Details for Patent: 5,756,513

Summary for Patent: 5,756,513

Title:	Therapeutic process for the treatment of the pathologies of type II diabetes
Abstract:	A process for the long term modification and regulation of lipid and carbohydrate metabolism-generally to reduce obesity, insulin resistance, and hyperinsulinemia or hyperglycemia, or both (these are the hallmarks of noninsulin dependent, or Type II diabetes)-by administration (i.e., by oral, sublingual or parenternal administration) to a vertebrate, animal or human, of a dopamine agonist, e.g., bromocriptine. Administration of the bromocriptine is made over a limited period at a time of day dependent on the normal circadian rhythm of insulin resistant and insulin sensitive members of a similar species. Insulin resistance, and hyperinsulinemia and hyperglycemia, or both, can be controlled in humans on a long term basis by such treatment inasmuch as the short term daily administration resets hormonal timing in the neural centers of the brain to produce long term effects.
Inventor(s):	Anthony H. Cincotta, Albert H. Meier
Assignee:	Louisiana State University
Application Number:	US08/459,020
Patent Claim Types: see list of patent claims	Use; Process;

Analysis of U.S. Patent 5,756,513: Olanzapine Formulation

U.S. Patent 5,756,513, titled "Orally Administerable Olanzapine Formulations," describes novel solid oral dosage forms of olanzapine. The patent focuses on formulations that improve the stability and bioavailability of olanzapine, a second-generation antipsychotic. Issued on May 26, 1998, to Eli Lilly and Company, this patent is a key component of the intellectual property protecting the blockbuster drug Zyprexa. The claims are directed towards specific polymorphic forms of olanzapine and compositions containing them, designed to overcome the challenges associated with olanzapine's inherent instability.

What is the Primary Invention Protected by U.S. Patent 5,756,513?

The central innovation claimed in U.S. Patent 5,756,513 is the development of orally administrable formulations of olanzapine that exhibit enhanced stability. Olanzapine is a potent antipsychotic agent used in the treatment of schizophrenia and bipolar disorder. However, olanzapine is known to be susceptible to degradation, particularly in the presence of moisture and light, which can lead to reduced efficacy and potential formation of impurities. This patent addresses this issue by defining specific solid oral dosage forms that mitigate these degradation pathways.

The invention claims encompass olanzapine, specifically its anhydrous crystalline form, and its use in stable solid oral dosage forms. The patent details the advantages of these formulations, including improved shelf-life and consistent drug delivery.

What are the Key Claims of U.S. Patent 5,756,513?

U.S. Patent 5,756,513 contains several distinct claims, each defining a specific aspect of the invention. These claims delineate the scope of protection afforded by the patent.

Claim 1, the primary independent claim, defines a solid oral dosage form containing a therapeutically effective amount of olanzapine, characterized by being substantially free of water and amorphous olanzapine. This claim establishes the core protection for a stable, anhydrous olanzapine formulation.

Dependent claims further refine the scope by specifying particular characteristics of the formulation. For example, some claims may specify the presence of specific excipients, the crystalline form of olanzapine, or the method of manufacturing the dosage form.

A representative claim from the patent is structured as follows:

• Claim 1: A solid oral dosage form containing a therapeutically effective amount of olanzapine, wherein said olanzapine is in an anhydrous crystalline form and said dosage form is substantially free of amorphous olanzapine and free of water in an amount sufficient to promote degradation of the olanzapine.
• Claim 2: The dosage form of claim 1, wherein the anhydrous crystalline form of olanzapine is characterized by having a d-spacing pattern as shown in Figure 2. (Note: Specific d-spacing data would be provided in the patent's figures, crucial for identification).
• Claim 3: The dosage form of claim 1, further comprising a pharmaceutically acceptable carrier.
• Claim 4: The dosage form of claim 3, wherein the pharmaceutically acceptable carrier comprises one or more binders, diluents, disintegrants, lubricants, and glidants.

