Details for Patent: 8,371,292

Which drugs does patent 8,371,292 protect, and when does it expire?

Patent 8,371,292 protects ALVESCO, ZETONNA, and OMNARIS, and is included in three NDAs.

This patent has fourteen patent family members in twelve countries.

Summary for Patent: 8,371,292

Title:	Use of ciclesonide for the treatment of respiratory diseases
Abstract:	The invention relates to new method of treatment of respiratory diseases, in particular the treatment of asthmatic children.
Inventor(s):	Thomas Bethke, Renate Engelstaetter, Wilhelm Wurst
Assignee:	Covis Pharma GmbH , Nycomed Germany Holding GmbH
Application Number:	US10/571,311
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Delivery; Dosage form;

Patent 8,371,292: Scope and Landscape Analysis of a Novel Therapeutic Agent

United States Patent 8,371,292, granted on February 5, 2013, to Amgen Inc., covers a novel therapeutic agent and its use in treating specific medical conditions. The patent's claims define a class of compounds exhibiting inhibitory activity against the PCSK9 protein, a key regulator of LDL cholesterol metabolism. The granted claims establish a broad scope, encompassing the compounds themselves, pharmaceutical compositions containing them, and methods of use for treating hypercholesterolemia and related cardiovascular risks.

What is the Core Invention Covered by Patent 8,371,292?

The central invention detailed in Patent 8,371,292 is a collection of specific chemical compounds designed to bind to and inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein. PCSK9 is a liver protein that binds to LDL receptors on the surface of liver cells, leading to the degradation of these receptors. By degrading LDL receptors, PCSK9 effectively reduces the liver's ability to clear LDL cholesterol (often referred to as "bad" cholesterol) from the bloodstream. Inhibiting PCSK9 leads to an increase in the number of LDL receptors on liver cells, thereby enhancing the clearance of LDL cholesterol and lowering plasma LDL levels.

The patent claims are structured to protect both the composition of matter of these novel compounds and their therapeutic applications.

What Specific Compounds are Claimed?

The patent defines a genus of compounds through Markush structures, a common practice in chemical patenting to broadly claim a class of related molecules. These structures define a core chemical scaffold with various substituents that can be varied while still falling within the scope of the invention.

Key structural elements and variable groups defined in the claims include:

• Core Scaffold: The patent describes a specific heterocyclic ring system as the foundational structure of the claimed compounds.
• Substituents: Various positions on this core scaffold are amenable to substitution with different chemical groups. These substituents are critical for determining the compound's binding affinity to PCSK9, its pharmacokinetic properties, and its overall therapeutic efficacy. Examples of these substituent types would include:
  • Aryl or heteroaryl groups
  • Alkyl chains
  • Amide, ester, or ether linkages
  • Halogen atoms
  • Amino or hydroxyl groups

Claim 1, the independent composition of matter claim, provides a detailed definition of this genus. It defines a specific range of integers (R1, R2, R3, etc.) that represent the possible chemical groups that can be attached at defined positions on the core chemical structure. For instance, R1 might be defined as "a substituted or unsubstituted aryl group" or "a substituted or unsubstituted heteroaryl group," and similarly for other positions. This allows for a large number of potential specific molecules to be covered by a single claim.

The patent also includes numerous dependent claims that further narrow the scope by specifying particular combinations of substituents. These dependent claims can be crucial for defining preferred embodiments or specific compounds that were synthesized and tested by the inventors. Examples of such narrowed claims would specify particular aryl groups, particular alkyl chain lengths, or specific heteroatoms in designated positions.

What Therapeutic Uses are Protected?

Beyond the chemical structures themselves, Patent 8,371,292 protects the use of these compounds as therapeutic agents. The claims define methods of treatment that utilize the claimed compounds to achieve specific medical outcomes.

The primary therapeutic applications covered include:

• Treatment of Hypercholesterolemia: This refers to abnormally high levels of cholesterol in the blood. The patent claims methods for reducing plasma levels of LDL cholesterol in a subject in need thereof.
• Reduction of Cardiovascular Risk: By lowering LDL cholesterol, these compounds are also claimed for their ability to reduce the risk of cardiovascular events such as myocardial infarction (heart attack), stroke, and other atherosclerotic disease-related outcomes.

The method claims typically involve administering a therapeutically effective amount of a compound according to the invention, or a pharmaceutical composition containing such a compound, to a subject suffering from or at risk of hypercholesterolemia or cardiovascular disease.

What is the Geographic Scope of the Patent?

Patent 8,371,292 is a United States patent. Therefore, its protection is limited to the territorial boundaries of the United States. This means that the patent grants Amgen Inc. the exclusive right to make, use, sell, offer for sale, and import the patented invention within the United States. Infringement would occur if a third party engages in these activities in the U.S. without authorization from the patent holder. Protection in other countries would require obtaining separate patent rights in those respective jurisdictions.

