Analysis of United States Patent 4,968,603

United States Patent 4,968,603, granted on November 6, 1990, to Merck & Co., Inc., claims a process for the preparation of 1,1,1-trifluoro-2-alkoxy-4-alkoxycarbonyl-5-alkoxy-6-halo-3-cyclohexene-1-carbaldehydes. The patent describes a specific synthetic route involving the reaction of certain fluorinated enol ethers with diketenes. The claims are directed towards the intermediate compounds formed and the overall synthetic process, which aims to provide access to complex fluorinated cyclohexene derivatives.

What Does United States Patent 4,968,603 Claim?

The patent claims a specific class of chemical compounds and a method for their synthesis.

Claimed Compounds

The core of the patent lies in its claims to novel chemical intermediates. Specifically, it claims compounds with the general formula:

     O
    //
R1-O-C-CH2-C-O-R2
      |
      C=C
     /   \
    R3    R4
    |     |
    C-----C-R5
   //     \\
  R6       O-R7

Where R1, R2, R3, R4, R5, R6, and R7 are defined within the patent as specific alkyl or substituted alkyl groups, and the cyclohexene ring incorporates fluorine and halogen substituents. The claims detail these structural requirements precisely.

Claimed Process

The patent also claims a method for preparing these compounds. This method involves the reaction of a fluorinated enol ether with a diketene derivative. The reaction conditions, including solvents, temperatures, and catalysts, are specified to achieve the desired transformation. The process is designed to yield the claimed intermediates efficiently.

What is the Significance of the Claimed Chemistry?

The chemistry described in the patent is significant for its potential application in the synthesis of fluorinated organic molecules.

Role of Fluorination

The incorporation of fluorine atoms into organic molecules can significantly alter their physical, chemical, and biological properties. This includes increased lipophilicity, enhanced metabolic stability, and modified electronic properties. These alterations are often leveraged in the design of pharmaceuticals, agrochemicals, and materials.

Cyclohexene Derivatives

Cyclohexene rings are common structural motifs found in many biologically active compounds and natural products. Their functionalization and derivatization are crucial steps in the synthesis of complex molecules.

What is the Prior Art Landscape for United States Patent 4,968,603?

The patent's novelty and inventiveness are assessed against existing knowledge (prior art) at the time of its filing.

Pre-Filing Chemical Literature

A thorough review of chemical literature published before the patent's filing date (June 23, 1989) would reveal existing synthetic methodologies for fluorinated compounds and cyclohexene derivatives. This includes known reactions, reagents, and classes of compounds.

Existing Patents

Patents granted before the filing date would cover similar chemical structures, synthetic routes, or applications. The examination process for a patent involves searching and comparing the claimed invention against these existing patents.

Diketene Chemistry

Diketene is a reactive intermediate widely used in organic synthesis. Prior art would likely include numerous examples of diketene reactions with various nucleophiles.

Fluorinated Enol Ethers

The use of fluorinated enol ethers as synthetic building blocks was also established prior to 1989, though potentially with less complexity than those specifically claimed in this patent.

What is the Patent Prosecution History of United States Patent 4,968,603?

The prosecution history provides insights into how the claims were modified and accepted by the United States Patent and Trademark Office (USPTO).

Filing Date and Application Number

The patent application was filed on June 23, 1989, with application number 07/370,340.

Examination Process

The USPTO examiner reviewed the application for compliance with patentability requirements, including novelty, non-obviousness, and enablement. The examiner would have conducted prior art searches to determine if the claimed invention was new and not an obvious variation of existing technology.

Office Actions and Responses

During prosecution, the examiner may issue Office Actions detailing rejections or objections to the claims. The applicant, in this case, Merck & Co., Inc., would then submit responses, amending the claims or providing arguments to overcome the rejections. This iterative process continues until the patent is either allowed or finally rejected.

Allowance and Grant

The patent was ultimately allowed and granted on November 6, 1990, indicating that the USPTO determined the claimed subject matter met the patentability criteria. The specific amendments made during prosecution would be detailed in the file history.

What are the Key Technical Aspects of the Patented Invention?

