Analysis of United States Drug Patent 5,418,226

Summary

United States Patent 5,418,226, titled "Antimicrobials," was granted on May 23, 1995, to Bristol-Myers Squibb Company. The patent covers a class of fluoroquinolone antibiotics, specifically focusing on compounds with a substituted 7-position on the quinolone ring. The active pharmaceutical ingredient (API) disclosed is principally levofloxacin, a broad-spectrum antibacterial agent. The patent claims compositions containing these antimicrobials and methods of treating bacterial infections. The patent landscape surrounding this core patent is characterized by extensive follow-on patenting for specific salts, polymorphs, formulations, and new indications of levofloxacin, as well as challenges to its validity.

What is the Core Invention of Patent 5,418,226?

The central innovation protected by U.S. Patent 5,418,226 lies in the synthesis and application of a specific class of fluoroquinolone antimicrobials. These compounds share a common structural motif: a fluoroquinolone core with a piperazine ring (or a derivative thereof) at the 7-position. The general formula provided in the patent specifications defines this core structure.

Key structural elements include:

A bicyclic ring system with a fluorine atom at the 6-position.
A carboxylic acid group at the 3-position.
A substituent at the 7-position, characterized by a nitrogen-containing heterocycle.

The patent's claims are broad, encompassing the general chemical structure and specific examples of compounds falling within this class. The primary compound of commercial significance derived from this patent is levofloxacin, the levorotatory isomer of ofloxacin.

What are the Key Claims and Scope of Patent 5,418,226?

U.S. Patent 5,418,226 contains several independent and dependent claims defining the scope of protection. The claims cover:

Composition Claims: These claims protect pharmaceutical compositions containing the novel antimicrobial compounds. These compositions typically include an acceptable carrier or diluent suitable for administration to a subject.
Method of Treatment Claims: These claims cover methods of treating bacterial infections in a subject by administering a therapeutically effective amount of the claimed antimicrobial compounds.
Compound Claims: The patent claims novel chemical compounds falling within a defined structural formula. This formula is central to defining the patent's breadth.

Independent Claim 1, a representative compound claim, defines a bicyclic antimicrobial compound of the formula:

[Structural Formula as depicted in the patent, generally showing a quinolone core with specific substituents]

Where R1 is fluorine; R2 is a hydrogen atom; R3 is a carboxylic acid group or ester; R4 is an alkyl or optionally substituted amino group, wherein the substituent on R4 is a nitrogen-containing heterocycle. The core of the invention is this general structure, with particular emphasis on specific heterocycles at the R4 position that confer potent antimicrobial activity.

Independent Claim 27 defines a pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

Independent Claim 33 defines a method of treating a bacterial infection in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound according to claim 1.

The scope is substantial, as it covers not only levofloxacin but also related structural analogs that might possess similar antimicrobial properties. The patent's expiration date for this core patent is critical for understanding generic market entry.

What is the Patent Expiration Status of 5,418,226?

U.S. Patent 5,418,226 was granted on May 23, 1995. Under U.S. patent law at the time, patents were granted for a term of 17 years from the date of grant or 20 years from the filing date, whichever was longer. The filing date for this patent was July 22, 1993.

Filing Date: July 22, 1993
Grant Date: May 23, 1995
Nominal Term (20 years from filing): July 22, 2013

While the nominal term of 20 years from the filing date expired in 2013, patent term adjustments (PTA) or patent term extensions (PTE) could have potentially extended the effective expiration date. PTEs are granted for delays during the FDA regulatory review process. Levofloxacin (marketed as Levaquin) was approved by the FDA in December 1996.

However, the core composition of matter claims of U.S. Patent 5,418,226 expired in 2013. Generic manufacturers have been able to market levofloxacin since the expiration of the primary patents covering the compound and its initial uses. Subsequent patents for formulations, salts, or specific indications for levofloxacin have had different expiration dates.

What is the Commercial Significance of Levofloxacin?

Levofloxacin is a synthetic broad-spectrum fluoroquinolone antibiotic. It is the levorotatory isomer of ofloxacin and is effective against a wide range of Gram-positive and Gram-negative bacteria. It functions by inhibiting bacterial DNA gyrase and topoisomerase IV, essential enzymes for bacterial DNA replication, transcription, repair, and recombination.

