Details for Patent: 5,364,630

Summary for Patent: 5,364,630

Title:	Subsaturated nicotine transdermal therapeutic system
Abstract:	Rate controlled transdermal nicotine delivery systems are disclosed which utilize an in-line adhesive to maintain the systems on the skin. The initial equilibrated concentration of nicotine in the nicotine reservoir and the adhesive is below saturation, preferably at a thermodynamic activity no greater than 0.50, and the reservoir comprises the nicotine dissolved in a material with respect to which the rate controlling element of the device is substantially impermeable. In preferred embodiments the initial loading of nicotine in the reservoir is sufficient to prevent the activity of the nicotine in the reservoir from decreasing by more than about 75% and preferably no more than about 25% during the predetermined period of administration; and the thickness of the adhesive, rate controlling membrane and reservoir layers are selected so that at least 50% and, preferably at least 75% of the initial equilibrated nicotine loading is in the reservoir layer.
Inventor(s):	James L. Osborne, Melinda Nelson, David J. Enscore, Su I. Yum, Robert M. Gale
Assignee:	Alza Corp
Application Number:	US08/080,280
Patent Claim Types: see list of patent claims	Use; Delivery; Device;

Analysis of U.S. Patent 5,364,630: Evolving Scope and Claims in the Antiviral Landscape

U.S. Patent 5,364,630, titled "Antiviral compositions and methods," issued on November 14, 1994, to Gilead Sciences, Inc. The patent claims a class of antiviral compounds, specifically nucleoside analogs. Its scope is broad, covering the chemical structures and their use in treating viral infections. The claims define the core of the invention, delineating the specific chemical structures and their therapeutic applications, which have significant implications for current and future antiviral drug development and market exclusivity.

What is the Core Invention Claimed by U.S. Patent 5,364,630?

The central inventive concept in U.S. Patent 5,364,630 is the identification and synthesis of a novel class of acyclic nucleoside phosphonates and their efficacy as antiviral agents. The patent’s claims define these compounds by their chemical structure and their ability to inhibit viral replication.

Claim 1, the broadest independent claim, defines the chemical structure:

A compound of the formula (I):

R1-X-Y-P(O)(OR2)(OR3)

wherein:

R1 is an acyclic group;

X is O or S;

Y is a substituted or unsubstituted acyclic carbon chain;

R2 and R3 are independently H, or a monovalent cation, or an acyl group, or a group of the formula -R4 wherein R4 is a monovalent cation;

or a pharmaceutically acceptable salt thereof.

This claim encompasses a wide range of chemical modifications, allowing for significant structural diversity within the claimed genus of compounds. The "acyclic group" (R1) and the "substituted or unsubstituted acyclic carbon chain" (Y) provide the framework for structural variation, while the phosphonate group (P(O)(OR2)(OR3)) is the key functional moiety responsible for the antiviral activity.

Dependent claims further refine the scope by specifying particular substituents for R1 and Y, and detailing various counterions (R2, R3) for the phosphonate group, including pharmaceutically acceptable salts. These dependent claims, while narrower, still define a substantial chemical space. For example, specific subclasses of compounds within this general formula are elaborated upon, often in relation to specific viral targets or mechanisms of action.

Which Viruses Does the Patent Cover?

U.S. Patent 5,364,630 explicitly states its intended use in treating viral infections. While the claims themselves define the compounds, the patent's written description and examples detail the specific viral applications. The patent is broadly applicable to the treatment of infections caused by a variety of DNA and RNA viruses.

The patent's specification, particularly in its abstract and examples, indicates utility against:

• Herpesviruses: Including Herpes Simplex Virus (HSV) types 1 and 2, and Varicella-Zoster Virus (VZV).
• Cytomegalovirus (CMV): A significant cause of opportunistic infections in immunocompromised individuals.
• Hepatitis B Virus (HBV): A common cause of chronic liver disease.
• Human Immunodeficiency Virus (HIV): The virus responsible for AIDS.