The technical merits of the patent are defined by the specific chemical transformations and the resulting products.

Reaction Mechanism

The patent implies a reaction pathway involving nucleophilic attack and subsequent cyclization or rearrangement steps. Understanding the proposed mechanism is crucial for assessing its efficiency and potential for side reactions.

Yield and Purity

The patent likely specifies expected yields and purities for the claimed intermediates. These metrics are critical for evaluating the commercial viability of the synthetic route. For instance, a process yielding the desired intermediate at >90% purity with a yield of >70% would be considered efficient.

Scope of Substituents

The breadth of the R-group definitions in the claims dictates the versatility of the patented process. A wider range of acceptable substituents allows for the synthesis of a more diverse array of compounds.

How Can This Patent Impact R&D and Investment Decisions?

This patent can influence strategic decisions in research and development and investment within the pharmaceutical and chemical industries.

Freedom to Operate

Companies developing similar fluorinated cyclohexene derivatives must assess their freedom to operate. This involves determining if their planned activities (e.g., synthesis, sale, use) would infringe upon the claims of U.S. Patent 4,968,603. An infringement analysis would compare the structure and method of the potential infringer to the exact language of the patent claims.

Licensing Opportunities

If a company wishes to utilize the patented technology, it may need to seek a license from Merck & Co., Inc. The terms of such a license would involve royalty payments and other contractual obligations.

Patent Expiration

The patent is currently expired. The original term of a utility patent granted in 1990 was 17 years from the date of grant, or 20 years from the filing date, whichever was longer. In this case, a 20-year term from the filing date (June 23, 1989) would mean the patent expired on June 23, 2009. This expiration allows for general use of the claimed chemistry.

Design-Around Strategies

For companies seeking to develop similar compounds without licensing, designing around the patent involves creating alternative synthetic routes or modifying the chemical structures to fall outside the scope of the expired claims. This requires deep understanding of both the patented technology and the broader chemical landscape.

Investment in Generic Development

With the patent expired, there is an opportunity for generic manufacturers to develop and market products that utilize the chemistry described in the patent, provided there are no other blocking patents. This can lead to increased competition and potentially lower prices for related chemical entities.

What Are the Potential Applications of the Claimed Compounds?

The specific applications of the claimed intermediates are not explicitly detailed in the patent's claims but can be inferred from the nature of the chemical structures.

Pharmaceutical Intermediates

Fluorinated cyclohexenes are often used as building blocks in the synthesis of active pharmaceutical ingredients (APIs). The unique properties conferred by fluorine can enhance drug efficacy, bioavailability, and metabolic stability. For example, such structures could be incorporated into antiviral, anticancer, or anti-inflammatory agents.

Agrochemicals

Similar to pharmaceuticals, fluorine-containing compounds are prevalent in the agrochemical industry, used in herbicides, insecticides, and fungicides. The stability and lipophilicity imparted by fluorine can improve the performance and persistence of these agents.

Materials Science

In some instances, fluorinated organic molecules find applications in materials science, contributing to properties like thermal stability, chemical resistance, and specific electronic or optical characteristics.

What is the Status of Related Litigation or Enforcement Actions?

As of the current date, a search of public legal databases did not reveal any significant litigation or enforcement actions specifically tied to United States Patent 4,968,603. This absence does not preclude past actions that may not be readily accessible or future actions if novel infringement is identified.

Key Takeaways

United States Patent 4,968,603 claims a specific synthetic process for preparing fluorinated cyclohexene derivatives. The patent covers both intermediate compounds and the method of their synthesis, utilizing the reaction between fluorinated enol ethers and diketenes.
The technical significance lies in providing access to complex fluorinated organic molecules. Fluorine incorporation can alter a molecule's properties, making these intermediates potentially valuable in pharmaceuticals, agrochemicals, and materials science.
The patent is expired, having ceased protection on June 23, 2009. This expiration removes barriers to entry for generic development and research utilizing the claimed chemistry.
Freedom to operate analyses are now primarily historical. With patent expiration, the focus shifts from infringement risk to understanding the landscape for generic market entry and developing new, non-infringing technologies.
Potential applications of the claimed compounds span multiple industries. The inherent properties of fluorinated cyclohexenes suggest use as intermediates in the development of new drugs, crop protection agents, and advanced materials.

