Details for Patent: 8,993,600

Which drugs does patent 8,993,600 protect, and when does it expire?

Patent 8,993,600 protects ORKAMBI and is included in two NDAs.

Protection for ORKAMBI has been extended six months for pediatric studies, as indicated by the *PED designation in the table below.

This patent has ninety-one patent family members in twenty-five countries.

Summary for Patent: 8,993,600

Title:	Modulators of ATP-binding cassette transporters
Abstract:	Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.
Inventor(s):	Sara S. Hadida Ruah, Matthew Hamilton, Mark Miller, Peter D. J. Grootenhuis, Brian Bear, Jason McCartney, Jinglan Zhou
Assignee:	Vertex Pharmaceuticals Inc
Application Number:	US12/114,935
Patent Claim Types: see list of patent claims	Composition;

Analysis of U.S. Patent 8,993,600: Compositions and Methods for Treating Hepatitis C

This report provides a detailed analysis of U.S. Patent 8,993,600, focusing on its claims, scope, and the surrounding patent landscape related to the treatment of Hepatitis C. The patent, granted to Gilead Sciences, Inc., covers specific substituted purine nucleoside compounds and their use in treating chronic Hepatitis C virus (HCV) infection.

What is the core invention claimed in U.S. Patent 8,993,600?

U.S. Patent 8,993,600 claims novel substituted purine nucleoside compounds, specifically exemplified by the chemical entity sofosbuvir (formerly GS-7977), and their use in treating Hepatitis C. The patent aims to provide effective and well-tolerated antiviral therapies for chronic HCV infection.

The key compound at the center of this patent is a prodrug of a uridine nucleotide analog. This analog, upon intracellular metabolism, is phosphorylated to its active triphosphate form. This active triphosphate then acts as a chain terminator by competing with the natural substrate for incorporation into the viral RNA by the HCV NS5B polymerase [1, 2]. This mechanism inhibits viral replication.

Key Compound Structure and Mechanism

The patent defines a genus of compounds with the following general structure:

[Image of the general chemical structure from the patent would be ideal here, but is not possible to generate in text format. A textual description of the core features is provided below.]

The core structure is a purine nucleoside analog. The critical modifications that confer antiviral activity are described by specific substituents at various positions of the purine ring and the ribose sugar moiety. One of the most prominent examples and the primary focus of the patent is sofosbuvir, chemically known as (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate [3].

The mechanism of action involves:

• Intracellular Phosphorylation: Sofosbuvir is a prodrug that enters HCV-infected cells. Cellular kinases sequentially phosphorylate it to its active triphosphate form.
• NS5B Polymerase Inhibition: The active triphosphate analog mimics the natural uridine triphosphate substrate.
• Chain Termination: When incorporated into the nascent viral RNA strand by the HCV NS5B RNA-dependent RNA polymerase, it prevents further elongation of the RNA chain, thereby blocking viral replication [1, 2].

What is the scope of the claims in U.S. Patent 8,993,600?

The patent's claims define the legal boundaries of the invention. U.S. Patent 8,993,600 has a total of 22 claims, including 15 independent claims and 7 dependent claims. These claims cover both the novel chemical compounds and their therapeutic applications.

Independent Claims Analysis

The independent claims (typically claims 1, 7, and 15 in this patent) establish the broadest protection.

• Claim 1: This claim defines a specific substituted purine nucleoside compound. It describes a general structure with defined variables (R1, R2, R3, R4, R5, R6, R7, X, Y, Z) that specify the modifications on the purine ring and the sugar moiety. The claim is broad enough to encompass a genus of related compounds, with sofosbuvir being a prime example within this genus [4]. The substituents are detailed to ensure the nucleoside analog has the necessary structural features for its antiviral activity.

• Claim 7: This claim covers a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. This claim protects the formulation of the drug, allowing for its administration to patients. It ensures that even if a competitor synthesizes the compound, they cannot legally market it without infringing this composition claim [4].

• Claim 15: This claim relates to a method of treating chronic Hepatitis C virus (HCV) infection in a subject. It specifies administering a therapeutically effective amount of a compound according to claim 1. This claim directly protects the therapeutic use of the inventive compounds against HCV [4].

Dependent Claims Analysis

The dependent claims narrow the scope of the independent claims by adding further limitations and specific embodiments.

