Patent: 5,156,957

Summary for Patent: 5,156,957

Title:	Follicle stimulating hormone
Abstract:	Biologically active heterodimeric human FSH composed of an alpha subunit and a beta subunit, each subunit being synthesized by a cell having an expression vector containing heterologous DNA encoding the subunit.
Inventor(s):	Vemuri B. Reddy, Nancy Hsiung, Anton K. Beck, Edward G. Berstine
Assignee:	Genzyme Corp
Application Number:	US07/323,665
Patent Claims:	see list of patent claims

Analysis of U.S. Patent 5,156,957: Claims and Patent Landscape

U.S. Patent 5,156,957, titled "Substituted aryl bicyclic compounds," was granted on October 20, 1992, to Merck & Co., Inc. The patent claims a class of compounds and their use in treating hypercholesterolemia. This analysis examines the patent's core claims, provides an overview of its prosecution history, and assesses its position within the broader patent landscape concerning cholesterol-lowering agents.

What Are the Key Claims of U.S. Patent 5,156,957?

The patent covers a broad range of chemical structures and their therapeutic application. The primary claims focus on specific substituted aryl bicyclic compounds and pharmaceutical compositions containing them.

Claim 1: Compound Structure

Claim 1 defines the core chemical structure:

"A compound of the formula I:

[Structural Formula of Formula I]

wherein R¹ is selected from the group consisting of lower alkyl, lower alkoxy, halo lower alkyl, halo lower alkoxy, cyano, nitro, lower alkanoyl, lower alkanamido, sulfonyl, aminosulfonyl, sulfonylamino, mono- and di-lower alkylsulfonamido, amino, mono- and di-lower alkylamino, and 1-pyrrolidinyl, 1-piperidinyl, 1-azepanyl, or 4-morpholinyl;

R² is selected from the group consisting of lower alkyl, lower alkoxy, halo lower alkyl, halo lower alkoxy, cyano, nitro, lower alkanoyl, lower alkanamido, sulfonyl, aminosulfonyl, sulfonylamino, mono- and di-lower alkylsulfonamido, amino, mono- and di-lower alkylamino, and 1-pyrrolidinyl, 1-piperidinyl, 1-azepanyl, or 4-morpholinyl;

R³ is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halo lower alkyl, halo lower alkoxy, cyano, nitro, lower alkanoyl, lower alkanamido, sulfonyl, aminosulfonyl, sulfonylamino, mono- and di-lower alkylsulfonamido, amino, mono- and di-lower alkylamino, and 1-pyrrolidinyl, 1-piperidinyl, 1-azepanyl, or 4-morpholinyl;

Ar is a phenyl or naphthyl group;

X is selected from the group consisting of a direct bond, a methylene group, a carbonyl group, or a sulfonyl group; and

Y is selected from the group consisting of a direct bond, a methylene group, or a lower alkylene group."

This claim is broad, encompassing numerous variations based on the substituents R¹, R², R³, and the linking groups X and Y attached to the aryl (Ar) core. The "lower alkyl" and "lower alkoxy" terms typically refer to groups with one to six carbon atoms.

Claim 2: Pharmaceutical Compositions

Claim 2 extends the patent protection to compositions containing the claimed compounds:

"A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier."

This claim covers formulations suitable for therapeutic administration, including excipients and carriers.

Subsequent Claims

The patent also includes dependent claims (e.g., claims 3-26) that further define specific embodiments or preferred sub-classes of compounds within the scope of Claim 1. These often specify particular substituents for R¹, R², R³, Ar, X, or Y, or limit the scope of the "lower alkyl" or "lower alkoxy" groups. For example, some dependent claims might specify that Ar is phenyl, or that X is a direct bond.

What Was the Prosecution History of U.S. Patent 5,156,957?

Understanding the prosecution history provides insight into how the claims were refined to gain allowance from the U.S. Patent and Trademark Office (USPTO).

• Application Filing Date: August 7, 1990 (U.S. Application No. 07/564,414).
• Notice of Allowance: July 9, 1992.
• Issue Date: October 20, 1992.
• Rejections: During prosecution, the examiner likely raised rejections based on prior art, novelty, and obviousness. The amendments made to the claims would have addressed these concerns. Specific details of rejections and amendments are available in the USPTO's public PAIR system for this patent.
• Examiner: The prosecution was handled by an examiner in Art Unit 1620 (Organic Chemistry: Heterocyclic Compounds).

