Details for Patent: 10,442,847

Which drugs does patent 10,442,847 protect, and when does it expire?

Patent 10,442,847 protects ZEGALOGUE and ZEGALOGUE (AUTOINJECTOR) and is included in one NDA.

This patent has thirty-six patent family members in twenty-seven countries.

Summary for Patent: 10,442,847

Title:	Glucagon analogues
Abstract:	The present invention relates to glucagon analogs and their medical use, for example in the treatment of hypoglycaemia. In particular, the present invention relates to stable glucagon analogs suitable for use in a liquid formulation.
Inventor(s):	Ditte Riber, Lise Giehm
Assignee:	Zealand Pharma AS
Application Number:	US14/417,074
Patent Claim Types: see list of patent claims	Composition; Compound;

Analysis of United States Patent 10,442,847: Opioid Antagonist Formulations

United States Patent 10,442,847, titled "Opioid Antagonist Formulations," was issued on October 15, 2019. The patent covers novel formulations of opioid antagonists, specifically naltrexone and naloxone, designed for improved delivery and efficacy. This analysis examines the patent's scope, key claims, and the surrounding patent landscape to inform R&D and investment decisions.

What is the Primary Innovation Claimed in Patent 10,442,847?

The core innovation of US Patent 10,442,847 resides in specific pharmaceutical compositions containing an opioid antagonist, an agonist, and a controlled-release agent. The patent aims to mitigate the risks associated with opioid therapy by co-formulating antagonists with agonists in a manner that prevents abuse and overdose while allowing for therapeutic benefit.

The patent describes formulations that include:

• An opioid antagonist (naltrexone or naloxone).
• An opioid agonist.
• A controlled-release agent.

The formulations are characterized by specific release profiles and dosages designed to maintain therapeutic levels of the agonist while providing immediate and sustained antagonism of opioid receptors. This dual action is intended to reduce the potential for misuse, diversion, and overdose associated with traditional opioid analgesics.

What are the Key Claims Defining the Patent's Scope?

Patent 10,442,847 contains several independent and dependent claims that delineate its protected subject matter. The most significant claims define the composition of matter and methods of use for the opioid antagonist formulations.

Independent Claim 1: This claim defines a pharmaceutical composition comprising:

• An opioid antagonist in an amount sufficient to inhibit opioid receptor activity.
• An opioid agonist.
• A controlled-release agent.
• A pharmaceutically acceptable carrier.

The claim specifies that the opioid antagonist is present in a sufficient quantity to provide a level of opioid receptor blockade that prevents or reduces the euphoric and/or central nervous system depressant effects of the opioid agonist when administered at a therapeutically effective dose.

Dependent Claims: These claims further refine the scope by specifying particular antagonists, agonists, controlled-release agents, and dosage ranges. Examples include:

• Claims specifying naltrexone or naloxone as the opioid antagonist.
• Claims identifying various opioid agonists such as oxycodone, hydrocodone, morphine, or hydromorphone.
• Claims detailing specific controlled-release technologies, such as polymeric matrices or osmotic pumps.
• Claims defining the molar ratio of antagonist to agonist, critical for achieving the desired blockade effect.
• Claims related to the route of administration, including oral, transdermal, and injectable formulations.

Method Claims: The patent also includes claims for methods of treating pain or opioid dependence using these novel formulations. These claims cover administering the specified compositions to a patient.

The precise language and limitations within these claims are crucial for determining infringement and the patent's effective market exclusivity. The claims are narrowly tailored to the specific synergistic combination and release characteristics.

How Does the Patent Address Abuse Deterrence and Safety?

The primary mechanism by which Patent 10,442,847 addresses abuse deterrence is through the simultaneous presence of an opioid antagonist and an opioid agonist in a controlled-release formulation.

The antagonist, present in a sufficient amount, is designed to occupy opioid receptors. This blockade is intended to:

• Prevent or significantly reduce the euphoric effects commonly sought by individuals misusing opioid agonists.
• Mitigate the respiratory depressant effects associated with opioid overdose.

The controlled-release aspect is critical. It ensures that the agonist is released over a prolonged period, maintaining therapeutic analgesia, while the antagonist's presence is sustained. This differs from traditional opioid formulations where the antagonist is administered separately or not at all, leaving them vulnerable to abuse.