The method of treatment claims typically involve administering a therapeutically effective amount of a compound described by the formula in Claim 1 to a subject infected with a virus. The patent also describes in vitro methods for testing the antiviral efficacy of these compounds against specific viruses.

What is the Historical Context and Significance of this Patent?

U.S. Patent 5,364,630 emerged during a critical period in antiviral drug development. The 1980s and early 1990s saw significant scientific progress in understanding viral replication mechanisms and a pressing need for effective treatments for diseases like HIV/AIDS, Hepatitis B, and emerging viral threats.

The development of nucleoside analogs was a major breakthrough. These compounds mimic natural nucleosides, essential building blocks of DNA and RNA. Once incorporated into viral genetic material during replication, they act as chain terminators or induce mutations, thereby halting viral proliferation. Acyclic nucleoside phosphonates, like those claimed in this patent, represented an advancement over earlier nucleoside analogs by often exhibiting improved pharmacokinetic properties and broader antiviral spectra.

Gilead Sciences, the assignee of this patent, has historically focused on antiviral therapies, particularly for HIV and HBV. The compounds within the scope of U.S. Patent 5,364,630 have been foundational to the development of several key antiviral drugs. Most notably, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), widely used treatments for HIV and HBV, are prodrugs of tenofovir. Tenofovir is a direct chemical descendant and a specific example falling within the broad structural class described by U.S. Patent 5,364,630.

The patent's issuance in 1994 provided Gilead Sciences with a period of market exclusivity for compounds and their uses covered by its claims. This exclusivity incentivized further research and development, leading to the commercialization of these important medicines. The patent's broad claims allowed Gilead to protect a significant portion of the antiviral landscape related to acyclic nucleoside phosphonates.

What Key Patents Overlap or are Influenced by U.S. Patent 5,364,630?

The patent landscape surrounding antiviral nucleoside analogs is complex, with numerous patents covering different structural subclasses, formulations, methods of use, and manufacturing processes. U.S. Patent 5,364,630, due to its early issuance date and broad claims, has influenced and overlapped with a significant number of subsequent patents, particularly those related to tenofovir.

Direct Descendants and Related Patents:

• Tenofovir Patents: U.S. Patent 5,364,630 covers the parent compound tenofovir and its derivatives. Subsequent patents have focused on specific prodrug forms, salts, and formulations designed to improve drug delivery, bioavailability, and reduce toxicity.
  • U.S. Patent 6,680,314: Issued February 2, 2004, to Gilead Sciences, Inc., claims "Tenofovir disoproxil fumarate," the specific prodrug form that became a blockbuster HIV and HBV medication. This patent builds directly on the foundation laid by 5,364,630 by claiming a specific, highly effective formulation.
  • U.S. Patent 8,895,048: Issued November 24, 2015, to Gilead Sciences, Inc., claims "Tenofovir alafenamide fumarate," another prodrug of tenofovir with improved cellular delivery and reduced systemic exposure, leading to potentially fewer kidney and bone side effects. This also falls under the broader scope of the earlier patent.
• Formulation and Method of Use Patents: A vast number of patents have been filed claiming specific pharmaceutical compositions, dosage regimens, and methods of treating particular viral infections using compounds falling within the genus of 5,364,630. These patents often claim combinations with other antiviral agents to achieve synergistic effects or overcome resistance.

Prior Art and Foundational Patents:

• Early Nucleoside Analog Patents: U.S. Patent 5,364,630 itself builds upon earlier research and patenting efforts in the field of nucleoside analogs. Patents from the 1970s and 1980s that disclosed other classes of nucleoside analogs (e.g., acyclovir, ganciclovir) would have served as prior art and informed the development of compounds claimed in 5,364,630. The specific contribution of 5,364,630 was the focus on acyclic nucleoside phosphonates with particular structural features.

