Analysis of U.S. Patent 4,087,544: Cyclopropyl Carboxamide Derivatives

U.S. Patent 4,087,544, issued on May 2, 1978, to Pfizer Inc., claims a class of cyclopropyl carboxamide derivatives exhibiting antimicrobial activity. The patent outlines synthesis methods and provides examples of specific compounds. The scope of the claims covers these derivatives and their pharmaceutical compositions. The patent landscape surrounding this core patent indicates a period of foundational research in antimicrobial agents with potential for further development and application.

What is the Core Invention Claimed in U.S. Patent 4,087,544?

The primary invention claimed in U.S. Patent 4,087,544 is a specific class of chemical compounds. These compounds are cyclopropyl carboxamide derivatives.

The generic structure of the claimed compounds is defined by the formula:

Formula I:

      R1
       |
  - C - CONH - R2
     / \
    CH2 CH2

Where:

R1 represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a 2-heterocyclic aromatic group.
R2 represents a substituted or unsubstituted cyclohexyl group.

The patent specifies variations within these definitions. For instance, the phenyl or naphthyl groups can be substituted with one or more halo, alkyl, alkoxy, or trifluoromethyl groups. The heterocyclic aromatic groups are defined as furyl, thienyl, pyridyl, or pyrimidyl. The cyclohexyl group can be substituted with one or more alkyl, halo, or hydroxy groups.

The claims also encompass pharmaceutically acceptable acid addition salts of these compounds.

What are the Specific Examples Provided in the Patent?

U.S. Patent 4,087,544 provides several specific examples of compounds within the claimed scope, illustrating the practical application of the generic formula. These examples serve to demonstrate the synthesis and expected properties of the claimed derivatives.

Key examples include:

Example 1: N-(4-Chlorocyclohexyl)-2-(2,4-dichlorophenyl)cyclopropanecarboxamide. This compound exemplifies a substituted phenyl group (2,4-dichlorophenyl) and a substituted cyclohexyl group (4-chlorocyclohexyl).
Example 2: N-(4-Chlorocyclohexyl)-2-(4-fluorophenyl)cyclopropanecarboxamide. This example features a monosubstituted phenyl group (4-fluorophenyl) and the same substituted cyclohexyl group.
Example 3: N-Cyclohexyl-2-(4-fluorophenyl)cyclopropanecarboxamide. Here, the cyclohexyl group is unsubstituted, while the phenyl group is monosubstituted.
Example 4: N-(4-Chlorocyclohexyl)-2-(4-trifluoromethylphenyl)cyclopropanecarboxamide. This compound demonstrates a phenyl group substituted with a trifluoromethyl moiety.
Example 5: N-(4-Chlorocyclohexyl)-2-(2-thienyl)cyclopropanecarboxamide. This example incorporates a heterocyclic aromatic group (2-thienyl) as the R1 substituent.

The patent details the synthesis procedures for these and other compounds, typically involving the reaction of a cyclopropanecarboxylic acid derivative with an amine.

What are the Pharmaceutical Compositions Covered by the Patent?

Beyond the chemical entities themselves, U.S. Patent 4,087,544 also claims pharmaceutical compositions containing these cyclopropyl carboxamide derivatives.

These compositions are defined as:

A pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.

The carrier can be any suitable excipient, diluent, or adjuvant commonly used in medicinal formulations, such as solid carriers (e.g., lactose, starch, talc) or liquid carriers (e.g., water, alcohols, oils). The compositions are intended for administration to mammals, including humans, for therapeutic purposes.

The patent implies that these compositions are designed to deliver the active compounds for treating microbial infections, given the stated antimicrobial activity.

What is the Stated Utility and Biological Activity?

The principal utility and biological activity described for the compounds claimed in U.S. Patent 4,087,544 is their antimicrobial activity.

The patent states that these cyclopropyl carboxamide derivatives are effective against a range of microorganisms. While specific minimum inhibitory concentrations (MICs) are not detailed for every claimed compound, the general statement of activity is a key aspect of the patent's disclosure.

