United States Drug Patent 5,543,152: Scope, Claims, and Landscape Analysis

Executive Summary

United States Patent 5,543,152, titled "Amides of 3-aminopyrrolidine," issued on August 6, 1996, to Parke-Davis Pharmaceutical Research, Inc. (now part of Pfizer Inc.). This patent covers a class of chemical compounds, specifically amides of 3-aminopyrrolidine, and their use in treating various diseases. The core claims focus on the chemical structure and pharmaceutical compositions containing these compounds. The patent landscape surrounding this technology is characterized by a broad scope of the claims and significant patent activity by major pharmaceutical entities, indicating potential for both therapeutic advancement and competitive challenges.

What is the core subject matter of Patent 5,543,152?

The patent claims a genus of chemical compounds defined by a specific structural formula, wherein a pyrrolidine ring is substituted with an amino group and an amide moiety. The claims detail stereochemistry, substituents on the amide nitrogen, and specific groups attached to the pyrrolidine ring. These compounds are described for their utility in inhibiting the activity of enzymes such as dipeptidyl peptidase IV (DPP-IV).

The representative chemical structure disclosed in the patent is:

     R2
     |
R1--N--C--N--X
     |  ||  |
     --Pyr--NH2

Where:

Pyr represents a pyrrolidine ring.
NH2 is attached to the 3-position of the pyrrolidine ring.
R1 is a hydrogen atom or a substituted alkyl group.
R2 is an alkyl or substituted alkyl group.
X is a substituted or unsubstituted carbocyclic or heterocyclic aromatic ring.

The patent further defines specific ranges and types for R1, R2, and X, as well as variations in the pyrrolidine ring itself. The primary therapeutic application identified is the treatment of diabetes mellitus by modulating glucose metabolism.

What are the key claims of the patent?

Patent 5,543,152 contains multiple claims, broadly categorized into compound claims, pharmaceutical composition claims, and method of treatment claims.

Compound Claims

Claim 1: This is the broadest compound claim, defining a class of compounds with the general formula. It specifies various allowable substituents for R1, R2, and X, as well as stereochemical requirements for the pyrrolidine ring.
Claims 2-10: These claims are dependent on Claim 1 and further limit the scope by providing specific examples of substituents for R1, R2, and X. For instance, specific aromatic or heteroaromatic rings for X are detailed, as well as particular alkyl or substituted alkyl groups for R1 and R2.
Claims 11-14: These claims relate to specific stereoisomers of the compounds claimed in Claim 1, emphasizing the importance of enantiomeric purity for biological activity.

Pharmaceutical Composition Claims

Claim 15: This claim covers pharmaceutical compositions comprising a therapeutically effective amount of at least one compound according to Claim 1, together with a pharmaceutically acceptable carrier.
Claims 16-18: These claims are dependent on Claim 15, specifying the use of specific types of carriers or dosage forms.

Method of Treatment Claims

Claim 19: This claim covers a method of treating diabetes mellitus in a subject, which involves administering a therapeutically effective amount of a compound according to Claim 1.
Claim 20: This claim is dependent on Claim 19 and specifies the type of diabetes treated (e.g., non-insulin dependent diabetes mellitus).

The claims are structured to provide a broad foundation with narrower, more specific embodiments, aiming to capture a wide range of potentially active molecules within the defined chemical space.

What is the asserted therapeutic utility of the claimed compounds?

The primary therapeutic utility asserted for the compounds claimed in Patent 5,543,152 is the treatment of diabetes mellitus. The mechanism of action described involves the inhibition of dipeptidyl peptidase IV (DPP-IV). DPP-IV is an enzyme that degrades incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). By inhibiting DPP-IV, the claimed compounds enhance the levels and activity of these incretin hormones, which in turn stimulate insulin secretion and suppress glucagon release in a glucose-dependent manner. This leads to improved glycemic control in patients with diabetes.

Beyond diabetes, the patent broadly mentions the potential utility in treating "diseases where modulation of glucose metabolism is beneficial." While the primary focus is diabetes, this wording suggests a broader applicability that could be explored for related metabolic disorders.

Who are the key entities holding patents related to this technology?

