BICYCLIC HETEROARENES AND METHODS OF THEIR USE

§102 §103 §112 §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 06/06/2024, is the national stage entry of PCT/US2022/052261, filed 12/08/2022, which claims priority to U.S. Provisional Patent Application No. 63/287,517, filed on 12/08/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR § 1.55. Information Disclosure Statement The eight Information Disclosure Statements of record are acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the Information Disclosure Statements have been considered. Application History Applicant’s preliminary amendments to the claims received on 04/08/2025 were entered. Applicant stated that the preliminary amendments affected the following changes: PNG media_image1.png 215 609 media_image1.png Greyscale Amendments received 04/08/2025, at 28. Claims 1, 7, 24, 29, 38, 40, 43, 44, 49, 72, 73, 79, 87, 89-91, 93, 94, and 96 were pending and subject to a Restriction/Election requirement mailed 07/01/2026. Applicant’s reply was received 08/26/2026. Election/Restriction Claims 1, 7, 24, 29, 38, 40, 43, 44, 49, 72, 73, 79, 87, 89-91, 93, 94, and 96 are subject to the Restriction/Election requirement mailed 07/01/2026. Applicant’s election in the reply received 08/26/2026 of the compound designated compound 136 at page 140 of the Specification is acknowledged. Applicant’s election was made without traverse. The elected compound has the following chemical structure: PNG media_image2.png 137 201 media_image2.png Greyscale Compound 136, or the elected compound Applicant states the elected compound is a compound of Formula 10 recited in claim 72: PNG media_image3.png 411 452 media_image3.png Greyscale Applicant states: PNG media_image4.png 33 399 media_image4.png Greyscale If the elected species is not anticipated by or obvious over the prior art, the examiner will extend the search and examination to a non-elected species or group of species that falls within the scope of a proper Markush grouping that includes the elected species. The restriction and election of species requirements are deemed proper and are therefore made FINAL. Status of Claims Claims 1, 7, 24, 29, 38, 40, 43, 44, 49, 72, 73, 79, 87, 89-91, 93, 94, and 96 are pending. Claims 1, 7, 24, 29, 38, 40, 43, 44, 49, 89-91, 93, 94, and 96 are withdrawn from further consideration pursuant to 37 CFR § 1.142(b), as being drawn to a non-elected invention and species. Therefore, claims 72, 73, 79, and 87 read on an elected invention and species and are therefore under consideration in the instant application. Claim Rejections - 35 USC § 112(b) The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. Claims 72, 73, 79 and 87 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 72 recites: PNG media_image5.png 527 753 media_image5.png Greyscale Regarding claims 72, 73, and 79, one of skill in the art would not reasonably understand the metes and the bounds of the claimed invention because the endless optional substitution leads to conflicting interpretations of what compounds are encompassed by the claims. See MPEP 2173.04. First, it is unclear if an “optionally substituted C6-C10 aryl” includes heteroaryl. Substituting a carbon of an aryl group with a heteroatom results in a heteroaryl group. It is unclear if Applicant intends for this interpretation. Second, it is unclear what degree of saturation is required for an optionally substituted heteroaryl or aryl because substituting pyridinyl and phenyl with hydrogen results in piperidinyl and cyclohexyl. One of skill in the art would not reasonably interpret piperidinyl and cyclohexyl as optionally substituted heteroaryl or aryl. It is unclear if Applicant intends for this interpretation. Third, it is unclear what compounds are claimed when R7 is “optionally substituted C2-C9 heteroaryl C1-C6 alkyl” because the claim does not specify whether the optionally substituted C2-C9 heteroaryl is attached to the oxygen in O-R7, or if the optionally substituted C1-C6 alkyl is attached to oxygen in O-R7. Claim 73 depends on claim 72 and fails to clarify the metes and bounds of claim. Claim 79 exemplifies these problems. It recites various options for the RA variable, one of which is “7-aza-5,6,7,8-tetrahydroindolizin-1-yl”, which has the following structure: PNG media_image6.png 102 163 media_image6.png Greyscale The above 8-aza-5,6,7,8-tetrahydroindolizin-1-yl moiety is not a standard C6-C10 aryl nor a standard C2-C9 heteroaryl. One of skill in the art would not reasonably interpret the