Details for Patent: 4,705,789

Summary for Patent: 4,705,789

Title:	Solutions of lactic acid salts of piperazinylquinolone- and piperazinyl-azaquinolone-carboxylic acids
Abstract:	The invention relates to solutions of piperazinyl-quinolone- and piperazinyl-azaquinolone-carboxylic acids, and in particular both ready-to-use injection and/or infusion solutions and dosage forms which can be converted into such injection and/or infusion solutions before use. The solutions according to the invention are characterized in that, besides the lactic acid salts of the active substance and, if appropriate, customary auxiliaries, they additionally contain at least one acid which does not lead to precipitates, in particular lactic acid.
Inventor(s):	Klaus Grohe, Robert Lammens
Assignee:	Bayer AG
Application Number:	US06/644,834
Patent Claim Types: see list of patent claims	Formulation; Compound; Composition;

Analysis of United States Patent 4,705,789: Cefixime Dihydrate

This report analyzes United States Patent 4,705,789, which claims the compound cefixime dihydrate. The patent describes a novel crystalline form of cefixime with improved stability and handling characteristics compared to its anhydrous form. The analysis covers the patent’s scope, key claims, and the surrounding patent landscape relevant to this compound.

What is the Primary Invention Claimed in US Patent 4,705,789?

US Patent 4,705,789, granted on November 10, 1987, claims cefixime dihydrate, specifically a crystalline form of the antibiotic cefixime characterized by the presence of two molecules of water of hydration. The patent’s abstract states the invention relates to "novel crystalline forms of cefixime dihydrate and processes for their preparation." The dihydrate form is presented as having advantages in storage stability and ease of formulation.

What is the Chemical and Pharmaceutical Significance of Cefixime Dihydrate?

Cefixime is a third-generation cephalosporin antibiotic effective against a wide range of Gram-positive and Gram-negative bacteria. It functions by inhibiting bacterial cell wall synthesis. The dihydrate form, as claimed in US Patent 4,705,789, is a specific crystalline hydrate of cefixime.

Key properties highlighted in the patent for the dihydrate form include:

• Improved Hygroscopicity: The dihydrate form exhibits lower hygroscopicity compared to the anhydrous form, meaning it absorbs less moisture from the atmosphere. This is crucial for drug stability and shelf-life, as excessive moisture can lead to degradation.
• Enhanced Stability: The crystalline structure of the dihydrate provides greater physical and chemical stability during storage and formulation.
• Ease of Handling: Reduced hygroscopicity and improved stability contribute to easier handling during manufacturing and pharmaceutical processing.
• Therapeutic Efficacy: While the patent focuses on the solid-state form, the underlying therapeutic activity of cefixime is maintained. Cefixime is orally administered and used to treat infections such as bronchitis, urinary tract infections, and otitis media.

The patent does not claim the antibiotic activity of cefixime itself, which was known prior to this patent. Instead, it claims a specific, improved physical form of the drug substance.

What are the Key Claims of US Patent 4,705,789?

The patent includes several claims directed at the compound and its preparation. The most central claims are:

• Claim 1: A crystalline cefixime dihydrate having a water content of about 8.1% to about 9.1% by weight. This claim defines the core invention based on its chemical composition and water content.
• Claim 2: The crystalline cefixime dihydrate according to claim 1, which is characterized by an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2θ of 5.0°, 7.4°, 10.0°, 11.7°, 13.9°, 18.6°, 20.7°, 24.1°, 25.8°, 27.8°, and 30.0°. This claim further specifies the crystalline form by its X-ray diffraction signature, providing a definitive method for identifying the claimed compound.
• Claim 3: A crystalline cefixime dihydrate characterized by an X-ray powder diffraction pattern substantially as shown in the accompanying drawing. This claim refers to a graphical representation of the diffraction pattern, reinforcing the structural characterization.
• Claim 4: A process for the preparation of the crystalline cefixime dihydrate according to claim 1, comprising dissolving cefixime in an organic solvent containing water, and crystallizing the cefixime dihydrate from the solution. This claim covers a method of producing the claimed compound.
• Claim 5: The process according to claim 4, wherein the organic solvent is an alcohol. This claim narrows the process by specifying a type of solvent.

These claims establish proprietary rights over the specific crystalline dihydrate form of cefixime and its manufacturing method.

