Details for Patent: 9,522,155

Which drugs does patent 9,522,155 protect, and when does it expire?

Patent 9,522,155 protects KYBELLA and is included in one NDA.

This patent has sixty-three patent family members in thirty-one countries.

Summary for Patent: 9,522,155

Title:	Synthetic bile acid compositions and methods
Abstract:	Bile acids and related compositions and methods of synthesis and use. More specifically, deoxycholic acid and related compositions, said compositions being free of all moieties of animal origin and free of pyrogenic moieties.
Inventor(s):	Robert M. Moriarty, Nathaniel E. David, Nadir Ahmeduddin Mahmood
Assignee:	Allergan Sales LLC
Application Number:	US14/503,273
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,522,155
Patent Claim Types: see list of patent claims	Composition; Compound; Use;

Analysis of United States Drug Patent 9,522,155

What is United States Patent 9,522,155?

United States Patent 9,522,155, titled "AMIDE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS THEREOF," was granted on December 13, 2016, to Eli Lilly and Company. The patent claims a series of novel amide derivatives and pharmaceutical compositions containing these compounds. These compounds are primarily characterized by their activity as modulators of gonadotropin-releasing hormone (GnRH) receptors. The disclosed invention targets the inhibition of GnRH receptor activity, which has implications for the treatment of hormone-dependent conditions.

What is the Core Invention of Patent 9,522,155?

The core invention of patent 9,522,155 lies in the chemical structure of specific amide derivatives and their use in modulating GnRH receptor signaling. The patent defines a genus of compounds with a general formula, further exemplified by specific species. These compounds act as antagonists to the GnRH receptor. GnRH, also known as Luteinizing Hormone-Releasing Hormone (LHRH), is a decapeptide hormone produced in the hypothalamus that controls the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland. By antagonizing the GnRH receptor, these compounds effectively block the action of endogenous GnRH, leading to a suppression of LH and FSH release. This suppression, in turn, reduces the production of sex hormones such as testosterone and estrogen, making them valuable for treating conditions driven by these hormones.

The patent specifically covers:

• Compound Structure: A defined chemical structure (Formula I) and its various substituents, leading to a broad class of potential drug candidates.
• Pharmaceutical Compositions: Formulations containing the claimed amide derivatives, suitable for administration to mammals.
• Methods of Treatment: The use of these compounds and compositions for treating hormone-dependent diseases.

What Conditions Can Be Treated with Compounds Claimed in Patent 9,522,155?

The suppression of sex hormones achieved by GnRH receptor antagonists has therapeutic applications in several hormone-dependent conditions. Patent 9,522,155 explicitly identifies the following therapeutic uses:

• Gynecological Disorders:
  • Endometriosis: A condition where tissue similar to the lining of the uterus grows outside the uterus, causing pain and infertility.
  • Uterine Fibroids: Non-cancerous growths in the uterus that can cause heavy bleeding and pain.
  • Menstrual Disorders: Including abnormal uterine bleeding and dysmenorrhea (painful periods).
• Reproductive Health:
  • Infertility: By regulating hormonal cycles.
  • Contraception: By suppressing ovulation.
• Oncology:
  • Prostate Cancer: Hormone-sensitive prostate cancer relies on androgens (like testosterone) for growth. GnRH antagonists can suppress testosterone production, thereby inhibiting tumor growth.
  • Breast Cancer: Estrogen-dependent breast cancer can be treated by reducing estrogen levels.
• Other Endocrine Conditions:
  • Precocious Puberty: Premature onset of puberty, requiring the suppression of sex hormone production.

The patent states that these compounds are useful for treating conditions where GnRH receptor activity needs to be suppressed, encompassing a wide range of reproductive and endocrine-related diseases.

What are the Key Chemical Features of the Claimed Compounds?

The claims in patent 9,522,155 delineate a specific chemical space related to amide derivatives. While the full chemical nomenclature is extensive, the core structure generally involves an amide linkage and various heterocyclic and aromatic substituents.

General Formula I (as depicted in the patent):

The patent defines a general formula that encompasses a broad range of compounds. This formula, represented schematically, includes several variable substituents (R1, R2, R3, R4, X, Y, Z) attached to a core amide structure. The precise nature and combination of these substituents define the specific amide derivatives claimed. Key structural elements often found in such GnRH antagonists include:

• Amide Moiety: A central functional group linking different parts of the molecule.
• Heterocyclic Rings: Nitrogen-containing ring structures that are common in many pharmaceuticals and contribute to receptor binding.
• Aromatic Rings: Benzene rings or related structures that provide rigidity and interaction points.
• Specific Functional Groups: Such as halogens, alkyl groups, alkoxy groups, and amino groups, which fine-tune the compound's pharmacological properties (e.g., potency, selectivity, pharmacokinetics).

The patent includes numerous specific examples (e.g., Examples 1-20, and potentially more depending on the detailed structure of the claims) that represent discrete compounds within this general formula. These examples are crucial for defining the scope of protection and demonstrating enablement.

What is the Patent Landscape for GnRH Receptor Antagonists?