The patent landscape for DPP-IV inhibitors, including compounds structurally related to those claimed in Patent 5,543,152, is populated by major pharmaceutical companies. While Patent 5,543,152 is assigned to Pfizer Inc. (via its predecessor Parke-Davis), other significant players in this field include:

Merck & Co.: Known for sitagliptin (Januvia), a prominent DPP-IV inhibitor.
Bristol-Myers Squibb: Developed saxagliptin (Onglyza).
Takeda Pharmaceutical Company: Holds patents related to alogliptin (Nesina).
Eli Lilly and Company: Has also been active in the diabetes therapeutic area with various compounds.
Novartis AG: Engaged in research and development of metabolic disease treatments.

The development of DPP-IV inhibitors has been a competitive area, with numerous patents covering novel compounds, formulations, and therapeutic uses. This suggests a history of substantial R&D investment and strategic patenting by multiple entities aiming to capture market share.

What is the patent term and remaining exclusivity?

United States Patent 5,543,152 issued on August 6, 1996. U.S. patent terms are generally 20 years from the filing date. Assuming a typical filing date around 1995 (based on the issue date and common patent prosecution timelines), the patent would have expired around 2015.

U.S. patent law provides for patent term extension (PTE) to compensate for delays in patent issuance due to regulatory review by the Food and Drug Administration (FDA). If the claimed compounds were subject to FDA review for marketing approval, a PTE may have been granted, extending the patent's effective term. However, without specific information on the filing date and any PTE granted, the general expiration would be approximately 20 years from the filing date.

Given the issue date of 1996, it is highly probable that Patent 5,543,152 has expired. However, it is crucial to verify the exact filing date and any applicable PTE to confirm the precise expiration. For drugs that gained market approval and utilized the technology claimed in this patent, subsequent patents on specific compounds, formulations, or methods of use may have provided extended exclusivity.

What are potential licensing or litigation risks associated with this patent?

Given the probable expiration of Patent 5,543,152, direct licensing or infringement litigation risks stemming from this specific patent are likely minimal for new market entrants. The primary risk would be if the patent is still in force due to a PTE, or if its claims are being asserted against ongoing activities.

However, the broader implications are significant:

Freedom-to-Operate (FTO) Analysis: Companies developing DPP-IV inhibitors or related metabolic therapies must conduct thorough FTO analyses. While this patent may have expired, the underlying chemical space and therapeutic targets are covered by a dense network of other patents.
Follow-on Patents: Pfizer Inc. and its predecessors have likely filed and obtained numerous patents that build upon the foundational technology described in Patent 5,543,152. These could include patents on specific DPP-IV inhibitors (e.g., sitagliptin, saxagliptin, alogliptin, if related), specific crystalline forms, formulations, combination therapies, or novel methods of use.
Anticipation and Obviousness: The existence of Patent 5,543,152 and the compounds it claims could be used as prior art to challenge the validity of later patents if their claims are not sufficiently novel or non-obvious over the disclosure in this 1996 patent.
Litigation Precedent: While direct litigation on this patent is unlikely due to expiration, its broad claims and the technology it covers have undoubtedly shaped the litigation landscape for DPP-IV inhibitors. Understanding the prosecution history and any litigation involving this patent or its progeny can provide insights into how patent offices and courts interpret claims in this domain.

Companies seeking to develop or market similar therapies must ensure they do not infringe on any currently active patents covering specific compounds, formulations, or uses, even if the foundational patent has expired.

Key Takeaways

Patent 5,543,152 covers a broad genus of 3-aminopyrrolidine amides with asserted utility in treating diabetes mellitus via DPP-IV inhibition.
The patent's claims encompass specific chemical structures, pharmaceutical compositions, and methods of treatment.
The technology is situated within a highly competitive patent landscape dominated by major pharmaceutical entities.
Given its 1996 issue date, Patent 5,543,152 has likely expired, reducing direct licensing and litigation risk from this specific patent.
However, extensive follow-on patenting in the DPP-IV inhibitor space by companies like Pfizer, Merck, Bristol-Myers Squibb, and Takeda necessitates thorough freedom-to-operate analyses for any new entrants or product development.

