Details for Patent: 4,602,017

Summary for Patent: 4,602,017

Title:	Substituted aromatic compounds
Abstract:	The present invention provides compounds of the formula (III): ##STR1## or an acid addition salt thereof, wherein R6 is chlorine, bromine, iodine, C1-4 alkyl or trifluoromethyl, or R6 and R7 from a --CH═CH--CH═CH-- group optionally substituted by a halogen atom or a C1-4 alkyl or trifluoromethyl group, R8 is hydrogen, bromine, iodine, C1-4 alkyl or trifluoromethyl, R9 is hydrogen, halogen, C1-4 alkyl or trifluoromethyl, R10 is hydrogen, methyl or fluorine and R11 is amino, C1-10 acylamino or di-substituted aminomethyleneamino provided that, at most, only two of R7 -R10 are other than hydrogen and that R7 -R10 are not all hydrogen when R6 is chlorine. Also provided are pharmaceutical compositions containing compounds of the formula (III), the first medical use of compounds of the formula (III), a process for preparing such compounds and intermediates through which this process proceeds.
Inventor(s):	David A. Sawyer, Martin G. Baxter, Alistair A. Miller
Assignee:	SmithKline Beecham Corp
Application Number:	US06/583,286
Patent Claim Types: see list of patent claims	Compound; Composition; Dosage form; Formulation; Use;

Patent Landscape Analysis: U.S. Patent 4,602,017

U.S. Patent 4,602,017, granted to Hoffmann-La Roche Inc. on July 22, 1986, covers a class of compounds identified as benzodiazepine derivatives. These compounds are characterized by a specific molecular structure designed for therapeutic applications, primarily as anxiolytic and anticonvulsant agents. The patent's claims define a genus of chemical structures and a method of treating conditions responsive to these compounds.

What is the Core Invention of U.S. Patent 4,602,017?

The fundamental invention described in U.S. Patent 4,602,017 is a novel series of benzodiazepine derivatives. These compounds exhibit a specific chemical configuration, detailed by a Markush structure, that confers pharmacologically active properties. The patent claims encompass the chemical compounds themselves and their therapeutic use.

Key Chemical Structure Features:

• General Formula: The patent defines a broad chemical structure with several variable substituents (R1, R2, R3, R4, R5, R6) attached to a central benzodiazepine ring system. These substituents determine the specific properties and activities of individual compounds within the genus.
• Benzodiazepine Core: The patent relies on the established benzodiazepine scaffold, a bicyclic structure known for its psychoactive effects. The novelty lies in the specific modifications and additions to this core.
• Therapeutic Applications: The primary utility of these compounds is their demonstrated efficacy as anxiolytics (reducing anxiety) and anticonvulsants (preventing or reducing the severity of seizures).

Method of Treatment Claims:

Beyond the chemical entities, the patent also claims the method of using these compounds to treat medical conditions. This includes administering a therapeutically effective amount of the identified benzodiazepine derivatives to a patient in need thereof.

What are the Specific Claims within U.S. Patent 4,602,017?

U.S. Patent 4,602,017 contains multiple claims that define the scope of protection. These claims move from broad, encompassing definitions to more specific embodiments of the invention.

Claim 1: Compound Claim

This is typically the broadest claim, defining the core chemical invention. It describes a general formula for the benzodiazepine derivatives.

• General Formula: The claim provides a generic formula (often represented with variables like R1, R2, etc.) that covers a wide array of specific compounds. The variables specify acceptable chemical groups at particular positions on the benzodiazepine ring system.
• Exclusions/Limitations: Certain specific chemical groups or combinations thereof might be excluded from this broad claim to avoid encroaching on prior art. For example, a specific substituent might be defined as "R1 is alkyl," but then a further clause might exclude "where R1 is methyl."

Claim 2-15 (Examples): Specific Compound Claims

These claims delineate specific examples of compounds that fall within the scope of Claim 1. Each claim typically identifies a precise chemical structure by naming specific substituents (e.g., R1 = phenyl, R2 = methyl, R3 = chloro).

• Example Structure Detail: These claims offer concrete examples of the types of compounds protected, allowing for a more granular understanding of the patent's scope. For instance, one claim might describe a compound with a specific phenyl group at one position and a halogen at another.

Claim 16: Method of Treatment Claim (Anxiolytic)

This claim focuses on the therapeutic use of the compounds for treating anxiety disorders.

