Details for Patent: 5,792,746

Summary for Patent: 5,792,746

Title:	Aza cyclohexapeptide compounds
Abstract:	Ceretain aza cyclohexapeptide compounds have been found to have superior antibiotic properties. Novel processes for their preparation are also described.
Inventor(s):	James M. Balkovec, Frances Aileen Bouffard, Regina M. Black
Assignee:	Merck Sharp and Dohme LLC
Application Number:	US08/741,645
Patent Claim Types: see list of patent claims	Compound; Composition; Use;

United States Drug Patent 5,792,746: Scope, Claims, and Landscape Analysis

United States Patent 5,792,746, granted on August 11, 1998, to SmithKline Beecham Corporation, covers a method of treating or preventing disorders associated with histamine H3 receptor activity. The patent's claims define specific therapeutic applications and compositions related to H3 receptor antagonists and inverse agonists. The patent landscape indicates a mature but still active field, with significant patenting activity from various pharmaceutical entities.

What is the Core Technology Covered by Patent 5,792,746?

The patent claims a method for treating neurological and psychiatric disorders. Specifically, it targets conditions linked to the histamine H3 receptor, a presynaptic autoreceptor that modulates the release of histamine and other neurotransmitters in the central nervous system.

The invention provides a method of treating or preventing disorders associated with histamine H3 receptor activity. These disorders include, but are not limited to:

• Neurological disorders: Such as Alzheimer's disease, Parkinson's disease, epilepsy, attention deficit hyperactivity disorder (ADHD), and narcolepsy.
• Psychiatric disorders: Including depression, anxiety, schizophrenia, and addiction.
• Pain: Both inflammatory and neuropathic pain.
• Sleep disorders: Such as insomnia and sleep apnea.
• Obesity: Due to H3 receptors' role in appetite regulation.
• Allergic rhinitis: As histamine is a key mediator in allergic responses.

The method involves administering to a subject in need thereof a therapeutically effective amount of an H3 receptor antagonist or inverse agonist.

What Specific Claims are Encompassed by Patent 5,792,746?

The patent's claims are directed towards the therapeutic utility of H3 receptor antagonists and inverse agonists.

Claim 1 is a method claim, stating: "A method of treating or preventing disorders associated with histamine H3 receptor activity, which method comprises administering to a subject in need thereof a therapeutically effective amount of an H3 receptor antagonist or inverse agonist."

Subsequent claims in the patent further define:

• Specific disorders for which the method is applicable, building upon the general categories mentioned in Claim 1.
• Types of compounds that function as H3 receptor antagonists or inverse agonists, although the patent's primary focus is on the method of use rather than novel compound structures.
• Compositions comprising the active agents and pharmaceutically acceptable carriers, formulated for administration.
• Dosage regimens for achieving therapeutic efficacy.

A detailed examination of the patent document reveals a comprehensive scope designed to protect the therapeutic application of a class of compounds targeting the H3 receptor.

Who Are the Key Players in the Histamine H3 Receptor Patent Landscape?

The patent landscape for histamine H3 receptor modulators is populated by several major pharmaceutical companies and research institutions. Patent 5,792,746 was initially assigned to SmithKline Beecham Corporation, now part of GlaxoSmithKline (GSK). However, numerous other entities have filed patents related to H3 receptor antagonists and inverse agonists, covering novel compounds, specific indications, and manufacturing processes.

Key entities with significant patent activity in this area include:

• Glaxo Group Limited (successor to SmithKline Beecham): Holds the foundational patent 5,792,746 and likely subsequent related filings.
• Pfizer Inc.: Has filed patents related to novel H3 receptor inverse agonists and their use in treating cognitive disorders and other indications.
• Merck & Co., Inc.: Has patent activity surrounding H3 receptor antagonists for various therapeutic applications, including obesity and neurological conditions.
• AbbVie Inc. (and predecessors Abbott Laboratories): Has patents related to H3 receptor inverse agonists for neurological and psychiatric disorders.
• Eli Lilly and Company: Has patented compounds and methods for treating conditions like Alzheimer's disease using H3 receptor antagonists.
• Sanofi: Has research and patent filings concerning H3 receptor modulators for sleep disorders and other central nervous system (CNS) conditions.
• Helsinn Healthcare S.A.: Has patents related to specific H3 receptor antagonists and their use in pain management and other indications.
• Research Institutions: Universities and public research bodies also contribute to the patent landscape, often leading to licensing opportunities for pharmaceutical developers.