Frequently Asked Questions

What is the specific chemical structure claimed in Patent 5,543,152? Patent 5,543,152 claims compounds of a specific general formula involving a 3-aminopyrrolidine core substituted with an amide moiety where the nitrogen of the amide is attached to an aromatic or heteroaromatic ring, and the pyrrolidine ring may have further substituents. The precise details of these substituents (R1, R2, X) and stereochemistry are specified in the claims.
Has any drug been approved and marketed based on the technology disclosed in Patent 5,543,152? While the patent claims a class of compounds for treating diabetes, specific approved drugs directly tracing their origin to this foundational patent require detailed analysis of subsequent patent filings by Pfizer and its predecessors. The DPP-IV inhibitor class includes blockbuster drugs, but their specific patent coverage may stem from later, more specific patents.
How does DPP-IV inhibition work to treat diabetes? DPP-IV is an enzyme that breaks down incretin hormones (GLP-1 and GIP). These hormones stimulate insulin release and reduce glucagon secretion in a glucose-dependent manner. By inhibiting DPP-IV, the claimed compounds increase the levels of active incretin hormones, thereby improving blood glucose control in diabetic patients.
What is the geographical scope of Patent 5,543,152? The patent number "United States Patent 5,543,152" indicates that the patent's protection is limited to the United States. To assess international protection, corresponding patent applications and grants in other countries would need to be examined.
Can a company still develop and sell generic versions of drugs if the original patent has expired? If Patent 5,543,152 has expired and a specific drug compound claimed by it has also had its compound patents expire, generic manufacturers may be able to produce and sell that drug. However, they must ensure they do not infringe on any other valid patents that may cover formulations, methods of use, manufacturing processes, or new chemical forms of the drug that are still in force.

Citations

[1] Parke-Davis Pharmaceutical Research, Inc. (1996). Amides of 3-aminopyrrolidine. U.S. Patent 5,543,152. Washington, DC: U.S. Patent and Trademark Office.

