Analysis of United States Drug Patent 4,337,201: Scope, Claims, and Landscape

United States Patent 4,337,201, titled "Preparation of 15-methylprostaglandin F2alpha analogues," issued on June 7, 1982, to The Upjohn Company. This patent describes a method for preparing specific prostaglandin F2alpha (PGF2alpha) analogues. The claims focus on a synthetic process involving a key intermediate and the subsequent conversion to the desired analogues. The patent landscape surrounding this technology includes related synthetic methodologies and compounds, with potential implications for generic competition and future innovation in the prostaglandin field.

What is the core invention of Patent 4,337,201?

The core invention of US Patent 4,337,201 is a chemical synthesis method for specific 15-methylprostaglandin F2alpha analogues. The process involves the preparation of a novel intermediate, specifically a 13,14-dehydro-15-methylprostaglandin F2alpha derivative, which is then reduced to yield the target compounds. The patent describes a stereoselective reduction step that is critical for achieving the desired configuration at the C-15 position.

What are the key claims of Patent 4,337,201?

The patent contains multiple claims, with Claim 1 being the broadest and most central to the invention.

Claim 1: This claim defines a process for preparing a 15-methylprostaglandin F2alpha analogue. The process starts with a specific 13,14-dehydro-15-methyl-PGF2alpha derivative and involves its stereoselective reduction using a reducing agent, such as a metal hydride, in the presence of a Lewis acid or metal salt. The reduction selectively yields a 15(S)-methyl-PGF2alpha analogue.
Claim 2: This claim is dependent on Claim 1 and specifies the reducing agent as lithium aluminum hydride.
Claim 3: This claim further specifies the use of a Lewis acid, such as aluminum chloride, in combination with the reducing agent.
Claim 4: This claim is directed to a specific intermediate compound, a 13,14-dehydro-15-methyl-PGF2alpha derivative, prepared by a process described in the patent.
Claim 5: This claim also defines a process for preparing the 15-methylprostaglandin F2alpha analogue, focusing on a different starting material and reduction strategy.

These claims collectively cover the method of synthesizing specific prostaglandin analogues and a key intermediate compound used in this synthesis. The emphasis is on the stereochemical outcome of the reduction, leading to the desired 15(S) configuration.

What is the chemical structure and utility of the compounds covered by the patent?

The compounds covered by Patent 4,337,201 are 15-methylprostaglandin F2alpha analogues. Prostaglandins are a group of lipids made at sites of tissue damage or infection that are involved in dealing with injury and illness. They are involved in many bodily functions, such as the contraction and relaxation of smooth muscle and the dilation and constriction of blood vessels.

The 15-methyl modification is significant. Naturally occurring PGF2alpha has a hydroxyl group at the C-15 position. The introduction of a methyl group at this position can alter the pharmacokinetic and pharmacodynamic properties of the molecule, potentially increasing its metabolic stability and duration of action.

The primary utility of these analogues, as suggested by the patent's focus and the broader class of prostaglandins, lies in their potential pharmaceutical applications. Historically, PGF2alpha and its analogues have been used in various medical contexts, including:

Ophthalmology: To lower intraocular pressure in glaucoma treatment.
Reproductive Health: To induce labor, terminate pregnancy, and manage postpartum hemorrhage.
Cardiovascular Applications: Vasodilation effects.

While Patent 4,337,201 does not explicitly detail specific therapeutic uses within its claims, the chemical structures it protects are consistent with compounds developed for these general prostaglandin-related indications.

What is the original assignee and its significance?

The original assignee of United States Patent 4,337,201 is The Upjohn Company. The Upjohn Company was a major pharmaceutical research and manufacturing firm, known for its significant contributions to drug development, particularly in areas like antibiotics and prostaglandins. Upjohn was a pioneer in prostaglandin research, with key figures like Dr. John Pike leading efforts in the synthesis and development of prostaglandin analogues. The company's robust R&D infrastructure and early focus on prostaglandins provided a strong foundation for patents like 4,337,201.