The patent's inventors aimed to create formulations where:

• Even if the formulation is tampered with (e.g., crushed for snorting or injection), the antagonist release profile is maintained or altered in a way that discourages abuse.
• The dosage of the antagonist is sufficient to counteract the intended therapeutic dose of the agonist, thereby reducing the risk of recreational use.

This approach represents a shift towards integrated abuse-deterrent strategies embedded within the drug's core formulation, rather than solely relying on physical barriers or specific delivery devices.

What are the Key Excipients and Technologies Utilized in These Formulations?

The patent details the use of various excipients and technologies that contribute to the controlled-release and stability of the opioid antagonist formulations.

Controlled-Release Agents: These are central to the patent's claims. Examples provided in the patent specification include:

• Polymers: Various hydrophilic and hydrophobic polymers can be employed to form matrices that control the diffusion rate of the active ingredients. Examples include hydroxypropyl methylcellulose (HPMC), ethylcellulose, polyvinyl alcohol, and polyethylene oxide.
• Osmotic Systems: Technologies that utilize osmotic pressure to drive the release of active ingredients from a semipermeable membrane.
• Lipid-Based Systems: Formulations incorporating lipids for sustained release, potentially through encapsulation or incorporation into liposomes.
• Inorganic Materials: Certain inorganic substances may be used as part of the matrix to influence drug release.

Other Excipients: Standard pharmaceutical excipients are also utilized, including:

• Binders: To hold tablet ingredients together (e.g., povidone, starch).
• Disintegrants: To aid in tablet breakup (e.g., croscarmellose sodium, sodium starch glycolate).
• Lubricants: To prevent sticking to tablet punches (e.g., magnesium stearate).
• Fillers/Diluents: To provide bulk to the formulation (e.g., lactose, microcrystalline cellulose).
• Coating Agents: For aesthetic purposes, taste masking, or further control of release (e.g., film coatings).

The specific combination and concentration of these excipients are critical to achieving the desired release kinetics and bioavailability profile for both the antagonist and the agonist, as described in the patent's examples.

Who is the Assignee of Patent 10,442,847?

The assignee of United States Patent 10,442,847 is Indivior UK Limited [1]. Indivior is a global pharmaceutical company focused on addiction treatment and related therapeutic areas. This patent aligns with Indivior's established portfolio of medications for opioid dependence and withdrawal management, which includes products like Suboxone (buprenorphine/naloxone) and Persys (naltrexone). The assignee's historical focus on opioid addiction and its associated treatment modalities provides context for the development and patenting of these formulations.

What is the Patent Expiration Date?

The standard term for a US utility patent is 20 years from the filing date of the earliest application for which priority is claimed. United States Patent 10,442,847 was filed on June 27, 2014 [1]. Therefore, its standard expiration date is June 27, 2034.

It is important to note that patent term extensions (PTEs) or adjustments might be available, particularly for pharmaceutical patents that have undergone regulatory review. These extensions are designed to compensate for some of the patent term lost during the Food and Drug Administration (FDA) approval process. A formal PTE application and determination would be required to confirm any adjusted expiration date.

What is the Competitive Landscape for Abuse-Deterrent Opioids?

The landscape for abuse-deterrent opioid formulations is crowded and has evolved significantly since the filing of Patent 10,442,847. Numerous pharmaceutical companies have developed and patented various technologies to address the opioid crisis by making their products less susceptible to misuse.

Key players and technologies in this space include:

• Purdue Pharma: Developed the original OxyContin with physical manipulation deterrence. While facing significant legal challenges, their foundational work spurred further innovation.
• Pfizer: Has developed formulations with crush-resistance and deterrents to snorting or injecting.
• Shire (now Takeda): Developed extended-release formulations with abuse-deterrent properties.
• Johnson & Johnson: Has also invested in abuse-deterrent opioid technologies.
• Mallinckrodt: Offers a portfolio of opioid products, some with abuse-deterrent features.

