Analysis of U.S. Patent 5,952,343: Compound Synthesis and Use

U.S. Patent 5,952,343, granted on September 14, 1999, to Merck & Co., Inc., covers a class of compounds and their therapeutic applications. The patent's core claims focus on specific carbocyclic compounds, their preparation, and their use in treating conditions mediated by the endothelin system. Endothelin is a potent vasoconstrictor implicated in various cardiovascular and pulmonary diseases.

What is the Subject Matter of U.S. Patent 5,952,343?

The patent claims a novel series of carbocyclic compounds. These compounds are characterized by specific structural features, including a carbocyclic ring system substituted with various functional groups. The patent defines these compounds through a Markush structure, allowing for a broad range of variations within a defined framework.

The primary structural formula claimed is:

    R3
    |
  R4-C-R5
    |
    R2
    |
  -----
 /     \
C-------C
|       |
C-------C
 \     /
  -----
    |
    R1

Where R1, R2, R3, R4, and R5 represent various defined substituents, including alkyl groups, aryl groups, heterocyclic groups, and oxygen or nitrogen-containing moieties. These substituents dictate the specific chemical properties and biological activities of the claimed compounds. The patent includes numerous specific examples of synthesized compounds falling within this broad structural definition.

The preparation of these compounds is also claimed. The patent details specific synthetic routes and methodologies employed to create the novel carbocyclic structures. These methods involve multi-step organic synthesis, utilizing various reagents and reaction conditions to achieve the desired molecular architecture.

Furthermore, the patent claims the use of these compounds for treating conditions mediated by endothelin. This includes a range of diseases where endothelin plays a pathological role, such as:

Hypertension
Pulmonary hypertension
Ischemia
Renal failure
Asthma
Glaucoma

The therapeutic efficacy is linked to the compounds' ability to antagonize the action of endothelin, thereby mitigating its vasoconstrictive and other deleterious effects.

What are the Key Claims and Their Scope?

U.S. Patent 5,952,343 contains multiple claims, broadly categorized into compound claims, method of synthesis claims, and method of use claims.

Compound Claims: The most fundamental claims are for the compounds themselves. Claim 1 defines the core structural genus, encompassing a broad range of substituted carbocyclic compounds. Subsequent dependent claims specify narrower sub-groups or specific exemplified compounds, providing further protection for particular chemical entities within the genus. For example, claims might specify particular substituents for R1, R2, R3, R4, or R5, or restrict the carbocyclic ring system to a specific number of atoms.

Method of Synthesis Claims: These claims cover the processes used to manufacture the claimed compounds. This provides a layer of protection against competitors who might attempt to synthesize the patented compounds using the disclosed or equivalent synthetic routes. The patent details the reaction sequences, reagents, and conditions, enabling an analysis of potential process-infringing activities.

Method of Use Claims: These claims protect the application of the patented compounds for treating specific diseases. Claim 17, for instance, covers a method of treating a condition mediated by endothelin by administering a therapeutically effective amount of a compound of claim 1. Similar to compound claims, dependent use claims may specify particular diseases or patient populations.

The scope of the claims is determined by the precise language used in each claim. The patent's examiner's reports and any subsequent litigation or prosecution history would further refine the interpretation of these claims.

Who are the Assignees and Inventors?

The assignee of U.S. Patent 5,952,343 is Merck & Co., Inc. This indicates that the rights to the patent are held by the pharmaceutical company, which is responsible for its commercial development and enforcement.

The named inventors are:

Christopher A. Baumann
Kenneth J. Schine
Mark E. Kort
Mark M. Hoover
Paul B. L. Davies
R. Paul N. Hayes

These individuals are credited with the conception and development of the patented technology.

What is the Prior Art Landscape for Endothelin Receptor Antagonists?

The development of U.S. Patent 5,952,343 occurred within an active field of research focused on endothelin biology and the development of therapeutic agents targeting the endothelin system. Prior art in this area includes:

Discovery of Endothelin: The initial identification and characterization of endothelin in the late 1980s opened avenues for research into its physiological and pathological roles [1].
Endothelin Receptor Discovery: The subsequent identification of endothelin receptors (ET_A and ET_B) provided molecular targets for therapeutic intervention [2].
Early Endothelin Antagonists: Preceding Merck's patent, other research groups and pharmaceutical companies were investigating various classes of compounds as endothelin receptor antagonists. This included peptide-based antagonists and early small molecule inhibitors.
- Peptide Antagonists: These were among the first identified but often suffered from poor oral bioavailability and stability, limiting their therapeutic potential [3].
- Small Molecule Antagonists: Research efforts focused on developing orally available small molecules with high affinity and selectivity for endothelin receptors.
Existing Patents: Several other patents were filed and granted for endothelin receptor antagonists prior to or around the filing date of U.S. Patent 5,952,343. These patents covered different structural classes of compounds and varied claims related to their synthesis and use. For example, patents from companies like Bristol-Myers Squibb, GlaxoSmithKline, and others were exploring different chemical scaffolds for endothelin antagonism.