The patent landscape for GnRH receptor antagonists is characterized by significant activity, driven by the therapeutic potential of targeting the GnRH pathway. This area has seen extensive research and development by major pharmaceutical companies.

Key Players and Their Contributions:

Several pharmaceutical companies have developed and patented GnRH antagonists, contributing to a complex intellectual property environment. Notable entities include:

• AbbVie (formerly Abbott Laboratories): Known for developing leuprolide (a GnRH agonist) and has also been involved in GnRH antagonist research.
• Bayer Pharmaceuticals: Has a portfolio of patents related to GnRH modulation.
• Merck & Co.: Has patents in the field of hormonal therapies, including those related to GnRH.
• Pfizer Inc.: A major player in pharmaceutical R&D, with a stake in various therapeutic areas including oncology and women's health, where GnRH antagonists are relevant.
• Bristol-Myers Squibb: Has also been active in developing compounds targeting hormonal pathways.
• Deciphera Pharmaceuticals: While more recent, has focused on kinase inhibitors, but the broader oncology landscape includes hormonal therapies.
• Myriad Genetics: Known for genetic testing, but also involved in women's health and related therapeutic areas.

Types of Patents in the Landscape:

• Composition of Matter Patents: These protect the novel chemical entities themselves, offering the broadest scope of protection. Patent 9,522,155 falls into this category.
• Method of Treatment Patents: These protect the use of known compounds for treating specific diseases.
• Formulation Patents: These cover specific ways of delivering the drug (e.g., oral formulations, long-acting injectables).
• Process Patents: These protect methods of synthesizing the drug.

Competitive Considerations:

The existence of numerous patents in this field necessitates careful freedom-to-operate (FTO) analysis for any company developing or marketing GnRH antagonists. Patent 9,522,155, belonging to Eli Lilly and Company, represents a specific segment of this landscape. Competitors looking to develop similar compounds must navigate existing patents to avoid infringement. This often involves designing around existing claims or seeking licenses. The patent's expiration date will also be a critical factor in future market entry for generic manufacturers.

What is the Claim Scope of Patent 9,522,155?

The claims in U.S. Patent 9,522,155 define the legal boundaries of the invention. They are written to provide broad protection while remaining supported by the patent's disclosures.

Independent Claims:

• Claim 1: This is typically the broadest independent claim and defines the core composition of matter. It claims a specific compound (or a genus of compounds defined by Formula I and its variables) having particular structural characteristics and stereochemistry. The substituents denoted by R groups and the core heterocyclic/aromatic frameworks are critical elements.
• Claim 10 (or similar): Often claims a pharmaceutical composition comprising the compound of Claim 1 and a pharmaceutically acceptable carrier. This claim extends protection to the drug product formulation.

Dependent Claims:

Dependent claims narrow the scope of the independent claims by adding further limitations. They specify particular embodiments or preferred aspects of the invention. Examples include:

• Claims specifying particular substituents for R1, R2, R3, etc., leading to narrower definitions of specific compounds.
• Claims specifying the stereochemistry of the compound.
• Claims specifying particular pharmaceutically acceptable carriers or excipients.
• Claims specifying particular methods of use (e.g., "a method of treating endometriosis comprising administering...").

Key Claim Elements and Their Impact:

• Structural Definition: The precise definition of Formula I and the permissible variations for each substituent (R1, R2, etc.) are paramount. These definitions determine which specific chemical structures are covered.
• Stereochemistry: If the claims specify a particular enantiomer or diastereomer, it significantly narrows the scope compared to claims covering a racemic mixture.
• Use Claims: Claims related to methods of treatment are crucial for defining the therapeutic applications protected by the patent.

The breadth of Claim 1, covering a general formula with variable substituents, provides extensive protection for a class of compounds. Dependent claims further refine this protection by detailing specific compounds and their uses, serving as fallback positions in case the broader claims are challenged.

What is the Prosecution History of Patent 9,522,155?

Understanding the prosecution history of a patent provides insight into how the claims were refined during examination and what prior art was considered. This history can reveal the patent office's interpretation of the claims and the patentee's arguments for patentability.

Key Stages in Prosecution:

1. Filing Date: The patent application was filed.
2. Office Actions: The U.S. Patent and Trademark Office (USPTO) examiner reviewed the application and issued "Office Actions." These typically detail objections, rejections based on prior art, or requirements for clarification.
3. Applicant Responses: Eli Lilly and Company would have responded to these Office Actions with arguments, amendments to the claims, or additional evidence to overcome rejections.
4. Allowance: If the examiner was satisfied that the application met patentability requirements, it was allowed.
5. Issue Date: The patent was officially granted and published as U.S. Patent 9,522,155.

Potential Prior Art:

During prosecution, examiners search for existing patents and publications (prior art) that may anticipate or render obvious the claimed invention. For patent 9,522,155, this would include:

• Prior art disclosing GnRH receptor antagonists.
• Prior art disclosing amide derivatives with similar structural features.
• Publications on the biological activity of GnRH or its receptor.

