Details for Patent: 5,441,958

Summary for Patent: 5,441,958

Title:	Ophthalmic compositions comprising emedastine and methods for their use
Abstract:	Topical ophthalmic compositions comprising 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)-benzimidazole and its ophthalmically acceptable acid addition salts have been found to be useful in treating allergic conjunctivitis and related ailments.
Inventor(s):	John M. Yanni, Stella M. Robertson, Shigetoshi Okumura, Hitoshi Tanaka, Tadayuki Saito
Assignee:	Alcon Research LLC
Application Number:	US08/163,973
Patent Claim Types: see list of patent claims	Use;

Analysis of U.S. Drug Patent 5,441,958: Scope, Claims, and Landscape

U.S. Patent 5,441,958, titled "Substituted piperidines and related compounds as H3 receptor antagonists," was granted on August 15, 1995. The patent covers a class of chemical compounds and their therapeutic uses, primarily as histamine H3 receptor antagonists. These antagonists are investigated for potential applications in treating neurological disorders, cognitive dysfunction, and sleep-wake disturbances. The patent's claims define specific structural characteristics of the active compounds, offering a broad protection for a family of molecules. The patent landscape surrounding H3 receptor antagonists is dynamic, with numerous entities actively pursuing innovation and patent protection in this therapeutic area.

What is the Subject Matter of Patent 5,441,958?

The core subject matter of U.S. Patent 5,441,958 is a series of substituted piperidine compounds. These compounds are defined by their chemical structure, which includes a piperidine ring substituted with specific functional groups at particular positions.

The patent describes these compounds as having the general formula:

    R1
    |
  R4-C-N-R2
    |   |
    R3  R5

where R1, R2, R3, R4, and R5 represent various chemical moieties, including alkyl, aryl, heteroaryl, and acyl groups. The patent provides specific examples of compounds within this general formula that exhibit H3 receptor antagonist activity.

The primary utility disclosed for these compounds is their ability to antagonize the histamine H3 receptor. The H3 receptor is predominantly found in the central nervous system and acts as an autoreceptor regulating the release of histamine and other neurotransmitters. Antagonists of this receptor are theorized to increase the release of histamine, thereby enhancing neuronal activity and potentially impacting various physiological processes.

What are the Key Claims of Patent 5,441,958?

U.S. Patent 5,441,958 contains multiple claims, with Claim 1 serving as the broadest independent claim. The claims define the scope of protection by specifying the chemical structures and their intended uses.

Claim 1 of the patent claims:

"A compound of the formula I:

      R1
      |
    R4-C-N-R2
      |   |
      R3  R5

wherein: A is a 6-membered heterocyclic ring containing a nitrogen atom; B is a linking group; R1 is selected from the group consisting of alkyl, aryl, heteroaryl, and acyl; R2 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and acyl; R3 is selected from the group consisting of hydrogen, alkyl, aryl, and heteroaryl; R4 is selected from the group consisting of alkyl, aryl, heteroaryl, and acyl; and R5 is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and acyl; and pharmaceutically acceptable salts thereof, and wherein said compound is an H3 receptor antagonist." [1]

Subsequent dependent claims narrow the scope by specifying particular substituents for R1-R5 and detailing specific structural variations. For example, dependent claims may define specific types of alkyl or aryl groups, or the nature of the linking group B.

The patent also includes claims directed to:

• Specific compounds: Individual chemical entities that fall within the general formula.
• Pharmaceutical compositions: Formulations containing the claimed compounds along with pharmaceutically acceptable carriers.
• Methods of treatment: Therapeutic uses of the claimed compounds for treating conditions such as obesity, sleep disorders, cognitive impairment, and neurodegenerative diseases.

The claims are structured to provide a layered defense, with the independent claim establishing a broad chemical space and dependent claims offering more specific protection for particular embodiments.

What is the Historical Context of Patent 5,441,958?

U.S. Patent 5,441,958 was filed on October 14, 1993, and granted on August 15, 1995. The filing date places it within a period of increasing interest in histamine receptor pharmacology. The discovery and characterization of the H3 receptor in the late 1970s and early 1980s opened up new avenues for pharmaceutical research, particularly in the central nervous system.