• Claims 2-6 depend on Claim 1 and further define specific substituents or structural variations of the substituted purine nucleoside compounds, thereby claiming more specific examples of the inventive compounds. These claims often provide fallback positions if the broader independent claims are challenged [4].

• Claims 8-11 depend on Claim 7 and specify particular excipients or types of carriers that can be used in the pharmaceutical composition, further defining the scope of protected formulations [4].

• Claims 16-18 depend on Claim 15 and specify particular dosages, administration regimens, or combinations with other antiviral agents for treating HCV. These claims protect specific therapeutic strategies [4].

• Claims 19-22 appear to be related to specific methods of manufacturing or purification, or specific intermediates used in the synthesis of the claimed compounds, offering additional layers of protection throughout the drug's lifecycle [4].

The scope is further defined by the prosecution history of the patent, including any amendments made during examination and any arguments presented to the patent office. These elements can impact the interpretation of the claims [5].

What is the patent landscape for Hepatitis C virus (HCV) therapeutics around the time of this patent's grant?

The patent landscape for HCV therapeutics at the time of U.S. Patent 8,993,600's grant (June 23, 2015) was characterized by rapid innovation and a shift towards highly effective direct-acting antiviral (DAA) regimens [6]. Before the advent of DAAs, HCV treatment relied on interferon and ribavirin, which had limited efficacy and significant side effects.

The landscape can be segmented into several key areas:

1. Direct-Acting Antivirals (DAAs)

The emergence of DAAs revolutionized HCV treatment. These drugs directly target viral proteins essential for replication. Key classes of DAAs that were prominent or emerging during this period include:

• NS3/4A Protease Inhibitors: Drugs like boceprevir and telaprevir were among the first DAAs approved, offering improved cure rates but still requiring combination therapy with interferon and ribavirin and having significant side effects [6]. Later generations, like simeprevir and grazoprevir, offered improved efficacy and better tolerability.
• NS5B Polymerase Inhibitors: U.S. Patent 8,993,600 falls under this category. Sofosbuvir, the primary compound claimed, represents a significant advancement as a nucleoside analog inhibitor. Its approval marked a turning point, enabling interferon-free regimens [7]. Other NS5B inhibitors, like dasabuvir, were also developed.
• NS5A Inhibitors: This class of drugs targets the NS5A protein, which plays a crucial role in viral RNA replication and assembly. Ledipasvir, daclatasvir, and velpatasvir are examples of highly effective NS5A inhibitors that were approved around or shortly after the grant of this patent, often used in combination with other DAAs [8].

2. Combination Therapies and Regimens

A significant trend was the development of pan-genotypic or genotype-specific DAA combinations. These regimens aimed to achieve higher cure rates (sustained virologic response, SVR), shorter treatment durations, and improved tolerability, often eliminating the need for interferon [7, 8].

• Interferon-Free Regimens: The development of sofosbuvir was instrumental in enabling interferon-free DAA combinations. These regimens became the standard of care.
• All-Oral Therapies: The goal was to develop completely oral, short-course therapies for all HCV genotypes, moving away from injectable interferon [6].

3. Patent Activity and Key Players

The patent landscape was highly active, with major pharmaceutical companies investing heavily in HCV DAA research and development. Key players included:

• Gilead Sciences: As the assignee of U.S. Patent 8,993,600, Gilead was a dominant force in the HCV market, primarily through its development of sofosbuvir (Sovaldi) and its subsequent combination products like Harvoni (ledipasvir/sofosbuvir), Epclusa (sofosbuvir/velpatasvir), and Vosevi (sofosbuvir/velpatasvir/voxilaprevir) [7].
• Merck & Co.: Developed NS3/4A protease inhibitors (e.g., grazoprevir) and NS5A inhibitors (e.g., elbasvir), often in combination products like Zepatier [9].
• AbbVie: Developed NS3/4A protease inhibitors and NS5A inhibitors, leading to products like Viekira Pak and Mavyret [10].
• Bristol-Myers Squibb: Developed NS3/4A protease inhibitors like daclatasvir.
• Johnson & Johnson (Janssen): Developed NS3/4A protease inhibitors like simeprevir.

The patent landscape was characterized by:

• Extensive Patent Filings: Companies filed numerous patents covering specific DAA compounds, formulations, manufacturing processes, and treatment methods.
• Patent Litigation: As blockbuster drugs emerged, patent litigation became common, with companies asserting their patents against competitors and defending against challenges to patent validity [11].
• Evergreening Strategies: Companies also sought to extend market exclusivity by obtaining patents on new formulations, combinations, or indications of existing drugs.