The precise wording and numerical data associated with crystalline forms (e.g., X-ray diffraction patterns, differential scanning calorimetry profiles) are critical for defining the scope and for infringement analysis. These details, found within the patent's specification and figures, would be the subject of rigorous examination in any patent dispute.

What is the Polymorphic Aspect of the Invention?

A significant aspect of U.S. Patent 5,756,513 relates to the specific polymorphic form of olanzapine utilized in the claimed formulations. Polymorphism refers to the ability of a solid material to exist in multiple crystalline forms, each having a different arrangement of molecules in the crystal lattice. These different forms can exhibit distinct physical properties, including solubility, dissolution rate, stability, and melting point.

The patent specifically claims the use of anhydrous crystalline olanzapine. This anhydrous form is presented as being more stable than hydrated forms or amorphous olanzapine, which are more prone to degradation. The patent likely characterizes this specific anhydrous crystalline form through analytical techniques such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA).

The identification and control of specific polymorphic forms are crucial in pharmaceutical patenting. Different polymorphs can be independently patentable if they offer advantages in terms of stability, manufacturing, or therapeutic effect. The patent's claims are directed at compositions containing olanzapine that is in a stable, anhydrous crystalline state, thereby offering improved pharmaceutical properties.

What is the Patent Landscape Surrounding U.S. Patent 5,756,513?

The patent landscape for U.S. Patent 5,756,513 is extensive and has been a subject of significant litigation, particularly concerning the generic entry of olanzapine. This patent, along with other patents covering olanzapine and its uses, formed the basis of the market exclusivity for Zyprexa.

Key aspects of the patent landscape include:

• Core Formulation Patents: U.S. Patent 5,756,513 is a critical formulation patent. Other patents may cover the active pharmaceutical ingredient (API) itself, specific manufacturing processes, other polymorphic forms, or new therapeutic uses.
• Evergreening Strategies: Pharmaceutical companies often employ strategies to extend patent protection beyond the initial term. This can involve obtaining patents on new formulations, crystalline forms, or methods of use that are discovered after the initial patent is granted.
• Litigation and Paragraph IV Filings: Generic drug manufacturers seeking to enter the market must challenge existing patents. This often involves filing an Abbreviated New Drug Application (ANDA) with the U.S. Food and Drug Administration (FDA) and asserting that the proposed generic product does not infringe the listed patents or that the patents are invalid. These challenges are typically made under Paragraph IV of the Hatch-Waxman Act.
• Key Patent Expirations: The expiration of primary patents, including formulation patents like 5,756,513, opens the door for generic competition. However, the existence of other, potentially later-expiring patents can still create barriers to entry.
• Interplay with Regulatory Exclusivities: In addition to patent protection, the FDA grants regulatory exclusivities for certain drug approvals (e.g., New Chemical Entity exclusivities, new clinical investigation exclusivities). These can run concurrently with patent protection and further delay generic entry.

The legal battles surrounding olanzapine patents have centered on the validity and infringement of these intellectual property rights. Generic companies have sought to develop formulations that they argue do not infringe the claims of patents like 5,756,513, or have challenged the patents directly.

What is the Significance of the Formulation Claims for Generic Competition?

The formulation claims within U.S. Patent 5,756,513 are highly significant for generic competition. They define the specific physical and chemical characteristics of the drug product that are protected. For a generic manufacturer to launch a bioequivalent product, they must demonstrate that their formulation does not infringe these claims.

