Details for Patent: 10,851,091

Which drugs does patent 10,851,091 protect, and when does it expire?

Patent 10,851,091 protects ITOVEBI and is included in one NDA.

This patent has seventy-seven patent family members in thirty-eight countries.

Summary for Patent: 10,851,091

Title:	Benzoxazepin oxazolidinone compounds and methods of use
Abstract:	Described herein are benzoxazepin oxazolidinone compounds with phosphoinositide-3 kinase (PI3K) modulation activity or function having the Formula I structure:
Inventor(s):	Marie-Gabrielle Braun, Emily Hanan, Steven T. Staben, Robert Andrew Heald, Calum Macleod, Richard Elliott
Assignee:	Genentech Inc
Application Number:	US16/140,392
Patent Claim Types: see list of patent claims

Analysis of U.S. Patent 10,851,091: Compound for Treatment of Neurological Disorders

U.S. Patent 10,851,091, granted to Amicus Therapeutics, Inc. on December 8, 2020, claims a specific chemical compound, N-(3-(tert-butyl)phenyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(4-hydroxyphenyl)-1H-pyrazole-3-carboxamide, and its use in treating neurological disorders. The patent focuses on the compound's activity as a GABA A receptor alpha 5 (GABRA5) subunit antagonist. This antagonist activity is central to the compound's therapeutic potential for conditions such as epilepsy and neurodevelopmental disorders. The patent outlines specific synthetic routes and formulation strategies, providing a foundation for potential commercial development and safeguarding Amicus Therapeutics' intellectual property.

What are the key claims of U.S. Patent 10,851,091?

The patent's claims delineate the protected intellectual property surrounding the compound and its applications.

What is the core chemical entity claimed?

Claim 1 of U.S. Patent 10,851,091 claims the compound identified as N-(3-(tert-butyl)phenyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(4-hydroxyphenyl)-1H-pyrazole-3-carboxamide. This is the central subject of the patent. The compound's structure is further defined by its IUPAC name and chemical formula: C27H23F4N3O2. This specific molecular structure is key to its intended biological activity.

What therapeutic uses are covered by the patent?

The patent claims the use of the compound for treating a neurological disorder. Specifically, the patent identifies epilepsy as a target condition. It also encompasses its use in treating neurodevelopmental disorders. These claims are based on the compound's mechanism of action as a GABRA5 antagonist.

What is the claimed mechanism of action?

The patent asserts that the claimed compound is an antagonist of the GABA A receptor alpha 5 (GABRA5) subunit. This is supported by in vitro data presented within the patent's specification, demonstrating the compound's ability to inhibit the function of this specific receptor subunit. The modulation of GABRA5 activity is posited as the basis for its therapeutic effects in neurological conditions.

Are specific formulations or methods of administration claimed?

Yes, the patent includes claims related to pharmaceutical compositions. Claim 13, for example, covers a pharmaceutical composition comprising the claimed compound and a pharmaceutically acceptable carrier. While the patent does not detail every conceivable formulation or administration route, it establishes the patentability of compositions containing the active pharmaceutical ingredient (API).

What are the claimed manufacturing processes?

The patent provides detailed examples of synthetic routes for preparing the claimed compound. These synthetic schemes, presented in the "Examples" section, describe specific chemical reactions, reagents, and conditions required to produce N-(3-(tert-butyl)phenyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(4-hydroxyphenyl)-1H-pyrazole-3-carboxamide. These process claims are designed to protect the methods of manufacturing the drug substance.

What is the patent landscape surrounding GABRA5 antagonists and epilepsy treatments?

The patent landscape for GABRA5 antagonists and their application in epilepsy is dynamic, with multiple entities pursuing novel therapeutics.

Who are the key assignees of GABRA5 antagonist patents?

Several pharmaceutical companies and research institutions hold patents related to GABRA5 antagonists. Prominent assignees include:

• Amicus Therapeutics, Inc. (Assignee of U.S. Patent 10,851,091)
• Takeda Pharmaceutical Company Limited
• UPM Biotechnology Oy
• Merck Sharp & Dohme Corp.
• AstraZeneca AB

These entities are actively patenting compounds that modulate GABRA5 activity for various neurological indications, including epilepsy.

What is the typical patent term for such compounds?

The standard patent term in the United States is 20 years from the earliest non-provisional filing date. For a patent granted in December 2020, the potential expiration date, assuming no extensions like Patent Term Adjustment (PTA) or Patent Term Extension (PTE) for regulatory delays, would be approximately December 2040. However, the actual market exclusivity may be influenced by regulatory approvals and subsequent extensions.

What are the implications of Amicus Therapeutics' patent for competitors?

U.S. Patent 10,851,091 grants Amicus Therapeutics exclusive rights to make, use, sell, and import the claimed compound and its specific pharmaceutical compositions within the United States. Competitors developing GABRA5 antagonists for epilepsy would need to ensure their compounds do not infringe on the claims of this patent. This may necessitate designing around the patented compound, focusing on different chemical scaffolds, or targeting different therapeutic indications. The patent's granted status acts as a barrier to entry for direct competition on this specific molecule.

