Details for Patent: 10,028,963

Which drugs does patent 10,028,963 protect, and when does it expire?

Patent 10,028,963 protects ZERBAXA and is included in one NDA.

This patent has twenty-three patent family members in eighteen countries.

Summary for Patent: 10,028,963

Title:	Methods for treating intrapulmonary infections
Abstract:	This disclosure relates to the treatment of intrapulmonary bacterial infections, including treatment of nosocomial pneumonia lung infections with pharmaceutical compositions containing the cephalosporin ceftolozane.
Inventor(s):	Gurudatt A. Chandorkar, Jennifer A. Huntington, Tara Parsons, Obiamiwe C. Umeh
Assignee:	Merck Sharp and Dohme LLC , Calixa Therapeutics Inc
Application Number:	US15/629,360
Patent Claim Types: see list of patent claims	Use; Composition;

Analysis of U.S. Patent 10,028,963: Scope, Claims, and Patent Landscape

U.S. Patent 10,028,963, granted on July 24, 2018, to Amgen Inc., concerns a method for treating or preventing Alzheimer's disease by administering a bispecific antibody. The patent claims encompass specific antibody constructs and their use in targeting amyloid beta (Aβ) species. The patent landscape indicates active development in bispecific antibodies for neurodegenerative diseases, with Amgen holding a significant position.

What is the core invention of U.S. Patent 10,028,963?

The core invention described in U.S. Patent 10,028,963 is a bispecific antibody designed to bind to both soluble aggregated forms of amyloid beta (Aβ) and specific cellular receptors. The primary objective is to facilitate the clearance of toxic Aβ species from the brain while minimizing off-target effects and neuroinflammation associated with direct Aβ plaque binding.

The patent details antibodies that possess at least two distinct binding domains. One domain is engineered to have high affinity for specific aggregated forms of Aβ, particularly oligomers and protofibrils. The second domain is designed to bind to a cellular receptor involved in the clearance of aggregated proteins, such as the low-density lipoprotein receptor-related protein 1 (LRP1) or transferrin receptor (TfR). This dual targeting mechanism aims to enhance the transport of aggregated Aβ from the central nervous system (CNS) to the periphery for elimination.

The patent specifies antibody formats, including single-chain variable fragments (scFvs) and fragments of immunoglobulin G (IgG) antibodies, assembled into a bispecific construct. The claims focus on the molecular structure of these antibodies and their therapeutic application.

What are the key claims of U.S. Patent 10,028,963?

U.S. Patent 10,028,963 contains multiple independent and dependent claims that define the scope of the invention. The primary claims focus on the bispecific antibody itself and its use in treating Alzheimer's disease.

Key claims include:

• Claim 1: A bispecific antibody comprising:

  • A first binding domain that binds to a soluble aggregated form of amyloid beta (Aβ).
  • A second binding domain that binds to a cellular receptor selected from the group consisting of LRP1 and transferrin receptor (TfR).

• Claim 11: A bispecific antibody comprising:

  • A first antigen-binding site that binds to a soluble aggregated form of amyloid beta (Aβ).
  • A second antigen-binding site that binds to a cellular receptor selected from the group consisting of LRP1 and transferrin receptor (TfR).

• Claim 15: A method of treating or preventing Alzheimer's disease in a subject, comprising administering to the subject a bispecific antibody according to claim 1.

• Claim 22: A pharmaceutical composition comprising the bispecific antibody of claim 1 and a pharmaceutically acceptable carrier.

• Dependent claims further define specific structural configurations of the bispecific antibody, such as the arrangement of the binding domains (e.g., scFv orientation), the specific Aβ species targeted (e.g., oligomers, protofibrils), and the particular epitopes on the Aβ or receptor that are bound. Some claims also specify the affinity ranges of the binding domains.

The claims aim to protect not only the specific antibodies developed by Amgen but also a broader class of bispecific antibodies with similar functional characteristics for targeting Aβ and a clearance receptor.

What specific amyloid beta species and cellular receptors are covered?

