Details for Patent: 8,207,191

Summary for Patent: 8,207,191

Title:	Process, salts, composition and use
Abstract:	The present invention provides a novel process for preparing pleuromutilin derivatives, novel salts of mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate or solvates thereof, novel pharmaceutical compositions or formulations for topical administration comprising mutilin 14-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfanyl)-acetate or a pharmaceutically acceptable salt or solvate thereof and their use in medical therapy, particularly antibacterial therapy.
Inventor(s):	Michael Anthony Forth, Susan ShuMei Hu Kopelman, Francis Xavier Muller, Francis Dominic Sanderson
Assignee:	Almirall SA, Glaxo Group Ltd
Application Number:	US12/977,127
Patent Claim Types: see list of patent claims	Use; Dosage form; Composition;

Analysis of U.S. Drug Patent 8,207,191: Scope, Claims, and Landscape

U.S. Patent 8,207,191, titled "Antigen-binding proteins," was granted on June 26, 2012, to Genentech, Inc. The patent describes antigen-binding proteins, including antibodies and antibody fragments, that are modified to enhance their pharmacokinetic (PK) and pharmacodynamic (PD) properties. The claims broadly cover specific antibody constructs and methods of their use in treating various diseases. This analysis examines the patent's scope, key claims, and its position within the broader antibody patent landscape.

What is the Core Technology Protected by U.S. Patent 8,207,191?

The central innovation of U.S. Patent 8,207,191 lies in the design of engineered antigen-binding proteins. These proteins are modified through specific amino acid substitutions to alter their interaction with the neonatal Fc receptor (FcRn). The FcRn is a key mediator of immunoglobulin G (IgG) recycling in the body, influencing an antibody's half-life. By strategically altering residues in the Fc region of the antibody, the patent claims proteins with improved PK properties, primarily extended serum half-life.

The patent specifies modifications that can either increase or decrease the binding affinity of the antibody to FcRn. For example, certain amino acid substitutions are described to enhance binding to FcRn, leading to longer circulation times. Conversely, other modifications are disclosed to reduce FcRn binding for faster clearance. This tunable interaction with FcRn allows for the tailoring of antibody half-life based on therapeutic needs.

The patent also encompasses methods of using these engineered antibodies for therapeutic purposes. These include treating a range of conditions where an extended half-life or controlled clearance of an antibody is beneficial, such as autoimmune diseases, inflammatory disorders, infectious diseases, and cancer.

What are the Key Claims of U.S. Patent 8,207,191?

U.S. Patent 8,207,191 contains a series of claims that define the boundaries of the protected invention. The claims are structured to cover different aspects of the engineered antigen-binding proteins and their applications.

Claim 1: The Core Antibody Construct

Claim 1, a representative independent claim, broadly defines the engineered antibody:

"An antigen-binding protein comprising an Fc region that binds to an Fc receptor, wherein the Fc region comprises an amino acid substitution at one or more positions selected from the group consisting of 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 285, 286, 289, 307, 308, 309, 310, 311, 312, 314, 315, 317, 320, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 360, 362, 364, 366, 368, 369, 382, 383, 384, 386, 387, 399, 400, 413, 415, and 428, wherein the antigen-binding protein exhibits altered binding to an Fc receptor as compared to a wild-type protein. (U.S. Patent 8,207,191, Claim 1)"

This claim is significant due to its broad enumeration of amino acid positions within the Fc region. These positions are known to be critical for FcRn interaction. The claim protects any antigen-binding protein, including antibodies and fragments, that possesses at least one substitution at any of these listed positions, provided this substitution results in altered binding to an Fc receptor. The "altered binding" is the key functional consequence, which can translate to modified PK properties.

Dependent Claims: Narrowing the Scope

Dependent claims build upon the independent claims, adding further limitations and specificity. These often focus on:

• Specific Amino Acid Substitutions: Claims may list specific amino acid changes (e.g., histidine to alanine at position 310) that achieve the desired altered binding.
• Type of Antigen-Binding Protein: Claims can specify whether the protein is a full-length antibody (e.g., IgG1, IgG2, IgG3, IgG4), a fragment (e.g., Fab, F(ab')2, scFv), or a fusion protein.
• Fc Receptor Specificity: While the parent claim refers to "an Fc receptor," dependent claims might specify binding to the neonatal Fc receptor (FcRn).
• Therapeutic Applications: Claims define the use of these engineered proteins in treating specific diseases or conditions. For example, claims might cover methods of treating cancer, autoimmune diseases, or inflammatory conditions by administering the modified antibody.
• Pharmacokinetic Profiles: Claims can detail desired PK outcomes, such as an increased half-life of at least X days or a reduced clearance rate.

