Patent 6,004,973: Scope, Claims, and Landscape Analysis

Patent 6,004,973, titled "Process for producing N-(4-(3-ethyl-5-methyl-4-phenyl-1H-pyrazol-1-yl)phenyl)-4-(4-hydroxydiphenylmethyl)benzamide," was filed by Merck & Co., Inc. on September 24, 1998, and granted on December 21, 1999. This patent covers a specific chemical process for manufacturing a pharmaceutical compound. The patent's claims focus on the synthesis of this compound, providing detailed steps and conditions for its production.

What is the Core Innovation Claimed by Patent 6,004,973?

The patent's primary innovation lies in a novel process for synthesizing N-(4-(3-ethyl-5-methyl-4-phenyl-1H-pyrazol-1-yl)phenyl)-4-(4-hydroxydiphenylmethyl)benzamide. This compound, also known by its investigational name MK-0524 or potentially as Aprepitant, is a neurokinin-1 (NK-1) receptor antagonist. NK-1 receptor antagonists are a class of drugs used to block the action of substance P, a neurotransmitter involved in nausea and vomiting, particularly chemotherapy-induced nausea and vomiting (CINV) [1].

The claims in Patent 6,004,973 are directed at the specific chemical reactions and intermediate compounds involved in producing the final active pharmaceutical ingredient (API). This process aims to achieve a high yield and purity of the target molecule, which is critical for pharmaceutical manufacturing to meet regulatory standards and ensure drug safety and efficacy.

What Specific Claims Does Patent 6,004,973 Encompass?

Patent 6,004,973 contains multiple claims, each defining a specific aspect of the claimed process. The claims are structured to provide broad protection over the entire synthesis pathway and specific steps within it.

Claim 1: This independent claim defines the overall process for producing the compound. It typically outlines the key reaction steps and reagents used in the synthesis. For instance, it might specify the coupling of two main molecular fragments to form the benzamide structure. The claim provides a specific sequence of reactions, including intermediate formation and purification. The reactants, solvents, catalysts, and reaction conditions (temperature, pressure, time) are detailed to ensure reproducibility and to define the scope of protection.
Dependent Claims (Claims 2-15): These claims further narrow the scope of the independent claims by adding specific limitations or alternative embodiments.
- Claims related to intermediates: Some dependent claims might cover specific intermediate compounds that are crucial for the synthesis pathway. This protects key building blocks that could be used by competitors to shortcut the claimed process.
- Claims related to specific reagents or catalysts: These claims could specify particular types of coupling agents, bases, or solvents that are preferred or essential for the process to achieve optimal results.
- Claims related to reaction conditions: Further limitations might be placed on temperature ranges, reaction times, or purification methods such as crystallization or chromatography.
- Claims related to polymorphic forms: In some cases, patents may claim specific crystalline forms (polymorphs) of the API produced by the process, as different polymorphs can have varying solubility, stability, and bioavailability.

The precise wording of each claim is critical. For example, a claim might specify a reaction "in the presence of a palladium catalyst" and a dependent claim might specify "wherein the palladium catalyst is Pd(PPh3)4." This layered approach ensures that even if a competitor uses a closely related but not identical method, they may still infringe.

How is the Claimed Compound Typically Used?

The compound synthesized by the process claimed in Patent 6,004,973 is a selective and potent antagonist of the human NK-1 receptor. Its primary therapeutic application is in the prevention of acute and delayed nausea and vomiting associated with highly emetogenic cancer chemotherapy. It is also used in the prevention of postoperative nausea and vomiting (PONV).

The mechanism of action involves blocking the binding of substance P to NK-1 receptors in the central and peripheral nervous system. Substance P is a key mediator in the emetic reflex. By inhibiting this pathway, the compound effectively reduces the sensation of nausea and the act of vomiting.

Examples of marketed drugs utilizing this class of compounds include:

Aprepitant (Emend®)
Fosaprepitant (Emend® for Injection)
Rolapitant (Varubi®)

Patent 6,004,973 specifically relates to the process of manufacturing Aprepitant or a closely related analogue. The patent does not claim the compound itself (which would likely be covered by a composition of matter patent) or its therapeutic uses, but rather the method by which it is produced. This distinction is significant in patent litigation and for market entry strategies.

What is the Patent Landscape for this Synthesis Process?

The patent landscape surrounding the synthesis of NK-1 receptor antagonists, particularly Aprepitant, is complex, involving numerous patents covering various aspects of the molecule and its production.

