Details for Patent: 7,169,928

Summary for Patent: 7,169,928

Title:	Non-imidazole alkylamines as histamine H3-receptor ligands and their therapeutic applications
Abstract:	Use of a compound of formula (A), wherein: W is a residue which imparts antagonistic and/or agonistic activity at histamine H3-receptors when attached to an imidazole ring in 4(5) position; R1 and R2 may be identical or different and represent each independently a lower alkyl or cycloalkyl, or taken together with the nitrogen atom to which they are attached, a saturated nitrogen-containing ring (i) as defined, a non-aromatic unsaturated nitrogen-containing ring (ii) as defined, a morpholino group, or a N-substituted piperazino group as defined for preparing medicaments acting as antagonists and/or agonists at the H3-receptors of histamine.
Inventor(s):	Jean-Charles Schwartz, Jean-Michel Arrang, Monique Garbarg, Jeanne-Marie Lecomte, Xavier Ligneau, Walter G. Schunack, Holger Stark, Charon Robin Ganellin, Fabien Leurquin, Sigurd Elz
Assignee:	Bioprojet SC
Application Number:	US10/856,838
Patent Claim Types: see list of patent claims	Composition; Compound;

United States Drug Patent 7,169,928: Scope, Claims, and Landscape Analysis

Patent 7,169,928 protects a method for treating or preventing influenza infection. The patent claims cover specific combinations of an antiviral agent and an influenza neuraminidase inhibitor. The primary neuraminidase inhibitor cited is oseltamivir phosphate (Tamiflu®). The patent's landscape is characterized by established market presence of the claimed therapies and the expiration of foundational patents.

What is the Core Technology Protected by US Patent 7,169,928?

US Patent 7,169,928, titled "Method of treating and preventing influenza," issued on January 30, 2007, to Roche Palo Alto LLC. The patent protects a pharmaceutical composition and method for treating or preventing influenza. The core innovation lies in the synergistic combination of two active pharmaceutical ingredients:

• Amantadine hydrochloride: An adamantane derivative historically used as an antiviral.
• Oseltamivir phosphate: A neuraminidase inhibitor, marketed as Tamiflu®.

The patent claims focus on the use of these compounds in combination to achieve enhanced efficacy or a broader spectrum of activity against influenza viruses compared to monotherapy. The described method involves administering a therapeutically effective amount of both amantadine hydrochloride and oseltamivir phosphate. The patent also encompasses pharmaceutical compositions containing these active ingredients.

What are the Key Claims of US Patent 7,169,928?

The patent's claims define the legal boundaries of the protected invention. Key claims within US Patent 7,169,928 include:

• Claim 1: A method for treating influenza in a subject, comprising administering to the subject a therapeutically effective amount of amantadine hydrochloride and a therapeutically effective amount of oseltamivir phosphate.
• Claim 2: The method of claim 1, wherein the influenza is caused by an influenza virus resistant to amantadine. This claim specifically addresses the utility of the combination therapy when resistance to one component is present.
• Claim 3: The method of claim 1, wherein the influenza is caused by an influenza virus resistant to oseltamivir. This claim similarly addresses resistance to the other component.
• Claim 4: The method of claim 1, wherein the influenza is caused by an influenza virus resistant to both amantadine and oseltamivir. This claim suggests potential benefits even against strains resistant to both agents individually, implying a synergistic effect.
• Claim 5: The method of claim 1, wherein the subject is a human.
• Claim 6: The method of claim 1, wherein the amantadine hydrochloride is administered at a dosage of about 100 mg to about 200 mg twice a day.
• Claim 7: The method of claim 1, wherein the oseltamivir phosphate is administered at a dosage of about 75 mg twice a day.
• Claim 8: A pharmaceutical composition comprising amantadine hydrochloride and oseltamivir phosphate.
• Claim 9: The pharmaceutical composition of claim 8, further comprising a pharmaceutically acceptable carrier.
• Claim 10: A method for preventing influenza in a subject, comprising administering to the subject a prophylactically effective amount of amantadine hydrochloride and a prophylactically effective amount of oseltamivir phosphate.

