MUTANT IDH1 AND IDH2 INHIBITOR AND APPLICATION THEREOF

§103 §DOUBLEPATENT

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 The instant application, filed 09/13/2024, is a national stage entry of PCT/CN2023/081225, filed 03/14/2023, which claims priority to Chinese Patent Application No. CN202210252930.0, filed on 03/15/2022. Receipt is acknowledged of certified copies of papers required by 37 CFR § 1.55. No certified translation of the priority application, CN202210252930.0, has been received. Status of Claims Claims 1-41 were originally presented on 09/13/2024. The preliminary amendments to the claims also received on 09/13/2024 are acknowledged and entered. Claims 1, 9-11, 13-15, 29-30, 37, and 39-41 were amended, claims 8, 12, 16-28, and 31-36 were cancelled, and claims 42-43 were added. Accordingly, claims 1, 9-11, 13-15, 29-30, and 37-43 are pending. Information Disclosure Statement The Information Disclosure Statement received on 09/13/2024 is acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the Information Disclosure Statement has been considered. Specification Objections The disclosure is objected to because of the following informalities: numerous reaction schemes in the Specification are blurry. See, e.g., Specification at 27, Example 1 (first scheme), at 28 (all schemes), at 29 (Step 2), at 30 (first scheme), at 31, at 32 (top scheme), at 33 (top schemes), at 37, at 38 (all schemes), at 41, at 42 (top and middle schemes), at 43 (bottom scheme). The blurry schemes need to be replaced so that they are clear like the other chemical structures and schemes present in the Specification. For example, this structure in the Specification at 3 is clear: PNG media_image1.png 194 114 media_image1.png Greyscale , whereas this structure at 27 PNG media_image2.png 78 69 media_image2.png Greyscale is not. Appropriate correction is required. Claim Objections Claim 29 objected to because of the following informalities: Claim 29 recites the following compound: PNG media_image3.png 83 891 media_image3.png Greyscale The large gap in the chemical name is improper and needs to be removed. There is likely an extra space between “yl)” and “-N2” that may simply be deleted. Appropriate correction is required. 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. 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 1, 9-11, 13-15, 29-30, and 37-43 Obvious over US’895 in view of Patani 1996 and Luo 2012 Claim(s) 1, 9-11, 13-15, 29-30, and 37-43 is/are rejected under 35 U.S.C. 103 as being unpatentable over US’8951 in view of Patani 19962 and Luo 2012.3 Applicant purports to have developed a series of formula (VIb) compounds that serve as isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) inhibitors, and that these compounds find therapeutic applicant in certain cancer treatments (Specification, pages 1-3). Applicant claims one of its compounds has increased solubility compared to a related analog (Specification at 50). Structures of formula (VIb) and one of its embodiments, the instant Example 5, are shown below. The instant Example 5 is encompassed by claims 1, 9, 10, 13-15, 29-30, and 37-43. PNG media_image4.png 248 177 media_image4.png Greyscale Instant formula (VIb) Instant PNG media_image5.png 410 289 media_image5.png Greyscale Similar to instant claims, US’895 at col. 2, teaches a class of compounds which are closely related to the claimed genus of compounds and certain claimed species. US’895 also teaches that these compounds have inhibitory activity towards IDH 1 and 2: PNG media_image6.png 410 427 media_image6.png Greyscale A preferred embodiment of US’895 is the active pharmaceutical ingredient (“API”) known as vorasidenib, shown below (biological data appears in US’895 Tables 4-5 at cols. 471 and 481): PNG media_image7.png 154 220 media_image7.png Greyscale Compound 101 of US’895, or AG-881, or vorasidenib Applicant’s Example 5 compound (also captured by claim 6 of US’895) is a structural analog of vorasidenib, with the only structural difference being the adjacent: 1) primary amine and 2) fluorine groups attached