COMPOUNDS, COMPOSITIONS, AND METHODS

§103 §112 §DP

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 . Specification The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The Examiner suggests the title should reflect the unifying structure of the disclosed species or genus in addition to the utility. The following title is suggested: SUBSTITUTED 1-OXOSPIRO-3H-ISOQUINOLINE-CYCLOPROPANES FOR TREATING NLRP3 MEDIATED DISEASES. Claim Objections Claim 1 is objected to because of the following informalities: Claim 1 appears to recite duplicate structures (see example below). Claim 1 Example 42 Claim 1 p. 12 Example 55 PNG media_image1.png 98 216 media_image1.png Greyscale PNG media_image2.png 96 226 media_image2.png Greyscale Appropriate correction is required. 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 1, 15-19 are 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 1 includes multiple scenarios that raise uncertainty regarding the metes and the bounds of the claim, described below. Claims 15-19 do not resolve these issues of indefiniteness, and are thus included in instant rejection. Scenario 1. Compounds with The Same Line Angle Structure, with No Stereochemistry, and Different Descriptors For exemplary purposes, the set of Examples 16 and 17 are used to describe the scenario issue. This exemplary set is non-exhaustive. Claim 1 Example 16 Claim 1 Example 17 PNG media_image3.png 158 404 media_image3.png Greyscale PNG media_image4.png 162 406 media_image4.png Greyscale Claim 1 lists pairs of compounds drawn as the same line-angle structure, with no stereochemistry fixed, and distinguishes the set by “first eluting isomer” and “second eluting isomer” descriptors. The instant specification shows the respective stereoisomers, PNG media_image5.png 102 442 media_image5.png Greyscale (see instant spec. at p. 93), but does not indicate which stereoisomer is first and which is second. The metes and bounds of what structure Example 16 or 17 is thus unclear, for either one could be referring to PNG media_image6.png 96 194 media_image6.png Greyscale . Scenario 2. Compounds with The Same Line-Angle Structure, with Fixed Stereochemistry, and Different Descriptors For exemplary purposes, the set of Examples 47 and 48 are used to describe the scenario issue. This exemplary set is non-exhaustive. Claim 1 Example 47 Claim 1 Example 48 PNG media_image7.png 152 408 media_image7.png Greyscale PNG media_image8.png 160 410 media_image8.png Greyscale Claim 1 lists pairs of compounds drawn as the same line-angle structure, with stereochemistry fixed, and distinguishes the set by “first eluting isomer” and “second eluting isomer” descriptors. The instant specification shows the respective stereoisomers, PNG media_image9.png 96 426 media_image9.png Greyscale (see instant spec. at p. 106), which clearly distinguishes the stereochemistry of the isomers, thus conflicting with the structure of one of Example 47 or Example 48 in the claim. The instant specification does not indicate which stereoisomer structure is first and which is second. The metes and bounds of what structure Example 47 or 48 is thus unclear, for neither appears to be PNG media_image10.png 90 202 media_image10.png Greyscale , which must be one of Example 47 or 48 as indicated in the specification. Moreover, the other scenario issues with claim 1 brings doubt to if Applicant truly intended to indicate the shown stereocenters in the claim, since a compound with two stereocenters could give four isomers, which brings more ambiguity to the “first” and “second” eluting descriptors. Scenario 3. Compounds with “Single Unknown Stereoisomer” Descriptor For exemplary purposes, Example 43 is used to describe the scenario issue. This exemplary species is non-exhaustive. Claim 1 Example 43 PNG media_image11.png 154 408 media_image11.png Greyscale Claim 1 lists species with stereochemistry fixed, and labels the species with a “single unknown stereoisomer” descriptor. This is confusing because the stereochemistry of the line-angle structure is fixed, which would indicate a clearly defined structural species, which suggests the species is “known”. The instant specification shows the same line-angle species, PNG media_image12.png 98 210 media_image12.png Greyscale (see instant spec. at p. 104) which indicates a known stereoisomer. It is unclear what Applicant is trying to claim by the descriptor “single unknown stereoisomer”. Is the line-angle structure a guess at