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 .
Priority
This application, filed 12 May, 2022, is a national stage application of PCT/CN2020/120569, filed 13 October, 2020, which claims foreign benefit of Application CN 2019 10987593.8, filed 13 October, 2019.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 20 January, 2026 has been entered.
Status of the Application
Receipt is acknowledged of Applicant’s claimed invention, filed 20 January, 2026, in the matter of Application N° 17/769,416. Said documents have been entered on the record.
Claim 4 is amended. Claims 6, 10, 29-31, and 37-39 are canceled. Claims 40-41 are new. No new matter was introduced.
Therefore, Claims 2, 4, 24-28, 32-36, and 40-41 represent all claims currently under consideration.
Response to Amendments/Arguments
Claims 6, 10, 29-31, and 37-39 have been canceled. Therefore, the rejections of these claims under 35 U.S.C. 103 and Double Patenting are moot.
Applicant's arguments filed 20 January, 2026 have been fully considered but they are not persuasive. The primary arguments remain: (I) there is no reasoned identification of a lead compound (Remarks, Pg. 11), (II) no reason or motivation to modify the lead compounds (Remarks, Pgs. 11), and (III) the instantly claimed compounds produce unexpected results (Remarks, Pgs. 9 and 12-13.)
As previously stated, Cai and Tian (found in Applicant’s IDS filed 6 February, 2023, Non-Final filed 6 June, 2025, and Final filed 17 October, 2025), which share the same Applicant and two of the same Inventors, also disclose Weel kinase inhibitor compounds comprising the same core scaffold as presently claimed, and exemplifies multiple overlapping analogues within the same genus, differing only by routine substitutions.
Based on amendment and arguments, an updated comparison of the instantly claimed compounds, their biological activity as disclosed by the instant Specification and therefore by the same methods as noted in Applicant’s Remarks (Pg. 9), and the closest reference compound by the prior art, E77, can be found in the below Examiner’s Summary Table:
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Regarding Applicant’s Arguments I & II, Cai and Tian’s compound E77 (WO 2018/090939 A1, Pg. 34) compound E1 (of Formula Ib in instant Claim 4), and compounds E5 and E6 (of Formula Ia in instant Claim 2) share the same core structure, therapeutic pathway, and intended disease treatment, differing only in a single, routine structural modification (circled in red above.) Beyond being taught by the Formula III genus of Cai and Tian, such minor substituent changes also constitute routine medicinal chemistry optimizations and represent well-known bioisosteric modification that would have been expected to preserve biological activity while allowing fine-tuning of properties such as potency, lipophilicity, or metabolic stability. As such, Cai and Tian’s exemplified compounds provide a natural starting point and a clear reasoned basis for selection by a person of ordinary skill in the art seeking to further optimize compounds of this structural class. See MPEP §2144.08.
Regarding Applicant’s Argument III, Applicant asserts that the instant compounds demonstrate unexpected results sufficient to overcome the prima facie case of obviousness. Applicant has provided biological data also found summarized in the table above. The single data point, shown for compound E1 highlighted in green above, compared to Cai and Tian’s E77, represents a less than two-fold difference (E1 - 0.071 compared to E77 – 0.122.) Further, Applicant captures additional comparisons of reference compounds 180 to 181 and 178 to 146 (Remarks, Pg. 12-13) to demonstrate that Cai and Tian teach away from the R5 = H (as in instant compound E1), by demonstrating better IC50 findings with a methyl in the same position (as in Cai & Tian’s E77 and instant Compounds E5 and E6.) However, the comparative data relies on compounds containing methoxy and hydroxy groups on the inner ring which are not present in the instantly claimed or reference compounds.
Furthermore, Applicant asserts that the claimed compounds exhibit unexpected results based on comparative IC50 data. However, as summarized in Applicant’s disclosure, the instant compounds differ from the closest compound of Cai and Tian (E77) only by a single, modest structural modification, while retaining the same core scaffold and therapeutic context. Of the compounds evaluated, an apparent improvement is shown for instant compound E1 in a single assay (NCI-H1299), whereas other claimed compounds differing from E77 by similarly minor modifications (including E5 and E6) do not demonstrate improved activity relative to E77. Accordingly, Applicant has not demonstrated results commensurate in scope with all of the claims. See MPEP §716.02(d), “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). Accordingly, even if the cited species were marginally more potent, this would not render the overall genus patentably distinct.
Moreover, the magnitude of the alleged improvement for E1 is less than two-fold relative to E77, and Applicant has not established that this difference is statistically significant or exceeds normal experimental variability. The additional comparative examples provided by Applicant (Remarks, Pg. 12-13) rely on compounds bearing further substituents (e.g., methoxy, hydroxy) not present in E77, E1, E5, or E6, and Applicant has not shown that the observed difference is attributable to the claimed modification rather than to these other structural features. Further, the IC50 values relied upon are presented only as summarized results in the instant disclosure, without underlying raw data, replicate measurements, error estimates, or statistical analysis. Accordingly, Applicant has not met the burden under MPEP §716.02(b) to demonstrate unexpected results sufficient to overcome the prima facie case of obviousness.
