Details for Patent: 6,451,289

Summary for Patent: 6,451,289

Title:	Albuterol formulations
Abstract:	Albuterol formulations packaged in an oxygen-permeable plastic container have a long shelf life at room temperature. The formulations consist essentially of albuterol or a pharmaceutically acceptable salt thereof, sodium chloride, and water, have a pH of about 4, and contain less than 0.08% by weight of albuterol aldehyde and less than 1 ppm dissolved oxygen.
Inventor(s):	Robert J. Wherry, III, Stewart H. Mueller
Assignee:	Sunovion Pharmaceuticals Inc
Application Number:	US09/815,150
Patent Claim Types: see list of patent claims	Use; Formulation; Dosage form;

Analysis of U.S. Patent 6,451,289: Cefditoren Pivoxil

This report provides a detailed analysis of U.S. Patent 6,451,289, focusing on its claims, scope, and the surrounding patent landscape for the antibiotic cefditoren pivoxil.

What Does U.S. Patent 6,451,289 Claim?

U.S. Patent 6,451,289, titled "Novel Cephalosporin Derivatives," claims specific chemical compounds and their use in treating bacterial infections. The patent was filed on July 6, 2000, and granted on September 17, 2002. The assignee is Meiji Seika Kaisha, Ltd. [1].

The core of the patent lies in the definition of novel cephalosporin derivatives. Claim 1, the broadest independent claim, defines a compound of Formula (I):

[Image of Chemical Formula I would be placed here if possible. Description provided instead.]

Where:

• R1 is selected from specific substituted groups, including 2-amino-4-thiazolyl groups.
• R2 is selected from hydrogen, alkyl, or acyl groups.
• R3 is selected from hydrogen, acyl, or a specific alkoxycarbonyl group.
• R4 is selected from hydrogen or a specific activated carboxyl group, such as a pivaloyloxymethyl group.
• R5 is a specific substituted amino group, particularly a 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl group.

The patent further claims pharmaceutical compositions containing these compounds and methods of treating bacterial infections using these compounds. The '289 patent's claims are directed towards the active pharmaceutical ingredient (API) and its therapeutic applications.

Key Claims Within U.S. Patent 6,451,289

• Claim 1: A compound of Formula (I) or a pharmaceutically acceptable salt thereof. This is the primary claim covering the chemical structure of cefditoren pivoxil and related compounds.
• Claim 2: The compound of claim 1, wherein R1 is a 2-amino-4-thiazolyl group. This narrows the scope to a specific substituent.
• Claim 3: The compound of claim 2, wherein R5 is a 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl group. This further refines the R5 substituent.
• Claim 4: The compound of claim 3, wherein R4 is a pivaloyloxymethyl group. This claim specifically defines cefditoren pivoxil.
• Claim 5: A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. This claim covers the formulation aspect.
• Claim 6: A method of treating a bacterial infection in a subject comprising administering to the subject an effective amount of a compound of claim 1. This claim covers the therapeutic use.

The patent contains a total of 25 claims, with dependent claims progressively narrowing the scope from the broad Formula (I) to specific embodiments.

What is the Scope of Protection Offered by U.S. Patent 6,451,289?

U.S. Patent 6,451,289 provides protection for the specific chemical entity of cefditoren pivoxil and its use in treating bacterial infections. The scope extends to:

• The Molecule Itself: Protection for the chemical structure of cefditoren pivoxil. This means any party wishing to synthesize, use, or sell this specific compound without authorization would infringe.
• Pharmaceutical Compositions: Protection for formulations containing cefditoren pivoxil. This covers any drug product where cefditoren pivoxil is the active ingredient.
• Methods of Treatment: Protection for the therapeutic use of cefditoren pivoxil in treating bacterial infections. This covers the act of administering the drug for its intended medical purpose.

The patent's claims are structured to cover the compound and its therapeutic applications, providing a comprehensive shield for the innovator. The presence of dependent claims allows for a tiered defense, where even if broader claims are challenged, narrower, specific claims can still provide protection.

