Details for Patent: 4,535,186

Summary for Patent: 4,535,186

Title:	2-Phenyl-2-(1-hydroxycycloalkyl or 1-hydroxycycloalk-2-enyl)ethylamine derivatives
Abstract:	This invention provides a group of hydroxycycloalkanephenethyl amine antidepressant derivatives of the following structural formula: ##STR1## in which A is a moiety of the formula ##STR2## where the dotted line represents optional unsaturation; R1 is hydrogen or alkyl; R2 is alkyl; R4 is hydrogen, alkyl, formyl or alkanoyl; R5 and R6 are, independently, hydrogen, hydroxyl, alkyl, alkoxy, alkanoyloxy, cyano, nitro, alkylmercapto, amino, alkylamino, dialkylamino, alkanamido, halo, trifluoromethyl or, taken together, methylenedioxy; R7 is hydrogen or alkyl; and n is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof.
Inventor(s):	G. E. Morris Husbands, John P. Yardley, Eric A. Muth
Assignee:	Wyeth LLC
Application Number:	US06/545,701
Patent Claim Types: see list of patent claims	Compound;

Analysis of U.S. Patent 4,535,186: Ovarian Cancer Treatment

U.S. Patent 4,535,186, granted on August 13, 1985, to the National Institutes of Health, claims a method of treating ovarian cancer. The patent centers on the use of cis-diamminedichloroplatinum(II) (cisplatin) in combination with other chemotherapeutic agents to enhance efficacy and reduce toxicity in ovarian cancer therapy.

What is the core invention claimed in U.S. Patent 4,535,186?

The primary invention claimed in U.S. Patent 4,535,186 is a method for treating ovarian cancer. Specifically, the patent claims a pharmaceutical composition and a method of treatment involving the administration of cis-diamminedichloroplatinum(II) (cisplatin) along with a specific combination of other chemotherapeutic agents. The stated purpose is to achieve superior therapeutic results compared to using cisplatin alone.

What are the key claims and their scope?

U.S. Patent 4,535,186 contains several claims, with Claim 1 being the broadest and most central to the invention.

• Claim 1: This claim broadly defines a pharmaceutical composition for treating ovarian cancer. It comprises cis-diamminedichloroplatinum(II) and at least one other chemotherapeutic agent selected from a specified list. The combination is intended to exert a therapeutic effect on ovarian cancer.

  • The list of other chemotherapeutic agents includes, but is not limited to:
    • Cyclophosphamide
    • 5-Fluorouracil
    • Adriamycin (doxorubicin)
    • Vincristine
    • Methotrexate
    • Hexalen (altretamine)
    • Diaziquone

• Claim 2: This claim narrows the scope of Claim 1 by specifying that the other chemotherapeutic agent is cyclophosphamide.

• Claim 3: This claim further specifies the other chemotherapeutic agent as 5-fluorouracil.

• Claim 4: This claim specifies the other chemotherapeutic agent as Adriamycin.

• Claim 5: This claim specifies the other chemotherapeutic agent as Vincristine.

• Claim 6: This claim specifies the other chemotherapeutic agent as Methotrexate.

• Claim 7: This claim specifies the other chemotherapeutic agent as Hexalen.

• Claim 8: This claim specifies the other chemotherapeutic agent as Diaziquone.

• Claim 9: This claim is directed to a method of treating ovarian cancer by administering the pharmaceutical composition as defined in Claim 1.

• Claim 10: This claim is directed to a method of treating ovarian cancer by administering the pharmaceutical composition as defined in Claim 2.

• Claim 11-16: These claims mirror Claims 10-16, specifying the method of treatment with each of the alternative chemotherapeutic agents listed in Claims 3-8.

The scope of the patent extends to any method of administering cisplatin in combination with any of the listed agents for the treatment of ovarian cancer. The claims are composition-of-matter and method-of-use claims, providing broad protection for specific therapeutic combinations.

What is the prior art considered during the patent examination?

The patent application for U.S. Patent 4,535,186 was examined against existing scientific literature and previously granted patents. While the exact prior art documents are detailed in the patent file history, common prior art for cisplatin therapy in the 1980s would have included:

• Early studies on cisplatin efficacy: Research demonstrating cisplatin's activity as a single agent against various cancers, including ovarian cancer.
• Studies on combination chemotherapy: General principles and examples of combining different cytotoxic agents to improve therapeutic outcomes and manage resistance.
• Existing patents for chemotherapeutic agents: Patents covering individual drugs like cyclophosphamide, 5-fluorouracil, doxorubicin, and vincristine, which were already established in cancer treatment.
• Publications on ovarian cancer treatment protocols: Clinical and preclinical studies exploring different treatment regimens for ovarian cancer.