the stereochemistry? Did Applicant mean to draw a line-angle structure with no stereochemistry? Scenario 4. Compounds with “Single Known Stereoisomer” Descriptor For exemplary purposes, Example 54 is used to describe the scenario issue. This exemplary species is non-exhaustive. Claim 1 Example 54 PNG media_image13.png 160 414 media_image13.png Greyscale Claim 1 lists species with stereochemistry fixed, and labels the species with a “single known stereoisomer” descriptor. This is confusing because is the descriptor indicating the species is fully characterized and known to have the shown stereochemistry, or already known in the art, or the only existing stereoisomer, or the only stereoisomer isolated? The instant specification shows the same line-angle species, PNG media_image14.png 92 196 media_image14.png Greyscale (see instant spec. at p. 109), but given the other scenario issues with claim 1 brings doubt to if Applicant truly intended to indicate the shown stereochemistry in the specification and the claim. Moreover, there are two stereocenters, meaning four potential isomers exist, so it is unclear if only one is “known” and if the one “known” is the one displayed. Scenario 5. A Line-Angle Structure with Multiple Stereocenters, Only One Fixed, and Different Descriptors For exemplary purposes, the set of Examples 10 and 11 are used to describe the scenario issue. This exemplary set is non-exhaustive. Claim 1 Example 10 Claim 1 Example 11 PNG media_image15.png 146 408 media_image15.png Greyscale PNG media_image16.png 148 408 media_image16.png Greyscale Claim 1 lists pairs of compounds drawn as the same line-angle structure, with one of the two stereocenters fixed, and distinguishes the set by “first eluting isomer” and “second eluting isomer” descriptors. The instant specification shows the respective stereoisomers, PNG media_image17.png 88 450 media_image17.png Greyscale (see instant spec. at p. 91), but does not indicate which stereoisomer is first and which is second. The metes and bounds of what structure Example 10 or 11 is thus unclear, for either one could be referring to PNG media_image18.png 94 208 media_image18.png Greyscale . Moreover, given the other scenario issues with claim 1 brings doubt to if Applicant truly intended to indicate the shown stereocenter in the claim, since a compound with two stereocenters could give four isomers, which brings more ambiguity to the “first” and “second” eluting descriptors. Scenario 6. A Line-Angle Structure with “Mixture of Enantiomers” Descriptor vs No Descriptor For exemplary purposes, Examples 63 and 9 are used to describe the scenario issue. This exemplary set is non-exhaustive. Claim 1 Example 63 Claim 1 Example 9 PNG media_image19.png 162 406 media_image19.png Greyscale PNG media_image20.png 122 406 media_image20.png Greyscale Claim 1 lists compounds drawn with no fixed stereochemistry, and labels the species “mixture of enantiomers (e.g. Example 63). The instant specification does not show the stereochemistry of the enantiomers, PNG media_image21.png 108 204 media_image21.png Greyscale (see instant spec. at p. 114) and does not appear to isolate the claimed mixture. Claim 1 also lists compounds with no fixed stereochemistry, but does not label the species (e.g. Example 9). It is unclear if these species are also mixtures of enantiomers or not. Why do some species get descriptors and others do not – is it to indicate a structural difference? Scenario 7. The Preamble Claim 1 recites “A compound…stereoisomer, mixture of stereoisomers…”. Since the claim uses descriptors such as “first eluting isomer” are the stereoisomers the preamble refers to just referencing the first/second eluting isomers? Or any envisionable stereoisomer? WO632 p. 38 Example 43 Instant Claim 1 Example 55 PNG media_image22.png 70 164 media_image22.png Greyscale PNG media_image23.png 94 224 media_image23.png Greyscale 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. Claim(s) 1-19 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2022109268 A1 to Bagdasarian et. al.1 The applied reference has a common assignee, applicant, and/or joint inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See MPEP § 2154.02. Regarding claim 1 and the listed species, Bagdasarian teaches compounds with significantly overlapping structures as in instant application such as Example 408, also known as CAS# 2771022-50-3 (see Bagdasarian at p. 319), which is structurally similar to instant