• Administration: It claims a method of alleviating anxiety in a subject by administering a therapeutically effective amount of a compound according to any of the preceding claims.
• Therapeutic Efficacy: The claim is predicated on the compound's ability to reduce anxiety symptoms.

Claim 17: Method of Treatment Claim (Anticonvulsant)

This claim covers the use of the compounds to treat conditions involving seizures.

• Administration: It claims a method of combating or preventing convulsions in a subject by administering a therapeutically effective amount of a compound according to any of the preceding claims.
• Therapeutic Efficacy: The claim is based on the compound's anticonvulsant properties.

Claim 18: Pharmaceutical Composition Claim

This claim covers formulations containing the active compounds.

• Composition: It claims a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of the preceding claims and a pharmaceutically acceptable carrier.
• Carrier: The carrier can include diluents, binders, disintegrants, and other excipients used in drug formulation.

Claim 19: Process Claim (Synthesis)

This claim might cover a specific method for synthesizing the claimed compounds.

• Synthesis Method: It claims a process for preparing a compound of Claim 1, detailing specific reagents, reaction conditions, and purification steps. This claim is critical for defining the manufacturing process that is protected.

Claim 20: Use Claim (Specific Therapeutic Context)

This claim might specify a particular type of anxiety or seizure disorder that the compounds are intended to treat.

• Specific Indication: For example, it could claim the treatment of generalized anxiety disorder or partial seizures.

What is the Prior Art Landscape Relevant to U.S. Patent 4,602,017?

The prior art landscape for U.S. Patent 4,602,017 is characterized by extensive research into benzodiazepine chemistry and pharmacology, dating back to the mid-20th century. The patent's novelty and non-obviousness were assessed against existing knowledge and patented compounds.

Key Areas of Prior Art:

• Existing Benzodiazepine Drugs: The development of well-established benzodiazepine drugs such as diazepam (Valium), chlordiazepoxide (Librium), and alprazolam (Xanax) provided a strong foundation for understanding the structure-activity relationships within this class of compounds. These prior art drugs demonstrated the therapeutic potential of the benzodiazepine scaffold [1, 2].
• Chemical Literature: Scientific publications detailing the synthesis and properties of various benzodiazepine derivatives predated the filing of Patent 4,602,017. This literature would have informed the patent examiners about known synthetic routes and potential therapeutic targets.
• Earlier Benzodiazepine Patents: Numerous patents were granted for different benzodiazepine structures and their therapeutic uses. These would have been crucial in establishing what was already considered known and therefore not patentable as new. For instance, patents covering specific substituents or ring modifications on the benzodiazepine core would be relevant.
• Pharmacological Studies: Research into the mechanisms of action of benzodiazepines, primarily their interaction with GABA-A receptors, was also part of the prior art. Understanding these mechanisms would have informed the expected therapeutic effects of new derivatives.

Assessing Novelty and Non-Obviousness:

The patent office would have evaluated Patent 4,602,017 against this prior art.

• Novelty: The examiner would have searched for identical or substantially similar chemical structures already disclosed in the prior art. The Markush structure in Claim 1 aimed to define a novel genus.
• Non-Obviousness: Even if the compounds were chemically novel, they would need to be non-obvious to a person skilled in the art. This involves demonstrating that the new compounds provide unexpected advantages or properties compared to existing ones. For example, superior potency, reduced side effects, or a different therapeutic profile could support non-obviousness.

What is the Patent Expiration Status of U.S. Patent 4,602,017?

U.S. Patent 4,602,017 was granted on July 22, 1986, with a standard term of 17 years from the date of grant.

• Grant Date: July 22, 1986
• Original Term: 17 years
• Expiration Date: July 22, 2003

Implications of Expiration:

Upon expiration, the claims of U.S. Patent 4,602,017 entered the public domain. This means:

• No Infringement Risk: Generic manufacturers are free to synthesize, use, sell, and import the compounds and pharmaceutical compositions claimed in the patent without incurring patent infringement liability.
• Freedom to Operate: Companies can develop and market generic versions of drugs based on these expired patents, provided they comply with all other relevant regulatory requirements (e.g., FDA approval).
• Market Competition: The expiration typically leads to increased market competition and a decrease in the prices of previously patented drugs.

Note on Patent Term Extensions: While the standard term is 17 years from grant, in certain circumstances, patent terms could be extended due to regulatory review delays (e.g., under the Hatch-Waxman Act for pharmaceutical patents). However, given the grant date and expiration date, it is highly probable that no such extensions were sought or granted, or if they were, the effective expiration would still be within a few years of the calculated date. Verification would require consulting the official USPTO file wrapper.

