DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-16 and 21-23, submitted on 1 July 2024, represent all claims currently under consideration.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
This application is a 371 of PCT/RU2021/000624, filed 30 December 2021. The effective filing date is 30 December 2021.
Information Disclosure Statement
One Information Disclosure Statement (IDS), submitted on 1 July 2024, is acknowledged and has been considered.
Specification
The Title is objected to because it contains the word “NEW”. All patentable inventions are necessarily new, so such words should not be included in the title (See MPEP § 606). The word “NEW” has been deleted from the title. No further action is required on Applicant’s part.
The disclosure is objected to because of the following informalities: The structure of Example 27
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has the CH3 moiety and SO2 moiety overlapping, making it difficult to interpret the structure.
Appropriate correction is required.
Claim Objections
Claims 1, 2, 4, and 9 are objected to because of the following informalities: Each of the claims references “NMe2” as a substituent. The Examiner believes this should be written as N(Me)2 to clarify that the two methyl groups are bound to the nitrogen. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 15-16 and 21-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of viral infections which are sensitive to non-nucleotide reverse transcriptase inhibitors such as HIV and other retroviruses, does not reasonably provide enablement for the treatment of all viral infections. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. Consideration of the relevant factors sufficient to establish a prima facie case for lack of enablement is set forth below:
The nature of the invention and breadth of the claims:
The claims are directed towards a method of treating or preventing a viral infection, comprising administering to a patient in need a therapeutically effective amount of a compound of Claim 1. The compounds of the invention are non-nucleotide reverse transcriptase inhibitors (NNRTIs). Thus, the claims are directed to a method which can be used to treat or prevent any viral infection using the compounds of the invention.
The state of the prior art and the predictability or unpredictability of the art:
Vanangamudi (Current Opinion in Pharmacology, 2020, 54, 179-187) provides a review of NNRTIs and their use as medicines. NNRTIs are allosteric inhibitors of HIV-1 reverse transcriptase. NNRTIs are often used in combination with other antiretroviral agents that target two or more enzymes in the viral life cycle. Combination regimens usually include a backbone of two nucleoside or nucleotide reverse transcriptase inhibitors and a third core agent among the NNRTIs or protease inhibitors (Abstract). HIV belongs to the Retroviridae family of viruses. The reverse transcriptase enzyme is an essential part of the replication cycle of HIV, and reverse-transcribes RNA into DNA. Most antiretroviral drugs treat HIV by targeting RT’s first step. RT inhibitors include nucleoside reverse transcriptase inhibitors, nucleotide reverse transcriptase inhibitors, and non-nucleoside reverse transcriptase inhibitors. NNRTIs are non-competitive and bind to the allosteric hydrophobic pocket of RT. Over 50 diverse chemical groups have been identified as NNRTIs targeting RT. Efficacy for the NNRTI drug class is reduced y mutations within or near the NNRTI binding pocket. Newer NNRTIs are highly active against mutant strains of HIV-01 compared to the earlier or more traditional NNRTIs. However, not all viruses can be successfully treated in this manner as not all viruses are retroviruses, and would lack the enzyme which is the target of the compounds of the examined application.
The relative skill of those in the art:
The artisan would generally have an advanced degree related to the treatment or study of viruses; however, their high level of training and knowledge would not be sufficient to overcome the lack of understanding of how to use the claimed compounds to treat all viral infections, as not all viruses are sensitive to the inhibition of reverse transcriptase.
The amount of direction or guidance presented and the presence or absence of working examples:
The compounds of the invention were shown to inhibit growth of HIV-1 IIIB virus, as well as NNRTI resistant mutants (Page 85). Additionally, the compounds were also shown to inhibit HIV I reverse transcriptase in vitro. Thus, the treatment or prevention of HIV viral infections, or other retroviral infections are enabled by the specification. However, the specification does not demonstrate the successful treatment of other viral infections such as those which are not retroviruses.
The quantity of experimentation necessary:
Considering the state of the art as described above, the high unpredictability of the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate with the scope of the claims.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-10, 14-16, and 21-23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claims are indefinite due to the reference to a “lower alkyl” as a substituent group. “Lower alkyl” is not a term of the art, leading to indefiniteness as to what constitutes a “lower alkyl” in the context of these compounds. The Specification does not define “lower alkyl”. The Examiner suggests amending to replace each instance of “lower alkyl” with “C1-C8 -alkyl” or similar to correct the indefiniteness.
Claims 4, 6, 8-10, 15, and 16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Regarding the claims, the phrase "optionally" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 14, 15, 21, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Bilotta (US 2014/0010783; Publication Date: 9 January 2014) in view of Thornber (Chemical Society Reviews, Issue 4, 1979).