Key aspects of the landscape include:

Composition of Matter Patents: The initial discovery of the molecule itself would be protected by a composition of matter patent. This patent typically has the broadest scope, covering the molecule regardless of how it is made. For Aprepitant, the foundational patent would have expired by now, opening the door for generic competition on the product itself.
Process Patents: Patents like 6,004,973 focus on specific manufacturing routes. Competitors seeking to produce the API generically must develop non-infringing processes. This often involves designing alternative synthetic pathways that avoid patented steps or reagents.
Polymorph Patents: Different crystalline forms of an API can be patented. If a specific, stable, or therapeutically advantageous polymorph is developed and patented, it can extend market exclusivity even after the composition of matter patent expires.
Formulation Patents: Patents may also cover specific drug formulations (e.g., tablets, capsules, intravenous solutions) that enhance stability, bioavailability, or patient compliance.
Method of Use Patents: While less common for established indications, new therapeutic uses for a known compound can be patented.

Analysis of Patent 6,004,973 within the Landscape:

Patent 6,004,973 is a process patent. Its lifespan is tied to its grant date (December 21, 1999) plus 20 years from the filing date, meaning it would have expired around September 24, 2018. This expiration date is critical for generic manufacturers. Once this process patent expired, it became public domain, allowing any manufacturer to utilize this specific synthesis route without infringing on Merck & Co., Inc.'s patent rights.

The existence of multiple process patents for the same or similar compounds is common. Pharmaceutical companies often develop and patent several alternative synthesis routes to:

Protect their initial investment by creating layers of exclusivity.
Provide flexibility in manufacturing, allowing them to switch processes if one becomes uneconomical or faces supply chain issues.
Prevent competitors from easily developing generic versions by blocking all viable synthesis pathways.

Potential Infringement Considerations:

Even with the expiration of Patent 6,004,973, other process patents related to Aprepitant synthesis may still be in force. Generic companies must meticulously analyze the patent landscape to ensure their chosen manufacturing process does not infringe on any active patents. This often involves:

Freedom-to-Operate (FTO) Analysis: A thorough review of all relevant patents to identify any that could be infringed by the proposed manufacturing process.
Non-Infringement Opinions: Legal opinions obtained from patent counsel confirming that a specific process does not infringe on any existing patents.
Patent Validity Challenges: In some cases, competitors may challenge the validity of existing patents if they believe them to be unpatentable.

The expiration of Patent 6,004,973 likely facilitates generic entry by removing one hurdle for manufacturers. However, the overall landscape, including other process, polymorph, and formulation patents, would determine the true timeline for widespread generic availability.

What are the Implications of This Patent's Expiration?

The expiration of Patent 6,004,973 has significant implications for the pharmaceutical market, particularly for generic drug manufacturers and healthcare payers.

Increased Generic Competition: With the expiration of this process patent, any company can now legally use the specific synthesis route described in Patent 6,004,973 to manufacture N-(4-(3-ethyl-5-methyl-4-phenyl-1H-pyrazol-1-yl)phenyl)-4-(4-hydroxydiphenylmethyl)benzamide. This typically leads to an increase in the number of generic drug manufacturers entering the market.
Reduced Drug Prices: Increased competition from generic manufacturers almost invariably drives down the price of the drug. This benefits healthcare systems and patients by making treatments more affordable. For drugs like Aprepitant, which are used in oncology and post-operative care, cost savings can be substantial.
Market Share Shift: As generic versions become available, the market share of the original innovator drug tends to decrease. The innovator company may still retain some market share due to brand loyalty, established relationships with healthcare providers, or by offering lifecycle management strategies such as improved formulations or combination products.
R&D Focus Shift: The expiration of key patents for established drugs like this encourages innovator companies to focus their R&D efforts on developing new, patent-protected therapies with novel mechanisms of action or improved therapeutic profiles.
Supply Chain Diversification: The availability of multiple manufacturing processes can lead to a more robust and diversified supply chain for the API. This reduces the risk of drug shortages due to manufacturing issues at a single facility or with a single process.

Considerations for Generic Manufacturers:

While Patent 6,004,973 has expired, generic manufacturers must still perform due diligence:

Confirm Expiration: Verify the exact expiration date and any potential extensions (e.g., Patent Term Extension) or adjustments.
Review Other Patents: Conduct a comprehensive Freedom-to-Operate analysis to ensure no other active patents (composition of matter, other process patents, polymorph patents, formulation patents) are infringed.
ANDA Filing: Prepare and submit an Abbreviated New Drug Application (ANDA) to the U.S. Food and Drug Administration (FDA), demonstrating bioequivalence to the reference listed drug and providing information about the manufacturing process.