through the pyridine structural feature: PNG media_image8.png 294 360 media_image8.png Greyscale Vorasidenib, or compound 101 of US’895 PNG media_image9.png 293 369 media_image9.png Greyscale Instant Example 5 Although US’895 does not specifically exemplify a compound with a pyridine moiety having F and NH2 groups in Applicant’s claimed configuration, one of ordinary skill in the art would have had a reasonable expectation of success in selecting these groups as substitutes for the H of vorasidenib because both F and NH2 are well-known bioisosteres of hydrogen. For example, see each of US’895 and Patani 1996, which teach this finding. Further, see Luo 2012, discussed below, which teaches that bioisosteric replacement of H with a primary amine was commonly used to increase the solubility of an API. US’895 teaches a core feature similar to Applicant’s described above with a variable genus feature, captures certain breadth in claim 1, and clearly identifies each of F and NH2 off of the pyridine ring: PNG media_image10.png 354 408 media_image10.png Greyscale … PNG media_image11.png 163 408 media_image11.png Greyscale …. US’895 claim 6 therefore provided a clear suggestion of Applicant’s example 5 compound. There was a small genus of variable groups suitable as replacements for this sub-genus that encompasses vorasidenib. Patani 1996 Patani 1996 has been cited thousands of times by numerous authors for its review of “Bioisosterism: A Rational Approach in Drug Design”. See Patani 1996 at Title. On the first page, it explains that “Bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents.” Patani 1996 at 3147. The approach was considered “intuitive”, id., and had its roots back to 1919, id. at 3148. Bioisosteres are “Compounds or groups that possess near-equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties...”. Id. “The critical component for bioisosterism is that bioisosteres affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other.” Id. “Bioisosteres have been classified as either classical or nonclassical.” Patani 1996 at 3148. One such group of classical bioisosteres were those “according to Grimm”, see id. at Table 2 and surrounding text (fourth column shows the F, NH2, and H exchange): PNG media_image12.png 439 571 media_image12.png Greyscale Patani 1996 at 3148, Table 2. First, regarding the bioisosteric H and F exchange, see Patani 1996 at 3149 (“The substitution of hydrogen by fluorine is one of the more commonly employed monovalent isosteric replacements.”). Patani 1996 at 3152-3154 teaches the “Fluorine and Hydroxyl, Amino, or Methyl Groups as Replacements for Hydrogen (Grimm's Hydride Displacement Law)” and its applications (emphasis added). “This monovalent group of isosteres is a result of the direct adaptation of Grimm's Hydride Displacement Law.” Id. Several classic examples were provided. See, e.g., id. at 3152, which remarks in discussing Figure 11,Table 9, that “Substitution with isosteres (−F, −OH, −NH2) as described by Grimm's Hydride Displacement Law (Table 2) resulted in retention of activity.” Note that CF3 was another known bioisosteric replacement for H. See, e.g., id. at 3152 (“CF3 (a bioisostere for a methyl group based on the replacement of hydrogen with fluorine)”). Accordingly, the exchange of H with F and NH2 results in bioisosteres, that by definition, affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other. Luo 2012 Luo 2012 teaches an example of where bioisosteric replacement of H with a primary amine, NH2, resulted in a significant increase in the solubility of a lead compound. In particular, it teaches the development of the API known as BMS-927711, or rimegepant. During the development of rimegepant, its inventors had issues with the solubility of an initial hit designated BMS-846372, which the article designates compound 5. Compound 5 “was highly crystalline with very low aqueous solubility”, Luo 2012 at 10644. See compound 5: PNG media_image13.png 247 264 media_image13.png Greyscale See Luo 2012 at 10645: We realized that one way to increase the aqueous solubility of an