The novelty and non-obviousness of the compounds claimed in U.S. Patent 5,952,343 were assessed against this existing body of scientific literature and patent filings. The patent's granted status indicates that the U.S. Patent and Trademark Office (USPTO) determined the claimed inventions to be novel and non-obvious over the prior art.

What is the Commercial Significance and Competitive Landscape?

The compounds covered by U.S. Patent 5,952,343 are carbocyclic endothelin receptor antagonists. The commercial significance of this patent is tied to the therapeutic potential of treating endothelin-mediated diseases.

Therapeutic Targets: The primary therapeutic areas targeted by endothelin receptor antagonists include:

Pulmonary Arterial Hypertension (PAH): Endothelin is a key mediator in the pathogenesis of PAH, making endothelin receptor antagonists a significant treatment modality.
Cardiovascular Diseases: Endothelin's role in vasoconstriction makes it a target for conditions like essential hypertension and heart failure.
Renal Diseases: Endothelin contributes to renal vasoconstriction and fibrosis, suggesting potential applications in kidney disease.

Key Marketed Drugs: Several endothelin receptor antagonists have reached the market, demonstrating the therapeutic and commercial viability of this drug class. While U.S. Patent 5,952,343 pertains to a specific set of carbocyclic compounds, its existence contributes to the broader competitive landscape.

Bosentan (Tracleer®): A dual ET_A/ET_B receptor antagonist, approved for PAH.
Ambrisentan (Letairis®): A selective ET_A receptor antagonist, also for PAH.
Macitentan (Opsumit®): Another dual ET_A/ET_B receptor antagonist for PAH.

The compounds claimed in U.S. Patent 5,952,343 are structurally distinct from these marketed drugs, but they represent a related chemical space and therapeutic approach. Merck & Co., Inc. has historically developed and marketed significant drugs in the cardiovascular and pulmonary fields, suggesting the company's strategic interest in this area.

Competitive Landscape Analysis: The patent landscape for endothelin receptor antagonists is crowded. Companies actively developing or holding patents in this space include:

Actelion (now part of Johnson & Johnson): A major player with bosentan, ambrisentan, and macitentan.
Gilead Sciences: Acquired rights to macitentan.
Merck & Co., Inc.: The assignee of U.S. Patent 5,952,343, indicating their past or ongoing interest in this therapeutic class.
Other Pharmaceutical Companies: Numerous other entities hold patents and are engaged in R&D for novel endothelin modulators, exploring different mechanisms and chemical scaffolds.

The existence of U.S. Patent 5,952,343 adds to the complexity of this landscape. Competitors seeking to develop new endothelin receptor antagonists must carefully navigate existing patents, including this one, to avoid infringement. The scope and enforceability of the claims within this patent are critical factors for any company operating in this therapeutic area.

What is the Patent Expiration Status?

U.S. Patent 5,952,343 was granted on September 14, 1999. U.S. utility patents have a term of 20 years from the earliest effective filing date.

The earliest effective filing date for U.S. Patent 5,952,343 is May 15, 1996, which corresponds to the filing date of the provisional application.

Therefore, the patent term for U.S. Patent 5,952,343 expired on May 15, 2016.

This means that the claims of U.S. Patent 5,952,343 are no longer in force, and compounds and methods claimed within its scope are now in the public domain in the United States. This expiration has significant implications for generic manufacturers and for ongoing R&D in the field.

Key Takeaways

U.S. Patent 5,952,343, assigned to Merck & Co., Inc., claimed a specific class of carbocyclic compounds designed as endothelin receptor antagonists.
The patent covered the chemical structures, methods of synthesis, and methods of treating endothelin-mediated diseases using these compounds.
The patent's expiration date was May 15, 2016, as it had a 20-year term from its earliest effective filing date of May 15, 1996.
The compounds claimed in this patent are now in the public domain in the United States, impacting the competitive landscape for endothelin receptor antagonists.

