IMIDAZOLE ORGANIC COMPOUNDS AND THEIR USE AGAINST INFLAMMATORY BOWEL DISEASE

§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 . Priority The instant application, filed on March 29, 2024, is a national stage entry of International Application No. PCT/GB2022/052010, filed July 29, 2022, which claims priority to Great Britain Patent Application No. GB2111001.0, filed on July 30, 2021. Receipt was acknowledged of certified copies of papers required by 37 CFR § 1.55. Status of Claims Claims 1-18, 21, 22, 25, and 26 were rejected in the Non-Final Rejection mailed 04/23/2026. Applicant’s amendments to the claims received 07/21/2026 are acknowledged and entered. Claims 1-3, 5, 6, 8-10, 12, 13-16, and 25 are amended. Accordingly, claims 1-18, 21, 22, 25, and 26 are pending and under consideration. Claim Rejections - 35 USC § 112 - withdrawn The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and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. Response to Arguments: Applicant’s arguments, see Remarks Received 07/21/2026, at 14 of 21, with respect to the rejections of claims 2, 3, 5, 6, 8, 9, 10, 12, 13, 15, 16, 25 and 26 under 35 U.S.C. 112(b) have been fully considered. The rejections under 35 U.S.C. 112(b) are withdrawn in view of the amendments to the claims resolving the indefiniteness issues introduced by certain claims reciting preferences. Claim Rejections - 35 USC § 103 – Maintained / Necessitated by Amendment 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. Previous Grounds of Rejection are Maintained Claims 1-8, 12-16, 18 and 25 rejected under 35 U.S.C. 103 as being unpatentable over WO’5271 in view of WO’798.2,3 Claims 9-11, 17 and 26 rejected under 35 U.S.C. 103 as being unpatentable over WO’527 in view of WO’798 and Patani 1996.4 Claims 21 and 22 rejected under 35 U.S.C. 103 as being unpatentable over WO’527 in view of WO’798, US’7835 and Hsu 2021.6 The rejections are reiterated following each Response to Arguments. Response to Arguments, WO’527 in view of WO’798: Applicant's arguments, see Remarks Received 07/21/2026, at 14-17 of 21, with respect to the rejections of claims 1-8, 12-16, 18 and 23-25 under 35 U.S.C. 103 over WO’527 in view of WO’798 as stated in the 04/23/2026 Non-Final Rejection have been fully considered but they are not persuasive because Applicant’s amended claims still encompass obvious subject matter. Applicant has argued that certain embodiments of the alleged invention exhibit a low Kpuu pharmacokinetics (“PK”) parameter which “is beneficial as it indicates the compound acts locally in gastrointestinal tissue where PDE10A is upregulated in IBD, and it avoids the CNS-mediated side effects (e.g. sedation) that are common for PDE10A inhibitors developed for neurological indications.” Remarks Received 07/21/2026, at 17 of 21 (emphasis added). Applicant argues that “This is relevant because it means the compounds of the present application are more suitable for application in the treatment of inflammatory bowel diseases than those of the cited art.” Id. (emphasis added). Applicant’s position is not persuasive because when it argues that “the compound acts locally”, its position applies to only three disclosed embodiments of its alleged invention, the Example 7, 24, and 32 compounds. See Table 11 from Specification at 87 and surrounding text, and the corresponding compounds from Specification: PNG media_image1.png 99 216 media_image1.png Greyscale “Example H” from WO’527 PNG media_image2.png 113 150 media_image2.png Greyscale Example 32 PNG media_image3.png 386 499 media_image3.png Greyscale PNG media_image4.png 216 324 media_image4.png Greyscale Example 7 PNG media_image5.png 105 147 media_image5.png Greyscale Example 24 However, “the compounds of the present application” as claimed include the following obvious embodiments, for which Applicant provides zero Kpuu PK measurements: PNG media_image6.png 167 226 media_image6.png Greyscale Embodiment of claim 1 PNG media_image7.png 387 547 media_image7.png Greyscale Embodiment of claim 2 PNG media_image8.png 397 524 media_image8.png Greyscale Embodiment of claim 3 No claim is presently drawn to non-obvious subject matter. Applicant has not amended out the subject matter that is obvious over WO’798 in view of WO’527. Applicants positions on the claim rejections over WO’527 in view of WO’798 are not persuasive On page 14-15 of the Remarks, Applicant states: PNG media_image9.png 218 681 media_image9.png Greyscale Remarks at 14-15. While Applicant is summarizing in the above segment, the highlighted sentence glances over what WO’527 teaches. In doing so, it sets Applicant’s positions on the wrong course. WO’527 at 13 and 16, respectively, teaches the following bioisosteres, values on the right are the IC50s from the PDE10A assay: PNG media_image10.png 168 464 media_image10.png Greyscale PNG media_image11.png 176 593 media_image11.png Greyscale WO’527 teaches that changing the central linker from ethyl to ethynyl results in compounds that are bioisosteres – they are of similar shapes and volumes, were known to affect the same pharmacological target in the same way, and have related properties. In the case of the receptors targeted, there was a preference for ethynyl linkage. WO’527 explained that one could put a morpholinyl group at the 4-position of the bioisosteres, and that doing so would increase activity towards the same