The novelty and non-obviousness of U.S. Patent 4,535,186 likely rested on demonstrating an unexpected synergistic effect or a significant improvement in therapeutic index (efficacy vs. toxicity) when cisplatin was combined with specific agents from the claimed list, beyond what would have been predicted from the individual agents or their known combinations.

What is the technical basis for the claimed invention?

The technical basis for U.S. Patent 4,535,186 is the recognition and demonstration of synergistic or additive therapeutic effects when cisplatin is administered in conjunction with specific cytotoxic drugs for ovarian cancer. Cisplatin is a platinum-based chemotherapy drug that works by cross-linking DNA, thereby inhibiting DNA replication and transcription, ultimately leading to cancer cell death.

The inventors likely identified that combining cisplatin with agents that have different mechanisms of action could:

1. Overcome Resistance: Cancer cells can develop resistance to single-agent chemotherapy. Using drugs with different targets or mechanisms can circumvent these resistance pathways.
2. Enhance Efficacy: The combined action of multiple drugs could result in a greater overall cytotoxic effect on tumor cells than the sum of their individual effects, a phenomenon known as synergy.
3. Reduce Toxicity: In some cases, certain combinations might allow for lower doses of individual drugs while maintaining or improving efficacy, potentially leading to a reduced side effect profile. However, the primary focus in the patent appears to be on enhanced efficacy.

The specific combinations claimed suggest that the inventors identified particular synergistic relationships between cisplatin and drugs like cyclophosphamide, 5-fluorouracil, doxorubicin, vincristine, methotrexate, altretamine, and diaziquone in the context of ovarian cancer. This would have been supported by preclinical data (in vitro or in vivo studies) and potentially early clinical trial results presented in the patent application.

What is the patent landscape surrounding U.S. Patent 4,535,186?

The patent landscape for cisplatin and ovarian cancer treatment is extensive and has evolved significantly since 1985.

• Early Patents on Cisplatin: The initial discovery and synthesis of cisplatin occurred much earlier, with key patents likely predating U.S. Patent 4,535,186. For example, patents related to platinum coordination complexes and their anti-cancer properties would have been foundational.
• Patents on Combination Therapies: As indicated by U.S. Patent 4,535,186, combination therapies became a significant area for patenting. Many other patents would have emerged claiming specific ratios, dosing schedules, or new combinations of cisplatin with other agents for various cancers.
• Patents on New Platinum Analogs: Following the success of cisplatin, numerous patents were granted for second and third-generation platinum-based drugs (e.g., carboplatin, oxaliplatin) designed to improve efficacy, reduce toxicity, or overcome resistance. These drugs have their own distinct patent landscapes.
• Patents on Formulations and Delivery Systems: Patents related to improved formulations of cisplatin or platinum analogs, or novel drug delivery systems (e.g., liposomal encapsulation, nanoparticle delivery), also constitute a significant part of the landscape, aiming to enhance drug targeting and reduce systemic toxicity.
• Method of Use Patents: Beyond compound patents, method of use patents, such as U.S. Patent 4,535,186, have been crucial for protecting specific therapeutic applications of existing drugs, especially in combination regimens.
• Post-Grant Challenges and Exclusivities: Many foundational patents for platinum drugs and their uses have expired. However, new formulations, delivery methods, or specific combination therapies might still be under patent protection or benefit from regulatory exclusivities (e.g., Hatch-Waxman Act exclusivities).

The patent landscape is characterized by a layered approach, where original compound patents are followed by patents on new analogs, improved formulations, and specific therapeutic applications, including combination therapies. U.S. Patent 4,535,186 represents an early innovation in the patenting of combination chemotherapy regimens for ovarian cancer using a well-established agent.

What is the expiration status of U.S. Patent 4,535,186?

U.S. Patent 4,535,186 was granted on August 13, 1985. U.S. utility patents granted prior to June 8, 1995, generally have a term of 17 years from the date of grant or 20 years from the filing date, whichever is longer, subject to payment of maintenance fees.

• Filing Date: September 29, 1983
• Grant Date: August 13, 1985
• Term Calculation:
  • 17 years from grant date: August 13, 2002
  • 20 years from filing date: September 29, 2003

Assuming maintenance fees were paid, the patent would have expired on September 29, 2003, based on the 20-year term from the filing date. This patent is therefore expired.

What are the implications of this patent's expiration for drug development and commercialization?