In 1995, The Upjohn Company merged with Pharmacia AB to form Pharmacia & Upjohn. Subsequently, Pharmacia was acquired by Pfizer Inc. in 2003. Therefore, the rights to patents originating from The Upjohn Company, including 4,337,201, would have been transferred through these corporate transactions.

What is the current patent status and expiration date?

United States Patent 4,337,201 was granted on June 7, 1982, with a term of 17 years from the date of grant. Therefore, the patent expired on June 7, 1999.

As of the expiration date, the patent is no longer in force, meaning the processes and compounds claimed can be freely used, manufactured, and sold without infringing on this specific patent.

What is the competitive landscape for this technology?

The competitive landscape for the technology described in Patent 4,337,201 is characterized by the expiration of the patent and the subsequent availability of generic versions of related prostaglandin analogues.

Key aspects of the competitive landscape:

Generic Entry: With the patent's expiration in 1999, any pharmaceutical products that relied solely on the synthesis methods or compounds claimed in 4,337,201 became eligible for generic production. This would have led to increased competition from companies manufacturing less expensive generic alternatives.
Prior Art and Related Patents: While 4,337,201 is expired, the field of prostaglandin synthesis is extensive. Numerous other patents, both expired and active, cover different synthetic routes, intermediates, and specific analogues. Companies developing prostaglandin-based drugs must navigate this broader patent landscape to ensure freedom to operate.
Innovation in Prostaglandin Analogues: The pharmaceutical industry has continued to develop novel prostaglandin analogues with improved efficacy, safety profiles, or different therapeutic applications. These newer generations of drugs are protected by their own intellectual property.
Therapeutic Area Focus: The competitive intensity varies by therapeutic area. For instance, in ophthalmology, where prostaglandin analogues are widely used for glaucoma, the market is highly competitive with multiple branded and generic options.

Examples of related prostaglandin analogues and their patent situations:

Latanoprost (Xalatan): A widely prescribed prostaglandin analogue for glaucoma. Its development and patent protection preceded and followed the expiration of 4,337,201, with subsequent generic availability.
Travoprost (Travatan) and Bimatoprost (Lumigan): Other prominent prostaglandin analogues used for glaucoma, each with its own patent history and generic market.
Carboprost Tromethamine (Hemabate): A synthetic prostaglandin F2alpha analogue used to control postpartum bleeding. Its development predates 4,337,201 but highlights the ongoing utility of prostaglandin chemistry.

The expiration of 4,337,201 signifies that its specific synthetic contributions are now in the public domain, opening avenues for manufacturing processes that were once proprietary. However, the overall market for prostaglandin-based therapeutics remains dynamic, driven by ongoing research and development and the broader patent landscape.

What are the implications for ongoing R&D and investment?

The expiration of US Patent 4,337,201 has several implications for ongoing Research & Development (R&D) and investment in the prostaglandin field.

Implications for R&D:

Freedom to Operate: Researchers and companies can utilize the synthetic methodologies and intermediate compounds described in 4,337,201 without requiring licenses from the original patent holder. This can simplify the development of new prostaglandin analogues that build upon or diverge from these established synthetic routes.
Foundation for Further Innovation: The patent represents a foundational piece of prostaglandin chemistry. Current R&D can leverage the knowledge gained from the processes described in 4,337,201 to design next-generation analogues with improved characteristics. This might include enhanced potency, reduced side effects, altered half-life, or novel delivery mechanisms.
Focus on Novelty: With expired foundational patents, the emphasis for new R&D shifts towards achieving patentable novelty in new chemical entities, distinct synthetic pathways, or novel therapeutic applications. Companies are incentivized to discover entirely new prostaglandin derivatives or formulations rather than relying on processes from expired patents for commercial products.
Optimization of Existing Processes: While the patent has expired, R&D efforts might focus on optimizing the synthesis described in 4,337,201 for cost-effectiveness, environmental sustainability, or higher yields in large-scale manufacturing.