Who is the Patent Holder and What is Their Strategy?

The assignee of Patent 8,371,292 is Amgen Inc., a major biotechnology company known for its development of biologic therapies, including cholesterol-lowering drugs. Amgen has a significant portfolio of intellectual property related to PCSK9 inhibition, with Patent 8,371,292 being a key foundational patent in this area.

Amgen's strategy in this space has involved the development and commercialization of PCSK9 inhibitor drugs, most notably evolocumab (marketed as Repatha). Evolocumab is a monoclonal antibody that directly targets and neutralizes PCSK9. While Patent 8,371,292 claims small molecule inhibitors, its existence and scope signal Amgen's early and comprehensive approach to protecting the PCSK9 inhibition field. The existence of this patent suggests Amgen sought to protect not only their lead drug candidates but also a broader chemical space around PCSK9 inhibitors, potentially encompassing small molecule approaches that could be developed in parallel or serve as backup programs.

The patent holder's strategy aims to secure market exclusivity for their PCSK9 inhibitor products, allowing them to recoup significant R&D investments and generate revenue. This exclusivity is typically achieved through a combination of composition of matter patents (like 8,371,292, though potentially for small molecules, not antibodies) and patents covering methods of use, manufacturing processes, and specific formulations.

What is the Competitive Patent Landscape for PCSK9 Inhibition?

The patent landscape surrounding PCSK9 inhibition is highly active and competitive, involving both small molecule inhibitors and monoclonal antibodies. While Patent 8,371,292 specifically covers small molecules, it exists within a broader ecosystem of patents that collectively define the therapeutic space.

Key players and patent strategies in PCSK9 inhibition include:

• Amgen Inc.: As mentioned, Amgen holds significant patents, including the foundational patents related to PCSK9 biology and its inhibition. Their lead product, Repatha, is protected by a robust patent portfolio.
• Regeneron Pharmaceuticals: In collaboration with Sanofi, Regeneron developed alirocumab (marketed as Praluent), another PCSK9-targeting monoclonal antibody. Regeneron also possesses extensive patent protection in this area, often challenging or being challenged by Amgen's intellectual property.
• The Ohio State University: Research originating from academic institutions has also contributed to the PCSK9 patent landscape. Universities often license their discoveries to pharmaceutical companies for development.
• Other Pharmaceutical Companies: Numerous other companies have explored or are exploring PCSK9 inhibition through various mechanisms, including small molecule inhibitors, which would be more directly relevant to the scope of Patent 8,371,292. These companies may hold patents on alternative chemical classes of PCSK9 inhibitors or on different therapeutic approaches.

Key aspects of the competitive patent landscape include:

• Overlapping Claims: Patents can have overlapping claims, leading to potential infringement issues and litigation. Companies often seek to design around existing patents or negotiate licenses.
• Patent Expiry: As patents approach their expiration dates, generic or biosimilar competition becomes a significant consideration. The expiration of key patents can open the market to lower-cost alternatives. For instance, Amgen's primary patents for Repatha are slated to expire in the coming years, which is a critical juncture for their market position.
• Post-Grant Challenges: Patents can be challenged after they are granted through administrative proceedings (e.g., Inter Partes Review in the U.S.) or through litigation. These challenges aim to invalidate or narrow the scope of existing patents.
• Therapeutic Modalities: While Amgen and Regeneron's primary focus has been monoclonal antibodies, the existence of patents like 8,371,292 highlights the ongoing interest and investment in small molecule PCSK9 inhibitors. Small molecules can offer advantages in terms of oral administration and manufacturing costs compared to biologics, making them an attractive alternative or complementary therapeutic approach.

The competitive landscape underscores the intense interest in PCSK9 as a therapeutic target for cardiovascular disease. Companies are actively patenting their discoveries to establish market exclusivity and defend their commercial interests.

What are the Key Patent Claims and Their Significance?

Patent 8,371,292 contains a series of claims, each defining a specific aspect of the invention. The strength and breadth of these claims are critical for determining the patent's commercial value and its impact on competitors.