organic molecule was to add hydrophilic groups. We hypothesized that the addition of small, polar groups such as OH or NH2 would provide “helpful polarity,” improving the solubility while maintaining the attractive properties of 5. In this vein, two target alcohols, 6 and 7 (Figure 2), were prepared. to test this hypothesis. These more polar analogues of 5 (6 and 7) maintained their potency as CGRP receptor antagonists, and this encouraged us to make the primary amine analogue 8 (Figure 2). A primary amine would also allow salt formation that might not facilitate decomposition of the carbamate linker. Luo 2012 at 10645. See Luo 2012 at 10645 at Figure 2 (compound 8 is rimegepant, a drug that was approved by FDA for migraines. The bioisosteric replacement of H with a primary amine is shown on the cycloheptane ring, compared to compound 5 above): PNG media_image14.png 304 698 media_image14.png Greyscale Luo 2012 at 10645, Figure 2. See Luo 2012 at 10648: The presence of a primary amino group greatly improved aqueous solubility without compromising bilayer permeability, resulting in enhanced ADME properties. Luo 2012 at 10648. The instant example 5 compound was obvious at the time of filing Accordingly, although US’895 does not specifically exemplify a compound with a pyridine moiety having F and NH2 groups in Applicant’s claimed configuration, one of ordinary skill in the art would have had a reasonable expectation of success in selecting these groups as substitutes for the H of vorasidenib because both F and NH2 are well-known bioisosteres of hydrogen. These adjustments were considered “intuitive” to ordinary chemists at the time of filing, and US’895 claim 6 itself suggested the structure of the instant Example 5 compound. Further, as a result of incorporating a primary amine, the person of ordinary skill in the art at the time of filing had a reasonable expectation that solubility would increase relative to vorasidenib. PNG media_image8.png 294 360 media_image8.png Greyscale Vorasidenib, or compound 101 of US’895 PNG media_image9.png 293 369 media_image9.png Greyscale Instant Example 5 Compound claims 1, 9-10, 13-15, and 29 encompass the instant Example 5 compound. Therefore, claims 1, 9-10, 13-15, and 29 were obvious at the time of filing. The example 14 compound was obvious at the time of filing The instant Example compound 14 is encompassed by claims 1, 9, 11, 13-15, 29-30, and 37-43. It is a bioisostere of another well-known API, AG-15056, or compound 2 of US’895. PNG media_image15.png 238 327 media_image15.png Greyscale US’895 at col. 58, compound 2, or AG-15056 PNG media_image16.png 318 375 media_image16.png Greyscale Instant Example 14 The instant Example 14 compound shows the same bioisosteric replacements of F and NH2 for H as seen with the instant Example 5 compound and vorasidenib. The biological data for AG-15056 appears in US’895 at col. 470, Table 4. Like vorasidenib, it was effective against both IDH1 and IDH2: PNG media_image17.png 308 873 media_image17.png Greyscale AG-15056 was a compound of Formula B as taught in US’895 (same claim 6 Formula B) but was not specifically claimed in US’895. See US’895 at col. 44-45, Formula B, R2 and R5 options for -(C0 -C6 alkylene)-Q, Q is carbocyclyl. US’895 taught the same limited genus of compounds about the core nucleus of AG-15056. Indeed, US’895 teaches a structural activity relationship study (a “SAR study”, or just a “SAR”) about both IDH1 and IDH2. AG-15056 was an initial hit in its SAR study that led to the development of vorasidenib. Both compounds were effective APIs. Although US’895 does not specifically exemplify a compound with a pyridine moiety having F and NH2 groups in Applicant’s claimed configuration, one of ordinary skill in the art would have had a reasonable expectation of success in selecting these groups as substitutes for the H of AG-15056 because both F and NH2 are well-known bioisosteres of hydrogen. These adjustments were considered “intuitive” to ordinary chemists at the time of filing, and US’895 Formula B itself suggested the structure of instant