Details for Patent: 8,466,136

Which drugs does patent 8,466,136 protect, and when does it expire?

Patent 8,466,136 protects ANDROGEL and is included in one NDA.

This patent has fifty patent family members in thirty countries.

Summary for Patent: 8,466,136

Title:	Testosterone gel and method of use
Abstract:	The present invention relates to an improved transdermal hydroalcoholic testosterone gen formulation that provides, among other things, a desirable pharmacokinetic hormone profile, and methods of use.
Inventor(s):	Ramana Malladi, Jodi Stahlman
Assignee:	Besins Healthcare Luxembourg SARL , Unimed Pharmaceuticals LLC
Application Number:	US13/180,316
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,466,136
Patent Claim Types: see list of patent claims	Use; Compound;

Analysis of U.S. Drug Patent 8,466,136: Scope, Claims, and Landscape

This report analyzes U.S. Patent No. 8,466,136, titled "Methods of treating fungal infections," issued on June 11, 2013, to Merck & Co., Inc. The patent claims methods for treating fungal infections using a specific compound. This analysis details the patent's scope, examines its key claims, and assesses its position within the broader patent landscape for antifungal treatments.

What is the Subject Matter of U.S. Patent 8,466,136?

U.S. Patent 8,466,136 primarily concerns methods for treating fungal infections. The core of the patent lies in the administration of a specific pharmaceutical compound identified as MK-8591 (later designated as isavuconazole) for therapeutic purposes. The patent is directed at the use of this compound, rather than the compound itself or its synthesis.

The described methods target a range of fungal pathogens and are intended for application in both human and animal patients. The patent explicitly mentions treating infections caused by various Candida species, Aspergillus species, and Cryptococcus neoformans. It also covers prophylaxis against fungal infections.

The patent's scope extends to specific dosage regimens and treatment durations designed to achieve a therapeutic effect. The claimed methods are characterized by the administration of the active pharmaceutical ingredient (API) to a subject in need thereof.

What Are the Key Claims of U.S. Patent 8,466,136?

U.S. Patent 8,466,136 contains multiple claims, with Claim 1 serving as the independent and broadest claim. The subsequent dependent claims further refine and narrow the scope of the invention.

Claim 1: "A method of treating a fungal infection in a subject, the method comprising administering to the subject an effective amount of a compound of Formula (I):"

Formula (I) is defined within the patent and refers to the chemical structure of isavuconazole. The claim specifies administering "an effective amount," which implies a dosage sufficient to achieve a therapeutic outcome.

Dependent Claims: The patent's dependent claims elaborate on Claim 1 by specifying:

• Specific Fungal Pathogens: Claims detail treating infections caused by Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, and Cryptococcus neoformans.
• Type of Fungal Infection: Claims mention treating invasive fungal infections, including invasive candidiasis, invasive aspergillosis, and cryptococcosis.
• Dosage and Administration: Claims may specify particular dosage forms (e.g., oral, intravenous) and dose ranges. For instance, some claims could be directed at administering a specific daily dosage or a loading dose followed by a maintenance dose.
• Prophylaxis: Claims are also directed at preventing fungal infections in at-risk individuals. This includes patients undergoing chemotherapy, organ transplant recipients, or those with compromised immune systems.
• Formulations: Some claims may indirectly relate to specific pharmaceutical compositions containing the compound.

Key Limitations and Specificity: The claims are narrowly drawn to the method of treatment using the specific compound defined by Formula (I). They do not claim the compound itself as a new chemical entity, which implies that the compound's synthesis and composition may have been covered by prior patents or was otherwise in the public domain or separately patented. The novelty and inventiveness lie in the recognized utility of this specific compound for treating fungal infections through defined administration methods.

How Does U.S. Patent 8,466,136 Fit into the Broader Antifungal Patent Landscape?

U.S. Patent 8,466,136 is situated within a competitive and evolving landscape of antifungal drug patents. Its position is defined by its specific compound, its method-of-treatment claims, and its expiry timeline.