above 8-aza-5,6,7,8-tetrahydroindolizin-1-yl as being a permitted option in the claimed compounds. It would warrant a 112(d) rejection but for the other reasonable interpretation of the claims possibly permitting endless optional substitution to destroy aromaticity and redefine standard chemical terms like aryl and heteroaryl to mean any cyclic ring structure of any size. Therefore, it is unclear which compounds are presently claimed, and claims 72, 73, and 79 are rejected as indefinite. In amending the claims to improve their clarity, Applicant should fix the clear typographical error in claim 79 which recites pyrazol-4-yl twice. The examiner interprets this as a typographical error because Applicant intends the claim to encompass compound 141 in claim 87, and therefore the second pyrazol-4-yl is instead “pyrazol-5-yl”. Regarding claim 87, it recites 151 independent species. This number of independent species exceeds a reasonable number. See 37 CFR 1.75(d)(2) and 37 CFR 1.141: 1.141 Different inventions in one national application. (a) Two or more independent and distinct inventions may not be claimed in one national application, except that more than one species of an invention, not to exceed a reasonable number, may be specifically claimed in different claims in one national application, provided the application also includes an allowable claim generic to all the claimed species and all the claims to species in excess of one are written in dependent form (§ 1.75 ) or otherwise include all the limitations of the generic claim. 37 CFR 1.141. Therefore, claim 87 fails to particularly point out and distinctly claim the subject matter which Applicant regards as the invention. Accordingly, claim 87 is rejected as indefinite. Applicant may rewrite the claim as a dependent claim or in a series of independent claims that contain no more than a reasonable number of species as permitted by the rule. Improper Markush Grouping Claims 72, 73, 79 and 87 rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117. The Markush groupings of a compound of claims 72 and 87 is improper because the alternatives defined by the Markush groupings do not share both a single structural similarity and a common use for the following reasons: First, formula 10 (claim 72) and claim 87 (mixed formulas I, 1a, 1a’, 1b, 1c, 1d, 1e, and 2-13) represent compounds of multiple distinct chemical scaffolds that share only the common structure of a fused pyrimidine: PNG media_image7.png 262 241 media_image7.png Greyscale , PNG media_image8.png 250 254 media_image8.png Greyscale , PNG media_image9.png 256 233 media_image9.png Greyscale , PNG media_image10.png 258 235 media_image10.png Greyscale , PNG media_image11.png 258 238 media_image11.png Greyscale , PNG media_image12.png 258 211 media_image12.png Greyscale , PNG media_image13.png 272 242 media_image13.png Greyscale , PNG media_image14.png 256 228 media_image14.png Greyscale , PNG media_image15.png 217 249 media_image15.png Greyscale , PNG media_image16.png 258 313 media_image16.png Greyscale , PNG media_image17.png 242 205 media_image17.png Greyscale , PNG media_image18.png 244 207 media_image18.png Greyscale , PNG media_image19.png 223 219 media_image19.png Greyscale , PNG media_image20.png 229 178 media_image20.png Greyscale , PNG media_image21.png 242 252 media_image21.png Greyscale , PNG media_image22.png 251 178 media_image22.png Greyscale , PNG media_image23.png 266 158 media_image23.png Greyscale , PNG media_image24.png 252 174 media_image24.png Greyscale , PNG media_image25.png 254 163 media_image25.png Greyscale Even if the permitted, completely unbounded optional substitution is set aside, these fixed fused pyrimidine portions represent just a small portion of the chemical structures of the many, if not infinite number of compounds embraced by the claims. Under the first prong of the analysis, for these compounds to have “single structural similarity”, all alternative members must be of the same recognized physical or chemical class or the same art-recognized class. MPEP 2117 gives a simple example where single structural similarity is established with analogy to a fastener mechanism, which may include a buckle, or a loop. In that case, “a review of the prior art would establish that it was well known that each member could be substituted for each other with the expectation that the intended result (repositionable and refastenable) would occur.” In this case, a review of the prior art did not establish that all members of these expansive