Example 14 compound. Further, as a result of incorporating a primary amine, the person of ordinary skill in the art at the time of filing had a reasonable expectation that solubility would increase relative to AG-15056. Compound claims 1, 9, 11, 13-15, and 29 encompass the instant Example 14 compound. Therefore, claims 1, 9, 11, 13-15, and 29 were obvious at the time of filing. Claim 30 was obvious Regarding claim 30¸ drawn to pharmaceutical compositions including the Example 5 or 14 compounds and at least one excipient, US’895 teaches how to make pharmaceutical compositions of its compounds with pharmaceutically acceptable excipients beginning at col. 242. The instant example 5 and 14 compounds were encompassed by the scope of the general formula (B) compounds taught in US’895. Therefore, one of ordinary skill in the art at the time of filing would have had a reasonable expectation of success in following the teachings of US’895 for preparing the same compositions it taught. Accordingly, claim 30 was obvious at the time of filing. Claims 37-43 were obvious Regarding claims 37- 43, these claims are drawn to the intended use of the instant Example 5 compound and pharmaceutical compositions. Claims 37-43 all read on administering the instant Example 5 compound or pharmaceutical composition for treating Acute Myeloid Leukemia (AML), a human disease. US’895 at col. 247 explains the disease targets of its assays: PNG media_image18.png 384 419 media_image18.png Greyscale US’895 at col. 247. US’895 Tables 4-5 at cols. 471 and 481 teach vorasidenib’s indication for treating AML.4 PNG media_image19.png 154 400 media_image19.png Greyscale PNG media_image20.png 180 422 media_image20.png Greyscale Patani 1996 teaches that bioisosteres affect the same pharmacological targets as antagonists and thereby have related properties. Therefore, one of ordinary skill in the art at the time of filing would have had a reasonable expectation of success in administering the instant Example 5 compound, which was a bioisostere of vorasidenib, for treating AML, because there was a reasonable expectation that the instant Example 5 compound would affect the same pharmacological targets as vorasidenib in the same way. The same applies to the administration of the pharmaceutical composition comprising the compound. The therapeutically effective amount is a result effective variable that requires only ordinary and routine experimentation to determine. Varying the dosage administered changes the strength of the treatment regimen. This ordinary and routine experimentation was well within the skills of an ordinary chemist at the time of filing. Further, the instant Example 5 compound was a compound embraced by the limited chemical structures of US’895. US’895 teaches how to administer its compounds. See, e.g., US’895 at col. 244. PNG media_image21.png 133 342 media_image21.png Greyscale US’895 at col. 244. Therefore, claims 37-43 were obvious at the time of filing. 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. NSDP to US’383 Claims 1, 9, 10, 13, 14, 15, 29-30, and 37-43 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2-26, 27-28, and 29-33 of copending Application No. 19/520,383 (reference application, hereinafter “US’383”, or “the US’383 application”). Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of US’383 recites a salt or crystalline form of 6-(5-amino-6-chloro-4-fluoropyridin-2-yl)-N2,N4-bis((R)-1,1,1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine, which is the same compound recited specifically in instant claim 29: See claim 1 of US’383 below: PNG media_image22.png 274 543 media_image22.png Greyscale Claim 1 of US’383. This compound is recited specifically in instant claim 29. To confirm the chemical structure of the compound recited in the instant claim 29, see Instant Specification at 33-34, Example 5: PNG media_image23.png 65 740 media_image23.png Greyscale … PNG media_image24.png 194 152 media_image24.png Greyscale Instant Specification at 33-34. Claim 1 of US’383 anticipates instant compound claims 1, 9, 10, 13, 14, 