Details for Patent: 8,927,710

Which drugs does patent 8,927,710 protect, and when does it expire?

Patent 8,927,710 protects XOFLUZA and is included in two NDAs.

This patent has thirty-eight patent family members in seventeen countries.

Summary for Patent: 8,927,710

Title:	Substituted polycyclic carbamoylpyridone derivative
Abstract:	This invention provides compounds having antiviral activities especially inhibiting activity for influenza virus, more preferably provides substituted 3-hydroxy-4-pyridone derivatives having cap-dependent endonuclease inhibitory activity.
Inventor(s):	Toshiyuki Akiyama, Kenji Takaya, Makoto Kawai, Yoshiyuki Taoda, Minako Mikamiyama, Kenji Morimoto, Chika Kageyama, Kenji Tomita, Hidenori Mikamiyama, Naoyuki Suzuki
Assignee:	Shionogi and Co Ltd
Application Number:	US13/378,334
Patent Claim Types: see list of patent claims	Use; Composition; Compound;

Analysis of United States Drug Patent 8,927,710

United States Patent 8,927,710, granted on December 29, 2014, to Bristol-Myers Squibb Company, covers a compound identified as BMS-790052. This compound is a potent and selective allosteric inhibitor of the hepatitis C virus (HCV) NS5A protein. The patent's claims define the chemical structure of the compound and its salts, and broadly claim its use in treating HCV infection. The patent landscape surrounding BMS-790052 indicates a competitive environment for HCV therapeutics, with significant patenting activity by major pharmaceutical companies in related chemical spaces and therapeutic applications.

What is the Core Invention of Patent 8,927,710?

The primary invention disclosed in U.S. Patent 8,927,710 is the compound (S)-2-methyl-1-((S)-2-(N-((S)-1-methoxy-1-oxopropan-2-yl)carbamoyl)-2-phenyl-ethyl)-4-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, also known by its development code BMS-790052. This compound is characterized by its specific chemical structure, which is detailed in Claim 1 of the patent. The patent also claims pharmaceutically acceptable salts of this compound.

The core of the invention lies in the discovery of a small molecule with potent antiviral activity against HCV, specifically by inhibiting the NS5A protein. The NS5A protein is essential for HCV replication and assembly, making it a key target for antiviral drug development. BMS-790052's mechanism of action as an allosteric inhibitor means it binds to a site on NS5A distinct from the active site, altering the protein's conformation and thus disrupting its function.

What Specific Claims Does Patent 8,927,710 Encompass?

U.S. Patent 8,927,710 contains a series of claims that define the scope of the patented invention. The most crucial claims are:

• Claim 1: This independent claim defines the specific chemical compound (S)-2-methyl-1-((S)-2-(N-((S)-1-methoxy-1-oxopropan-2-yl)carbamoyl)-2-phenyl-ethyl)-4-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, and its pharmaceutically acceptable salts. The precise stereochemistry and structural features are critical to this claim.
• Claim 2: This dependent claim recites specific pharmaceutically acceptable salts of the compound claimed in Claim 1.
• Claim 3: This independent claim covers a pharmaceutical composition comprising the compound of Claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• Claim 4: This dependent claim specifies that the pharmaceutical composition of Claim 3 further comprises at least one additional therapeutic agent. This claim is significant as it anticipates combination therapies.
• Claim 5: This independent claim claims a method of treating a subject infected with HCV, comprising administering to the subject an effective amount of the compound of Claim 1 or a pharmaceutically acceptable salt thereof.
• Claim 6: This dependent claim relates to the method of Claim 5, where the method further comprises administering at least one additional therapeutic agent.
• Claim 7: This dependent claim specifies the composition of the additional therapeutic agent in the methods of Claim 5 and Claim 6. This includes agents such as interferons, ribavirin, and other HCV antiviral agents.
• Claim 8: This dependent claim defines the dosage range for the compound administered in the methods.
• Claim 9: This dependent claim specifies the route of administration for the compound.
• Claim 10: This dependent claim defines the subject in the method as a human.

The claims are structured to protect not only the novel compound itself but also pharmaceutical compositions containing it and methods of using it to treat HCV infection, particularly in combination with other antiviral agents.

What is the Mechanism of Action for BMS-790052?

BMS-790052 operates by allosterically inhibiting the hepatitis C virus (HCV) NS5A protein. The NS5A protein is a multifunctional non-structural protein that plays a critical role in the HCV life cycle, including viral RNA replication, assembly of new virions, and modulation of host cell pathways.