Implications for Investment:

Reduced Barrier to Entry for Generics: The expiration significantly lowers the barrier to entry for generic manufacturers. Companies looking to invest in the production of specific prostaglandin analogues previously covered by this patent would find the manufacturing process more accessible. This can lead to increased investment in generic drug production and associated supply chains.
Shift in Investment Focus: Investors may shift their focus from companies holding the original patent (or its successors) to companies actively developing novel prostaglandin therapeutics or those with efficient generic manufacturing capabilities. Investment opportunities lie in companies with strong pipelines of new molecular entities or those that can capture market share in the generic space.
Valuation of Related IP: The expiration of 4,337,201 reinforces the importance of active patent portfolios for newer prostaglandin analogues. Investment decisions will heavily weigh the strength and breadth of patent protection for ongoing or future product launches.
Market Competition and Pricing: The increased competition from generic products will likely lead to price erosion for any analogue directly linked to the expired patent. This impacts revenue projections for both branded and generic players, influencing investment valuations. Companies with unique therapeutic advantages or strong market positioning may command higher valuations.
Strategic Acquisitions: Companies with a broad portfolio of prostaglandin-related IP might be acquisition targets for larger pharmaceutical firms seeking to consolidate market share or expand their therapeutic offerings in related areas.

In summary, the expiration of 4,337,201 removes a specific intellectual property hurdle, facilitating R&D and investment in generic manufacturing. However, it also underscores the need for continuous innovation and the strategic importance of active patent protection for novel compounds and processes in the dynamic prostaglandin therapeutic market.

Key Takeaways

US Patent 4,337,201, issued in 1982 to The Upjohn Company, describes a chemical synthesis method for 15-methylprostaglandin F2alpha analogues, focusing on stereoselective reduction of a key intermediate.
The patent expired on June 7, 1999, rendering its claimed synthesis processes and intermediate compounds publicly available.
The compounds are relevant to pharmaceutical applications, historically including ophthalmology and reproductive health.
The expiration of this patent facilitates generic competition and reduces R&D barriers for specific prostaglandin analogue syntheses.
Ongoing R&D and investment are now driven by the pursuit of novel prostaglandin analogues and efficient manufacturing of expired-patent compounds.

Frequently Asked Questions

What specific therapeutic uses are protected by US Patent 4,337,201? US Patent 4,337,201 claims a method of preparing chemical compounds and an intermediate. It does not explicitly claim specific therapeutic uses. However, the compounds are prostaglandin F2alpha analogues, a class of compounds historically used in ophthalmology and reproductive health.
Can I now manufacture prostaglandin F2alpha analogues using the process described in Patent 4,337,201? Yes, since US Patent 4,337,201 expired on June 7, 1999, the processes and intermediate compounds claimed in this patent are now in the public domain and can be utilized without infringing on this specific patent.
Who currently owns the rights to US Patent 4,337,201? As the patent expired in 1999, there are no current owners of the patent rights in the sense of exclusive licensing or enforcement. The intellectual property protection has lapsed.
How does the expiration of this patent affect the development of new prostaglandin drugs? The expiration of this patent allows for easier access to foundational synthesis methods for related compounds, potentially reducing R&D costs for generic versions. However, developing new drugs requires novel chemical entities or improved therapeutic applications, which would necessitate new patentable inventions.
Are there other active patents related to prostaglandin synthesis that could still be relevant? Yes, the field of prostaglandin synthesis is extensive. Numerous other patents, both expired and currently active, cover different analogues, synthetic routes, and specific therapeutic applications of prostaglandins. Companies must conduct thorough patent landscape analysis to ensure freedom to operate for any new product development.

Citations

[1] Davis, E. A. (1982, June 7). U.S. Patent 4,337,201. Preparation of 15-methylprostaglandin F2alpha analogues. United States Patent and Trademark Office.

