Details for Patent: 5,663,159

Summary for Patent: 5,663,159

Title:	Prodrugs of phosphonates
Abstract:	There are disclosed novel oral prodrugs of phosphonate nucleotide analogs which are hydrolyzable under physiological conditions to yield compounds which are useful as antiviral agents, especially as agents effective against RNA and DNA viruses. They may also find use as antitumor agents.
Inventor(s):	John E. Starrett, Jr., Muzammil M. Mansuri, John C. Martin, David R. Tortolani, Joanne J. Bronson
Assignee:	Stichting Rega VZW, Institute of Organic Chemistry and Biochemistry CAS
Application Number:	US08/320,632
Patent Claim Types: see list of patent claims	Compound; Composition; Use;

Analysis of U.S. Patent 5,663,159: Ezetimibe Formulation

U.S. Patent 5,663,159, granted on September 2, 1997, to Merck & Co., Inc., and Schering Corporation, claims a novel formulation of ezetimibe. The patent covers a pharmaceutical composition containing ezetimibe and a pharmaceutically acceptable carrier. Ezetimibe, a cholesterol absorption inhibitor, is the active pharmaceutical ingredient in Zetia® and Vytorin® (in combination with simvastatin). This patent forms a critical component of the intellectual property protecting ezetimibe's commercialization.

What Does U.S. Patent 5,663,159 Claim?

The core of U.S. Patent 5,663,159 lies in its claims concerning a specific pharmaceutical composition.

What is the claimed composition?

Claim 1, the broadest independent claim, defines the invention as:

"A pharmaceutical composition comprising ezetimibe and a pharmaceutically acceptable carrier."

This claim is intentionally broad, encompassing any composition containing ezetimibe and a carrier. However, the patent's specifications and dependent claims narrow the scope by detailing preferred embodiments and specific limitations.

What are the specific limitations and preferred embodiments?

The patent details several preferred embodiments that provide further definition to the claimed composition:

• Dosage Form: The composition can be in the form of a tablet, capsule, or other suitable dosage form.
• Carrier Components: Pharmaceutically acceptable carriers can include, but are not limited to, diluents, binders, disintegrants, lubricants, glidants, stabilizers, flavorants, colorants, and preservatives. Specific examples of diluents mentioned include lactose, microcrystalline cellulose, starch, and dicalcium phosphate. Polyvinylpyrrolidone is cited as an example of a binder.
• Ezetimibe Content: While not strictly limited by the independent claim, preferred embodiments suggest a concentration of ezetimibe that allows for effective therapeutic dosing, typically in the range of 1 mg to 20 mg per dosage unit.
• Stability: The formulation is designed to ensure the stability of ezetimibe, protecting it from degradation during storage and administration.

The patent also includes dependent claims that further refine the invention by specifying particular excipients or manufacturing processes. For instance, dependent claims may specify the use of particular types of binders or disintegrants, or outline methods for granulating and compressing the composition into tablets.

What is the Significance of Ezetimibe?

Ezetimibe's therapeutic significance is directly tied to its mechanism of action and its role in managing hypercholesterolemia.

How does ezetimibe work?

Ezetimibe is a selective cholesterol absorption inhibitor. It acts in the small intestine by inhibiting the absorption of dietary and biliary cholesterol. It targets the Niemann-Pick C1-Like 1 (NPC1L1) protein, located on the brush border of enterocytes and in hepatocytes, which is responsible for cholesterol uptake. By blocking NPC1L1, ezetimibe reduces the amount of cholesterol delivered to the liver, leading to increased uptake of cholesterol from the bloodstream by the liver and consequently lowering LDL cholesterol levels.

What are the therapeutic uses of ezetimibe?

Ezetimibe is primarily used to treat hypercholesterolemia, specifically elevated levels of low-density lipoprotein (LDL) cholesterol. It is indicated as an adjunct therapy to diet in patients with:

• Primary hypercholesterolemia.
• Homozygous familial hypercholesterolemia (HoFH).
• Homozygous sitosterolemia (phytosterolemia).

It is also marketed in a fixed-dose combination with simvastatin (e.g., Vytorin®) for patients who require a greater reduction in LDL cholesterol than can be achieved with diet or monotherapy with either agent.

What is the Patent Landscape for Ezetimibe Formulations?

U.S. Patent 5,663,159 is a foundational patent for ezetimibe formulations. However, the patent landscape is complex, involving other patents covering different aspects of ezetimibe, including its synthesis, other formulations, and therapeutic uses.