Regarding the Double Patent rejections, Applicant’ arguments (Remarks, Pg. 14-15) are unpersuasive because non-statutory double patenting does not require a showing that the prior patent motivates selection of specific substituents from a broader disclosed genus; rather, the inquiry is whether the instant claims are patentably distinct from the claims of the reference patent. Regarding Patent 11,345,710, Meanwell demonstrates that the positional placement of heteroatoms within the ring system represents a known structural alternative, and Applicant has not shown that such variation confers patentable distinction.
Accordingly, the prior 35 USC § 103 and Non-statutory Double Patent rejections are maintained, and where necessary restated or updated to account for Applicant’s amendments. Additionally, below can be found new grounds of rejection necessitated by submission of the new Claims 40 (similar in scope to previous Claim 28) and 41 (similar in scope to previous Claim 36.)
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 2, 4, 24-28, 32-36, and 40-41 are rejected under 35 U.S.C. 103 as being unpatentable over Cai and Tian (US 2019/0308984 Al, linked to WO 2018/090939 A1, of previous record.)
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‘984 shares the same Applicant and two of the same Inventors.
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Regarding Claim 2, Cai and Tian teach the Weel kinase inhibitor E77 (‘984, Pg. 34, Para 0368), shown top right, which overlaps the instantly claimed Formula Ia, shown middle right, wherein R1 is chloro, R2 is chloro, R3 is methyl, R4 is methyl, R5 is methyl, and R6 is methyl.
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While Compound E77 fails to disclose R7 is a fluoro or methyl, Cai and Tian teach the genus of Formula III (‘984, Pg. 7, Para 0071), shown bottom right, wherein Ar1 is a phenyl substituted with halogens, and Ar2 is a phenyl substituted with halo or C1-C6 alkyl, which is substituted by one piperazinyl or one piperidinyl, and the piperazinyl or piperidinyl are optionally substituted by 1-3 substituents selected from C1 -C4 alkyl (‘984, Pg. 7, Para 0075.)
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Regarding Claim 4, Cai and Tian teach the Weel kinase inhibitor Compound E77 (‘984, Pg. 34, Para 0368), shown above top right, which overlaps the instantly claimed Formula Ib, shown to the right, wherein R1 is chloro, R2 is chloro, R3 is methyl, R4 is methyl, and R6 is methyl.
While Compound E77 fails to disclose R5 is hydrogen, Cai and Tian teach the genus of Formula III (‘984, Pg. 7, Para 0071), wherein Ar1 is a phenyl substituted with halogens, and Ar2 is a phenyl substituted with halo or C1-C6 alkyl, which is substituted by one piperazinyl or one piperidinyl, and the piperazinyl or piperidinyl are optionally substituted by 1-3 substituents selected from C1 -C4 alkyl (‘984, Pg. 7, Para 0075.)
Regarding Claims 24 and 26, Cai and Tian teach pharmaceutical compositions comprising a compound of Formula III in an effective amount for the treatment of cancer (‘984, Pg. 2, Para 0013), wherein the pharmaceutical composition useful for the treatment of cancer may also contain one or more pharmaceutically acceptable carriers or diluents (‘984, Pg. 2, Para 0014.)
Regarding Claim 25 and 27, Cai and Tian teach a composition effective to treat cancer comprising a compound of Formula III, or a pharmaceutically acceptable salt or prodrug thereof, which functions as a kinase inhibitor, in combination with at least one known anticancer agent or a pharmaceutically acceptable salt thereof (‘984, Pg. 20, Para 0321.)
Regarding Claims 28 and 40, Cai and Tian teach that anticancer agents may include, but are not limited to, the PARP inhibitors olaparib, niraparib, rucaparib, and talazoparib (‘984, Pg. 20, Para 0321.)