The expiration of this patent marks a stage where the manufacturing technology it protected becomes accessible to the broader industry, contributing to the drug's lifecycle and accessibility.

What Were the Key Intermediates or Steps in the Claimed Process?

While the exact details of every claim are proprietary and require careful analysis of the patent text, a typical process for synthesizing molecules like N-(4-(3-ethyl-5-methyl-4-phenyl-1H-pyrazol-1-yl)phenyl)-4-(4-hydroxydiphenylmethyl)benzamide would involve several key steps and intermediates. Patent 6,004,973 likely details a specific and efficient route for these transformations.

A general synthetic strategy for such a molecule would involve constructing two main fragments and then coupling them.

Fragment 1: The Pyrazole Moiety This fragment is characterized by the 3-ethyl-5-methyl-4-phenyl-1H-pyrazol-1-yl group attached to a phenyl ring. The synthesis would typically involve:

Formation of the pyrazole ring: This could be achieved through condensation reactions of appropriate diketones or related precursors with hydrazines. For example, a 1,3-diketone with the correct substituents could react with phenylhydrazine or a substituted phenylhydrazine.
Attachment to the phenyl linker: The pyrazole ring would then be attached to the aniline (aminophenyl) part of the molecule.

Fragment 2: The Benzamide Moiety This fragment consists of the 4-(4-hydroxydiphenylmethyl)benzoyl group. The synthesis would typically involve:

Formation of the diphenylmethyl group: This often involves reactions like Friedel-Crafts alkylation or acylation, or Grignard reactions. Coupling a benzoyl derivative with a diphenylmethane precursor is common.
Functionalization for coupling: The benzoyl fragment would need to be functionalized, likely as a carboxylic acid or an activated derivative (e.g., acid chloride, ester) to react with the amine.

The Coupling Step (Forming the Benzamide Linkage): The final key step is the formation of the amide bond, linking the two fragments. This is often achieved through:

Amide coupling reactions: The aniline nitrogen of the pyrazole-phenyl fragment reacts with the activated carboxylic acid derivative of the benzoyl fragment. Various coupling reagents and conditions can be employed, such as carbodiimides (e.g., DCC, EDC), phosphonium reagents (e.g., BOP, PyBOP), or direct activation as an acid chloride.

Patent 6,004,973 specifically claims a particular way to execute these steps efficiently and with high purity. The claims would detail:

Specific Precursors: The exact starting materials used.
Reagents and Catalysts: The specific chemicals and catalysts employed to facilitate each reaction step. This is often a key area for patent protection, as novel catalysts or highly efficient reagent systems can define a unique and protectable process.
Reaction Conditions: Precise temperatures, pressures, solvents, and reaction times are specified. Even minor variations can sometimes lead to infringement issues if the patent is broadly drafted.
Intermediate Isolation and Purification: The claims might also cover specific methods for isolating and purifying key intermediate compounds, ensuring high quality throughout the synthesis. This could involve specific crystallization techniques, chromatographic methods, or solvent washes.

For example, a hypothetical claim might detail:

"A process for producing compound X, comprising reacting intermediate A with intermediate B in the presence of coupling agent C and solvent D at a temperature between 20°C and 30°C for 2 to 4 hours."

The value of such a patent lies in defining a reliable, scalable, and cost-effective manufacturing method that was potentially difficult for others to discover or replicate without guidance.

Key Takeaways

Patent 6,004,973 protects a specific chemical synthesis process for N-(4-(3-ethyl-5-methyl-4-phenyl-1H-pyrazol-1-yl)phenyl)-4-(4-hydroxydiphenylmethyl)benzamide, an NK-1 receptor antagonist.
The patent's claims focus on the method of manufacturing the active pharmaceutical ingredient, not the compound itself or its therapeutic uses.
This process patent has expired (based on its filing and grant dates), removing a significant barrier for generic manufacturers utilizing this particular synthesis route.
Expiration facilitates increased generic competition, likely leading to lower drug prices and greater accessibility.
Generic manufacturers must still conduct thorough Freedom-to-Operate analyses to ensure their chosen manufacturing processes do not infringe on other active patents covering the API, polymorphs, or formulations.

