FUSED TRICYCLIC COMPOUNDS AS INHIBITORS OF KRAS G12V MUTANTS

§103 §DOUBLEPATENT

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 The present applications claimed priority to the applications, 63/368,124 and 63/496,840, with effective filing dates of 11 July 2022 and 18 April 2023, respectively. Claim Status This Office Action is in response to Applicant’s Amendment filed, 10 July 2026, wherein Applicant amended claims 1-2 and 4. Claims 35-52 and 55-60 were previously canceled. Applicant previously elected Group I (claims 1-34 and 53-54) and species ( PNG media_image1.png 194 188 media_image1.png Greyscale ). Claims 2, 4, 6-7, 9-11, 14, 16, 18-19, 22, 25-26, 28, 30, and 32-33 were withdrawn as they were directed to a nonelected species. Claims 1, 3, 5, 8, 12-13, 15, 17, 20-21, 23-24, 27, 29, 31, 34, and 53-54 are under consideration in the instant office action. Rejections Maintained/New Claim Rejections – 35 U.S.C. § 103 1. (Maintained) Claims 1, 3, 5, 8, 12-13, 15, 17, 20-21, 23-24, 27, 29, 31, 34, and 53-54 were rejected as being unpatentable under 35 U.S.C. 103 over Zhu (WO 2021/211864, published 21 Oct 2021, filed 15 Apr 2021, see IDS filed 26 Mar 2026) in view of Lanman (J. Med. Chem., 2020, 63, 52- 65; of record, see PTO-892 mailed 13 April 2026) and Petri (Topics in Current Chemistry, 2021, 379(34), 1-46; of record, see PTO-892 mailed 13 April 2026). Applicant’s arguments, see pages 13-16, have been fully considered but they are not persuasive. Applicant argues that Lanman fails to provide the necessary teachings to modify the compounds of Zhu to arrive at the instantly claimed compounds, because the compounds of Lanman are structurally distinct from the claimed compounds and that a person having ordinary skill in the art would fail to select how to modify the compounds of Zhou. Additionally, Applicant argues that Lanman teaches how to optimize compounds that selectively inhibit KRAS harboring a G12C mutation, while the present claims are inhibitors of KRAS harboring a G12D or G12V mutation. Applicant further argues that Petri fails to cure the structural and biological deficiencies of Lanman and that Petri fails to suggest that pyrrolidine can be beneficial in targeting KRAS G12D or G12V mutations nor where to modify the compounds. Applicant further asserts that the references to Zhu, Lanman, and Petri were random, unguided selections that relied on impermissible hindsight as the Examiner did not provide a reasonable explanation as to why the skilled artisan would 1) select those particular compounds in Zhu and 2) select the particular functional groups on those particular compounds for further modification. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., that the compounds only have KRAS G12D and KRAS G12V activity and not KRAS G12C activity) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, one of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because: -Zhu teaches KRAS inhibitors of Formula (I): PNG media_image2.png 206 154 media_image2.png Greyscale , -Zhu teaches Example 48: PNG media_image3.png 240 189 media_image3.png Greyscale , -Zhu teaches Example 48 possesses an IC50 of ≤ 100 nM (Table 2, page 269), -Zhu teaches Examples 50 and 67: PNG media_image4.png 265 284 media_image4.png Greyscale and PNG media_image5.png 214 272 media_image5.png Greyscale , -Zhu teaches Examples 50 and 67 possess an IC50 of ≤ 100 nM (Tables 1 and 2, pages 266-269), -Zhu teaches that Example 67 has KRAS G12C potency but that Examples 48 and 50 both had excellent potency against KRAS G12D and G12V mutations (Tables 1 and 2, pages 266-269), -Zhu teaches that the KRAS mutations predominate in different cancers: G12D predominate in pancreatic cancers, colorectal adenocarcinoma, and lung cancers; G12V are associated with pancreatic cancers, colorectal adenocarcinoma, and lung adenocarcinoma; and G12C predominate in non-small cell lung cancer (page 1, lines 32-37), -Lanman teaches the KRAS inhibitor, PNG media_image6.png 134 195 media_image6.png Greyscale , and its SAR, -Lanman teaches derivatives of AMG 510, wherein the fluorophenol tail is replaced with a naphthyl alcohol and indazole in order to optimize contact with lipophilic residues (V9 and I100) and modulate polar interactions with R68 and D69, -Lanman teaches that both substituents did show enhanced activity in ERK phosphorylation and viability assays, but the analogs continued to demonstrate poor aqueous solubility and low MDCK permeability, -Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99, -Petri teaches motivations to utilize pyrrolidine: efficient exploration of pharmacophore space due to sp3-hybridization, contribution to stereochemistry of the molecule, and increased three-dimensional coverage due to non-planarity of the ring, -Petri teaches that chemical complexity and globular three-dimensional shape offer more opportunities to improve druggability by modifying parameters such as solubility, lipophilicity, and other ADME properties, and -Petri teaches that molecules with growing hetero-aliphatic character showed an increase in aqueous solubility compared with those comprising three aromatic rings and that each portion of molecules influences the balance of the physicochemical parameters. As such, a person or ordinary skill would have been motivated to combine the selected teachings to predictably arrive at PNG media_image7.png 168 179 media_image7.png Greyscale . 