15, and 29 that encompass this compound. Claims 2-26 of US’383 recite various salt and polymorphic forms of the same compound, all of which read on the instant compound claims 1, 9, 10, 13, 14, 15, and 29. Claims 27-28 of US’383 recite the same compound in pharmaceutical compositions. See claims 27-28 of US’383: PNG media_image25.png 368 575 media_image25.png Greyscale Claims 27-28 of US’383. Claims 27-28 of US’383 anticipate the instant claim 30, which encompasses a pharmaceutical composition containing this compound. Claims 29-33 of US’383 recite the indications and intended use of this compound – for treating the cancers recited in the instant claims 37-43. See claims 29-33 of US’383: PNG media_image26.png 119 540 media_image26.png Greyscale PNG media_image27.png 294 543 media_image27.png Greyscale Claims 29-33 of US’383. Claim 33 of US’383, for example, anticipates the instant claims 37-43, all of which encompass the method claim 33 of US’383 recites. In the event that the claims of the copending applications are amended in such a way that the claims of US’383 no longer anticipate the instant claims, the instant claims were nevertheless obvious over claims 1, 2-26, 27-28, and 29-33 of US’383. One of ordinary skill in the art at the time of filing the US’383 application, and in possession of its subject matter, would have a reasonable expectation of success in obtaining the subject matter of instant claims because US’383 specifically teaches pharmaceutically acceptable salt and crystal forms of the compounds instantly claimed, and how to use them in treating diseases such as cancers. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Prior Art Cited but not Applied The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure. US’1075 at col. 341, claims 4-9, teach methods of treating cancer characterized by the presence of an IDH2 mutation comprising administering the API known as enasidenib, which US’107 at col. 70 designates as compound 409: PNG media_image28.png 221 332 media_image28.png Greyscale Enasidenib, or compound 409 of US’107 Enasidenib was developed prior to the development of vorasidenib and AG-15056 by the same group of inventors at Agios Pharmaceuticals. Like US’895, US’107 teaches a SAR about IDHs, with IDH2 exemplified. Compounds disclosed were in the general formula I, which overlaps significantly with the compounds of US’895: PNG media_image29.png 187 277 media_image29.png Greyscale From US’107 alone, it was known that the IDH2 receptors were significantly inhibited when the aromatic cycle across from the triazine had a primary amine at the 4-position, as well as fluorine and chlorine at the 3,5-positions. Biological data appears in Table 2, beginning at col. 332. “A” means an IC50 of less than 100 nM: PNG media_image30.png 234 314 media_image30.png Greyscale Compound 645, at col. 109 PNG media_image31.png 209 313 media_image31.png Greyscale Compound 649, at col. 109 PNG media_image32.png 202 307 media_image32.png Greyscale Compound 647, at col. 109 PNG media_image33.png 143 425 media_image33.png Greyscale PNG media_image34.png 65 531 media_image34.png Greyscale Konteatis 20206 teaches the development of vorasidenib, enasidenib and AG-15056. It discloses that each of these compounds are potent inhibitors of IDH1 and 2, with some variations like enasidenib being more selective for IDH2. See, e.g., id. at 102, Table 1: PNG media_image35.png 659 574 media_image35.png Greyscale Konteatis 2020 at 102, Table 1. Konteatis 2020 at 105-106 (“Vorasidenib demonstrated excellent biochemical inhibition against mIDH1 and mIDH2…”; “Vorasidenib is a promising brain-penetrant dual mIDH1/2 inhibitor under late-stage development for the treatment of low-grade mIDH glioma….”). Crystal structures of both AG-15056 and Vorasidenib were known in their targets. See, e.g., Konteatis 2020 at 102 (showing the cocrystal structure of AG-15056): PNG media_image36.png 452 580 media_image36.png Greyscale Konteatis 2020 at 102. Konteatis 2020 at 102-103 discusses that AGI-15056 and enasidenib, despite having different chemical structures, have