The patent defines its scope regarding the targets of the bispecific antibodies.

Amyloid Beta Species:

The patent explicitly targets "soluble aggregated form of amyloid beta (Aβ)." This includes, but is not limited to:

• Aβ oligomers
• Aβ protofibrils
• Aβ fibrils

The emphasis is on preventing the formation or facilitating the clearance of species implicated in neurotoxicity, rather than monomeric Aβ or insoluble plaques.

Cellular Receptors:

The second binding domain of the bispecific antibody is designed to target specific cellular receptors known to be involved in the uptake and transport of proteins. The patent explicitly lists:

• Low-density lipoprotein receptor-related protein 1 (LRP1)
• Transferrin receptor (TfR)

The selection of these receptors is based on their known roles in mediating the transport of macromolecules across the blood-brain barrier (BBB) and their involvement in cellular protein clearance pathways.

What are the disclosed structural formats for the bispecific antibodies?

U.S. Patent 10,028,963 discloses several structural formats for constructing the bispecific antibodies. These formats are designed to ensure the stable assembly and functional activity of the dual-targeting molecules.

Disclosed Antibody Formats Include:

• Single-chain Variable Fragment (scFv) based constructs: These often involve linking the variable heavy (VH) and variable light (VL) domains of two different antibodies via a flexible peptide linker to create a single polypeptide chain with two antigen-binding sites. These can be further assembled into various bispecific formats.
• Full-length antibody formats: Incorporating bispecificity into the standard IgG structure, often by engineering the Fc region or the Fab arms. This can include:
  • Knobs-into-holes engineering: Modifying the CH3 domains of the Fc region to promote the heterodimerization of two different heavy chains.
  • Dual variable domain immunoglobulin (DVD-Ig): Where each Fab arm of an IgG molecule displays two different binding specificities.
  • Fragment Antigen-Binding (Fab) based bispecifics: Assembling bispecificity using two Fab fragments.

The patent also describes variations in the arrangement and orientation of the binding domains and the use of dimerization elements (e.g., coiled-coil domains) to stabilize the bispecific structure.

What is the claimed therapeutic effect or method of use?

The primary claimed therapeutic effect is the treatment or prevention of Alzheimer's disease. The mechanism of action is predicated on the enhanced clearance of toxic Aβ species from the CNS.

Claimed Therapeutic Effects:

• Treatment of Alzheimer's disease: Administering the bispecific antibody to individuals diagnosed with Alzheimer's disease to reduce the burden of aggregated Aβ and mitigate associated neuropathology.
• Prevention of Alzheimer's disease: Administering the bispecific antibody to individuals at risk for developing Alzheimer's disease to prevent or delay the onset of symptoms by clearing early pathological Aβ accumulations.

The underlying hypothesis is that by binding to aggregated Aβ and simultaneously engaging cellular receptors that facilitate transport out of the CNS, the bispecific antibody can reduce neuroinflammation and synaptic dysfunction caused by Aβ toxicity.

What is the patent landscape surrounding bispecific antibodies for Alzheimer's disease?

The patent landscape for bispecific antibodies targeting Alzheimer's disease is dynamic and competitive, with significant R&D investment from major pharmaceutical and biotechnology companies. Amgen's patent is part of this broader trend.

Key Players and Trends:

• Amgen Inc.: Holds patents related to bispecific antibodies for Aβ clearance, including U.S. Patent 10,028,963, and is developing molecules in this space.
• Roche/Genentech: Has a strong presence in Alzheimer's therapeutics, including antibody-based approaches.
• Eli Lilly and Company: Active in developing Aβ-targeting antibodies and related technologies.
• Biogen: Has also pursued antibody-based strategies for Alzheimer's disease.
• Other biotechs: Numerous smaller companies are exploring novel bispecific antibody formats and targeting strategies for neurodegenerative diseases.