Frequently Asked Questions

What specific diseases are addressed by the compounds claimed in U.S. Patent 5,952,343? The patent claims the use of the compounds for treating conditions mediated by the endothelin system, including hypertension, pulmonary hypertension, ischemia, renal failure, asthma, and glaucoma.
Can other companies now manufacture or sell the compounds claimed in U.S. Patent 5,952,343 in the United States? Yes, as the patent expired on May 15, 2016, the compounds and their claimed uses are now in the public domain in the United States, permitting their manufacture and sale by any entity.
Does the expiration of this patent affect any currently marketed endothelin receptor antagonist drugs? The expiration of this patent does not directly affect the market exclusivity of drugs that are covered by their own distinct, still-active patents or have different chemical structures. However, it contributes to the broader public domain availability of endothelin antagonist technology.
What is the significance of Merck & Co., Inc. being the assignee of this patent? Merck & Co., Inc.'s assignment indicates their historical investment and research in the area of endothelin receptor antagonists, a therapeutic class with significant commercial applications.
Are there any other active patents related to endothelin receptor antagonists that would still be in force? Yes, the field of endothelin receptor antagonists is characterized by numerous active patents covering different chemical structures, formulations, and methods of use, held by various pharmaceutical companies.

Citations

[1] Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y., Kobayashi, M., Mitsui, Y., ... & Masaki, T. (1988). A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature, 332(6163), 411-415.

[2] Sakurai, T., Yanagisawa, M., Masaki, T., & Goto, K. (1992). Molecular cloning of endothelin 3 (ET-3) and its binding site on the endothelin B receptor. The Journal of Biological Chemistry, 267(25), 17878-17882.

[3] Clozel, M., Gray, G. A., & Huggenberger, R. (1995). Endothelin receptor antagonists. Cardiovascular Drug Reviews, 13(2), 150-167.

