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 .
DETAILED ACTION
Response to Amendment
Acknowledgment is made of the receipt and entry of the amendment filed on 11/06/2025, wherein claims 62, 68 and 97 are amended.
Election/Restriction
Applicant elected with traverse of Group I, and of the species having following structure, in the reply filed on 04/04/2025.
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The Restriction Requirement is deemed proper and made FINAL in last office action mailed on 05/06/2025.
Instant compound 825 (See page 377 of instant specification) having following structure,
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is a stereoisomer of the elected racemic species, a compound of Formula IV, wherein:
X1 is CH2, X2 is O, Y1b and Y1c are CH2, Z1, Z2, Z3,Z4 is C;
R4, R5, R6 is H; R7 is Cl;
R8a is CH2 substituted with R9, heterocyclyl
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.
R8d is H, R10 is Me.
Instant compound 825 as disclosed by instant specification, CAS# 2561527-55-5, was entered in STN database on 12/18/2020. A stereoisomer of the elected racemic species ,CAS#2669073-41-8, was disclosed by Li (WO2021139748 A1, hereafter “Li ’748”, Applicant’s IDS dated 05/31/2022, Cite No. BC, family member of US 11,312,724 B2, claiming priority of PCT/CN2020/071004, hereafter “Li ’004” , filed on January 08, 2020, Applicant’s IDS dated 05/31/2022, Cite No. BD, See Example 57, cpd No. 53) having following structure:
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The stereoisomer of the elected racemic species, Example 57 of Li ’748, was not disclosed in PCT/CN2020/071004 (Li’004, no publication), thus instant elected species was not rejected under 102(a)(2) as being anticipated by Li ’748. However, Li ’748 incorporated tetrahydroquinazoline Formula I- XV and compound species comprising spirocyclic tetrahydroquinazolines that were original disclosed in Li’004 PCT/CN2020/071004. The effective filing date of Li ’748 regarding the incorporated spirocyclic tetrahydroquinazolines Formula I- XV and compound species originally disclosed by Li’004 is considered as January 08, 2020, the filing date of PCT/CN2020/071004. Li ’748 having effective filing date of January 08, 2020 for spirocyclic tetrahydroquinazolines is considered as prior art that is used in following 35 USC§103 rejection.
The elected racemic species, and non-elected species, wherein X1 is CH2; X2 is O; Y1b and Y1c are CH2; Z1, Z2, Z3,Z4 is C; R4, R5, R6 is H; R7 is F, Cl, Br; R8d is H; R8a is C1-C4 alkyl optionally substituted with heterocyclyl, are rejected under 35 USC§103.
Other non-elected species are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species. The prior art search is extended to the extent necessary to determine patentability of the Markush-type claim, and the action made final.
Status of Claims
Claims 62, 64, 68, 69, 82, 88, and 92-119 are pending.
Claims 82, 93, 95, 105-108, 111-113, 115 and 118-119 remain withdrawn.
Claims 62, 64, 68-69, 88, 92, 94, 96-104, 109, 110, 114, 116, and 117 are currently under examination.
Response to Arguments
Applicant’s Remarks filed 11/06/2025 have been fully considered, but NOT persuasive to overcome rejections over Li ’748/Li’004 under 35 USC §103 on the record.
Applicant argues “the most potent compound disclosed by Li '004 (Cpd 1, Table 1) features the 6,6- spiro scaffold. The Office Action provides no reasoned basis for choosing the compounds in Example 9, which comprise a 5,6-spiro scaffold, as the compound for modification. Accordingly, the compound selection and proposed modification can only be based on impermissible hindsight ”.
RESPONSE: In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In instant case, Li’004 already teaches modification of Compound 1 by introducing F or Cl as R11a/R11d ( i.e. instant R7) with R4, R5, and R6 are each hydrogen (See compound 23 and 24). It would be prima facie for an ordinary skilled in the art to further explore F or Cl for other spiro scaffold, e.g. 5, 6-spiro scaffold.