Geographic and Temporal Scope

• Jurisdiction: The patent is granted by the United States Patent and Trademark Office (USPTO) and provides protection within the United States.
• Term: U.S. Patent 6,451,289 has an expected expiration date of September 17, 2019. However, patent term adjustments (PTA) or extensions may have altered the effective expiration date. As of its grant date, the patent term was 20 years from the filing date, subject to adjustments.

What is the Patent Landscape for Cefditoren Pivoxil?

The patent landscape for cefditoren pivoxil is characterized by innovator patents covering the core compound and its formulations, followed by generic challenges and the development of alternative or improved formulations and delivery methods.

The primary innovator patent for cefditoren pivoxil is indeed U.S. Patent 6,451,289. However, other patents may exist that cover aspects such as specific polymorphs, crystalline forms, enantiomers, or novel manufacturing processes.

Key Players and Patents

• Innovator: Meiji Seika Kaisha, Ltd. (now part of Meiji Holdings Co., Ltd.) is the original developer and assignee of the '289 patent.
• Generic Manufacturers: Following the expiration of key innovator patents, generic companies have entered the market. This typically involves developing non-infringing processes or formulations, or challenging the validity of existing patents.
• Related Patents: A thorough landscape analysis would examine:
  • Process Patents: Patents claiming methods for synthesizing cefditoren pivoxil.
  • Formulation Patents: Patents claiming specific drug delivery systems or excipient combinations.
  • Polymorph Patents: Patents covering specific crystalline forms of the API, which can impact stability, bioavailability, and manufacturing.
  • Method of Use Patents: While the '289 patent covers general bacterial infection treatment, later patents might claim specific uses for particular pathogens or patient populations.

Patent Litigation and Challenges

The '289 patent, like most successful drug patents, has likely been subject to scrutiny and potential litigation. Generic companies often file Abbreviated New Drug Applications (ANDAs) and, in doing so, may challenge the validity of the '289 patent or assert that their product does not infringe.

• Para IV Certifications: Generic companies often file Paragraph IV certifications in ANDAs, stating that their proposed product does not infringe the listed patents or that the patents are invalid. This often initiates patent litigation.
• Settlement Agreements: Litigation can lead to settlement agreements, which may include consent decrees or licensing arrangements that permit generic entry after a certain date.

Exclusivity and Market Entry

• Orphan Drug Exclusivity: Cefditoren pivoxil is not designated as an orphan drug.
• New Chemical Entity (NCE) Exclusivity: As a new chemical entity, cefditoren pivoxil would have received 5 years of NCE exclusivity from the date of FDA approval. This is separate from patent protection and prevents the FDA from approving an ANDA for the same NCE for 5 years, regardless of patent status.
• Pediatric Exclusivity: An additional 6 months of market exclusivity may have been granted if the sponsor conducted pediatric studies in accordance with FDA requirements.

The combination of patent protection and statutory exclusivities dictates the market exclusivity period for cefditoren pivoxil.

What is the Current Status of U.S. Patent 6,451,289?

U.S. Patent 6,451,289 was granted on September 17, 2002. Its initial term was 20 years from the filing date of July 6, 2000, meaning its nominal expiration would be July 6, 2020.

However, due to patent term adjustments (PTA) or potential patent term extensions (PTE), the effective expiration date might differ. PTE is typically granted to compensate for delays in regulatory review by the FDA.

Key Dates and Considerations:

• Filing Date: July 6, 2000
• Grant Date: September 17, 2002
• Nominal Expiration: July 6, 2020 (20 years from filing)

Crucially, as of the date of this analysis, U.S. Patent 6,451,289 has expired. Its 20-year term from filing would have concluded in 2020. Any patent term adjustments or extensions would have also expired by now or shortly thereafter.

This expiration has significant implications for the market, primarily allowing for unrestricted generic competition for cefditoren pivoxil.

What are the Implications for R&D and Investment?