receptors, e.g., the following compound on page 14: PNG media_image12.png 210 584 media_image12.png Greyscale WO’527 teaches the compound disclosed in WO’527 at 16 and with a morpholinyl group at the 4-position. By this, the examiner means that one of skill in the art reading WO’527 would at once envisage the compound. Alternatively, it was an obvious embodiment of the invention of WO’527 that its inventors did not exemplify in the specification. It was reasonably expected to inhibit PDE10A. PNG media_image13.png 212 207 media_image13.png Greyscale Immediately following the above highlighted sentence, on page 14-15 of the Remarks, Applicant is mistaken that any compound has to be modified and misunderstands what WO’798 teaches: PNG media_image14.png 218 681 media_image14.png Greyscale Remarks at 14-15. WO’798 explained that when one prepared a PDE10A inhibitor, the pyrimidine group could be fused to either a benzene ring, a 5-6 membered heteroaryl, or a 5-6 membered cycloalkyl. See, e.g., claim 1, A variable: PNG media_image15.png 175 405 media_image15.png Greyscale PNG media_image16.png 119 1269 media_image16.png Greyscale WO’798 teaches the PNG media_image17.png 62 110 media_image17.png Greyscale is PNG media_image18.png 41 73 media_image18.png Greyscale . As explained, WO’798 encompasses the compounds of WO’527. As explained, combining the teachings immediately results in the following compound that was reasonably expected to function as a PDE10A inhibitor. Applicant has not amended this compound out of its claims: PNG media_image19.png 198 267 media_image19.png Greyscale Embodiment of claim 1 Therefore, Applicant’s claims still include what was already known from WO’527 in view of WO’798. Namely, that Ring A of WO’798, which is Applicant’s Ring C, may be “a 5-6-membered heteroaryl, or a 5-6-membered cycloalkyl”. See instant claim 1: PNG media_image20.png 234 723 media_image20.png Greyscale … PNG media_image21.png 69 766 media_image21.png Greyscale Instant claim 1. In Remarks at 15, Applicant argues that its compounds are PDE10A inhibitors. This is not persuasive because that is what was reasonably expected at the time of filing. Applicant then states because they are PDE10A inhibitors, they may be used to treat IBD. This is not persuasive because claiming an obvious PDE10A inhibitor compound and stating that it may be used to treat IBD does not overcome the fact that the compound was obvious. Further, Applicant never exemplifies using any of its compounds to treat IBD. See Remarks at 15: PNG media_image22.png 305 1100 media_image22.png Greyscale Remarks at 15. In the following paragraph of Remarks at 15, Applicant states that prior art compounds PF-02545920, TAK-063, and Examples A to G “were found to significantly reduce the secreted levels of the inflammatory cytokines IL-6 and IL-8 when compared to control”. However, Applicant’s remarks also state that its instant “compounds of Formula (I) … were found to significantly reduce the secreted levels of the inflammatory cytokines IL-6 and IL-8 when compared to control”. Applicant points to page 89, line 21 to page 90, line 8 of the instant specification and Figures 4-9. Applicant presents no data from compounds of Formula (I) in this section, nor the Figures referenced. Applicant’s assertion here is therefore not persuasive: PNG media_image23.png 371 949 media_image23.png Greyscale Remarks at 15. Applicant’s following statement regarding the in vitro assay data of select compounds reported in “Table 10, pages 82 to 83”, just summarizes what was obvious at the time of filing – that certain compounds of Applicant’s formula (I) were reasonably expected to potently inhibit PDE10A. It is therefore not persuasive. Applicant continues to argue in Remarks at 15-16 a position regarding a treatment axis is relevant to a method of treatment claim. While this treatment axis combined with the low Kpuu values reported for the Example 7, 24, and 32 compounds would overcome the rejections over WO’527 in view of WO’798 if Applicant had a claim drawn to just those three compounds, Applicant presents no claim drawn to just these compounds. Accordingly, Applicant’s discussion of a treatment axis is not persuasive to the subject matter as claimed. Applicant’s obvious Markush grouping is far broader than its three data points. In Remarks at 16, Applicant argues there is no motivation to modify the compounds of WO’527 and WO’798. PNG media_image24.png 234 961 media_image24.png Greyscale Remarks at 16. Applicant’s position is not persuasive because no modification is even required. The following compound is a compound of WO’798 and Applicant has not amended it out of its claims: PNG media_image25.png 141 191 media_image25.png Greyscale Embodiment of claim 1 Immediately following, Applicant provides an example that is not persuasive. Applicant is reminded that WO’527 itself taught a structural activity relationship study, and in it, disclosed the ethyl bioisostere of the “reference example H”, and explained that adding a morpholinyl group improves the IC50. See Remarks at 16: PNG media_image26.png 301 962 media_image26.png Greyscale Remarks at 16. Applicant then argues that because WO’798 does not disclose a compound with ethynyl linkage, that there is “no teaching, suggestion, or motivation to apply this particular to reference example H…”. See Remarks at 16: PNG media_image27.png 349 954 media_image27.png