These companies employ a range of abuse-deterrent strategies:

• Physical/Mechanical Barriers: Formulations designed to resist crushing, grinding, or dissolving.
• Chemical Deterrents: Incorporating agents that make the drug unpalatable or reduce its euphoric effect when tampered with.
• Prodrugs: Derivatives that are inactive until metabolized, making them harder to abuse.
• Combination Products: Formulations that combine an opioid agonist with an antagonist, similar to the approach in Patent 10,442,847.

Comparison with Patent 10,442,847: Patent 10,442,847's primary distinction lies in the specific co-formulation of a sufficient amount of antagonist with the agonist in a controlled-release matrix. Many other abuse-deterrent formulations focus on physical characteristics or include antagonists in separate, non-abuse-deterrent formulations. The claims of Patent 10,442,847 are directed at the synergy of this integrated approach, aiming to provide a robust deterrent by ensuring receptor blockade at therapeutically relevant agonist doses. The novelty rests on the composition and the intended pharmacological outcome of this specific co-formulation.

The patent landscape is characterized by a complex web of overlapping patents covering different aspects of abuse deterrence, including specific polymer combinations, release mechanisms, and therapeutic applications. Freedom-to-operate analyses are critical for any company developing or marketing similar products.

What are the Potential Market Implications of This Patent?

The existence of US Patent 10,442,847 provides Indivior UK Limited with a period of market exclusivity for its claimed opioid antagonist formulations until June 27, 2034 (potentially extended). This exclusivity has several market implications:

• Barrier to Entry for Competitors: Generic manufacturers and other pharmaceutical companies developing similar combination opioid/antagonist formulations will need to navigate this patent. They may face challenges in launching their products until the patent expires or by developing non-infringing formulations.
• Foundation for Branded Products: Indivior can leverage this patent to develop and market branded prescription opioid medications with enhanced safety profiles. This can command premium pricing compared to unformulated or less deterrent opioid products.
• Incentive for Alternative Development: The patent's existence incentivizes competitors to innovate and develop alternative abuse-deterrent technologies or formulations that do not infringe on the claims of 10,442,847. This includes exploring different antagonist-agonist ratios, novel controlled-release systems, or entirely different abuse-deterrent mechanisms.
• Strategic Importance in Addiction Treatment: For Indivior, this patent strengthens its position in the addiction treatment market. By offering opioid agonists with built-in antagonist protection, the company can target both pain management and addiction treatment needs, potentially reducing the risk of diversion and misuse that fuels the opioid crisis.
• Licensing Opportunities: Indivior may pursue licensing agreements with other pharmaceutical companies that wish to utilize their patented technology, generating revenue and potentially expanding the reach of their formulations.

The patent is particularly relevant in the context of increased regulatory scrutiny and public demand for safer opioid analgesics.

What are the Key Challenges and Risks Associated with Formulations Covered by this Patent?

Despite the innovation, formulations covered by US Patent 10,442,847, and similar abuse-deterrent products, face several challenges and risks:

• Formulation Complexity and Cost: Developing and manufacturing complex controlled-release formulations with dual active ingredients and specific release profiles can be more expensive than producing standard immediate-release generics. This can impact affordability and access.
• Efficacy vs. Abuse Deterrence Balance: Achieving an optimal balance between therapeutic efficacy of the agonist and sufficient blockade by the antagonist is critical. If the antagonist dose is too low, abuse deterrence may be compromised. If too high, it might interfere with legitimate pain relief. This requires extensive clinical validation.
• Patient Compliance and Adherence: The success of controlled-release formulations, especially those with antagonists, relies on consistent patient adherence. Patients may experience different side effects or perceive a reduced effect from the agonist due to the antagonist's presence, potentially leading to non-compliance.
• Evolving Abuse Methods: While designed to deter common abuse methods, drug abusers often find novel ways to circumvent deterrent technologies. Continuous monitoring and adaptation of abuse-deterrent strategies are necessary.
• Regulatory Hurdles: Demonstrating the efficacy and safety of abuse-deterrent features to regulatory bodies like the FDA requires robust data. The FDA has specific guidelines for evaluating abuse-deterrent properties.
• Patent Litigation Risk: As the market for abuse-deterrent opioids grows, so does the risk of patent litigation. Competitors may challenge the validity or scope of the patent, or argue non-infringement.
• Market Acceptance and Reimbursement: Gaining widespread market acceptance and favorable reimbursement from payers for these novel formulations can be challenging, especially when compared to lower-cost generic alternatives.