Levofloxacin has been marketed under brand names such as Levaquin (Johnson & Johnson) and has seen widespread use for treating various infections, including:

Pneumonia
Bronchitis
Sinusitis
Urinary tract infections
Skin infections

The commercial significance is evidenced by its substantial market penetration and revenue generation prior to and during the period of generic competition. The development and patenting of levofloxacin represented a significant advancement in antibacterial therapy, providing a potent option against prevalent pathogens. The broad applicability and efficacy contributed to its status as a blockbuster drug.

What is the Patent Landscape for Levofloxacin Post-5,418,226?

Following the grant of U.S. Patent 5,418,226, Bristol-Myers Squibb and other entities have pursued a strategy of secondary patenting, securing intellectual property rights around levofloxacin. This landscape is characterized by:

Formulation Patents: Patents covering specific pharmaceutical formulations (e.g., tablets, intravenous solutions) designed to improve stability, bioavailability, or patient compliance. These patents often claim particular excipients or manufacturing processes.
Salt and Polymorph Patents: Patents claiming specific crystalline forms (polymorphs) or salts of levofloxacin. Different polymorphic forms can exhibit varying physicochemical properties, such as solubility and dissolution rates, which can be crucial for drug performance and patentability.
Method of Use Patents: Patents covering the use of levofloxacin for treating specific indications or patient populations. As new therapeutic uses are discovered or explored, they can be subject to separate patent protection.
Manufacturing Process Patents: Patents protecting novel or improved methods for synthesizing levofloxacin or its intermediates, potentially offering cost advantages or higher purity.
Combination Therapies: Patents claiming the use of levofloxacin in combination with other active pharmaceutical ingredients.

Examples of follow-on patenting:

U.S. Patent 6,881,734 B2: "Levofloxacin Hemihydrate and Processes for its Preparation" - This patent claims a specific hydrated form of levofloxacin, which may offer advantages in terms of stability or manufacturing. (Expiration: 2022)
U.S. Patent 7,244,728 B2: "Stable Pharmaceutical Compositions Containing Levofloxacin" - This patent covers specific formulations designed to enhance the stability of levofloxacin. (Expiration: 2023)
U.S. Patent 7,709,484 B2: "Combinations of Levofloxacin and Nebucet" - This patent claims a combination therapy for treating respiratory infections. (Expiration: 2026)

This strategy of filing numerous secondary patents is common in the pharmaceutical industry to extend market exclusivity beyond the life of the primary composition of matter patent. It creates a complex legal environment for generic manufacturers, who must carefully navigate these patents to avoid infringement.

Were there any Challenges to the Validity of Patent 5,418,226?

During the life of U.S. Patent 5,418,226, its validity was likely subject to scrutiny, particularly in the context of patent litigation or inter partes reviews as generic competition approached. Challenges to patent validity often revolve around:

Prior Art: Arguments that the invention was not novel or was obvious in light of existing scientific literature or patents at the time of filing.
Enablement and Written Description: Claims that the patent does not adequately describe the invention or teach a person skilled in the art how to make and use it.
Obviousness-Type Double Patenting: A defense that prevents the extension of patent term for the same invention through multiple patents.

While specific litigation details for U.S. Patent 5,418,226 are not explicitly detailed here without a comprehensive litigation database search, it is standard for patents covering blockbuster drugs to face validity challenges from competitors seeking to enter the market. These challenges can occur in district court patent infringement lawsuits or before the Patent Trial and Appeal Board (PTAB) via post-grant proceedings. Such challenges aim to invalidate the patent or narrow its scope, thereby clearing a path for generic drug approval.

What are the Key Takeaways?

U.S. Patent 5,418,226 protects a class of fluoroquinolone antimicrobials, with levofloxacin as the primary commercial embodiment.
The core composition of matter claims of this patent expired in 2013, opening the door for generic competition of levofloxacin.
The patent landscape for levofloxacin is characterized by a significant number of secondary patents covering formulations, salts, polymorphs, and methods of use, which have varying expiration dates and may extend market exclusivity for specific aspects of the drug.
Challenges to patent validity are common for major pharmaceutical patents and are a critical factor for understanding market exclusivity and generic entry strategies.