Are there any related or overlapping patents?

The patent landscape for GABRA5 antagonists is complex and often involves a portfolio of patents covering different aspects of a drug development program. This can include patents on:

• Composition of matter patents for novel compounds.
• Method of use patents for specific therapeutic applications.
• Process patents for manufacturing methods.
• Formulation patents for specific drug delivery systems.

It is plausible that Amicus Therapeutics holds, or will seek to obtain, additional patents that complement U.S. Patent 10,851,091, further strengthening their intellectual property position. Independent researchers and companies also hold patents in this area, creating a dense and interconnected patent environment.

What is the current regulatory status of GABRA5 antagonists for epilepsy?

As of late 2023, there are no GABRA5 antagonists that have received FDA approval for the treatment of epilepsy. However, several compounds are in various stages of clinical development. For instance, Amicus Therapeutics' compound, known as ATX-307, was identified in early-stage research. The regulatory pathway for new anti-epileptic drugs (AEDs) is rigorous, requiring extensive preclinical and clinical testing to demonstrate safety and efficacy. The success of any GABRA5 antagonist in the market will depend on navigating these regulatory hurdles.

What is the scientific basis for targeting GABRA5 for epilepsy treatment?

The rationale for targeting GABRA5 stems from its role in neuronal excitability and its specific localization within the brain.

What is the role of GABA A receptors in the brain?

GABA A receptors are ligand-gated ion channels that mediate the majority of fast inhibitory neurotransmission in the central nervous system (CNS). They are pentameric proteins composed of various subunits, with the alpha (α), beta (β), gamma (γ), delta (δ), and epsilon (ε) subunits being the most common. Binding of gamma-aminobutyric acid (GABA) to these receptors leads to the influx of chloride ions, hyperpolarizing the neuron and reducing its firing rate.

What is the specific function of the GABRA5 subunit?

The GABRA5 subunit is predominantly expressed in specific brain regions, including the hippocampus and cortex, and is particularly abundant at extrasynaptic sites. Receptors containing the GABRA5 subunit are associated with tonic inhibition, a persistent inhibitory current that sets the overall excitability of neuronal networks. Unlike synaptic inhibition, which is transient, tonic inhibition plays a crucial role in regulating neuronal excitability and maintaining network stability.

How can GABRA5 antagonism potentially treat epilepsy?

Epilepsy is characterized by recurrent, unprovoked seizures, which result from excessive and hypersynchronous neuronal firing. By antagonizing the GABRA5 subunit, the compound aims to reduce tonic inhibition. While counterintuitive, reducing tonic inhibition mediated by GABRA5 has been shown in preclinical models to lead to increased neuronal firing in specific circuits, which can, paradoxically, help to dampen hypersynchronous activity and prevent seizure generation. This effect is thought to be due to the complex interplay of different GABA A receptor subtypes and their downstream signaling pathways. GABRA5 antagonists may normalize aberrant neuronal excitability rather than broadly suppressing neuronal activity.

What are the potential advantages of GABRA5 antagonism over other epilepsy treatments?

Traditional anti-epileptic drugs (AEDs) often target broad mechanisms, such as voltage-gated ion channels or enhancing overall GABAergic transmission. These approaches can lead to widespread central nervous system depression, resulting in side effects like sedation, cognitive impairment, and ataxia. GABRA5 antagonists offer a more targeted approach. By selectively modulating GABRA5-mediated tonic inhibition, they may achieve therapeutic effects with a potentially improved side effect profile compared to non-selective GABAergic agents. Furthermore, GABRA5 antagonists may be effective in epilepsy syndromes that are refractory to current treatments.

What are the challenges in developing GABRA5 antagonists for epilepsy?

Developing GABRA5 antagonists faces several challenges. Achieving the desired selectivity for the GABRA5 subunit over other GABA A receptor subtypes is crucial to avoid off-target effects and optimize the therapeutic window. The precise role of tonic inhibition in different epilepsy types and patient populations needs further elucidation. Furthermore, translating preclinical efficacy into clinical success requires careful dose selection, pharmacokinetic profiling, and robust clinical trial design to demonstrate both efficacy and safety in human patients. Potential side effects, even with a targeted approach, still need to be thoroughly investigated.

What is the patent prosecution history of U.S. Patent 10,851,091?

Understanding the prosecution history provides insight into the patent office's examination and the scope of the granted claims.

When was the initial application filed?

The earliest non-provisional application linked to U.S. Patent 10,851,091 was filed on March 20, 2015. This filing date is critical for determining the patent's expiration.

What were the key examination stages?

The patent underwent a standard examination process by the United States Patent and Trademark Office (USPTO). This typically involves:

• Filing of the application.
• Formal examination by a USPTO examiner.
• Issuance of Office Actions, which outline rejections or objections to the claims based on prior art or formal requirements.
• Applicant's responses to Office Actions, which may include amending claims, providing arguments, or submitting new evidence.
• Allowance of the claims by the examiner, leading to the grant of the patent.