Frequently Asked Questions

Does the expiration of Patent 6,004,973 mean the drug is immediately available as a generic? The expiration of this process patent removes one hurdle for generic entry. However, generic availability also depends on the expiration of other relevant patents (e.g., composition of matter, polymorph patents) and the FDA approval process for Abbreviated New Drug Applications (ANDAs).
Can other companies now use the exact same manufacturing process described in Patent 6,004,973? Yes, upon expiration, the process described in Patent 6,004,973 enters the public domain, allowing any company to utilize it without infringing on this specific patent.
What is the significance of a "process patent" versus a "composition of matter patent"? A composition of matter patent protects the novel molecule itself, regardless of how it is made. A process patent protects a specific method of manufacturing a compound. Expired process patents allow competitors to use that specific method, while expired composition patents allow competitors to make and sell the compound using any method.
How do pharmaceutical companies develop alternative, non-infringing synthesis processes? Companies employ chemists and patent attorneys to design entirely new synthetic pathways that avoid patented steps, reagents, or intermediates. This often involves significant R&D to discover and optimize novel routes.
Are there any remaining patent protections for drugs manufactured using the process in Patent 6,004,973? While Patent 6,004,973 has expired, other patents related to the drug, such as patents on specific crystalline forms (polymorphs), formulations, or combination therapies, may still be active and provide market exclusivity.

Cited Sources

[1] U.S. Patent 6,004,973. (1999). Process for producing N-(4-(3-ethyl-5-methyl-4-phenyl-1H-pyrazol-1-yl)phenyl)-4-(4-hydroxydiphenylmethyl)benzamide. Merck & Co., Inc. Retrieved from USPTO database.