Greyscale Remarks at 16. Applicant’s position is not persuasive because it misunderstands what WO’798 teaches, which is the Embodiment of claim 1. No “two simultaneous, independent structural modifications to Reference Example H” are required to arrive at the compound. WO’527 simply exemplified that there was a preference for ethynyl linkage for the compounds of WO’798. The following compound was a compound of WO’798, even if it did not exemplify it. PNG media_image28.png 151 205 media_image28.png Greyscale Embodiment of claim 1 In Remarks at 17, Applicant’s position is that WO’527 and WO’798 teach away from “features” of the claimed compounds. PNG media_image29.png 167 966 media_image29.png Greyscale Remarks at 17. Applicant’s position here is persuasive for “exemplary compounds 7, 24, and 32”. Applicant has not shown that the low Kpuu PK measures for exemplary compounds 7, 24, and 32 extend to its enormously large Markush grouping that is obvious over WO’527 in view of WO’798. Therefore, Applicant positions regarding the rejections of claims 1-8, 12-16, 18 and 23-25 under 35 U.S.C. 103 as being unpatentable over WO’527 in view of WO’798 are not persuasive. The rejection is reiterated below. Claims 1-8, 12-16, 18 and 23-25 Obvious over WO’527 in view of WO’798 Claims 1-8, 12-16, 18 and 25 rejected under 35 U.S.C. 103 as being unpatentable over WO’527 in view of WO’798. The following compound is an embodiment of instant claim 1. PNG media_image30.png 133 180 media_image30.png Greyscale Embodiment of claim 1 WO’527 at 13 and 16, respectively, teaches the following bioisosteres, values on the right are the IC50s from the PDE10A assay: PNG media_image10.png 168 464 media_image10.png Greyscale PNG media_image11.png 176 593 media_image11.png Greyscale WO’527 teaches that changing the central linker from ethyl to ethynyl results in compounds that are bioisosteres – they are of similar shapes and volumes, were known to affect the same pharmacological target in the same way, and have related properties. In the case of the receptors targeted, there was a preference for ethynyl linkage. WO’527 explained that one could put a morpholinyl group at the 4-position of the bioisosteres, see, e.g., claim 1 permitting “morpholinyl” for R2, claim 9 stating HET is “4-morpholin-4-yl-quinazoline”, and that by doing so, it would increase activity towards the same receptors, e.g., the following compound on page 14: PNG media_image12.png 210 584 media_image12.png Greyscale WO’527 teaches the compound disclosed in WO’527 at 16 and with a morpholinyl group at the 4-position. By this, the examiner means that one of skill in the art reading WO’527 would at once envisage the compound. Alternatively, it was an obvious embodiment of the invention of WO’527 that its inventors did not exemplify in the specification. It was reasonably expected to inhibit PDE10A. PNG media_image31.png 188 184 media_image31.png Greyscale While WO’527 does not exemplify the Embodiment of claim 1 that instead has a 6-membered cycloalkyl ring fused the pyrimidine group, one of ordinary skill in the art at the time of filing would recognize that WO’527 suggests it would function equally as well as a PDE10A inhibitor through the simple principles of bioisosterism and shared structural similarity. One of ordinary skill in the art at the time of filing would have had a reasonable expectation of success in inhibiting PDE10A with the Embodiment of claim 1 compound because WO’798 explained that the compound was reasonably expected to inhibit PDE10A. For example, WO’798 explained that when one prepared a PDE10 inhibitor, the pyrimidine group could be fused to either a benzene ring, a 5-6 membered heteroaryl, or a 5-6 membered cycloalkyl group as suitable bioisosteric equivalents. See, e.g., claim 1, A variable: PNG media_image32.png 153 353 media_image32.png Greyscale PNG media_image16.png 119 1269 media_image16.png Greyscale WO’798 teaches the linker PNG media_image17.png 62 110 media_image17.png Greyscale is PNG media_image18.png 41 73 media_image18.png Greyscale . WO’798 claim 1 encompasses the compounds of WO’527. These compounds are bioisosteres. See also WO’798 at 5/89 – 6/89, explaining in paragraph [0016] that the compounds are PDE10 inhibitors, in paragraph [0017] providing the formula (I), paragraph [0018] explaining that the A ring may be a 5-6 membered cycloalkyl, and paragraph [0019] explaining that the linker PNG media_image17.png 62 110 media_image17.png Greyscale may be PNG media_image18.png 41 73 media_image18.png Greyscale . The compounds of WO’527 with ethynyl linkage represented a subgenus of the compounds of WO’798. The following compound is encompassed by the PDE10A inhibitors taught in WO’798: PNG media_image33.png 132 179 media_image33.png Greyscale Embodiment of claim 1 There was a reasonable expectation of success in inhibiting PDE10A with the above compound because it adopted the preferential ethynyl linkage taught by WO’527, and WO’798 explained that the compound would function as a PDE10 inhibitor. In view of the shared structural similarity, the person of ordinary skill in the art at the time of filing had a reasonable expectation that the compound would inhibit the same pharmacological targets in the same way. Moreover, both WO’527 and WO’798 teach a structural activity relationship study (a “SAR study”, or just a “SAR”), about various compounds