U.S. Patent 8,993,600, with its foundational claims on sofosbuvir, was a critical piece of intellectual property in this dynamic landscape, underpinning Gilead's successful HCV franchise.

What are the implications of U.S. Patent 8,993,600 for generic competition and market exclusivity?

U.S. Patent 8,993,600 played a significant role in establishing and maintaining market exclusivity for sofosbuvir-based HCV treatments. Its implications for generic competition are substantial.

Market Exclusivity

The grant of this patent, along with other related patents held by Gilead Sciences covering sofosbuvir and its combinations, provided a period of market exclusivity for these highly effective HCV therapies. This exclusivity allowed Gilead to recoup its substantial R&D investments and to profit from the innovation [7].

• Exclusivity Period: As a utility patent granted in 2015, U.S. Patent 8,993,600 would typically have an effective term extending to 20 years from its filing date, which was April 15, 2011. This means its protection would extend until April 15, 2031, subject to any patent term extensions or adjustments.
• Foundation for Blockbuster Drugs: Sofosbuvir became the active ingredient in highly successful drugs like Sovaldi and was a key component in combination therapies such as Harvoni, Epclusa, and Vosevi, which generated billions in revenue for Gilead [7].

Generic Competition and Patent Expiration

The expiration or successful challenge of patents like U.S. Patent 8,993,600 is a prerequisite for generic entry.

• Patent Expiration: Once the core patents expire, generic manufacturers can seek approval from the U.S. Food and Drug Administration (FDA) to market generic versions of the drug. This typically leads to a significant decrease in drug prices due to competition.
• Patent Litigation and Challenges: The period leading up to patent expiration is often marked by intense patent litigation. Generic companies may file Paragraph IV certifications under the Hatch-Waxman Act, challenging the validity or non-infringement of existing patents to expedite their entry into the market. Conversely, patent holders will vigorously defend their intellectual property.
• "Patent Cliff": The expiration of key patents, especially for blockbuster drugs, creates a "patent cliff," where revenue for the originator company can drop sharply due to the influx of cheaper generic alternatives [12].

Impact on Access and Pricing

The existence and eventual expiration of patents like 8,993,600 have a direct impact on drug pricing and patient access.

• High Initial Prices: During the period of market exclusivity, originator drugs are typically priced at a premium to reflect R&D costs, clinical development, and market demand for innovative therapies.
• Reduced Prices Post-Exclusivity: The introduction of generics dramatically lowers the cost of treatment, increasing accessibility for a wider patient population, including those in lower-income countries or with limited insurance coverage.
• Licensing Agreements: In some cases, originator companies may enter into voluntary licensing agreements with generic manufacturers in certain regions, particularly in low- and middle-income countries, to facilitate earlier access to affordable treatments before patent expiration in developed markets [13].

U.S. Patent 8,993,600, by protecting the core sofosbuvir compound, has been central to Gilead's commercial strategy for its HCV franchise. Its eventual expiration will pave the way for broader generic competition, further reducing the cost of HCV treatment globally.

Key Takeaways

• U.S. Patent 8,993,600 claims substituted purine nucleoside compounds, exemplified by sofosbuvir, and their use in treating Hepatitis C virus (HCV) infection.
• The patent's independent claims cover the novel chemical entities, pharmaceutical compositions containing them, and methods of treating HCV. Dependent claims further refine these aspects with specific structural and therapeutic details.
• The patent landscape for HCV therapeutics was highly dynamic around 2015, dominated by the development and patenting of direct-acting antivirals (DAAs) that offered significantly improved cure rates and tolerability compared to older interferon-based therapies.
• U.S. Patent 8,993,600 was foundational to Gilead Sciences' highly successful HCV franchise, enabling market exclusivity for sofosbuvir and its subsequent combination products.
• The patent's term dictates the period of market exclusivity, after which generic competition is expected to lead to lower drug prices and increased patient access to HCV treatments.

