DETAILED ACTION
Status of Claims
Receipt is acknowledged of the Applicants’ Amendments and Remarks filed July 6, 2026.
Claims 15-23 remain pending.
Claims 1-14 were previously cancelled by Applicant.
Claims 20-23 remain withdrawn as explained below in the Election/Restriction section.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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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Claims 20-23 are drawn to non-elected inventions and are withdrawn.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 OBJECTIONS
Claim Objections
The examiner withdraws objections to claim 16 based on corrections made by Applicant to remedy the deficiencies.
MODIFIED/MAINTAINED REJECTIONS
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 remain 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/admitted in the declaration in paragraph 5 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 remain rejected as being obvious.
Response to Arguments
The Remarks of July 6, 2026 have been fully considered but are not fully persuasive for the reasons below.
35 USC § 103
Applicant’s Arguments:
D1 (US 11,090,304 B2) did not disclose any information of the stereochemistry of all examples, in some cases only referring as a "single isomer". The earliest disclosure of the stereochemistry of AMG510 was on December 10, 2019 (Journal of Medicinal Chemistry, 62/921,513) is June 24, 2019, which is nearly 6 months earlier than the JMC publication of AMG510. Without the 3-dimentional stereochemistry information of the compounds in D1, it would be very challenging to know where and how to form these macrocyclic ring structures. The sites to be selected for ring formation and the choice of linker structures and functionalities would be considered non-obvious, given the information disclosed in D1.
Although there are several macrocyclic drugs approved by FDA, each case is different. Indeed, the synthetic chemistry of amide and ether formation are well-documented in literature, however, the challenge lies in the designs of these macrocyclic molecules with these functional groups. It would be impossible to design these specific macrocyclic molecules without deep understanding and analysis of each specific case.
Examiner’s Response:
The examiner respectfully disagrees. Page 5 of Applicant’s own affidavit acknowledges that the compounds “can be easily designed as in the following scheme and achieved by a person in the field of medicinal/synthetic chemistry with ordinary skills.” This contradicts Applicant’s position that it is impossible to design the molecules of the claimed invention and Applicant has failed to provide evidence supporting this position. Applicant’s affidavit additionally admits the use of an “amide formation reaction is an obvious method to synthesize these amide-containing macrocyclic molecules.”
Applicant is reminded that as per MPEP 2145. I: “An argument by the applicant is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art.
Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.").
Applicant’s Arguments:
Although D2 and D3 describe some strategies of using macrocyclic structures to achieve conformational control, the cases described in D2 and D3 are mostly peptide molecules. As the authors pointed out, the conformational analysis of macrocycles is a complex and challenging problem. Each molecule and its target protein provide a unique situation in which there are many factors that contribute to this complexity. The information provided in D2 and D3 would not teach us where and how to form the macrocyclic rings. In addition, D2 and D3 do not teach us what types of linkers to choose since not all of the linkers that are suitable for the desired pharmacological activities and pharmacokinetics properties.
The structural designs of Claims 15-19 of the present application are the optimal ones based on our designs. For example, a linker with a length of 4 to 5 atoms and ether and amine functional groups are best suited for the choices of linkers. The positions of attaching the linkers in the macrocyclic molecules are also found best at the two ortho-positions of the two rings to be linked.
Examiner’s Response:
Applicant’s own affidavit outlines how amide formation is an obvious strategy used in the design of amide-containing macrocycles (pages 5-8). Applicant’s affidavit further acknowledges that the principle of conformation restriction is a common tool used in medicinal chemistry. Applicant also admits that the synthesis of such compounds would be obvious based on “simple retrosynthetic analysis and amide/ether synthesis.”
Applicant has failed to provide evidence supporting that it would be non-obvious to simply optimize the linker length as part of routine optimization as is standard for structure-activity relationship studies in medicinal chemistry.
Again, arguments presented by Applicant cannot take the place of evidence in the record.
Applicant’s Arguments:
The best choices for the linkers are the ether, amide or amine groups, even if the linker has the same number of atoms. For example, the linker containing an urea groups (Example 16) provided a macrocyclic compound as a much weaker Kras G12C inhibitor (IC50 > 1 mM in the Heck 358 cell proliferation assay), whereas molecule with an amine linker (Example 7B) afforded a much potent Kras inhibitor (IC50 < 0.1 mM in the Heck 358 cell proliferation assay). Therefore, not all of the linkers in the designs of macrocyclic molecules provide the desired pharmacological activities.
Examiner’s Response:
Applicant’s range of compounds contains various types of linkers and linker lengths. It is not unexpected that such variation in linker would result in different properties. Applicant’s comparisons are between species within its own invention; however, Applicant has provided no evidence suggesting unexpected results compared to what was known in the prior art at the effective time of filing.
Applicant is reminded that as per MPEP 2145 “Rebuttal evidence may include evidence of "secondary considerations," such as "commercial success, long felt but unsolved needs, [and] failure of others." Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 4459, 467. See also, e.g., In re Piasecki, 745 F.2d 1468, 1473, 223 USPQ 785, 788 (Fed. Cir. 1984) (commercial success). Rebuttal evidence may also include evidence that the claimed invention yields unexpectedly improved properties or properties not present in the prior art. Rebuttal evidence may consist of a showing that the claimed compound possesses unexpected properties. Dillon, 919 F.2d at 692-93, 16 USPQ2d at 1901. A showing of unexpected results must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997).”
Applicant is further reminded that as per MPEP 716.02: “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).”
Applicant is further reminded that as per MPEP 716.02 (d): “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).”
Finally, Applicant is reminded that the burden is on the Applicant to establish results are unexpected and significant. Please see MPEP 716.02(b).
Therefore, for these reasons, Applicant’s arguments are not persuasive.
Conclusion
Claims 15-19 are pending and remain rejected. No claims allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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.
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, James H. Alstrum-Acevedo can be reached at 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.L.L./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