these configurations. Strong inhibition of PDE10A was consistently observed when the compounds bore a morpholinyl group at the same position, see compounds 1, 2, 3, 4, 6, 7, 8, and 26 of WO’798 alone. Each of these compounds occupy the same space in the same receptor and all inhibit PDE10 activity despite the structural variety in the ring fused to the pyrimidine group. One of ordinary skill in the art at the time of filing would not reasonably expect that the result of fusing a cyclohexane ring to the pyrimidine ring as expressly taught by WO’798 would be zero activity towards PDE10. Instead, he would reasonably expect to succeed in preparing the compound as taught by WO’798 with the preferential ethynyl linkage learned from WO’527. The structural difference was only four hydrogens, and far bulker groups were permitted in the same space. Once WO’527 exemplified that the ethynyl linkage was preferred, it was obvious to prepare its variants as taught by WO’798. PNG media_image34.png 295 346 media_image34.png Greyscale WO’798 at 61/89, assay towards PDE10A, ++ means <5 nM, + means <50 nM7 PNG media_image35.png 202 203 media_image35.png Greyscale PNG media_image36.png 199 206 media_image36.png Greyscale PNG media_image37.png 196 205 media_image37.png Greyscale PNG media_image38.png 188 206 media_image38.png Greyscale PNG media_image39.png 185 190 media_image39.png Greyscale PNG media_image40.png 203 218 media_image40.png Greyscale PNG media_image41.png 190 216 media_image41.png Greyscale PNG media_image42.png 197 180 media_image42.png Greyscale WO’798 compounds from pages 16-17, and 20 of 89 Accordingly, claim 1 was obvious at the time of filing. The above embodiment of claim 1 compound is encompassed by claim 5, which was obvious at the time of filing for the same reasons stated above. Claims 2, 6, 8, and 12-16 were obvious The following compound is an embodiment of claim 2: PNG media_image7.png 387 547 media_image7.png Greyscale Embodiment of claim 2 While WO’798 did not exemplify the embodiment of claim 2 compound, one of ordinary skill in the art at the time of filing would have had a reasonable expectation of success in inhibiting PDE10A with the above compound because it adopted the preferential ethynyl linkage taught by WO’527, and WO’798 explained that the compound would function as a PDE10 inhibitor. For example, WO’798 explained that when one prepared a PDE10 inhibitor, the pyrimidine group could be fused to either a benzene ring, a 5-6 membered heteroaryl, or a 5-6 membered cycloalkyl group as suitable bioisosteric equivalents. See, e.g., claim 1, A variable: PNG media_image16.png 119 1269 media_image16.png Greyscale WO’798 at 7 of 89 itself taught that the exact 5-membered heteroaryl group was a preferred bioisosteric equivalent to use in its compounds: PNG media_image43.png 552 562 media_image43.png Greyscale In view of the shared structural similarity, the person of ordinary skill in the art at the time of filing had a reasonable expectation that the compound would inhibit the same pharmacological targets in the same way. Both WO’527 and WO’798 teach that the pharmacological target accepts a variety of substituents in the same space, and WO’798 expressly teaches that a compound bearing the exact 5-membered heteroaryl group of the embodiment of claim 2 compound was preferred. Once WO’527 exemplified that the ethynyl linkage was preferred, it was obvious to prepare its variants as taught by WO’798. The embodiment of claim 2 compound is one of these compounds, which the person of ordinary skill in the art at the time of filing would have had a reasonable expectation of success in inhibiting PDE10A with. PNG media_image7.png 387 547 media_image7.png Greyscale Embodiment of claim 2 Accordingly, claim 2 was obvious at the time of filing. The above compound is encompassed by claims 6, 8, and 12-16, which were obvious at the time of filing for the same reasons stated above. Claims 3, 4, 7, and 25 were obvious The following compound is an embodiment of claim 3: PNG media_image8.png 397 524 media_image8.png Greyscale Embodiment of claim 3 While WO’798 did not exemplify the embodiment of claim 3 compound, one of ordinary skill in the art at the time of filing would have had a reasonable expectation of success in inhibiting PDE10A with the above compound because it adopted the preferential ethynyl linkage taught by WO’527, and WO’798 explained that the compound would function as a PDE10 inhibitor. For example, WO’798 explained that when one prepared a PDE10 inhibitor, the pyrimidine group could be fused to either a benzene ring, a 5-6 membered heteroaryl, or a 5-6 membered cycloalkyl group as suitable bioisosteric equivalents. See, e.g., claim 1, A variable: PNG media_image16.png 119 1269 media_image16.png Greyscale WO’798 at 7 of 89 itself taught that the exact 5-membered heteroaryl group was a preferred bioisosteric equivalent to use in its compounds: PNG media_image43.png 552 562 media_image43.png Greyscale WO’798 taught that the morpholinyl group could be substituted with standard replacements for morpholinyl commonly used in medicinal chemistry such as 1-N-Methylmorpholinyl. See WO’798 at 5/89, paragraph [0017], stating “the 4-6-membered heteroaliphatic ring in R 1 may be substituted with … C1-6 alkyl”, and WO’798 at 26/89, paragraph [0152], stating this includes the standard 1-N-Methylmorpholinyl widely used in