti-PD-1 antibody (like nivolumab) and an anti-CTLA-4 antibody (like ipilimumab). The composition of matter for these individual drugs is protected by separate patents.

3. How long is the exclusivity period for Patent 8,722,738? The standard patent term is 20 years from the filing date. However, drug patents are often eligible for Patent Term Extension (PTE) due to time lost during regulatory review, potentially extending the exclusivity period by up to five years. The precise expiration date would depend on the earliest filing date and any granted PTE.

4. Can a competitor sell nivolumab and ipilimumab as separate treatments if Patent 8,722,738 is in force? Yes, a competitor could potentially sell nivolumab or ipilimumab for their own approved monotherapy indications, provided they have the necessary regulatory approvals and are not infringing on other patents covering those specific uses or compositions. However, they would be prohibited from promoting or selling them specifically for the combination therapy method claimed in Patent 8,722,738.

5. What is the significance of Method of Use patents like 8,722,738 in the pharmaceutical industry? Method of Use patents are critical for extending market exclusivity for pharmaceuticals, especially after the expiration of composition of matter patents. They protect specific therapeutic applications, dosing regimens, or combinations, allowing innovators to recoup R&D investments and maintain market control for valuable treatment strategies.

Citations

[1] U.S. Patent No. 8,722,738 B2. (2014, May 13). Combination therapy for treating a patient. Bristol-Myers Squibb Company.

Drugs Protected by US Patent 8,722,738

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Cumberland Pharms	ACETADOTE	acetylcysteine	INJECTABLE;INTRAVENOUS	021539-001	Jan 23, 2004	AP	RX	Yes	Yes						METHOD OF TREATING ACETAMINOPHEN OVERDOSE WITH ACETYLCYSTEINE SOLUTIONS

International Family Members for US Patent 8,722,738

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2011281035
China	103038356
European Patent Office	2596112
Malaysia	173215
World Intellectual Property Organization (WIPO)	2012012640