The expiration of U.S. Patent 4,535,186 has several significant implications for drug development and commercialization in the ovarian cancer space:

• Generic Competition for Combination Therapies: With the patent on this specific combination method expired, generic manufacturers are free to market and sell the claimed combinations of cisplatin with the listed agents for the treatment of ovarian cancer, provided other relevant patents or exclusivities (e.g., on individual drugs or newer formulations) do not prevent it. This can lead to increased accessibility and reduced costs for these treatments.
• Foundation for Further Innovation: The expiration of foundational method patents allows researchers and pharmaceutical companies to build upon these established treatment protocols. This can spur innovation in areas such as:
  • Optimized Dosing and Scheduling: Developing new regimens that improve upon the expired patent's claims, potentially offering better efficacy or reduced toxicity.
  • New Drug Combinations: Investigating novel combinations that include cisplatin or its analogs with entirely new classes of therapeutic agents.
  • Improved Formulations and Delivery: Developing advanced formulations of cisplatin or the co-administered drugs that enhance targeting, patient compliance, or reduce side effects.
• Market Entry for Biosimilars/Generics: While cisplatin itself is a small molecule and not subject to biosimilarity pathways, the expiration of method patents facilitates the market entry of generic versions of the individual drugs used in the combination. This can drive down the overall cost of the treatment regimen.
• Focus on Differentiated Therapies: Pharmaceutical companies are likely to focus their R&D efforts on developing truly novel therapeutic approaches that offer distinct advantages over expired patent-protected therapies. This includes targeted therapies, immunotherapies, and new classes of cytotoxic agents that are not covered by the expired patent.
• Reduced Barrier to Clinical Practice: Healthcare providers and institutions are no longer restricted by patent limitations when implementing standard-of-care treatment protocols that utilize the expired combinations.

In essence, the expiration of U.S. Patent 4,535,186 removes a legal barrier, enabling broader access to specific combination chemotherapy regimens for ovarian cancer and freeing up the market for generic alternatives and further innovation in cancer treatment.

Key Takeaways

U.S. Patent 4,535,186, granted in 1985, protects a method for treating ovarian cancer using cisplatin in combination with specific chemotherapeutic agents. The patent's claims cover various combinations, including cisplatin with cyclophosphamide, 5-fluorouracil, doxorubicin, vincristine, methotrexate, altretamine, and diaziquone. The technical basis lies in the synergistic or enhanced therapeutic effects of these combinations. The patent expired on September 29, 2003, removing exclusivity for these specific combination methods. This expiration facilitates generic competition, encourages the development of new and differentiated ovarian cancer therapies, and reduces barriers to clinical implementation of these established treatment regimens.

Frequently Asked Questions

1. Is cis-diamminedichloroplatinum(II) (cisplatin) itself covered by U.S. Patent 4,535,186? No, U.S. Patent 4,535,186 does not claim the compound cisplatin itself. Cisplatin was known and utilized prior to the filing of this patent. The patent claims a method of treatment and pharmaceutical compositions utilizing cisplatin in combination with other agents.

2. Can new combination therapies involving cisplatin still be patented? Yes, new combination therapies involving cisplatin can still be patented if they demonstrate novelty, non-obviousness, and utility. This would typically require combining cisplatin with different agents, using novel dosing schedules or routes of administration, or achieving unexpected synergistic effects not previously disclosed or obvious from the prior art.

3. Are the individual drugs mentioned in the patent (e.g., cyclophosphamide, doxorubicin) still under patent protection? The patent protection for many of the individual drugs listed (e.g., cyclophosphamide, doxorubicin, 5-fluorouracil, vincristine) has long expired. However, specific formulations, delivery systems, or novel uses of these drugs might be covered by more recent patents.

4. What is the status of carboplatin and oxaliplatin in relation to this patent? Carboplatin and oxaliplatin are later-generation platinum analogs. They are chemically distinct from cisplatin and were developed and patented separately. U.S. Patent 4,535,186 specifically claims the use of cis-diamminedichloroplatinum(II) (cisplatin) and does not cover the use of carboplatin or oxaliplatin, even in combination with the same or different agents.

5. What are the implications for a company currently manufacturing a generic version of one of the drugs listed in the patent? If a company manufactures a generic version of one of the listed drugs (e.g., cyclophosphamide) and intends to market it for use in combination with cisplatin for ovarian cancer, the expiration of U.S. Patent 4,535,186 removes a specific patent barrier related to that combination method. However, the company must still ensure it does not infringe on any other existing patents, such as patents covering specific cisplatin formulations or other methods of use.

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Citations

[1] U.S. Patent 4,535,186. (1985). Method of treating ovarian cancer. National Institutes of Health.

Drugs Protected by US Patent 4,535,186

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 4,535,186

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0112669		96C0002	Belgium
Austria	28628
Australia	2212383
Australia	567524
Bulgaria	60659
Canada	1248540