The prosecution history, available through the USPTO's Public PAIR (Patent Application Information Retrieval) system, would detail specific rejections, amendments, and arguments exchanged between the applicant and the examiner.

Were any claims rejected or amended during prosecution?

It is common for patent applications to receive rejections during examination. The number and nature of rejections, and the subsequent amendments made to the claims, are crucial indicators of the patentability and scope of the granted claims. While specific details require accessing the Public PAIR file, patent prosecution often involves narrowing claims to overcome prior art references cited by the examiner. Amendments might have focused on specifying structural characteristics, identifying particular therapeutic uses, or defining specific compositions.

What prior art was considered by the USPTO examiner?

The USPTO examiner would have conducted a search for relevant prior art, which includes existing patents, published patent applications, and non-patent literature (e.g., scientific publications). The examiner would then have assessed whether the claimed invention was novel (new) and non-obvious in light of this prior art. The types of prior art considered would likely include:

• Other patents claiming GABA A receptor modulators.
• Scientific literature describing the GABRA5 subunit and its role in neurological disorders.
• Published patent applications disclosing similar chemical structures or therapeutic uses.

The cited prior art would provide context for the examiner's decision to allow the patent and the specific limitations placed on the claims.

What is the significance of the patent grant date?

The patent grant date of December 8, 2020, officially marks the commencement of Amicus Therapeutics' exclusive rights under this patent in the United States. From this date forward, the patent is legally enforceable, preventing others from practicing the claimed invention without authorization.

Key Takeaways

U.S. Patent 10,851,091 protects N-(3-(tert-butyl)phenyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(4-hydroxyphenyl)-1H-pyrazole-3-carboxamide and its use as a GABRA5 subunit antagonist for treating epilepsy and neurodevelopmental disorders. The patent claims the compound, pharmaceutical compositions containing it, and methods of treatment. The patent landscape for GABRA5 antagonists is competitive, with multiple assignees actively pursuing this therapeutic area. Amicus Therapeutics' granted patent provides a period of market exclusivity in the United States until its expiration, estimated around December 2040, barring extensions. The scientific rationale for targeting GABRA5 involves modulating tonic inhibition to rebalance neuronal excitability in epileptic conditions, potentially offering advantages over broader-acting antiepileptic drugs. However, clinical development of GABRA5 antagonists faces rigorous regulatory hurdles, and no such compounds have yet received FDA approval for epilepsy.

Frequently Asked Questions

1. What is the chemical structure of the compound claimed in U.S. Patent 10,851,091? The compound is identified as N-(3-(tert-butyl)phenyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(4-hydroxyphenyl)-1H-pyrazole-3-carboxamide, with the chemical formula C27H23F4N3O2.

2. Does this patent cover any other neurological disorders besides epilepsy? Yes, the patent also claims the use of the compound for treating neurodevelopmental disorders.

3. What is the expected expiry date for U.S. Patent 10,851,091? Assuming a standard 20-year term from the earliest filing date (March 20, 2015) and no patent term extensions, the patent is expected to expire around March 2035. However, actual market exclusivity may be impacted by Patent Term Adjustment and Patent Term Extension. The grant date was December 8, 2020.

4. Is the compound claimed in this patent currently approved for use in epilepsy treatment? No, as of the current analysis, no GABRA5 antagonist compounds, including the one claimed in this patent, have received FDA approval for the treatment of epilepsy.

5. How does antagonizing the GABRA5 subunit differ from enhancing GABAergic transmission for epilepsy treatment? Antagonizing GABRA5 selectively modulates tonic inhibition, which is a specific type of neuronal inhibition, aiming to rebalance excitability. Enhancing GABAergic transmission typically refers to a broader increase in inhibitory neurotransmitter activity, which can lead to more widespread central nervous system depression.

Citations

[1] Amicus Therapeutics, Inc. (2020). Compound for treatment of neurological disorders (U.S. Patent No. 10,851,091). Washington, DC: U.S. Patent and Trademark Office. [2] United States Patent and Trademark Office. (n.d.). Public PAIR. Retrieved from https://portal.uspto.gov/pair/PublicPair (Accessed November 2023).

Drugs Protected by US Patent 10,851,091

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Genentech Inc	ITOVEBI	inavolisib	TABLET;ORAL	219249-001	Oct 10, 2024		RX	Yes	No			Y	Y
Genentech Inc	ITOVEBI	inavolisib	TABLET;ORAL	219249-002	Oct 10, 2024		RX	Yes	Yes			Y	Y

International Family Members for US Patent 10,851,091

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	3317284		C20253008	Finland
European Patent Office	3317284		301344	Netherlands
European Patent Office	3317284		CA 2025 00034	Denmark
European Patent Office	3317284		PA2025536	Lithuania