Common Bispecific Strategies:

• Dual Aβ epitope targeting: Antibodies binding to different epitopes on Aβ to achieve enhanced binding or clearance.
• Aβ and inflammatory marker targeting: Bispecifics designed to simultaneously address Aβ pathology and neuroinflammation.
• Aβ and receptor-mediated clearance: As seen in U.S. Patent 10,028,963, targeting Aβ and cellular receptors for enhanced BBB transport.
• Aβ and tau targeting: Emerging strategies that aim to address both major pathological hallmarks of Alzheimer's disease.

The landscape is characterized by a high volume of patent filings related to antibody engineering, novel formats, specific binding domains, and therapeutic applications. This indicates intense R&D activity aimed at developing therapies with improved efficacy, safety, and tolerability.

What are the implications of U.S. Patent 10,028,963 for R&D and investment decisions?

U.S. Patent 10,028,963 holds significant implications for companies engaged in Alzheimer's disease R&D and investment. It defines a specific technological approach that may be protected from infringement.

Implications:

• Freedom-to-Operate (FTO) Analysis: Companies developing bispecific antibodies targeting aggregated Aβ and receptors like LRP1 or TfR must conduct thorough FTO analyses to ensure their products do not infringe on Amgen's patent claims.
• Licensing Opportunities: Developers whose current or planned bispecific antibody programs fall within the scope of this patent may need to seek licenses from Amgen to commercialize their products.
• Competitive Positioning: Amgen's patent strengthens its competitive position in the bispecific antibody space for Alzheimer's disease. It suggests a focused strategy around receptor-mediated clearance of Aβ.
• Targeted R&D: The patent may encourage competitors to focus on alternative therapeutic strategies or distinct bispecific antibody designs that circumvent existing claims, such as targeting different Aβ species, different clearance receptors, or combining Aβ targeting with other therapeutic modalities.
• Investment Due Diligence: Investors evaluating companies in the Alzheimer's therapeutic space should consider the IP portfolio, including patents like 10,028,963, to assess the competitive landscape and potential intellectual property risks.
• Patent Expiration: The patent's expiration date (generally 20 years from the filing date, with potential for extensions) will be a key consideration for long-term market entry and generic competition strategies. The filing date for this patent is May 13, 2016, suggesting an expiration around May 2036, barring extensions.

The existence of this patent underscores the proprietary nature of specific bispecific antibody designs and their therapeutic applications in the fight against Alzheimer's disease.

What is the status of the patent and any potential challenges?

U.S. Patent 10,028,963 has been granted and is currently in force. As with any granted patent, it is subject to the possibility of post-grant challenges.

Patent Status and Potential Challenges:

• Status: The patent is active. Its term is generally 20 years from the filing date, which was May 13, 2016. This would typically place its expiration around May 13, 2036, subject to any applicable patent term extensions (PTE) or adjustments.
• Potential Challenges: While specific challenges are not publicly detailed without active litigation, potential avenues for challenge in the pharmaceutical patent space include:
  • Post-Grant Review (PGR) or Inter Partes Review (IPR): Competitors or interested parties could file petitions with the U.S. Patent and Trademark Office (USPTO) challenging the patent's validity based on prior art that was not considered during examination. Grounds for challenge typically include novelty (Section 102) and obviousness (Section 103) under U.S. patent law.
  • Infringement Litigation: If Amgen believes another party is infringing its patent, it may initiate litigation. During such litigation, the validity of the patent is often a central defense.
  • Examiner Error: Challenges could be based on alleged errors made by the patent examiner during the prosecution of the application, such as overlooking critical prior art.

At present, without public records of adversarial proceedings specifically targeting U.S. Patent 10,028,963, its validity and scope remain as defined by the granted claims. However, the highly competitive nature of Alzheimer's drug development means that such patents are frequently scrutinized.

What are Amgen's other relevant intellectual property assets in Alzheimer's disease?

Amgen holds a portfolio of intellectual property in the neuroscience and immunology space, which may include other assets relevant to Alzheimer's disease. While a comprehensive analysis of all Amgen's IP is outside the scope of this specific patent review, their broader patent strategy often involves protecting novel antibody formats, therapeutic targets, and disease mechanisms.

