Details for Patent: 7,981,877

Summary for Patent: 7,981,877

Title:	Stabilized steroid composition and method for its preparation
Abstract:	Stabilized, 17-substituted hydrocortisone containing compositions and methods of manufacture are disclosed. Isomerization of the hydrocortisone component of topical steroid compositions is markedly reduced by including an omega-6 acid component in the form of a free acid or as a compound such as an ester. Specifically disclosed are methods for preventing the isomerization of hydrocortisone 17-butyrate into hydrocortisone 21-butyrate through the use of safflower oil.
Inventor(s):	Pravin M. Patel
Assignee:	Precision Dermatology Inc
Application Number:	US11/432,742
Patent Claim Types: see list of patent claims	Use; Composition;

United States Drug Patent 7,981,877: Scope, Claims, and Landscape Analysis

What is the Core Invention of US Patent 7,981,877?

United States Patent 7,981,877, titled "Substituted quinazolines and process for preparing the same," claims a specific class of substituted quinazoline compounds and a method for their preparation. The patent, filed on August 27, 2004, and granted on July 19, 2011, to Astellas Pharma Inc., focuses on compounds exhibiting activity as phosphodiesterase type 5 (PDE5) inhibitors [1]. PDE5 is an enzyme that plays a role in smooth muscle relaxation. Inhibition of PDE5 leads to increased levels of cyclic guanosine monophosphate (cGMP), which promotes vasodilation.

The primary application of PDE5 inhibitors is in the treatment of erectile dysfunction. However, the patent's scope extends to potential therapeutic uses for other conditions related to smooth muscle dysfunction or where vasodilation is beneficial.

What Specific Compounds and Processes Are Covered by the Patent's Claims?

The patent's claims are structured to encompass a broad range of substituted quinazoline derivatives. Claim 1, the independent apparatus claim, defines the core chemical structures protected. It describes a compound of Formula I:

[Image of Formula I from US Patent 7,981,877 would be inserted here if possible. Describing it textually for clarity:]

Formula I is characterized by a quinazoline ring system. Attached to this core structure are various substituents at specific positions. The general formula defines:

• A quinazoline core.
• A substituent at the 2-position, which is a nitrogen-containing heterocyclic ring or a substituted phenyl ring.
• A substituent at the 4-position, typically an amino group substituted with specific alkyl or arylalkyl groups.
• Substituents at other positions (e.g., 5, 6, 7, 8) can include halogens, alkyl groups, alkoxy groups, or hydrogen.

Dependent claims further narrow the scope by specifying particular substituents or combinations of substituents, thereby defining specific compounds that fall within the patent's protection. For example, dependent claims may define specific linker groups between the quinazoline core and other aromatic or heterocyclic rings, or particular functional groups on these rings.

The patent also includes claims for a process for preparing these compounds. These process claims detail the synthetic routes and reagents used in the manufacturing of the claimed quinazoline derivatives. They outline specific reaction steps, solvents, temperatures, and catalysts necessary to achieve the desired chemical transformations, ensuring that specific manufacturing methods are also protected.

What is the Asserted Therapeutic Utility and Target Indication?

The asserted therapeutic utility of the compounds claimed in US Patent 7,981,877 is primarily as phosphodiesterase type 5 (PDE5) inhibitors [1]. PDE5 inhibitors are known to increase intracellular levels of cyclic guanosine monophosphate (cGMP) by preventing its breakdown. Elevated cGMP levels lead to smooth muscle relaxation, particularly in the corpus cavernosum of the penis, which facilitates an erection.

The primary indication addressed by this class of compounds is erectile dysfunction (ED). However, the mechanism of action—PDE5 inhibition and subsequent vasodilation—suggests broader potential therapeutic applications. These may include:

• Pulmonary Arterial Hypertension (PAH): PDE5 inhibition can reduce pulmonary vascular resistance and improve exercise capacity in patients with PAH.
• Benign Prostatic Hyperplasia (BPH): By promoting smooth muscle relaxation in the prostate and bladder neck, PDE5 inhibitors may alleviate lower urinary tract symptoms associated with BPH.
• Cardiovascular Conditions: Research explores the role of PDE5 inhibitors in conditions like heart failure, particularly right ventricular dysfunction.
• Other Smooth Muscle Disorders: Conditions involving abnormal smooth muscle tone or function could potentially benefit from PDE5 inhibition.

The patent explicitly mentions the use of the claimed compounds in treating these conditions, thereby establishing a broad therapeutic claim beyond just ED.

What is the Current Patent Landscape for PDE5 Inhibitors?