Markush groupings were “well known” to be interchangeable. For example, while certain formula I compounds were known, such as the following compound of US’2051 at col. 441, PNG media_image26.png 365 536 media_image26.png Greyscale , the prior art did not establish that all alternative members expressly permitted by the claimed inventions were well known to be interchangeable. Moreover, “single structural similarity” under the first prong requires that all alternatives are disclosed in the Specification or known in the art to be functionally equivalent and have a common use. Here, neither the art nor Specification establishes common use for all the alternatives. Claim 87 recites compounds like PNG media_image27.png 210 459 media_image27.png Greyscale and PNG media_image28.png 203 445 media_image28.png Greyscale , which are disclosed in the Specification as being inactive: PNG media_image29.png 301 407 media_image29.png Greyscale . Therefore, a review of the prior art fails to establish “single structural similarity”, and the Specification itself fails to establish a common use for all of the alternatives. For the second prong of the analysis, “single structural similarity” and a common use can be established from a substantial structural feature and a common use that flows from the substantial structural feature. As discussed above, for the multiple distinct chemical scaffolds, the only fixed portion embraced by all the alternatives is a fused pyrimidine ring. Even if the permitted optional substitution is set aside, these fixed portions represent just a small portion of the chemical structures of the many, if not infinite number of compounds embraced by the claims. For this prong to be satisfied, the examiner has to find that this small, fixed portion shared by all the alternatives is “substantial”, and that common use flows from that feature. As shown above, the fixed portion of a fused pyrimidine was known and therefore is not “substantial” over the prior art. Also shown above, common use does not flow from this small, fixed portion shared by all the alternatives. Further looking at the data applicant proffered, the claim 72 scaffold, which includes four distinct chemical scaffolds, appears to encompass Applicant’s embodiments 133-150. Applicant fails to disclose data for many of these compounds, as indicated by the NA in the assays below. See Specification at the Table beginning on page 150. Compounds like 133 and 134 are critical for understanding Formula 13 activity (encompassed by claim 72), yet there appears to be no data: PNG media_image30.png 112 409 media_image30.png Greyscale PNG media_image31.png 453 411 media_image31.png Greyscale PNG media_image32.png 101 398 media_image32.png Greyscale PNG media_image33.png 62 925 media_image33.png Greyscale Therefore, nowhere in the record has it been established that the variety of compounds included within the explicit scope of the claims are recognized by the art as being functionally equivalent, nor that common use flows from the relatively small, fixed portion of a fused pyrimidine shared by all the alternatives. Accordingly, the Markush grouping instantly recited lacks a “single structural similarity” and a common use. To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use. The examiner recommends amending the claims and basing the Markush grouping upon the structure of the elected species compound with alternatives that share a single structural similarity as well as a common use. PNG media_image2.png 137 201 media_image2.png Greyscale Compound 136, or the elected compound Claim Rejections - 35 USC § 102 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. Claim 87 Anticipated by US’205 Claim 87 is rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US’205.2 Claim 87 recites the following compounds: PNG media_image34.png 215 463 media_image34.png Greyscale PNG media_image35.png 216 456 media_image35.png Greyscale US’205 at cols. 91 and 67 teaches the following compounds: PNG media_image36.png 136 296 media_image36.png Greyscale PNG media_image37.png 178 415 media_image37.png Greyscale US’205 at cols. 91 and 67. Accordingly, claim 87 is anticipated by US’205. 