medicinal chemistry. In view of the shared structural similarity, the person of ordinary skill in the art at the time of filing had a reasonable expectation that the compound would inhibit the same pharmacological targets in the same way. Both WO’527 and WO’798 teach that the pharmacological target accepts a variety of substituents in the same space, and WO’798 expressly teaches that a compound bearing the exact 5-membered heteroaryl group of the embodiment of claim 3 compound was preferred. Once WO’527 exemplified that the ethynyl linkage was preferred, it was obvious to prepare its variants as taught by WO’798. The embodiment of claim 3 compound is one of these compounds, which the person of ordinary skill in the art at the time of filing would have had a reasonable expectation of success in inhibiting PDE10A with. PNG media_image8.png 397 524 media_image8.png Greyscale Embodiment of claim 3 Accordingly, claim 3 was obvious at the time of filing. The above compound is encompassed by claims 4, 7, and 25, which were obvious at the time of filing for the same reasons stated above. Claim 18 was obvious The embodiment of claim 1, 2, and 3 compounds are all compounds of WO’798. WO’798 teaches how to prepare pharmaceutical compositions comprising its compounds with one or more excipients. See, e.g., WO’798 at 29-30/89, paragraphs [0167] and [0169]. One of ordinary skill in the art at the time of filing would have had a reasonable expectation of success in preparing pharmaceutical compositions comprising the embodiment of claim 1, 2, or 3 compounds and one or more excipients because WO’798 taught how to prepare such pharmaceutical compositions and the embodiment of claim 1, 2, or 3 compounds were compounds of WO’798. Therefore, claim 18 was obvious at the time of filing. Response to Arguments, WO’527 in view of WO’798 and Patani 1996: Applicant's arguments, see Remarks Received 07/21/2026, at 17-18 of 21, with respect to the rejections of claims 9-11, 17 and 26 under 35 U.S.C. 103 over WO’527 in view of WO’798 and Patani 1996 as stated in the 04/23/2026 Non-Final Rejection have been fully considered but they are not persuasive because Applicant’s amended claims still encompass obvious subject matter. Applicant’s position regarding Patani 1996 is that it is merely “a general text-book level survey article discussing the concept of bioisosterism across dozens of unrelated therapeutic classes and pharmacological targets.” Remarks at 18. Applicant’s initial summary of the reference is not persuasive and does not further its position because if bioisosterism were so unrelated it would not be used “by a medicinal chemist in the rational modification of lead compounds into safer and more clinically effective agents.” Remarks at 17. Applicant then argues that Patani 1996 destroys a reasonable expectation of success because Patani 1996 expressly cautions that "not all of these replacements will necessarily result in a compound with comparable biological activity to the template drug" and that "[m]inor structural modifications in these agonistic molecules has frequently resulted in a marked or complete loss of activity." Patani 1996, p. 3165. Remarks at 18. Applicant’s position is not persuasive, quotes two separate portions of Patani 1996 that require context, and Applicant is reminded that a reasonable expectation of success does not require absolute predictability of success. The expectation of success must be reasonable. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). The sections that Applicant quotes appear in two separate parts of Patani 1996. The first quotation “not all of these replacements will necessarily result in a compound with comparable biological activity to the template drug” is in a section regarding “Nonclassical Bioisosteric Replacements of Functional Groups”, and in its full context, it expressly “encourage[s] the use of these isosteres in future structure activity studies”. The quotation therefore does not destroy a reasonable expectation of success as Applicant purports. See Patani 1996 at 3165: PNG media_image44.png 369 623 media_image44.png Greyscale Patani 1996 at 3165. The second quotation appears in Patani 1996 at 3164 in a section regarding GABA agonists. It discusses “cyclic and noncyclic bioisosteres” and expressly states that in this regard, “this concept of cyclic and noncyclic bioisosteres has played a major role.” GABA is a tiny neurotransmitter molecule (compound 44, PNG media_image45.png 110 142 media_image45.png Greyscale ). Therefore, “[m]inor structural modifications in these agonistic molecules has frequently resulted in a marked or complete loss of activity.” Id. Nevertheless, Patani 1996 provides 13 examples where “cyclic and noncyclic bioisosteres” were successfully applied compared to this tiny molecule GABA, compound 44, e.g., PNG media_image46.png 212 409 media_image46.png Greyscale PNG media_image47.png 209 409 media_image47.png Greyscale PNG media_image48.png 216 412 media_image48.png Greyscale The quotation therefore does not destroy a reasonable expectation of success as Applicant purports. Applicant continues and argues that Patani 1996 itself teaches that bioisosteres should be empirically correlated with biological activity through quantitative structure activity relationships (QSARs). Remarks at 18. Applicant is reminded that each of WO’527 and WO’798 provide an actual SAR. If