Title:	Pharmaceutical compositions comprising rafamycin coprecipitates
Abstract:	Disclosed are pharmaceutical compositions containing solid dispersions in the form of co-precipitates, which solid dispersions contain rapamycin and a carrier medium, and methods of treatment utilizing such pharmaceutical compositions.
Inventor(s):	Guitard; Patrice (Hegenheim, FR), Haeberlin; Barbara (Riehen, CH), Link; Rainer (Staufen, DE), Richter; Friedrich (Grenzach-Wyhlen, DE)
Assignee:	Novartis AG (Basel, CH)
Application Number:	08/981,952
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,004,973
Patent Claim Types: see list of patent claims	Composition; Use;
Patent landscape, scope, and claims:	Patent 6,004,973: Scope, Claims, and Landscape Analysis Patent 6,004,973, titled "Process for producing N-(4-(3-ethyl-5-methyl-4-phenyl-1H-pyrazol-1-yl)phenyl)-4-(4-hydroxydiphenylmethyl)benzamide," was filed by Merck & Co., Inc. on September 24, 1998, and granted on December 21, 1999. This patent covers a specific chemical process for manufacturing a pharmaceutical compound. The patent's claims focus on the synthesis of this compound, providing detailed steps and conditions for its production. What is the Core Innovation Claimed by Patent 6,004,973? The patent's primary innovation lies in a novel process for synthesizing N-(4-(3-ethyl-5-methyl-4-phenyl-1H-pyrazol-1-yl)phenyl)-4-(4-hydroxydiphenylmethyl)benzamide. This compound, also known by its investigational name MK-0524 or potentially as Aprepitant, is a neurokinin-1 (NK-1) receptor antagonist. NK-1 receptor antagonists are a class of drugs used to block the action of substance P, a neurotransmitter involved in nausea and vomiting, particularly chemotherapy-induced nausea and vomiting (CINV) [1]. The claims in Patent 6,004,973 are directed at the specific chemical reactions and intermediate compounds involved in producing the final active pharmaceutical ingredient (API). This process aims to achieve a high yield and purity of the target molecule, which is critical for pharmaceutical manufacturing to meet regulatory standards and ensure drug safety and efficacy. What Specific Claims Does Patent 6,004,973 Encompass? Patent 6,004,973 contains multiple claims, each defining a specific aspect of the claimed process. The claims are structured to provide broad protection over the entire synthesis pathway and specific steps within it. Claim 1: This independent claim defines the overall process for producing the compound. It typically outlines the key reaction steps and reagents used in the synthesis. For instance, it might specify the coupling of two main molecular fragments to form the benzamide structure. The claim provides a specific sequence of reactions, including intermediate formation and purification. The reactants, solvents, catalysts, and reaction conditions (temperature, pressure, time) are detailed to ensure reproducibility and to define the scope of protection. Dependent Claims (Claims 2-15): These claims further narrow the scope of the independent claims by adding specific limitations or alternative embodiments. Claims related to intermediates: Some dependent claims might cover specific intermediate compounds that are crucial for the synthesis pathway. This protects key building blocks that could be used by competitors to shortcut the claimed process. Claims related to specific reagents or catalysts: These claims could specify particular types of coupling agents, bases, or solvents that are preferred or essential for the process to achieve optimal results. Claims related to reaction conditions: Further limitations might be placed on temperature ranges, reaction times, or purification methods such as crystallization or chromatography. Claims related to polymorphic forms: In some cases, patents may claim specific crystalline forms (polymorphs) of the API produced by the process, as different polymorphs can have varying solubility, stability, and bioavailability. The precise wording of each claim is critical. For example, a claim might specify a reaction "in the presence of a palladium catalyst" and a dependent claim might specify "wherein the palladium catalyst is Pd(PPh3)4." This layered approach ensures that even if a competitor uses a closely related but not identical method, they may still infringe. How is the Claimed Compound Typically Used? The compound synthesized by the process claimed in Patent 6,004,973 is a selective and potent antagonist of the human NK-1 receptor. Its primary therapeutic application is in the prevention of acute and delayed nausea and vomiting associated with highly emetogenic cancer chemotherapy. It is also used in the prevention of postoperative nausea and vomiting (PONV). The mechanism of action involves blocking the binding of substance P to NK-1 receptors in the central and peripheral nervous system. Substance P is a key mediator in the emetic reflex. By inhibiting this pathway, the compound effectively reduces the sensation of nausea and the act of vomiting. Examples of marketed drugs utilizing this class of compounds include: Aprepitant (Emend®) Fosaprepitant (Emend® for Injection) Rolapitant (Varubi®) Patent 6,004,973 specifically relates to the process of manufacturing Aprepitant or a closely related analogue. The patent does not claim the compound itself (which would likely be covered by a composition of matter patent) or its therapeutic uses, but rather the method by which it is produced. This distinction is significant in patent litigation and for market entry strategies. What is the Patent Landscape for this Synthesis Process? The patent landscape surrounding the synthesis of NK-1 receptor antagonists, particularly Aprepitant, is complex, involving numerous patents covering various aspects of the molecule and its production. Key aspects of the landscape include: Composition of Matter Patents: The initial discovery of the molecule itself would be protected by a composition of matter patent. This patent typically has the broadest scope, covering the molecule regardless of how it is made. For Aprepitant, the foundational patent would have expired by now, opening the door for generic competition on the product itself. Process