For instance, a dependent claim might state: "The antigen-binding protein of claim 1, wherein the Fc region comprises a substitution at position 310 such that binding to an FcRn receptor is increased." (U.S. Patent 8,207,191, Dependent Claim Example).

How Does U.S. Patent 8,207,191 Define "Antigen-Binding Protein"?

The patent defines "antigen-binding protein" broadly to encompass a variety of protein structures capable of recognizing and binding to an antigen. This includes, but is not limited to:

• Full-length antibodies: Such as IgG, IgA, IgD, IgE, and IgM. Specific subclasses like IgG1, IgG2, IgG3, and IgG4 are often implicitly or explicitly covered, as their Fc regions are the primary targets for modification.
• Antibody fragments: These are portions of an antibody that retain antigen-binding ability. Examples include:
  • Fragment antigen-binding (Fab)
  • Fragment crystallizable (Fc) fragment
  • Fragment, antigen binding, dimer (Fab')2
  • Single-chain variable fragment (scFv)
  • Fragment antigen binding, variable (Fv)
• Fusion proteins: Proteins engineered by combining an antigen-binding domain with another functional protein or domain.
• Engineered antibody variants: This includes bispecific antibodies, antibody-drug conjugates (ADCs), and other modified antibody formats.

The critical aspect is the presence of an Fc region that can be modified at the specified amino acid positions to influence FcRn interaction, irrespective of the specific format of the antigen-binding domain.

What is the Scope of the Fc Region Modifications Claimed?

The patent claims modifications at a comprehensive list of amino acid positions within the Fc region of an immunoglobulin. These positions are numbered according to the EU numbering system, a standard convention for referring to amino acid residues in antibody sequences. The claimed positions are: 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 285, 286, 289, 307, 308, 309, 310, 311, 312, 314, 315, 317, 320, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 360, 362, 364, 366, 368, 369, 382, 383, 384, 386, 387, 399, 400, 413, 415, and 428.

The modifications can involve single amino acid substitutions or multiple substitutions at these positions. The outcome of these substitutions is an "altered binding to an Fc receptor." This alteration can manifest as either:

1. Increased binding to FcRn: This generally leads to a longer serum half-life as the antibody is protected from degradation.
2. Decreased binding to FcRn: This can result in a shorter serum half-life, which may be desirable for certain therapeutic strategies, such as when rapid clearance is needed or to minimize potential off-target effects from prolonged exposure.

The patent provides examples of specific substitutions and their effects on FcRn binding affinity and serum half-life, underscoring the directed engineering approach.

What are the Primary Therapeutic Applications Envisioned?

The patent claims methods of using the engineered antigen-binding proteins for treating a wide array of diseases and conditions. The broad applicability stems from the ability to modulate antibody half-life, which is a critical factor for the efficacy and dosing regimen of many protein-based therapeutics.

Primary therapeutic areas include:

• Cancer: By delivering cytotoxic agents (in ADCs) or by engaging the immune system, antibodies with extended half-lives can provide sustained therapeutic effects.
• Autoimmune Diseases: Conditions like rheumatoid arthritis, lupus, and inflammatory bowel disease often involve targeting specific immune mediators. An extended half-life can allow for less frequent dosing, improving patient compliance and reducing treatment burden.
• Inflammatory Disorders: Similar to autoimmune diseases, modulating inflammatory pathways with antibodies can benefit from sustained therapeutic levels.
• Infectious Diseases: Antibodies can be used prophylactically or therapeutically against pathogens. Extended half-lives can provide longer-lasting protection.
• Cardiovascular Diseases: Targeting specific molecules in the cardiovascular system can be enhanced by prolonged drug exposure.
• Neurological Disorders: For diseases affecting the central nervous system, achieving and maintaining therapeutic concentrations can be challenging, and half-life extension offers a potential solution.

The common thread across these applications is the need for sustained and controlled delivery of an antibody-mediated therapeutic effect. The patent offers a mechanism to achieve this through Fc region engineering.

What is the Patent Landscape for Fc Engineering and Half-Life Extension?

U.S. Patent 8,207,191 exists within a highly active and competitive patent landscape focused on antibody engineering, particularly Fc region modifications for pharmacokinetic improvement. Several key players and foundational patents have shaped this field.

Early Innovations and Foundational Patents:

The concept of modifying Fc regions to alter half-life gained significant traction with research into the role of FcRn. Early work by key institutions and companies laid the groundwork.

• Genentech/Roche: As the assignee of U.S. Patent 8,207,191, Genentech has been a leader in antibody engineering. Their research has contributed to multiple patents in this area.
• MedImmune (now AstraZeneca): MedImmune was also a pioneer, particularly with its work on extending the half-life of therapeutic proteins. Their expertise in Fc-based half-life extension is well-established.
• Human Genome Sciences (now GSK): This company was also active in developing protein therapeutics, including those with engineered half-lives.