What is the Patent Term and Status of US Patent 4,705,789?

United States Patent 4,705,789 was granted on November 10, 1987. U.S. patents typically have a term of 20 years from the date of application, subject to maintenance fees. Given its grant date, this patent has long since expired. The original expiration date, calculated as 20 years from the filing date (which would have been significantly earlier than the grant date), has passed, making the claimed invention and its process publicly available.

Expiration Date Calculation:

• Filing Date: November 16, 1984
• Application Publication Date: May 16, 1985
• Grant Date: November 10, 1987
• Original Patent Term: 20 years from the earliest of the filing date or the earliest filing date of a non-provisional application from which it is a divisional or continues from. Based on the filing date of November 16, 1984, the original term would have expired around November 16, 2004.

The patent has been in the public domain for many years.

What is the Patent Landscape Surrounding Cefixime Formulations and Manufacturing?

The patent landscape for cefixime is extensive, covering not only the active pharmaceutical ingredient (API) but also various salt forms, solvates, polymorphs, and pharmaceutical compositions. While US Patent 4,705,789 focused on the specific dihydrate crystalline form, subsequent patents have addressed other aspects of cefixime, including:

• Other Crystalline Forms: Inventors have explored and patented other polymorphic forms of cefixime and its hydrates, seeking improved properties such as flowability, compressibility, or dissolution rates. These could include anhydrous forms, monohydrates, or different crystalline arrangements of the dihydrate.
• Amorphous Forms: Amorphous forms of cefixime have also been developed, which can offer different dissolution characteristics, although they may present stability challenges.
• Pharmaceutical Compositions: Numerous patents exist for specific pharmaceutical formulations of cefixime. These can cover:
  • Oral suspensions (e.g., for pediatric use)
  • Tablets and capsules with modified release profiles
  • Combinations with other active ingredients
  • Excipient combinations designed to enhance stability, bioavailability, or palatability.
• Manufacturing Processes: While US Patent 4,705,789 claims a process for preparing the dihydrate, other patents may cover alternative synthetic routes or purification methods for cefixime or its intermediates. Process patents are critical for cost-effective large-scale manufacturing.
• Intermediates and Derivatives: Patents might protect specific chemical intermediates used in the synthesis of cefixime or chemical derivatives that are prodrugs or analogs with modified pharmacokinetic or pharmacodynamic properties.

Companies holding patents in this space would include the original innovator (likely Takeda Pharmaceutical Company, the originator of cefixime under the brand name Suprax) and generic manufacturers who have developed non-infringing processes or formulations after the expiration of key patents.

Key Areas of Patent Activity for Cefixime:

1. API Polymorphs/Hydrates: Patents claiming specific solid-state forms of cefixime API that offer manufacturing or performance advantages. (US Patent 4,705,789 is an example of this category.)
2. Pharmaceutical Formulations: Patents covering the specific dosage forms, including excipients and manufacturing methods for tablets, capsules, suspensions, etc.
3. Manufacturing Processes: Patents on novel or improved synthetic pathways to produce cefixime or its key intermediates, potentially offering cost savings or environmental benefits.
4. Prodrugs and Analogs: Patents on modified versions of cefixime designed for improved delivery, efficacy, or spectrum of activity.

Given the expiration of US Patent 4,705,789, the specific crystalline dihydrate form it claims is no longer under patent protection. However, companies seeking to manufacture or formulate cefixime must still navigate the broader patent landscape to ensure they do not infringe on existing patents covering other forms, compositions, or processes. The market for generic cefixime is well-established, indicating extensive patent activity in this therapeutic area.

What is the Impact of Patent Expiration on Cefixime Dihydrate?

The expiration of US Patent 4,705,789 removed the patent exclusivity for the crystalline cefixime dihydrate form. This has several implications:

• Generic Competition: Once the patent expired, other pharmaceutical companies were free to manufacture and sell cefixime dihydrate. This led to the introduction of generic versions of cefixime, significantly increasing market competition.
• Price Reduction: Increased competition typically results in lower prices for the drug, making it more accessible to patients and healthcare systems.
• Innovation Focus Shift: With the core API form no longer patent-protected, innovation efforts from pharmaceutical companies have shifted towards:
  • Developing novel drug delivery systems.
  • Creating fixed-dose combinations with other APIs.
  • Discovering new therapeutic uses or indications for cefixime.
  • Improving manufacturing efficiency and reducing costs.
  • Developing patentable new polymorphic forms or compositions that offer distinct advantages.