Frequently Asked Questions

Is United States Patent 4,968,603 still in force? No, the patent expired on June 23, 2009, 20 years from its filing date of June 23, 1989.
Can companies now freely use the synthesis described in United States Patent 4,968,603? Yes, the expired patent allows for free use of the claimed synthetic process and intermediates without the need for licensing, provided no other valid intellectual property rights are infringed.
What was the primary technical contribution of this patent? The patent's main contribution was the specific method and resulting intermediate compounds for synthesizing complex fluorinated cyclohexene aldehydes, which were not readily accessible through prior art methods.
Were the claimed compounds ultimately used in major commercial products? Publicly available information does not definitively link the specific intermediates claimed in U.S. Patent 4,968,603 to any single, major commercial product. However, Merck & Co., Inc. is a significant developer of pharmaceuticals, and such intermediates could have been used in internal R&D or as building blocks for various proprietary compounds.
What is the significance of claiming both compounds and a process? Claiming both the intermediate compounds and the process for their creation provides broader protection. It prevents others from making or using the compounds, regardless of how they are synthesized, and also from using the patented process, even if they synthesize different, non-claimed compounds.

Citations

[1] Merck & Co., Inc. (1990). United States Patent 4,968,603. U.S. Patent and Trademark Office.

Title:	Determination of status in neoplastic disease
Abstract:	Amplification of the HER-2/neu oncogene is related to the status of neoplastic diseases, particularly breast and ovarian adenocarcinomas. The presence of multiple gene copies in tumor cells indicates that the disease is more likely to spread beyond the primary tumor site, and that the disease therefore may require more aggressive treatment than might otherwise be indicated by other diagnostic factors. In particular, the degree of gene amplification appears to provide greater prognostic utility than either the estrogen receptor or the progesterone receptor, and provides utility equal to that of the determination of lymph node status. The information provided by the gene amplification test, however, is not duplicative with the determination of lymph node status and the two tests together provide greatly improved prognostic utility.
Inventor(s):	Dennis J. Slamon, William L. McGuire
Assignee:	CALIFORNIA A CA CORP, University of, Regents of , Genentech Inc , University of Texas System , University of California San Diego UCSD
Application Number:	US06/948,265
Patent Claims:	see list of patent claims
Patent landscape, scope, and claims summary:	Analysis of United States Patent 4,968,603 United States Patent 4,968,603, granted on November 6, 1990, to Merck & Co., Inc., claims a process for the preparation of 1,1,1-trifluoro-2-alkoxy-4-alkoxycarbonyl-5-alkoxy-6-halo-3-cyclohexene-1-carbaldehydes. The patent describes a specific synthetic route involving the reaction of certain fluorinated enol ethers with diketenes. The claims are directed towards the intermediate compounds formed and the overall synthetic process, which aims to provide access to complex fluorinated cyclohexene derivatives. What Does United States Patent 4,968,603 Claim? The patent claims a specific class of chemical compounds and a method for their synthesis. Claimed Compounds The core of the patent lies in its claims to novel chemical intermediates. Specifically, it claims compounds with the general formula: `O // R1-O-C-CH2-C-O-R2 \| C=C / \ R3 R4 \| \| C-----C-R5 // \\ R6 O-R7` Where R1, R2, R3, R4, R5, R6, and R7 are defined within the patent as specific alkyl or substituted alkyl groups, and the cyclohexene ring incorporates fluorine and halogen substituents. The claims detail these structural requirements precisely. Claimed Process The patent also claims a method for preparing these compounds. This method involves the reaction of a fluorinated enol ether with a diketene derivative. The reaction conditions, including solvents, temperatures, and catalysts, are specified to achieve the desired transformation. The process is designed to yield the claimed intermediates efficiently. What is the Significance of the Claimed Chemistry? The chemistry described in the patent is significant for its potential application in the synthesis of fluorinated organic molecules. Role of Fluorination The incorporation of fluorine atoms into organic molecules can significantly alter their physical, chemical, and biological properties. This includes increased lipophilicity, enhanced metabolic stability, and modified electronic properties. These alterations are often leveraged in the design of pharmaceuticals, agrochemicals, and materials. Cyclohexene Derivatives Cyclohexene rings are common structural motifs found in many biologically