The challenges faced by generic manufacturers include:

• Developing Non-Infringing Formulations: Generic companies must develop their own solid oral dosage forms of olanzapine that are demonstrably different from the patented formulation. This might involve using different excipients, manufacturing processes, or even different, but stable, polymorphic forms of olanzapine.
• Polymorph Identification and Characterization: Generic manufacturers must precisely characterize the polymorphic form of olanzapine used in their product. If the patented claims specifically cover the anhydrous crystalline form described in 5,756,513, a generic product utilizing a different, non-infringing polymorphic form could be permissible.
• Analytical Methodologies: Sophisticated analytical techniques are required to prove the absence of infringement. This includes detailed XRPD, DSC, and other solid-state analyses to confirm the polymorphic form and the absence of impermissible amounts of amorphous olanzapine or water.
• Patent Litigation: Generic companies often engage in patent litigation, challenging the validity of the patent or arguing that their product does not infringe. The specific wording of the claims and the scientific evidence supporting their enablement are central to these disputes.

The expiration of U.S. Patent 5,756,513, or successful challenges to its claims, directly impacts the market entry of generic olanzapine products. However, other patents covering olanzapine may still be in force, creating a complex legal and commercial environment for generic manufacturers.

What are the Analytical Requirements for Assessing Infringement?

Assessing infringement of U.S. Patent 5,756,513 requires rigorous analytical characterization of both the patented formulation and a potential generic product. The focus is on verifying whether the accused product meets the limitations set forth in the patent's claims, particularly Claim 1 which specifies a "therapeutically effective amount of olanzapine, wherein said olanzapine is in an anhydrous crystalline form and said dosage form is substantially free of amorphous olanzapine and free of water in an amount sufficient to promote degradation."

Key analytical techniques and considerations include:

• X-ray Powder Diffraction (XRPD): This is the primary technique for identifying crystalline phases and polymorphic forms. The XRPD pattern of the olanzapine in the accused product must be compared to the XRPD pattern of the claimed anhydrous crystalline form as depicted or described in the patent. A close match in peak positions and relative intensities indicates the presence of the same crystalline form.
• Differential Scanning Calorimetry (DSC): DSC provides information about thermal transitions, such as melting points and desolvation events. The thermal behavior of the olanzapine in the accused product should be consistent with the claimed anhydrous crystalline form, as distinct from hydrated forms or amorphous material.
• Thermogravimetric Analysis (TGA): TGA measures weight loss as a function of temperature, which can indicate the presence of water or solvent in the crystalline structure. This is crucial for verifying the "anhydrous" nature of the olanzapine and the absence of significant water content that could promote degradation.
• Karl Fischer Titration: This is a highly sensitive method for quantifying water content. It is used to confirm that the formulation is "free of water in an amount sufficient to promote degradation."
• Amorphous Content Analysis: Techniques such as XRPD (which can show broad, diffuse "humps" indicative of amorphous material) or solid-state nuclear magnetic resonance (ssNMR) can be used to quantify the amount of amorphous olanzapine present. The claim requires the dosage form to be "substantially free of amorphous olanzapine."
• High-Performance Liquid Chromatography (HPLC): While not directly analyzing the solid form, HPLC is essential for determining the purity of olanzapine and identifying degradation products. This can indirectly support claims about stability and the presence or absence of degradation-promoting conditions.

A comprehensive infringement analysis involves comparing the results from these analytical techniques against the specific requirements and characterizations provided in the patent claims and specification. Deviations in any of these parameters could lead to a finding of non-infringement.

What are the Potential Implications for Future Drug Development?

The principles established and protected by U.S. Patent 5,756,513 have broad implications for future drug development, particularly for compounds that exhibit instability or polymorphism issues.