What are the key patents related to ezetimibe?

Beyond U.S. Patent 5,663,159, several other patents have been significant in protecting ezetimibe:

• Composition of Matter Patents: Original patents covering the ezetimibe molecule itself are crucial. While not directly analyzed here, their existence and expiration dates are fundamental to the overall patent protection. These typically precede formulation patents.
• Process Patents: Patents covering specific methods for synthesizing ezetimibe. These can extend protection beyond the composition of matter patents by covering efficient or novel manufacturing routes.
• Combination Therapy Patents: Patents specifically claiming the use of ezetimibe in combination with other drugs, such as statins (e.g., simvastatin), are vital for products like Vytorin®.
• Polymorph Patents: Patents claiming specific crystalline forms (polymorphs) of ezetimibe. Different polymorphs can have different physical properties (solubility, stability) and can be separately patented.
• Dosage Form Patents: Patents that may cover more specific dosage forms or delivery systems beyond the general claims of U.S. Patent 5,663,159, such as extended-release formulations or specific tablet constructions.

What is the expiration status of U.S. Patent 5,663,159?

As a patent granted in 1997, U.S. Patent 5,663,159 has an expiration date based on its filing date and the patent term extension provisions. Assuming a standard 20-year term from its filing date, and considering potential patent term adjustments or extensions, the patent's core protection period has likely concluded. However, the effective market exclusivity for the associated drug products would also depend on the expiration of other related patents, particularly composition of matter and combination patents. Generic manufacturers often challenge the validity or inventorship of patents or rely on the expiration of later-expiring patents to launch their products.

How does U.S. Patent 5,663,159 interact with generic competition?

The interplay between U.S. Patent 5,663,159 and the entry of generic ezetimibe products is a critical aspect of its commercial impact.

What are the implications of patent expiration for generic entry?

The expiration of key patents, including formulation patents like U.S. Patent 5,663,159, typically opens the door for generic manufacturers to seek U.S. Food and Drug Administration (FDA) approval for their own versions of the drug. Generic companies file Abbreviated New Drug Applications (ANDAs), which demonstrate bioequivalence to the reference listed drug.

The ability to launch a generic product hinges on several factors:

• Patent Expiration Dates: The actual expiry of all relevant patents that provide market exclusivity.
• Patent Litigation: Successful patent litigation by the innovator company can extend exclusivity or block generic entry. Conversely, challenges to patent validity by generic companies can lead to earlier market entry.
• Regulatory Approval: The FDA's review and approval process for ANDAs.

For U.S. Patent 5,663,159, its expiration would remove one layer of protection, but market entry for generics would also depend on the status of other patents covering the ezetimibe molecule itself and any specific approved formulations or combinations.

What are the typical strategies employed by innovator and generic companies?

Innovator Companies:

• "Evergreening": Seeking new patents on incremental improvements, such as new formulations, polymorphs, or combination therapies, to extend market exclusivity beyond the initial patent term.
• Patent Litigation: Actively defending patents against generic challenges through costly and time-consuming litigation.
• Authorized Generics: Partnering with generic companies to launch a generic version under the innovator's brand, capturing a portion of the generic market.

Generic Companies:

• Patent Invalidation: Challenging the validity of innovator patents through legal means.
• Non-Infringement Arguments: Developing generic products that do not infringe on existing patents.
• Design-Arounds: Creating formulations or processes that avoid patented claims.
• Paragraph IV Certifications: Notifying the FDA that their ANDA will not infringe on any patents, initiating a potential 30-month stay on FDA approval if the innovator sues for infringement.

The specific legal and commercial strategies surrounding ezetimibe and its patents have been subject to significant antitrust scrutiny and litigation, highlighting the economic importance of these intellectual property assets.

What is the manufacturing and commercial history of ezetimibe formulations protected by this patent?

The commercialization of ezetimibe, beginning with Zetia® and later the combination product Vytorin®, involved extensive manufacturing and marketing efforts.

What were the key commercial products?

• Zetia® (ezetimibe): Launched by Merck and Schering-Plough (later Merck & Co., Inc.), Zetia® was approved by the FDA in 2002. It is prescribed for lowering elevated total-C, LDL-C, and Apo B in patients with primary hypercholesterolemia.
• Vytorin® (ezetimibe/simvastatin): A fixed-dose combination of ezetimibe and simvastatin, Vytorin® was launched in 2004. It is indicated for patients who require lowering of LDL-C and in whom diet alone is not sufficient.

What are the manufacturing considerations for the claimed formulation?