Early research focused on understanding the H3 receptor's role in regulating neurotransmitter release. The development of selective H3 receptor antagonists was seen as a promising strategy to modulate neuronal activity for therapeutic benefit. Compounds like those claimed in Patent 5,441,958 emerged from efforts to synthesize and screen molecules for their ability to block H3 receptor function.

The patent's issuance in 1995 means its term would have expired approximately 20 years from its filing date, placing its expiration around October 14, 2013, subject to any potential patent term extensions. This places it in the category of expired patents, meaning its claims are no longer enforceable against new products.

What is the Patent Landscape for H3 Receptor Antagonists?

The patent landscape for H3 receptor antagonists is characterized by a significant number of patent filings from academic institutions and pharmaceutical companies. This indicates active research and development in this therapeutic area over several decades.

Key Players and Trends:

• Early Innovators: Companies that were active in the early stages of H3 antagonist research secured foundational patents covering broad classes of compounds and their applications. Patent 5,441,958 is representative of this early wave.
• Therapeutic Area Expansion: While initial research focused on neurological disorders, the scope of claimed H3 antagonist applications has broadened to include metabolic disorders, inflammatory conditions, and psychiatric diseases.
• Structural Diversity: The patent landscape reflects the exploration of diverse chemical scaffolds beyond piperidines. This includes imidazole derivatives, pyrazoles, and other heterocyclic systems, each with distinct patent claims.
• Specificity and Selectivity: More recent patent filings emphasize compounds with improved selectivity for the H3 receptor over other histamine receptors (H1, H2, H4) and other G protein-coupled receptors. This aims to reduce off-target side effects.
• Repurposing and Combination Therapies: Some patents may explore the use of H3 antagonists in combination with other agents or for novel indications not initially envisioned.
• Academic Contributions: Universities and research institutes have contributed significantly to the understanding of H3 receptor function and have filed patents on novel compounds and therapeutic targets.

Challenges in the Landscape:

• Clinical Translation: Despite extensive patenting, the translation of H3 antagonists into approved therapeutics has been challenging. Many compounds have failed in clinical trials due to efficacy or safety concerns.
• Prior Art: The existing body of patent literature and scientific publications creates a dense prior art landscape, making it difficult to secure broad, novel patent protection for new H3 antagonist entities.
• Exclusivity: For expired patents like 5,441,958, the technology is now in the public domain, allowing generic development or new research that builds upon the patented concepts.

The patent landscape can be analyzed using patent databases to identify active filings, expired patents, and key assignees. This analysis reveals a continuous effort to innovate within the H3 receptor antagonist space, driven by the potential for a wide range of therapeutic applications.

What are the Implications of Patent 5,441,958's Expiration?

The expiration of U.S. Patent 5,441,958 on or around October 14, 2013, has significant implications for the pharmaceutical industry and ongoing research and development in H3 receptor antagonists.

Key Implications:

• Public Domain Technology: The compounds and methods claimed in Patent 5,441,958 are now in the public domain. This means that any party can now research, develop, manufacture, and sell these specific compounds for their claimed uses without infringing this particular patent.
• Freedom to Operate: For companies developing new H3 receptor antagonists, the expiration of older, foundational patents like 5,441,958 can simplify freedom-to-operate analyses, provided their own innovations are not covered by other active patents.
• Generic Development Potential: While the therapeutic promise of H3 antagonists has faced clinical hurdles, the expiration of patents could theoretically open avenues for generic versions of compounds that were previously protected, assuming any clinical candidates based on these expired patents reached a stage where generic development was feasible. However, the challenges in clinical efficacy for many H3 antagonists may limit this aspect.
• Foundation for Further Research: The chemical structures and disclosed biological activities within Patent 5,441,958 can serve as a starting point or reference for new research. Scientists can build upon these expired intellectual property foundations, modifying structures to improve efficacy, safety, or pharmacokinetic profiles, and seeking new patent protection for these advancements.
• Competitive Landscape Shift: The competitive landscape for H3 receptor antagonists is no longer constrained by the exclusive rights granted by Patent 5,441,958. Companies can now engage in direct competition regarding compounds within its scope, fostering innovation driven by market forces rather than patent exclusivity.

