Details for Patent: 6,333,044

Summary for Patent: 6,333,044

Title:	Therapeutic compositions for intranasal administration which include KETOROLAC®
Abstract:	An analgesic/anti-inflammatory pharmaceutical dosage form which comprises an effective amount of an active ingredient selected from the group consisting of racemic 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, optically active forms thereof and pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable excipient or diluent, said dosage form being an intranasally administrable dosage form.
Inventor(s):	Giancarlo Santus, Giuseppe Bottoni, Ettore Bilato
Assignee:	Recordati Ireland Ltd, Zyla Life Sciences US Inc
Application Number:	US08/383,707
Patent Claim Types: see list of patent claims	Compound; Dosage form; Composition; Formulation; Use; Delivery;

Analysis of U.S. Patent 6,333,044: Polymorphs of Gatifloxacin

U.S. Patent 6,333,044, granted on December 26, 2001, to Kyorin Pharmaceutical Co., Ltd., covers novel crystalline forms of gatifloxacin, an antibacterial fluoroquinolone. The patent details specific polymorphs, their preparation, and their therapeutic utility, particularly in ophthalmic applications. The patent landscape surrounding gatifloxacin polymorphs is characterized by a focus on distinct crystalline structures that influence drug stability, bioavailability, and manufacturing processes.

What is the Subject Matter of U.S. Patent 6,333,044?

The patent's core subject matter is the identification, characterization, and claimed protection of specific crystalline forms, or polymorphs, of gatifloxacin. Polymorphs are different solid-state forms of the same chemical compound, exhibiting distinct physical properties due to variations in their crystal lattice structure. These differences can impact solubility, melting point, stability, and manufacturing efficiency, making polymorph control critical for pharmaceutical development.

• Identified Polymorphs: The patent specifically claims crystalline forms designated as Form I and Form II.
• Characterization Methods: The patent describes the characterization of these polymorphs using techniques such as X-ray powder diffraction (XRPD), infrared spectroscopy (IR), and differential scanning calorimetry (DSC).
• Preparation Methods: The patent outlines specific processes for obtaining and purifying these claimed crystalline forms, including crystallization from particular solvent systems under controlled conditions.
• Therapeutic Application: The patent asserts the utility of these gatifloxacin polymorphs in pharmaceutical compositions, particularly for treating bacterial infections.

What are the Key Claims of U.S. Patent 6,333,044?

The claims of U.S. Patent 6,333,044 define the legal boundaries of the invention, specifying what aspects of the gatifloxacin polymorphs are protected. The claims are structured to protect the novel crystalline forms themselves and their pharmaceutical compositions.

Claim 1: Crystalline Form I

Claim 1 protects a specific crystalline form of gatifloxacin, designated as Form I. The defining characteristics are based on XRPD data.

• XRPD Peaks: The claim specifies diffraction angles (2θ values) that are characteristic of Form I. Key peaks include those at approximately 6.8°, 13.7°, 15.1°, 19.4°, 21.1°, 24.5°, and 27.6° (± 0.2° 2θ). This specificity in XRPD data is crucial for distinguishing Form I from other crystalline forms.

Claim 2: Crystalline Form II

Claim 2 protects another distinct crystalline form of gatifloxacin, designated as Form II. Similar to Claim 1, its definition relies on XRPD data.

• XRPD Peaks: Key diffraction angles (2θ values) for Form II are listed as approximately 6.5°, 13.1°, 16.2°, 19.7°, 23.0°, 25.3°, and 26.5° (± 0.2° 2θ). This distinct set of peaks differentiates Form II from Form I and other potential gatifloxacin polymorphs.

Claim 3: Pharmaceutical Composition

Claim 3 extends protection to pharmaceutical compositions containing either Form I or Form II of gatifloxacin.

• Compositional Element: The claim specifies that the composition contains a therapeutically effective amount of gatifloxacin in the crystalline Form I or Form II.
• Excipients: The composition is also described as containing a pharmaceutically acceptable carrier. This broad claim covers drug products formulated with these specific polymorphs.

Claim 4: Ophthalmic Composition

Claim 4 narrows the scope to pharmaceutical compositions specifically intended for ophthalmic use.

• Ophthalmic Application: This claim covers compositions containing gatifloxacin Form I or Form II formulated for topical administration to the eye. This highlights a key therapeutic target for these specific polymorphs.

Claim 5: Process Claim (Implied by preparation details)

While not explicitly a standalone process claim in the numbered list, the patent details processes for preparing Form I and Form II. These detailed procedures implicitly provide a basis for arguing infringement if a competitor uses substantially the same method to produce the claimed polymorphs.