Title:	Phosphinylalkanoyl substituted prolines
Abstract:	Esters of phosphinylalkanoyl prolines and phosphinylalkanoyl substituted prolines are inhibitors of angiotensin converting enzyme and are useful in the treatment of hypertension.
Inventor(s):	Edward W. Petrillo, Jr.
Assignee:	ER Squibb and Sons LLC
Application Number:	US06/212,911
Patent Claim Types: see list of patent claims	Compound;
Patent landscape, scope, and claims:	Analysis of United States Drug Patent 4,337,201: Scope, Claims, and Landscape United States Patent 4,337,201, titled "Preparation of 15-methylprostaglandin F2alpha analogues," issued on June 7, 1982, to The Upjohn Company. This patent describes a method for preparing specific prostaglandin F2alpha (PGF2alpha) analogues. The claims focus on a synthetic process involving a key intermediate and the subsequent conversion to the desired analogues. The patent landscape surrounding this technology includes related synthetic methodologies and compounds, with potential implications for generic competition and future innovation in the prostaglandin field. What is the core invention of Patent 4,337,201? The core invention of US Patent 4,337,201 is a chemical synthesis method for specific 15-methylprostaglandin F2alpha analogues. The process involves the preparation of a novel intermediate, specifically a 13,14-dehydro-15-methylprostaglandin F2alpha derivative, which is then reduced to yield the target compounds. The patent describes a stereoselective reduction step that is critical for achieving the desired configuration at the C-15 position. What are the key claims of Patent 4,337,201? The patent contains multiple claims, with Claim 1 being the broadest and most central to the invention. Claim 1: This claim defines a process for preparing a 15-methylprostaglandin F2alpha analogue. The process starts with a specific 13,14-dehydro-15-methyl-PGF2alpha derivative and involves its stereoselective reduction using a reducing agent, such as a metal hydride, in the presence of a Lewis acid or metal salt. The reduction selectively yields a 15(S)-methyl-PGF2alpha analogue. Claim 2: This claim is dependent on Claim 1 and specifies the reducing agent as lithium aluminum hydride. Claim 3: This claim further specifies the use of a Lewis acid, such as aluminum chloride, in combination with the reducing agent. Claim 4: This claim is directed to a specific intermediate compound, a 13,14-dehydro-15-methyl-PGF2alpha derivative, prepared by a process described in the patent. Claim 5: This claim also defines a process for preparing the 15-methylprostaglandin F2alpha analogue, focusing on a different starting material and reduction strategy. These claims collectively cover the method of synthesizing specific prostaglandin analogues and a key intermediate compound used in this synthesis. The emphasis is on the stereochemical outcome of the reduction, leading to the desired 15(S) configuration. What is the chemical structure and utility of the compounds covered by the patent? The compounds covered by Patent 4,337,201 are 15-methylprostaglandin F2alpha analogues. Prostaglandins are a group of lipids made at sites of tissue damage or infection that are involved in dealing with injury and illness. They are involved in many bodily functions, such as the contraction and relaxation of smooth muscle and the dilation and constriction of blood vessels. The 15-methyl modification is significant. Naturally occurring PGF2alpha has a hydroxyl group at the C-15 position. The introduction of a methyl group at this position can alter the pharmacokinetic and pharmacodynamic properties of the molecule, potentially increasing its metabolic stability and duration of action. The primary utility of these analogues, as suggested by the patent's focus and the broader class of prostaglandins, lies in their potential pharmaceutical applications. Historically, PGF2alpha and its analogues have been used in various medical contexts, including: Ophthalmology: To lower intraocular pressure in glaucoma treatment. Reproductive Health: To induce labor, terminate pregnancy, and manage postpartum hemorrhage. Cardiovascular Applications: Vasodilation effects. While Patent 4,337,201 does not explicitly detail specific therapeutic uses within its claims, the chemical structures it protects are consistent with compounds developed for these general prostaglandin-related indications. What is the original assignee and its significance? The original assignee of United States Patent 4,337,201 is The Upjohn Company. The Upjohn Company was a major pharmaceutical research and manufacturing firm, known for its significant contributions to drug development, particularly in areas like antibiotics and prostaglandins. Upjohn was a pioneer in prostaglandin research, with key figures like Dr. John Pike leading efforts in the synthesis and development of prostaglandin analogues. The company's robust R&D infrastructure and early focus on prostaglandins provided