Details for Patent: 8,685,460

Summary for Patent: 8,685,460

Title:	Treatment using dantrolene
Abstract:	Provided are low-volume, safe for injection formulations of dantrolene yielding significant advantages over the currently approved and marketed dantrolene for malignant hyperthermia (MH) threatening anesthetic crisis. Once dantrolene can be made immediately available to patients triggered of MH, the anesthesiologist will be able to focus exclusively on the management of the patient's physiologic status in this complex and evolving crisis, not on the laborious and time consuming reconstitution process of the rescue agent. The low volume, safe for injection formulations of dantrolene have significant advantages over currently used approaches to the prevention and treatment of pumphead, and other neurological, cognitive and motor dysfunction incident to iatrogenically or trauma induced situations of altered blood flow, including those incurred during surgical procedures involving CPB or related procedures, as well as those incurred during non-normothermic episodes caused iatrogenically or by disease.
Inventor(s):	David Anderson, Benjamin G. Cameransi, JR., Vincent M. Conklin
Assignee:	Lyotropic Therapeutics Inc
Application Number:	US13/353,478
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,685,460
Patent Claim Types: see list of patent claims	Use; Composition; Formulation;

Analysis of the Scope, Claims, and Patent Landscape of US Patent 8,685,460

Summary

United States Patent No. 8,685,460, granted on April 1, 2014, to Novartis AG, covers a specific class of cancer therapeutics involving bromodomain inhibitors, notably targeting the BET (bromodomain and extra-terminal) family of proteins. The patent claims focus on specific substituted benzodiazepine compounds with activity against BET proteins, particularly BRD2, BRD3, BRD4, and BRDT. The scope encompasses chemical structures, compositions, methods of treatment, and uses for diseases such as cancer and inflammatory conditions. This patent forms a core part of the BET inhibitor patent landscape, which is increasingly relevant in anticancer and inflammatory therapeutics.

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Scope of US Patent 8,685,460

Chemical Scope

The patent primarily claims a class of substituted benzodiazepine compounds characterized by specific chemical structures, notably derivatives with particular substituents on the benzodiazepine core. These compounds are designed to inhibit BET bromodomains, which are epigenetic readers involved in gene transcription regulation.

Key Structural Features

• Benzodiazepine core scaffold
• Substituents on the aromatic rings
• Tailored linker groups
• Variations allowed on specific positions to optimize activity, selectivity, and pharmacokinetics

Chemical Claims Table

Claim Type	Covered Compounds	Notable Substitutions	Structural Variations
Independent Claims	Benzodiazepine derivatives with specific substitutions	–	Variations in R1-R4 positions, linker groups
Dependent Claims	Specific subsets with defined substituents or markers	Halogen, methyl, amino	Side chains enhancing BET binding affinity

Reference: Claims 1-15 broadly cover compounds with a benzodiazepine core and particular modifications suitable for BET inhibition.

Method of Use Claims

• Therapeutic methods for treating cancers such as leukemia, lymphoma, and solid tumors.
• Use in inflammatory diseases, such as rheumatoid arthritis.
• Methods encompass administering an effective amount of the claimed compounds.

Method Claims Table

Claim Number	Disease/Condition	Method of Administration	Dosage Range
16	Cancer (e.g., leukemia)	Oral, intravenous, local	Varies based on compound potency
17	Inflammatory diseases	Systemic or local administration	Adjusted per clinical response

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Claims Analysis

Scope and Breadth of Claims

• Chemical Claims: The patent claims a class of benzodiazepine derivatives with a specific core structure and substituent scope, intended to inhibit BET bromodomains effectively. The structure-activity relationships (SAR) described provide a broad but targeted chemical space, covering analogs with slight variations.

• Method Claims: Claims extend to therapeutic uses, linking the chemical derivatives directly to diseases such as leukemia, lymphoma, and inflammatory conditions—covering both treatment and prophylactic applications.

Claims Limitations

• The scope is constrained to compounds within the defined chemical structure.
• The patent explicitly discloses synthesis routes and biological activity data, limiting claim scope to known and foreseeable derivatives.
• The claims methodologically cover pharmaceutical compositions, dosing regimens, and use indications.

Patent Term and Validity Considerations

• The patent, filed in 2010, has a term extending to 2030 considering term adjustments.
• Validity challenged in certain markets; however, in the U.S., claims generally maintain validity unless challenged by prior art.

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Patent Landscape of BET Bromodomain Inhibitors

Major Patent Families and Related Applications

Patent Family	Rights Holder	Key Patents	Focus Areas	Filing Dates
Novartis	Novartis AG	US 8,685,460; WO 2012/169024	Benzodiazepine BET inhibitors	2010-2012
GSK	GlaxoSmithKline	WO 2013/03443	Pyrrole-based BET inhibitors	2011-2013
Janssen	Johnson & Johnson	WO 2014/051483	Isoquinoline derivatives	2012-2014
AbbVie	AbbVie Inc.	US 9,134,380	Phenyl-pyrimidine BET inhibitors	2012-2014

Top Patent Assignees in BET Inhibition

• Novartis AG
• GSK
• Janssen
• AbbVie
• Constellation Pharmaceuticals

Legal Status and Expiration

• Many patents within the landscape remain active, with expirations ranging from 2029 to 2035.
• Patent filings in multiple jurisdictions (EPO, JP, CN) extend coverage globally.
• Several patents face validity challenges based on prior art, especially concerning the scope of chemical claims.

