DERIVATIVES OF 2-OXO-N-(4-(PYRIMIDIN-4-YLOXY/THIO)PHENYL)-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE FOR USE AS PROTEIN KINASE INHIBITORS FOR THERAPY

§103 §112

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 . Status of the Claims Claims 1-2, 6-7, 10, 12-13, 15-17, 19, 21-23, and 25-26 are pending in this application. Claims 3-5, 8-9, 11, 14, 18, 20, and 24 have been cancelled by applicants. Claims 1-2, 6-7, 10, 12-13, 15-17, 21, and 25-26 are under examination herein. Claims 19 and 22-23 remain withdrawn from consideration. 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 1-2, 6, 12-13, 15-17, 21, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Traoré et al. (Eur. J. Med. Chem. 70, 2013, 789-801 – From IDS – previously cited) (“Traoré”). Regarding claims 1-2, 6, 12-13, 15-17, and 25, Traoré discloses the compound below, which reads on the instant compounds when R1 is H; R2 is amino; R3 is chloro (halo); R4 is F (reading on new claim 25); R5-7 are all H; R8 is -OEt; R9-10 are H; and R11 is p-F-Ph (reading on R14 being F and R11 being phenyl-R14) – the compound below is also not one of the compounds in the proviso of claim 1 (Table 1, row 1). PNG media_image1.png 311 465 media_image1.png Greyscale Traoré discloses this compound as a potent inhibitor of different kinases – see below, taken from Table 1. PNG media_image2.png 321 910 media_image2.png Greyscale These results are comparable to the instantly disclosed activities for related compound 2 (see below, taken from Table 2 of the specification, page 36) – It is noted that the instant table shows “%Residual enzymatic activity at 1 µM”, while Traoré discloses “%inhibition at 0.5, 1, and 75 µM” – thus, for a direct comparison, only inhibitions at 1 µM from Traoré were considered. PNG media_image3.png 131 427 media_image3.png Greyscale PNG media_image4.png 97 231 media_image4.png Greyscale While Traoré does not specifically disclose the instant compound 2 (with a pyrimidine instead of a pyridine), Traoré discloses a study aimed at exploring the effects of the position of the amino group in BMS-777607 and specifically teaches replacement of the pyridine in BMS-777607 with pyrimidines substituted at 2 and 6 respectively (page 791, col. 1, and Scheme 3), and specifically teaches that substitution of the pyridine ring by a pyrimidine ring seems to increase the specificity towards the four proteins of the HGFR/TAM family (page 792, col. 1, para. 1). Therefore, regarding claims 1-2, 6, 12-13, 15-17, and 25, one having ordinary skill in the art would have found the claimed compounds prima facie obvious, in view of Traoré’s disclosure of their TAM inhibitors, including BMS-777607, and structure-activity-relationship studies. One of ordinary skill would have been motivated to prepare the claimed compounds because Traoré teaches BMS-777607 as a highly active inhibitor of Tyro3, Axl, Mer, and Met, and their disclosure that substitution of BMS-777607’s pyridine for a pyrimidine resulted in increased specificity towards the 4 proteins in the HGFR/TAM family. Therefore, one of ordinary skill would have been motivated to replace the pyridine in BMS-777607 with a pyrimidine to arrive at the instant invention, with a reasonable expectation of success. Further regarding claim 17, the compound 2 below is particularly obvious in view of Traoré. PNG media_image5.png 55 637 media_image5.png Greyscale Regarding claim 21, Traoré discloses their kinase assays were conducted in DMSO (section 4.2, page 800). Claims 7, 10, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Traoré et al. (Eur. J. Med. Chem. 70, 2013, 789-801 – From IDS – previously cited) (“Traoré”); as applied to claims 1-2, 6, 12-13, 15-17, 21, and 25; in view of Morita et al. (Obtained From gousei.f.u-tokyo.ac.jp [Retrieved on September 11th, 2025] <URL: https://gousei.f.u-tokyo.ac.jp/seminar/index.html#2012> - Published May 2012 – previously cited) (“Morita”). The teachings of Traoré are disclosed above and incorporated herein. While Traoré doesn’t specifically teach their compounds wherein the groups corresponding to instant R5 or R6 are F or wherein instant R4 is H (as required by claims 7, 10, and/or 26); the teachings of Morita are relied upon for these disclosures. Morita teaches bioisosteres to introduce structural changes that can be beneficial in the development of lead compounds by allowing modulation of size, shape, lipophilicity, and polarity of compounds, among other variables, which may result in improvements in potency, selectivity, toxicity, and metabolism (page 3, bottom section). Morita further discloses -H and -F as monovalent bioisosteres; and that -F and -Me are also monovalent bioisosteres. Therefore, regarding instant claims 7, 10, and 26, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to swap the H in the position corresponding to instant R5 or R6 for an F, and the F in the position corresponding to instant R4 for an H in Traoré’s compound BMS-777607, in view of Morita, to arrive at the instant invention. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Traoré discloses their compound BMS-777607 above as a potent inhibitors of TAM kinases for the treatment of cancer (see page 789, col. 1), which is the same intended use as the instantly claimed invention; further because Morita teaches H for F replacements are obvious, given the fact that H and F are monovalent bioisosteres. One would have been further motivated, with a reasonable expectation of success, in view of Morita’s teachings that bioisosteres introduce structural changes that can be beneficial for improvements in potency, selectivity, toxicity, and metabolism of drugs. Response to Arguments Claims Claim amendments are acknowledged and have been entered. No new matter has been added. Claim Rejections - 35 USC § 112(b) In view of claim amendments, 35 USC § 112(b) rejections have been withdrawn. Claim Rejections - 35 USC § 103 and Affidavit Applicant’s arguments filed 09/08/2026 have been fully considered but they are not persuasive. Applicant’s arguments in the response filed 09/08/2026 and those cited in the Affidavit filed 09/08/2026 are more or less all the same, and therefore, these arguments have all been addressed herein. As an initial matter, The Affidavit under 37 CFR 1.132 filed 09/08/2026 is insufficient to overcome the rejections of record as set forth in the last Office action. The reasons are outlined below. Applicant states the claimed compounds do not encompass BMS-777607 (a thing which was never alleged by examiner – see rejections herein). Applicant states Traore does not direct reader to redesign its compounds to obtain a particular activity against TAM kinases and does not identify a deficiency that would be addressed by replacing pyridine with pyrimidine or suggest any substitution on pyridine as advantageous. Applicant asserts the motivation to swap H for F or Cl is allegedly born out of a desire to modify the interaction of a drug with its target, and that Traore provides no motivation for such a modification. Applicant states that Traore says the ring linked to the pyrimidine ring, the presence or absence of F has no bearing on activity (page 792, para. 2) – this is not an accurate interpretation, see the actual statement from Traore below: PNG media_image6.png 215 587 media_image6.png Greyscale PNG media_image7.png 182 255 media_image7.png Greyscale PNG media_image8.png 335 550 media_image8.png Greyscale (13d) PNG media_image9.png 142 266 media_image9.png Greyscale As we can see from Traore’s statement, the presence of the Fluorine may not be crucial for inhibitory activity, however, it is also not detrimental and one of ordinary skill would understand that such a change may be beneficial for optimization of other pharmacokinetic properties, such as lipophilicity, blocking metabolism, etc., as admitted by Applicant in para. 3, page 8 of arguments and in the Affidavit filed. Applicant argues instant compound 2 has a Cl at R3, not an F or an H, and states there’s no discussion in Traore that this change would be useful – To this, applicant is advised Examiner never suggested this change of Cl for F or H, and thus this argument has no weight in overcoming the obviousness rejections of record. Traore’s compound BMS-777607 (disclosed herein) also has a Cl at the position corresponding to instant R3. Applicant states the following: PNG media_image10.png 212 637 media_image10.png Greyscale PNG media_image11.png 398 347 media_image11.png Greyscale PNG media_image12.png 271 633 media_image12.png Greyscale The specific argument regarding the presence of ethoxy has been removed from the rejections presented herein, however, claims still stand rejected over the prior art of record. It is noted that the courts have stated “[A] prior art reference must be considered in its entirety, i.e., as a whole” W.L. Gore& Associates, Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983) (see MPEP 2141.02 VI).  Thus, while the rejections listed above present a modified interpretation of the teachings of the previously cited prior solely for the purpose of clarity, the claims remain rejected over the prior art of record. Applicant’s argument that one of ordinary skill would have just as well elected compound 2 since compounds 13a, 13c-d, 21, and 23 allegedly showed lower inhibition than BMS-777607 - as clearly stated in the non-final rejection filed 05/08/2026 - Traoré dislcoses a study aimed at exploring the effects of the position of the amino group in BMS-777607 and specifically teaches replacement of the pyridine in BMS-777607 with pyrimidines substituted at 2 and 6 respectively (page 791, col. 1, and Scheme 3), and specifically teaches that substitution of the pyridine ring by a pyrimidine ring seems to increase the specificity towards the four proteins of the HGFR/TAM family (page 792, col. 1, para. 1). Thus, while Traore provides motivation for electing compound 2, as stated by Applicant, Traore also provides motivation for electing BMS-777607 and replacing the pyridine for a pyrimidine, as stated in the rejections presented herein, (see page 792, col. 1). PNG media_image13.png 145 591 media_image13.png Greyscale Applicant is advised, per MPEP 2123 (I): “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. "The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.").” Applicant states Morita presents general educational concepts rather than compound specific experimental guidance and repeats that Traore does not provide guidance or motivation for replacing H for F. Applicant reinstates that Traore teaches the presence of F did not affect activity, comparing compounds 23 to 13d. As previously stated, fluorination is also not detrimental and one of ordinary skill would understand that such a change may be beneficial for optimization of other pharmacokinetic properties, such as lipophilicity, blocking metabolism, etc., as admitted by applicant in para. 2, page 13 of arguments and in the Affidavit. Applicant states the following: PNG media_image14.png 190 642 media_image14.png Greyscale Applicant admits, once again, that the importance of fluorination goes beyond optimizing activity. In response to Applicant’s argument that fluorination will not provide predictable or universal improvement, Applicant is advised, per MPEP 2143.02 (I): “Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")).” 