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 72 and 79 Obvious over US’488 in view of US’932 and Patani 1996 Claim(s) 72 and 79 is/are rejected under 35 U.S.C. 103 as being unpatentable over US’4883 in view of US’932,4 and Patani 1996.5 US’488 at col. 7 discloses the following compound: PNG media_image38.png 356 394 media_image38.png Greyscale , hereinafter “US’488 compound A”. The above compound is a 3-methylmorphlinyl variant of a compound of Formula 10 as recited in the instant claim 72. The above compound would anticipate the instant claims 72 and 79 but for the methyl group attached to the morpholinyl functional group.6 It represents a simple bioisostere that Applicant’s broad claims encompass. The compounds of US’488 are kinase inhibitors, ATR exemplified. See US’488 at col. 75, Table 1. US’488 exemplifies the use of its compounds with their classical bioisostere variants (CH-N exchange), see, e.g., Compound 3 at col. 5, PNG media_image39.png 301 375 media_image39.png Greyscale , and some of its biological data at cols. 75-77, e.g., PNG media_image40.png 293 529 media_image40.png Greyscale PNG media_image41.png 308 657 media_image41.png Greyscale Compounds 3 and compound A of US’488 are non-classical bioisosteres of the active pharmaceutical ingredient (“API”) elimusertib (BAY-1895344), which is a well known ATR inhibitor that was disclosed in WO2016020320. WO2016020320 is cited in US’488 at col. 1, line 60. US’932 cited herein was the first U.S. Patent granted from the international application that published as WO2016020320. US’488 itself suggests that unsubstituted morpholinyl would work through the well known bioisosteric equivalence of methyl and hydrogen. One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in instead utilizing unsubstituted morpholinyl because methyl and hydrogen are well known classical bioisosteric exchanges, and by making the exchange from 3-methylmorphlinyl to unsubstituted morpholinyl, one would reasonably expect the resulting bioisostere to affect the same pharmacological targets in the same way. See US’932 and Patani 1996. US’932 US’932 at col. 226 discloses its example 111 compound, which is the well known API elimusertib: PNG media_image42.png 394 394 media_image42.png Greyscale US’932 compound 111, or elimusertib US’932 at col. 425 teaches its compound 348, which is the unsubstituted morpholinyl classical bioisostere of elimusertib: PNG media_image43.png 252 706 media_image43.png Greyscale US’932 Table 7, beginning at col. 474, explains that both compounds are bioisosteres. PNG media_image44.png 144 404 media_image44.png Greyscale PNG media_image45.png 21 438 media_image45.png Greyscale See also, US’932 Table 9, beginning at col. 484, teaching the same: PNG media_image46.png 178 397 media_image46.png Greyscale PNG media_image47.png 95 505 media_image47.png Greyscale PNG media_image48.png 18 505 media_image48.png Greyscale PNG media_image49.png 17 497 media_image49.png Greyscale As shown in US’932, methyl and hydrogen are bioisosteric exchanges. By replacing one for the other, one has a reasonable expectation that the bioisosteric compounds will affect the same pharmacological targets in the same way. See Patani 1996. Patani 1996 The exchange of the methyl group with hydrogen represents a classical bioisosteric exchange “according to Grimm”. See Patani 1996 at 3148, right column, Table 2, discussed below. 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.” Id. One such group of classical bioisosteres were those “according to Grimm”, see Patani 1996 at 3148, Table 2 and surrounding text (fourth column shows the H and CH3 exchange; see also the second column, teaching the classical bioisosteric exchange of N with CH utilized in the ring atoms of Compounds 3 and compound A of US’488): PNG media_image50.png 439 571 media_image50.png Greyscale Patani 1996 at 3148, Table 2. See also, Patani 1996 at 3149 (“(4) fluorine, hydroxyl, amino, and methyl group interchanges (Grimm's Hydride Displacement Law);”), id. at 3152-3154 (“4. Fluorine and Hydroxyl, Amino, or Methyl Groups as Replacements for Hydrogen (Grimm's Hydride Displacement Law)”). “This monovalent group of isosteres is a result of the direct adaptation of Grimm’s Hydride Displacement Law.” Id. at 3152. Moreover, the classical bioisosteric exchange of N and CH was well known. See, e.g., Patani 1996 at 3158, Ring Equivalents section. Accordingly, the exchange of methyl with hydrogen results in classical bioisosteres, that by definition, affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other. Further, as noted above, elimusertib, and Compounds 3 and A of US’488 are non-classical bioisosteres. See Patani 1996 at 3149, discussing nonclassical bioisosteres. Nonclassical isosteres do not obey the steric and electronic definition of classical isosteres. A second notable characteristic of