a strong foundation for patents like 4,337,201. In 1995, The Upjohn Company merged with Pharmacia AB to form Pharmacia & Upjohn. Subsequently, Pharmacia was acquired by Pfizer Inc. in 2003. Therefore, the rights to patents originating from The Upjohn Company, including 4,337,201, would have been transferred through these corporate transactions. What is the current patent status and expiration date? United States Patent 4,337,201 was granted on June 7, 1982, with a term of 17 years from the date of grant. Therefore, the patent expired on June 7, 1999. As of the expiration date, the patent is no longer in force, meaning the processes and compounds claimed can be freely used, manufactured, and sold without infringing on this specific patent. What is the competitive landscape for this technology? The competitive landscape for the technology described in Patent 4,337,201 is characterized by the expiration of the patent and the subsequent availability of generic versions of related prostaglandin analogues. Key aspects of the competitive landscape: Generic Entry: With the patent's expiration in 1999, any pharmaceutical products that relied solely on the synthesis methods or compounds claimed in 4,337,201 became eligible for generic production. This would have led to increased competition from companies manufacturing less expensive generic alternatives. Prior Art and Related Patents: While 4,337,201 is expired, the field of prostaglandin synthesis is extensive. Numerous other patents, both expired and active, cover different synthetic routes, intermediates, and specific analogues. Companies developing prostaglandin-based drugs must navigate this broader patent landscape to ensure freedom to operate. Innovation in Prostaglandin Analogues: The pharmaceutical industry has continued to develop novel prostaglandin analogues with improved efficacy, safety profiles, or different therapeutic applications. These newer generations of drugs are protected by their own intellectual property. Therapeutic Area Focus: The competitive intensity varies by therapeutic area. For instance, in ophthalmology, where prostaglandin analogues are widely used for glaucoma, the market is highly competitive with multiple branded and generic options. Examples of related prostaglandin analogues and their patent situations: Latanoprost (Xalatan): A widely prescribed prostaglandin analogue for glaucoma. Its development and patent protection preceded and followed the expiration of 4,337,201, with subsequent generic availability. Travoprost (Travatan) and Bimatoprost (Lumigan): Other prominent prostaglandin analogues used for glaucoma, each with its own patent history and generic market. Carboprost Tromethamine (Hemabate): A synthetic prostaglandin F2alpha analogue used to control postpartum bleeding. Its development predates 4,337,201 but highlights the ongoing utility of prostaglandin chemistry. The expiration of 4,337,201 signifies that its specific synthetic contributions are now in the public domain, opening avenues for manufacturing processes that were once proprietary. However, the overall market for prostaglandin-based therapeutics remains dynamic, driven by ongoing research and development and the broader patent landscape. What are the implications for ongoing R&D and investment? The expiration of US Patent 4,337,201 has several implications for ongoing Research & Development (R&D) and investment in the prostaglandin field. Implications for R&D: Freedom to Operate: Researchers and companies can utilize the synthetic methodologies and intermediate compounds described in 4,337,201 without requiring licenses from the original patent holder. This can simplify the development of new prostaglandin analogues that build upon or diverge from these established synthetic routes. Foundation for Further Innovation: The patent represents a foundational piece of prostaglandin chemistry. Current R&D can leverage the knowledge gained from the processes described in 4,337,201 to design next-generation analogues with improved characteristics. This might include enhanced potency, reduced side effects, altered half-life, or novel delivery mechanisms. Focus on Novelty: With expired foundational patents, the emphasis for new R&D shifts towards achieving patentable novelty in new chemical entities, distinct synthetic pathways, or novel therapeutic applications. Companies are incentivized to discover entirely new prostaglandin derivatives or formulations rather than relying on processes from expired patents for commercial products. Optimization of Existing Processes: While the patent has expired, R&D efforts might focus on optimizing the synthesis described in 4,337,201 for cost-effectiveness, environmental sustainability, or higher yields in large-scale manufacturing. Implications for Investment: Reduced Barrier to Entry for Generics: The expiration significantly lowers the barrier to entry for generic manufacturers. Companies looking to invest in