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 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 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, Traoré discloses the compound below, which reads on the instant compounds when R1 is H; R2 is amino; R3 is chloro (halo); R4 is F (reading on new claim 25); R5-7 are all H; R8 is -OEt; R9-10 are H; and R11 is p-F-Ph (reading on R14 being F and R11 being phenyl-R14) – the compound below is also not one of the compounds in the proviso of claim 1 (Table 1, row 1). PNG media_image1.png 311 465 media_image1.png Greyscale Traoré discloses this compound as a potent inhibitor of different kinases – see below, taken from Table 1. PNG media_image2.png 321 910 media_image2.png Greyscale These results are comparable to the instantly disclosed activities for claimed compound 2 (see below, taken from Table 2 of the specification, page 36) – It is noted that the instant table shows “%Residual enzymatic activity at 1 µM”, while Traoré discloses “%inhibition at 0.5, 1, and 75 µM” – thus, for a direct comparison, only inhibitions at 1 µM from Traoré were considered. PNG media_image3.png 131 427 media_image3.png Greyscale PNG media_image4.png 97 231 media_image4.png Greyscale While Traoré does not specifically disclose the instant compound 2 (with a pyrimidine instead of a pyridine), Traoré discloses a study aimed at exploring the effects of the position of the amino group in BMS-777607 and specifically teaches replacement of the pyridine in BMS-777607 with pyrimidines substituted at 2 and 6 respectively (page 791, col. 1, and Scheme 3), and specifically teaches that substitution of the pyridine ring by a pyrimidine ring seems to increase the specificity towards the four proteins of the HGFR/TAM family (page 792, col. 1, para. 1) – thus providing clear motivation for one of ordinary skill to make this substitution. Therefore, one having ordinary skill in the art would have found the claimed compounds prima facie obvious, in view of Traoré’s disclosure of their inhibitors, including BMS-777607, and structure-activity-relationship studies. One of ordinary skill would have been motivated to prepare the claimed compounds because Traoré teaches BMS-777607 as a highly active inhibitor of Tyro3, Axl, Mer, and Met, and their disclosure that substitution of BMS-777607’s pyridine for a pyrimidine resulted in increased specificity towards the 4 proteins in the HGFR/TAM family. Therefore, one of ordinary skill would have been motivated to replace the pyridine in BMS-777607 with a pyrimidine to arrive at the instant invention, with a reasonable expectation of success. Furthermore, Morita teaches bioisosteres to introduce structural changes that can be beneficial in the development of lead compounds by allowing modulation of size, shape, lipophilicity, and polarity of compounds, among other variables, which may result in improvements in potency, selectivity, toxicity, and metabolism (page 3, bottom section). Morita further discloses -H and -F as monovalent bioisosteres; and that -F and -Me are also monovalent bioisosteres. Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to swap the H in the position corresponding to instant R5 or R6 for an F, and the F in the position corresponding to instant R4 for an H in Traoré’s compound BMS-777607, in view of Morita, to arrive at the instant invention. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Traoré discloses their compound BMS-777607 above as a potent inhibitors of TAM kinases for the treatment of cancer (see page 789, col. 1), which is the same intended use as the instantly claimed invention; further because Morita teaches H for F replacements are obvious, given the fact that H and F are monovalent bioisosteres. One would have been further motivated, with a reasonable expectation of success, in view of Morita’s teachings that bioisosteres introduce structural changes that can be beneficial for improvements in potency, selectivity, toxicity, and metabolism of drugs. In response to Applicant’s argument that Traore does not direct reader to redesign its compounds to obtain a particular activity against TAM kinases and does not identify a deficiency that would be addressed by replacing pyridine with pyrimidine or suggest any substitution on pyridine as advantageous, Traore specifically states: substitution of the pyridine ring by a pyrimidine ring seems to increase the specificity towards the four proteins of the HGFR/TAM family (page 792, col. 1, para. 1). Furthermore, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Applicant's arguments do not comply with 37 CFR 1.111(c) because they do not clearly point out the patentable novelty which he or she thinks the claims present in view of the state of the art disclosed by the references cited or the objections made. Further, they do not show how the amendments avoid such references or objections. Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references. In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness. Conclusion 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 JACKSON J HERNANDEZ whose telephone number is (571)272-5382. The examiner can normally be reached Mon - Thurs 7:30 to 5. 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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. /JACKSON J HERNANDEZ/Examiner, Art Unit 1627 /SARAH PIHONAK/Primary Examiner, Art Unit 1627