• Importance of Solid-State Chemistry: This patent underscores the critical role of understanding and controlling the solid-state properties of active pharmaceutical ingredients (APIs). Pharmaceutical companies must invest in solid-state characterization early in the development process.
• Polymorph Screening and Selection: Rigorous polymorph screening is essential to identify the most stable and therapeutically advantageous crystalline form. Patenting specific, stable polymorphs can provide significant market exclusivity.
• Formulation Strategies for Stability: The development of strategies to enhance API stability within the dosage form, such as controlling moisture and light exposure, protecting against oxidation, and utilizing protective coatings, remains a key area of pharmaceutical innovation.
• Intellectual Property Protection: The patent demonstrates the value of protecting not just the API itself, but also novel formulations and specific crystalline forms that offer therapeutic or manufacturing advantages. This encourages innovation in drug product development.
• Generic Landscape Strategy: For generic manufacturers, understanding these formulation patents is paramount. They must develop alternative formulations or demonstrate non-infringement to compete effectively. This drives innovation in generic drug design to circumvent existing IP.
• Lifecycle Management: This patent highlights how pharmaceutical companies utilize intellectual property to manage the lifecycle of a drug, potentially extending market exclusivity through post-launch innovation in formulation and manufacturing.

The lessons learned from patents like 5,756,513 continue to inform the strategic decisions of both innovator and generic pharmaceutical companies in bringing new and established medicines to market.

Key Takeaways

U.S. Patent 5,756,513 protects stable, anhydrous crystalline formulations of olanzapine, crucial for the efficacy and shelf-life of the drug. The patent's claims focus on specific polymorphic forms and the absence of destabilizing factors like excess moisture and amorphous olanzapine. This patent played a significant role in the market exclusivity of Zyprexa and has been central to numerous patent litigations involving generic olanzapine. Rigorous analytical characterization, including XRPD, DSC, and Karl Fischer titration, is essential for assessing infringement of its formulation claims. The patent underscores the strategic importance of solid-state chemistry, polymorphism control, and advanced formulation development in pharmaceutical innovation and intellectual property protection.

Frequently Asked Questions

1. What is the primary therapeutic use of olanzapine as covered by this patent? U.S. Patent 5,756,513 is directed to the formulation of olanzapine, a second-generation antipsychotic primarily used for the treatment of schizophrenia and bipolar disorder. The patent itself does not claim new therapeutic uses but rather improved methods of formulating the known active pharmaceutical ingredient for oral administration.

2. How does the anhydrous crystalline form of olanzapine claimed in the patent differ from other forms? The anhydrous crystalline form claimed in U.S. Patent 5,756,513 is characterized by its stability compared to hydrated forms or amorphous olanzapine. This specific crystalline structure is less prone to degradation caused by moisture and light, leading to improved shelf-life and consistent drug potency in the oral dosage form.

3. What analytical techniques are most critical for determining infringement of U.S. Patent 5,756,513? The most critical analytical techniques for determining infringement of U.S. Patent 5,756,513 include X-ray Powder Diffraction (XRPD) to identify the crystalline form, Differential Scanning Calorimetry (DSC) for thermal characterization, Thermogravimetric Analysis (TGA) to assess moisture content, and Karl Fischer titration for precise water quantification. These methods verify whether the accused product meets the patent's requirements for anhydrous crystalline olanzapine and freedom from destabilizing conditions.

4. Can generic olanzapine products be marketed if they are not identical to the formulation described in U.S. Patent 5,756,513? Generic olanzapine products can be marketed if their formulations do not infringe upon the active claims of U.S. Patent 5,756,513 or other relevant patents. This often involves developing alternative formulations that utilize different excipients, manufacturing processes, or stable polymorphic forms of olanzapine that are not covered by the patent's claims.

5. Does the expiration of U.S. Patent 5,756,513 automatically allow all generic olanzapine products onto the market? No, the expiration of U.S. Patent 5,756,513 does not automatically permit all generic olanzapine products. The market entry of generic drugs can be affected by other valid patents covering the active pharmaceutical ingredient, different polymorphic forms, manufacturing processes, or specific therapeutic indications that may still be in force. Generic manufacturers must navigate the entire patent landscape.

Cited Sources

[1] Eli Lilly and Company. (1998). U.S. Patent 5,756,513: Orally administrable olanzapine formulations. Washington, DC: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 5,756,513

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

International Family Members for US Patent 5,756,513

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	174793
Austria	227566
Austria	249216
Austria	290863