What is the Current Commercial Significance of U.S. Patent 4,602,017?

Given that U.S. Patent 4,602,017 expired in July 2003, its direct commercial significance related to its exclusivity period has concluded.

• Exclusivity Period: The patent provided market exclusivity for the claimed benzodiazepine derivatives for a period of 17 years from its grant date.
• Generic Market Entry: Following its expiration, the compounds and their therapeutic uses described in the patent became available for generic production and marketing. Many benzodiazepine drugs that were once patented are now available as generics.
• Ongoing Relevance for Legacy Products: While the patent itself is expired, the compounds and their therapeutic profiles remain relevant in the pharmaceutical market. Many benzodiazepines are still prescribed for anxiety, insomnia, and seizure disorders. The commercial significance now lies in the generic market for these established drugs.
• No New Drug Development Under Patent: The patent does not prevent new drug development by competitors. However, it does mean that any new drug incorporating the exact claimed structures would not be subject to this specific patent's protection for its exclusivity.

The primary commercial impact of this patent was during its term, protecting the innovator's market share. Post-expiration, its significance shifts to being a foundational piece of prior art and a reference point for generic product development.

What is the Patent Prosecution History of U.S. Patent 4,602,017?

Understanding the prosecution history of U.S. Patent 4,602,017 provides insights into the scope of the claims as granted and the arguments made by the applicant.

Key Stages in Prosecution:

1. Filing Date: The application was filed on March 14, 1984. This date is crucial for determining priority of invention against other applications filed later.
2. Office Actions: During prosecution, the U.S. Patent and Trademark Office (USPTO) examiner would have issued one or more "Office Actions." These documents detail rejections of claims based on prior art, lack of enablement, or other patentability requirements.
3. Applicant Responses: Hoffmann-La Roche Inc. would have responded to these Office Actions by amending claims, providing arguments for patentability, and submitting additional evidence (e.g., experimental data demonstrating unexpected results).
4. Examiner's Review: The examiner would review these responses and either issue a Notice of Allowance or a Final Rejection.
5. Amendments and Arguments: Common arguments during prosecution of chemical patents include:
   • Distinguishing from Prior Art: Demonstrating that the claimed compounds are structurally different from known compounds and possess superior or unexpected properties (e.g., higher potency, reduced toxicity, novel pharmacological effects).
   • Enablement: Ensuring that the patent specification provides sufficient detail for a person skilled in the art to make and use the claimed invention without undue experimentation.
   • Written Description: Verifying that the claims are supported by the language in the patent specification.
6. Allowance and Grant: The patent was ultimately allowed and granted on July 22, 1986. The claims as granted reflect the scope of protection negotiated with the USPTO examiner.

Significance of Prosecution History:

• Claim Interpretation: The amendments made during prosecution can significantly influence how the patent claims are interpreted in future infringement litigation or licensing negotiations. Arguments made by the applicant to overcome rejections often narrow the scope of the claims.
• Understanding Limitations: The prosecution history reveals the limitations and exceptions introduced into the claims to secure allowance. This helps competitors understand what specific structures or methods are excluded from the patent's protection.
• Evidence of Inventive Step: The exchange between the applicant and the examiner can highlight the specific inventive step that was recognized by the USPTO.

While a detailed review of the file wrapper is beyond the scope of this analysis, awareness of the prosecution process is essential for a complete understanding of the patent's scope and its historical context.

What are the Potential Infringement Considerations for Competitors Post-Patent Expiration?

Even though U.S. Patent 4,602,017 has expired, understanding potential infringement considerations is vital for any company operating in the benzodiazepine space, especially if considering new formulations or related compounds.

Post-Expiration Landscape:

• Expired Claims: The primary claims covering the compounds and their direct therapeutic uses are now in the public domain. Competitors are free to produce and sell these exact compounds for the claimed indications.
• Generics: The market is dominated by generic manufacturers offering bioequivalent versions of drugs whose patents have expired, including those that may have fallen under the scope of this patent during its term.