nonclassical bioisosteres is that they do not have the same number of atoms as the substituent or moiety for which they are used as a replacement. Nonclassical bioisosteres can be further divided into groups:  (A) rings vs noncyclic structures; and (B) exchangeable groups. Patani 1996 at 3149. Claims 72 and 79 Obvious Accordingly, the chemist of ordinary skill in the art at the time of filing would have a reasonable expectation of success in utilizing unsubstituted morpholinyl to prepare the classical bioisostere of compound A of US’488. By preparing the bioisostere, he had the reasonable expectation that the resulting compound would be an effective ATR kinase inhibitor like compounds 3 and A of US’488, elimusertib, and compound 348 of US’488. PNG media_image51.png 334 356 media_image51.png Greyscale Obvious bioisostere of US’488 compound A encompassed by claims 72 and 79 PNG media_image38.png 356 394 media_image38.png Greyscale US’488 compound A Accordingly, claims 72 and 79 were obvious at the time of filing. Claims 72, 73, 79 and 87 Obvious over US’205 in view of US’458, Poulsen 2014 and Patani 1996 Claim(s) 72, 73, 79 and 87 is/are rejected under 35 U.S.C. 103 as being unpatentable over US’2057 in view of US’458,8 Poulsen 20149 and Patani 1996. US’205 and Patani 1996 are the same references discussed above. Claim 72 recites: PNG media_image52.png 510 750 media_image52.png Greyscale Applicant elected the following compound as the embodiment of its invention: PNG media_image2.png 137 201 media_image2.png Greyscale Compound 136, or the elected compound As discussed, US’205 teaches compounds like its B-29 compound: PNG media_image26.png 365 536 media_image26.png Greyscale Many other compounds are taught in a similar configuration. See, e.g., US’205 at col 67, teaching compounds like: PNG media_image53.png 139 328 media_image53.png Greyscale PNG media_image37.png 178 415 media_image37.png Greyscale US’205 at col. 67. The central scaffold in the compounds of US’205 is a 5H,6H,7H-pyrrolo[2,3-d]pyrimidine. Applicant’s elected compound is built upon a 5-pyrrolo[3,2-d] pyrimidine scaffold. Both scaffolds are known bioisosteres of purine and have widespread use in medicinal chemistry. Ergo, Applicant’s elected compound and B-29 from US’205 are simple bioisosteres. PNG media_image54.png 128 129 media_image54.png Greyscale PNG media_image55.png 297 666 media_image55.png Greyscale The compounds of US’205 are kinase inhibitors, with PI3K exemplified. See, e.g., US’205 at col. 1. US’205 teaches a structural activity relationship study (a “SAR study” or just a “SAR”) about compounds built in its configuration. See, e.g., the Table of US’205 at cols. 852-853. By modifying the various rings attached to the purine-isostere scaffold, one can tune activity towards different cancers. While US’205 does not exemplify the use of the bioisosteric 5-pyrrolo[3,2-d] pyrimidine scaffold, a chemist of ordinary skill at the time of filing would recognize that it suggests that the scaffold would work towards the same pharmacological targets through the simple principles of bioisosterism. One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in scaffold hopping to the bioisosteric 5-pyrrolo[3,2-d] pyrimidine scaffold because US’458 teaches scaffold hopping to the same bioisosteric scaffold, and Poulsen 2014 teaches the preferential location of the morpholinyl substituent. Patani 1996 provides definitions. US’458 See US’458 at Abstract, teaching the bioisosteric 5-pyrrolo[3,2-d] pyrimidine scaffold. PNG media_image56.png 490 465 media_image56.png Greyscale Simple compounds constructed in this manner are also highly potent PI3K inhibitors. See US’458 at 34, Table 2. They were also known to inhibit mTOR kinase depending upon the substituent chosen. PNG media_image57.png 287 415 media_image57.png Greyscale The compound names appear in Table 1 at page 32. For example, see compounds 2, 4, and 5. PNG media_image58.png 281 306 media_image58.png Greyscale US’458 compound 2 PNG media_image59.png 332 273 media_image59.png Greyscale US’458 compound 4 PNG media_image60.png 271 314 media_image60.png Greyscale US’458 compound 5 They differ from the compounds of US’205 by the location the morpholinyl group is attached. For example, below shows US’205 compound B-29 and US’458 compound 2 together. This helps show the different location of the morpholinyl group. US’205 places the morpholinyl group at the 2-position of the purine isostere scaffold, whereas US’458 places it at the 4-position: PNG media_image26.png 