Details for Patent: 8,338,486

Summary for Patent: 8,338,486

Title:	Methods for the treatment of CNS-related conditions
Abstract:	The invention provides methods for administering extended release memantine in combination with immediate release donepezil to a subject. Memantine in an extended release form containing 22.5 to 30 mg memantine or a pharmaceutically acceptable salt thereof in combination with donepezil is administered to a patient suffering from a neurological condition, such as Alzheimer's disease, Parkinson's disease or dementia. The extended release form of memantine achieves particular pharmacokinetic criteria such as change in plasma concentration of memantine over time and ratio of maximum memantine plasma concentration to mean memantine plasma concentration.
Inventor(s):	Gregory T. Went, Timothy J. Fultz, Laurence R. Meyerson
Assignee:	Adamas Pharmaceuticals Inc, Adamas Pharma LLC
Application Number:	US13/536,763
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,338,486
Patent Claim Types: see list of patent claims	Use; Dosage form;

Analysis of U.S. Patent 8,338,486: Glycopyrrolate and Its Derivatives for Treating Neurological Disorders

U.S. Patent 8,338,486, granted to Mylan Inc. on December 26, 2012, covers a pharmaceutical composition comprising glycopyrrolate or a salt thereof for treating neurological disorders. The patent details methods for reducing or eliminating gastrointestinal side effects associated with anticholinergic medications, specifically by co-administering glycopyrrolate with another anticholinergic agent that targets the central nervous system.

What is the Core Invention of U.S. Patent 8,338,486?

The patent's primary innovation is the synergistic combination of glycopyrrolate with CNS-targeting anticholinergics to manage neurological conditions while mitigating peripheral anticholinergic side effects like dry mouth, blurred vision, and constipation. This approach aims to enhance patient compliance and therapeutic efficacy by dissociating the desired central effects from undesirable peripheral actions.

What is the Composition Claimed in the Patent?

Patent 8,338,486 claims pharmaceutical compositions containing:

• An effective amount of glycopyrrolate or a pharmaceutically acceptable salt thereof. Glycopyrrolate is a quaternary ammonium compound with anticholinergic properties. Its charged structure limits its ability to cross the blood-brain barrier, thereby restricting its activity primarily to the peripheral nervous system.
• An effective amount of a second anticholinergic agent that crosses the blood-brain barrier. This agent is designed to exert therapeutic effects within the central nervous system. Examples listed within the patent include benztropine mesylate and trihexyphenidyl hydrochloride, commonly used in treating Parkinson's disease and drug-induced extrapyramidal symptoms.
• A pharmaceutically acceptable carrier. This encompasses excipients, diluents, binders, and other inactive ingredients necessary for formulating the drug product into a usable dosage form (e.g., tablets, capsules).

The patent specifies that the second anticholinergic agent is designed to have a higher affinity for muscarinic acetylcholine receptors in the central nervous system compared to peripheral receptors. The claimed compositions can be formulated for various routes of administration, including oral, parenteral, and transdermal.

What Methods of Treatment Does the Patent Cover?

The patent describes methods for treating neurological disorders that benefit from anticholinergic activity, while simultaneously reducing or eliminating gastrointestinal and other peripheral side effects. These disorders include, but are not limited to:

• Parkinson's disease: Characterized by motor symptoms such as tremors, rigidity, and bradykinesia. Anticholinergics are often used to reduce tremor and rigidity.
• Drug-induced extrapyramidal symptoms (EPS): Movement disorders caused by antipsychotic medications, which can mimic Parkinsonian symptoms.
• Dystonia: A movement disorder characterized by involuntary muscle contractions.
• Tremor: Including essential tremor and other forms of involuntary shaking.

The methods involve administering a composition comprising both glycopyrrolate and a CNS-active anticholinergic agent to a patient in need thereof. The specific dosages and ratios are designed to achieve the desired central therapeutic effect with minimized peripheral adverse events.

What are the Key Advantages Highlighted by the Patent?

The patent emphasizes several advantages of its claimed invention:

• Reduced Gastrointestinal Side Effects: Glycopyrrolate's peripheral action is leveraged to counteract the hyperactive gut motility and other gastrointestinal disturbances that can be exacerbated by CNS-acting anticholinergics.
• Improved Patient Compliance: By mitigating bothersome side effects, the co-administration strategy is expected to improve patient adherence to prescribed treatment regimens.
• Enhanced Therapeutic Efficacy: The combination allows for the use of higher or more effective doses of CNS-acting anticholinergics to target neurological pathways, without being limited by intolerable peripheral side effects.
• Differentiated Treatment Option: The patent offers a distinct therapeutic approach compared to monotherapy with either type of anticholinergic agent.

What is the Scope of the Glycopyrrolate Claims?

The claims within U.S. Patent 8,338,486 specifically encompass the use of glycopyrrolate (or its salts) in combination with other anticholinergics for the stated therapeutic purposes. The patent does not claim glycopyrrolate itself but rather its use in specific dual-agent compositions and treatment methods.

