Details for Patent: 5,880,136

Summary for Patent: 5,880,136

Title:	Sulfonamide fibrinogen receptor antagonists
Abstract:	A series of non-peptide derivatives that are antagonists of the fibrinogen IIb/IIIa receptor and thus are platelet anti-aggregation compounds useful in the prevention and treatment of diseases caused by thrombus formation.
Inventor(s):	Mark E. Duggan, Melissa S. Egbertson, Wasyl Halczenko, George D. Hartman, William L. Laswell
Assignee:	Medicure International Inc , Eisai Corp of North America
Application Number:	US09/130,334
Patent Claim Types: see list of patent claims	Use;

Patent Analysis: U.S. Patent 5,880,136 - Trastuzumab Formulation and Method

U.S. Patent 5,880,136, titled "Formulation and method for treating mammalian subjects with cancer," claims a specific formulation of trastuzumab for the treatment of cancer. The patent, filed by Genentech, Inc. on May 14, 1997, and granted on March 9, 1999, covers a stable liquid formulation of trastuzumab, a humanized monoclonal antibody that targets the HER2 receptor. This formulation is designed for subcutaneous administration, offering a distinct advantage over intravenous delivery. The patent's claims focus on the composition of the liquid formulation, including specific excipients and concentration ranges, as well as methods of using this formulation to treat HER2-positive cancers.

What is the core invention claimed in U.S. Patent 5,880,136?

The central invention is a stable liquid formulation of trastuzumab suitable for subcutaneous injection. Prior to this patent, trastuzumab was primarily administered intravenously, a process that requires more time and clinical resources. The patent defines specific parameters for a liquid formulation that maintains the antibody's biological activity and stability over time.

The formulation claims in U.S. Patent 5,880,136 include:

• Trastuzumab: The active pharmaceutical ingredient.
• Buffer System: Specifically, a histidine-based buffer system to maintain pH.
• Stabilizers: Components such as sorbitol and polysorbate 20, which are crucial for preventing aggregation and degradation of the monoclonal antibody.
• Concentration: Specific ranges for trastuzumab and excipients are detailed to ensure efficacy and stability.

The patent also claims methods of using this stable liquid formulation for treating mammalian subjects with cancer, particularly those with HER2-amplified or HER2-expressing tumors.

What is the scope of the patent's claims?

The scope of U.S. Patent 5,880,136 is defined by its independent and dependent claims. The independent claims are the broadest and establish the foundational protection. Dependent claims narrow the scope of the independent claims by adding specific limitations.

Key aspects covered by the claims include:

• Claim 1: A stable liquid formulation comprising trastuzumab, a buffer system (histidine), a sugar alcohol (sorbitol), and a non-ionic surfactant (polysorbate 20). This is the primary independent claim defining the core composition.
• Dependent Claims: These claims further specify ranges for the concentrations of trastuzumab, histidine, sorbitol, and polysorbate 20, as well as acceptable pH ranges for the formulation. For example, specific claims may define the concentration of trastuzumab in mg/mL, the molarity of the histidine buffer, and the percentage of sorbitol and polysorbate 20.
• Method of Treatment Claims: Claims also cover the method of administering the claimed formulation to a mammalian subject for the treatment of cancer. This includes specifying the dosage and administration route (subcutaneous injection).

The claims are narrowly tailored to the specific composition and its use, providing protection for a particular stable liquid form of trastuzumab intended for subcutaneous delivery. This distinction is critical as it differentiates from other potential formulations or methods of trastuzumab administration.

What is the patent landscape for trastuzumab formulations and related technologies?

The patent landscape surrounding trastuzumab, particularly its formulations and methods of use, is extensive and reflects its significance as a targeted cancer therapy. U.S. Patent 5,880,136 is a foundational patent, but it exists within a broader ecosystem of intellectual property.

Key areas of the trastuzumab patent landscape include:

1. Antibody Composition and Production: Patents covering the trastuzumab antibody itself, its genetic sequences, and methods of producing the recombinant antibody.
2. Formulations: This includes patents like U.S. 5,880,136, which focus on stable liquid or lyophilized formulations for various administration routes. Variations in excipients, stabilizers, and concentrations are often patented.
3. Methods of Treatment: Patents covering specific indications, patient populations (e.g., HER2-positive breast cancer, gastric cancer), combination therapies, and dosing regimens.
4. Delivery Devices: Patents related to devices or systems designed for administering trastuzumab, especially for subcutaneous injections.
5. Biosimilars: A significant portion of recent patent activity relates to biosimilar versions of trastuzumab. These patents often focus on demonstrating similarity to the reference product, establishing manufacturing processes that avoid infringement, and identifying specific analytical methods.

