DETAILED ACTION
Status of Claims
The amendment submitted October 14, 2025 has been entered.
Claims 15-23 are pending.
Claims 1-14 were previously cancelled by Applicant.
Claims 20-23 are withdrawn as explained below in the Election/Restriction section.
Claims 15-19 are currently under examination and are the subject of this office action as explained below in the Election/Restriction section.
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on October 14, 2025 has been entered.
Election/Restrictions
Previously, Applicant’s election without traverse of Group I, claims 5-11 drawn to a compound of Formula VIIA and a pharmaceutical composition, in the reply filed on November 5, 2024 is acknowledged.
Applicant cancelled claims 5-11 and introduced new claims 15-23.
Claims 15-19 are drawn to a compound of Formula VIIA and a pharmaceutical composition, which reads on Group I and are therefore elected.
Claims 20-23 are drawn to non-elected inventions and are withdrawn.
Applicant’s election of species without traverse from the following structure (page 83 of specification, example 7A, shown below) is likewise acknowledged and applied to new claims 15-19.
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As indicated in the last Office Action dated December 4, 2024, the elected species was searched; however, for the purpose of compact prosecution, the search was expanded.
Notably, both the previously elected species and compounds identified in the expanded search are encompassed by Formula VII as per instant new claim 15.
Applicant is reminded that they cannot change the election of species.
As per MPEP 818, “Election becomes fixed when the claims in an application have received an action on their merits by the Office. If, after receiving an action on the merits of an invention, one or more properly divisible additional inventions are subsequently presented for examination, the examiner may deem the examined invention to be the invention elected by original presentation.”
Claims 20-23 are withdrawn from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to a non-elected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on November 5, 2024 is acknowledged.
Claims 15-19 are currently under examination and are the subject of this office action.
Affidavit
The declaration under 37 CFR 1.132 filed October 14, 2025 is sufficient to overcome the rejection of Claims 15-19 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Bharathan et al. (USPN 11,697,657 B2) (herein referred to as Bharathan) based on the remarks provided by Dr. Zhaoyin Wang regarding macrocyclization, design using conformation restriction and state of the art regarding macrocyclization chemistry related to instant invention.
Consequently, the Examiner has reconsidered the written support requirement for the compounds claimed in instant invention in light of the declaration regarding US Provisional Applications 62/921,513, filed June 24, 2019 and has determined it does contain sufficient written support. Therefore, the effective filing date is June 24, 2019. Consequently, Bharathan et al. (USPN 11,697,657 B2) no longer qualifies as prior art and Applicant has overcome this rejection.
Priority
Acknowledgment is made that this application is a Continuation-in-Part of PCT/CN2020/097802 filed June 6, 2020, which claims benefit of US Provisional Applications 62/921,513, filed June 24, 2019 and 62/995,304, filed January 23, 2020.
Claims 15-19 are directed towards compounds that are macrocycles, the contents of which is disclosed in US Provisional Application 62/995,304, filed January 23, 2020.
As stated above, the Examiner has reconsidered the written support requirement in light of Applicant’s submitted declaration and determined that US Provisional Applications 62/921,513, filed June 24, 2019 does contain sufficient written support for the compounds claimed in instant application.
Consequently, the effective filing date for claims 15-19 is updated to June 24, 2019 based on US Provisional Applications 62/921,513, filed June 24, 2019.
Information Disclosure Statement
No additional Information Disclosure Statements have been submitted.
WITHDRAWN REJECTIONS
The examiner withdraws rejections to claims 15 and 17-19 under 35 U.S.C. 112(b) based on claim amendments by Applicant, which have remedied the ambiguities.
The examiner withdraws rejections to claims 15-19 under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Bharathan et al. (USPN 11,697,657 B2) (herein referred to as Bharathan) based on Applicant’s declaration, which has updated the effective filing date; therefore, Bharathan no longer qualifies as prior art.
MAINTAINED/MODIFIED OBJECTIONS
Claim Objections
Claim 16 remains objected to because of the following informalities: at line 2, the claim appears to be constructed as a Markush claim; however, there are no commas between the chemical structures presumably listed as alternatives and there is no conjunction provided between the last and penultimate structures in the presumed listing of alternatives. Appropriate correction is required.