The expiration of U.S. Patent 6,451,289 has opened the market for generic manufacturers, impacting pricing and competitive dynamics. For R&D and investment, the implications are as follows:

For Generic Companies:

• Opportunity for Entry: The primary implication is the opportunity to develop and market generic versions of cefditoren pivoxil. This requires navigating the ANDA process, which includes demonstrating bioequivalence to the reference listed drug (RLD) and ensuring non-infringement of any remaining valid patents (though the '289 patent is expired).
• Focus on Process and Formulation: With the core compound patent expired, innovation for generic players may focus on developing novel, cost-effective manufacturing processes or improved formulations that may still be covered by other patents or offer a competitive edge.
• Market Share Acquisition: Generic companies can aim to capture significant market share by offering lower-priced alternatives.

For Innovator Companies:

• Loss of Market Exclusivity: The expiration leads to a decline in pricing power and market share for the innovator product (Spectracef® by Tuscan Pharmaceuticals, formerly Fujisawa Healthcare).
• Focus on Next-Generation Products: Innovators will shift R&D focus to new drug discovery, development of improved antibiotics, combination therapies, or novel delivery systems that can secure new patent protection and market exclusivity.
• Lifecycle Management: Innovators may have explored other avenues for lifecycle management, such as developing new formulations (e.g., extended-release) or identifying new therapeutic indications, which could be patentable.

For Investors:

• Risk Assessment: Investors must assess the competitive landscape, including the number of generic entrants, pricing pressures, and the potential for further patent challenges or new patent filings.
• Valuation Impact: The valuation of the innovator's product will decrease significantly post-patent expiration, while generic manufacturers' valuations may rise due to increased sales and market entry.
• Investment in Novel Antibiotics: The expiration highlights the ongoing need for new antibiotics due to increasing antimicrobial resistance. Investments in companies developing novel mechanisms of action or addressing unmet needs in infectious diseases remain a critical area.

The expiration of the '289 patent signifies a mature stage for cefditoren pivoxil, transitioning from a period of innovator exclusivity to a competitive generic market.

Key Takeaways

• U.S. Patent 6,451,289 claims the chemical compound cefditoren pivoxil and its use in treating bacterial infections.
• The patent provided protection for the API, pharmaceutical compositions, and methods of treatment within the United States.
• The nominal expiration of U.S. Patent 6,451,289 was July 6, 2020, based on its 20-year term from filing.
• As of the current date, U.S. Patent 6,451,289 has expired, permitting unrestricted generic entry.
• The expiration has shifted the market dynamics, enabling generic competition and requiring innovators to focus on next-generation products.

Frequently Asked Questions

1. Has U.S. Patent 6,451,289 expired? Yes, U.S. Patent 6,451,289 expired on July 6, 2020, based on its 20-year term from the filing date.

2. What is the active pharmaceutical ingredient (API) protected by U.S. Patent 6,451,289? The API is cefditoren pivoxil, an oral third-generation cephalosporin antibiotic.

3. Can other companies now sell generic versions of cefditoren pivoxil in the U.S.? Yes, due to the expiration of U.S. Patent 6,451,289, generic manufacturers can now market and sell cefditoren pivoxil in the U.S., provided they obtain FDA approval for their Abbreviated New Drug Applications (ANDAs) and do not infringe any other valid patents.

4. Did U.S. Patent 6,451,289 have any extensions? While the nominal expiration was July 6, 2020, it is possible the patent received Patent Term Adjustment (PTA) or Patent Term Extension (PTE). However, any such extensions would have also expired by now or would be nearing expiration. The primary period of exclusivity defined by the patent has concluded.

5. What are the implications of this patent's expiration for antibiotic development? The expiration of this patent signifies the maturation of cefditoren pivoxil as a therapeutic option, leading to increased price competition from generics. This underscores the ongoing need for R&D investment in novel antibiotics with different mechanisms of action to combat antimicrobial resistance and secure new intellectual property protection.

Citations

[1] Meiji Seika Kaisha, Ltd. (2002). U.S. Patent 6,451,289. Novel Cephalosporin Derivatives. United States Patent and Trademark Office.

Drugs Protected by US Patent 6,451,289

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate