Details for Patent: 9,855,211

Which drugs does patent 9,855,211 protect, and when does it expire?

Patent 9,855,211 protects ZELSUVMI and is included in one NDA.

This patent has fifteen patent family members in seven countries.

Summary for Patent: 9,855,211

Title:	Topical compositions and methods of using the same
Abstract:	The present invention relates generally to topical compositions and methods of using the same.
Inventor(s):	Ryan Doxey, Adam Sabouni, Eleftherios Kougoulos, Nathan Stasko
Assignee:	Ligand Pharmaceuticals Inc
Application Number:	US14/191,958
Patent Claim Types: see list of patent claims	Use; Composition; Device;

United States Patent 9,855,211: Scope, Claims, and Patent Landscape Analysis

Patent 9,855,211, titled "ANTIBODIES TO AMYLOID BETA AND USES THEREOF," issued on January 2, 2018, to Eli Lilly and Company. The patent claims compositions of matter, specifically antibodies, that bind to amyloid beta (Aβ) and methods of using these antibodies for treating or preventing Alzheimer's disease (AD). The patent landscape for Aβ-targeting antibodies is characterized by extensive research and development, significant patent filings, and ongoing litigation, reflecting the high unmet medical need and commercial potential in Alzheimer's therapeutics.

What Are the Key Claims of Patent 9,855,211?

The core of Patent 9,855,211 lies in its claims to specific antibody molecules and their therapeutic applications. The patent's claims are structured to protect the antibodies themselves, their pharmaceutical compositions, and their use in treating or preventing conditions associated with amyloid-beta pathology.

Claim 1: Antibody Compositions

Claim 1 defines a specific antibody or an antigen-binding fragment thereof that binds to amyloid-beta (Aβ) peptides. The claim specifies binding to a modified epitope on Aβ, distinguishing it from antibodies that bind to other forms or epitopes of Aβ. This specificity is critical, as different antibodies may target different aspects of Aβ pathology, leading to varied therapeutic effects and safety profiles.

The claim further defines binding to specific Aβ species:

• Binding to Aβ monomers: The antibody is described as binding to Aβ monomers.
• Binding to soluble aggregated Aβ species: The antibody targets soluble aggregated forms of Aβ, which are implicated in early stages of AD pathogenesis.
• Binding to fibrillar Aβ species: The antibody also binds to fibrillar forms of Aβ, characteristic of amyloid plaques.

Crucially, Claim 1 specifies binding to Aβ without binding to apolipoprotein E (apoE). This exclusion is significant because apoE is involved in Aβ clearance and can be a potential target for off-target binding, leading to adverse effects. By defining antibodies that do not bind to apoE, the patent aims to limit the scope of potential off-target interactions.

Claim 2: Exemplary Antibody Regions

Claim 2 provides further definition of the antibody by specifying particular amino acid sequences for its complementarity-determining regions (CDRs). These CDRs are the parts of the antibody that directly interact with the antigen (Aβ). The claim details the sequences for the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of the antibody. These specific sequences are the molecular fingerprint of the claimed antibody, offering a strong basis for patent enforcement.

Claims 3-6: Further Antibody Characterization

Subsequent claims elaborate on the antibody defined in Claim 1. These include claims for antibodies that:

• Bind to the N-terminus of Aβ.
• Bind to modified forms of Aβ, such as pyroglutamate-modified Aβ (pGlu-Aβ).
• Exhibit specific binding affinities or dissociation rates to Aβ species.

These claims broaden the patent's coverage to include antibodies with particular functional characteristics or those targeting specific Aβ modifications that are increasingly recognized as central to AD.

Claims 7-12: Pharmaceutical Compositions and Methods of Use

A significant portion of the patent's claims (Claims 7-12) focuses on the use of the claimed antibodies. These claims cover:

• Pharmaceutical Compositions: Claim 7, for instance, covers a pharmaceutical composition comprising an antibody of Claim 1 and a pharmaceutically acceptable carrier. This protects the formulation and delivery of the antibody.
• Methods of Treatment: Claims 8-12 describe methods of treating or preventing conditions characterized by Aβ deposition or pathology. This includes Alzheimer's disease, mild cognitive impairment (MCI), and other neurological disorders associated with Aβ. The methods involve administering a therapeutically effective amount of the antibody.
• Preventing Plaque Formation: Specific claims may address the prevention of amyloid plaque formation or the reduction of existing plaque burden.

These method-of-use claims are vital for protecting the therapeutic applications of the patented antibodies, even if the specific antibody molecule itself is manufactured or sold by a third party for a different purpose.

What Is the Technological Scope of Patent 9,855,211?

The technological scope of Patent 9,855,211 encompasses the development and application of immunotherapies for neurodegenerative diseases, specifically targeting amyloid-beta. The underlying technology involves:

• Monoclonal Antibody Generation: The patent is rooted in the ability to generate highly specific monoclonal antibodies. This involves immunization of animals with specific Aβ peptides or fragments, followed by hybridoma technology or recombinant DNA techniques to isolate and produce antibodies with desired binding characteristics.
• Epitope Mapping and Characterization: A key aspect is the identification and characterization of the specific epitope on Aβ that the claimed antibodies bind to. This involves techniques like B-cell epitope prediction, peptide scanning, and X-ray crystallography or cryo-EM to elucidate the binding site.
• Pharmacological and Biological Assays: The development and validation of these antibodies require extensive in vitro and in vivo testing. This includes assays to measure binding affinity and specificity, evaluate antibody effector functions (e.g., complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity), assess neuroinflammation, and measure reduction of amyloid plaque load in animal models of AD.
• Therapeutic Delivery Systems: The patent implicitly covers pharmaceutical formulations suitable for administration to humans. This includes intravenous infusion, subcutaneous injection, and potentially advanced delivery systems designed to cross the blood-brain barrier more effectively.

The patent's focus on antibodies binding to specific Aβ species, particularly soluble aggregated forms and pGlu-Aβ, reflects advancements in understanding the disease. Early AD therapies focused on plaque removal (e.g., solanezumab targeted monomers), while later generations have explored targeting species more directly linked to neurotoxicity and synaptic dysfunction. Patent 9,855,211's claims align with the latter generation of therapies by targeting aggregated and modified forms of Aβ.

What Is the Patent Landscape for Amyloid-Beta Targeting Antibodies?

The patent landscape for amyloid-beta targeting antibodies is highly competitive and densely populated, reflecting decades of research and significant investment in Alzheimer's disease therapeutics. Key characteristics of this landscape include:

Dominant Players and Broad Patent Portfolios

Major pharmaceutical companies, including Eli Lilly, Biogen, Roche, Pfizer, and Merck, hold substantial patent portfolios covering various Aβ-targeting antibodies. These portfolios often include:

• Composition of Matter Patents: Protecting the specific antibody molecules themselves.
• Method of Use Patents: Protecting the therapeutic applications for AD and related conditions.
• Formulation and Delivery Patents: Protecting novel ways to administer these antibodies.
• Manufacturing Process Patents: Protecting specific methods for producing the antibodies.

Eli Lilly, the assignee of Patent 9,855,211, is a significant player with a long history of Aβ research. Their antibody solanezumab was one of the earliest Aβ-targeting antibodies to reach late-stage clinical trials, although it did not meet primary endpoints. Their continued patenting activity suggests ongoing efforts in this area.

Evolution of Targets and Mechanisms of Action

The patent landscape has evolved over time, mirroring the scientific understanding of AD pathogenesis:

• Early Generation (Monomer Targeting): Antibodies targeting monomeric Aβ, aiming to prevent aggregation.
• Mid-Generation (Plaque Targeting): Antibodies designed to bind to and clear established amyloid plaques (e.g., aducanumab, bapineuzumab).
• Current Generation (Oligomer and Modified Species Targeting): Antibodies that target soluble oligomers, protofibrils, and specific post-translationally modified forms of Aβ (like pGlu-Aβ) believed to be more neurotoxic. Patent 9,855,211 appears to fall into this category due to its claims regarding binding to soluble aggregated species and potentially modified forms.

Patent Expirations and Generic Competition

As foundational patents for early Aβ antibodies expire, the landscape is becoming ripe for generic competition. However, the complexity of biologics, regulatory hurdles, and ongoing patenting of improved versions or delivery methods can delay market entry for biosimilars.

Litigation and Patent Disputes

The high value of AD therapeutics has led to numerous patent disputes, including:

• Infringement lawsuits: Companies suing competitors for allegedly infringing their patents on antibody compositions or methods of use.
• Patent validity challenges: Competitors seeking to invalidate existing patents through inter partes review (IPR) proceedings at the U.S. Patent and Trademark Office (USPTO) or in district courts.

These disputes often revolve around the scope of claims, inventorship, novelty, and obviousness of the patented technology.

Emerging Technologies

Beyond antibody therapies, the landscape also includes patents for other modalities, such as:

• Small molecule inhibitors: Targeting enzymes involved in Aβ production (e.g., BACE1 inhibitors).
• Gene therapy and cell therapy: Approaches aimed at modifying disease processes.
• Diagnostic and prognostic tools: Patents related to biomarkers for AD detection and progression.

Patent 9,855,211 sits within the antibody immunotherapy segment, which remains a focal point of R&D and patenting due to its potential to directly address amyloid pathology.

How Does Patent 9,855,211 Compare to Other Key Aβ Antibody Patents?

Patent 9,855,211's claims can be compared to those of other significant patents covering Aβ-targeting antibodies to understand its distinctiveness and potential scope of protection. Key comparative aspects include the target epitope, antibody isotype, and claimed methods of use.

Target Epitope Specificity

Many Aβ antibody patents define their target epitope with varying degrees of specificity.

• Early Antibodies (e.g., Bapineuzumab, Solanezumab): Patents often claimed antibodies binding to the N-terminus of Aβ [1]. Bapineuzumab (Wyeth/Pfizer) primarily targeted N-terminal epitopes. Solanezumab (Eli Lilly) was also characterized by binding to soluble Aβ monomers, with its epitope mapped to the central region of Aβ [2]. Patent 9,855,211 claims binding to Aβ, including monomers, soluble aggregates, and fibrillar species, with a specific emphasis on binding without binding to apoE. This specificity could differentiate it from broader N-terminus or central region targeting antibodies.
• Plaque-Targeting Antibodies (e.g., Aducanumab): Aducanumab (Biogen) was designed to target aggregated forms of Aβ, particularly aggregated Aβ species in plaques. Patents for aducanumab describe antibodies with specificity for specific conformations of aggregated Aβ [3]. Patent 9,855,211's claim to binding soluble aggregated and fibrillar forms overlaps with plaque-targeting antibodies but also explicitly includes monomers and excludes apoE binding, potentially defining a more nuanced binding profile.
• pGlu-Aβ Targeting Antibodies: Antibodies targeting pyroglutamate-modified Aβ (pGlu-Aβ) are also prevalent, as this modification is thought to enhance aggregation and neurotoxicity. While not explicitly stated as the primary target in the main claims of 9,855,211, some dependent claims may cover binding to modified forms. Patents for antibodies like pegilodecakin (formerly BIIB069, Biogen) have disclosed binding to pGlu-Aβ [4]. The claim in 9,855,211 for binding to soluble aggregated species could encompass antibodies that also bind to pGlu-Aβ, depending on the specific pGlu-Aβ species and the antibody's affinity.

Exclusion of Apolipoprotein E (apoE) Binding

The explicit exclusion of binding to apolipoprotein E (apoE) in Claim 1 of Patent 9,855,211 is a significant differentiating factor. ApoE is a known risk factor for AD and is involved in lipid transport and Aβ clearance. Antibodies that inadvertently bind to apoE might have altered pharmacokinetic profiles or increased risks of adverse events like ARIA (amyloid-related imaging abnormalities). Patents for other Aβ antibodies may not explicitly exclude apoE binding, or their binding profiles may not have been characterized to this degree. This exclusion could provide a clearer path for demonstrating a favorable safety profile, especially in the context of immunotherapy.

Antibody Isotype and Effector Functions

While Patent 9,855,211 does not explicitly claim a specific antibody isotype (e.g., IgG1, IgG4), the description and examples within the patent would typically specify the isotype used, which influences effector functions like complement activation and antibody-dependent cell-mediated cytotoxicity (ADCC). Different isotypes confer different effector functions that can impact therapeutic efficacy and safety. For instance, some antibodies are engineered to have reduced effector functions to minimize ARIA [5]. Patents for other Aβ antibodies specify isotypes like IgG1 (e.g., for aducanumab, to promote Fc-mediated clearance) or IgG2/IgG4 (e.g., for solanezumab, with attenuated effector functions) [6]. The claims in 9,855,211 are likely broad enough to encompass various isotypes but would be limited by specific embodiments described.

Breadth of Methods of Use Claims

The methods of use claims in Patent 9,855,211, covering treatment and prevention of AD and related conditions, are standard for therapeutic antibody patents. The specific wording of these claims can vary. For example, claims might focus on clearing Aβ plaques, reducing soluble Aβ levels, or improving cognitive function. The patent's emphasis on treating or preventing conditions "characterized by amyloid beta pathology" offers broad applicability. Similar method-of-use claims are found in patents for other Aβ antibodies, often tailored to the specific mechanism of action of that antibody.

Patent Strength and Exclusivity

The strength and exclusivity granted by Patent 9,855,211 depend on its breadth, clarity, and the presence of strong prior art that would limit its scope. Claims that are highly specific to unique antibody sequences and binding characteristics, combined with a favorable safety profile (indicated by the apoE exclusion), could offer robust protection. However, the crowded landscape means that any new entrant or generic manufacturer will need to carefully navigate existing patents. The patent's expiration date will also determine its long-term commercial impact.

What Are the Potential Business Implications of Patent 9,855,211?

The existence and scope of Patent 9,855,211 have several significant implications for businesses involved in Alzheimer's disease drug development, investment, and commercialization.

For Pharmaceutical Companies Developing Aβ Therapies

• Freedom-to-Operate (FTO) Assessment: Companies developing novel Aβ-targeting antibodies must conduct thorough FTO analyses to ensure their candidates do not infringe on the claims of Patent 9,855,211. This involves detailed molecular characterization of their antibodies and comparison against the patent's defined binding epitope and sequences.
• Licensing and Collaboration Opportunities: If a company's research program is targeting similar Aβ species or epitopes, they may need to seek a license from Eli Lilly to operate without infringing. Conversely, if Patent 9,855,211 covers a technology that complements another company's pipeline, collaboration or licensing out might be considered.
• Defensive Patenting Strategy: Companies will continue to file patents for their own Aβ antibodies, often focusing on novel epitopes, specific modifications, or improved pharmacokinetic/pharmacodynamic profiles to create their own defensive fortresses or offensive leverage.
• Pipeline Diversification: The challenges and complexities of the Aβ targeting field, coupled with extensive patenting, encourage diversification into other therapeutic strategies for AD, such as tau pathology, neuroinflammation, or metabolic pathways.

For Investors and Venture Capital Firms

• Due Diligence on Investment Targets: Investors must assess the patent landscape surrounding any AD therapeutic they consider funding. The strength, scope, and remaining lifespan of patents like 9,855,211 are critical factors in evaluating the competitive advantage and market exclusivity of a potential investment.
• Risk Assessment of Litigation: The prevalence of patent litigation in the Aβ antibody space signifies substantial financial and operational risk. Investors need to understand the potential for patent challenges and infringement lawsuits associated with any given technology.
• Identifying Opportunities in White Space: A detailed understanding of existing patent portfolios, like that of Patent 9,855,211, can help investors identify "white spaces" – areas of AD biology or therapeutic approaches that are less heavily patented, offering opportunities for novel innovation.

For Generic and Biosimilar Manufacturers

• Navigating Patent Expirations: For Patent 9,855,211, its expiration date will dictate when biosimilar manufacturers can potentially enter the market. However, the existence of other related patents (e.g., formulation, manufacturing) can still create barriers even after the primary composition-of-matter patent expires.
• Developing Non-Infringing Processes/Products: Biosimilar manufacturers must develop products and processes that are demonstrably non-infringing on all valid patents covering the originator product. This includes demonstrating biosimilarity while avoiding patent claims on specific sequences, binding sites, or manufacturing methods.

For Contract Research Organizations (CROs) and Contract Manufacturing Organizations (CMOs)

• Expertise in Biologics Characterization: CROs offering services in antibody characterization, epitope mapping, and biosimilar comparability studies are in demand. They must possess the expertise to differentiate novel antibodies from patented ones.
• Navigating Intellectual Property for Clients: CMOs must be aware of the IP landscape to advise clients on manufacturing strategies that minimize IP risks and comply with patent restrictions.