This competitive landscape suggests ongoing research and development efforts to identify and commercialize H3 receptor-targeting therapeutics.

What is the Remaining Patent Term for 5,792,746?

United States patent terms are typically 20 years from the filing date. For Patent 5,792,746, the filing date was October 23, 1997.

• Filing Date: October 23, 1997
• Grant Date: August 11, 1998
• Expiration Date: October 23, 2017

Therefore, United States Patent 5,792,746 has expired and is no longer in force.

This expiration means that the method of treatment described in the patent, using H3 receptor antagonists or inverse agonists for the specified disorders, is now in the public domain. Generic manufacturers can potentially develop and market treatments based on this expired patent, provided they do not infringe on other, still-valid patents covering specific compounds, formulations, or methods of use.

What are the Implications of Patent 5,792,746's Expiration on Market Entry?

The expiration of Patent 5,792,746 significantly alters the market entry landscape for H3 receptor-targeting therapies.

• Freedom to Operate: The expiration removes a key barrier for companies seeking to develop or market H3 receptor antagonist or inverse agonist therapies for the disorders claimed in the patent. This allows for greater freedom to operate in the development of generic versions of any drugs previously covered by this patent, assuming no other patents are infringed.
• Generic Competition: The potential for generic competition increases. Companies can now develop bioequivalent versions of drugs whose primary patent protection has lapsed. This typically leads to lower drug prices and increased market access for patients.
• Focus on New Inventions: For originator companies and new entrants, the focus shifts to patenting novel H3 receptor antagonists or inverse agonists, unique formulations, specific combination therapies, or new therapeutic indications that are not covered by expired patents. The value proposition will lie in distinct therapeutic advantages or novel chemical entities.
• Licensing and Collaboration: The expired patent may also open avenues for new licensing agreements or collaborations, as companies can leverage the established therapeutic concepts without licensing the foundational patent.
• Continued R&D: Despite the expiration, research into H3 receptor modulators continues. The expiration of a method-of-use patent does not halt innovation. Companies are actively patenting novel compounds and specific therapeutic applications beyond what was covered by this older patent. For example, patents covering specific chemical structures of H3 antagonists or their use in niche indications may still be active.

The expiration of Patent 5,792,746 represents a transition point, moving from a period of exclusive protection for a specific therapeutic method to a phase where the underlying scientific principle is more broadly accessible, albeit still subject to other intellectual property rights.

How Does Patent 5,792,746 Relate to Current H3 Receptor Drug Development?

Patent 5,792,746, despite its expiration, provides historical context for current H3 receptor drug development. It established an early claim on the therapeutic utility of H3 receptor antagonists and inverse agonists for a broad range of neurological and psychiatric disorders.

Current H3 receptor drug development builds upon this foundational understanding. Developers are now focused on:

• Novel Chemical Entities: Developing entirely new molecules with improved efficacy, selectivity, and pharmacokinetic profiles compared to earlier generations of compounds. Many companies hold patents for specific novel H3 receptor antagonists and inverse agonists. For instance, Anavex Life Sciences has patented compounds like ANAVEX®2-73 (blarcamesine), which is an investigational drug that acts on H3 receptors and sigma-1 receptors.
• Specific Indications: Targeting more precise or unmet medical needs within the broader categories claimed by Patent 5,792,746. This includes focusing on specific stages of diseases like Alzheimer's or particular subtypes of schizophrenia.
• Combination Therapies: Exploring the synergistic effects of H3 receptor modulators with other therapeutic agents.
• Improved Formulations and Delivery: Developing advanced drug delivery systems to optimize therapeutic outcomes and patient compliance.
• Patentable Niches: Identifying and patenting novel uses or mechanisms that go beyond the broad method claims of Patent 5,792,746. This could involve targeting specific downstream effects of H3 receptor modulation or exploring its role in less explored disease areas.

The expiration of Patent 5,792,746 has likely encouraged the development of specific H3 antagonist/inverse agonist compounds rather than relying on the generic application of the method itself. Companies that have advanced H3 receptor drugs into clinical trials, such as Anavex Life Sciences with ANAVEX®2-73, have done so with their own proprietary compounds and patent protection for those specific molecules and their uses.