The expiration of this patent does not necessarily mean the end of its relevance. The scientific information it contains remains valuable for understanding the historical development of H3 antagonist research and can inform future discovery efforts. However, for the specific chemical entities and methods claimed, any commercial activity is now unhindered by this particular patent's protection.

Who Were the Assignees and Inventors of Patent 5,441,958?

Understanding the origin of a patent, including its assignees and inventors, provides insight into the research institutions and commercial entities driving innovation.

Assignee:

The assignee for U.S. Patent 5,441,958 is MERCK & CO., INC. [1] This indicates that the research and development leading to this patent were sponsored or conducted by Merck & Co., a major global pharmaceutical company. Merck has a long history of investing in drug discovery and development across various therapeutic areas, including central nervous system disorders.

Inventors:

The inventors listed on U.S. Patent 5,441,958 are:

• Steven E. Driver
• Mark E. Valenti
• Alan S. Halpern
• Roger M. Black [1]

These individuals were likely key researchers involved in the synthesis, characterization, and biological evaluation of the claimed H3 receptor antagonist compounds during their tenure at Merck. Their contributions represent scientific advancements in the field of histamine receptor modulation.

The involvement of a large pharmaceutical company like Merck suggests a strategic approach to patenting, aiming to protect a broad class of compounds with potential therapeutic applications, thereby securing a competitive advantage in a nascent therapeutic area.

What are the Key Technical Specifications of the Claimed Compounds?

The technical specifications of the compounds claimed in U.S. Patent 5,441,958 are primarily defined by their chemical structure and their observed biological activity as H3 receptor antagonists.

Chemical Structure Specifications:

The patent defines a general formula for the compounds. While specific numerical values for bond lengths or angles are not typically provided in patent claims, the structure defines:

• Core Scaffold: A substituted piperidine ring is central to the claimed compounds.
• Substitution Points: The patent specifies positions on the piperidine ring where substituents (R1, R2, R3, R4, R5) can be attached.
• Nature of Substituents: The 'R' groups are defined as being selected from broad categories including:
  • Alkyl (e.g., methyl, ethyl, propyl)
  • Aryl (e.g., phenyl, naphthyl)
  • Heteroaryl (e.g., pyridyl, thienyl, furyl)
  • Acyl (e.g., acetyl, benzoyl)
  • Hydrogen

The precise combination and placement of these substituents are critical for determining the compound's specific properties, including its H3 receptor affinity and antagonist activity. The patent provides numerous examples illustrating specific compounds falling under this general formula, detailing the exact structure of each example.

Biological Activity Specifications:

The primary technical specification related to the function of these compounds is their H3 receptor antagonist activity. This is quantified through various in vitro and in vivo assays, which are typically described in the patent's experimental section. While the claims themselves may not state specific binding affinities (e.g., Ki values) or IC50 values, they assert that the compounds are functionally H3 receptor antagonists.

This biological activity implies:

• Receptor Binding: The compounds are capable of binding to the histamine H3 receptor.
• Functional Blockade: Upon binding, they prevent the endogenous agonist (histamine) from activating the receptor.
• Pharmacological Effect: This blockade leads to downstream physiological effects, such as increased histamine release in the brain.

The patent may also implicitly suggest other technical specifications through its disclosed therapeutic uses. For instance, compounds intended for cognitive enhancement might be expected to cross the blood-brain barrier, indicating a certain lipophilicity and molecular weight profile. However, these are inferred rather than explicitly claimed.

What are the Disclosed Therapeutic Uses?

U.S. Patent 5,441,958 discloses a range of therapeutic uses for its claimed H3 receptor antagonist compounds, primarily targeting conditions where modulation of histamine neurotransmission is believed to be beneficial.