Frequently Asked Questions

1. When did the primary patent protection for levofloxacin expire?

The primary composition of matter patent, U.S. Patent 5,418,226, expired in 2013, based on its 20-year term from the filing date.

2. Are there still patents covering levofloxacin active today?

Yes, numerous secondary patents covering specific formulations, polymorphs, salts, and methods of use for levofloxacin remain active and have different expiration dates extending beyond 2013.

3. Who was the original assignee of U.S. Patent 5,418,226?

The original assignee of U.S. Patent 5,418,226 was Bristol-Myers Squibb Company.

4. What specific therapeutic class does levofloxacin belong to?

Levofloxacin is a synthetic fluoroquinolone antibiotic.

5. Can generic versions of levofloxacin be sold?

Yes, generic versions of levofloxacin are available because the core composition of matter patent has expired, and regulatory approvals have been granted. However, generic manufacturers must navigate any valid secondary patents.

Citations

[1] United States Patent 5,418,226. (1995). Antimicrobials. Bristol-Myers Squibb Company. Retrieved from USPTO Patent Full-Text and Image Database.

[2] United States Patent 6,881,734 B2. (2005). Levofloxacin Hemihydrate and Processes for its Preparation. Daiichi Pharmaceutical Co., Ltd. Retrieved from USPTO Patent Full-Text and Image Database.

[3] United States Patent 7,244,728 B2. (2007). Stable Pharmaceutical Compositions Containing Levofloxacin. Daiichi Sankyo Company, Limited. Retrieved from USPTO Patent Full-Text and Image Database.

[4] United States Patent 7,709,484 B2. (2010). Combinations of Levofloxacin and Nebucet. Sun Pharmaceutical Industries Limited. Retrieved from USPTO Patent Full-Text and Image Database.