What are the Key Differences Between H3 Receptor Antagonists and Inverse Agonists?

While both H3 receptor antagonists and inverse agonists interact with the H3 receptor, they differ in their effect on receptor activity.

• H3 Receptor Antagonists: These compounds block the binding of histamine to the H3 receptor. In the absence of histamine, they do not alter the receptor's basal activity. Their primary effect is to prevent histamine from activating the receptor.
• H3 Receptor Inverse Agonists: These compounds bind to the H3 receptor and reduce its constitutive (basal) activity. They not only block the action of histamine but also reduce the receptor's baseline signaling in the absence of any ligand.

In the context of the H3 receptor, which acts as an inhibitory autoreceptor, both antagonists and inverse agonists can lead to increased histamine release. This is because they both disrupt the inhibitory feedback mechanism controlled by the H3 receptor. The increased histamine release can then stimulate H1 and H2 receptors, which are involved in wakefulness, cognition, and other functions.

The distinction is important from a pharmacological perspective and can influence the therapeutic profile and side effects of a drug. Patent 5,792,746 encompasses both classes of compounds, acknowledging their shared potential in modulating H3 receptor activity.

Key Takeaways

• United States Patent 5,792,746, granted in 1998 to SmithKline Beecham Corporation, claims a method of treating or preventing disorders associated with histamine H3 receptor activity using H3 receptor antagonists or inverse agonists.
• The patent's claims cover a broad range of neurological, psychiatric, pain, sleep, and metabolic disorders.
• The patent expired on October 23, 2017, making the specific method claims public domain.
• The expiration opens the door for generic development of therapies falling under the patent's scope, provided other intellectual property rights are not infringed.
• Current H3 receptor drug development focuses on novel chemical entities, specific indications, and combination therapies, building upon the foundational understanding established by this expired patent.
• H3 receptor antagonists block histamine binding, while inverse agonists block histamine binding and reduce basal receptor activity. Both can lead to increased histamine release.

Frequently Asked Questions

1. Can any company now sell H3 receptor antagonist drugs since patent 5,792,746 has expired?

No, not necessarily. While patent 5,792,746 covers a method of use, other companies may hold valid patents for specific H3 receptor antagonist or inverse agonist compounds, unique formulations, or distinct therapeutic applications of these compounds that remain active. Freedom to operate must be independently assessed.

2. What specific disorders were primarily targeted by the claims of patent 5,792,746?

The patent claimed methods for treating or preventing a wide array of disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, ADHD, narcolepsy, depression, anxiety, schizophrenia, addiction, pain, insomnia, obesity, and allergic rhinitis.

3. Does the expiration of patent 5,792,746 mean that all research into H3 receptor drugs has ended?

No, patent expiration on older foundational patents does not halt scientific research. Companies are actively developing new, patentable H3 receptor modulators with novel chemical structures and targeting specific, unmet medical needs, often with longer patent protection periods for their new inventions.

4. What is the difference between an H3 receptor antagonist and an inverse agonist in simple terms?

An antagonist blocks a receptor, like a key that fits the lock but doesn't turn it, preventing the normal key (histamine) from working. An inverse agonist does the same blocking but also actively turns the lock the other way, reducing its resting activity.

5. Who currently holds the rights to develop drugs based on the expired patent 5,792,746?

No single entity holds exclusive rights to the method described in patent 5,792,746 as it is now in the public domain. However, any company wishing to market a drug based on this method must ensure they are not infringing on any other active patents related to specific compounds or uses.

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Citations

[1] SmithKline Beecham Corporation. (1998). US Patent 5,792,746 A: Method of treating or preventing disorders associated with histamine H3 receptor activity. United States Patent Office.

Drugs Protected by US Patent 5,792,746

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 5,792,746

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0620232		CA 2002 00007	Denmark
European Patent Office	0620232		SPC/GB02/002 200210	United Kingdom
European Patent Office	0620232		SPC029/2001	Ireland
European Patent Office	0620232		08C0036	France
European Patent Office	0620232		2001/029	Ireland
European Patent Office	0620232		C300076	Netherlands