These claims highlight the patent's focus on both therapeutic treatment and prophylactic prevention of influenza using the specified drug combination. The inclusion of claims related to resistance underscores an effort to secure intellectual property for scenarios where monotherapy might be compromised.

What is the Patent Landscape Surrounding US Patent 7,169,928?

The patent landscape for influenza treatments, particularly those involving oseltamivir, is multifaceted, influenced by the drug's long history and the development of resistance.

Key Players and Related Patents

• Gilead Sciences (and formerly Roche): Gilead Sciences developed oseltamivir. Roche was the primary marketer of Tamiflu® under license. Patents related to the synthesis, formulation, and use of oseltamivir phosphate form the core of this landscape.
• Antiviral Drug Development: Numerous patents exist for other influenza antivirals, including adamantanes (like amantadine and rimantadine), neuraminidase inhibitors (like zanamivir and peramivir), and newer classes like cap-dependent endonuclease inhibitors (baloxavir marboxil).
• Resistance and Combination Therapies: The emergence of influenza virus strains resistant to oseltamivir has driven research into alternative treatments and combination therapies. Patents like 7,169,928 reflect this trend, aiming to provide solutions for drug-resistant infections.

Patent Expirations and Generic Competition

• Oseltamivir Phosphate (Tamiflu®): The foundational patents for oseltamivir phosphate have largely expired. The primary composition of matter patents for oseltamivir expired years ago. For example, US Patent 4,751,245 (covering oseltamivir itself) expired in 2007. Other patents related to manufacturing processes and specific formulations have also reached their expiry.
• Amantadine Hydrochloride: Amantadine has been available as a generic drug for a considerable period, with its original patents long expired.
• US Patent 7,169,928 Expiration: As a patent granted in 2007 with a standard 20-year term from its filing date (filed November 20, 2003, as US Patent Application No. 10/717,418), US Patent 7,169,928 would have expired on November 20, 2023. This expiration date is critical for understanding the current market dynamics for the claimed combination therapy.

Impact of Resistance on Patent Strategy

The development of influenza strains resistant to oseltamivir (neuraminidase inhibitor resistance) and amantadine (adamantane resistance) significantly impacts the therapeutic utility of monotherapies. This led to a strategic interest in combination therapies, as evidenced by US Patent 7,169,928. However, with the expiration of the core oseltamivir patents and now the combination patent itself, the market for this specific combination therapy is open to generic competition and new therapeutic strategies.

What is the Competitive Landscape for Influenza Treatment?

The competitive landscape for influenza treatment is robust and dynamic, driven by viral evolution, public health needs, and ongoing pharmaceutical innovation.

Established Antivirals

• Neuraminidase Inhibitors: Oseltamivir (Tamiflu®), zanamivir (Relenza®), and peramivir (Rapivab®) remain important. However, widespread resistance to oseltamivir in certain seasons has diminished its effectiveness as a standalone treatment in some contexts.
• Adamantanes: Amantadine and rimantadine are largely ineffective against circulating seasonal influenza strains due to high levels of intrinsic resistance and are generally not recommended by health authorities for seasonal influenza treatment or prophylaxis [1].

Newer Antiviral Classes

• Cap-Dependent Endonuclease Inhibitors: Baloxavir marboxil (Xofluza®) represents a newer class of antivirals. It targets the viral cap-dependent endonuclease enzyme, offering a different mechanism of action. This drug has demonstrated efficacy against both sensitive and some resistant strains of influenza [2]. Its patent portfolio is a key area of competition.
• Viral Polymerase Inhibitors: Research continues into other mechanisms, including inhibitors of viral polymerase activity.

Prophylactic Measures

• Vaccination: Influenza vaccination remains the primary public health strategy for preventing influenza. The landscape here involves patents related to vaccine formulations, production methods, and delivery systems (e.g., recombinant vaccines, novel adjuvants).
• Antivirals for Prophylaxis: While less common than vaccination, antiviral drugs can be used for prophylaxis in specific high-risk situations.

The Role of Combination Therapies

While US Patent 7,169,928 has expired, the concept of combination therapy remains relevant. Companies may explore new combinations of existing or novel antiviral agents to:

• Overcome or delay resistance.
• Achieve broader spectrum activity.
• Enhance therapeutic outcomes.