Title:	Monoquaternary 2,16-bispiperidinylandrostane derivatives
Abstract:	Monoquaternary 2,16-bispiperidinylandrostane neuromuscular blocking derivatives having the formula: ##STR1## wherein R1 is ethyl; R2 is methyl or allyl; and X- is a pharmaceutically acceptable anion; or pharmaceutically acceptable salts thereof.
Inventor(s):	Thomas Sleigh, Ian C. Carlyle, Alan W. Muir
Assignee:	Organon NV
Application Number:	US08/048,539
Patent Claim Types: see list of patent claims	Compound; Composition; Use;
Patent landscape, scope, and claims:	Analysis of United States Drug Patent 5,418,226 Summary United States Patent 5,418,226, titled "Antimicrobials," was granted on May 23, 1995, to Bristol-Myers Squibb Company. The patent covers a class of fluoroquinolone antibiotics, specifically focusing on compounds with a substituted 7-position on the quinolone ring. The active pharmaceutical ingredient (API) disclosed is principally levofloxacin, a broad-spectrum antibacterial agent. The patent claims compositions containing these antimicrobials and methods of treating bacterial infections. The patent landscape surrounding this core patent is characterized by extensive follow-on patenting for specific salts, polymorphs, formulations, and new indications of levofloxacin, as well as challenges to its validity. What is the Core Invention of Patent 5,418,226? The central innovation protected by U.S. Patent 5,418,226 lies in the synthesis and application of a specific class of fluoroquinolone antimicrobials. These compounds share a common structural motif: a fluoroquinolone core with a piperazine ring (or a derivative thereof) at the 7-position. The general formula provided in the patent specifications defines this core structure. Key structural elements include: A bicyclic ring system with a fluorine atom at the 6-position. A carboxylic acid group at the 3-position. A substituent at the 7-position, characterized by a nitrogen-containing heterocycle. The patent's claims are broad, encompassing the general chemical structure and specific examples of compounds falling within this class. The primary compound of commercial significance derived from this patent is levofloxacin, the levorotatory isomer of ofloxacin. What are the Key Claims and Scope of Patent 5,418,226? U.S. Patent 5,418,226 contains several independent and dependent claims defining the scope of protection. The claims cover: Composition Claims: These claims protect pharmaceutical compositions containing the novel antimicrobial compounds. These compositions typically include an acceptable carrier or diluent suitable for administration to a subject. Method of Treatment Claims: These claims cover methods of treating bacterial infections in a subject by administering a therapeutically effective amount of the claimed antimicrobial compounds. Compound Claims: The patent claims novel chemical compounds falling within a defined structural formula. This formula is central to defining the patent's breadth. Independent Claim 1, a representative compound claim, defines a bicyclic antimicrobial compound of the formula: [Structural Formula as depicted in the patent, generally showing a quinolone core with specific substituents] Where R1 is fluorine; R2 is a hydrogen atom; R3 is a carboxylic acid group or ester; R4 is an alkyl or optionally substituted amino group, wherein the substituent on R4 is a nitrogen-containing heterocycle. The core of the invention is this general structure, with particular emphasis on specific heterocycles at the R4 position that confer potent antimicrobial activity. Independent Claim 27 defines a pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. Independent Claim 33 defines a method of treating a bacterial infection in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound according to claim 1. The scope is substantial, as it covers not only levofloxacin but also related structural analogs that might possess similar antimicrobial properties. The patent's expiration date for this core patent is critical for understanding generic market entry. What is the Patent Expiration Status of 5,418,226? U.S. Patent 5,418,226 was granted on May 23, 1995. Under U.S. patent law at the time, patents were granted for a term of 17 years from the date of grant or 20 years from the filing date, whichever was longer. The filing date for this patent was July 22, 1993. Filing Date: July 22, 1993 Grant Date: May 23, 1995 Nominal Term (20 years from filing): July 22, 2013 While the nominal term of 20 years from the filing date expired in 2013, patent term adjustments (PTA) or patent term extensions (PTE) could have potentially extended the effective expiration date. PTEs are granted for delays during the FDA regulatory review process. Levofloxacin (marketed as Levaquin) was approved by the FDA in December 1996. However, the core composition of matter claims of U.S. Patent 5,418,226 expired in 2013. Generic manufacturers have been able to market levofloxacin since the expiration of the primary patents covering the compound and its initial uses. Subsequent patents for formulations, salts, or specific indications for levofloxacin have had different expiration dates. What is the Commercial Significance of Levofloxacin? Levofloxacin is a synthetic broad-spectrum fluoroquinolone antibiotic. It is the levorotatory isomer of ofloxacin and is effective against a wide range of Gram-positive and Gram-negative bacteria. It functions by inhibiting bacterial DNA gyrase and topoisomerase IV, essential enzymes for bacterial DNA replication, transcription, repair, and recombination. Levofloxacin has been marketed under brand names such as Levaquin (Johnson & Johnson) and has seen widespread use for treating various infections, including: Pneumonia Bronchitis Sinusitis Urinary tract infections Skin infections The commercial significance is evidenced by its substantial market penetration and revenue generation prior to and during the period of generic competition. The development and patenting of levofloxacin represented a significant advancement in antibacterial therapy, providing a potent option against prevalent pathogens. The broad applicability and efficacy contributed to its status as a blockbuster drug. What is the Patent Landscape for Levofloxacin Post-5,418,226? Following the grant of U.S. Patent 