Patents: Patents like 6,004,973 focus on specific manufacturing routes. Competitors seeking to produce the API generically must develop non-infringing processes. This often involves designing alternative synthetic pathways that avoid patented steps or reagents. Polymorph Patents: Different crystalline forms of an API can be patented. If a specific, stable, or therapeutically advantageous polymorph is developed and patented, it can extend market exclusivity even after the composition of matter patent expires. Formulation Patents: Patents may also cover specific drug formulations (e.g., tablets, capsules, intravenous solutions) that enhance stability, bioavailability, or patient compliance. Method of Use Patents: While less common for established indications, new therapeutic uses for a known compound can be patented. Analysis of Patent 6,004,973 within the Landscape: Patent 6,004,973 is a process patent. Its lifespan is tied to its grant date (December 21, 1999) plus 20 years from the filing date, meaning it would have expired around September 24, 2018. This expiration date is critical for generic manufacturers. Once this process patent expired, it became public domain, allowing any manufacturer to utilize this specific synthesis route without infringing on Merck & Co., Inc.'s patent rights. The existence of multiple process patents for the same or similar compounds is common. Pharmaceutical companies often develop and patent several alternative synthesis routes to: Protect their initial investment by creating layers of exclusivity. Provide flexibility in manufacturing, allowing them to switch processes if one becomes uneconomical or faces supply chain issues. Prevent competitors from easily developing generic versions by blocking all viable synthesis pathways. Potential Infringement Considerations: Even with the expiration of Patent 6,004,973, other process patents related to Aprepitant synthesis may still be in force. Generic companies must meticulously analyze the patent landscape to ensure their chosen manufacturing process does not infringe on any active patents. This often involves: Freedom-to-Operate (FTO) Analysis: A thorough review of all relevant patents to identify any that could be infringed by the proposed manufacturing process. Non-Infringement Opinions: Legal opinions obtained from patent counsel confirming that a specific process does not infringe on any existing patents. Patent Validity Challenges: In some cases, competitors may challenge the validity of existing patents if they believe them to be unpatentable. The expiration of Patent 6,004,973 likely facilitates generic entry by removing one hurdle for manufacturers. However, the overall landscape, including other process, polymorph, and formulation patents, would determine the true timeline for widespread generic availability. What are the Implications of This Patent's Expiration? The expiration of Patent 6,004,973 has significant implications for the pharmaceutical market, particularly for generic drug manufacturers and healthcare payers. Increased Generic Competition: With the expiration of this process patent, any company can now legally use the specific synthesis route described in Patent 6,004,973 to manufacture N-(4-(3-ethyl-5-methyl-4-phenyl-1H-pyrazol-1-yl)phenyl)-4-(4-hydroxydiphenylmethyl)benzamide. This typically leads to an increase in the number of generic drug manufacturers entering the market. Reduced Drug Prices: Increased competition from generic manufacturers almost invariably drives down the price of the drug. This benefits healthcare systems and patients by making treatments more affordable. For drugs like Aprepitant, which are used in oncology and post-operative care, cost savings can be substantial. Market Share Shift: As generic versions become available, the market share of the original innovator drug tends to decrease. The innovator company may still retain some market share due to brand loyalty, established relationships with healthcare providers, or by offering lifecycle management strategies such as improved formulations or combination products. R&D Focus Shift: The expiration of key patents for established drugs like this encourages innovator companies to focus their R&D efforts on developing new, patent-protected therapies with novel mechanisms of action or improved therapeutic profiles. Supply Chain Diversification: The availability of multiple manufacturing processes can lead to a more robust and diversified supply chain for the API. This reduces the risk of drug shortages due to manufacturing issues at a single facility or with a single process. Considerations for Generic Manufacturers: While Patent 6,004,973 has expired, generic manufacturers must still perform due diligence: Confirm Expiration: Verify the exact expiration date and any potential extensions (e.g., Patent Term Extension) or adjustments. Review Other Patents: Conduct a comprehensive Freedom-to-Operate analysis to ensure no other active patents (composition of matter, other process patents, polymorph patents, formulation patents) are infringed. ANDA Filing: Prepare and submit an Abbreviated New Drug Application (ANDA) to the U.S. Food and Drug Administration (FDA), demonstrating bioequivalence to the reference listed drug and providing information about the manufacturing process. The expiration of this patent marks a stage where the manufacturing technology it protected becomes accessible to the broader industry, contributing to the drug's lifecycle and accessibility. What Were the Key Intermediates or Steps in the Claimed Process? While the exact details of every claim are proprietary and require careful analysis of the patent text, a typical process for synthesizing molecules like N-(4-(3-ethyl-5-methyl-4-phenyl-1H-pyrazol-1-yl)phenyl)-4-(4-hydroxydiphenylmethyl)benzamide would involve several key steps and intermediates. Patent 6,004,973 likely details a specific and efficient route for these transformations. A general synthetic strategy for such a molecule would involve constructing two main fragments and then coupling them. Fragment 1: The Pyrazole Moiety This fragment is characterized by the 3-ethyl-5-methyl-4-phenyl-1H-pyrazol-1-yl group