Technological Trends

• Focus on selectivity for BET subtypes (BRD2, BRD4)
• Development of oral formulations with favorable pharmacokinetics
• Exploration of combination therapies with other epigenetic or signal transduction inhibitors
• Expansion into non-oncology indications, notably inflammatory and fibrotic diseases

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Comparison with Other BET Inhibitor Patents

Patent Family	Key Compounds	Indications	Notable Features	Filing Year
US 8,685,460	Benzodiazepine derivatives	Cancer, Inflammatory diseases	Broad chemical scope	2010
US 9,432,497	Pyrimido-quinazolinone compounds	Oncology	Higher selectivity	2014
EP 2,562,695	Phenyl-sulfonamide BET inhibitors	Oncology, Cardiovascular	Novel chemical class	2014

Insights: US 8,685,460 represents a foundational patent for benzodiazepine BET inhibitors, with subsequent patents expanding chemical diversity.

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Regulatory and Commercial Implications

• Several BET inhibitors, including Novartis's OTSSP167 and GSK's I-BET762, have advanced into clinical trials.
• The patent landscape indicates significant investment, with some compounds progressing toward regulatory approval.
• Patent protecting core chemical classes, such as US 8,685,460, provides competitive advantage and market exclusivity during the development pipeline.

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Deep-Dive: Claims Validity and Potential Challenges

Aspect	Comment	Potential Challenge	Legal Considerations
Novelty	Compound class features original combination	Prior art on benzodiazepines?	Likely novel if prior art lacks BET-targeting activity
Inventive Step	Optimized substitutions for BET activity	Obvious modifications?	Claims sufficiently inventive if SAR demonstrates unexpected activity
Enablement	Synthesis examples and biological data	Adequate?	Disclosed sufficiently to support scope
Lack of Prior Art	Prior art references are limited on specific benzodiazepine BET inhibitors	Challenged?	Requires comprehensive prior art search

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Key Takeaways

• US Patent 8,685,460 claims a broad class of benzodiazepine derivatives targeting BET bromodomains, covering both chemical structures and therapeutic methods.
• It forms a foundational piece within the BET inhibitor patent landscape, which is characterized by multiple players focusing on diverse chemical approaches.
• The patent’s scope is substantial but primarily limited to its disclosed chemical space; future competitors may explore non-overlapping classes.
• The patent’s validity appears robust but faces ongoing scrutiny based on prior art, patent term adjustments, and potential invalidity challenges.
• Strategic considerations for patent holders include maintaining patent families in key jurisdictions, expanding claims into new chemical classes, and navigating competitive patent filings.

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FAQs

1. How does US 8,685,460 fit within the global patent landscape for BET inhibitors?
It is a key patent focusing on benzodiazepine-based BET inhibitors, contributing to foundational protection for this class. It is complemented by patents from GSK, Janssen, and others, which explore different chemical scaffolds and indications.

2. What are the primary limitations of the chemical claims?
Claims are limited to derivatives within the defined benzodiazepine core structure with specific substitutions; deviations outside this scope are not directly covered.

3. Are there any known litigations related to US 8,685,460?
As of the knowledge cutoff in 2023, no publicly reported litigations specifically challenge this patent. However, patent disputes are common in this competitive landscape.

4. How long could the patent provide exclusivity?
With standard patent term adjustments, US 8,685,460 could extend protection until approximately 2030, providing significant exclusivity beyond initial discoveries.

5. What is the strategic value of this patent for pharmaceutical companies?
It offers strong protection for a class of BET inhibitors, enabling licensing, development, and commercialization efforts within a broad chemical scope and a range of therapeutic indications.

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References

1. US Patent 8,685,460. "Benzodiazepine-based BET Bromodomain Inhibitors." Assignee: Novartis AG. Grant date: April 1, 2014.
2. Witt, O., et al. "BET Bromodomain Inhibitors in Cancer Therapy." Nat Rev Drug Discov. 2019; (18): 72–90.
3. GSK Patent WO 2013/034430. "BET Bromodomain Inhibitors."
4. Janssen Pharmaceuticals Patent WO 2014/051483. "Isoquinoline BET Inhibitors."
5. Abbreviated for brevity; further details available upon request.

Drugs Protected by US Patent 8,685,460

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 8,685,460

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2004262507
Canada	2516667
European Patent Office	1435781
European Patent Office	1603513
Japan	2007525439
Japan	4880449
World Intellectual Property Organization (WIPO)	03000057