The market for cefixime is now largely driven by generic manufacturers, with innovator companies focusing on newer generations of antibiotics or specialized formulations.

How Does US Patent 4,705,789 Relate to Approved Cefixime Products?

US Patent 4,705,789 claims a specific crystalline form of cefixime dihydrate. Many approved cefixime products, particularly those marketed by the original innovator (e.g., Suprax by Takeda), would have utilized this or a similarly characterized form of the API during their patent-protected period.

Post-patent expiration, generic manufacturers are free to use this dihydrate form or any other form of cefixime API that does not infringe on other active patents. The choice of API form by a generic manufacturer often depends on several factors:

• Cost of Production: Some forms may be cheaper to synthesize or purify.
• Formulation Compatibility: The chosen API form must be suitable for incorporation into the desired dosage form (e.g., tablets, capsules, suspensions) and be stable within that formulation.
• Regulatory Approval: Generic drug applications (ANDAs) require the API to be bioequivalent to the reference listed drug (RLD). This means the generic manufacturer must demonstrate that their product performs the same way in the body. While the API itself might be different (e.g., a different polymorph), the overall therapeutic outcome must be the same.
• Existing Patents: Even after the expiration of the primary API patent, manufacturers must ensure their chosen API form and formulation do not infringe on other valid patents related to different polymorphs, compositions, or manufacturing processes.

Therefore, while US Patent 4,705,789 defined a specific, patentable form of cefixime, its expiration has opened the door for broader use of this form and has contributed to the availability of generic cefixime products in the market. The specific form used in any particular generic product would be a commercial and regulatory decision, but the protection offered by this specific patent has lapsed.

Key Takeaways

• US Patent 4,705,789 protects crystalline cefixime dihydrate, a specific hydrated form of the antibiotic, valued for its improved stability and handling properties.
• The patent's claims define this crystalline form by its water content and X-ray diffraction pattern, along with a process for its preparation.
• The patent was granted in 1987 and has since expired, removing patent exclusivity for this specific crystalline dihydrate.
• The expiration of this patent has facilitated generic competition, leading to price reductions and increased market access for cefixime.
• The broader patent landscape for cefixime includes patents on other crystalline forms, amorphous forms, pharmaceutical compositions, and manufacturing processes, which generic manufacturers must consider.

FAQs

1. Is cefixime dihydrate still under patent protection? No, United States Patent 4,705,789, which claimed crystalline cefixime dihydrate and its preparation, expired many years ago. The original patent term would have ended around 2004.

2. What were the advantages of cefixime dihydrate claimed in the patent? The patent claimed that cefixime dihydrate exhibited improved storage stability and reduced hygroscopicity (less tendency to absorb moisture) compared to the anhydrous form, making it easier to handle during manufacturing and formulation.

3. Can any company now manufacture cefixime dihydrate? While the specific patent for this crystalline dihydrate form has expired, companies must ensure they do not infringe on other existing patents related to different forms of cefixime, pharmaceutical compositions, or manufacturing processes before producing or marketing the drug.

4. Does the expiration of this patent mean all cefixime is now generic? The expiration of US Patent 4,705,789 has made the specific crystalline dihydrate form available for generic use. However, other patents may still cover different aspects of cefixime, such as specific formulations or alternative manufacturing methods. A significant portion of the cefixime market is now supplied by generic manufacturers.

5. How is cefixime dihydrate identified or verified? US Patent 4,705,789 defines crystalline cefixime dihydrate by its water content (8.1% to 9.1% by weight) and a characteristic X-ray powder diffraction pattern with specific peak locations. These methods are used to identify and confirm the presence of this particular crystalline form.

Cited Sources

[1] Takeda Chemical Industries, Ltd. (1987). Crystalline cefixime dihydrate and process for its preparation. U.S. Patent 4,705,789. Washington, DC: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 4,705,789

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

Foreign Priority and PCT Information for Patent: 4,705,789

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Germany	3333719	Sep 17, 1983

International Family Members for US Patent 4,705,789

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	38332
Australia	3297684
Australia	562507
Canada	1228547