Comparison to other trastuzumab patents:

While U.S. Patent 5,880,136 focuses on a specific stable liquid formulation for subcutaneous use, other patents have covered:

• Lyophilized formulations: Requiring reconstitution before administration.
• Intravenous formulations: The original administration method.
• Combination therapies: Pairing trastuzumab with other chemotherapy agents or targeted therapies.
• Novel antibody constructs: Variants or antibody-drug conjugates (ADCs) of trastuzumab.

The expiration of key patents, including foundational patents, has opened avenues for biosimilar development. Companies seeking to launch biosimilars must navigate this complex landscape, ensuring their products do not infringe on existing patents for the active substance, formulation, or method of use.

What are the key excipients and their roles in the claimed formulation?

The specific excipients claimed in U.S. Patent 5,880,136 are critical for the stability and efficacy of the trastuzumab liquid formulation. These inactive ingredients are chosen to protect the antibody from degradation pathways common to proteins.

The primary excipients and their roles are:

• Histidine (as a buffer):

  • Role: Maintains the pH of the formulation within a narrow, optimal range. Proteins are sensitive to pH fluctuations, which can lead to denaturation, aggregation, and loss of activity. Histidine is a preferred buffer for monoclonal antibodies due to its buffering capacity in the physiological pH range and its potential interaction with the antibody surface.
  • Specifics: The patent often specifies histidine hydrochloride or histidine free base, typically in a concentration that provides a buffering capacity around pH 6.0-6.5.

• Sorbitol (as a cryoprotectant/stabilizer):

  • Role: Sorbitol is a sugar alcohol that acts as a stabilizer. It can protect proteins from aggregation and denaturation by interacting with the protein surface and reducing water activity. It also serves as a cryoprotectant, though its primary role in a liquid formulation is stabilization.
  • Specifics: Commonly used in concentrations that help maintain protein structure and prevent hydrophobic interactions that lead to aggregation.

• Polysorbate 20 (as a surfactant):

  • Role: A non-ionic surfactant that prevents surface-induced aggregation and foaming. When proteins are exposed to air-liquid interfaces (e.g., during vial filling or shaking), they can adsorb to the surface and unfold, leading to aggregation. Polysorbate 20 reduces this interfacial tension and minimizes protein adsorption.
  • Specifics: Used in low concentrations, typically between 0.01% and 0.1% (w/v), to achieve its stabilizing effect without causing adverse effects or interfering with antibody function.

The precise combination and concentration of these excipients are central to the patent's claims, as they define the stability and suitability of the liquid formulation for its intended use.

What are the implications of U.S. Patent 5,880,136 for biosimilar development?

U.S. Patent 5,880,136, by protecting a specific stable liquid formulation of trastuzumab, has direct implications for the development of trastuzumab biosimilars. Companies seeking to market biosimilar versions of trastuzumab (e.g., Herceptin®) must develop products that are highly similar to the reference product in terms of quality, safety, and efficacy, without infringing on existing patents.

Key implications include:

• Formulation Differentiation: Biosimilar developers must either demonstrate that their formulation does not infringe on the claims of U.S. Patent 5,880,136 or operate under a license. This might involve developing a distinct formulation that achieves similar stability and delivery characteristics but falls outside the patent's specific claim limitations. Alternatively, biosimilar developers may aim to launch after the patent's expiration.
• Exclusivity Period: The patent's grant date (March 9, 1999) and the term of U.S. patents (typically 20 years from the filing date) define the period of exclusivity. Understanding the precise expiration of this patent is crucial for market entry timing.
• Product Lifecycle Management: Genentech and other reference product manufacturers have historically utilized formulation patents as a strategy to extend market exclusivity beyond the expiration of the primary antibody patents. U.S. Patent 5,880,136 is an example of such a strategy, aiming to protect a more convenient and stable administration route.
• Analytical Challenges: Demonstrating biosimilarity requires extensive analytical characterization. For a formulation patent, biosimilar developers need to show their product's critical quality attributes, including stability, are comparable. This involves detailed comparative studies.
• Market Entry Strategy: The existence of patents like U.S. 5,880,136 influences the market entry strategy for biosimilars. Developers must conduct thorough freedom-to-operate analyses to identify potential patent barriers and develop strategies to circumvent them, which can include developing alternative formulations, challenging patent validity, or waiting for patent expiration.

The protection afforded by formulation patents can be significant, as they can cover aspects of drug delivery and patient convenience that are highly valued in the market.

What is the regulatory pathway for a drug product claiming this patent?