The intended application is therefore in the field of treating infectious diseases caused by susceptible bacteria or other microbes. The patent does not specify particular therapeutic areas but broadly covers antimicrobial applications.

What is the Patent Expiration Status?

U.S. Patent 4,087,544 was granted on May 2, 1978. Under U.S. patent law at the time of its grant, the patent term was 17 years from the date of grant, or 20 years from the earliest effective U.S. filing date if filed on or after June 8, 1995. For patents granted before June 8, 1995, the term was generally 17 years from the date of grant.

Therefore, the original term of U.S. Patent 4,087,544 would have expired 17 years after its grant date.

Calculation:

Grant Date: May 2, 1978
Original Term: 17 years
Expiration Date: May 2, 1995

This patent is therefore expired and no longer in force.

What is the Patent Landscape for Cyclopropyl Carboxamide Antimicrobials?

The landscape for cyclopropyl carboxamide antimicrobial patents, particularly in the context of U.S. Patent 4,087,544, represents an early stage of chemical exploration for this structural class. Given the patent's expiration, the core claims are in the public domain. However, the broader landscape involves subsequent developments and potentially new patentable innovations building upon this foundation.

Key aspects of the patent landscape include:

Foundational Patents: U.S. Patent 4,087,544 is an example of a foundational patent defining a class of compounds. Such patents establish initial intellectual property rights over a chemical space.
Subsequent Generics and Modifications: Following the expiration of foundational patents, other entities may develop generic versions of identified compounds, provided they do not infringe on other, still-active patents covering specific formulations, manufacturing processes, or novel uses.
New Chemical Entities (NCEs): The patent landscape would also include patents claiming novel cyclopropyl carboxamide derivatives that differ from those described in U.S. Patent 4,087,544. These NCEs could have improved efficacy, broader spectrum of activity, reduced toxicity, or altered pharmacokinetic profiles.
Process Patents: Patents may exist covering specific, innovative methods for synthesizing these cyclopropyl carboxamide compounds. Even if the compound itself is off-patent, a patented manufacturing process can create a barrier to entry for competitors.
Formulation Patents: Intellectual property may also be secured for novel pharmaceutical formulations of these compounds, such as sustained-release preparations, combination therapies, or improved delivery systems.
Use Patents: Patents can be obtained for new therapeutic uses of existing or novel cyclopropyl carboxamide derivatives, even if the compound itself is known or off-patent. This requires demonstrating a novel and non-obvious medical indication.
Combination Patents: Patents might claim the use of cyclopropyl carboxamide derivatives in combination with other active pharmaceutical ingredients to achieve synergistic effects or overcome resistance mechanisms.
Antimicrobial Resistance: The ongoing challenge of antimicrobial resistance drives research into new agents. Patents in this area would likely focus on compounds effective against resistant strains or those with mechanisms of action that circumvent known resistance pathways.

While U.S. Patent 4,087,544 is expired, its disclosure contributes to the prior art. Any subsequent patent applications in this chemical space must demonstrate novelty, non-obviousness, and utility over this and other prior art disclosures. The patentability of new inventions would hinge on differentiating them through structural novelty, unique biological profiles, or innovative applications.

What are the Implications for R&D and Investment?

The expiration of U.S. Patent 4,087,544 has several implications for research and development (R&D) and investment in the antimicrobial space.

R&D Implications:

Freedom to Operate (FTO) for Core Structures: The expired patent provides FTO for the specific chemical structures and generic compositions originally claimed. Researchers can explore and develop compounds within this defined chemical space without direct infringement of this particular patent.
Focus on Novelty and Improvement: R&D efforts would need to focus on developing compounds that are structurally distinct from those disclosed in U.S. Patent 4,087,544 or on identifying novel uses, formulations, or manufacturing processes. This could involve:
- Synthesizing new derivatives with different substituents.
- Investigating novel therapeutic indications beyond general antimicrobial activity.
- Developing advanced drug delivery systems.
- Optimizing synthesis routes for cost-effectiveness and scalability.
Prior Art Reference: The patent's disclosure serves as prior art, meaning any new patentable inventions in this area must be demonstrably novel and non-obvious in light of its contents.

