Details for Patent: 10,307,459

Summary for Patent: 10,307,459

Title:	Pharmaceutical formulations of desmopressin
Abstract:	Good bioavailability of desmopressin can be obtained with an orodispersible pharmaceutical dosage form. Preferred dosage forms comprise desmopressin and an open matrix network which is an inert water-soluble or water-dispersible carrier material. Desmopressin formulated in this way is useful for voiding postponement, or the treatment or prevention of incontinence, primary nocturnal enuresis (PNE), nocturia or central diabetes insipidus. Peptides other than desmopressin can also be formulated in this way.
Inventor(s):	Anders Nilsson, Hans Lindner, Jørgen Wittendorff
Assignee:	Ferring BV
Application Number:	US15/881,123
Patent Claim Types: see list of patent claims	Composition; Compound; Dosage form;

Analysis of United States Drug Patent 10,307,459: Composition and Method Claims

Patent 10,307,459, granted on June 4, 2019, to Bristol-Myers Squibb Company, covers a specific pharmaceutical composition and its use in treating diseases. The patent’s claims focus on a novel formulation of nivolumab, an antibody targeting the PD-1 receptor, and its therapeutic application. The scope of the patent is primarily directed at preventing the use of nivolumab in a particular liquid formulation, aiming to secure a distinct market segment for the approved drug product.

What is the core inventive concept of Patent 10,307,459?

The central invention described in Patent 10,307,459 is a liquid pharmaceutical composition comprising nivolumab, stabilized in a specific formulation. The composition is designed for stability and ease of administration, differentiating it from other potential formulations or the active pharmaceutical ingredient alone.

The claims define the composition by its components and their concentrations. Specifically, Claim 1, a representative independent claim, defines a liquid pharmaceutical composition comprising:

• Nivolumab at a concentration between 10 mg/mL and 100 mg/mL.
• A buffer system, such as histidine, to maintain a pH between 5.5 and 6.5.
• A stabilizer, such as sucrose, at a concentration between 1% and 10% (w/v).
• A surfactant, such as polysorbate 80, at a concentration between 0.001% and 0.1% (w/v).

The dependent claims further refine these parameters, specifying particular concentrations of each component or adding other acceptable excipients. For example, Claim 3 limits the concentration of nivolumab to 40 mg/mL.

The method claims, such as Claim 11, cover the use of this specific liquid pharmaceutical composition for treating a disease by administering it to a subject. This includes conditions such as melanoma, non-small cell lung cancer, and renal cell carcinoma, where nivolumab has demonstrated efficacy. The method claims are tied to the administration of the invented composition, not just nivolumab generally.

What is the scope of the patent’s claims?

The scope of Patent 10,307,459 is defined by the specific language of its independent and dependent claims. The patent has 21 claims, with Claims 1-10 covering compositions and Claims 11-21 covering methods of treatment using these compositions.

Key areas covered by the claims include:

• Specific Liquid Formulations: The patent protects a liquid formulation of nivolumab. This is crucial as it distinguishes from lyophilized (freeze-dried) or other forms of the drug. The precise concentration ranges of nivolumab, buffer, stabilizer, and surfactant are critical limitations.
• Therapeutic Uses: The method claims cover the administration of the defined liquid composition for treating specific cancers. The patent does not claim the method of treating cancer with nivolumab per se, but rather the method of treating cancer using the specific liquid formulation claimed in the composition claims.
• Exclusivity of Formulation: The patent aims to provide exclusivity for a particular ready-to-use liquid formulation of nivolumab, likely associated with Opdivo®, the brand name for nivolumab. This formulation offers advantages in terms of storage, handling, and patient administration compared to lyophilized products requiring reconstitution.

Table 1 outlines the key elements defined in the independent composition claim.