Title:	Sphingosomes for enhanced drug delivery
Abstract:	Liposomal formulations having extended circulation time in vivo and increased drug retention are comprised of sphingomyelin and cholesterol and have an acidic intraliposomal pH. The formulations have enhanced stability and thus are used in methods which provide improved drug delivery and more effective treatment. The delivery of lipophilic drugs such as the vinca alkaloids, and particularly vincristine and vinblastine, to tumors is significantly improved.
Inventor(s):	Murray S. Webb, Marcel B. Bally, Lawrence D. Mayer
Assignee:	Arbutus Biopharma Corp
Application Number:	US08/263,603
Patent Claim Types: see list of patent claims	Composition; Compound; Process; Delivery; Dosage form;
Patent landscape, scope, and claims:	United States Drug Patent 5,543,152: Scope, Claims, and Landscape Analysis Executive Summary United States Patent 5,543,152, titled "Amides of 3-aminopyrrolidine," issued on August 6, 1996, to Parke-Davis Pharmaceutical Research, Inc. (now part of Pfizer Inc.). This patent covers a class of chemical compounds, specifically amides of 3-aminopyrrolidine, and their use in treating various diseases. The core claims focus on the chemical structure and pharmaceutical compositions containing these compounds. The patent landscape surrounding this technology is characterized by a broad scope of the claims and significant patent activity by major pharmaceutical entities, indicating potential for both therapeutic advancement and competitive challenges. What is the core subject matter of Patent 5,543,152? The patent claims a genus of chemical compounds defined by a specific structural formula, wherein a pyrrolidine ring is substituted with an amino group and an amide moiety. The claims detail stereochemistry, substituents on the amide nitrogen, and specific groups attached to the pyrrolidine ring. These compounds are described for their utility in inhibiting the activity of enzymes such as dipeptidyl peptidase IV (DPP-IV). The representative chemical structure disclosed in the patent is: `R2 \| R1--N--C--N--X \| \|\| \| --Pyr--NH2` Where: Pyr represents a pyrrolidine ring. NH2 is attached to the 3-position of the pyrrolidine ring. R1 is a hydrogen atom or a substituted alkyl group. R2 is an alkyl or substituted alkyl group. X is a substituted or unsubstituted carbocyclic or heterocyclic aromatic ring. The patent further defines specific ranges and types for R1, R2, and X, as well as variations in the pyrrolidine ring itself. The primary therapeutic application identified is the treatment of diabetes mellitus by modulating glucose metabolism. What are the key claims of the patent? Patent 5,543,152 contains multiple claims, broadly categorized into compound claims, pharmaceutical composition claims, and method of treatment claims. Compound Claims Claim 1: This is the broadest compound claim, defining a class of compounds with the general formula. It specifies various allowable substituents for R1, R2, and X, as well as stereochemical requirements for the pyrrolidine ring. Claims 2-10: These claims are dependent on Claim 1 and further limit the scope by providing specific examples of substituents for R1, R2, and X. For instance, specific aromatic or heteroaromatic rings for X are detailed, as well as particular alkyl or substituted alkyl groups for R1 and R2. Claims 11-14: These claims relate to specific stereoisomers of the compounds claimed in Claim 1, emphasizing the importance of enantiomeric purity for biological activity. Pharmaceutical Composition Claims Claim 15: This claim covers pharmaceutical compositions comprising a therapeutically effective amount of at least one compound according to Claim 1, together with a pharmaceutically acceptable carrier. Claims 16-18: These claims are dependent on Claim 15, specifying the use of specific types of carriers or dosage forms. Method of Treatment Claims Claim 19: This claim covers a method of treating diabetes mellitus in a subject, which involves administering a therapeutically effective amount of a compound according to Claim 1. Claim 20: This claim is dependent on Claim 19 and specifies the type of diabetes treated (e.g., non-insulin dependent diabetes mellitus). The claims are structured to provide a broad foundation with narrower, more specific embodiments, aiming to capture a wide range of potentially active molecules within the defined chemical space. What is the asserted therapeutic utility of the claimed compounds? The primary therapeutic utility asserted for the compounds claimed in Patent 5,543,152 is the treatment of diabetes mellitus. The mechanism of action described involves the inhibition of dipeptidyl peptidase IV (DPP-IV). DPP-IV is an enzyme that degrades incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). By inhibiting DPP-IV, the claimed compounds enhance the levels and activity of these incretin hormones, which in turn stimulate insulin secretion and suppress glucagon release in a glucose-dependent manner. This leads to improved glycemic control in patients with diabetes. Beyond diabetes, the patent broadly mentions the potential utility in treating "diseases where modulation of glucose metabolism is beneficial." While the primary focus is diabetes, this wording suggests a broader applicability that could be explored for related metabolic disorders. Who are the key entities holding patents related to this technology? The patent landscape for DPP-IV inhibitors, including compounds structurally related to those claimed in Patent 5,543,152, is populated by major pharmaceutical companies. While Patent 5,543,152 is assigned to Pfizer Inc. (via its predecessor Parke-Davis), other significant players in this field include: Merck & Co.: Known for sitagliptin (Januvia), a prominent DPP-IV inhibitor. Bristol-Myers Squibb: Developed saxagliptin (Onglyza). Takeda Pharmaceutical Company: Holds patents related to alogliptin (Nesina). Eli Lilly and Company: Has also been active in the diabetes therapeutic area with various compounds. Novartis AG: Engaged in research and development of metabolic disease treatments. The development of DPP-IV inhibitors has been a competitive area, with numerous patents covering novel compounds, formulations, and therapeutic uses. This suggests a history of substantial R&D investment and strategic patenting by