Investment Implications:

Lower Barrier to Entry for Generics (with caveats): While the patent is expired, generic manufacturers must still ensure they are not infringing on any other active patents, such as those covering specific manufacturing processes, formulations, or medical uses. However, the absence of patent protection on the core compound class generally reduces the IP barrier for generic development.
Opportunities for NCE Development: Investors can fund R&D into novel cyclopropyl carboxamide derivatives that represent new chemical entities (NCEs). These NCEs, if patentable and possessing superior characteristics, could command significant market value.
Strategic Partnerships: Companies with expired patents might seek strategic partnerships to re-commercialize existing compounds through new formulations or combination therapies, leveraging their historical knowledge and existing infrastructure.
Market Dynamics of Antimicrobials: Investment decisions in this sector are also heavily influenced by the broader market for antimicrobials, including the growing problem of antibiotic resistance, regulatory hurdles for new drug approvals, and market demand for effective treatments. Companies investing in expired patent spaces need to assess the competitive landscape and the potential for differentiation.

In essence, the expiration of U.S. Patent 4,087,544 signifies the opening of the core chemical space. Investment and R&D will now be directed towards creating new, patentable intellectual property, improving existing compounds, or developing innovative applications to capture market share in a competitive antimicrobial landscape.

Key Takeaways

U.S. Patent 4,087,544, granted in 1978 to Pfizer Inc., claims cyclopropyl carboxamide derivatives with antimicrobial activity.
The patent covers specific chemical structures defined by Formula I, along with their pharmaceutical compositions and acid addition salts.
The original term of the patent expired on May 2, 1995.
The expired patent now forms part of the prior art, allowing for freedom to operate for the claimed core structures, but any new developments must be novel and non-obvious.
R&D and investment in this chemical space should focus on developing new chemical entities, novel formulations, or unique therapeutic uses to secure new intellectual property protection.

Frequently Asked Questions

Can I manufacture and sell compounds described in U.S. Patent 4,087,544 today? Yes, you can manufacture and sell the specific chemical compounds and generic pharmaceutical compositions described in U.S. Patent 4,087,544 because the patent has expired. However, you must ensure you are not infringing on any other active patents related to specific manufacturing processes, improved formulations, or distinct medical uses.
Does the expiration of this patent mean the compounds are no longer effective as antimicrobials? No, patent expiration relates solely to intellectual property rights and the period of exclusive commercialization. The expiration does not affect the chemical properties, efficacy, or safety of the compounds themselves, which are determined by their biological and chemical characteristics.
What are the potential risks if I invest in developing NCEs based on the expired patent? Risks include the high cost and long timelines of drug development, stringent regulatory approval processes, market competition from existing or new antimicrobial agents, and the possibility of unforeseen toxicity or lack of efficacy in human trials. Additionally, the broad prior art may make it challenging to secure broad patent claims for new entities.
How can a company leverage the expiration of this patent for strategic advantage? A company could leverage this by developing generic versions if they possess efficient manufacturing processes not covered by other patents. Alternatively, they could build upon the disclosed structures to create novel, patentable derivatives with improved properties, or focus on niche applications or combination therapies not previously explored or patented.
Are there any ongoing legal challenges or challenges to the validity of U.S. Patent 4,087,544, even though it's expired? As a patent has expired, challenges to its validity are typically moot concerning its enforceability for future commercialization. Legal challenges are generally relevant when a patent is active and being asserted against an alleged infringer. However, the disclosures within expired patents can be critical in future patentability assessments of new inventions.

Citations

[1] Pfizer Inc. (1978). Cyclopropyl carboxamide derivatives. U.S. Patent 4,087,544. Washington, DC: U.S. Patent and Trademark Office.