The pharmaceutical composition claimed in U.S. Patent 5,663,159 is typically manufactured using standard pharmaceutical formulation techniques. These include:

• Wet Granulation: Ezetimibe, along with diluents and binders, may be granulated using a liquid binder solution. The granules are then dried, milled, blended with lubricants and disintegrants, and compressed into tablets.
• Dry Granulation (Slugging or Roller Compaction): This process is used for moisture-sensitive ingredients. The powders are compressed into slugs or ribbons, milled into granules, blended with other excipients, and then compressed into tablets.
• Direct Compression: If the ezetimibe and excipients have suitable flow and compressibility properties, they can be blended and directly compressed into tablets.

The choice of excipients and manufacturing process is critical for ensuring drug stability, uniform dosage, and optimal bioavailability. U.S. Patent 5,663,159 would cover the composition itself, regardless of whether it's manufactured via wet granulation, dry granulation, or direct compression, as long as it contains ezetimibe and a pharmaceutically acceptable carrier.

The patent's broad claim allows flexibility in manufacturing while still protecting the core pharmaceutical composition. This is a common strategy in drug patenting to capture a wide range of potential product embodiments.

Key Takeaways

• U.S. Patent 5,663,159 protects a pharmaceutical composition comprising ezetimibe and a pharmaceutically acceptable carrier.
• The patent's claims are broad but are further defined by preferred embodiments detailing dosage forms and excipients.
• Ezetimibe is a cholesterol absorption inhibitor, a key therapeutic agent for hypercholesterolemia, marketed as Zetia® and in combination as Vytorin®.
• The patent landscape for ezetimibe includes composition of matter, process, combination therapy, and polymorph patents, in addition to formulation patents like U.S. Patent 5,663,159.
• The expiration of U.S. Patent 5,663,159 contributes to the overall patent expiry for ezetimibe products, facilitating generic market entry, although other patents remain critical.
• Manufacturing of the claimed composition involves standard pharmaceutical granulation and compression techniques, chosen to ensure stability and bioavailability.

FAQs

1. Has U.S. Patent 5,663,159 expired? U.S. Patent 5,663,159, granted in 1997, is based on a filing date that places its primary term within the scope of prior patent law interpretations. For patents filed before the Uruguay Round Agreements Act (URAA) in 1995, the term was 17 years from grant. For patents filed after, it is 20 years from filing. Assuming a filing date consistent with a 1997 grant, the 20-year term from filing would have expired. However, the effective market exclusivity also depends on other related patents and potential extensions.

2. Can generic ezetimibe be manufactured without infringing on U.S. Patent 5,663,159? Once U.S. Patent 5,663,159 has expired, generic manufacturers are generally free to manufacture ezetimibe formulations that fall within its claims, provided they do not infringe on any other valid and unexpired patents covering the ezetimibe molecule itself, its manufacturing process, or specific combination therapies.

3. What is the significance of "pharmaceutically acceptable carrier" in the patent claims? The term "pharmaceutically acceptable carrier" is a broad descriptor that encompasses a wide range of inactive ingredients (excipients) used in drug formulations. These include diluents, binders, disintegrants, lubricants, and others that are safe for human consumption and compatible with the active pharmaceutical ingredient. The patent's claim relies on this broad term, with specifics often detailed in the patent's specification and dependent claims.

4. Does U.S. Patent 5,663,159 cover the active ingredient ezetimibe itself? No, U.S. Patent 5,663,159 is a formulation patent. It covers a pharmaceutical composition containing ezetimibe. The active ingredient ezetimibe itself would have been protected by separate composition of matter patents, which are typically filed earlier than formulation patents.

5. What is the role of patents like U.S. Patent 5,663,159 in drug development? Formulation patents like U.S. Patent 5,663,159 are crucial for drug development by protecting novel ways of delivering an active pharmaceutical ingredient. They extend market exclusivity beyond the initial composition of matter patent, incentivizing further investment in developing stable, bioavailable, and patient-friendly dosage forms. This protection allows companies to recoup their R&D expenses and fund future innovation.

Citations

[1] Merck & Co., Inc. & Schering Corporation. (1997). Pharmaceutical composition comprising ezetimibe (U.S. Patent No. 5,663,159). Washington, DC: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 5,663,159

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

International Family Members for US Patent 5,663,159

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0481214		91036	Luxembourg
European Patent Office	0481214		300131	Netherlands
European Patent Office	0481214		SPC/GB03/030	United Kingdom
European Patent Office	0481214		C300131	Netherlands