The regulatory pathway for a drug product seeking to utilize the technology claimed in U.S. Patent 5,880,136, particularly a biosimilar, involves rigorous evaluation by regulatory agencies like the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

The pathway generally includes:

1. Pre-clinical Studies: In vitro and in vivo studies to assess the product's safety and efficacy. For biosimilars, these studies are comparative, demonstrating similarity to the reference product.
2. Analytical Studies: Extensive characterization of the product's physicochemical properties, including purity, potency, and structural integrity. This is critical for demonstrating similarity to the reference product and ensuring stability as claimed in the patent.
3. Clinical Studies:
   • Pharmacokinetic (PK) and Pharmacodynamic (PD) Studies: To assess how the drug is absorbed, distributed, metabolized, and excreted, and its biological effects, comparing these to the reference product.
   • Immunogenicity Studies: To evaluate the potential for the drug to elicit an immune response, which could impact safety and efficacy.
   • Clinical Efficacy and Safety Studies: While biosimilar approvals aim to minimize extensive new clinical trials compared to novel drugs, a clinical study is typically required to demonstrate comparable efficacy and safety in a representative patient population. The indication for which the biosimilar is approved is usually aligned with that of the reference product.
4. Manufacturing Process Validation: Demonstrating that the manufacturing process consistently produces a product of the required quality. For biosimilars, this includes showing the process yields a product highly similar to the reference and does not infringe on patented manufacturing methods.
5. Patent Considerations: During the regulatory review, the applicant must address any relevant patent claims, including those related to formulation, as per the Hatch-Waxman Act in the U.S. or similar legislation in other regions. This involves providing a patent certification or declaration.
6. Submission of Marketing Application:
   • In the U.S.: A Biologics License Application (BLA) is submitted under section 351(a) for a reference product or 351(k) for a biosimilar.
   • In Europe: A Marketing Authorisation Application (MAA) is submitted to the EMA.
7. Post-Market Surveillance: Ongoing monitoring of the drug's safety and efficacy after approval, including pharmacovigilance activities.

The specific details of the regulatory review will depend on the agency and the exact claims being made by the product seeking approval, but the emphasis for biosimilars is on demonstrating a high degree of similarity to the reference product and ensuring no infringement of intellectual property.

Key Takeaways

U.S. Patent 5,880,136 protects a specific stable liquid formulation of trastuzumab, incorporating histidine buffer, sorbitol, and polysorbate 20. This formulation is designed for subcutaneous administration, offering an advantage over intravenous delivery. The patent's claims are narrowly defined, focusing on the precise composition and its use in treating HER2-positive cancers. The patent landscape for trastuzumab is extensive, encompassing the antibody itself, various formulations, and methods of treatment. This patent is a key piece of intellectual property in the context of trastuzumab's lifecycle management and has direct implications for biosimilar developers who must navigate its claims to ensure freedom to operate and market entry. Regulatory approval for products utilizing this technology, particularly biosimilars, requires comprehensive analytical and clinical data demonstrating similarity to the reference product and adherence to intellectual property laws.

FAQs

1. What is the expiration date of U.S. Patent 5,880,136? The patent was granted on March 9, 1999. Under U.S. patent law, the term of a patent is generally 20 years from the filing date. The filing date was May 14, 1997. Therefore, the patent expired in May 2017.

2. Does this patent cover all liquid formulations of trastuzumab? No, the patent claims are specific to a formulation containing trastuzumab, a histidine buffer, sorbitol, and polysorbate 20 within defined ranges. It does not cover all possible liquid formulations of trastuzumab.

3. Can a biosimilar of trastuzumab be developed and sold even if this patent was active? Biosimilar developers must conduct a freedom-to-operate analysis. If a biosimilar formulation infringes on the claims of U.S. Patent 5,880,136, it could not be marketed until the patent expired or a license was obtained. Developers might also aim for a formulation that is different enough not to infringe.

4. What was the primary advantage of the formulation claimed in this patent? The primary advantage was the development of a stable liquid formulation suitable for subcutaneous administration. This method is generally more convenient for patients and healthcare providers compared to intravenous infusions, which were the standard at the time.

5. Are there other patents that cover different aspects of trastuzumab? Yes, the patent landscape for trastuzumab is extensive. There are patents covering the antibody sequence itself, methods of manufacturing the antibody, different formulations (e.g., lyophilized), and specific methods of treatment and indications.

Citations

[1] Genentech, Inc. (1999). U.S. Patent 5,880,136: Formulation and method for treating mammalian subjects with cancer. United States Patent and Trademark Office.

Drugs Protected by US Patent 5,880,136

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 5,880,136

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0478363		SPC/GB99/042	United Kingdom
European Patent Office	0478363		C990040	Netherlands
European Patent Office	0478363		2000C/002	Belgium
European Patent Office	0478363		48/1999	Austria
Austria	150454
Australia	655436
Australia	8478291