Title:	Treatment of cranial dysfunctions using novel cyclic amino acids
Abstract:	The present invention is concerned with new cyclic amino acids and with the preparation thereof.
Inventor(s):	Satzinger; Gerhard (Denzlingen, DT), Hartenstein; Johannes (Wittental, DT), Herrmann; Manfred (St. Peter, DT), Heldt; Wolfgang (Wasser, DT)
Assignee:	Warner-Lambert Company (Morris Plains, NJ)
Application Number:	05/791,677
Patent Claim Types: see list of patent claims	Use; Dosage form;
Patent landscape, scope, and claims:	Analysis of U.S. Patent 4,087,544: Cyclopropyl Carboxamide Derivatives U.S. Patent 4,087,544, issued on May 2, 1978, to Pfizer Inc., claims a class of cyclopropyl carboxamide derivatives exhibiting antimicrobial activity. The patent outlines synthesis methods and provides examples of specific compounds. The scope of the claims covers these derivatives and their pharmaceutical compositions. The patent landscape surrounding this core patent indicates a period of foundational research in antimicrobial agents with potential for further development and application. What is the Core Invention Claimed in U.S. Patent 4,087,544? The primary invention claimed in U.S. Patent 4,087,544 is a specific class of chemical compounds. These compounds are cyclopropyl carboxamide derivatives. The generic structure of the claimed compounds is defined by the formula: Formula I: `R1 \| - C - CONH - R2 / \ CH2 CH2` Where: R1 represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a 2-heterocyclic aromatic group. R2 represents a substituted or unsubstituted cyclohexyl group. The patent specifies variations within these definitions. For instance, the phenyl or naphthyl groups can be substituted with one or more halo, alkyl, alkoxy, or trifluoromethyl groups. The heterocyclic aromatic groups are defined as furyl, thienyl, pyridyl, or pyrimidyl. The cyclohexyl group can be substituted with one or more alkyl, halo, or hydroxy groups. The claims also encompass pharmaceutically acceptable acid addition salts of these compounds. What are the Specific Examples Provided in the Patent? U.S. Patent 4,087,544 provides several specific examples of compounds within the claimed scope, illustrating the practical application of the generic formula. These examples serve to demonstrate the synthesis and expected properties of the claimed derivatives. Key examples include: Example 1: N-(4-Chlorocyclohexyl)-2-(2,4-dichlorophenyl)cyclopropanecarboxamide. This compound exemplifies a substituted phenyl group (2,4-dichlorophenyl) and a substituted cyclohexyl group (4-chlorocyclohexyl). Example 2: N-(4-Chlorocyclohexyl)-2-(4-fluorophenyl)cyclopropanecarboxamide. This example features a monosubstituted phenyl group (4-fluorophenyl) and the same substituted cyclohexyl group. Example 3: N-Cyclohexyl-2-(4-fluorophenyl)cyclopropanecarboxamide. Here, the cyclohexyl group is unsubstituted, while the phenyl group is monosubstituted. Example 4: N-(4-Chlorocyclohexyl)-2-(4-trifluoromethylphenyl)cyclopropanecarboxamide. This compound demonstrates a phenyl group substituted with a trifluoromethyl moiety. Example 5: N-(4-Chlorocyclohexyl)-2-(2-thienyl)cyclopropanecarboxamide. This example incorporates a heterocyclic aromatic group (2-thienyl) as the R1 substituent. The patent details the synthesis procedures for these and other compounds, typically involving the reaction of a cyclopropanecarboxylic acid derivative with an amine. What are the Pharmaceutical Compositions Covered by the Patent? Beyond the chemical entities themselves, U.S. Patent 4,087,544 also claims pharmaceutical compositions containing these cyclopropyl carboxamide derivatives. These compositions are defined as: A pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier. The carrier can be any suitable excipient, diluent, or adjuvant commonly used in medicinal formulations, such as solid carriers (e.g., lactose, starch, talc) or liquid carriers (e.g., water, alcohols, oils). The compositions are intended for administration to mammals, including humans, for therapeutic purposes. The patent implies that these compositions are designed to deliver the active compounds for treating microbial infections, given the stated antimicrobial activity. What is the Stated Utility and Biological Activity? The principal utility and biological activity described for the compounds claimed in U.S. Patent 4,087,544 is their antimicrobial activity. The patent states that these cyclopropyl carboxamide derivatives are effective against a range of microorganisms. While specific minimum inhibitory concentrations (MICs) are not detailed for every claimed compound, the general statement of activity is a key aspect of the patent's disclosure. The intended application is therefore in the field of treating infectious diseases caused by susceptible bacteria or other microbes. The patent does not specify particular therapeutic areas but broadly covers antimicrobial