Determining the Scope and Contents of the Prior Art:
Bilotta (See IDS, 1 July 2024) discloses compounds of formula I
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, their pharmaceutical compositions, and methods for using the compounds in the prevention or treatment of viral infections (Abstract). The application provides compounds of Formula I
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wherein
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(Paragraph 0006-0007). The application provides a method for treating a hepatitis C virus infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I (Paragraph 0009). The application provides a composition comprising a compound of Formula I and a pharmaceutically acceptable excipient (Paragraph 0010). One disclosed compound is I-89
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(Page 21). This compound has R1 as Cl, R2 as CN, X as CR6 with R6 as Cl, variables R3 and R4 each as H, and variable R5 as phenyl substituted with CF3.
Billota does not teach a compound wherein the analogous R5 is
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.
Thornber teaches the concept of bioisosterism, which is the concept wherein groups or molecules which have chemical and physical similarities produce broadly similar biological properties (Page 563). Table 1 (Page 564) lists the classical isosteres, and includes ring equivalents. Such ring equivalents include -CH=CH-, =CH-, =N-, and S. These atoms have similar electronic properties and as such, their replacement within a ring system is not expected to significantly alter the properties of that ring.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
The prior art of Billota does not teach a compound with the analogous variable R5 being
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.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would be a medicinal chemist, or pharmaceutical chemist with extensive experience in the synthesis of novel therapeutics through SAR.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
Billota and Thornber are considered analogous to the claimed invention as all are involved in the study of biologically active compounds. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to modify Compound I-89 of Billota by replacing the phenyl ring with pyridine as Thornber teaches that =N- and =CH- function as ring equivalents, and thus the artisan would not expect the properties of these compounds to be significantly altered by performing this substitution as due to the close chemical structure (See MPEP § 2144.09 I). The compounds of Billota are inhibitors of hepatitis C virus, and the artisan would not expect this substitution to significantly alter the properties of the resulting compound.
Claims 1, 3, 14-16, and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Janssen (WO 02/078708; Publication Date: 10 October 2002) in view of Bilotta (US 2014/0010783; Publication Date: 9 January 2014).
Determining the Scope and Contents of the Prior Art:
Janssen (See IDS, 1 July 2024) discloses compounds of formula I, their use as a medicine for inhibiting HIV replication, their processes for preparation and pharmaceutical compositions comprising them (Abstract). Compounds of the invention have the formula
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, wherein
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(Pages 2-3). The compounds of Formula I show antiretroviral properties, in particular against HIV (Page 17). Due to their antiretroviral properties, particularly their anti-HIV properties, the compounds of formula I are useful in the treatment of individuals infected by HIV and for the prophylaxis of these infections (Page 17). The present invention also provides compositions for treating viral infections comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier or diluent (Page 18). Compounds 15-17 (Page 36) have the structure
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with the variable groups as:
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, corresponding to a compound of the examined application having variable R2 as CN, X as CH, variables R1, R3, and R4 each as H, and variable R5 as phenyl substituted with CH3. These compounds have IC50 values between 0.03 and 0.004 µM against an HIV transformed cell line (Pages 37-38).
Janssen does not teach a triazole moiety in the compound, rather teaching compounds with a pyrazinone ring.
The teachings of Bilotta are previously described and are fully incorporated into this rejection.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
Janssen does not teach a triazole moiety in the compound, rather teaching compounds with a pyrazinone ring, while Bilotta teaches similar compounds with different functionalities present.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would be a medicinal chemist, or pharmaceutical chemist with extensive experience in the synthesis of novel therapeutics through SAR.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
Janssen and Bilotta are considered analogous to the claimed invention as all are involved in the development of antiviral therapies and compounds. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to modify the Compounds 15, 16, or 17 of Janssen by replacing the pyrazinone ring with the triazole ring disclosed in compound 89 of Bilotta. Bilotta discloses that this moiety results in a similarly anti-viral compound having a triazole ring as the central ring, and thus the artisan would not expect replacing the pyrazinone ring with triazole to significantly alter the resulting compound as Bilotta shows that this moiety results in antiviral activity in a compound of similar structure to those disclosed by Janssen.
Allowable Subject Matter
Claims 11-13 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is an examiner’s statement of reasons for allowance: There is no prior art which teaches, suggests, or provides motivation for the specific compounds of Claims 11-13 (See STN Search, Search Notes). These compounds have naphthalene or heteroaromatic rings in the R5 position. The prior art, cited above, does not teach, suggest, or provide motivation to replace the phenyl ring with these groups, and there is no reasonable expectation that inserting these groups would result in a compound with similar properties.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
Claims 11-13 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claims 1-10, 14-16, and 21-23 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHILLIP MATTHEW RZECZYCKI whose telephone number is (703)756-5326. The examiner can normally be reached Monday Thru Friday 730AM-5PM EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at 571-272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.M.R./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
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