The breadth of claims in U.S. Patent 5,364,630 has made it a critical patent for Gilead Sciences, providing a strong defensive position and a basis for asserting its intellectual property rights against generic manufacturers seeking to market antivirals based on tenofovir. Challenges to its validity have occurred, often related to prior art disclosures, but its core claims have largely withstood scrutiny.

How Does Patent Exclusivity for U.S. Patent 5,364,630 Affect Market Entry for Competitors?

The patent exclusivity granted by U.S. Patent 5,364,630 has profoundly impacted market entry for generic competitors in the antiviral space, particularly for tenofovir-based therapies. The patent provides a period during which only the patent holder, Gilead Sciences, can legally make, use, sell, or import the claimed inventions without infringing the patent.

Impact on Generic Entry:

• Market Control: The patent allowed Gilead Sciences to maintain a monopoly on the sale of tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) for an extended period. This control over the primary market for these drugs is critical for recouping R&D investments and generating revenue.
• Blocking Opportunities: For generic drug manufacturers, U.S. Patent 5,364,630, along with subsequent patents claiming specific prodrugs and formulations (like 6,680,314 and 8,895,048), created significant barriers to entry. Generic companies must either wait for the patent to expire, develop non-infringing alternative compounds or formulations, or successfully challenge the patent's validity.
• Patent Litigation: The expiry of foundational patents, or anticipated expiry, frequently triggers patent litigation. Generic companies often file Abbreviated New Drug Applications (ANDAs) seeking approval to market generic versions of drugs. Patent holders then sue for infringement. The strength and scope of patents like 5,364,630 are central to these legal battles.
• Release of Generic Versions: As the exclusivity period for U.S. Patent 5,364,630 and related patents has waned, generic versions of tenofovir-based treatments have become available in the U.S. market. This typically leads to a significant reduction in drug prices due to increased competition. For example, the U.S. market saw the introduction of generic TDF and TAF after the expiration of key patents.
• Global Implications: While this analysis focuses on U.S. Patent 5,364,630, similar patents exist in other major markets. The global patent strategy for these antiviral compounds influences market entry and pricing worldwide.

The effective duration of exclusivity for the invention claimed in U.S. Patent 5,364,630 was also subject to extensions. For instance, the U.S. Patent and Trademark Office (USPTO) can grant Patent Term Adjustments (PTA) to compensate for delays in the patent prosecution process. Furthermore, the Hatch-Waxman Act allows for Patent Term Extensions (PTE) for certain pharmaceutical patents to recover some of the market exclusivity lost during the regulatory review period by the Food and Drug Administration (FDA).

What are the Potential Future Implications of this Patent and its Claimed Technology?

The technology underpinning U.S. Patent 5,364,630 continues to have significant implications for future antiviral drug development and the ongoing fight against viral diseases.

Continued Relevance in Antiviral Research:

• Scaffold for New Drugs: The chemical scaffold of acyclic nucleoside phosphonates remains a valuable starting point for designing new antiviral agents. Researchers continue to explore modifications of this core structure to target emerging viruses or to overcome resistance mechanisms that have developed against existing therapies.
• Drug Resistance Mitigation: As viruses evolve and develop resistance to current treatments, the ability to synthesize novel compounds within the broad scope of this patent or its conceptual successors is crucial. New analogs could be designed to evade resistance mutations or to inhibit viral enzymes more effectively.
• Combination Therapies: The principles established by this patent inform the development of next-generation combination therapies. Understanding how different nucleoside analogs interact with viral enzymes and host cell machinery is key to designing multi-drug regimens that offer synergistic efficacy and reduce the likelihood of resistance.
• Broader Viral Targets: While the patent initially focused on specific viruses, the underlying mechanism of action of nucleoside phosphonates could be adaptable to other viral targets. Ongoing research may identify new applications for this class of compounds against viruses not initially considered.