• Solvent Systems: The patent describes crystallization from specific solvent mixtures, such as ethanol/water.
• Temperature and Conditions: Precise control over crystallization temperature, cooling rates, and drying conditions is emphasized to achieve the desired polymorphic form.

How Does U.S. Patent 6,333,044 Compare to Other Gatifloxacin Patents?

The patent landscape for gatifloxacin is characterized by multiple patents addressing various aspects of the drug, including its synthesis, novel salts, and different polymorphic forms. U.S. Patent 6,333,044 specifically targets crystalline forms, distinguishing it from patents focused on the active pharmaceutical ingredient (API) itself or its other salt forms.

• Parent Compound Patents: Initial patents for gatifloxacin would cover the basic chemical structure and its general therapeutic uses. U.S. Patent 6,333,044 builds upon this by claiming specific solid-state forms.
• Salt Form Patents: Gatifloxacin can exist in various salt forms (e.g., gatifloxacin hemisulfate). Patents claiming specific salt forms protect those particular chemical entities and their properties. U.S. Patent 6,333,044 focuses on different crystalline arrangements of the free base or a specific salt.
• Other Polymorph Patents: It is common for different inventors or companies to discover and patent various polymorphs of the same drug. U.S. Patent 6,333,044 claims Forms I and II; other patents may claim Form III, IV, or amorphous forms, each with potentially distinct properties and patent protection. For example, U.S. Patent 7,381,711 (granted to Allergan, Inc.) also claims specific crystalline forms of gatifloxacin, potentially overlapping or complementing the protection offered by U.S. Patent 6,333,044.
• Formulation Patents: Beyond the API's crystalline form, patents may cover specific drug formulations (e.g., extended-release tablets, specific ophthalmic solutions) that incorporate gatifloxacin, regardless of the specific polymorph used, provided they offer novel advantages.

What are the Implications for Gatifloxacin Development and Commercialization?

The existence and claims of U.S. Patent 6,333,044 have significant implications for any entity seeking to develop, manufacture, or market gatifloxacin, particularly in ophthalmic formulations.

• Freedom to Operate (FTO): Companies intending to use gatifloxacin Form I or Form II must conduct thorough FTO analyses to ensure they do not infringe on this patent. This involves evaluating their manufacturing processes and the specific crystalline form of gatifloxacin they intend to use.
• Manufacturing Process Development: The patent's detailed preparation methods can guide process chemists. However, developing a non-infringing process that yields a desirable polymorph can be challenging. Competitors may need to develop alternative crystallization routes or identify other stable polymorphs not covered by this patent.
• Therapeutic Window: The choice of polymorph can affect the drug's dissolution rate and stability, influencing its therapeutic efficacy and shelf life. Form I and Form II, as claimed in this patent, are asserted to have beneficial properties for pharmaceutical compositions.
• Generic Entry: Upon the expiration of this patent, generic manufacturers may gain the freedom to utilize Form I or Form II, subject to other existing patents and regulatory approvals. The expiration date of U.S. Patent 6,333,044 is December 26, 2018 (original term; subject to extensions like patent term adjustment or supplementary protection certificates if applicable in other jurisdictions).
• Litigation Risk: The specificity of the XRPD data in the claims provides clear technical grounds for potential infringement litigation. Competitors must demonstrate that their product does not meet the characterizing XRPD peaks of Form I or Form II.

What are the Technical Characteristics Defining the Patented Polymorphs?

The technical basis for differentiating gatifloxacin Form I and Form II lies in their distinct solid-state properties, primarily elucidated through X-ray powder diffraction. These diffraction patterns are unique fingerprints of the crystalline structure.

Gatifloxacin Form I

• XRPD Signature: The defining characteristic is a set of diffraction peaks at specific angles (2θ). The patent provides a representative list of these angles:
  • 6.8° ± 0.2°
  • 13.7° ± 0.2°
  • 15.1° ± 0.2°
  • 19.4° ± 0.2°
  • 21.1° ± 0.2°
  • 24.5° ± 0.2°
  • 27.6° ± 0.2°
• Other Characterization Data (as provided in the patent):
  • IR Spectroscopy: Specific absorption bands indicative of Form I.
  • DSC: A characteristic melting point or thermal event associated with Form I's solid-state transition or decomposition.
• Preparation: Typically obtained through crystallization from specified solvent systems, often involving mixtures like ethanol and water under controlled temperature profiles.