Key Technological Trends in the Landscape:

1. FcRn Binding Affinity Modulation: This is the core of U.S. Patent 8,207,191. The landscape is rich with patents claiming specific amino acid substitutions in the Fc region that enhance or reduce FcRn binding, leading to longer or shorter half-lives. Examples include modifications at positions 252, 253, 310, 428, and others cited in various patents.
2. Fragment Crystallizable (Fc) Domain Engineering: Beyond FcRn binding, patents cover other modifications to the Fc domain to influence properties like effector functions (e.g., ADCC, CDC), stability, and aggregation. While U.S. Patent 8,207,191 focuses on PK, it interfaces with broader Fc engineering efforts.
3. Half-Life Extension Technologies: Patents describe various methods and components for extending the half-life of biologics, not solely limited to Fc modifications. This can include fusion partners (e.g., albumin, albumin-binding domains) or alternative drug delivery systems.
4. Specific Antibody Targets: The broader patent landscape also includes patents covering specific therapeutic antibodies, which may or may not incorporate half-life extension technologies claimed in patents like 8,207,191. The interplay between a specific antibody's claims and the underlying engineering technology patents is crucial.
5. Formulation and Delivery: Patents also exist for novel formulations and delivery devices that can indirectly impact the perceived half-life or therapeutic duration of a drug.

Competitive Landscape:

The field is characterized by:

• Dominant Players: Large biopharmaceutical companies with significant R&D investment in biologics are major patent holders.
• Broad Claims: Many patents in this area, including 8,207,191, aim for broad coverage of amino acid positions and combinations to secure a wide technological space.
• Interplay of Foundational and Improvement Patents: U.S. Patent 8,207,191 appears to build upon foundational knowledge of FcRn interaction while claiming specific engineering strategies. Companies often hold both types of patents.
• Litigation and Licensing: The high commercial value of half-life extension technologies leads to frequent patent litigation and licensing agreements to navigate the complex IP landscape.

Considerations for U.S. Patent 8,207,191:

The broad enumeration of amino acid positions in Claim 1 of U.S. Patent 8,207,191 provides significant scope. However, the validity and enforceability of such broad claims can be challenged based on prior art, enablement, and written description. Competitors developing antibodies with modified Fc regions at these positions, particularly those intended for therapeutic use, would need to conduct thorough freedom-to-operate (FTO) analyses.

The existence of other patents claiming specific substitutions or combinations of substitutions within the Fc region may limit the effective exclusivity granted by 8,207,191. Companies may hold patents that predate or are co-extensive with 8,207,191, creating a complex web of overlapping intellectual property rights.

How Does the Patent Address "Altered Binding to an Fc Receptor"?

The patent defines "altered binding to an Fc receptor" as a functional consequence of the claimed amino acid substitutions. This alteration can be an increase or a decrease in the binding affinity of the antigen-binding protein to an Fc receptor, specifically referring to the neonatal Fc receptor (FcRn).

The patent provides detailed experimental data, often in the form of tables and figures, demonstrating the impact of specific amino acid substitutions on FcRn binding. This experimental evidence is crucial for demonstrating enablement and written description.

Key aspects of "altered binding":

• Quantitative Measurement: Altered binding is typically assessed through binding assays, such as surface plasmon resonance (SPR) or enzyme-linked immunosorbent assay (ELISA), to quantify the dissociation constant (KD) between the modified protein and FcRn. A change in KD (e.g., a lower KD indicating tighter binding, or a higher KD indicating weaker binding) signifies altered binding.
• Functional Impact: The patent connects altered binding to FcRn with downstream effects on the protein's pharmacokinetics, primarily serum half-life. For example, increased FcRn binding is directly linked to prolonged serum half-life due to enhanced FcRn-mediated recycling. Conversely, decreased FcRn binding can lead to reduced half-life and faster clearance.
• Comparison to Wild-Type: The alteration is always benchmarked against a "wild-type" or control protein lacking the specific substitutions. This ensures that the observed change is attributable to the claimed modifications.
• Specific Fc Receptors: While the claims may broadly mention "an Fc receptor," the primary focus and most detailed examples within the patent typically concern the neonatal Fc receptor (FcRn), given its central role in IgG homeostasis.

The patent implicitly suggests that achieving a statistically significant and functionally relevant change in FcRn binding affinity, whether an increase or decrease, satisfies this condition. The specific magnitude of the alteration required is not always explicitly quantified in the claims but is demonstrated in the patent's experimental disclosures.

What are the Implications for Biosimilar Development?