a “similar binding pocket arrangement”, and discusses binding to the “aminotriazine core” as well as certain carbon−fluoride−oxygen bond “tetrel σ bond[s]”. See, e.g., Konteatis 2020 at 103: The similar binding pocket arrangement exhibited by this inhibitor and enasidenib/IDH2-R140Q, and the specific interactions common to both systems, explain the observed affinity of AGI-15056 to both mIDH1 and mIDH2 enzymes. The majority of residues in the binding site are conserved between mIDH1 and mIDH2. Structural comparison suggests that enasidenib interacts with mIDH2-specific hydrophobic residue pairs V297, L298, I319, and L320 (compared with A258, M259, S280, and V281 for mIDH1), which likely explains its selectivity. The symmetry of inhibitor binding, the mostly hydrophobic pocket environment, and the similarities and differences observed in the specific interactions were major insights that became the central theme in our SAR exploration. Konteatis 2020 at 103. See also, Konteatis 2020 at 105 (showing the cocrystal structure of vorasidenib): PNG media_image37.png 516 575 media_image37.png Greyscale Konteatis 2020 at 105. More detailed structures are shown in the Konteatis 2020 SI at page 2. Beaufils 20177 teaches the extremely relevant SAR of bimiralisib, a brain penetrant chemotherapy agent from the same class of pyridine-triazine-diamine scaffolds: PNG media_image38.png 154 204 media_image38.png Greyscale Bimiralisib Doak 19558 teaches pKa values for pyridine and 3-amino pyridine, which is relevant to the solubility of the example 5 compound. Conclusion No claims allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Christopher Evan Redwood whose telephone number is (571) 272-8882. The examiner can normally be reached Monday - Friday 6:15 AM - 4:45 PM. 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, Jeffrey S. Lundgren can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. 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. /C.E.R./ Examiner, Art Unit 1629 /JEFFREY S LUNDGREN/ Supervisory Patent Examiner, Art Unit 1629 1Konteatis; Zenon D., et al., “Therapeutically Active Compounds And Their Methods Of Use”, U.S. Patent No. US 12433895 B2, published 2025-10-07, priority to 2013-07-11, Applicant Servier Pharmaceuticals LLC, hereinafter “US’895”. 2 Patani, George A., and Edmond J. LaVoie. "Bioisosterism: a rational approach in drug design." Chemical reviews 96.8 (1996): 3147-3176, hereinafter “Patani 1996”. 3 Luo, Guanglin, et al. "Discovery of (5 S, 6 S, 9 R)-5-Amino-6-(2, 3-difluorophenyl)-6, 7, 8, 9-tetrahydro-5 H-cyclohepta [b] pyridin-9-yl 4-(2-oxo-2, 3-dihydro-1 H-imidazo [4, 5-b] pyridin-1-yl) piperidine-1-carboxylate (BMS-927711): An Oral Calcitonin Gene-Related Peptide (CGRP) Antagonist in Clinical Trials for Treating Migraine." Journal of medicinal chemistry 55.23 (2012): 10644-10651, hereinafter “Luo 2012”. 4 See also, US’895 at Page 7, left column which states in the title of the article (“Konteantis et al., Vorasidenib (AG-881 ): A First-in-Class, Brain Penetrant Dual Inhibitor of Mutant IDHl and 2 for Treatment of Glioma, ACS Med. Chem Lett. 2020, 11, 101-107 (Year: 2020).”) (emphases added). 5 Cianchetta; Giovanni, et al., “Therapeutically Active Compositions And Their Methods Of Use”, U.S. Patent No. US 9512107 B2, published 2016-12-06, Applicant Agios Pharmaceuticals, Inc., hereinafter “US’107”. 6 Konteatis, Zenon, et al. "Vorasidenib (AG-881): a first-in-class, brain-penetrant dual inhibitor of mutant IDH1 and 2 for treatment of glioma." ACS medicinal chemistry letters 11.2 (2020): 101-107, hereinafter “Konteatis 2020”. The supporting information of Konteatis 2020, attached hereto 7 Beaufils, Florent, et al. "5-(4, 6-Dimorpholino-1, 3, 5-triazin-2-yl)-4-(trifluoromethyl) pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology." Journal of medicinal chemistry 60.17 (2017): 7524-7538, hereinafter “Beaufils 2017”. 8 H. H. Jaffé, G. O. Doak; The Basicities of Substituted Pyridines and their 1-Oxides. Journal American Chemical Society 1 September 1955; 77 (17): 4441–4444, hereinafter “Doak 1955”.