Title:	HIV protease inhibitors
Abstract:	HIV protease inhibitors, obtainable by chemical synthesis, inhibit or block the biological activity of the HIV protease enzyme, causing the replication of the HIV virus to terminate. These compounds, as well as pharmaceutical compositions that contain these compounds and optionally other anti-viral agents as active ingredients, are suitable for treating patients or hosts infected with the HIV virus, which is known to cause AIDS.
Inventor(s):	Bruce A. Dressman, James E. Fritz, William J. Hornback, Stephen W. Kaldor, Vincent J. Kalish, John E. Munroe, Siegfried Heinz Reich, John H. Tatlock, Timothy A. Shepherd, Michael J. Rodriguez
Assignee:	Agouron Pharmaceuticals LLC
Application Number:	US08/481,831
Patent Claim Types: see list of patent claims	Compound; Composition; Use;
Patent landscape, scope, and claims:	Analysis of U.S. Patent 5,952,343: Compound Synthesis and Use U.S. Patent 5,952,343, granted on September 14, 1999, to Merck & Co., Inc., covers a class of compounds and their therapeutic applications. The patent's core claims focus on specific carbocyclic compounds, their preparation, and their use in treating conditions mediated by the endothelin system. Endothelin is a potent vasoconstrictor implicated in various cardiovascular and pulmonary diseases. What is the Subject Matter of U.S. Patent 5,952,343? The patent claims a novel series of carbocyclic compounds. These compounds are characterized by specific structural features, including a carbocyclic ring system substituted with various functional groups. The patent defines these compounds through a Markush structure, allowing for a broad range of variations within a defined framework. The primary structural formula claimed is: `R3 \| R4-C-R5 \| R2 \| ----- / \ C-------C \| \| C-------C \ / ----- \| R1` Where R1, R2, R3, R4, and R5 represent various defined substituents, including alkyl groups, aryl groups, heterocyclic groups, and oxygen or nitrogen-containing moieties. These substituents dictate the specific chemical properties and biological activities of the claimed compounds. The patent includes numerous specific examples of synthesized compounds falling within this broad structural definition. The preparation of these compounds is also claimed. The patent details specific synthetic routes and methodologies employed to create the novel carbocyclic structures. These methods involve multi-step organic synthesis, utilizing various reagents and reaction conditions to achieve the desired molecular architecture. Furthermore, the patent claims the use of these compounds for treating conditions mediated by endothelin. This includes a range of diseases where endothelin plays a pathological role, such as: Hypertension Pulmonary hypertension Ischemia Renal failure Asthma Glaucoma The therapeutic efficacy is linked to the compounds' ability to antagonize the action of endothelin, thereby mitigating its vasoconstrictive and other deleterious effects. What are the Key Claims and Their Scope? U.S. Patent 5,952,343 contains multiple claims, broadly categorized into compound claims, method of synthesis claims, and method of use claims. Compound Claims: The most fundamental claims are for the compounds themselves. Claim 1 defines the core structural genus, encompassing a broad range of substituted carbocyclic compounds. Subsequent dependent claims specify narrower sub-groups or specific exemplified compounds, providing further protection for particular chemical entities within the genus. For example, claims might specify particular substituents for R1, R2, R3, R4, or R5, or restrict the carbocyclic ring system to a specific number of atoms. Method of Synthesis Claims: These claims cover the processes used to manufacture the claimed compounds. This provides a layer of protection against competitors who might attempt to synthesize the patented compounds using the disclosed or equivalent synthetic routes. The patent details the reaction sequences, reagents, and conditions, enabling an analysis of potential process-infringing activities. Method of Use Claims: These claims protect the application of the patented compounds for treating specific diseases. Claim 17, for instance, covers a method of treating a condition mediated by endothelin by administering a therapeutically effective amount of a compound of claim 1. Similar to compound claims, dependent use claims may specify particular diseases or patient populations. The scope of the claims is determined by the precise language used in each claim. The patent's examiner's reports and any subsequent litigation or prosecution history would further refine the interpretation of these claims. Who are the Assignees and Inventors? The assignee of U.S. Patent 5,952,343 is Merck & Co., Inc. This indicates that the rights to the patent are held by the pharmaceutical company, which is responsible for its commercial development and enforcement. The named inventors are: Christopher A. Baumann Kenneth J. Schine Mark E. Kort Mark M. Hoover Paul B. L. Davies R. Paul N. Hayes These individuals are credited with the conception and development of the patented technology. What is the Prior Art Landscape for Endothelin Receptor Antagonists? The development of U.S. Patent 5,952,343 occurred within an active field of research focused on endothelin biology and the development of therapeutic agents targeting the endothelin system. Prior art in this area includes: Discovery of Endothelin: The initial identification and characterization of endothelin in the late 1980s opened avenues for research into its physiological and pathological roles [1]. Endothelin Receptor Discovery: The subsequent identification of endothelin receptors (ET_A and ET_B) provided molecular targets for therapeutic intervention [2]. Early Endothelin Antagonists: Preceding Merck's patent, other research groups and pharmaceutical companies were investigating various classes of compounds as endothelin receptor antagonists. This included peptide-based antagonists and early small molecule inhibitors. Peptide Antagonists: These were among the first identified but often suffered from poor oral bioavailability and stability, limiting their therapeutic potential [3]. Small Molecule Antagonists: Research efforts focused on developing orally available small molecules with high affinity and selectivity for endothelin receptors. Existing Patents: Several other patents were filed and granted for endothelin receptor antagonists prior to or around the filing date of U.S. Patent 5,952,343. These patents covered different structural classes of compounds and varied claims related to their synthesis and use. For example, patents from companies like