the Patani 1996 was inconsistent with the SARs of WO’527 and WO’798, Applicant might have persuasively argued that. However, one of ordinary skill in the art at the time of filing would have reviewed the SARs of WO’527 and WO’798 and recognized that throughout they exemplified the use of bioisosterism for “the rational modification of lead compounds into safer and more clinically effective agents”. For example, as discussed, WO’527 at 14 teaches the following PDE10A inhibitor on the left, which had IC50 of 19 nM in the PDE10A assay in nM. WO’798 at 16-17/89 teaches the compounds on the right. “[A]ccording to Grimm”, Patani 1996 at 3148, Table 2, the compounds on the right are classical bioisosteres of the compound of WO’527 on the left. The only difference in the chemicals is the classical bioisosteric exchange of CH2 for NH and O. Therefore, “according to Grimm”, the compounds on the right should “affect the same pharmacological target as … antagonists and, thereby, have biological properties which are related”. Id. PNG media_image49.png 190 303 media_image49.png Greyscale 2-[2-(1-Methyl-4-phenyl-1 H-imidazol-2-yl)-ethyl]-4-morpholin-4-yl-quinazoline, IC50 of 19 nM PDE10A inhibitor of WO’527 PNG media_image50.png 210 230 media_image50.png Greyscale PNG media_image51.png 189 240 media_image51.png Greyscale Classical bioisosteres of the PDE10A inhibitor of WO’527, from WO’798 Grimm was again right, because the compounds on the right had IC50s of less than 50 nM in the same assay, exactly as reasonably expected. See WO’798 at 61/89, Table 1. PNG media_image52.png 339 385 media_image52.png Greyscale WO’798 at 61/89, assay towards PDE10A, ++ means <5 nM, + means <50 nM8 Other examples exist throughout the SARs of WO’527 and WO’798. Applicant’s assertion that Patani 1996 destroys a reasonable expectation of success in applying the well-known principles of bioisosterism is not persuasive. Its allegation in Remarks at 18 that Patani 1996 “does not supply a reasonable expectation of success” is inconsistent with the well-known principles of bioisosterism and the SARs of WO’527 and WO’798, which themselves demonstration its application. Therefore, Applicant positions regarding the rejections of claims 9-11, 17 and 26 under 35 U.S.C. 103 as being unpatentable over WO’527 in view of WO’798 and Patani 1996 are not persuasive. The rejection is reiterated below. Claims 9-11, 17 and 26 Obvious over WO’527 in view of WO’798 and Patani 1996 Claims 9-11, 17 and 26 rejected under 35 U.S.C. 103 as being unpatentable over WO’527 in view of WO’798 and Patani 1996. Claim 9 depends on claim 8 which depends on claim 1 and changes the ring structure slightly as shown below: PNG media_image53.png 191 569 media_image53.png Greyscale Thus claim 9 now requires a 6-membered heterocycle as shown above. The following compound is an embodiment of the claim: PNG media_image54.png 183 264 media_image54.png Greyscale Embodiment of claim 9 This compound is encompassed by claims 9-11, 17 and 26, as well as others. WO’527 and WO’798 are relied upon as above. As discussed previously, the following compound is an embodiment of instant claim 1. PNG media_image55.png 172 232 media_image55.png Greyscale Embodiment of claim 1 As previously explained, the above compound is a compound of WO’798, and one of ordinary skill in the art at the time of filing had a reasonable expectation of success in inhibiting PDE10A with the above compound because it adopted the preferential ethynyl linkage taught by WO’527, and WO’798 explained that the compound would function as a PDE10 inhibitor. While the variables permitted for the ring fused to the pyrimidine ring of WO’798 do not expressly teach that the ring may be a “6-membered heterocycle”, PNG media_image16.png 119 1269 media_image16.png Greyscale one of ordinary skill in the art at the time of filing would recognize that WO’798 suggested that certain 6-membered heterocycles would function equally as well in view of the shared structural similarity and the well-known concepts of bioisosterism. One of ordinary skill in the art at the time of filing would have had a reasonable expectation of success in inhibiting PDE10A with the embodiment of claim 9 compound because Patani 1996 taught that there was a reasonable expectation that it would affect the same pharmacological targets as the embodiment of claim 1 compound in the same way and, thereby, have biological properties that were related. For example, see Patani 1996. Patani 1996 The exchange of CH2 with NH 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 (third column shows the CH2 and NH exchange): PNG media_image56.png 439 571 media_image56.png Greyscale Patani 1996 at 3148, Table 2. Accordingly, the exchange of CH2 with NH 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. Patani 1996 provides classic examples of exchanges of CH2 with NH throughout. The exchange results in classical bioisosteres when it involves divalent exchanges outside of ring systems, see, e.g.