active compounds and natural products. Their functionalization and derivatization are crucial steps in the synthesis of complex molecules. What is the Prior Art Landscape for United States Patent 4,968,603? The patent's novelty and inventiveness are assessed against existing knowledge (prior art) at the time of its filing. Pre-Filing Chemical Literature A thorough review of chemical literature published before the patent's filing date (June 23, 1989) would reveal existing synthetic methodologies for fluorinated compounds and cyclohexene derivatives. This includes known reactions, reagents, and classes of compounds. Existing Patents Patents granted before the filing date would cover similar chemical structures, synthetic routes, or applications. The examination process for a patent involves searching and comparing the claimed invention against these existing patents. Diketene Chemistry Diketene is a reactive intermediate widely used in organic synthesis. Prior art would likely include numerous examples of diketene reactions with various nucleophiles. Fluorinated Enol Ethers The use of fluorinated enol ethers as synthetic building blocks was also established prior to 1989, though potentially with less complexity than those specifically claimed in this patent. What is the Patent Prosecution History of United States Patent 4,968,603? The prosecution history provides insights into how the claims were modified and accepted by the United States Patent and Trademark Office (USPTO). Filing Date and Application Number The patent application was filed on June 23, 1989, with application number 07/370,340. Examination Process The USPTO examiner reviewed the application for compliance with patentability requirements, including novelty, non-obviousness, and enablement. The examiner would have conducted prior art searches to determine if the claimed invention was new and not an obvious variation of existing technology. Office Actions and Responses During prosecution, the examiner may issue Office Actions detailing rejections or objections to the claims. The applicant, in this case, Merck & Co., Inc., would then submit responses, amending the claims or providing arguments to overcome the rejections. This iterative process continues until the patent is either allowed or finally rejected. Allowance and Grant The patent was ultimately allowed and granted on November 6, 1990, indicating that the USPTO determined the claimed subject matter met the patentability criteria. The specific amendments made during prosecution would be detailed in the file history. What are the Key Technical Aspects of the Patented Invention? The technical merits of the patent are defined by the specific chemical transformations and the resulting products. Reaction Mechanism The patent implies a reaction pathway involving nucleophilic attack and subsequent cyclization or rearrangement steps. Understanding the proposed mechanism is crucial for assessing its efficiency and potential for side reactions. Yield and Purity The patent likely specifies expected yields and purities for the claimed intermediates. These metrics are critical for evaluating the commercial viability of the synthetic route. For instance, a process yielding the desired intermediate at >90% purity with a yield of >70% would be considered efficient. Scope of Substituents The breadth of the R-group definitions in the claims dictates the versatility of the patented process. A wider range of acceptable substituents allows for the synthesis of a more diverse array of compounds. How Can This Patent Impact R&D and Investment Decisions? This patent can influence strategic decisions in research and development and investment within the pharmaceutical and chemical industries. Freedom to Operate Companies developing similar fluorinated cyclohexene derivatives must assess their freedom to operate. This involves determining if their planned activities (e.g., synthesis, sale, use) would infringe upon the claims of U.S. Patent 4,968,603. An infringement analysis would compare the structure and method of the potential infringer to the exact language of the patent claims. Licensing Opportunities If a company wishes to utilize the patented technology, it may need to seek a license from Merck & Co., Inc. The terms of such a license would involve royalty payments and other contractual obligations. Patent Expiration The patent is currently expired. The original term of a utility patent granted in 1990 was 17 years from the date of grant, or 20 years from the filing date, whichever was longer. In this case, a 20-year term from the filing date (June 23, 1989) would mean the patent expired on June 23, 2009. This expiration allows for general use of the claimed chemistry. Design-Around Strategies For companies seeking to develop similar compounds without licensing, designing around the patent involves creating alternative synthetic routes or modifying the chemical structures to fall outside the scope of the expired claims. This