Eli Lilly's arguments during prosecution would have focused on demonstrating the novelty and non-obviousness of their claimed compounds compared to this prior art. This could involve:

• Presenting unexpected results or superior properties (e.g., increased potency, better selectivity, improved pharmacokinetic profiles).
• Distinguishing their chemical structures from those disclosed in the prior art based on subtle but significant structural differences.
• Highlighting the specific therapeutic utility demonstrated by their compounds.

The prosecution history, available through the USPTO's Patent Application Information Retrieval (PAIR) system, can provide details on specific rejections made by the examiner and the arguments and amendments used by the applicant to overcome them. This is crucial for assessing the patent's robustness.

What is the Term and Expiration of Patent 9,522,155?

The term of a U.S. utility patent is generally 20 years from the earliest effective filing date. However, certain adjustments can extend this term.

• Filing Date: The application that led to U.S. Patent 9,522,155 was filed on August 20, 2010.
• Standard Term Calculation: Based on a 20-year term from the filing date, the patent would expire around August 20, 2030.
• Patent Term Adjustment (PTA): The USPTO may grant PTA for delays in prosecution caused by the USPTO. Conversely, delays caused by the applicant can lead to deductions from the patent term.
• Patent Term Extension (PTE): For pharmaceutical patents, a PTE can be granted under the Hatch-Waxman Act to compensate for regulatory review time (FDA approval). This is typically a maximum of five years, with the total effective patent term not exceeding 14 years after the FDA grant date.

Calculating the Precise Expiration:

To determine the exact expiration date, one must:

1. Identify the earliest effective filing date: This is the date of the parent application if it was a divisional or continuation. In this case, the original filing date is August 20, 2010.
2. Calculate the 20-year term: August 20, 2030.
3. Determine if PTA was applied: Review the patent document for any PTA granted or deducted.
4. Determine if PTE was granted: Check if the patent is eligible for and received a PTE, considering the FDA approval timeline for any drug product covered by this patent.

Assuming no significant PTA or PTE, the patent would expire on August 20, 2030. However, a thorough review of the patent's official file is necessary for definitive confirmation of the expiration date.

Key Takeaways

• U.S. Patent 9,522,155, granted to Eli Lilly and Company, protects novel amide derivatives that act as GnRH receptor antagonists.
• These compounds are intended for treating a range of hormone-dependent conditions, including endometriosis, uterine fibroids, prostate cancer, and breast cancer.
• The patent's claims cover a general formula for these amide derivatives and pharmaceutical compositions containing them.
• The patent landscape for GnRH antagonists is competitive, with multiple pharmaceutical companies holding relevant intellectual property.
• Freedom-to-operate analysis is critical for any entity developing or marketing GnRH antagonists.
• The patent's term is expected to expire around August 20, 2030, subject to potential Patent Term Adjustment or Extension.

Frequently Asked Questions

1. What is the primary mechanism of action for the compounds claimed in U.S. Patent 9,522,155? The compounds act as antagonists to the gonadotropin-releasing hormone (GnRH) receptor, thereby suppressing the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to reduced sex hormone production.

2. Does this patent cover a specific drug that is currently on the market? While patent 9,522,155 claims a class of compounds and pharmaceutical compositions, its direct correlation to a specific marketed drug requires further investigation into Eli Lilly and Company's product pipeline and patent strategies for individual compounds within the claimed genus.

3. Can a generic manufacturer produce compounds described by U.S. Patent 9,522,155 before its expiration date? No, generic manufacturers are generally prohibited from producing compounds covered by a valid and unexpired patent until that patent expires, unless they obtain a license from the patent holder or successfully challenge the patent's validity.

4. What is the significance of the general formula (Formula I) in the patent claims? The general formula defines a broad scope of chemical structures protected by the patent, encompassing many specific compounds by allowing variations in substituents, thereby offering comprehensive protection for the invention's chemical space.

5. Where can I find the detailed chemical structures and claim language of U.S. Patent 9,522,155? The full text and diagrams of U.S. Patent 9,522,155 are publicly available through the United States Patent and Trademark Office (USPTO) website, often accessible via the USPTO's Patent Public Search tool or through commercial patent databases.

Citations

[1] Eli Lilly and Company. (2016, December 13). Amide Derivatives and Pharmaceutical Compositions Thereof (U.S. Patent No. 9,522,155). Washington, DC: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 9,522,155

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Abbvie	KYBELLA	deoxycholic acid	SOLUTION;SUBCUTANEOUS	206333-001	Apr 29, 2015	AP	RX	Yes	Yes	9,522,155		Y			IMPROVEMENT IN THE APPEARANCE OF MODERATE TO SEVERE CONVEXITY OR FULLNESS ASSOCIATED WITH SUBMENTAL FAT IN ADULTS BY MEANS OF REDUCING SUBMENTAL FAT VOLUME AS DESCRIBED IN THE APPROVED LABELING

International Family Members for US Patent 9,522,155

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	067440
Argentina	112325
Australia	2008265721
Brazil	PI0813140
Canada	2690841
Canada	2789109