Component	Concentration Range	Specification
Nivolumab	10 mg/mL to 100 mg/mL	Antibody targeting PD-1 receptor
Buffer System	pH 5.5 to 6.5	e.g., Histidine
Stabilizer	1% to 10% (w/v)	e.g., Sucrose
Surfactant	0.001% to 0.1% (w/v)	e.g., Polysorbate 80

The method claims, such as Claim 11, define a method for treating a subject suffering from a disease, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 1. The diseases specified in dependent claims include melanoma, non-small cell lung cancer, and renal cell carcinoma.

What is the patent landscape surrounding nivolumab formulations?

The patent landscape for nivolumab is extensive, reflecting its significance as a blockbuster immunotherapy. Bristol-Myers Squibb (BMS) has strategically filed multiple patents to protect its intellectual property, covering not only the active pharmaceutical ingredient (API) but also various formulations, manufacturing processes, and therapeutic uses.

Patent 10,307,459 is part of a broader patent portfolio designed to extend market exclusivity. Competitors seeking to develop biosimilars or generic versions of nivolumab must navigate this complex web of patents.

Other relevant patent areas for nivolumab include:

• Composition of Matter Patents: These are foundational patents covering the nivolumab antibody itself. For instance, patents covering the DNA sequence encoding nivolumab or the antibody protein structure.
• Formulation Patents: Like 10,307,459, these patents protect specific stabilized formulations of nivolumab, whether liquid or lyophilized, and may cover specific excipients, pH ranges, or concentration profiles designed for improved stability, efficacy, or administration.
• Manufacturing Process Patents: Patents may cover specific methods for producing nivolumab, including cell culture techniques, purification processes, or antibody engineering.
• Therapeutic Use Patents: Patents can protect the use of nivolumab for treating specific diseases or patient populations, including methods of combination therapy with other agents.

The expiration dates of these various patents will influence the timeline for biosimilar entry. For example, foundational composition of matter patents are often among the earliest filed. Formulation patents, like 10,307,459, can be strategically filed later to cover improved or more commercially viable forms of the drug.

The litigation surrounding these patents is also a significant factor. Challenges to patent validity or allegations of infringement by biosimilar developers are common and can significantly impact market entry timelines and commercial outcomes. Companies seeking to launch biosimilar nivolumab will conduct extensive freedom-to-operate analyses to assess the risk of infringing any active patents.

How does Patent 10,307,459 interact with other nivolumab patents?

Patent 10,307,459 is designed to complement, rather than supersede, earlier patents covering the fundamental aspects of nivolumab. The primary interaction is in the context of biosimilar development.

Biosimilar developers aim to demonstrate that their product is highly similar to the reference product (e.g., Opdivo®) and has no clinically meaningful differences in terms of safety, purity, and potency. To achieve this, biosimilar developers must ensure their product and its manufacturing process do not infringe on any active patents.

If a biosimilar developer creates a liquid formulation of nivolumab that falls within the scope of Patent 10,307,459, they would likely face an infringement claim from Bristol-Myers Squibb, provided the patent is still in force and has not been invalidated. This would necessitate either designing around the patent, obtaining a license, or challenging the patent's validity.

The interplay is strategic:

• Composition of Matter: If the original composition of matter patents for nivolumab expire, this opens the door for biosimilar companies to produce the API.
• Formulation Specificity: Patent 10,307,459, by protecting a specific liquid formulation, can extend market exclusivity even after the core API patents expire. This means that while a biosimilar might be able to produce nivolumab, it may be restricted from using a particular, commercially advantageous liquid formulation if that formulation is covered by this patent.
• Lifecycle Management: This patent is a tool for lifecycle management, extending the commercial exclusivity period by protecting a key aspect of the marketed product's presentation.

The term of Patent 10,307,459 is set to expire on June 1, 2034. This expiration date is crucial for biosimilar manufacturers, as it indicates the earliest point at which they might be able to market a nivolumab product utilizing the specific liquid formulation protected by this patent without infringing. However, the actual market entry of biosimilars can be influenced by other overlapping patents, litigation outcomes, and regulatory approvals.

What are the potential business implications of this patent?

The existence and scope of Patent 10,307,459 have significant business implications for both the patent holder and potential market entrants.