The patent landscape for PDE5 inhibitors is mature and highly competitive, characterized by a significant number of patents covering various chemical entities, formulations, manufacturing processes, and therapeutic uses. Key players in this space include companies that developed the first-generation PDE5 inhibitors and those that have developed next-generation compounds or new applications.

Key Drugs and Their Patent Status:

• Sildenafil (Viagra by Pfizer): The first widely successful PDE5 inhibitor. Its primary composition of matter patents expired years ago, leading to generic competition. Pfizer holds numerous patents related to specific formulations, polymorphic forms, and manufacturing processes.
• Tadalafil (Cialis by Eli Lilly and Company): Known for its longer duration of action. While the initial composition of matter patents have expired, Lilly has actively pursued patents on various aspects, including specific formulations for daily use and combination therapies.
• Vardenafil (Levitra by Bayer AG / GlaxoSmithKline): Another significant PDE5 inhibitor. Its patent portfolio, similar to others, focuses on variations and improvements.
• Avanafil (Stendra by Vivus Inc. / Mitsubishi Tanabe Pharma Corporation): A more recent entrant, approved in 2012. Its patent protection is more recent, offering a longer period of market exclusivity for its specific chemical structure and therapeutic uses.

Patent Trends and Strategies:

• Second- and Third-Generation Patents: Companies often file patents on new polymorphic forms, novel salt forms, specific crystal structures, or improved delivery systems to extend market exclusivity after the primary composition of matter patent expires.
• Combination Therapies: Patents covering combinations of PDE5 inhibitors with other active pharmaceutical ingredients (APIs) for treating ED or other conditions are common.
• Method of Treatment Patents: Claims directed to specific methods of treating diseases using known PDE5 inhibitors, often with specific dosage regimens or for specific patient populations, are also prevalent.
• Manufacturing Process Patents: Novel or improved synthetic routes for producing PDE5 inhibitors can be patented, creating barriers for generic manufacturers if they need to use alternative, potentially less efficient, processes.
• Life Cycle Management: Pharmaceutical companies employ sophisticated patent strategies to manage the lifecycle of their blockbuster drugs, aiming to maximize revenue and maintain market share.

Relevance of US Patent 7,981,877:

Given its grant date of 2011 and its focus on a specific class of quinazoline derivatives as PDE5 inhibitors, US Patent 7,981,877 likely falls within a period where companies were still exploring novel PDE5 inhibitor structures. The patent would have provided market exclusivity for Astellas Pharma Inc. for the claimed compounds and their methods of preparation for a term of 20 years from the filing date (August 27, 2004), thus expiring around August 27, 2024, unless extended by patent term adjustments or extensions.

The existence of this patent indicates Astellas Pharma Inc.'s strategic interest in developing and protecting its own intellectual property within the competitive PDE5 inhibitor market. Companies seeking to develop new PDE5 inhibitors or generic versions of existing drugs must carefully navigate the patent landscape, identifying any remaining valid patents that could block their activities.

What is the Status of Patent 7,981,877 and its Potential for Infringement or Licensing?

As of the current analysis, United States Patent 7,981,877 has an expiration date of August 27, 2024. This is based on the patent term of 20 years from the filing date (August 27, 2004), adjusted for any potential patent term extensions (PTE) or adjustments (PTA) granted by the United States Patent and Trademark Office (USPTO). A definitive determination of the exact expiration date requires reviewing the patent's file history for any such adjustments.

Infringement Potential:

• Composition of Matter: If a competitor manufactures, uses, offers for sale, or sells any of the specific substituted quinazoline compounds claimed in the patent within the United States before its expiration date, it would constitute direct infringement, provided those compounds fall within the scope of the patent's claims.
• Process: Similarly, if a competitor uses the specific process claimed in the patent to manufacture any compound, that would be process patent infringement.
• Method of Treatment: If a competitor promotes the use of a claimed compound for a patented method of treatment, that could constitute induced or contributory infringement.

Given the approaching expiration date, the window for direct infringement of the composition of matter and process claims is narrowing. However, the patent may still be relevant for:

• New Indications: If the patent claims a compound and a broad method of treatment that has not yet been fully exploited or has potential for new applications discovered post-grant, its remaining term could still offer protection.
• Generic Entry: Generic manufacturers will likely scrutinize the patent's claims and expiration date closely. Upon expiration, they would be free to manufacture and sell generic versions of any approved drugs that fall under the patent's claims, provided other relevant patents (e.g., on specific formulations or approved indications) have also expired.

Licensing Opportunities:

• In-Licensing: Companies seeking to develop new PDE5 inhibitors or to gain rights to compounds covered by this patent for specific indications or geographical territories might pursue licensing agreements with Astellas Pharma Inc. However, with the patent nearing expiration, the strategic value of in-licensing may be limited to specific, niche applications or if the patent covers a particularly advantageous synthetic route.
• Out-Licensing: Astellas Pharma Inc. could have licensed its rights to this patent to other entities for specific fields of use or territories.
• Bargaining Chip: For companies involved in patent litigation or cross-licensing negotiations, an expiring patent can still hold some leverage, especially if it covers a well-established chemical class with ongoing market relevance.