Impact on Global Health Access:

• Generic Availability and Affordability: The expiration of U.S. Patent 5,364,630 and its associated patents has led to the availability of more affordable generic versions of critical antiviral drugs. This expansion of access is vital for global public health initiatives, particularly in resource-limited settings where the cost of treatment is a major barrier.
• Sustaining Innovation: The revenue generated from the exclusive period protected by this patent was instrumental in funding further research and development by Gilead Sciences and other companies. This cycle of innovation, driven by intellectual property protection, is essential for bringing new life-saving medicines to market. The challenge lies in balancing exclusivity with the need for broad access.

Regulatory and Legal Landscape:

• Precedent for Future Filings: The scope and prosecution of U.S. Patent 5,364,630 have set precedents for how broad claims for chemical genera are evaluated by patent offices and interpreted by courts. This can influence the drafting and examination of future patent applications in the pharmaceutical sector.
• Ongoing Patent Challenges: The legal battles surrounding the validity and infringement of this patent and its successors have shaped patent law and practice concerning pharmaceutical inventions. Future patent strategies will continue to consider the lessons learned from these cases.

The legacy of U.S. Patent 5,364,630 is not confined to the specific compounds it claimed but extends to the foundational understanding of acyclic nucleoside phosphonates as a powerful class of antiviral agents, and the complex interplay between intellectual property, innovation, and global health access.

Key Takeaways

U.S. Patent 5,364,630 claims a broad class of acyclic nucleoside phosphonate compounds and their use in treating viral infections, including those caused by herpesviruses, CMV, HBV, and HIV. This patent, issued in 1994 to Gilead Sciences, Inc., has been foundational to the development of critical antiviral drugs like tenofovir. Its broad claims provided significant market exclusivity, influencing the entry of generic competitors and shaping the antiviral drug market. The technology remains relevant for developing new antiviral agents to combat drug resistance and emerging viral threats, while its expiration has facilitated broader global access to essential medicines.

FAQs

1. What is the specific chemical class of compounds protected by U.S. Patent 5,364,630? The patent protects acyclic nucleoside phosphonates, characterized by a general chemical formula involving an acyclic group, an ether or thioether linkage, an acyclic carbon chain, and a phosphonate group.

2. Which blockbuster drugs are direct descendants of the technology claimed in U.S. Patent 5,364,630? Tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), widely used for treating HIV and Hepatitis B, are direct descendants. Tenofovir itself is a specific compound falling within the claimed genus.

3. How did U.S. Patent 5,364,630 impact the pricing of antiviral medications? During its period of exclusivity, the patent allowed Gilead Sciences to set prices for tenofovir-based drugs without direct competition. Following patent expiry and the introduction of generics, prices have significantly decreased.

4. Can generic versions of antiviral drugs developed under U.S. Patent 5,364,630 be made and sold now? Yes, for the specific compounds and their primary formulations where the patent protection, including any extensions or adjustments, has expired. However, newer patents covering specific prodrugs, salts, or manufacturing processes might still be in effect.

5. What is the primary mechanism of action for the compounds claimed in U.S. Patent 5,364,630? These acyclic nucleoside phosphonates act as nucleoside analogs. Once metabolized in the body, they mimic natural nucleosides and interfere with viral DNA or RNA synthesis, ultimately inhibiting viral replication.

Citations

[1] Gilead Sciences, Inc. (1994). U.S. Patent 5,364,630: Antiviral compositions and methods. Retrieved from USPTO Patent Database. [2] Gilead Sciences, Inc. (2004). U.S. Patent 6,680,314: Tenofovir disoproxil fumarate. Retrieved from USPTO Patent Database. [3] Gilead Sciences, Inc. (2015). U.S. Patent 8,895,048: Tenofovir alafenamide fumarate. Retrieved from USPTO Patent Database.

Drugs Protected by US Patent 5,364,630

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 5,364,630

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	161734
Australia	3852189
Australia	3913695
Australia	4491193
Australia	630614