365 536 media_image26.png Greyscale US’205 compound B-29 PNG media_image61.png 227 188 media_image61.png Greyscale US’458 compound 2 Poulsen 2014 Poulsen 2014 teaches that the 2-position of the purine isostere scaffold is the preferred location for a morpholinyl group when preparing a PI3K inhibitor, rather than the 4-position. Computations were performed using the purine core. See Poulsen 2014 at 3240, showing the different scaffolds explored. The compounds of US’205 were based upon Scaffold A, whereas the compounds of US’458 were based upon Scaffold B. PNG media_image62.png 667 1214 media_image62.png Greyscale PNG media_image63.png 277 277 media_image63.png Greyscale US’205 compound B-29, rotated to show Scaffold A PNG media_image64.png 287 262 media_image64.png Greyscale US’458 compound 2, rotated to show Scaffold B See Poulsen 2014 at 3248 (“With our aim of making dual mTOR and PI3Kα as well as selective mTOR inhibitors, picking scaffold A proved to be the right choice.”) (emphasis added). Patani 1996 Patani 1996 was discussed in the preceding rejection under 103. 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. at 3148. “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. The elected species compound was obvious US’205 taught a potent family of PI3K inhibitors based upon a purine isostere scaffold. When the inventors of US’458 prepared their early PI3K inhibitors based upon the bioisosteric 5-pyrrolo[3,2-d] pyrimidine scaffold, they made the wrong choice in the selection of the location for the morpholinyl group according to Poulsen 2014. Therefore, at the time of filing, it was quite clear to the ordinary chemist seeking to improve the design of the PI3K inhibitors taught in US’205 and US’458, that he could take an exemplary compound of US’205, scaffold hop to the bioisosteric 5-pyrrolo[3,2-d] pyrimidine scaffold as shown in US’458, but retain the morpholinyl group at the 2-position of the purine isostere. There was a reasonable expectation of success in making the scaffold hop because the compound would be a bioisosteric equivalent of the compounds of US’205, and therefore could be used for the same purposes in oncology. PNG media_image65.png 239 748 media_image65.png Greyscale The compound obtained from making the immediate scaffold hop from US’205 compound B-29 alone renders claims 72, 73, and 79 obvious at the time of filing. The only difference between that compound and Applicant’s elected compound is a 2-pyridinyl and a 3-pyridinyl group. Both are bioisosteres. Further, US’205 teaches multiple examples of a 2-pyridinyl, e.g.: PNG media_image66.png 260 607 media_image66.png Greyscale , at col. 63, PNG media_image67.png 265 664 media_image67.png Greyscale at col. 147, or PNG media_image68.png 230 636 media_image68.png Greyscale at 211. It was known from the SAR of US’205 that changing the substituent slightly tweaks the activity of the resulting compound. Accordingly, there was a reasonable expectation of success in selecting 2-pyridinyl instead of 3-pyridiyl as shown in the US’205 compound B-29. Accordingly, the elected species compound, and claim 87, were obvious at the time of filing. Secondary considerations Applicant may argue that it was unexpected that its compounds would inhibit PIKfyve. Such an argument would not be persuasive because the elected compound is not a stellar PIKfyve inhibitor and the instant claims are not drawn towards its use for that purpose. Further, WO’00310 suggests that the family of formula 10 compounds Applicant claims are expected to inhibit PIKfyve, see, e.g., WO’003 at 141, claim 1, which encompasses Applicant’s purported invention. PNG media_image69.png 160 282 media_image69.png Greyscale WO’003 exemplifies variants wherein the morpholinyl group is at the 4-position of the purine isostere. See, e.g., claim 18 at 149. Other purine scaffold isosteres exemplified throughout. PNG media_image70.png 377 520 media_image70.png Greyscale Many of the compounds of WO’003 also perform well in such configurations. See WO’003 at 134-137, where the biological data is reported, e.g., PNG media_image71.png 528 705 media_image71.png Greyscale While WO’003 does not exemplify the configuration Applicant selected, it nevertheless suggests through its general formulas that one of ordinary skill in the art at the time of filing would reasonably expect the PI3K inhibitors disclosed in US’205 and US’458, and bioisosteric derivatives thereof, to also inhibit PIKfyve. The kinase inhibitors built in these configurations had broad activity. Therefore, if there is some feature other than PIKfyve inhibition relevant to the elected compound, Applicant should identify that in its response. 