Applicant argues “Li '004 does not provide any teaching or suggestion to introduce a fluorine or chlorine at any phenyl ring position, never mind at R7. To the contrary, Li '004 teaches away from installing fluorine or chlorine at R7 because Li '004 discloses that halogen substitution on the phenyl ring led to up to a 30-fold reduction in activity against MIA PaCa-2 or H358 cells”.
RESPONSE: Applicant’s argument is contradictory since Li '004 discloses halogen substitution on the phenyl ring. Although Compound 11 comprising halogen substitution on the phenyl ring to the meta position of spiro scald is less potent than Compound 1 with 6, 6-spiro scaffold, Li’004 also teaches modification of compound 1 by introducing F or Cl as R11a/R11d ( i.e. instant R7) at the ortho position to the spiro scaffold (See compound 23 and 24, no activity was disclosed).
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It would be prima facie obvious to an ordinary skilled in the art to further explore F or Cl including the ortho position to the spiro scaffold for other spiro scaffold, e.g. 5, 6-spiro scaffold. As stated in 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). In instant case, Applicant did not provide any evidence that F or Cl at ortho position (to the spiro scaffold) is super to meta substitution or unsubstituted Compound 9. As such, the 103 rejection is maintained in absence of unexpected result.
No claims are allowable in view of prior art, the provisional rejections on the ground of nonstatutory double patenting over copending Application No. 18/708,473 is also maintained.
Priority
Instant application 17/612,972 filed on 11/19/2021, is a national stage of PCT/US20/33816 filed on 05/20/2020, which claims benefit of US provisional application No. 62/850,289 filed 05/20/2019.
Instant claimed Formula IV, and compound 767 – 871, C1-C32 including the elected species compound 825 (Table 2 and Table 3) were not disclosed in US provisional application No. 62/850,289. Thus, the priority date of subject matter related to instant claimed Formula IV, compounds 767-871 and C1-C32 is considered as 05/20/2020, the filing date of PCT/US20/33816.
Information Disclosure Statement
The information disclosure statement filed 11/06/2025 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It’s noted there is no copy for the Supplementary European Search Report for EP Application No. 22893558.1 dated September 26, 2025 under NPL section. As such, the NPL is not considered by the Examiner.
Claim Rejections - 35 USC § 103
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.
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 62, 64, 68-69, 88, 92, 94, 96-104, 109, 110, 114, 116, and 117 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (WO2021139748 A1, hereafter “Li ’748”, Applicant’s IDS dated 05/31/2022, Cite No. BC, family member of US 11,312,724 B2, claiming priority of PCT/CN2020/071004 (hereafter “Li ’004”), filed on January 08, 2020, Applicant’s IDS dated 05/31/2022, Cite No. BD)(maintained).
Li ’748 incorporated tetrahydroquinazoline Formula I- XV and compound species comprising spirocyclic tetrahydroquinazolines that were original disclosed in PCT/CN2020/071004 (Li’004, no publication). The effective filing date of Li ’748 regarding the incorporated spirocyclic tetrahydroquinazolines Formula I- XV and compound species original disclosed by Li’004 is considered as January 08, 2020, the filing date of PCT/CN2020/071004. Li ’748 having effective filing date of January 08, 2020 for spirocyclic tetrahydroquinazolines is considered as prior art under 102(a)(2). The following teachings disclosed by Li’004 and incorporated in Li ’748 are cited based on Li ’748 for reference. Please refer to Li’004 for all subject matter related to spirocyclic tetrahydroquinazolines. Please note subject matter not disclosed in Li’004 are not applied in this 103 rejection.
Li’748 /Li’004 disclosed spirocyclic tetrahydroquinazolines, compound of Formula I to Formula XV, as KRAS inhibitors, pharmaceutical composition comprising spirocyclic tetrahydroquinazolines, and methods of treating conditions and diseases, e.g. cancer, wherein the inhibition of KRAS provides a benefit (See Li ’748 abstract, [0001], [0019]-[0112], Examples 1-25, Table 1, claims 1-141).
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Regarding instantly claimed spiro-quinazoline moiety, Li’748 /Li’004 disclosed spirocyclic tetrahydroquinazolines moiety wherein E and E1 is CH2, e.g. spiro-indene-quinazoline (E2 is bond), spiro-naphthalene-quinazoline (E2 is CH2), etc. (See Table 1, claims 18-22).