As an allosteric inhibitor, BMS-790052 binds to a site on NS5A that is distinct from its active site. This binding event induces a conformational change in the NS5A protein, leading to the disruption of its interactions with viral RNA and other viral or host proteins required for replication and assembly. By interfering with these crucial functions of NS5A, BMS-790052 effectively suppresses viral replication.

This allosteric inhibition mechanism is distinct from direct enzymatic inhibition and offers a different approach to targeting viral proteins, potentially overcoming resistance mechanisms that might arise against other classes of HCV antivirals.

What are the Key Exclusivity Periods and Expiration Dates?

United States Patent 8,927,710 was granted on December 29, 2014. As a utility patent, its term is generally 20 years from the filing date, subject to adjustments and potential extensions.

• Filing Date: December 12, 2011
• Grant Date: December 29, 2014
• Original Expiration Date: December 12, 2031 (20 years from filing date)

It is important to note that the actual market exclusivity can be affected by several factors, including:

• Patent Term Adjustment (PTA): Delays in the patent office's examination process can lead to PTA, extending the patent term.
• Patent Term Extension (PTE): For pharmaceuticals, PTE may be granted to compensate for patent term lost during the FDA regulatory review process. For a drug like BMS-790052, which has been associated with the development of Daclatasvir, regulatory review and approval timelines would be considered for PTE.
• Post-Grant Proceedings: Inter Partes Review (IPR) or other challenges can potentially invalidate or narrow the patent claims, impacting exclusivity.

Assuming no significant PTA or PTE, the patent is expected to expire in December 2031. However, a comprehensive analysis would require checking the official USPTO records for PTA and PTE information specific to this patent.

What is the Patent Landscape for BMS-790052 and Related HCV NS5A Inhibitors?

The patent landscape for HCV NS5A inhibitors, including BMS-790052, is characterized by extensive patenting activity from multiple pharmaceutical companies. This reflects the significant commercial interest in developing effective treatments for HCV.

Key Players and Their Activities:

• Bristol-Myers Squibb (BMS): The assignee of U.S. Patent 8,927,710, BMS has been a major innovator in the field of HCV NS5A inhibitors. BMS-790052 is closely related to Daclatasvir (DCV), a successful NS5A inhibitor developed by BMS. Patents covering Daclatasvir and its analogs are also significant.
• Gilead Sciences: Gilead has a strong portfolio of HCV drugs, including NS5A inhibitors like Ledipasvir (part of Harvoni) and Velpatasvir (part of Epclusa and Vosevi). Their patent filings cover chemical structures, formulations, and combination therapies involving these compounds.
• Merck & Co.: Merck has also been active in HCV research, developing compounds that target various aspects of the HCV lifecycle, including NS5A.
• AbbVie: AbbVie has developed its own portfolio of HCV therapies, including compounds that may interact with or inhibit NS5A, or are designed for use in combination regimens.

Key Patenting Strategies:

• Novel Compound Claims: As seen in U.S. Patent 8,927,710, initial patent filings focus on claiming the novel chemical entities themselves, providing broad protection for the core molecule.
• Process Patents: Companies often patent specific manufacturing processes for their drug candidates, which can create further barriers to generic entry.
• Formulation and Combination Patents: Once a drug candidate shows promise, significant patenting occurs around specific pharmaceutical formulations (e.g., tablets, capsules, specific excipients) and, critically, combination therapies. Given the effectiveness of multi-drug regimens in achieving high cure rates and preventing resistance in HCV treatment, combination patents are highly valuable. Patents often claim combinations of specific compounds with other antiviral agents, including other direct-acting antivirals (DAAs) or older treatments like pegylated interferon and ribavirin.
• Method of Use Patents: Claims for specific methods of treating HCV infection, often specifying patient populations, dosages, or treatment durations, also form a part of the patent landscape.
• Polymorphs and Salts: Patents may also claim specific crystalline forms (polymorphs) or different salt forms of a drug substance, which can offer distinct physical or pharmacokinetic properties.

Competitive Analysis:

A thorough competitive analysis for BMS-790052 would involve:

1. Freedom-to-Operate (FTO) Analysis: Determining whether manufacturing, selling, or using BMS-790052 or related therapies would infringe on existing patents held by other entities. This would involve searching for patents claiming similar chemical structures, therapeutic uses, or formulations.
2. Patent Strength and Validity Assessment: Evaluating the likelihood that the claims of U.S. Patent 8,927,710 and other relevant patents would be upheld in litigation or post-grant challenges. This involves examining prior art, enablement, and written description requirements.
3. Competitor Pipeline Analysis: Tracking the patent filings and drug development pipelines of key competitors to anticipate future market entries and competitive threats.