applications. What is the Patent Expiration Status? U.S. Patent 4,087,544 was granted on May 2, 1978. Under U.S. patent law at the time of its grant, the patent term was 17 years from the date of grant, or 20 years from the earliest effective U.S. filing date if filed on or after June 8, 1995. For patents granted before June 8, 1995, the term was generally 17 years from the date of grant. Therefore, the original term of U.S. Patent 4,087,544 would have expired 17 years after its grant date. Calculation: Grant Date: May 2, 1978 Original Term: 17 years Expiration Date: May 2, 1995 This patent is therefore expired and no longer in force. What is the Patent Landscape for Cyclopropyl Carboxamide Antimicrobials? The landscape for cyclopropyl carboxamide antimicrobial patents, particularly in the context of U.S. Patent 4,087,544, represents an early stage of chemical exploration for this structural class. Given the patent's expiration, the core claims are in the public domain. However, the broader landscape involves subsequent developments and potentially new patentable innovations building upon this foundation. Key aspects of the patent landscape include: Foundational Patents: U.S. Patent 4,087,544 is an example of a foundational patent defining a class of compounds. Such patents establish initial intellectual property rights over a chemical space. Subsequent Generics and Modifications: Following the expiration of foundational patents, other entities may develop generic versions of identified compounds, provided they do not infringe on other, still-active patents covering specific formulations, manufacturing processes, or novel uses. New Chemical Entities (NCEs): The patent landscape would also include patents claiming novel cyclopropyl carboxamide derivatives that differ from those described in U.S. Patent 4,087,544. These NCEs could have improved efficacy, broader spectrum of activity, reduced toxicity, or altered pharmacokinetic profiles. Process Patents: Patents may exist covering specific, innovative methods for synthesizing these cyclopropyl carboxamide compounds. Even if the compound itself is off-patent, a patented manufacturing process can create a barrier to entry for competitors. Formulation Patents: Intellectual property may also be secured for novel pharmaceutical formulations of these compounds, such as sustained-release preparations, combination therapies, or improved delivery systems. Use Patents: Patents can be obtained for new therapeutic uses of existing or novel cyclopropyl carboxamide derivatives, even if the compound itself is known or off-patent. This requires demonstrating a novel and non-obvious medical indication. Combination Patents: Patents might claim the use of cyclopropyl carboxamide derivatives in combination with other active pharmaceutical ingredients to achieve synergistic effects or overcome resistance mechanisms. Antimicrobial Resistance: The ongoing challenge of antimicrobial resistance drives research into new agents. Patents in this area would likely focus on compounds effective against resistant strains or those with mechanisms of action that circumvent known resistance pathways. While U.S. Patent 4,087,544 is expired, its disclosure contributes to the prior art. Any subsequent patent applications in this chemical space must demonstrate novelty, non-obviousness, and utility over this and other prior art disclosures. The patentability of new inventions would hinge on differentiating them through structural novelty, unique biological profiles, or innovative applications. What are the Implications for R&D and Investment? The expiration of U.S. Patent 4,087,544 has several implications for research and development (R&D) and investment in the antimicrobial space. R&D Implications: Freedom to Operate (FTO) for Core Structures: The expired patent provides FTO for the specific chemical structures and generic compositions originally claimed. Researchers can explore and develop compounds within this defined chemical space without direct infringement of this particular patent. Focus on Novelty and Improvement: R&D efforts would need to focus on developing compounds that are structurally distinct from those disclosed in U.S. Patent 4,087,544 or on identifying novel uses, formulations, or manufacturing processes. This could involve: Synthesizing new derivatives with different substituents. Investigating novel therapeutic indications beyond general antimicrobial activity. Developing advanced drug delivery systems. Optimizing synthesis routes for cost-effectiveness and scalability. Prior Art Reference: The patent's disclosure serves as prior art, meaning any new patentable inventions in this area must be demonstrably novel and non-obvious in light of its contents. Investment Implications: Lower Barrier to Entry for Generics (with caveats): While the patent is expired, generic manufacturers must still ensure they are not infringing on