Example 55. CAS# 2771022-50-3 has an NMe in lieu of NH as in Example 55. Bagdasarian Example 408 CAS# 2771022-50-3 Instant Claim 1 Example 55 PNG media_image24.png 148 369 media_image24.png Greyscale PNG media_image23.png 94 224 media_image23.png Greyscale Regarding claim 2 and the listed species, Bagdasarian teaches Example 408, also known as CAS# 2771022-50-3 (see Bagdasarian at p. 319), which is structurally similar to species listed in instant claim 2 (see claim 2 p. 21). CAS# 2771022-50-3 does not have a fluoropropyl as in the exemplary claim 2 species, and has an NMe in lieu of NH. Bagdarian Example 408 CAS# 2771022-50-3 Instant Claim 2 Species PNG media_image24.png 148 369 media_image24.png Greyscale PNG media_image25.png 98 214 media_image25.png Greyscale Regarding instant claims 3-14 and a compound of Formulas I, IC, VII, VIII, or VIIIA, Bagdasarian teaches Example 408, also known as CAS# 2771022-50-3 (see Bagdasarian at p. 319). Bagdasarian Example 408 CAS# 2771022-50-3 Instant Claim 3 Formula I Instant Claim 9 Formula IIIA PNG media_image24.png 148 369 media_image24.png Greyscale PNG media_image26.png 112 254 media_image26.png Greyscale PNG media_image27.png 92 262 media_image27.png Greyscale CAS# 2771022-50-3 corresponds with instant Formula I when A1, A3 and A4 are CH, A2 is CR1, R1 is halo specifically bromo, X is C(X1), X1 is O, Y is C(Y1), Y1 is O, Z is N, R2 and R3 together form a C3-10 cycloalkyl ring specifically cyclopropyl, R4 and R5 are H, R6 and R7 are H, R9 and R10 are H, and R12 is H. CAS# 2771022-50-3 also corresponds to instant Formulas IC, VII, VIII, or VIIIA as described above. Regarding claim 15 and a composition, Bagdasarian teaches pharmaceutical compositions comprising the disclosed compounds and a pharmaceutically acceptable carrier (see Bagdasarian at claim 38). Regarding claims 16 and a method of treating a disease or condition at least in part mediated by NLRP3, Bagdasarian teaches the disclosed compounds are small molecule modulators of NLRP3 (see Bagdasarian at Abstract). Bagdasarian teaches methods for treating a disease or condition at least in part mediated by NLRP3 comprising administering an effective amount of a composition comprising the disclosed compound to a subject (see Bagdasarian at claim 38). Regarding claims 17, 19 and a disease such as Alzheimer’s, Bagdasarian teaches wherein the disease may be selected from a list including Alzheimer’s disease (see Bagdasarian at claims 40, 42). Regarding claim 18 and a disease such as NAFLD or NASH, Bagdasarian teaches wherein the disease may be selected from a list including NAFLD or NASH (see Bagdasarian at claims 40, 41). The prior art differs from the instant claims as follows: While Bagdasarian teaches CAS# 2771022-50-3 for treating NLR3P mediated diseases, CAS# 2771022-50-3 differs from the instantly claimed species and genus by i) NMe vs NH (as in instant claims 1, 3) or i) NMe vs NH, H vs F, and specified stereochemistry (as in instant claim 2). However, Regarding Me vs H, Bagdasarian teaches a genus of Formula IX (see Bagdasarian at p. 31). Bagdasarian Example 408 CAS# 2771022-50-3 Bagdasarian Formula IX PNG media_image24.png 148 369 media_image24.png Greyscale PNG media_image28.png 110 178 media_image28.png Greyscale Bagdasarian teaches R5 or ring A may be pyrazolo[3,4-d]pyrimidinyl (see Bagdasarian at p. 32 ¶[0125], first line), reading on a non-methyl variant of Bagdasarian Example 408. Regarding H vs F, Bagdasarian teaches a genus of Formula IX (see above). Bagdasarian teaches Z1 may be a halogen (see Bagdasarian at p. 36 ¶[0142]). Bagdasarian teaches species wherein Z1 is fluorine such as Example 109 (see Bagdasarian at p. 44). Bagdasarian Example 109 Bagdasarian Formula IX PNG media_image29.png 122 220 media_image29.png Greyscale PNG media_image28.png 110 178 media_image28.png Greyscale Regarding stereochemistry, Bagdasarian teaches the same defined stereochemistry of the oxospiro-isoquinoline moiety as in instant claim 2 species (see Bagdasarian Example 109 at p. 44). Bagdasarian Example 109 Instant Claim 2 Species PNG media_image29.png 122 220 media_image29.png Greyscale PNG media_image25.png 98 214 media_image25.png Greyscale Bagdasarian also contemplates the various stereoisomers present for substituted oxospiro-isoquinoline moieties (see, e.g., Bagdasarian at p. 57 Examples 280 and 281, p. 60 Examples 321 and 327, and also p. 71 species, a selection cropped and shown below). PNG media_image30.png 90 70 media_image30.png Greyscale PNG media_image31.png 88 74 media_image31.png Greyscale PNG media_image32.png 86 70 media_image32.png Greyscale PNG media_image33.png 88 72 media_image33.png Greyscale Bagdasarian even claims in the genus of Formula I stereoisomers or mixtures of stereoisomers (see Bagdasarian at claim 1). Bagdasarian is thus well aware of the stereoisomer possibilities for an oxospiro-isoquinoline with two stereocenters. Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s): Regarding Me vs H, the prior art suggests pyrazolo[3,4-d]pyrimidinyl at the R5 position or ring A position (as taught by Bagdasarian). It would have been obvious to substitute H for Me in CAS# 2771022-50-3 as this is specifically contemplated by the reference to be a suitable alternative. Regarding H vs F, the prior art suggests a halogen substituent at the same position as in instantly claimed species, and even discloses defined species with a fluorine on the spirocyclopropyl (as taught by Bagdasarian). It would have been obvious to substitute H for F in CAS# 2771022-50-3 as this is specifically contemplated by the reference to be a suitable alternative. Regarding stereochemistry, per MPEP § 2144.09(I)-(II), “[a] prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities” because “[c]ompounds which are…isomers…are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties” (see, e.g., MPEP § 2144.09(I)-(II)), and the Court has stated that “[i]f a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” KSR, 127 S.Ct. at 1740. Here, the prior art teaches highly similar structural isomers of the instantly claimed invention, and specifically contemplates isomer variants of the same stereocenters, wherein such isomers have the same, exact utility as the instantly claimed NLRP3 modulators; accordingly, an artisan would readily appreciate that such compounds could be utilized in the treatment of NLRP3 diseases, exactly as taught and suggested in view of the prior art. Furthermore, it is well-within the ordinary skill in art to: substitute a methyl for a hydrogen on a known compound, substitute a hydrogen for a fluorine on a known compound, and/or identify and isolate stereoisomers of a known compound for the same purpose as taught by the prior art. Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art. Claim(s) 1, 2, 15-19 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2022/232632 A1 to Bagdasarian et. al.2 The applied reference has a common assignee, applicant, and/or joint inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See MPEP § 2154.02. Regarding instant claims 1-2, WO’632 teaches a genus of Formula VII (see WO’632 at p. 27, Pro’741 at p. 20, Pro’393 at p. 23) wherein R2 and R3 may join to form a cycloalkyl substituted with one to eight Z1 (see WO’632 at p. 17, Pro’741 at p. 13, Pro’393 p. 16) which may be halo (see WO’632 at p. 18, Pro’741 at p. 14, Pro’393 p. 16). WO’632 Formula VII PNG media_image34.png 78 174 media_image34.png Greyscale WO’632 teaches species structurally similar to those instantly claimed, such as Example 110 also known as CAS# 2771019-27-1 (see WO’632 at p. 43, Pro’741 at p. 35 and Pro’393 at p. 38), which is structurally similar to instantly claimed species shown below. WO’632 p. 43 Example 110 CAS# 2771019-27-1 Instant Claim 2 CAS# 2993491-66-8 Instant Claim 1 Examples 16/17 PNG media_image35.png 88 180 media_image35.png Greyscale PNG media_image36.png 110 230 media_image36.png Greyscale PNG media_image37.png 135 288 media_image37.png Greyscale Regarding claim 15 and a composition, WO’632 teaches pharmaceutical compositions comprising the disclosed compounds and a pharmaceutically acceptable carrier (see WO’632 at claim 2, Pro’741 at claim 38 and Pro’393 at claim 38). Regarding claims 16 and a method of treating a disease or condition at least in part mediated by NLRP3, WO’632 teaches the disclosed compounds are small molecule modulators of NLRP3 (see WO’632 at Abstract). WO’632 teaches methods for treating a disease or condition at least in part mediated by NLRP3 comprising administering an effective amount of a composition comprising the disclosed compound to a subject (see WO’632 at claim 3, Pro’741 at claim 39 and Pro’93 at claim 39). Regarding claims 17, 19 and a disease such as Alzheimer’s, WO’632 teaches wherein the disease may be selected from a list including Alzheimer’s disease (see WO’632 at claims 4, 6, Pro’741 at claims 40, 42 and Pro’393 at claims 40, 42). Regarding claim 18 and a disease such as NAFLD or NASH, WO’632 teaches wherein the disease may be selected from a list including NAFLD or NASH (see WO’632 at claim 5 Pro’741 at claim 41 and Pro’393 at claim 41). The prior art differs from the instant claims as follows: While WO’632 teaches CAS# 2771019-27-1, CAS# 2771019-27-1 differs from instant species in a difference of hydrogen for fluorine. However, Regarding H vs F, Recall WO’632 teaches a genus of Formula VII wherein the cyclopropyl may be substituted with more than one Z1, and Z1 may be a halogen, and species wherein Z1 is fluorine such as Example 110. Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s): Regarding H vs F, the prior art suggests a halogen substituent at the same position as in instantly claimed species, and even discloses defined species with a fluorine on the spirocyclopropyl (as taught by WO’632). It would have been obvious to substitute H for F in CAS# 2771019-27-1 as this is specifically contemplated by the reference to be a suitable alternative. Furthermore, it is well-within the ordinary skill in art to substitute a hydrogen for a fluorine on a known compound for the same purpose as taught by the prior art. Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art. 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. Claims 1-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 10-11, 13, 15-16, 18-19, 21-22, 24-28, 30-31, 34-35, 37, 51-52 of copending Application No. 18/037,9993. Although the claims at issue are not identical, they are not patentably distinct from each other. The applicable analysis for Nonstatutory Double Patenting is set forth in MPEP § 804(II), and specifically MPEP § 804(II)(B). MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis. The instant analysis is an obviousness analysis. Regarding instant claim 1, App’999 claims obvious variants of the instantly claimed species, such as App’999 Examples 290 and 291 (see App’999 claim 37). The species differ from each other in halogen identity. App’999 Claim 37 Example 290/291 Instant Claim 1 Example 16/17 PNG media_image38.png 108 220 media_image38.png Greyscale PNG media_image39.png 104 224 media_image39.png Greyscale Regarding instant claim 2, App’999 claims obvious variants of the instantly claimed species, such as App’999 Example 321(see App’999 claim 51) and others shown below (see App’999 claim 52). The species differ from each other in hydrogen vs fluorine. App’999 Claim 51 Example 321 Instant Claim 2 Species PNG media_image40.png 106 226 media_image40.png Greyscale PNG media_image41.png 104 220 media_image41.png Greyscale App’999 Claim 52 p.68 Instant Claim 2 Species PNG media_image42.png 104 224 media_image42.png Greyscale PNG media_image41.png 104 220 media_image41.png Greyscale Claim 52 p. 58 Instant Claim 2 Species PNG media_image43.png 102 220 media_image43.png Greyscale PNG media_image44.png 110 216 media_image44.png Greyscale Regarding claim 3 and instant Formula I, App’999 claims genae that significantly overlap with instant Formula I (see selection below and App’999 claims 1, 4, 10-11, 13, 15-16, 18-19, 21-22, 24-28, 30-31, 34-35), and species such as Example 408 (see App’999 claim 37 p.44) which only differs from instant formula I in methyl vs hydrogen. App’999 Claim 37 Example 408 Instant Formula I PNG media_image45.png 100 214 media_image45.png Greyscale PNG media_image46.png 110 244 media_image46.png Greyscale App’999 Formula IB Instant Formula IC PNG media_image47.png 100 184 media_image47.png Greyscale PNG media_image48.png 108 254 media_image48.png Greyscale App’999 Formula VII Instant Formula VII PNG media_image49.png 96 218 media_image49.png Greyscale PNG media_image50.png 96 262 media_image50.png Greyscale App’999 Formula VIII Instant Formula VIIIA PNG media_image51.png 88 198 media_image51.png Greyscale PNG media_image52.png 100 252 media_image52.png Greyscale App’999 genae allow for R5 or ring A to be heteroaryl, which embraces instant Formula I’s PNG media_image53.png 90 88 media_image53.png Greyscale ring. Regarding instant claim 15 and a composition, App’999 claims a pharmaceutical composition comprising a disclosed compound, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier (see App’999 claim 38). Regarding instant claim 16 and a method, App’999 claims a method for treating a disease or condition mediated, at least in part, by NLRP3, the method comprising administering an effective amount of the pharmaceutical composition