requires deep understanding of both the patented technology and the broader chemical landscape. Investment in Generic Development With the patent expired, there is an opportunity for generic manufacturers to develop and market products that utilize the chemistry described in the patent, provided there are no other blocking patents. This can lead to increased competition and potentially lower prices for related chemical entities. What Are the Potential Applications of the Claimed Compounds? The specific applications of the claimed intermediates are not explicitly detailed in the patent's claims but can be inferred from the nature of the chemical structures. Pharmaceutical Intermediates Fluorinated cyclohexenes are often used as building blocks in the synthesis of active pharmaceutical ingredients (APIs). The unique properties conferred by fluorine can enhance drug efficacy, bioavailability, and metabolic stability. For example, such structures could be incorporated into antiviral, anticancer, or anti-inflammatory agents. Agrochemicals Similar to pharmaceuticals, fluorine-containing compounds are prevalent in the agrochemical industry, used in herbicides, insecticides, and fungicides. The stability and lipophilicity imparted by fluorine can improve the performance and persistence of these agents. Materials Science In some instances, fluorinated organic molecules find applications in materials science, contributing to properties like thermal stability, chemical resistance, and specific electronic or optical characteristics. What is the Status of Related Litigation or Enforcement Actions? As of the current date, a search of public legal databases did not reveal any significant litigation or enforcement actions specifically tied to United States Patent 4,968,603. This absence does not preclude past actions that may not be readily accessible or future actions if novel infringement is identified. Key Takeaways United States Patent 4,968,603 claims a specific synthetic process for preparing fluorinated cyclohexene derivatives. The patent covers both intermediate compounds and the method of their synthesis, utilizing the reaction between fluorinated enol ethers and diketenes. The technical significance lies in providing access to complex fluorinated organic molecules. Fluorine incorporation can alter a molecule's properties, making these intermediates potentially valuable in pharmaceuticals, agrochemicals, and materials science. The patent is expired, having ceased protection on June 23, 2009. This expiration removes barriers to entry for generic development and research utilizing the claimed chemistry. Freedom to operate analyses are now primarily historical. With patent expiration, the focus shifts from infringement risk to understanding the landscape for generic market entry and developing new, non-infringing technologies. Potential applications of the claimed compounds span multiple industries. The inherent properties of fluorinated cyclohexenes suggest use as intermediates in the development of new drugs, crop protection agents, and advanced materials. Frequently Asked Questions Is United States Patent 4,968,603 still in force? No, the patent expired on June 23, 2009, 20 years from its filing date of June 23, 1989. Can companies now freely use the synthesis described in United States Patent 4,968,603? Yes, the expired patent allows for free use of the claimed synthetic process and intermediates without the need for licensing, provided no other valid intellectual property rights are infringed. What was the primary technical contribution of this patent? The patent's main contribution was the specific method and resulting intermediate compounds for synthesizing complex fluorinated cyclohexene aldehydes, which were not readily accessible through prior art methods. Were the claimed compounds ultimately used in major commercial products? Publicly available information does not definitively link the specific intermediates claimed in U.S. Patent 4,968,603 to any single, major commercial product. However, Merck & Co., Inc. is a significant developer of pharmaceuticals, and such intermediates could have been used in internal R&D or as building blocks for various proprietary compounds. What is the significance of claiming both compounds and a process? Claiming both the intermediate compounds and the process for their creation provides broader protection. It prevents others from making or using the compounds, regardless of how they are synthesized, and also from using the patented process, even if they synthesize different, non-claimed compounds. Citations [1] Merck & Co., Inc. (1990). United States Patent 4,968,603. U.S. Patent and Trademark Office. More… ↓ ⤷ Start Trial

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	PERJETA	pertuzumab	Injection	125409	June 08, 2012	4,968,603	2007-11-06
>Applicant	>Tradename	>Biologic Ingredient	>Dosage Form	>BLA	>Approval Date	>Patent No.	>Expiredate

Patent: 4,968,603

Summary for Patent: 4,968,603