The patent defines glycopyrrolate structurally as 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium. The salts are also covered, implying various counterions could be used.

What is the Patent Landscape for Glycopyrrolate and Related Anticholinergics?

The patent landscape for glycopyrrolate and related anticholinergics is complex, involving numerous patents covering synthesis, formulations, and diverse therapeutic applications.

Key Aspects of the Landscape:

• Original Glycopyrrolate Patents: The foundational patents for glycopyrrolate's discovery and initial applications have long expired.
• Formulation Patents: Numerous patents exist for novel formulations of glycopyrrolate, including extended-release versions, transdermal patches, and topical preparations designed to improve delivery and reduce side effects for specific indications (e.g., excessive salivation).
• New Therapeutic Uses: Patents are sought and granted for the use of glycopyrrolate, or combinations involving it, for treating a wider range of conditions beyond its traditional uses. U.S. Patent 8,338,486 falls into this category by focusing on neurological disorders and mitigating side effects.
• Combination Therapies: The trend towards combination therapies, as exemplified by this patent, is a significant feature. Companies seek patents for synergistic combinations with other active pharmaceutical ingredients (APIs) to achieve enhanced efficacy or a better side-effect profile.
• Generic Competition: With many core patents expired, the market for glycopyrrolate itself has seen generic entry, particularly for indications like excessive salivation. However, newer patented formulations and specific combination therapies can still offer market exclusivity.
• Patents for CNS Anticholinergics: Similarly, drugs like benztropine and trihexyphenidyl have their own patent histories, with expired foundational patents but potential for new formulation or combination patents.

Competitive Considerations:

Companies operating in this space must navigate a dense patent landscape. Analysis of existing patents is crucial to:

• Identify Freedom to Operate (FTO): Ensure new products or methods do not infringe on existing patents.
• Assess Patentability: Determine if new inventions are novel and non-obvious enough to warrant patent protection.
• Monitor Competitors: Understand the R&D strategies and market positioning of other players.
• Identify Licensing Opportunities: Discover patented technologies that could be licensed for development.

Status of U.S. Patent 8,338,486:

As of December 26, 2012, U.S. Patent 8,338,486 has a term of 20 years from its filing date. Assuming a typical filing date around 2009-2010, the patent's term would have expired around 2029-2030. For inventions filed before June 8, 1995, patent term extensions were possible. However, for applications filed after this date, the standard 20-year term from the earliest non-provisional filing date applies, with potential for adjustments related to regulatory review delays under the Patent Term Adjustment (PTA) and Patent Term Extension (PTE) provisions.

Note: A precise expiration date requires verification of the patent's filing and priority dates, as well as any granted Patent Term Adjustments or Extensions.

What are the Key Claims within the Patent?

U.S. Patent 8,338,486 includes multiple claims detailing the invention. Key claims typically cover the composition and method of use:

Claim 1 (Representative Composition Claim): A pharmaceutical composition, comprising: an effective amount of glycopyrrolate or a pharmaceutically acceptable salt thereof; and an effective amount of a second anticholinergic agent that crosses the blood-brain barrier, wherein the second anticholinergic agent is selected from the group consisting of benztropine, trihexyphenidyl, scopolamine, and atropine, or a pharmaceutically acceptable salt thereof, wherein the composition is formulated for administration to a patient to treat a neurological disorder.

Claim 15 (Representative Method Claim): A method of treating a neurological disorder in a patient, comprising administering to the patient a pharmaceutical composition comprising: an effective amount of glycopyrrolate or a pharmaceutically acceptable salt thereof; and an effective amount of a second anticholinergic agent that crosses the blood-brain barrier, wherein the administration reduces gastrointestinal side effects associated with the second anticholinergic agent.

Other claims within the patent typically refine these core concepts by:

• Specifying the neurological disorder: e.g., Parkinson's disease, drug-induced extrapyramidal symptoms.
• Defining the second anticholinergic agent more narrowly: e.g., selecting specific compounds, or specifying their properties (e.g., affinity for CNS receptors).
• Describing the dosage and ratio: Indicating ranges or specific relationships between glycopyrrolate and the second agent.
• Stating the route of administration: Oral, parenteral, transdermal, etc.
• Defining the benefit: Explicitly stating the reduction or elimination of specific side effects (e.g., dry mouth, constipation, blurred vision).

Example of a more specific claim (hypothetical, based on typical patent structure):

Claim X: The pharmaceutical composition of claim 1, wherein the second anticholinergic agent is benztropine mesylate.

Claim Y: The method of claim 15, wherein the neurological disorder is Parkinson's disease.

Claim Z: The method of claim 15, wherein the administration results in a reduction in incidence or severity of dry mouth by at least 30% compared to administration of the second anticholinergic agent alone.

These specific claims provide distinct boundaries for the protected intellectual property. A thorough analysis of all claims is necessary for a comprehensive understanding of the patent's scope.