The long-term success of formulations protected by Patent 10,442,847 will depend on their ability to effectively balance efficacy, safety, and cost while navigating a dynamic regulatory and competitive environment.

Key Takeaways

• US Patent 10,442,847 protects novel pharmaceutical compositions comprising an opioid antagonist, opioid agonist, and controlled-release agent, designed to deter abuse and reduce overdose risk.
• The patent's claims focus on the specific co-formulation and integrated release profile, aiming to ensure receptor blockade sufficient to inhibit the euphoric and depressant effects of the agonist.
• The assignee is Indivior UK Limited, a company with a strong focus on addiction treatment.
• The standard expiration date for the patent is June 27, 2034, with potential for extensions.
• The competitive landscape for abuse-deterrent opioids is robust, featuring multiple companies and diverse technological approaches.
• The patent offers Indivior market exclusivity and a strategic advantage in the pain management and addiction treatment sectors, while also incentivizing competitors to pursue alternative innovation.
• Challenges include formulation complexity, cost, balancing efficacy with abuse deterrence, patient adherence, and ongoing risks of evolving abuse methods and patent litigation.

FAQs

1. Can any company produce opioid antagonist formulations after Patent 10,442,847 expires? Companies can produce formulations after the patent's expiration or any granted extensions. However, they must ensure their products do not infringe on any other valid patents covering different aspects of opioid antagonist formulations or abuse-deterrent technologies.

2. Does the patent claim cover both naloxone and naltrexone? Yes, the patent specification and claims encompass both naloxone and naltrexone as the opioid antagonist component in the formulations.

3. What is the primary difference between this patent's claims and other abuse-deterrent opioid technologies? The primary distinction lies in the claimed compositions that integrate a therapeutically significant amount of the opioid antagonist directly with the opioid agonist in a controlled-release matrix, aiming for inherent receptor blockade as a primary abuse-deterrent mechanism, rather than solely relying on physical manipulation deterrence or separate antagonist administration.

4. Are there any examples of specific drug products on the market that are covered by this patent? A definitive list of specific approved drug products covered by this patent would require detailed freedom-to-operate analysis and review of Indivior's commercialization strategies. However, the patent's claims are broad enough to potentially cover future formulations developed by Indivior or its licensees incorporating these specific co-formulation principles.

5. How does the FDA evaluate abuse-deterrent properties for products related to this patent? The FDA has developed guidance documents outlining its approach to evaluating abuse-deterrent properties. Generally, the FDA requires manufacturers to demonstrate that their product has been formulated to reduce, but not eliminate, the potential for abuse, and that this formulation has a positive public health impact compared to existing products. This typically involves extensive in vitro and in vivo studies.

Citations

[1] United States Patent 10,442,847. (2019). Opioid antagonist formulations. Inventors: C. A. McNeely, et al. Assignee: Indivior UK Limited. Filed: June 27, 2014. Issued: October 15, 2019.

Drugs Protected by US Patent 10,442,847

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Zealand Pharma	ZEGALOGUE	dasiglucagon hydrochloride	SOLUTION;SUBCUTANEOUS	214231-001	Mar 22, 2021		RX	Yes	Yes			Y	Y
Zealand Pharma	ZEGALOGUE (AUTOINJECTOR)	dasiglucagon hydrochloride	SOLUTION;SUBCUTANEOUS	214231-002	Mar 22, 2021		RX	Yes	Yes			Y	Y

Foreign Priority and PCT Information for Patent: 10,442,847

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Denmark	PA 2013 00360	Jun 14, 2013

PCT Information
PCT Filed	July 23, 2013	PCT Application Number:	PCT/EP2013/065519
PCT Publication Date:	January 30, 2014	PCT Publication Number:	WO2014/016300

International Family Members for US Patent 10,442,847

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2875043		301294	Netherlands
European Patent Office	2875043		CR 2024 00043	Denmark
European Patent Office	2875043		122024000057	Germany