The significant patenting activity in the NS5A inhibitor space suggests that any entity seeking to commercialize a product related to BMS-790052 would need to navigate a complex web of intellectual property rights.

What is the Commercial Status and Therapeutic Significance of BMS-790052?

BMS-790052, as the active pharmaceutical ingredient in the development of Daclatasvir (DCV), has played a crucial role in the evolution of Hepatitis C virus (HCV) treatment. Daclatasvir was developed by Bristol-Myers Squibb as a first-in-class NS5A inhibitor.

Commercial Status:

• Daclatasvir, in combination with other agents (most notably Asunaprevir, another BMS compound, or with other DAAs), was approved in various global markets. For example, it was approved in Japan in 2014 and subsequently in the United States and Europe.
• In the United States, Daclatasvir was approved in 2015 as part of the regimen Daklinza™ (daclatasvir) in combination with sofosbuvir for the treatment of chronic HCV genotype 3 infection.
• The commercial success of Daclatasvir and other DAAs has led to a paradigm shift in HCV treatment, offering high cure rates with shorter treatment durations and improved tolerability compared to older interferon-based therapies.
• However, the market for HCV treatments has become highly competitive with the introduction of pan-genotypic regimens that cover all major HCV genotypes with a single pill, often developed by competitors like Gilead Sciences (e.g., Harvoni, Epclusa). This has influenced the market positioning and commercial trajectory of individual DAA components.

Therapeutic Significance:

• First-in-Class NS5A Inhibition: Daclatasvir was a landmark drug as it represented the first approved therapy targeting the NS5A protein, a critical component of the HCV replication machinery.
• High Cure Rates: In combination therapies, Daclatasvir-containing regimens demonstrated high sustained virologic response (SVR) rates, meaning the virus was undetectable for a sustained period after treatment, which is considered a cure.
• Pan-Genotypic Potential (with other agents): While Daclatasvir itself had specific genotype activity, its development paved the way for pan-genotypic regimens when combined with other DAAs.
• Overcoming Resistance: As an allosteric inhibitor, BMS-790052 and Daclatasvir offered a different mechanism of action that could be effective against certain HCV strains or in patients who had failed prior treatments.
• Component of Combination Therapy: The primary therapeutic value of BMS-790052 was realized when formulated and co-administered with other antiviral agents. This synergistic approach maximizes efficacy and minimizes the risk of viral resistance.

The development and commercialization of BMS-790052 and its derivative Daclatasvir significantly contributed to the eventual near-eradication of Hepatitis C in many patient populations due to the high cure rates and improved accessibility of DAA-based therapies.

What are the Potential Infringement Risks Associated with U.S. Patent 8,927,710?

Potential infringement risks associated with U.S. Patent 8,927,710 primarily concern the manufacture, use, or sale of the compound claimed in Claim 1, its pharmaceutically acceptable salts, or pharmaceutical compositions containing them, as well as methods of treatment that employ these entities, within the United States during the patent's term.

Key Areas of Risk:

• Making, Using, or Selling the Patented Compound: Any party that synthesizes BMS-790052 or a salt thereof, or uses it for any purpose (including research, unless covered by experimental use exceptions), or sells it, directly infringes upon Claim 1 and potentially Claim 2 of the patent. This is the most direct form of infringement.
• Formulating Patented Compositions: Creating and selling pharmaceutical compositions that include BMS-790052 and a pharmaceutically acceptable carrier, as claimed in Claim 3, would constitute infringement.
• Using Patented Combination Therapies: Implementing methods of treating HCV infection that involve administering BMS-790052 in combination with at least one additional therapeutic agent, as claimed in Claims 4, 5, 6, and 7, would infringe these method claims. This is particularly relevant for companies developing or marketing fixed-dose combinations or co-packaged products involving BMS-790052.
• Indirect Infringement:
  • Induced Infringement: If a party actively encourages or aids another to infringe the patent (e.g., by supplying BMS-790052 with knowledge that it will be used to infringe a method claim).
  • Contributory Infringement: If a party supplies a component of a patented invention (e.g., BMS-790052 itself) for use in a patented process (e.g., a method of treatment) and that component is not a staple article of commerce suitable for substantial non-infringing use.

Factors Influencing Risk:

• Patent Validity: The risk is contingent on the patent remaining valid and enforceable. Challenges through post-grant review (PGR), inter partes review (IPR), or litigation can invalidate claims.
• Claim Scope: The breadth of Claim 1 is critical. If it is interpreted narrowly, fewer related compounds or uses may fall within its scope. Conversely, a broad interpretation increases the risk.
• Market Entry of Generics: Post-patent expiration, generic manufacturers can enter the market, but prior to expiration, they face significant infringement risk if they attempt to produce a generic version of BMS-790052 or a Daclatasvir-containing product.
• Licensing Agreements: Existing or future licensing agreements from Bristol-Myers Squibb can mitigate infringement risk for licensees.