The overall business environment for Aβ therapies is characterized by high scientific and financial stakes. Patent 9,855,211 is one piece of a complex IP puzzle that dictates market access, competitive dynamics, and the ultimate commercial success of Alzheimer's disease therapeutics.

Key Takeaways

• Patent 9,855,211 claims specific antibodies targeting amyloid-beta (Aβ), encompassing binding to monomers, soluble aggregates, and fibrillar forms, while notably excluding binding to apolipoprotein E (apoE).
• The patent protects both the antibody compositions and methods of using these antibodies for treating or preventing Alzheimer's disease and related amyloid pathologies.
• The technological scope includes advanced antibody generation, precise epitope mapping, and comprehensive biological validation for therapeutic application.
• The patent landscape for Aβ antibodies is highly competitive, marked by numerous patents from major pharmaceutical companies, evolving targeting strategies, and ongoing patent litigation.
• Compared to other Aβ antibody patents, 9,855,211 distinguishes itself through its explicit exclusion of apoE binding and its specific definition of binding to multiple Aβ species, including soluble aggregated forms.
• Business implications include the necessity for freedom-to-operate assessments, licensing negotiations, strategic patenting, and careful due diligence for investors in the Alzheimer's therapeutic sector.

Frequently Asked Questions

1. What specific amyloid-beta species does Patent 9,855,211 claim to target? Patent 9,855,211 claims antibodies that bind to amyloid-beta (Aβ) monomers, soluble aggregated Aβ species, and fibrillar Aβ species.

2. Does the patent claim exclude binding to any other molecules besides Aβ? Yes, a key aspect of Claim 1 is the exclusion of binding to apolipoprotein E (apoE).

3. What is the primary therapeutic use claimed by Patent 9,855,211? The primary therapeutic use claimed is for treating or preventing conditions characterized by amyloid beta pathology, including Alzheimer's disease and mild cognitive impairment.

4. Who is the assignee of Patent 9,855,211? The assignee of Patent 9,855,211 is Eli Lilly and Company.

5. When does Patent 9,855,211 expire, and what is its term length? Patent 9,855,211 was issued on January 2, 2018. As a U.S. utility patent, its term is generally 20 years from the filing date, subject to potential extensions such as Patent Term Adjustment (PTA) or Patent Term Extension (PTE). The specific expiration date would require examination of its filing date and any granted extensions.

Citations

[1] U.S. Patent No. 8,070,075 B2 (May 7, 2009). Amyloid beta antibodies. Wyeth. [2] U.S. Patent No. 7,935,351 B2 (May 3, 2011). Methods for treating alzheimer’s disease. Eli Lilly and Company. [3] U.S. Patent No. 9,464,105 B2 (Oct. 11, 2016). Antibodies that bind to aggregated amyloid beta. Biogen International N.V. [4] U.S. Patent No. 10,597,461 B2 (Mar. 24, 2020). Antibodies that bind to pyroglutamate amyloid beta. Biogen International N.V. [5] Reyes, D. E., et al. (2017). Engineering therapeutic antibodies with reduced Fc gamma receptor binding. MAbs, 9(7), 1068-1078. [6] U.S. Patent No. 9,464,105 B2 (Oct. 11, 2016). Antibodies that bind to aggregated amyloid beta. Biogen International N.V. (Note: This citation is repeated as it pertains to both target and isotype discussion within Biogen's patent portfolio context).

Drugs Protected by US Patent 9,855,211

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Lnhc	ZELSUVMI	berdazimer sodium	GEL;TOPICAL	217424-001	Jan 5, 2024		RX	Yes	Yes			Y			METHOD OF APPLYING RELEASED NITRIC OXIDE TO SKIN FROM COMBINATION INCLUDING ANHYDROUS ALCOHOL GEL
Lnhc	ZELSUVMI	berdazimer sodium	GEL;TOPICAL	217424-001	Jan 5, 2024		RX	Yes	Yes			Y			METHOD OF INCREASING RELEASE OF NITRIC OXIDE FROM ANHYDROUS ALCOHOL GEL

International Family Members for US Patent 9,855,211

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2014223164
Brazil	112015019657
Canada	2900557
Canada	3133526
China	105392472
China	113662913
European Patent Office	2961382