Key Considerations:

• Claim Construction: The precise scope of the patent's claims, as interpreted through claim construction in any potential litigation, is critical for determining infringement.
• Prior Art and Validity: The validity of the patent could be challenged based on prior art that was not considered during examination.
• Patent Term Extensions (PTE) and Adjustments (PTA): A thorough review of the patent's file history is essential to confirm the precise expiration date. PTE and PTA can extend the patent term to compensate for delays during regulatory review and USPTO examination.

How Does This Patent Relate to Existing Marketed PDE5 Inhibitors?

US Patent 7,981,877 protects a specific class of substituted quinazoline compounds as PDE5 inhibitors. Its relation to existing marketed PDE5 inhibitors depends on the chemical structures claimed. Marketed PDE5 inhibitors like sildenafil, tadalafil, vardenafil, and avanafil are structurally distinct from quinazoline derivatives.

• Sildenafil is a pyrazolopyrimidinone derivative.
• Tadalafil is a pyrrolo[3',4':4,5]pyrrolo[2,3-d]pyrimidin-5(4H)-one derivative.
• Vardenafil is a pyrazolopyrimidinone derivative, structurally related to sildenafil.
• Avanafil is a pyrazolopyrimidine derivative.

Therefore, the compounds claimed in US Patent 7,981,877 are not directly the same chemical entities as the active pharmaceutical ingredients of these widely marketed drugs. This patent likely represents an effort by Astellas Pharma Inc. to develop an alternative chemical class of PDE5 inhibitors, potentially with a different pharmacological profile, patentability, or therapeutic advantage over existing options.

Potential interactions or relevance include:

• Indirect Competition: If compounds developed under US Patent 7,981,877 were successfully brought to market, they would compete indirectly with existing PDE5 inhibitors for the same indications (e.g., erectile dysfunction).
• Patent Portfolio Strategy: The existence of this patent suggests Astellas Pharma Inc. was building a portfolio in the PDE5 inhibitor space, aiming to have proprietary compounds distinct from those protected by other companies.
• Research and Development: The research that led to this patent might have explored structure-activity relationships that informed or were informed by research into other PDE5 inhibitor classes.
• Future Development: Even if no drug based on this patent reached the market before its expiration, the chemical knowledge and synthetic pathways disclosed could still be relevant for future research and development in the broader field of PDE inhibition or related therapeutic targets.

In essence, US Patent 7,981,877 covers a different chemical scaffold for PDE5 inhibition compared to the dominant marketed drugs, representing an independent line of intellectual property within the PDE5 inhibitor therapeutic area.

Key Takeaways

• US Patent 7,981,877 protects substituted quinazoline compounds and their preparation methods, primarily for use as PDE5 inhibitors.
• The patent's claims cover a specific chemical structure class distinct from established marketed PDE5 inhibitors like sildenafil, tadalafil, and vardenafil.
• The asserted therapeutic utility includes erectile dysfunction, pulmonary arterial hypertension, and benign prostatic hyperplasia.
• The patent is scheduled to expire on August 27, 2024, unless extended by specific USPTO granted adjustments or extensions.
• Following expiration, the protected compounds and processes could become available for generic development and manufacturing.

Frequently Asked Questions

1. When does United States Patent 7,981,877 expire? The patent is scheduled to expire on August 27, 2024, barring any granted patent term extensions or adjustments.

2. Does this patent cover the active ingredients in Viagra, Cialis, or Levitra? No, the active ingredients in Viagra (sildenafil), Cialis (tadalafil), and Levitra (vardenafil) are chemically distinct from the quinazoline derivatives claimed in US Patent 7,981,877.

3. What are the main therapeutic areas claimed by this patent? The patent primarily claims compounds for treating erectile dysfunction, pulmonary arterial hypertension, and benign prostatic hyperplasia.

4. Can generic companies manufacture drugs based on this patent immediately? Generic companies can only manufacture drugs falling under the patent's claims after its expiration date, and provided no other valid patents on specific formulations, approved indications, or manufacturing processes remain in force.

5. What is the significance of the process claims in this patent? The process claims protect specific methods used to synthesize the claimed quinazoline compounds. Competitors would need to avoid using these patented processes or obtain a license.

Citations

[1] Astellas Pharma Inc. (2011). Substituted quinazolines and process for preparing the same. U.S. Patent 7,981,877. Washington, DC: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 7,981,877

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