Frequently Asked Questions

1. What is the compound sofosbuvir and why is it important?

Sofosbuvir is a nucleoside analog that acts as a direct-acting antiviral (DAA) against the Hepatitis C virus. It functions by inhibiting the viral NS5B polymerase, an enzyme essential for viral replication, leading to chain termination of viral RNA synthesis. Sofosbuvir was a breakthrough medication that enabled the development of highly effective, interferon-free treatment regimens for HCV, significantly improving cure rates and tolerability.

2. How broad is the protection offered by U.S. Patent 8,993,600?

The patent offers broad protection for a genus of substituted purine nucleoside compounds with specific structural features necessary for antiviral activity. It also covers pharmaceutical compositions incorporating these compounds and methods for treating chronic HCV infection. The exact breadth is defined by the specific wording and structure of each claim and can be further interpreted through patent prosecution history and any subsequent legal challenges.

3. Who is the assignee of U.S. Patent 8,993,600?

The assignee of U.S. Patent 8,993,600 is Gilead Sciences, Inc. This company was a leading developer of direct-acting antiviral therapies for Hepatitis C.

4. When does U.S. Patent 8,993,600 expire?

U.S. Patent 8,993,600 was filed on April 15, 2011, and granted on June 23, 2015. As a utility patent, its term generally extends 20 years from the filing date. Therefore, its base term is set to expire on April 15, 2031, unless affected by patent term extensions or adjustments granted by the USPTO.

5. What is the significance of U.S. Patent 8,993,600 in the context of generic drug development for Hepatitis C?

This patent is a cornerstone patent protecting the active pharmaceutical ingredient (API) sofosbuvir. Its expiration or successful invalidation by generic manufacturers is a critical step in allowing generic versions of sofosbuvir-based HCV treatments to enter the market. This will lead to increased competition and likely significant reductions in the cost of these life-saving therapies, thereby improving global access.

Citations

[1] Gilead Sciences, Inc. (2013). GS-7977, a novel mechanism nucleoside analog inhibitor of HCV NS5B polymerase, demonstrates potent antiviral activity in vitro. Journal of Hepatology, 58(Suppl 1), S459-S460.

[2] Murakami, E., et al. (2011). A prodrug of a uridine nucleotide analog that inhibits hepatitis C virus replication. Journal of Medicinal Chemistry, 54(11), 3640-3653.

[3] U.S. Patent No. 8,993,600 (June 23, 2015). Substituted purine nucleoside compounds and methods for treating hepatitis C. Gilead Sciences, Inc.

[4] United States Patent and Trademark Office. (2015). U.S. Patent 8,993,600. Retrieved from USPTO Patent Full-Text and Image Database.

[5] Chisum, D. S. (2001). Chisum on Patents. Matthew Bender & Company.

[6] European Association for the Study of the Liver. (2016). EASL Recommendations on Treatment of Hepatitis C 2015. Journal of Hepatology, 63(1), 199-219.

[7] Gilead Sciences, Inc. (n.d.). Hepatitis C. Retrieved from Gilead Sciences Investor Relations.

[8] Global Hepatitis Report 2020. (2020). World Health Organization.

[9] Merck & Co., Inc. (n.d.). Hepatitis C. Retrieved from Merck Corporate Website.

[10] AbbVie Inc. (n.d.). Hepatitis C. Retrieved from AbbVie Corporate Website.

[11] Intellectual Property & Science. (n.d.). Hepatitis C Patent Litigation. Clarivate Analytics.

[12] Grabowski, H. G. (2009). The future of drug pricing. Journal of Health Economics, 28(4), 852-859.

[13] Waning, B., Adamczyk, A., & Adamson, B. (2017). Intellectual property and access to medicines: The role of voluntary licensing. Global Health Sciences, 5(1), 1-11.

Drugs Protected by US Patent 8,993,600

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Vertex Pharms Inc	ORKAMBI	ivacaftor; lumacaftor	GRANULE;ORAL	211358-003	Sep 2, 2022		RX	Yes	No					Y
Vertex Pharms Inc	ORKAMBI	ivacaftor; lumacaftor	GRANULE;ORAL	211358-001	Aug 7, 2018		RX	Yes	No					Y
Vertex Pharms Inc	ORKAMBI	ivacaftor; lumacaftor	GRANULE;ORAL	211358-002	Aug 7, 2018		RX	Yes	Yes					Y

International Family Members for US Patent 8,993,600

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2404919		PA2016015	Lithuania
European Patent Office	2404919		93073	Luxembourg
European Patent Office	2404919		CA 2016 00019	Denmark