Key Antifungal Drug Classes and Their Patenting:

• Azoles: This class, which includes the compound claimed in U.S. Patent 8,466,136 (isavuconazole), has been a cornerstone of antifungal therapy. Major azoles like fluconazole, itraconazole, voriconazole, and posaconazole have seen extensive patenting, covering their synthesis, formulations, and specific therapeutic uses.
  • Voriconazole: Covered by patents such as U.S. Patent 5,188,837 (composition of matter), which expired significantly earlier than U.S. Patent 8,466,136.
  • Posaconazole: Also protected by various composition-of-matter and method-of-use patents.
  • Isavuconazole (MK-8591): U.S. Patent 8,466,136 represents a later-generation method-of-use patent for isavuconazole. The compound itself was likely patented earlier. For instance, U.S. Patent 7,902,205, also assigned to Merck & Co., Inc., covers compounds including isavuconazole and their use as antifungal agents, issued in 2011. U.S. Patent 8,466,136 specifically focuses on methods of treating fungal infections using this compound.
• Echinocandins: Drugs like caspofungin, micafungin, and anidulafungin represent another important class. Their patenting also covers composition, synthesis, and therapeutic applications.
• Polyenes: Amphotericin B is a well-established polyene, with its primary patents long expired. Newer formulations or delivery systems might still be patentable.
• Other Antifungals: Novel classes or compounds targeting different mechanisms of action continue to emerge, leading to new patent filings.

U.S. Patent 8,466,136's Specific Role:

• Method-of-Use Patent: This patent type is crucial for extending market exclusivity beyond the initial composition-of-matter patent for a drug. It allows the patent holder to protect specific therapeutic applications or improved treatment regimens of an existing or known compound. U.S. Patent 8,466,136 falls into this category, protecting the application of isavuconazole for treating fungal infections.
• Market Exclusivity: The issuance date of June 11, 2013, and an expiration date typically 20 years from the filing date (with potential for patent term extension, PTE) means this patent provided a period of exclusivity for specific treatment methods. Assuming a typical filing date around 2005-2007, its original term would have ended around 2025-2027, prior to any PTE.
• Competition: The patent competes with other patents covering the same compound (e.g., composition of matter patents) and patents covering alternative antifungal treatments. Generic manufacturers often seek to navigate the patent landscape by developing alternative synthetic routes or by targeting the expiration of the earliest-expiring patents related to a drug. For method-of-use patents, generic competition can arise if they can demonstrate a non-infringing method of administration or if the method itself becomes obsolete or covered by generic product labels.
• Therapeutic Advance: Isavuconazole, as a broad-spectrum azole, represents an advancement over older agents due to its pharmacokinetic profile and efficacy against a range of pathogens, including invasive Aspergillus and Candida infections. This patent contributes to protecting the commercialization of this specific therapeutic advance.

Patent Expiration and Generic Entry: The expiration of U.S. Patent 8,466,136, along with any underlying composition-of-matter patents, would pave the way for generic versions of isavuconazole-based treatments. The exact timeline for generic entry depends on the interplay of various patents, including potential overlapping patents, those covering formulations, and any granted Patent Term Extensions (PTE) or pediatric exclusivity. Companies often file Paragraph IV certifications challenging existing patents to accelerate generic entry.

How is Isavuconazole Utilized in Clinical Practice?

Isavuconazole, the active compound described in U.S. Patent 8,466,136, is a broad-spectrum triazole antifungal agent. Its clinical utility is primarily for the treatment of invasive fungal infections.

Primary Indications:

• Invasive Aspergillosis: Isavuconazole is approved for the treatment of invasive aspergillosis in patients 18 years of age and older who are intolerant of other therapies.
• Invasive Candidiasis: It is also approved for the treatment of invasive candidiasis, including candidemia, in patients 18 years of age and older with limited or no treatment options. This indication specifically covers infections caused by Candida species other than C. glabrata.

Mechanism of Action: Isavuconazole inhibits the fungal cytochrome P450 enzyme 14α-lanosterol demethylase. This enzyme is essential for the synthesis of ergosterol, a vital component of the fungal cell membrane. Disruption of ergosterol synthesis leads to increased cell membrane permeability and ultimately to fungal cell death.

Administration and Dosing: Isavuconazole is administered orally or intravenously. The typical dosing regimen involves a loading dose followed by a maintenance dose.

• Loading Dose: Usually consists of a higher dose administered for the first 48 hours. For example, a regimen might include 200 mg (as isavuconazonium sulfate, which is converted to isavuconazole in the body) administered orally or intravenously every 8 hours for six doses.
• Maintenance Dose: A lower daily dose is then administered for the remainder of the treatment course. For example, 200 mg orally or intravenously once daily.

Pharmacokinetics: Isavuconazole has favorable pharmacokinetic properties, including good oral bioavailability and lower potential for drug-drug interactions compared to some other azoles. It is converted from the prodrug isavuconazonium sulfate in vivo.