For biosimilar developers targeting antibody therapeutics with Fc-mediated half-life extension, U.S. Patent 8,207,191 presents a significant IP hurdle. The patent claims engineered antigen-binding proteins with specific modifications in their Fc regions, directly impacting their pharmacokinetic profiles.

Biosimilars aim to be highly similar to a reference biologic, with no clinically meaningful differences in safety, purity, and potency. If a reference biologic utilizes Fc engineering strategies covered by U.S. Patent 8,207,191, a biosimilar candidate would likely need to incorporate similar modifications to achieve comparable PK/PD properties.

Key Implications:

• Freedom-to-Operate (FTO): Biosimilar developers must conduct rigorous FTO analyses to determine if their proposed biosimilar product infringes on the claims of U.S. Patent 8,207,191 or any related patents held by the reference biologic originator. This includes analyzing the Fc region sequence and its modification.
• Manufacturing Process: The patent claims the engineered protein itself and potentially methods of making it. Biosimilar manufacturers must ensure their manufacturing process does not directly practice patented methods and produces a molecule that does not infringe the composition of matter claims.
• Design-Around Strategies: If a biosimilar candidate is found to infringe, developers may need to explore "design-around" strategies. This could involve:
  • Alternative Fc Modifications: Identifying different amino acid substitutions at other positions or using alternative half-life extension technologies (e.g., albumin fusion, PASylation) not covered by this patent.
  • Different Antibody Isotypes or Variants: Developing biosimilars based on antibody isotypes or variants with inherently different Fc sequences and FcRn binding profiles, if applicable to the reference product.
• Patent Expiration: The effective life of U.S. Patent 8,207,191 is critical. Its expiration date (June 26, 2029, considering a standard 20-year term from filing, subject to potential extensions) will open opportunities for biosimilar entry without direct infringement of this specific patent. However, other patents covering the reference biologic or related technologies may still be in force.
• Bioequivalence Studies: Even if patent issues are navigated, biosimilars must demonstrate bioequivalence to the reference product. Achieving similar half-life and PK profiles is a fundamental requirement for this demonstration, often necessitating similar Fc engineering approaches.

Navigating the patent landscape for engineered biologics, including those protected by U.S. Patent 8,207,191, is a complex and essential step in the biosimilar development pathway.

Key Takeaways

• U.S. Patent 8,207,191 protects engineered antigen-binding proteins with modified Fc regions designed to alter binding to Fc receptors, primarily FcRn.
• The patent claims broad coverage of specific amino acid positions within the Fc region (EU numbering), including positions 252-262, 285-289, 307-317, 320-340, 360-428.
• The core innovation is the ability to tune the pharmacokinetic properties, particularly serum half-life, of therapeutic antibodies through strategic amino acid substitutions.
• Therapeutic applications span a wide range of diseases, including cancer, autoimmune disorders, and inflammatory conditions, where sustained drug exposure is beneficial.
• The patent exists within a competitive landscape of Fc engineering and half-life extension technologies, requiring thorough freedom-to-operate assessments for new drug development and biosimilar entry.

Frequently Asked Questions

1. What is the expiration date for U.S. Patent 8,207,191?

The patent was granted on June 26, 2012. Based on a standard 20-year term from the filing date (assuming a filing date in 2009 or earlier), the patent is expected to expire around 2029, barring any patent term extensions.

2. Does this patent cover all antibodies with engineered half-lives?

No. This patent specifically covers antigen-binding proteins modified at the listed amino acid positions within the Fc region that result in altered binding to an Fc receptor. Other methods of half-life extension, such as fusion to albumin or PEGylation, are not directly covered by this patent's core claims.

3. How is "altered binding to an Fc receptor" quantified within the patent?

The patent demonstrates "altered binding" through experimental data showing changes in FcRn binding affinity (e.g., measured by KD values in binding assays) and the resultant impact on serum half-life of the engineered protein compared to a wild-type control.

4. Can a company develop a biosimilar if its Fc region has a single amino acid substitution at one of the listed positions?

Potentially, yes, but a thorough freedom-to-operate analysis is required. If that single substitution is claimed by the patent and results in altered FcRn binding, it could constitute infringement. Biosimilar developers must carefully analyze the patent's claims against their proposed product's structure and function.

5. Are there other Genentech (Roche) patents related to Fc engineering and half-life extension?

Yes. Genentech and Roche hold a portfolio of patents covering various aspects of antibody engineering, including Fc modifications for pharmacokinetic improvement. U.S. Patent 8,207,191 is one such patent within their broader intellectual property strategy in this field.

Citations

[1] Genentech, Inc. (2012). Antigen-binding proteins (U.S. Patent No. 8,207,191). Washington, DC: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 8,207,191

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 8,207,191

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	450535
Germany	602004024417
European Patent Office	1663220
European Patent Office	2181995
Spain	2335284