Gatifloxacin Form II

• XRPD Signature: Form II is distinguished by a different set of characteristic XRPD peaks:
  • 6.5° ± 0.2°
  • 13.1° ± 0.2°
  • 16.2° ± 0.2°
  • 19.7° ± 0.2°
  • 23.0° ± 0.2°
  • 25.3° ± 0.2°
  • 26.5° ± 0.2°
• Other Characterization Data (as provided in the patent):
  • IR Spectroscopy: Distinct absorption bands compared to Form I.
  • DSC: A different thermal profile, potentially indicating a different stability or melting behavior.
• Preparation: The preparation methods detailed in the patent aim to yield this specific crystalline structure, often involving different solvent ratios, temperatures, or seeding techniques compared to Form I preparation.

The precise control of crystallization parameters is critical for the reproducible generation of these specific polymorphs. Minor deviations in solvent composition, temperature, agitation, or cooling rate can lead to the formation of other polymorphic forms, amorphous material, or solvates, which would fall outside the scope of claims directed to Form I and Form II.

What is the Regulatory Status and History of Gatifloxacin Ophthalmic Products?

Gatifloxacin has been approved for ophthalmic use. The development and approval of ophthalmic formulations containing specific polymorphs, like those claimed in U.S. Patent 6,333,044, are subject to stringent regulatory review by agencies like the U.S. Food and Drug Administration (FDA).

• Approved Products: Gatifloxacin ophthalmic solutions (e.g., Zymar® by Alcon) have been marketed in the U.S. for the treatment of bacterial conjunctivitis.
• Form Polymorph Inclusion: The approved drug product would need to specify and be manufactured using a gatifloxacin polymorph that is stable and provides the desired therapeutic profile. Given the patent's focus on Form I and Form II, it is highly probable that these forms were utilized in the development of these commercial products.
• Post-Market Surveillance: Regulatory agencies monitor approved drugs for safety and efficacy, including any changes in the manufacturing process or API characteristics that could affect performance.
• ANDA Filings: For generic versions, applicants must demonstrate bioequivalence and that their product is therapeutically equivalent to the reference listed drug. This includes demonstrating that the gatifloxacin API used is equivalent in form and purity.

The patent protection for specific polymorphs can influence the timeline for generic entry. A generic manufacturer cannot launch a product using a patented polymorph until the patent expires or is successfully challenged.

Key Takeaways

U.S. Patent 6,333,044 protects specific crystalline forms of gatifloxacin, designated Form I and Form II, characterized by distinct X-ray powder diffraction patterns. The patent covers these crystalline forms and pharmaceutical compositions containing them, with a notable emphasis on ophthalmic applications. The existence of this patent influences freedom-to-operate assessments for companies developing gatifloxacin products, requiring careful consideration of the crystalline form and manufacturing processes to avoid infringement. The expiration of this patent on December 26, 2018, has implications for generic market entry, provided other patent protections and regulatory requirements are met. The precise XRPD data provided in the claims forms the technical basis for defining and enforcing the patent's scope.

Frequently Asked Questions

What is the primary difference between Gatifloxacin Form I and Form II as claimed in U.S. Patent 6,333,044?

The primary difference lies in their distinct X-ray powder diffraction (XRPD) patterns, which reflect unique crystal lattice structures. Each form is defined by a specific set of diffraction angles (2θ values).

When did U.S. Patent 6,333,044 expire?

U.S. Patent 6,333,044 expired on December 26, 2018. This expiration date is relevant for assessing freedom to operate regarding the use of the claimed gatifloxacin polymorphs.

Can a company manufacture gatifloxacin without infringing on U.S. Patent 6,333,044?

Yes, a company can manufacture gatifloxacin if it does not use crystalline Form I or Form II as defined by the patent's claims, or if it operates under a license. Developing and manufacturing a different, non-patented crystalline form or an amorphous form would be a strategy to avoid infringement.

Are there other patents covering different crystalline forms of gatifloxacin?

The pharmaceutical landscape often involves multiple patents for different polymorphs of the same active ingredient. Therefore, it is possible that other patents exist claiming distinct crystalline forms of gatifloxacin not covered by U.S. Patent 6,333,044.

What is the significance of controlling polymorphs in drug development?

Controlling polymorphs is critical because different crystalline forms can exhibit varying solubility, dissolution rates, stability, and manufacturing properties. These variations can impact drug efficacy, bioavailability, shelf life, and the feasibility of large-scale production.

Citations

[1] Kyorin Pharmaceutical Co., Ltd. (2001). Crystalline polymorphs of gatifloxacin and process for preparation thereof (U.S. Patent No. 6,333,044). United States Patent Office.

Drugs Protected by US Patent 6,333,044

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: 6,333,044

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Italy	MI91A2024	Jul 22, 1991

International Family Members for US Patent 6,333,044

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	130758
Germany	69206345
Denmark	0524587