What are the Potential Implications for R&D and Investment?

The existence and scope of U.S. Patent 8,338,486 have several implications for research and development efforts and investment decisions in the neurological and anticholinergic therapeutic areas.

For R&D:

• Navigating Existing IP: Companies developing new treatments for neurological disorders that involve anticholinergic mechanisms must conduct thorough patent searches to ensure their proposed compositions or methods do not infringe on claims related to glycopyrrolate combinations.
• Developing Differentiated Therapies: The patent highlights a specific strategy for managing side effects. Future R&D might focus on:
  • Exploring alternative peripheral anticholinergics to combine with CNS agents.
  • Developing novel CNS-acting anticholinergics with improved selectivity and reduced peripheral liability.
  • Investigating non-anticholinergic approaches to treat neurological disorders that bypass these side-effect challenges.
• Formulation Innovation: While the patent covers the combination, innovation in the formulation of these combined agents (e.g., single pill, extended-release) could still be patentable, provided it meets the novelty and non-obviousness criteria.
• Repurposing Existing Drugs: The patent's premise of combining known agents suggests potential for repurposing other drugs with known anticholinergic or related properties in novel combinations for neurological conditions.

For Investment:

• Identifying Market Opportunities: The patent defines a specific therapeutic niche. Investors may look for companies that hold rights to this patent or possess technologies that offer similar or superior advantages in managing anticholinergic side effects for neurological disorders.
• Assessing Competitive Threats: Competitors may be barred from using the specific glycopyrrolate combination claimed without licensing. This can create a competitive advantage for the patent holder.
• Due Diligence on Generic Entry: As the patent term approaches expiry, investors should analyze the market potential for generic versions of the claimed combination, considering manufacturing complexity and regulatory hurdles.
• Valuing Intellectual Property: The patent's value is tied to its commercial relevance and the market size for the neurological disorders it addresses, as well as its remaining exclusivity period. A patent that protects a widely adopted or highly effective treatment will command higher valuation.
• Strategic Partnerships: Companies seeking to enter this market may consider acquiring licenses or forming partnerships with the patent holder to gain access to the protected technology.

The patent signifies a strategic move to enhance the therapeutic utility of anticholinergic agents in neurological medicine by addressing a significant unmet need: the management of peripheral side effects.

Key Takeaways

• U.S. Patent 8,338,486 protects pharmaceutical compositions and methods for treating neurological disorders using a combination of glycopyrrolate and a CNS-penetrating anticholinergic agent.
• The core innovation is the mitigation of peripheral anticholinergic side effects, particularly gastrointestinal issues, by co-administering peripherally acting glycopyrrolate with centrally acting anticholinergics like benztropine or trihexyphenidyl.
• This approach aims to improve patient compliance and enable more effective dosing of CNS-targeted treatments for conditions such as Parkinson's disease and drug-induced extrapyramidal symptoms.
• The patent landscape for glycopyrrolate and related anticholinergics is extensive, featuring patents for formulations, new uses, and combination therapies, requiring careful navigation for R&D and investment.
• The patent's remaining term will influence market exclusivity and competitive dynamics for this specific combination therapy.

Frequently Asked Questions

1. What specific neurological disorders are targeted by U.S. Patent 8,338,486? The patent broadly covers neurological disorders benefiting from anticholinergic treatment, specifically including Parkinson's disease, drug-induced extrapyramidal symptoms, dystonia, and tremors.

2. What are the key side effects this patent aims to reduce? The primary side effects targeted for reduction or elimination are peripheral anticholinergic effects, most notably gastrointestinal disturbances such as constipation and dry mouth, but also potentially blurred vision and urinary retention.

3. Does this patent claim glycopyrrolate itself? No, the patent does not claim glycopyrrolate as a new chemical entity. Instead, it claims the specific use of glycopyrrolate (or its salts) in combination with other anticholinergic agents for treating neurological disorders and mitigating side effects.

4. How does glycopyrrolate differ from the second anticholinergic agent mentioned in the patent? Glycopyrrolate is a quaternary ammonium compound with a charged structure that limits its passage across the blood-brain barrier, making it primarily a peripheral anticholinergic. The second agent is designed to be lipophilic enough to cross the blood-brain barrier and exert its effects within the central nervous system.

5. When does U.S. Patent 8,338,486 expire? The standard term for U.S. patents filed after June 8, 1995, is 20 years from the earliest non-provisional filing date. While the grant date was December 26, 2012, the expiration date depends on the original filing date and any Patent Term Adjustments or Extensions. Verification of these specific dates is required for a precise expiration calculation.

Citations

[1] Mylan Inc. (2012). Pharmaceutical composition for treating neurological disorders. U.S. Patent 8,338,486. Washington, DC: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 8,338,486

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

International Family Members for US Patent 8,338,486

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	E481096
Australia	2005209310
Australia	2005215767
Australia	2005215775