As previously detailed for cancelled claim 9, please similarly correct claim 16 accordingly based on this guidance.
NEW REJECTIONS
Applicant’s amendments have necessitated new grounds of rejection.
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.
Claims 15-19 are rejected under 35 U.S.C. 103 as being unpatentable over Allen et al (USPN 11,090,304 B2) in view of Appavoo et al. (Appavoo, S.D., Huh, S., Diaz, D.B. and Yudin, A.K., 2019. Conformational Control of Macrocycles by Remote Structural Modification: Focus Review. Chemical reviews, 119(17), pp.9724-9752) and further in view of Ermert (Ermert, P., 2017. Design, properties and recent application of macrocycles in medicinal chemistry. Chimia, 71(10), pp.678-678).
Claims 15-19 are directed towards macrocycles. Allen’s disclosure is directed towards non-cyclized compounds, which are known in the art to be active as KRAS inhibitors.
By example only, Allen discloses the following compound (Claim 1, column 1147, compound 1) as shown below, which is the non-cyclized version of similar compounds claimed in instant invention of claim 15 (page 3, compounds shown below).
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As per MPEP 2144.09, I: “A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963).”
Additionally, as per MPEP 2144.09, III: “Prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979).”
Appavoo teaches that “The three-dimensional preorganization of binding elements afforded by macrocycles is useful for the development of biologically active ligands… Cyclization of a linear precursor can diminish the entropic penalties associated with the formation of a protein/ligand complex by reducing the amount of unfavorable conformations that the ligand can adopt. Macrocycles are particularly well-suited for targeting complex protein–protein interactions (PPIs), which is a challenge with small molecules because they are not well suited to interact with the shallow and relatively featureless binding surfaces that typify PPIs. ”
Ermert teaches that “Pre-organization of a molecule in the active conformation is the basis of an entropic advantage leading to improved binding….Design of macrocyclic inhibitors on the basis of structural information obtained from X-ray crystal structures of protein ligand complexes was successful in providing compounds with improved potency and selectivity, as compared to acyclic controls. Often macrocyclization also went along with an improvement of the pharmacokinetic properties.”
Ermert also teaches that “Progress in synthetic methodologies, miniaturization, and automation allowed the synthesis of libraries of macrocyclic compounds for hit identification. Modular architecture of macrocycle libraries is important to synthesize significant numbers of compounds and to also facilitate rapid hit amplification and optimization. Based on synthetic organic chemistry, a variety of platforms have been elaborated over the last two decades.”
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to modify Allen’s compounds to access common macrocycle versions because Allen discloses compounds that are known KRAS inhibitors, Appavoo teaches that cyclization of linear precursors can diminish entropic penalties associated with formation of a protein/ligand complex, and because Ermert teaches that macrocyclization of acylic precursors can improve potency and pharmacokinetic properties in addition to that progress in automation and chemical synthesis has enable facile access towards libraries of macrocyclic compounds.
Additional, as disclosed in the declaration on page 9, “There are numerous examples that utilize amide or ether formation reactions to achieve the synthesis of macrocyclic molecules, including several drugs approved by FDA. Especially, intramolecular macrocyclic ring closure by amide or ether formation reactions is well documented in literature. Those of ordinary skill in the art would obviously know how to synthesize these compounds based on a simple retrosynthetic analysis and amide/ether synthesis,” supporting the obviousness of the invention.
Therefore, an ordinarily-skilled artisan would be motivated to modify Allen’s invention to access macrocyclic variants based on the well-known benefits in the art pertaining improved potency and pharmacokinetic properties arriving at instant invention as a predictable result with a reasonable expectation of success through standard SAR optimization as is common the art of medicinal chemistry and additionally, based on advances in the filed pertaining automation and synthesis towards accessing modular libraries of macrocycles.
It would have been further prima facie obvious to access the pharmaceutical compositions containing the elected species as a highly predictable result with a reasonable expectation of success.
Therefore, claims 15-19 are rejected as being obvious.
Conclusion
Claims 15-19 are pending and remain rejected. No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROLYN L. LADD whose telephone number is (703)756-5313. The examiner can normally be reached M-Th, 7:00 am to 5:30 pm EST.
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/C.L.L./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622