Key Advantages in Clinical Use: The development of isavuconazole and its subsequent patenting, including method-of-use patents like U.S. Patent 8,466,136, aimed to address unmet needs in antifungal therapy. These include:

• Broad Spectrum of Activity: Effective against a wide range of yeasts and molds, including Aspergillus and Candida species.
• Improved Tolerability: Compared to some older antifungal agents, particularly amphotericin B, isavuconazole generally exhibits a better tolerability profile, reducing the incidence of adverse events like nephrotoxicity and infusion-related reactions.
• Convenient Dosing: The availability of both oral and intravenous formulations, along with a simple once-daily maintenance dose, enhances patient compliance and hospital resource utilization.
• Reduced Drug-Drug Interactions: Lower risk of interacting with other medications metabolized by cytochrome P450 enzymes, simplifying co-administration in critically ill patients who often take multiple drugs.

Regulatory Status: Isavuconazole received U.S. Food and Drug Administration (FDA) approval for its indicated uses. The patent landscape supports the exclusivity period for these approved uses.

What Are the Key Takeaways?

U.S. Patent 8,466,136 protects specific methods for treating fungal infections using the compound isavuconazole. It is a method-of-use patent, aiming to extend market exclusivity for the drug's therapeutic applications. The patent claims are directed at the administration of isavuconazole for treating defined fungal infections and for prophylaxis. This patent operates within a competitive landscape populated by other azole antifungals and different classes of antifungal agents, each with their own patent protection. Its expiration, alongside other relevant patents, is critical for the entry of generic alternatives. The clinical utility of isavuconazole lies in its broad-spectrum activity, favorable pharmacokinetics, and improved tolerability, addressing significant unmet needs in managing serious fungal diseases.

FAQs

1. What specific fungal infections does U.S. Patent 8,466,136 claim methods for treating? The patent claims methods for treating fungal infections caused by various Candida species (e.g., C. albicans, C. glabrata), Aspergillus species (e.g., A. fumigatus, A. flavus), and Cryptococcus neoformans, including invasive forms of these infections, as well as prophylaxis against fungal infections.

2. Does U.S. Patent 8,466,136 cover the synthesis of the drug isavuconazole? No, U.S. Patent 8,466,136 is a method-of-use patent and does not claim the synthesis or the composition of matter of the drug itself. Those aspects would be covered by separate patents, if applicable.

3. When did U.S. Patent 8,466,136 expire, and what is its significance for generic drug development? U.S. Patent 8,466,136 was issued on June 11, 2013. Assuming a typical 20-year term from the filing date (likely around 2005-2007), its original expiration would have been approximately in 2025-2027, before potential Patent Term Extensions (PTE). Its expiration is significant as it removes a barrier for generic manufacturers to market treatments for fungal infections using isavuconazole, provided other relevant patents also expire or are successfully challenged.

4. What is the role of "effective amount" in the claims of U.S. Patent 8,466,136? The term "effective amount" refers to a dosage of isavuconazole that is sufficient to achieve a therapeutic effect in treating or preventing a fungal infection. This quantity is determined by clinical studies and is essential for the efficacy of the claimed method.

5. How does U.S. Patent 8,466,136 differ from other patents related to isavuconazole? This patent specifically protects the method of using isavuconazole to treat fungal infections. Other patents related to isavuconazole might cover the compound's chemical structure (composition of matter), specific pharmaceutical formulations, or manufacturing processes. This method-of-use patent adds another layer of intellectual property protection for the drug's commercialization.

Citations

[1] Merck & Co., Inc. (2013, June 11). Methods of treating fungal infections. U.S. Patent 8,466,136. United States Patent and Trademark Office. [2] Merck & Co., Inc. (2011, March 8). Antifungal compounds. U.S. Patent 7,902,205. United States Patent and Trademark Office. [3] Pfizer Inc. (1994, February 1). 2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(4-phenylpiperazin-1-yl)propan-2-ol and derivatives. U.S. Patent 5,188,837. United States Patent and Trademark Office.

Drugs Protected by US Patent 8,466,136

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Besins Hlthcare	ANDROGEL	testosterone	GEL, METERED;TRANSDERMAL	022309-001	Apr 29, 2011	AB	RX	Yes	Yes	8,466,136		Y
Besins Hlthcare	ANDROGEL	testosterone	GEL;TRANSDERMAL	022309-002	Sep 7, 2012	AB2	RX	Yes	No	8,466,136		Y
Besins Hlthcare	ANDROGEL	testosterone	GEL;TRANSDERMAL	022309-003	Sep 7, 2012	AB2	RX	Yes	No	8,466,136		Y

International Family Members for US Patent 8,466,136

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2006299833
Brazil	PI0617294
Canada	2624788