¸ Figures 23 and 24 at 3156, and within, see, e.g. id. at 3158, Ring Equivalents (“Classical isosteric substitutions when applied within ring systems result in different heterocyclic analogues which can be effective bioisosteres.”). See also examples at Figures 33, 34, and 36 at 3158-3159. The SARs of WO’527 and WO’798 provide additional examples of classical isosteric substitutions, including those applied within ring systems. For example, compare compound 11 of WO’798 to its classical bioisostere from WO’527. This concept was well established at the time of filing. PNG media_image57.png 215 185 media_image57.png Greyscale , Ic50 under 5 nM PNG media_image49.png 190 303 media_image49.png Greyscale 2-[2-(1-Methyl-4-phenyl-1 H-imidazol-2-yl)-ethyl]-4-morpholin-4-yl-quinazoline, IC50 of 19 nM Therefore, the person of ordinary skill in the art at the time of filing had a reasonable expectation that a classical bioisostere of a PDE10 inhibitor of WO’798 would affect the same pharmacological target as an antagonist and, thereby, have biological properties that were related. Thus, the person of ordinary skill in the art at the time of filing had a reasonable expectation that the embodiment of claim 9 compound would inhibit PDE10A because it was classical bioisostere of the embodiment of claim 1 compound, which was a PDE10 inhibitor of WO’798 Therefore, claims 9-11, 17 and 26 were obvious at the time of filing. PNG media_image58.png 184 248 media_image58.png Greyscale Embodiment of claim 1 PNG media_image54.png 183 264 media_image54.png Greyscale Embodiment of claim 9 Response to Arguments, WO’527 in view of WO’798, US’783 and Hsu 2021: Applicant's arguments, see Remarks Received 07/21/2026, at 19-21 of 21, with respect to the rejections of claims 21 and 22 under 35 U.S.C. 103 over WO’527 in view of WO’798, US’783 and Hsu 2021 as stated in the Non-Final Rejection mailed 04/23/2026, have been fully considered but they are not persuasive because Applicant’s amended claims still encompass obvious subject matter. Applicant does not appear to contest the indication of claim 21 (any PDE10 inhibition). Applicant focuses on claim 22 and the IBD indication. Applicant’s position regarding claim 22 is that, even though it appears to agree US'783 discloses that PDE10A is highly expressed in the gastrointestinal tract, and administering an agent to inhibit PDE10A would drive down IL-6 cytokine expression as explained in Hsu 2021, Applicant disagrees that it provides a reasonable expectation of success because US'783 did not provide evidence of administering a PDE10A inhibitor to drive down IL-6 cytokine expression in the in the gastrointestinal tract. Applicant also argues that Hsu 2021 is limited to inflammation in the lungs. Applicant’s position regarding Hsu 2021 is not persuasive because Applicant may have missed several statements in Hsu 2021 that indicate otherwise. “Our findings indicate that PDE10A induction plays a causative role in inflammatory molecule expression and acute lung inflammation.” Hsu 2021 at Abstract (emphases added). “Our present data suggest that PDE10A is a key mediator of lung inflammation and cytokine secretion…”. Hsu 2021 at 12 (emphases added). Therefore, Applicant’s position is not persuasive because it follows if PDE10A is highly expressed in the gastrointestinal tract, and that administering an agent to inhibit PDE10A would drive down IL-6 cytokine expression as explained in Hsu 2021, then one would reasonably expect to succeed in driving down IL-6 cytokine expression and therefore treat inflammation in the bowels where the PDE10A is highly expressed. Further, as the Specification states, it was well-established that IL-6 drives chronic inflammation and is correlated to disease severity in patients with ulcerative colitis, a form of IBD. See, e.g., Specification at 89: PNG media_image59.png 508 843 media_image59.png Greyscale Specification at 89. Nothing appears to be inconsistent with the finding that one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in using a PDE10A inhibitor to treat inflammation in these patients. When Applicant presents a compound claim that is non-obvious and enabled to administer with this indication, the method of treatment will be allowed. Therefore, Applicant positions regarding the rejections of claims 21 and 22 under 35 U.S.C. 103 as being unpatentable over WO’527 in view of WO’798, US’783 and Hsu 2021 are not persuasive. The rejection is reiterated below. Claims 21 and 22 were Obvious over WO’527 in view of WO’798, and Hsu 2021 at the Time of Filing Claims 21 and 22 rejected under 35 U.S.C. 103 as being unpatentable over WO’527 in view of WO’798, US’783 and Hsu 2021. WO’527 and WO’798 are relied upon as above. Claim 21 recites a method for the treatment of a disease or condition susceptible to PDE10 inhibition, comprising administering to a subject in need thereof a compound claimed in claim 1. WO’798 discloses such methods for the compounds of its invention. See, e.g., WO’798 at 25/89, paragraph [0113]: PNG media_image60.png 59 939 media_image60.png Greyscale WO’798 at 25/89, paragraph [0113]. See also, WO’798 at 27/89, paragraph [0136]: PNG media_image61.png 146 960 media_image61.png Greyscale See also WO’798 at 27/89, paragraph [0136]. The embodiment of claim 1, 2, or 3 compounds were compounds of WO’798 and could administered with a reasonable expectation of success for the same purpose. Therefore, one of ordinary skill in the art at the time of filing would have had a reasonable expectation of success treating an anxiety disorder by administering the previously discussed embodiment of claim 1, 2, or 3 compounds. Accordingly, claim 21 was obvious at the time of filing. Regarding claim 22, WO’527 and WO’798 do not expressly teach the IBD indications. However, one