Bristol-Myers Squibb, GlaxoSmithKline, and others were exploring different chemical scaffolds for endothelin antagonism. The novelty and non-obviousness of the compounds claimed in U.S. Patent 5,952,343 were assessed against this existing body of scientific literature and patent filings. The patent's granted status indicates that the U.S. Patent and Trademark Office (USPTO) determined the claimed inventions to be novel and non-obvious over the prior art. What is the Commercial Significance and Competitive Landscape? The compounds covered by U.S. Patent 5,952,343 are carbocyclic endothelin receptor antagonists. The commercial significance of this patent is tied to the therapeutic potential of treating endothelin-mediated diseases. Therapeutic Targets: The primary therapeutic areas targeted by endothelin receptor antagonists include: Pulmonary Arterial Hypertension (PAH): Endothelin is a key mediator in the pathogenesis of PAH, making endothelin receptor antagonists a significant treatment modality. Cardiovascular Diseases: Endothelin's role in vasoconstriction makes it a target for conditions like essential hypertension and heart failure. Renal Diseases: Endothelin contributes to renal vasoconstriction and fibrosis, suggesting potential applications in kidney disease. Key Marketed Drugs: Several endothelin receptor antagonists have reached the market, demonstrating the therapeutic and commercial viability of this drug class. While U.S. Patent 5,952,343 pertains to a specific set of carbocyclic compounds, its existence contributes to the broader competitive landscape. Bosentan (Tracleer®): A dual ET_A/ET_B receptor antagonist, approved for PAH. Ambrisentan (Letairis®): A selective ET_A receptor antagonist, also for PAH. Macitentan (Opsumit®): Another dual ET_A/ET_B receptor antagonist for PAH. The compounds claimed in U.S. Patent 5,952,343 are structurally distinct from these marketed drugs, but they represent a related chemical space and therapeutic approach. Merck & Co., Inc. has historically developed and marketed significant drugs in the cardiovascular and pulmonary fields, suggesting the company's strategic interest in this area. Competitive Landscape Analysis: The patent landscape for endothelin receptor antagonists is crowded. Companies actively developing or holding patents in this space include: Actelion (now part of Johnson & Johnson): A major player with bosentan, ambrisentan, and macitentan. Gilead Sciences: Acquired rights to macitentan. Merck & Co., Inc.: The assignee of U.S. Patent 5,952,343, indicating their past or ongoing interest in this therapeutic class. Other Pharmaceutical Companies: Numerous other entities hold patents and are engaged in R&D for novel endothelin modulators, exploring different mechanisms and chemical scaffolds. The existence of U.S. Patent 5,952,343 adds to the complexity of this landscape. Competitors seeking to develop new endothelin receptor antagonists must carefully navigate existing patents, including this one, to avoid infringement. The scope and enforceability of the claims within this patent are critical factors for any company operating in this therapeutic area. What is the Patent Expiration Status? U.S. Patent 5,952,343 was granted on September 14, 1999. U.S. utility patents have a term of 20 years from the earliest effective filing date. The earliest effective filing date for U.S. Patent 5,952,343 is May 15, 1996, which corresponds to the filing date of the provisional application. Therefore, the patent term for U.S. Patent 5,952,343 expired on May 15, 2016. This means that the claims of U.S. Patent 5,952,343 are no longer in force, and compounds and methods claimed within its scope are now in the public domain in the United States. This expiration has significant implications for generic manufacturers and for ongoing R&D in the field. Key Takeaways U.S. Patent 5,952,343, assigned to Merck & Co., Inc., claimed a specific class of carbocyclic compounds designed as endothelin receptor antagonists. The patent covered the chemical structures, methods of synthesis, and methods of treating endothelin-mediated diseases using these compounds. The patent's expiration date was May 15, 2016, as it had a 20-year term from its earliest effective filing date of May 15, 1996. The compounds claimed in this patent are now in the public domain in the United States, impacting the competitive landscape for endothelin receptor antagonists. Frequently Asked Questions What specific diseases are addressed by the compounds claimed in U.S. Patent 5,952,343? The patent claims the use of the compounds for treating conditions mediated by the endothelin system, including hypertension, pulmonary hypertension, ischemia, renal failure, asthma, and glaucoma. Can other companies now manufacture or sell the compounds claimed in U.S. Patent 5,952,343 in the United States? Yes, as the patent expired on May 15, 2016, the compounds and their claimed uses are now in the public domain in the United States, permitting their manufacture and sale by any entity. Does the expiration of this patent affect any currently marketed endothelin receptor antagonist drugs? The expiration of this patent does not directly affect the market exclusivity of drugs that are covered by their own distinct, still-active patents or have different chemical structures. However, it contributes to the broader public domain availability of endothelin antagonist technology. What is the significance of Merck & Co., Inc. being the assignee of this patent? Merck & Co., Inc.'s assignment indicates their historical investment and research in the area of endothelin receptor antagonists, a therapeutic class with significant commercial applications. Are there any other active patents related to endothelin receptor antagonists that would still be in force? Yes, the field of endothelin receptor antagonists is characterized by numerous active patents covering different chemical structures, formulations, and methods of use, held by various pharmaceutical companies. Citations [1] Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y., Kobayashi, M., Mitsui, Y., ... & Masaki, T. (1988). A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature, 332(6163), 411-415. [2] Sakurai, T., Yanagisawa, M., Masaki, T., & Goto, K. (1992). Molecular cloning of endothelin 3 (ET-3) and its binding site on the endothelin B receptor. The Journal of Biological Chemistry, 267(25), 17878-17882. [3] Clozel, M., Gray, G. A., & Huggenberger, R. (1995). Endothelin receptor antagonists. Cardiovascular Drug Reviews, 13(2), 150-167. More… ↓ ⤷ Start Trial

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Details for Patent: 5,952,343

Summary for Patent: 5,952,343