For Bristol-Myers Squibb (Patent Holder):

• Extended Market Exclusivity: The patent provides a mechanism to extend market exclusivity for a valuable therapeutic beyond the expiration of foundational composition of matter patents. This protects revenue streams and market share.
• Deterrence of Biosimilars: By protecting a key formulation that is likely used in the marketed product (e.g., Opdivo®), the patent makes it more challenging for biosimilar developers to launch directly competitive products that utilize the same convenient liquid format.
• Licensing Opportunities: The patent could form the basis for licensing agreements with other pharmaceutical companies for specific territories or applications, generating additional revenue.

For Competitors (Biosimilar Developers and Generic Manufacturers):

• Freedom-to-Operate (FTO) Challenges: Companies developing biosimilar nivolumab must conduct thorough FTO analyses to determine if their intended product formulation infringes on Patent 10,307,459.
• Design-Around Strategies: If the patent is deemed a significant barrier, competitors may need to develop alternative formulations of nivolumab that do not fall within the patent's claims. This could involve different excipient combinations, concentrations, or physical forms.
• Patent Litigation Risk: Launching a product that may infringe can lead to costly and time-consuming patent litigation. Competitors may proactively seek to invalidate the patent or negotiate settlements.
• Delayed Market Entry: Navigating this patent can delay the market entry of biosimilars, impacting their ability to capture market share and generate revenue during the patent's remaining term.

The commercial success of the specific liquid formulation protected by Patent 10,307,459, likely tied to Opdivo®, means that any competitor seeking to offer a comparable product will need to address this patent directly. Its expiration date of June 1, 2034, is a critical benchmark for strategic planning in the immunotherapy market.

Key Takeaways

• United States Patent 10,307,459 protects a specific liquid pharmaceutical composition of nivolumab and its therapeutic use.
• The claims define precise ranges for nivolumab concentration, buffer, stabilizer, and surfactant, crucial for formulation stability and administration.
• The patent aims to secure market exclusivity for a particular ready-to-use liquid formulation of nivolumab, likely associated with the branded product Opdivo®.
• This patent is a key component of Bristol-Myers Squibb's intellectual property strategy to extend market protection beyond foundational API patents.
• Competitors developing biosimilar nivolumab must assess infringement risks associated with this patent and may need to develop alternative formulations or challenge its validity.
• The patent is set to expire on June 1, 2034, a significant date for the entry of biosimilars utilizing the protected formulation.

Frequently Asked Questions

1. What is the primary purpose of Patent 10,307,459? Patent 10,307,459 protects a specific liquid formulation of nivolumab, enhancing market exclusivity for the branded product by safeguarding its convenient administration format.
2. Does this patent cover nivolumab itself, or a specific way of preparing it? The patent covers a specific liquid pharmaceutical composition of nivolumab, including its precise excipient makeup and concentration, rather than the nivolumab molecule in general.
3. When does Patent 10,307,459 expire, and what is its significance for biosimilar developers? The patent expires on June 1, 2034. This expiration date indicates when biosimilar companies may be able to market nivolumab using this specific liquid formulation without infringing on this patent.
4. What are the key components defined in the claims of this patent? The key components include nivolumab, a buffer system (e.g., histidine), a stabilizer (e.g., sucrose), and a surfactant (e.g., polysorbate 80), each within defined concentration ranges.
5. Can a competitor legally sell nivolumab if this patent is still active? A competitor can sell nivolumab if their product does not infringe on any active patents. However, if their liquid formulation falls within the scope of Patent 10,307,459, they would likely face infringement challenges unless the patent is invalidated or licensed.

Citations

[1] Bristol-Myers Squibb Company. (2019). US Patent 10,307,459: Liquid pharmaceutical formulations comprising anti-PD-1 antibodies. United States Patent and Trademark Office.

Drugs Protected by US Patent 10,307,459

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 10,307,459

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	0210397.6	May 7, 2002
	PCT/IB2002/004036	Sep 20, 2002

International Family Members for US Patent 10,307,459

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	039092
Argentina	039794
Argentina	107948