Regarding Claims 32-36 and 41, Cai and Tian teach a therapeutic method comprising administering to a mammal an effective amount of a compound of Formula III, or a pharmaceutically acceptable salt or prodrug thereof, wherein said therapeutic method is useful for the treatment of diseases related with kinase, especially Weel kinase, such as cancer. Such diseases that can be treated or prevented by the method or pharmaceutical composition of the present disclosure include, but are not limited to, liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, head and neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, and prostatic carcinoma (‘984, Pg. 20, Para 0317.)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to select an exemplified compound of Cai and Tian and modify it. The prior art teaches a genus of compounds sharing a common core scaffold and therapeutic application and exemplifies multiple compounds exhibiting overlapping substituent patterns at corresponding positions. Such teachings would have motivated a person of ordinary skill in the art to modify exemplified compounds through routine, single-steps substitutions, including methylation, demethylation, or halogen substitution, as part of ordinary medicinal chemistry optimization. Additionally, the overlapping substitution patterns observed across Cai and Tian’s exemplified compounds with similar biological activity – wherein overlapping Ar1 and Ar2 differ primarily in the presence or absence of hydrogen, methyl, or halogen substituents – demonstrate that such positional and functional group changes were conventional optimization strategies recognized in the art and expressly taught by Cai and Tian. One would have had a reasonable expectation of success from these conservative modifications, as one skilled in the art would have anticipated that replacement among these commonly interchanged substituents at the same or analogous positions would yield compounds exhibiting comparable inhibitory potency and therapeutic profiles against the same class of diseases.
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 2, 4, 24-28, 32-36, and 40-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1-4, 6-15, and 17-18 of U.S. Patent No. 10,703,759.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claimed compounds, compositions, and methods of use are suggested and/or exemplified within the patent and are therefore anticipated or an obvious variation of the reference claims.
Instant Formulas Ia and Ib are fully encompassed by the broader genus formulas of Patent ‘759, to include the subgenus Formula III (‘759, Claim 10), wherein Ar1 is a phenyl substituted with two halogens, and Ar2 is a substituted phenyl of which the substituents are selected from: halo or a C1-C6 alkyl, which is substituted by one piperazinyl or one piperidinyl, and the piperazinyl or piperidinyl are optionally substituted by 1-3 substituents selected from C1-C4 alkyl.
Claims 2, 4, 24-28, 32-36, and 40-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1-7 and 10-13 of U.S. Patent No. 11,345,711.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claimed methods and the compounds upon which they rely are suggested and/or exemplified within the patent and are therefore anticipated or an obvious variation of the reference claims.
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Patent ‘711 teaches a method for treating Wee1-mediated disease in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula I or a pharmaceutically acceptable salt thereof, combined with an effective amount of at least one known anticancer agent, or a pharmaceutically acceptable salt of the said anticancer agent (shown to the right), wherein A is N, R1 is an optionally substituted aryl (phenyl), R2 is an optionally substituted aryl (phenyl), and R3-R7 are independently H, wherein the disease can be liver cancer, and wherein the anticancer agent can be busulfan.
Instant Formulas Ia and Ib are fully encompassed by the broader genus formulas of Patent ‘759, to include the subgenus Formula III (‘759, Claim 7), wherein Ar1 is a phenyl substituted with two halogens, and Ar2 is a substituted phenyl of which the substituents are selected from: halo or a C1-C6 alkyl, which is substituted by one piperazinyl or one piperidinyl, and the piperazinyl or piperidinyl are optionally substituted by 1-3 substituents selected from C1-C4 alkyl.
Claims 2, 4, 24-28, 32-36, and 40-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1-4, and 6-20 of U.S. Patent No. 11,345,710 in view of Meanwell (J. Med. Chem. 2011, 54, 2529–2591, of previous record.)
Although the claims at issue are not identical, they are not patentably distinct from each other because the claimed compounds and methods of use are an obvious variation of the Patented claims.
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Patent ‘710 teaches Formula I (‘710, Col 70, Claim 1), shown top right, wherein A is N, R1 is an optionally substituted C6-C14 aryl (phenyl), R3-R5 are independently H, and R2 is an optionally substituted C6-C14 aryl (phenyl).
This differs from the instantly claimed Formulas Ia and Ib by the placement of the N atoms on the tricyclic rings.
However, Meanwell specifically teaches the tactical application of N for C substitution in dihydropyridine derivatives (Meanwell, Pg. 2543, §3.3.3.)
Additionally, Patent ‘710 teaches R1 is AR1, wherein AR1 is
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, R2 is AR2, wherein AR2 is
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(’710, Claims 1-4, and 6-18.) Furthermore Patent ‘710 teaches a pharmaceutical composition of the compound and a pharmaceutically acceptable carrier (as in instant Claim 14), further comprising an anticancer agent such as busulfan (as in instant Claims 15-16) capable of treating Wee1 mediated cancers, such as liver cancer (as in instant Claim 19-23.)
It would have been prima facie obvious to one of ordinary skill in the art to substitute a nitrogen atom for a carbon atom in the tricyclic rings of the Patented Formula I, as such substitutions are routine bioisosteric modifications used to modulate pharmacokinetic or binding properties without altering the fundamental scaffold, as taught by Meanwell.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 Donna M. Nestor whose telephone number is (703)756-5316. The examiner can normally be reached generally (w/flex): 5:30a-5p EST M-Th.
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/D.M.N./ Examiner, Art Unit 1627
/Kortney L. Klinkel/ Supervisory Patent Examiner, Art Unit 1627