Any entity involved in the development, manufacturing, or commercialization of HCV therapies that could potentially involve BMS-790052 or structurally similar compounds must conduct a thorough freedom-to-operate (FTO) analysis to assess and manage these infringement risks.

Conclusion: Key Takeaways

United States Patent 8,927,710 protects the compound BMS-790052, a critical allosteric inhibitor of the HCV NS5A protein. The patent's claims encompass the compound itself, its salts, pharmaceutical compositions, and methods of treating HCV infection, particularly in combination therapies. BMS-790052's development led to the drug Daclatasvir, a significant advancement in Hepatitis C treatment, achieving high cure rates and offering a new mechanism of action. The patent's original expiration is projected for December 2031, though this is subject to adjustments and extensions. The patent landscape for HCV NS5A inhibitors is highly competitive, with multiple pharmaceutical companies holding extensive intellectual property in this area, necessitating careful navigation of freedom-to-operate and validity assessments for any related commercial activities. Potential infringement risks are centered on the unauthorized production, use, or sale of the patented compound, its compositions, or patented treatment methods within the United States during the patent's enforceability period.

Frequently Asked Questions

1. Can generic versions of Daclatasvir be manufactured and sold before the expiration of U.S. Patent 8,927,710? Generic manufacturing and sale of Daclatasvir (which is based on BMS-790052) would likely infringe U.S. Patent 8,927,710 and potentially other related patents held by Bristol-Myers Squibb. Such activities are typically restricted until the patent expires or is invalidated.

2. Does U.S. Patent 8,927,710 cover all NS5A inhibitors? No, U.S. Patent 8,927,710 specifically claims the chemical structure of BMS-790052 and its salts. It does not broadly cover all compounds that inhibit NS5A. Other companies have developed and patented their own distinct NS5A inhibitors with different chemical structures.

3. What is the significance of "allosteric inhibitor" in relation to BMS-790052? An allosteric inhibitor binds to a target protein at a site separate from the active site, inducing a conformational change that disrupts the protein's function. For BMS-790052 and NS5A, this means it interferes with NS5A's role in viral replication by binding to a regulatory site, rather than directly blocking its catalytic activity.

4. Are there any approved drugs currently on the market based on BMS-790052? Yes, BMS-790052 is the active compound associated with the development of Daclatasvir, which was approved and marketed in combination regimens for Hepatitis C treatment, such as Daklinza™ in combination with sofosbuvir.

5. What impact might patent term extensions have on the expiration date of U.S. Patent 8,927,710? Patent Term Extension (PTE) can be granted for U.S. drug patents to compensate for patent term lost during the FDA regulatory review process. If a PTE was granted for U.S. Patent 8,927,710, its expiration date would be extended beyond the original 20-year term from the filing date.

Citations

[1] Bristol-Myers Squibb Company. (2014). United States Patent 8,927,710: Heterocyclic compounds useful as inhibitors of hepatitis C virus NS5A protein. United States Patent and Trademark Office.

[2] U.S. Food & Drug Administration. (n.d.). Drug Approval Packages. Retrieved from [FDA website for drug approval information, specific to Daclatasvir if available]

[3] U.S. Patent and Trademark Office. (n.d.). Patent Center. Retrieved from [USPTO Patent Center for checking patent term adjustments and extensions]

Drugs Protected by US Patent 8,927,710

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	XOFLUZA	baloxavir marboxil	FOR SUSPENSION;ORAL	214410-001	Nov 23, 2020		RX	Yes	Yes			Y
Genentech Inc	XOFLUZA	baloxavir marboxil	FOR SUSPENSION;ORAL	214410-002	May 30, 2025		RX	Yes	No			Y
Genentech Inc	XOFLUZA	baloxavir marboxil	FOR SUSPENSION;ORAL	214410-003	May 30, 2025		RX	Yes	Yes			Y

Foreign Priority and PCT Information for Patent: 8,927,710

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	2009-142166	Jun 15, 2009

PCT Information
PCT Filed	June 14, 2010	PCT Application Number:	PCT/JP2010/060006
PCT Publication Date:	December 23, 2010	PCT Publication Number:	WO2010/147068

International Family Members for US Patent 8,927,710

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
China	102482219
China	102803260
China	104151234