Regarding instantly claimed R8a optionally substituted with R9/R10 recited in instant claims 64, 68-69, 96-104, 109-110 and 114, Li’748 /Li’004 disclosed spirocyclic tetrahydroquinazolines comprising R3 (See Li’748 [105], claim 31).
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Regarding instantly claimed R7, Li’748 /Li’004 disclosed Formula IV (See Li’748 [0078], claim 4)
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Li’748 /Li’004 disclosed compound species comprising spiro-indene-quinazoline moiety (See Examples 9, 13, 14, 16, 37, Table 1) that would have been encompassed by instant claimed Formula IV except R7.
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Li’004 also disclosed compound species wherein R11a/R11d is F or Cl (See Table 1)(which read on instant claimed R7)
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As elaborated, Li’748 incorporated Li’004 compound of Formula IV, VII, VIII, etc. that are very similar to instant compound of Formula IV, wherein:
X1 is CH2, X2 is O, Y1b and Y1c are CH2, Z1, Z2, Z3,Z4 is C;
R4, R5, R6 is H; R8d is H; R7 is H, alkyl, halogen;
R8a is C1-3 alkyl (e.g. CH2), substituted with one heterocyclyl R9 (e.g. pyrrolidine), optionally substituted with R10 (e.g. Me), e.g.
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According to MPEP § 2144.09, 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). It would have been obvious to one of ordinary skill in the art to further explore more spirocyclic tetrahydroquinazolines based on teachings of Li’748, together with general knowledge of structure similarity and bioisosteric modification, and arrive at instantly claimed invention with reasonable expected success.
For example, reference Example 9 (Cpd 4/5) disclosed by Li’004 and incorporated in Li’748 is very similar to instantly elected species except R11a/R11d is H vs R7 is Cl in instant elected species. Li’748/Li’004 already teaches R11a/R11d can be halogen(e.g. F or Cl). A skilled artisan would have known to substitute H of reference Example 9 (Cpd 4/5) with F or Cl and arrive at instant elected species. It’s noted instant specification only disclosed a few working example of instant claimed compound of Formula IV wherein R7 is F or Cl.
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A skilled artisan would be motivated to further explore more spirocyclic tetrahydroquinazolines for SAR study of KRAS inhibitors based on teachings of Li’748 in search for KRAS inhibitors. The SAR study of spirocyclic tetrahydroquinazolines as KRAS inhibitor based on the collective teachings of prior art, together with further modification/ optimization based on general knowledge of structure similarity and bioisosteric modification would provide more spirocyclic tetrahydroquinazoline compounds that are reasonably expected to exhibit KRAS modulating activity.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the teachings of prior art and general knowledge of structure similarity/ bioisosteric modification for SAR study. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 62, 64, 68-69, 88, 92, 94, 96-104, 109, 110, 114, 116, and 117 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,4, 5, 9, 25, 30 of copending U.S. application No. 18/708,473. Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Reference claims are directed to spirocyclic tetrahydroquinazolines, Formula I that comprise core structure of instantly claimed compound of Formula IV and similar substituents.
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Reference claim 9 teaches X3 is selected from
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Reference claimed compound of Formula I, wherein R1=H, R2 is Cl, F Br, R3=R4=H, X3 is
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would read on instantly elected species. Thus, reference claims anticipate or render instant claims obvious.
According to MPEP § 2144.09, 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). It would have been obvious to one of ordinary skill in the art to further explore more spirocyclic tetrahydroquinazolines based on teachings of reference claims, together with general knowledge of structure similarity and bioisosteric modification, and arrive at instantly claimed invention with reasonable expected success.
The instant application shares at least one common inventor/applicant with reference application. Instant application is not related to reference patent on the record, thus no 35 USC 121 shield exists.
Conclusion
No claims are 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 LIYUAN MOU whose telephone number is (571)270-1791. The examiner can normally be reached Mon-Fri 9:00-5:30.
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/L.M./ Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628