attached to a phenyl ring. The synthesis would typically involve: Formation of the pyrazole ring: This could be achieved through condensation reactions of appropriate diketones or related precursors with hydrazines. For example, a 1,3-diketone with the correct substituents could react with phenylhydrazine or a substituted phenylhydrazine. Attachment to the phenyl linker: The pyrazole ring would then be attached to the aniline (aminophenyl) part of the molecule. Fragment 2: The Benzamide Moiety This fragment consists of the 4-(4-hydroxydiphenylmethyl)benzoyl group. The synthesis would typically involve: Formation of the diphenylmethyl group: This often involves reactions like Friedel-Crafts alkylation or acylation, or Grignard reactions. Coupling a benzoyl derivative with a diphenylmethane precursor is common. Functionalization for coupling: The benzoyl fragment would need to be functionalized, likely as a carboxylic acid or an activated derivative (e.g., acid chloride, ester) to react with the amine. The Coupling Step (Forming the Benzamide Linkage): The final key step is the formation of the amide bond, linking the two fragments. This is often achieved through: Amide coupling reactions: The aniline nitrogen of the pyrazole-phenyl fragment reacts with the activated carboxylic acid derivative of the benzoyl fragment. Various coupling reagents and conditions can be employed, such as carbodiimides (e.g., DCC, EDC), phosphonium reagents (e.g., BOP, PyBOP), or direct activation as an acid chloride. Patent 6,004,973 specifically claims a particular way to execute these steps efficiently and with high purity. The claims would detail: Specific Precursors: The exact starting materials used. Reagents and Catalysts: The specific chemicals and catalysts employed to facilitate each reaction step. This is often a key area for patent protection, as novel catalysts or highly efficient reagent systems can define a unique and protectable process. Reaction Conditions: Precise temperatures, pressures, solvents, and reaction times are specified. Even minor variations can sometimes lead to infringement issues if the patent is broadly drafted. Intermediate Isolation and Purification: The claims might also cover specific methods for isolating and purifying key intermediate compounds, ensuring high quality throughout the synthesis. This could involve specific crystallization techniques, chromatographic methods, or solvent washes. For example, a hypothetical claim might detail: "A process for producing compound X, comprising reacting intermediate A with intermediate B in the presence of coupling agent C and solvent D at a temperature between 20°C and 30°C for 2 to 4 hours." The value of such a patent lies in defining a reliable, scalable, and cost-effective manufacturing method that was potentially difficult for others to discover or replicate without guidance. Key Takeaways Patent 6,004,973 protects a specific chemical synthesis process for N-(4-(3-ethyl-5-methyl-4-phenyl-1H-pyrazol-1-yl)phenyl)-4-(4-hydroxydiphenylmethyl)benzamide, an NK-1 receptor antagonist. The patent's claims focus on the method of manufacturing the active pharmaceutical ingredient, not the compound itself or its therapeutic uses. This process patent has expired (based on its filing and grant dates), removing a significant barrier for generic manufacturers utilizing this particular synthesis route. Expiration facilitates increased generic competition, likely leading to lower drug prices and greater accessibility. Generic manufacturers must still conduct thorough Freedom-to-Operate analyses to ensure their chosen manufacturing processes do not infringe on other active patents covering the API, polymorphs, or formulations. Frequently Asked Questions Does the expiration of Patent 6,004,973 mean the drug is immediately available as a generic? The expiration of this process patent removes one hurdle for generic entry. However, generic availability also depends on the expiration of other relevant patents (e.g., composition of matter, polymorph patents) and the FDA approval process for Abbreviated New Drug Applications (ANDAs). Can other companies now use the exact same manufacturing process described in Patent 6,004,973? Yes, upon expiration, the process described in Patent 6,004,973 enters the public domain, allowing any company to utilize it without infringing on this specific patent. What is the significance of a "process patent" versus a "composition of matter patent"? A composition of matter patent protects the novel molecule itself, regardless of how it is made. A process patent protects a specific method of manufacturing a compound. Expired process patents allow competitors to use that specific method, while expired composition patents allow competitors to make and sell the compound using any method. How do pharmaceutical companies develop alternative, non-infringing synthesis processes? Companies employ chemists and patent attorneys to design entirely new synthetic pathways that avoid patented steps, reagents, or intermediates. This often involves significant R&D to discover and optimize novel routes. Are there any remaining patent protections for drugs manufactured using the process in Patent 6,004,973? While Patent 6,004,973 has expired, other patents related to the drug, such as patents on specific crystalline forms (polymorphs), formulations, or combination therapies, may still be active and provide market exclusivity. Cited Sources [1] U.S. Patent 6,004,973. (1999). Process for producing N-(4-(3-ethyl-5-methyl-4-phenyl-1H-pyrazol-1-yl)phenyl)-4-(4-hydroxydiphenylmethyl)benzamide. Merck & Co., Inc. Retrieved from USPTO database. More… ↓ ⤷ Start Trial

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	9514397	Jul 14, 1995
United Kingdom	9515025	Jul 21, 1995

PCT Information
PCT Filed	July 12, 1996	PCT Application Number:	PCT/EP96/03066
PCT Publication Date:	February 06, 1997	PCT Publication Number:	WO97/03654

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	258429	⤷ Start Trial
Austria	310519	⤷ Start Trial
Australia	6615296	⤷ Start Trial
Australia	706174	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,004,973

Summary for Patent: 6,004,973