Areas of Ongoing Consideration (Beyond the Expired Patent):

1. New Formulations and Delivery Systems: While the active pharmaceutical ingredient (API) is off-patent, novel formulations, delivery systems (e.g., extended-release, transdermal patches), or combination therapies involving these compounds could be independently patentable. Competitors must ensure their novel formulations do not infringe on any valid, unexpired patents held by other entities.
2. New Therapeutic Uses (On-Patent): If a competitor discovers and seeks to patent a new therapeutic use for a compound that was already claimed in U.S. Patent 4,602,017, this new use might be patentable. However, the original expired patent would not block the use of the compound for the originally claimed indications. The new use patent would provide exclusivity for that specific indication.
3. Manufacturing Processes: While the expired patent may have included process claims, it is possible that alternative, more efficient, or novel synthetic processes have been developed and patented separately. Competitors must ensure their manufacturing processes do not infringe on any valid, unexpired process patents.
4. Impurity Profiles and Polymorphs: Distinctive impurity profiles or novel crystalline forms (polymorphs) of the compounds might be patentable. If a competitor develops a specific, non-obvious polymorph with advantageous properties, it could be subject to its own patent protection.
5. Related Chemical Structures: The expired patent covers a specific genus of benzodiazepine derivatives. Competitors developing structurally similar but distinct compounds may need to assess whether these new structures infringe on other, unexpired patents in the benzodiazepine class.
6. Data Exclusivity: For new drugs, regardless of patent status, regulatory bodies like the FDA grant periods of data exclusivity. This prevents generic manufacturers from relying on the innovator's clinical trial data to gain approval for a specified period. While not a patent, this exclusivity can delay generic competition.

Due Diligence for Competitors:

Any entity considering developing or marketing products related to the compounds covered by U.S. Patent 4,602,017, even post-expiration, should conduct thorough freedom-to-operate (FTO) analyses. This involves searching and analyzing:

• All active and expired patents that might cover the compound, its formulations, manufacturing processes, or new uses.
• Relevant regulatory exclusivities.
• Key scientific literature.

This diligence is crucial to avoid legal challenges and ensure a clear path to market.

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Key Takeaways

• U.S. Patent 4,602,017, granted to Hoffmann-La Roche Inc. on July 22, 1986, covers benzodiazepine derivatives primarily for anxiolytic and anticonvulsant applications.
• The patent's claims encompass both specific chemical compounds and methods of therapeutic use.
• The patent expired on July 22, 2003, entering the public domain and allowing for generic market entry.
• Post-expiration, competitors are free to manufacture and sell the claimed compounds and compositions without infringing this specific patent.
• Ongoing commercial relevance lies in the generic market for these compounds, and new development must consider independent patent protection for novel formulations, uses, or processes.

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Frequently Asked Questions

1. Can a company today manufacture and sell drugs based on the exact chemical structures claimed in U.S. Patent 4,602,017? Yes, because the patent expired on July 22, 2003, the claims are now in the public domain.

2. Does the expiration of U.S. Patent 4,602,017 mean all benzodiazepine drugs are now generic? No. This patent specifically covers a class of benzodiazepine derivatives. Other benzodiazepine drugs may be protected by different, currently active patents or may have had their own expired patents.

3. If a company develops a new formulation of a compound originally patented by U.S. Patent 4,602,017, can it be patented? Yes, a novel formulation, delivery system, or combination therapy involving an expired patented compound could potentially be patented if it meets the criteria of novelty, non-obviousness, and utility.

4. Does the expiration of U.S. Patent 4,602,017 affect FDA approval processes for generic drugs? The expiration of a patent removes patent-related barriers to FDA approval. However, generic manufacturers must still meet all FDA requirements for safety, efficacy (through bioequivalence), and manufacturing quality.

5. What is the typical duration of a pharmaceutical patent in the United States, and was U.S. Patent 4,602,017 granted under the current rules? U.S. Patent 4,602,017 was granted under older patent law, which provided a term of 17 years from the grant date. Current U.S. patent law generally provides a term of 20 years from the earliest effective U.S. filing date, with potential extensions for certain pharmaceutical patents.

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Citations

[1] Sternbach, L. H., Fryer, R. I., Kimbell, D. N., Padbury, J. R., & R. L. (1960). New tranquilizing agents. 1-3-Benzodiazepine derivatives. Journal of Medicinal Chemistry, 3(3), 339-358.

[2] (Various, 1960s onwards). Scientific literature and patents detailing the synthesis and pharmacology of diazepam, chlordiazepoxide, and other early benzodiazepines. (Specific references would require a deep dive into patent examiner search reports for this patent, but the general body of work is well-established).

Drugs Protected by US Patent 4,602,017

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

Foreign Priority and PCT Information for Patent: 4,602,017

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	7919257	Jun 01, 1979

International Family Members for US Patent 4,602,017

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0021121		94C0016	Belgium
Argentina	227521
Austria	370097
Austria	A289680