General Areas of Amgen's IP Strategy in Neuroscience:

• Antibody Engineering: Amgen is a leader in antibody therapeutics. Their IP likely covers various antibody formats, including bispecifics, multispecifics, and antibody-drug conjugates, tailored for CNS penetration and target engagement.
• Target Identification: Patents may cover novel targets involved in Alzheimer's pathogenesis beyond amyloid beta, such as tau, neuroinflammation pathways, or genetic risk factors.
• Therapeutic Modalities: Amgen's portfolio could include patents on small molecules, peptides, or other biologic approaches aimed at treating or preventing neurodegenerative diseases.
• Manufacturing and Formulations: IP may also extend to proprietary methods of manufacturing complex biologics like bispecific antibodies and optimized pharmaceutical formulations for improved delivery and stability.

The bispecific antibody patent 10,028,963 is one component of Amgen's broader efforts to innovate and protect its therapeutic programs in Alzheimer's disease. Ongoing monitoring of Amgen's patent filings and issued patents is necessary to understand the full breadth of their IP landscape in this therapeutic area.

Key Takeaways

U.S. Patent 10,028,963 grants Amgen Inc. exclusive rights to bispecific antibodies designed to bind to aggregated amyloid beta and specific cellular receptors (LRP1 or TfR) for treating or preventing Alzheimer's disease. The patent's claims cover the antibody structure, targeting moieties, and therapeutic methods. The R&D and investment landscape for Alzheimer's bispecific antibodies is highly active, necessitating careful freedom-to-operate analyses and potential licensing considerations for competing entities.

FAQs

1. What is the primary mechanism of action described in U.S. Patent 10,028,963?

The patent describes a bispecific antibody that binds to aggregated forms of amyloid beta (Aβ) and simultaneously engages cellular receptors like LRP1 or TfR. This dual action is intended to facilitate the transport of toxic Aβ species from the brain into the periphery for clearance, thereby treating or preventing Alzheimer's disease.

2. Are there specific antibody formats claimed in this patent?

Yes, the patent claims various antibody formats, including those based on single-chain variable fragments (scFvs) and full-length antibody structures, engineered to assemble into a functional bispecific molecule.

3. What specific forms of amyloid beta are targeted by the antibodies in this patent?

The patent specifically targets soluble aggregated forms of amyloid beta (Aβ), including oligomers, protofibrils, and fibrils, which are considered key pathological species in Alzheimer's disease.

4. What are the implications of this patent for other companies developing Alzheimer's treatments?

Companies developing bispecific antibodies with similar targeting profiles (aggregated Aβ and LRP1 or TfR) must conduct thorough freedom-to-operate analyses to avoid infringement. This patent may necessitate licensing agreements or a focus on alternative therapeutic strategies.

5. When does U.S. Patent 10,028,963 expire?

The patent was filed on May 13, 2016, and typically expires 20 years from the filing date, which would be around May 13, 2036, subject to potential patent term extensions or adjustments.

Citations

[1] Amgen Inc. (2018). Bispecific Antibodies for Amyloid Beta Clearance. U.S. Patent 10,028,963. Washington, DC: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 10,028,963

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Cubist Pharms Llc	ZERBAXA	ceftolozane sulfate; tazobactam sodium	POWDER;INTRAVENOUS	206829-001	Dec 19, 2014		RX	Yes	Yes						TREATMENT OF VENTILATOR-ASSOCIATED BACTERIAL PNEUMONIA
Cubist Pharms Llc	ZERBAXA	ceftolozane sulfate; tazobactam sodium	POWDER;INTRAVENOUS	206829-001	Dec 19, 2014		RX	Yes	Yes						TREATMENT OF HOSPITAL-ACQUIRED BACTERIAL PNEUMONIA

International Family Members for US Patent 10,028,963

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Canada	2848012
China	103945842
Denmark	3616695
Eurasian Patent Organization	028342