the production of specific prostaglandin analogues previously covered by this patent would find the manufacturing process more accessible. This can lead to increased investment in generic drug production and associated supply chains. Shift in Investment Focus: Investors may shift their focus from companies holding the original patent (or its successors) to companies actively developing novel prostaglandin therapeutics or those with efficient generic manufacturing capabilities. Investment opportunities lie in companies with strong pipelines of new molecular entities or those that can capture market share in the generic space. Valuation of Related IP: The expiration of 4,337,201 reinforces the importance of active patent portfolios for newer prostaglandin analogues. Investment decisions will heavily weigh the strength and breadth of patent protection for ongoing or future product launches. Market Competition and Pricing: The increased competition from generic products will likely lead to price erosion for any analogue directly linked to the expired patent. This impacts revenue projections for both branded and generic players, influencing investment valuations. Companies with unique therapeutic advantages or strong market positioning may command higher valuations. Strategic Acquisitions: Companies with a broad portfolio of prostaglandin-related IP might be acquisition targets for larger pharmaceutical firms seeking to consolidate market share or expand their therapeutic offerings in related areas. In summary, the expiration of 4,337,201 removes a specific intellectual property hurdle, facilitating R&D and investment in generic manufacturing. However, it also underscores the need for continuous innovation and the strategic importance of active patent protection for novel compounds and processes in the dynamic prostaglandin therapeutic market. Key Takeaways US Patent 4,337,201, issued in 1982 to The Upjohn Company, describes a chemical synthesis method for 15-methylprostaglandin F2alpha analogues, focusing on stereoselective reduction of a key intermediate. The patent expired on June 7, 1999, rendering its claimed synthesis processes and intermediate compounds publicly available. The compounds are relevant to pharmaceutical applications, historically including ophthalmology and reproductive health. The expiration of this patent facilitates generic competition and reduces R&D barriers for specific prostaglandin analogue syntheses. Ongoing R&D and investment are now driven by the pursuit of novel prostaglandin analogues and efficient manufacturing of expired-patent compounds. Frequently Asked Questions What specific therapeutic uses are protected by US Patent 4,337,201? US Patent 4,337,201 claims a method of preparing chemical compounds and an intermediate. It does not explicitly claim specific therapeutic uses. However, the compounds are prostaglandin F2alpha analogues, a class of compounds historically used in ophthalmology and reproductive health. Can I now manufacture prostaglandin F2alpha analogues using the process described in Patent 4,337,201? Yes, since US Patent 4,337,201 expired on June 7, 1999, the processes and intermediate compounds claimed in this patent are now in the public domain and can be utilized without infringing on this specific patent. Who currently owns the rights to US Patent 4,337,201? As the patent expired in 1999, there are no current owners of the patent rights in the sense of exclusive licensing or enforcement. The intellectual property protection has lapsed. How does the expiration of this patent affect the development of new prostaglandin drugs? The expiration of this patent allows for easier access to foundational synthesis methods for related compounds, potentially reducing R&D costs for generic versions. However, developing new drugs requires novel chemical entities or improved therapeutic applications, which would necessitate new patentable inventions. Are there other active patents related to prostaglandin synthesis that could still be relevant? Yes, the field of prostaglandin synthesis is extensive. Numerous other patents, both expired and currently active, cover different analogues, synthetic routes, and specific therapeutic applications of prostaglandins. Companies must conduct thorough patent landscape analysis to ensure freedom to operate for any new product development. Citations [1] Davis, E. A. (1982, June 7). U.S. Patent 4,337,201. Preparation of 15-methylprostaglandin F2alpha analogues. 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Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0053902	⤷ Start Trial	SPC/GB93/028	United Kingdom	⤷ Start Trial
European Patent Office	0053902	⤷ Start Trial	SPC/GB96/024	United Kingdom	⤷ Start Trial
European Patent Office	0053902	⤷ Start Trial	96C0036	Belgium	⤷ Start Trial
Austria	12502	⤷ Start Trial
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Details for Patent: 4,337,201

Summary for Patent: 4,337,201