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. Provisional NSDP to US’797 Claim 87 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 81 of copending Application No. 18/007,797 (reference application, or “US’797”, which published as US 20230271965 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because claim 81 of the reference application presently claims the same compounds or pharmaceutically acceptable salts thereof the same compounds claimed in the instant claim 87. See, e.g., claim 81 of the reference application: PNG media_image72.png 290 625 media_image72.png Greyscale See, e.g., claim 87 of the instant application: PNG media_image73.png 528 973 media_image73.png Greyscale At least compound 17 of the reference application and compound 3 of the instant application are the same. Others are obvious variants. E.g., compound 4 of instant claim 87. 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. Jorda, Radek, Kamil Paruch, and Vladimir Krystof. "Cyclin-dependent kinase inhibitors inspired by roscovitine: purine bioisosteres." Current pharmaceutical design 18.20 (2012): 2974-2980. See, e.g., Fig. 2 at 2975. PNG media_image74.png 761 929 media_image74.png Greyscale De Coen, Laurens M., et al. "Synthetic entries to and biological activity of pyrrolopyrimidines." Chemical Reviews 116.1 (2016): 80-139. Teaches numerous examples of purine bioisosteres. E.g., page 113. PNG media_image75.png 136 469 media_image75.png Greyscale CN 112142744 A: Teaches the following compound encompassed by certain claims. The compound is also a bioisostere of elimusertib and compounds of US’932. PNG media_image76.png 249 653 media_image76.png Greyscale Chen, Dizhong, et al. "Synthesis and biological evaluation of 6-phenylpurine linked hydroxamates as novel histone deacetylase inhibitors." Bioorganic Chemistry 98 (2020): 103724. See also the graphical abstract available online at https://doi.org/10.1016/j.bioorg.2020.103724 : PNG media_image77.png 195 500 media_image77.png Greyscale Gilbert, Adam M., et al. "Novel purine and pyrazolo [3, 4-d] pyrimidine inhibitors of PI3 kinase-α: Hit to lead studies." Bioorganic & medicinal chemistry letters 20.2 (2010): 636-639. Pyrazolo[3,4-d]pyrimidine bioisostere scaffold of purines used in the same targets. US 20240150358 A1, U.S. Patent Application No. 18/007,983. Presently unclear whether this application is a double patent due to the nature of the instant claims. US 20250353851 A1, U.S. Patent Application No. 18/717,174. Presently unclear whether this application is a double patent due to the nature of the instant claims. 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 1 Shimma; Nobuo, et al., “Pyrimidine Derivatives As PI3K Inhibitor And Use Thereof”, U.S. Patent No. US 8022205 B2, published 2011-09-20, hereinafter “US’205”. 2 Cited in the section regarding improper Markush grouping. Shimma; Nobuo, et al., “Pyrimidine Derivatives As PI3K Inhibitor And Use Thereof”, U.S. Patent No. US 8022205 B2, published 2011-09-20, hereinafter “US’205”. 3 Li; Xin, et al., “Substituted Morpholines As ATR Kinase Inhibitors”, U.S. Patent No. US 12559488 B2, published 2026-02-24, priority to 2019-11-21, hereinafter “US’488”. 4 Wortmann; Lars, et al., “2-(morpholin-4-yl)-1,7-naphthyridines”, U.S. Patent No. US 9549932 B2, published 2017-01-24, hereinafter “US’932”. 5 Patani, George A., and Edmond J. LaVoie. "Bioisosterism: a rational approach in drug design." Chemical reviews 96.8 (1996): 3147-3176, hereinafter “Patani 1996”. 6 As discussed in the 112(b) section, the examiner interprets the second pyrazol-4-yl in claim 79 as pyrazol-5-yl . 7 Same reference used in the 102 section regarding claim 87. 8 CHEN; Zecheng, et al., “PYRROLO[3,2-d]PYRIMIDINE COMPOUNDS AND THEIR USE AS PI3 KINASE AND MTOR KINASE INHIBITORS”, U.S. Patent Publication No. US 20090149458 A1, published 2009-06-11, hereinafter “US’458”. 9 Poulsen, Anders, et al. "Structure and ligand-based design of mTOR and PI3-kinase inhibitors leading to the clinical candidates VS-5584 (SB2343) and SB2602." Journal of chemical information and modeling 54.11 (2014): 3238-3250, hereinafter “Poulsen 2014”. 10 PATEL VINOD F, “NOVEL INHIBITORS OF PIKFYVE AND METHODS USING SAME”, International Publication No. WO 2023058003 A1, published 2023-04-13, priority to 2021-10-07, TME THERAPEUTICS LLC Applicant, hereinafter “WO’003”.