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). Thus, the rejection of claims 1, 3, 5, 8, 12-13, 15, 17, 20-21, 23-24, 27, 29, 31, 34, and 53-54 over Zhu in view of Lanman and Petri is maintained. 2. (Maintained) Claims 1, 3, 5, 8, 12-13, 15, 17, 20-21, 23-24, 27, 29, 31, 34, and 53-54 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 37, and 42 of copending Application No. 19/242,281 in view of Lanman (J. Med. Chem., 2020, 63, 52- 65; of record, see PTO-892 mailed 13 April 2026) and Petri (Topics in Current Chemistry, 2021, 379(34), 1-46; of record, see PTO-892 mailed 13 April 2026). Applicant’s arguments, see pages 16-17, have been fully considered but they are not persuasive. Applicant argues that Lanman fails to provide the necessary teachings to modify the compound of ‘281 to arrive at the instantly claimed compounds, because the compounds of Lanman are structurally distinct from the claimed compounds and that a person having ordinary skill in the art would fail to select how to modify the compound of ‘281. Additionally, Applicant argues that Lanman teaches how to optimize compounds that selectively inhibit KRAS harboring a G12C mutation, while the present claims are inhibitors of KRAS harboring a G12D or G12V mutation. Applicant further argues that Petri fails to cure the structural and biological deficiencies of Lanman and that Petri fails to suggest that pyrrolidine can be beneficial in targeting KRAS G12D or G12V mutations nor where to modify the compounds. Applicant further asserts that the references to ‘281, Lanman, and Petri were random, unguided selection that there was no reasonable expectation of success in combining the compound of ‘281, Lanman, and Petri. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., that the compounds only have KRAS G12D and KRAS G12V activity and not KRAS G12C activity) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, one of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because: -‘281 claims a method of treating a KRAS disease (claim 43 of ‘281), -‘281 claims the compound: PNG media_image8.png 243 237 media_image8.png Greyscale (claim 37 of ‘281), -Lanman teaches the KRAS inhibitor, PNG media_image6.png 134 195 media_image6.png Greyscale , and its SAR, -Lanman teaches derivatives of AMG 510, wherein the fluorophenol tail is replaced with a naphthyl alcohol and indazole in order to optimize contact with lipophilic residues (V9 and I100) and modulate polar interactions with R68 and D69, -Lanman teaches that both substituents did show enhanced activity in ERK phosphorylation and viability assays, but the analogs continued to demonstrate poor aqueous solubility and low MDCK permeability, -Lanman teaches optimization of the binding in the H95 groove: the isopropyl of Compound 9 has close contact with Y96, H95, and Q99, -Petri teaches motivations to utilize pyrrolidine: efficient exploration of pharmacophore space due to sp3-hybridization, contribution to stereochemistry of the molecule, and increased three-dimensional coverage due to non-planarity of the ring, -Petri teaches that chemical complexity and globular three-dimensional shape offer more opportunities to improve druggability by modifying parameters such as solubility, lipophilicity, and other ADME properties, and -Petri teaches that molecules with growing hetero-aliphatic character showed an increase in aqueous solubility compared with those comprising three aromatic rings and that each portion of molecules influences the balance of the physicochemical parameters. As such, a person or ordinary skill would have been motivated to combine the selected teachings to predictably arrive at PNG media_image7.png 168 179 media_image7.png Greyscale . 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). Thus, the rejection of claims 1, 3, 5, 8, 12-13, 15, 17, 20-21, 23-24, 27, 29, 31, 34, and 53-54 over ‘281 in view of Lanman and Petri is maintained. Conclusion No claim is 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 Madeline M Dekarske whose telephone number is (571)272-1789. 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Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /MADELINE M. DEKARSKE/Examiner, Art Unit 1622 /JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622