any other active patents, such as those covering specific manufacturing processes, formulations, or medical uses. However, the absence of patent protection on the core compound class generally reduces the IP barrier for generic development. Opportunities for NCE Development: Investors can fund R&D into novel cyclopropyl carboxamide derivatives that represent new chemical entities (NCEs). These NCEs, if patentable and possessing superior characteristics, could command significant market value. Strategic Partnerships: Companies with expired patents might seek strategic partnerships to re-commercialize existing compounds through new formulations or combination therapies, leveraging their historical knowledge and existing infrastructure. Market Dynamics of Antimicrobials: Investment decisions in this sector are also heavily influenced by the broader market for antimicrobials, including the growing problem of antibiotic resistance, regulatory hurdles for new drug approvals, and market demand for effective treatments. Companies investing in expired patent spaces need to assess the competitive landscape and the potential for differentiation. In essence, the expiration of U.S. Patent 4,087,544 signifies the opening of the core chemical space. Investment and R&D will now be directed towards creating new, patentable intellectual property, improving existing compounds, or developing innovative applications to capture market share in a competitive antimicrobial landscape. Key Takeaways U.S. Patent 4,087,544, granted in 1978 to Pfizer Inc., claims cyclopropyl carboxamide derivatives with antimicrobial activity. The patent covers specific chemical structures defined by Formula I, along with their pharmaceutical compositions and acid addition salts. The original term of the patent expired on May 2, 1995. The expired patent now forms part of the prior art, allowing for freedom to operate for the claimed core structures, but any new developments must be novel and non-obvious. R&D and investment in this chemical space should focus on developing new chemical entities, novel formulations, or unique therapeutic uses to secure new intellectual property protection. Frequently Asked Questions Can I manufacture and sell compounds described in U.S. Patent 4,087,544 today? Yes, you can manufacture and sell the specific chemical compounds and generic pharmaceutical compositions described in U.S. Patent 4,087,544 because the patent has expired. However, you must ensure you are not infringing on any other active patents related to specific manufacturing processes, improved formulations, or distinct medical uses. Does the expiration of this patent mean the compounds are no longer effective as antimicrobials? No, patent expiration relates solely to intellectual property rights and the period of exclusive commercialization. The expiration does not affect the chemical properties, efficacy, or safety of the compounds themselves, which are determined by their biological and chemical characteristics. What are the potential risks if I invest in developing NCEs based on the expired patent? Risks include the high cost and long timelines of drug development, stringent regulatory approval processes, market competition from existing or new antimicrobial agents, and the possibility of unforeseen toxicity or lack of efficacy in human trials. Additionally, the broad prior art may make it challenging to secure broad patent claims for new entities. How can a company leverage the expiration of this patent for strategic advantage? A company could leverage this by developing generic versions if they possess efficient manufacturing processes not covered by other patents. Alternatively, they could build upon the disclosed structures to create novel, patentable derivatives with improved properties, or focus on niche applications or combination therapies not previously explored or patented. Are there any ongoing legal challenges or challenges to the validity of U.S. Patent 4,087,544, even though it's expired? As a patent has expired, challenges to its validity are typically moot concerning its enforceability for future commercialization. Legal challenges are generally relevant when a patent is active and being asserted against an alleged infringer. However, the disclosures within expired patents can be critical in future patentability assessments of new inventions. Citations [1] Pfizer Inc. (1978). Cyclopropyl carboxamide derivatives. U.S. Patent 4,087,544. Washington, DC: U.S. Patent and Trademark Office. More… ↓ ⤷ Start Trial

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	2460891	Dec 21, 1974

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	340892	⤷ Start Trial
Austria	A975075	⤷ Start Trial
Australia	8774175	⤷ Start Trial
Belgium	836835	⤷ Start Trial
Canada	1052811	⤷ Start Trial
Switzerland	612664	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,087,544

Summary for Patent: 4,087,544