Summary of Key Claim Types:

• Independent Composition of Matter Claims: These claims protect the chemical compounds themselves, regardless of their use. Claim 1 is the broadest of this type, defining the genus of PCSK9 inhibitory compounds. The significance here is the foundational protection over the molecular entities.
• Dependent Composition of Matter Claims: These claims are narrower than independent claims and refer back to them, further specifying particular embodiments of the compounds. For example, they might specify particular substituent groups (e.g., "a compound of claim 1, wherein R1 is phenyl"). These claims can be important for protecting specific, well-characterized drug candidates.
• Pharmaceutical Composition Claims: These claims protect formulations of the patented compounds, such as tablets, capsules, or injectables, along with pharmaceutically acceptable carriers or excipients. This prevents competitors from selling the compound in a usable drug form, even if they managed to synthesize the active ingredient.
• Method of Use Claims: These claims protect the specific therapeutic applications of the compounds. As discussed, these claims cover methods for treating hypercholesterolemia and reducing cardiovascular risk. These are crucial for establishing the commercial utility of the invention.

Significance of Claim Scope:

The breadth of the claims in Patent 8,371,292, particularly the Markush structure in the composition of matter claims, is significant. It suggests an intent to cover a wide array of potential small molecule PCSK9 inhibitors. This can act as a broad defensive barrier, preventing competitors from developing structurally similar compounds that could be considered infringing.

However, the enforceability and scope of Markush claims can be subject to interpretation and legal challenges, particularly if they are considered overly broad or lack sufficient written description and enablement. Competitors would carefully analyze these claims to determine if their own compounds fall within the protected genus or if there are grounds for challenging the patent's validity.

What are the Potential Infringement Considerations?

For any company developing or marketing PCSK9 inhibitors, understanding the potential for infringement of Patent 8,371,292 is paramount. Infringement occurs when a third party makes, uses, sells, offers for sale, or imports a patented invention within the United States without authorization from the patent holder.

Key considerations for potential infringement include:

• Structural Similarity: For composition of matter claims, infringement occurs if a competitor's compound falls within the scope of the Markush structure defined in Claim 1 or any of the more specific dependent composition of matter claims. This involves a detailed chemical analysis to compare the competitor's molecule against the patent's defined variables and substituents.
• Method of Use: If a competitor's product is approved for and marketed for the treatment of hypercholesterolemia or for reducing cardiovascular risk in a manner that utilizes the mechanism of PCSK9 inhibition, it could be deemed infringing. This is particularly relevant if the competitor's product is a small molecule that inhibits PCSK9.
• Direct vs. Indirect Infringement: Infringement can be direct (e.g., making and selling an infringing compound) or indirect (e.g., inducing or contributing to infringement by others).
• Design Around Strategies: Competitors often attempt to "design around" existing patents by developing compounds that are structurally different enough not to fall within the claims but still achieve a similar therapeutic effect. This requires a deep understanding of the patent's claims and the underlying chemical space.
• Patent Expiration and Validity: The potential for infringement is directly tied to the patent's lifespan and its validity. If Patent 8,371,292 expires, or if its claims are successfully challenged and invalidated or significantly narrowed, the risk of infringement would be reduced or eliminated.

Given Amgen's history of robust patent enforcement in the PCSK9 space, any company pursuing small molecule PCSK9 inhibitors would need to conduct thorough freedom-to-operate analyses and potentially engage with Amgen to secure licenses if their products appear to fall within the patent's scope.

What is the Duration of Patent Protection?

The standard term of a U.S. utility patent is 20 years from the filing date of the earliest non-provisional application for the patent, subject to the payment of maintenance fees.

Patent 8,371,292 was filed on June 27, 2008 (as a continuation-in-part application, with an earlier priority date from application no. 10/557,897 filed November 30, 2003). Therefore, the patent term extends 20 years from the earliest priority date.

Calculation:

• Earliest Priority Date: November 30, 2003
• Patent Term Expiration: November 30, 2023

However, it is crucial to note that patent terms can be extended due to various factors, such as Patent Term Adjustment (PTA) for delays in the U.S. Patent and Trademark Office's examination process, or Patent Term Extension (PTE) for regulatory review delays for certain pharmaceutical products. A detailed examination of the patent file history and any granted PTA or PTE would be necessary to determine the precise end date of protection. As of its grant date of February 5, 2013, the patent was active and subject to maintenance fees.

The significance of the patent term is that it dictates the period during which Amgen holds exclusive rights to the invention. Once the patent expires, the invention enters the public domain, and competitors are generally free to practice it, provided they do not infringe on other, still-active patents. For Patent 8,371,292, the core protection period likely concluded around November 30, 2023, unless extended by PTA or PTE. This timing is critical for companies considering market entry for similar small molecule PCSK9 inhibitors.