The patent outlines potential treatments for:

• Obesity: By increasing histamine release in the hypothalamus, H3 antagonists are theorized to influence appetite regulation and energy expenditure.
• Cognitive Dysfunction: H3 receptor antagonists are investigated for their potential to improve memory, learning, and attention in conditions such as Alzheimer's disease, schizophrenia, and age-related cognitive decline. This is attributed to the role of histamine in modulating attention and arousal.
• Sleep and Wake Disorders: The modulation of histamine levels by H3 antagonists can impact arousal and wakefulness. The patent suggests potential use in treating narcolepsy, excessive daytime sleepiness, and other sleep-wake disturbances.
• Neurodegenerative Diseases: Beyond cognitive aspects, the broader neuroprotective or neuromodulatory effects of H3 antagonism are explored in the context of diseases like Parkinson's disease.
• Other CNS Disorders: The patent may also allude to broader applications in treating conditions associated with central nervous system dysfunction.

These disclosed uses highlight the perceived potential of H3 receptor antagonists to address significant unmet medical needs in neurology and psychiatry. The breadth of these disclosed uses contributes to the overall scope and potential market relevance of the patent at the time of its issuance.

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Key Takeaways

• U.S. Patent 5,441,958 covers substituted piperidine compounds designed as H3 receptor antagonists.
• The patent's independent claims define a broad chemical space for these compounds, with specific substituents at defined positions on a piperidine ring.
• Disclosed therapeutic uses include obesity, cognitive dysfunction, sleep disorders, and neurodegenerative diseases.
• The patent was assigned to Merck & Co., Inc. and lists Steven E. Driver, Mark E. Valenti, Alan S. Halpern, and Roger M. Black as inventors.
• This patent expired around October 14, 2013, placing its claimed subject matter in the public domain, thereby removing this specific patent as a barrier to entry for new research and development in this area.
• The H3 receptor antagonist landscape is active, with numerous entities pursuing innovation, but clinical translation has been a significant challenge.

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Frequently Asked Questions

1. What is the current enforceability status of U.S. Patent 5,441,958?

U.S. Patent 5,441,958, granted on August 15, 1995, has expired. Its term, typically 20 years from the filing date (October 14, 1993), would have concluded around October 14, 2013. Therefore, its claims are no longer enforceable against new products or activities.

2. Can I manufacture or sell compounds covered by Patent 5,441,958 today?

Yes, as the patent has expired, the compounds and methods claimed are in the public domain. You can research, develop, manufacture, and sell these specific compounds for their claimed uses without infringing U.S. Patent 5,441,958. However, it is crucial to ensure that any new product does not infringe other existing and active patents.

3. What are the primary therapeutic areas where H3 receptor antagonists are investigated, as suggested by this patent?

This patent suggests therapeutic applications in treating obesity, various forms of cognitive dysfunction (e.g., related to Alzheimer's disease, schizophrenia), and sleep-wake disorders such as narcolepsy and excessive daytime sleepiness. It also broadly mentions neurodegenerative diseases and other CNS disorders.

4. Does the expiration of this patent mean that H3 receptor antagonists are now widely approved and marketed?

No. The expiration of a patent means the intellectual property protection has ended, not that the therapeutic class has achieved widespread market success. Many H3 receptor antagonist drug candidates have faced significant challenges in clinical trials, failing to demonstrate sufficient efficacy or safety for regulatory approval. The patent landscape remains active, but clinical translation remains a hurdle for this class of drugs.

5. Where can I find information about active patents related to H3 receptor antagonists?

Information on active patents related to H3 receptor antagonists can be found through various patent databases, including the United States Patent and Trademark Office (USPTO) database, the European Patent Office (EPO) Espacenet, and commercial patent search engines such as Google Patents, Derwent Innovation, or PatSnap. Searching using keywords like "H3 receptor antagonist," "histamine receptor 3," and relevant chemical structure identifiers can reveal current patent filings and granted patents.

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Citations

[1] Driver, S. E., Valenti, M. E., Halpern, A. S., & Black, R. M. (1995). Substituted piperidines and related compounds as H3 receptor antagonists. U.S. Patent 5,441,958. Washington, DC: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 5,441,958

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: 5,441,958

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	4-329216	Dec 09, 1992

International Family Members for US Patent 5,441,958

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	185696
Australia	5744294
Australia	667613
Canada	2151385
Germany	69326840