of ordinary skill in the art at the time of filing would have had a reasonable expectation of success in treating IBD with a PDE10A inhibitor because US’783 discloses that PDE10A is highly expressed in the gastrointestinal tract, and that one can administer an agent to modulate the unwanted activity of PDE10A, Hsu 2021 explained that one would reasonably expect that by administering a PDE10A inhibitor, it would drive down IL-6 cytokine expression, and the Specification explains that it was well-known that IL-6 cytokine expression was correlated to disease severity in patients with ulcerative colitis, a form of IBD. See US’783 at 18, paragraph [0202], which discloses a number of gastrointestinal diseases, including “disorders of the bowel like chronic inflammatory disease of the bowel, Chron’s disease, … and ulcerative colitis”. Further see US’783 at 22, paragraph [0204], which discloses that “[t]he human PDE10A is highly expressed in the following tissues of the gastroenterological system: esophagus, esophagus tumor, stomach, stomach tumor, rectum, ….” (emphasis added). US’783 states that “the activity of the human PDE10A can be modulated to treat gastroenterological disorders.” Id. US’783 further states that diseases such as “gastroenterological diseases” can be treated by administering an “agent” that “inhibits one or more of the biological activities of PDE10A.” US’783 at 21-22, paragraphs [0230] and [0231]. As US’783 explains, such methods include “methods of treating an individual afflicted with a disease or disorder characterized by unwanted expression or activity of PDE10A or protein in the PDE10A signaling pathway.” Id. Hsu 2021 explains that “PDE10A plays a critical role in lung inflammation by promoting the activation of resident macrophages and infiltration of neutrophils.” See Hsu 2021 at Abstract. “Our findings indicate that PDE10A induction plays a causative role in inflammatory molecule expression and acute lung inflammation.” Hsu 2021 at Abstract (emphases added). Hsu 2021 at 3017 explains that in “global PDE10A-KO mice, PDE10A deficiency can significantly reduce lung inflammation” resulting from LPS exposure. “Furthermore, with systemic application of PDE10A inhibitor TP-10, we obtained similar results that PDE10A deficiency and activity inhibition significantly suppressed the expression of inflammatory molecules such as MCP-1, IL-6, and IL-1β in the lung and the BAL fluid as well as inhibited inflammatory cell infiltration into the lung”. Id. The effects of PDE10A inhibition extend past the local injury to the lungs. The effects were additionally observed in peritoneal macrophages used as standard models of “macrophage inflammation”. Hsu 2021 at 3013. See also the following excerpt (TP-10 is the PDE10 inhibitor): PNG media_image62.png 603 587 media_image62.png Greyscale Hsu 2021 at 3013. Accordingly, Hsu 2021 uncovers a direct link between PDE10A activity and inflammatory cytokines, including IL-6, wherein suppressing PDE10A activity with a PDE10A inhibitor decreases IL-6 expression. “Our present data suggest that PDE10A is a key mediator of lung inflammation and cytokine secretion…”. Hsu 2021 at 3015. Further, as the Specification states, it was well-established that IL-6 drives chronic inflammation and is correlated to disease severity in patients with ulcerative colitis, a form of IBD. See, e.g., Specification at 89: PNG media_image59.png 508 843 media_image59.png Greyscale Specification at 89. Therefore, it was reasonable to expect that by administering a PDE10A inhibitor, it would drive down IL-6 cytokine expression in the gastrointestinal tract where PDE10A is highly expressed. As a result, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in treating inflammation of the bowels by administering the embodiment of claim 1, 2, or 3 compounds, because the compounds were reasonably expected to inhibit PDE10A. Accordingly, claim 22 was obvious at the time of filing. Conclusion No claims allowed. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a). A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. 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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 International Publication No. WO 2013/050527 A1, published April 11, 2013, hereinafter “WO’527”. 2 International Publication No. WO 2013/005798 A1, published January 10, 2013, hereinafter “WO’798”. 3 WO’798 was published in Japanese. The supplied translation is the Edge browser’s machine translation of the application publication text from WIPO PATENTSCOPE. Page numbers refer to those shown in the bottom right of the annexed printout. 4 George A. Patani and Edmond J. LaVoie, “Bioisosterism: A Rational Approach in Drug Design”, Chem. Rev., vol. 96, no. 8, pp. 3147-3176 (1996), hereinafter “Patani 1996”. 5 Stefan Golz et al., “Diagnostics And Therapeutics For Diseases Associated With Human Phosphodiesterase 10a (Pde10a)”, U.S. Patent Application Publication No. 2006/0110783 A1, published May 25, 2006, hereinafter “US’783” 6 Chia George Hsu et al., “Phosphodiesterase 10A is a key mediator of lung inflammation”, The Journal of Immunology, vol. 206, no. 12, pp. 3010-3020 (June 15, 2021), hereinafter “Hsu 2021”. 7 The untranslated text, when passed through Google Translate, translates to “Example number”. 8 The untranslated text, when passed through Google Translate, translates to “Example number”.