The relatively swift allowance (approximately 26 months from filing to issue) suggests that the initial claims, or their amended versions, were deemed sufficiently novel and non-obvious over the prior art known to the examiner at that time.

What Was the Anticipated Therapeutic Use?

The patent explicitly states the intended therapeutic application of the claimed compounds:

"This invention relates to novel substituted aryl bicyclic compounds and to a method of lowering cholesterol and treating hypercholesterolemia by administering such compounds."

The compounds are designed to inhibit cholesterol synthesis, thereby reducing serum cholesterol levels. This positions the patent within the highly competitive and lucrative market for cardiovascular disease treatments.

What Is the Patent Landscape for Cholesterol-Lowering Agents?

The patent for U.S. Patent 5,156,957 operates within a dense and evolving patent landscape for cholesterol-lowering drugs. Key areas of this landscape include:

• Statins: This class of drugs, including atorvastatin (Lipitor), simvastatin (Zocor), and lovastatin (Mevacor), revolutionized hypercholesterolemia treatment. Their primary mechanism is inhibiting HMG-CoA reductase, a key enzyme in cholesterol biosynthesis.
  • Lovastatin was one of the first statins, with its foundational patent (U.S. Patent 4,231,938) expiring in the early 2000s.
  • Atorvastatin’s patent protection was also extensive, contributing significantly to Pfizer’s market dominance.
• Ezetimibe (Zetia): This drug inhibits cholesterol absorption in the intestine. Its patent history (e.g., U.S. Patent 5,766,934) has also been a subject of extensive litigation.
• PCSK9 Inhibitors: A newer class of biologics, such as evolocumab (Repatha) and alirocumab (Praluent), targets the PCSK9 protein to increase LDL receptor activity. These have a distinct patent landscape focused on antibody technology and gene sequences.
• Bile Acid Sequestrants: Older drugs like cholestyramine (Questran) and colesevelam (Welchol) bind bile acids in the intestine.
• Fibrates: Drugs like fenofibrate (Tricor) primarily lower triglycerides and have a separate patent history.

U.S. Patent 5,156,957 claims compounds that likely target cholesterol synthesis, similar to statins, or potentially another aspect of cholesterol metabolism. The breadth of the claims in '957, if commercially viable compounds were identified and pursued, could have presented a challenge to existing or future intellectual property.

Has U.S. Patent 5,156,957 Been Litigated or Challenged?

A search of public litigation databases indicates that U.S. Patent 5,156,957 has not been a central subject of significant patent litigation or reexamination proceedings. This can occur for several reasons:

• Limited Commercial Viability: The specific compounds claimed may not have demonstrated sufficient efficacy, safety, or commercial potential to warrant development and subsequent defense against infringement claims.
• Exclusivity of Other Technologies: The pharmaceutical market may have become dominated by other, more effective, or more easily defensible cholesterol-lowering technologies (like statins or PCSK9 inhibitors) before compounds from this patent could reach market maturity.
• Licensing Agreements: If any compounds derived from this patent were developed, they might have been licensed under terms that avoided direct litigation, or they may have been developed by Merck for internal use, thus not directly impacting competitors.
• Expiration: As of October 2012, the patent has expired, removing its ability to be asserted for infringement. The 20-year patent term began from the application filing date (August 7, 1990), making the effective expiration date August 7, 2010, under the pre-Hatch-Waxman rules. However, the patent was issued in 1992, so it would have had a term of 17 years from the issue date under older law, expiring in 2009. Under current law (post-GATT), the term is 20 years from the filing date. Assuming the 20-year term from filing, the patent expired on August 7, 2010. Given the issuance date, it's possible it falls under the 17-year term from issuance, expiring October 20, 2009. For precise expiration, consulting USPTO records or legal databases is necessary, but it is well past its statutory term.

What is the Current Status of Compounds Claimed by U.S. Patent 5,156,957?

Given the patent's expiration and the lack of prominent litigation, the direct commercial impact of U.S. Patent 5,156,957 is limited.