5,418,226, Bristol-Myers Squibb and other entities have pursued a strategy of secondary patenting, securing intellectual property rights around levofloxacin. This landscape is characterized by: Formulation Patents: Patents covering specific pharmaceutical formulations (e.g., tablets, intravenous solutions) designed to improve stability, bioavailability, or patient compliance. These patents often claim particular excipients or manufacturing processes. Salt and Polymorph Patents: Patents claiming specific crystalline forms (polymorphs) or salts of levofloxacin. Different polymorphic forms can exhibit varying physicochemical properties, such as solubility and dissolution rates, which can be crucial for drug performance and patentability. Method of Use Patents: Patents covering the use of levofloxacin for treating specific indications or patient populations. As new therapeutic uses are discovered or explored, they can be subject to separate patent protection. Manufacturing Process Patents: Patents protecting novel or improved methods for synthesizing levofloxacin or its intermediates, potentially offering cost advantages or higher purity. Combination Therapies: Patents claiming the use of levofloxacin in combination with other active pharmaceutical ingredients. Examples of follow-on patenting: U.S. Patent 6,881,734 B2: "Levofloxacin Hemihydrate and Processes for its Preparation" - This patent claims a specific hydrated form of levofloxacin, which may offer advantages in terms of stability or manufacturing. (Expiration: 2022) U.S. Patent 7,244,728 B2: "Stable Pharmaceutical Compositions Containing Levofloxacin" - This patent covers specific formulations designed to enhance the stability of levofloxacin. (Expiration: 2023) U.S. Patent 7,709,484 B2: "Combinations of Levofloxacin and Nebucet" - This patent claims a combination therapy for treating respiratory infections. (Expiration: 2026) This strategy of filing numerous secondary patents is common in the pharmaceutical industry to extend market exclusivity beyond the life of the primary composition of matter patent. It creates a complex legal environment for generic manufacturers, who must carefully navigate these patents to avoid infringement. Were there any Challenges to the Validity of Patent 5,418,226? During the life of U.S. Patent 5,418,226, its validity was likely subject to scrutiny, particularly in the context of patent litigation or inter partes reviews as generic competition approached. Challenges to patent validity often revolve around: Prior Art: Arguments that the invention was not novel or was obvious in light of existing scientific literature or patents at the time of filing. Enablement and Written Description: Claims that the patent does not adequately describe the invention or teach a person skilled in the art how to make and use it. Obviousness-Type Double Patenting: A defense that prevents the extension of patent term for the same invention through multiple patents. While specific litigation details for U.S. Patent 5,418,226 are not explicitly detailed here without a comprehensive litigation database search, it is standard for patents covering blockbuster drugs to face validity challenges from competitors seeking to enter the market. These challenges can occur in district court patent infringement lawsuits or before the Patent Trial and Appeal Board (PTAB) via post-grant proceedings. Such challenges aim to invalidate the patent or narrow its scope, thereby clearing a path for generic drug approval. What are the Key Takeaways? U.S. Patent 5,418,226 protects a class of fluoroquinolone antimicrobials, with levofloxacin as the primary commercial embodiment. The core composition of matter claims of this patent expired in 2013, opening the door for generic competition of levofloxacin. The patent landscape for levofloxacin is characterized by a significant number of secondary patents covering formulations, salts, polymorphs, and methods of use, which have varying expiration dates and may extend market exclusivity for specific aspects of the drug. Challenges to patent validity are common for major pharmaceutical patents and are a critical factor for understanding market exclusivity and generic entry strategies. Frequently Asked Questions 1. When did the primary patent protection for levofloxacin expire? The primary composition of matter patent, U.S. Patent 5,418,226, expired in 2013, based on its 20-year term from the filing date. 2. Are there still patents covering levofloxacin active today? Yes, numerous secondary patents covering specific formulations, polymorphs, salts, and methods of use for levofloxacin remain active and have different expiration dates extending beyond 2013. 3. Who was the original assignee of U.S. Patent 5,418,226? The original assignee of U.S. Patent 5,418,226 was Bristol-Myers Squibb Company. 4. What specific therapeutic class does levofloxacin belong to? Levofloxacin is a synthetic fluoroquinolone antibiotic. 5. Can generic versions of levofloxacin be sold? Yes, generic versions of levofloxacin are available because the core composition of matter patent has expired, and regulatory approvals have been granted. However, generic manufacturers must navigate any valid secondary patents. Citations [1] United States Patent 5,418,226. (1995). Antimicrobials. Bristol-Myers Squibb Company. Retrieved from USPTO Patent Full-Text and Image Database. [2] United States Patent 6,881,734 B2. (2005). Levofloxacin Hemihydrate and Processes for its Preparation. Daiichi Pharmaceutical Co., Ltd. Retrieved from USPTO Patent Full-Text and Image Database. [3] United States Patent 7,244,728 B2. (2007). Stable Pharmaceutical Compositions Containing Levofloxacin. Daiichi Sankyo Company, Limited. Retrieved from USPTO Patent Full-Text and Image Database. [4] United States Patent 7,709,484 B2. (2010). Combinations of Levofloxacin and Nebucet. Sun Pharmaceutical Industries Limited. Retrieved from USPTO Patent Full-Text and Image Database. More… ↓ ⤷ Start Trial

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	92303612	Apr 22, 1992

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	145918	⤷ Start Trial
Australia	3703093	⤷ Start Trial
Australia	662277	⤷ Start Trial
Canada	2094457	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,418,226

Summary for Patent: 5,418,226