multiple entities aiming to capture market share. What is the patent term and remaining exclusivity? United States Patent 5,543,152 issued on August 6, 1996. U.S. patent terms are generally 20 years from the filing date. Assuming a typical filing date around 1995 (based on the issue date and common patent prosecution timelines), the patent would have expired around 2015. U.S. patent law provides for patent term extension (PTE) to compensate for delays in patent issuance due to regulatory review by the Food and Drug Administration (FDA). If the claimed compounds were subject to FDA review for marketing approval, a PTE may have been granted, extending the patent's effective term. However, without specific information on the filing date and any PTE granted, the general expiration would be approximately 20 years from the filing date. Given the issue date of 1996, it is highly probable that Patent 5,543,152 has expired. However, it is crucial to verify the exact filing date and any applicable PTE to confirm the precise expiration. For drugs that gained market approval and utilized the technology claimed in this patent, subsequent patents on specific compounds, formulations, or methods of use may have provided extended exclusivity. What are potential licensing or litigation risks associated with this patent? Given the probable expiration of Patent 5,543,152, direct licensing or infringement litigation risks stemming from this specific patent are likely minimal for new market entrants. The primary risk would be if the patent is still in force due to a PTE, or if its claims are being asserted against ongoing activities. However, the broader implications are significant: Freedom-to-Operate (FTO) Analysis: Companies developing DPP-IV inhibitors or related metabolic therapies must conduct thorough FTO analyses. While this patent may have expired, the underlying chemical space and therapeutic targets are covered by a dense network of other patents. Follow-on Patents: Pfizer Inc. and its predecessors have likely filed and obtained numerous patents that build upon the foundational technology described in Patent 5,543,152. These could include patents on specific DPP-IV inhibitors (e.g., sitagliptin, saxagliptin, alogliptin, if related), specific crystalline forms, formulations, combination therapies, or novel methods of use. Anticipation and Obviousness: The existence of Patent 5,543,152 and the compounds it claims could be used as prior art to challenge the validity of later patents if their claims are not sufficiently novel or non-obvious over the disclosure in this 1996 patent. Litigation Precedent: While direct litigation on this patent is unlikely due to expiration, its broad claims and the technology it covers have undoubtedly shaped the litigation landscape for DPP-IV inhibitors. Understanding the prosecution history and any litigation involving this patent or its progeny can provide insights into how patent offices and courts interpret claims in this domain. Companies seeking to develop or market similar therapies must ensure they do not infringe on any currently active patents covering specific compounds, formulations, or uses, even if the foundational patent has expired. Key Takeaways Patent 5,543,152 covers a broad genus of 3-aminopyrrolidine amides with asserted utility in treating diabetes mellitus via DPP-IV inhibition. The patent's claims encompass specific chemical structures, pharmaceutical compositions, and methods of treatment. The technology is situated within a highly competitive patent landscape dominated by major pharmaceutical entities. Given its 1996 issue date, Patent 5,543,152 has likely expired, reducing direct licensing and litigation risk from this specific patent. However, extensive follow-on patenting in the DPP-IV inhibitor space by companies like Pfizer, Merck, Bristol-Myers Squibb, and Takeda necessitates thorough freedom-to-operate analyses for any new entrants or product development. Frequently Asked Questions What is the specific chemical structure claimed in Patent 5,543,152? Patent 5,543,152 claims compounds of a specific general formula involving a 3-aminopyrrolidine core substituted with an amide moiety where the nitrogen of the amide is attached to an aromatic or heteroaromatic ring, and the pyrrolidine ring may have further substituents. The precise details of these substituents (R1, R2, X) and stereochemistry are specified in the claims. Has any drug been approved and marketed based on the technology disclosed in Patent 5,543,152? While the patent claims a class of compounds for treating diabetes, specific approved drugs directly tracing their origin to this foundational patent require detailed analysis of subsequent patent filings by Pfizer and its predecessors. The DPP-IV inhibitor class includes blockbuster drugs, but their specific patent coverage may stem from later, more specific patents. How does DPP-IV inhibition work to treat diabetes? DPP-IV is an enzyme that breaks down incretin hormones (GLP-1 and GIP). These hormones stimulate insulin release and reduce glucagon secretion in a glucose-dependent manner. By inhibiting DPP-IV, the claimed compounds increase the levels of active incretin hormones, thereby improving blood glucose control in diabetic patients. What is the geographical scope of Patent 5,543,152? The patent number "United States Patent 5,543,152" indicates that the patent's protection is limited to the United States. To assess international protection, corresponding patent applications and grants in other countries would need to be examined. Can a company still develop and sell generic versions of drugs if the original patent has expired? If Patent 5,543,152 has expired and a specific drug compound claimed by it has also had its compound patents expire, generic manufacturers may be able to produce and sell that drug. However, they must ensure they do not infringe on any other valid patents that may cover formulations, methods of use, manufacturing processes, or new chemical forms of the drug that are still in force. Citations [1] Parke-Davis Pharmaceutical Research, Inc. (1996). Amides of 3-aminopyrrolidine. U.S. Patent 5,543,152. Washington, DC: U.S. Patent and Trademark Office. More… ↓ ⤷ Start Trial

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Details for Patent: 5,543,152

Summary for Patent: 5,543,152