comprising a disclosed compound to a subject in need thereof (see App’999 claim 39). Regarding instant claims 17-19 and diseases, wherein the disease or condition is Alzheimer disease, atherosclerosis, asthma, allergic airway inflammation, cryopyrin-associated periodic syndromes, gout, intlammatory bowel disease and related disorders, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis(NASH), hypertension, myocardial infarction, multiple sclerosis, experimental autoimmune encephalitis, oxalate-induced nephropathy, hyperinflammation following influenza infection, graft-versus-host disease, stroke, silicosis, type I diabetes, obesity- induced inflammation or insulin resistance, rheumatoid arthritis, myelodysplastic syndrome, contact hypersensitivity, joint inflammation triggered by chikungunya virus, or traumatic brain injury (see App’999 claim 40). The copending applications differ as follows: some species differ from each other in halogen identity (e.g. Cl vs F), some species differ from each other in hydrogen vs fluorine, and App’999 Example 408 only differs from instant formula I in methyl vs hydrogen. However, these are all obvious variant changes. Therefore, it would have been obvious to one of ordinary skill in the art to arrive at the instantly claimed invention with a reasonable expectation of success in view of the copending claims for at least the following reason(s): Regarding a change in halogen identity (Cl vs F), per MPEP § 2144.06(II), a prima facie case of obviousness exists for substituting equivalents known for the same purpose. Halogens are a well-known, art-recognized class of functional equivalents, which Applicant acknowledges (see e.g. instant claim 3 “each Z1 is independently halo…”) and the copending app acknowledges (see e.g. App’999 claim 1 “each Z1 is independently halo…”). Regarding Me vs H, per MPEP § 2144.09(I)-(II), “[a] prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities” because “[c]ompounds which are…homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups…are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties” (see, e.g., MPEP § 2144.09(I)-(II)), and the Court has stated that “[i]f a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” KSR, 127 S.Ct. at 1740. In addition, per MPEP § 2144.08(II)(A)(4)(c), the closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. Here, the copending application teaches highly similar compounds differing by a -CH2- of the instantly claimed invention, wherein such homologs have the same, exact utility as the instantly claimed NLRP3 modulators; accordingly, an artisan would readily appreciate that such compounds could be utilized in the treatment of NLRP3-mediated diseases, exactly as taught and suggested in view of the copending application. Regarding H vs F, the copending application suggests a halogen substituent at the same position as in instantly claimed species (see App’999 claim 1 “R2 and R3 together form a C3-10 cycloalkyl or heterocyclyl ring; wherein the C3-10 cycloalkyl or heterocyclyl is optionally substituted with one to eight Z1… ach Z1 is independently halo”, and even claims defined species with two fluorines on the spirocyclopropyl (see App’999 claim 37 p. 34). It would have been obvious to substitute H for F in a claimed species of App’999 such as App’999 Claim 51 Example 321 to arrive at an instant species of claim 2 as this is specifically contemplated in the claims of the copending application to be a suitable alternative. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Conclusion The title is objected to. Claim 1 is objected to. Claims 1-19 are rejected. Any inquiry concerning this communication or earlier communications from the examiner should be directed to SOPHIA J REILLY whose telephone number is (703)756-5669. The examiner can normally be reached 9:00 am - 5:00 pm EST M-F. 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, KORTNEY KLINKEL can be reached at 571-270-5239. 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. /SOPHIA REILLY/Examiner, Art Unit 1627 1 Filed November 19, 2021. Has an inventor in common with instant application. 2 Cited in the IDS filed 9/27/24. Filed April 29, 2022. Claims priority to domestic provisional Application Nos. 63/256,393 filed October 15, 2021 (hereinafter Pro’393 and 63/182,741 filed April 30, 2021 hereinafter Pro’741. Has an inventor in common with instant application, Hereinafter WO’632. 3 PCT/US2021/060088 filed November 19, 2021.