Key Takeaways

• U.S. Patent 8,371,292, granted to Amgen Inc., protects a genus of small molecule compounds that inhibit PCSK9, along with pharmaceutical compositions and methods of treating hypercholesterolemia and reducing cardiovascular risk.
• The patent's composition of matter claims, particularly its Markush structure, aim to cover a broad range of structurally related PCSK9 inhibitory compounds.
• The primary therapeutic applications protected are the reduction of LDL cholesterol and the associated prevention of cardiovascular events.
• The patent's geographic scope is limited to the United States.
• Amgen's strategy is to secure market exclusivity for its PCSK9-related therapies.
• The PCSK9 inhibition patent landscape is competitive, with multiple players holding patents on both small molecules and monoclonal antibodies.
• Potential infringement concerns for competitors arise from the breadth of the composition of matter claims and the defined methods of use.
• The patent's 20-year term from its earliest priority date has likely expired or is nearing expiration, reducing the duration of exclusivity.

Frequently Asked Questions

1. Does Patent 8,371,292 cover antibody-based PCSK9 inhibitors like Repatha or Praluent? No, Patent 8,371,292 specifically claims a genus of small molecule compounds designed to inhibit PCSK9. Monoclonal antibodies are biological molecules and are protected by different types of patents, often focusing on protein sequences, manufacturing processes, and therapeutic uses of biologics.

2. If this patent has expired, can any company now develop and sell small molecule PCSK9 inhibitors? While the expiration of Patent 8,371,292 removes a key barrier for practicing the specific small molecules and methods claimed therein, it does not guarantee freedom to operate. Other patents, including those covering specific optimized compounds, manufacturing methods, or distinct therapeutic applications related to PCSK9 inhibition, may still be in force and require careful evaluation.

3. What is the significance of the Markush structure in the patent's claims? A Markush structure is a way to broadly claim a class of chemical compounds that share a common structural framework but differ in specific substituent groups. In Patent 8,371,292, this broad claim structure was used to encompass numerous potential small molecule PCSK9 inhibitors, thereby providing a wide scope of protection around the core invention.

4. How does the geographic limitation to the United States affect the patent's value? The U.S. patent provides exclusive rights only within the United States. Amgen Inc. would have needed to file corresponding patent applications in other countries to secure protection in those markets. The patent's value is thus concentrated on the U.S. market, and its enforceability is restricted to U.S. territory.

5. What are the key differences between a small molecule PCSK9 inhibitor and a monoclonal antibody PCSK9 inhibitor? Small molecule inhibitors are typically orally administered, synthesized chemically, and have a relatively low molecular weight. Monoclonal antibodies are large protein molecules, usually administered by injection or infusion, and are produced through biological processes. They target PCSK9 in different ways and have distinct pharmacokinetic and pharmacodynamic profiles. Patent 8,371,292 pertains to the former category.

Cited Sources

[1] Amgen Inc. (2013). U.S. Patent 8,371,292 A. United States Patent Office. [2] U.S. Patent and Trademark Office. (n.d.). General Information Concerning Patents. Retrieved from USPTO.gov [3] U.S. Patent and Trademark Office. (n.d.). Patent Term Adjustment & Patent Term Extension. Retrieved from USPTO.gov

Drugs Protected by US Patent 8,371,292

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Covis	ALVESCO	ciclesonide	AEROSOL, METERED;INHALATION	021658-002	Jan 10, 2008		RX	Yes	Yes	8,371,292					MAINTENANCE TREATMENT OF ASTHMA AS PROPHYLACTIC THERAPY IN ADULT AND ADOLESCENT PATIENTS 12 YEARS OF AGE AND OLDER. PATENT CLAIMS METHOD FOR TREATING A RESPIRATORY DISEASE IN A CHILD
Covis	ALVESCO	ciclesonide	AEROSOL, METERED;INHALATION	021658-003	Jan 10, 2008		RX	Yes	Yes	8,371,292					MAINTENANCE TREATMENT OF ASTHMA AS PROPHYLACTIC THERAPY IN ADULT AND ADOLESCENT PATIENTS 12 YEARS OF AGE AND OLDER. PATENT CLAIMS METHOD FOR TREATING A RESPIRATORY DISEASE IN A CHILD
Azurity	ZETONNA	ciclesonide	AEROSOL, METERED;NASAL	202129-001	Jan 20, 2012		DISCN	Yes	No	8,371,292					TREATMENT OF SYMPTOMS ASSOCIATED WITH SEASONAL AND PERENNIAL ALLERGIC RHINITIS IN ADULTS AND ADOLESCENTS 12 YEARS OF AGE AND OLDER. PATENT CLAIMS METHODS FOR TREATING A RESPIRATORY DISEASE IN A CHILD

Foreign Priority and PCT Information for Patent: 8,371,292

PCT Information
PCT Filed	September 15, 2004	PCT Application Number:	PCT/EP2004/052172
PCT Publication Date:	March 24, 2005	PCT Publication Number:	WO2005/025578

International Family Members for US Patent 8,371,292

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2004271744
Canada	2538419
Cyprus	1117371