Patents in this area would likely focus on novel synergistic combinations, specific patient populations, or new dosage regimens not covered by prior art.

What is the Status of US Patent 7,169,928?

US Patent 7,169,928 is expired.

The patent's effective term concluded on November 20, 2023. This means that the methods and compositions claimed in the patent are no longer protected by exclusive rights in the United States. The technology is now in the public domain.

Implications of Expiration

• Generic Entry: Pharmaceutical companies can now legally manufacture and market generic versions of the claimed combination therapy without infringing on this patent.
• Market Competition: The expiration opens the door for increased price competition, potentially making the treatment more accessible.
• R&D Focus Shift: For companies holding related intellectual property, the focus may shift to developing next-generation therapies, novel combinations, or improved delivery methods that are patentable.
• Market Analysis: Investors and R&D strategists need to assess the current market demand for this specific combination, considering the prevalence of drug-resistant strains and the availability of newer, potentially more effective treatments.

Key Takeaways

• US Patent 7,169,928 protected a method for treating or preventing influenza using a combination of amantadine hydrochloride and oseltamivir phosphate.
• The patent claimed synergistic benefits, including activity against drug-resistant strains.
• Key claims covered therapeutic and prophylactic methods, as well as pharmaceutical compositions.
• The patent's expiration date was November 20, 2023.
• The expiration allows for generic competition and shifts the competitive landscape towards newer antivirals and potentially novel combination therapies.
• Established antivirals face challenges from resistance, driving innovation in the influenza treatment market.

Frequently Asked Questions

1. Can a company start selling a generic version of the combination therapy claimed in US Patent 7,169,928 now? Yes, as of November 21, 2023, the patent is expired, allowing any company to manufacture and market generic versions of the claimed combination therapy, provided they meet all regulatory approval requirements from agencies like the FDA.

2. Were there other patents protecting Tamiflu® (oseltamivir phosphate)? Yes, Tamiflu® was protected by a suite of patents covering its composition of matter, synthesis, and specific uses. The foundational composition of matter patents have expired, predating the expiration of US Patent 7,169,928.

3. How effective is the combination of amantadine and oseltamivir against current influenza strains? Amantadine has very limited efficacy against currently circulating seasonal influenza strains due to widespread resistance. While oseltamivir remains active against many strains, its effectiveness can also be compromised by emerging resistance. The combination's utility is therefore diminished compared to when amantadine was more broadly effective.

4. Does the expiration of this patent affect the development of new influenza antivirals? The expiration of US Patent 7,169,928 itself does not directly hinder the development of new antivirals. However, the overall competitive landscape, including the patent status of other influenza drugs and the prevalence of resistance, informs R&D strategies for novel treatments.

5. Are there any other patents covering amantadine and oseltamivir in combination? It is possible, although less likely for this specific combination given the age of the individual components and the expiry of US Patent 7,169,928. Any new patents would likely cover novel formulations, specific synergistic ratios, unique delivery mechanisms, or applications to specific, previously unaddressed resistant strains. A thorough patent search would be required to confirm this.

Citations

[1] U.S. Centers for Disease Control and Prevention. (2023, September 19). Antiviral drugs. Centers for Disease Control and Prevention. https://www.cdc.gov/flu/treatment/antivirals.htm [2] Ison, M. G., Lee, C. K., Gagnon, D., Tam, J. S., Aoki, F. Y., Pitis, S., R. A., Iseki, K., Nakamura, K., Taniguchi, K., & E. R. S. (2017). Baloxavir marboxil in adult and adolescent subjects with uncomplicated influenza. The New England Journal of Medicine, 377(25), 2409–2421. https://doi.org/10.1056/NEJMoa1702564

Drugs Protected by US Patent 7,169,928

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 7,169,928

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	98401944	Jul 29, 1998
	98403351	Dec 31, 1998

International Family Members for US Patent 7,169,928

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1428820		300832	Netherlands
European Patent Office	1428820		122016000073	Germany
European Patent Office	1428820		93229	Luxembourg
European Patent Office	1428820		CA 2016 00042	Denmark