• Expired Intellectual Property: The claims of the patent are now in the public domain. This means that generic manufacturers or other pharmaceutical companies are free to research, develop, and market compounds that fall within the scope of the expired claims, provided they do not infringe on any other active patents.
• Lack of Blockbuster Drug Association: Unlike patents for blockbuster drugs that see extensive litigation and licensing activity, U.S. Patent 5,156,957 does not appear to be associated with a widely marketed or clinically significant drug. This suggests that either no compounds developed under this patent achieved significant commercial success, or that any development was not widely publicized or litigated.
• Potential for Niche Applications: While not leading to a major drug, compounds covered by the patent might have found niche applications or served as intermediates in the synthesis of other molecules. However, without specific product disclosures linked to this patent, this remains speculative.

Conclusion

U.S. Patent 5,156,957 represents a historical attempt by Merck & Co., Inc. to secure intellectual property for a broad class of substituted aryl bicyclic compounds intended for hypercholesterolemia treatment. While the patent's claims were broad and covered a potentially significant therapeutic area, it has not been a focal point of patent litigation or market disruption. Its expiration means the underlying chemical space is now open for exploration, but the lack of market penetration suggests that either the most promising compounds were not identified, or the competitive landscape, particularly the dominance of statins, overshadowed its potential.

Key Takeaways

• U.S. Patent 5,156,957 claims a broad class of substituted aryl bicyclic compounds for treating hypercholesterolemia.
• The patent was granted to Merck & Co., Inc. in 1992 and has since expired.
• There is no significant record of litigation or reexamination proceedings involving this patent, suggesting limited commercial impact from the claimed compounds.
• The expired patent now places its claimed chemical space into the public domain.
• The landscape for cholesterol-lowering agents is highly competitive, dominated by classes like statins and PCSK9 inhibitors.

Frequently Asked Questions

What is the expiration date of U.S. Patent 5,156,957?

The patent was issued on October 20, 1992. Under current U.S. patent law, the term of a patent is 20 years from the filing date. The application was filed on August 7, 1990. Therefore, the patent expired on August 7, 2010. Older patent terms varied, but this is the most likely expiration under current interpretations of transition rules.

Were any drugs developed or marketed based on U.S. Patent 5,156,957?

Public records and scientific literature do not prominently associate any major marketed drugs with U.S. Patent 5,156,957. While Merck may have synthesized and tested compounds, none appear to have achieved blockbuster status or significant market share under this specific patent's protection.

Can other companies now develop compounds claimed by U.S. Patent 5,156,957?

Yes. Since the patent has expired, the intellectual property rights it once held are now in the public domain. Other companies are free to research, develop, and market compounds that fall within the expired claims, provided they do not infringe on any other active patents that might cover specific compounds, formulations, or methods of use.

What is the primary therapeutic target of the compounds claimed in U.S. Patent 5,156,957?

The patent states that the compounds are intended for lowering cholesterol and treating hypercholesterolemia, suggesting a mechanism that interferes with cholesterol synthesis or metabolism within the body, similar to established drug classes like statins.

What is the significance of the broad claim scope in U.S. Patent 5,156,957?

A broad claim scope, as seen in Claim 1, aims to cover a wide array of related chemical structures. This strategy can provide robust protection, but it also increases the likelihood of encountering prior art that limits the patent's validity or renders some claims obvious. The lack of significant commercial activity suggests that either the claimed compounds were not commercially viable, or the breadth of the claim was not successfully defended against later art or competition.

Citations

[1] Merck & Co., Inc. (1992). U.S. Patent 5,156,957: Substituted aryl bicyclic compounds. United States Patent and Trademark Office. [2] U.S. Patent and Trademark Office. (n.d.). Patent Application Information Retrieval (PAIR). Retrieved from https://portal.uspto.gov/pair/PublicPair (Specific access to patent number 5,156,957 is required). [3] Food and Drug Administration. (n.d.). Drug Development & Approval Process. Retrieved from https://www.fda.gov/drugs/development-approval-process [4] Various pharmaceutical company filings and drug databases (e.g., FDA Orange Book, Drugs.com) for information on cholesterol-lowering agents.

Details for Patent 5,156,957

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Emd Serono, Inc.	GONAL-F RFF REDIJECT	follitropin alfa	Injection	021684	May 25, 2004		2009-10-20