DIHYDROPYRROLO[3,4C]-PYRAZOLE DERIVATIVES AND THEIR USE IN DIAGNOSIS

§103 §112 §DOUBLEPATENT

DETAILED ACTION This Office Action details a first action on the merits for the above referenced application No. Claims 1-14, 18, 26, 37-42, and 44-46 are pending in this application. 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 This application is a 35 USC 371 National Stage filing of international application No. PCT/EP2022/081550 filed on 10 Nov. 2022 and claims benefit under 35 USC 119(a)-(d) to foreign application No. EP 21207637.6 filed on 10 Nov. 2021. Information Disclosure Statement The information disclosure statements (IDSs) submitted on 9 May 2024 and 7 Aug. 2024 have been considered. Election/Restrictions Applicants’ election of Group I, claims 1-13, 37-39, and 44-46 in the reply filed on 24 Sep. 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claims 14, 18, 26, and 40-42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups II-III, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 24 Sep. 2026. Applicant’s election of species (see below) in the reply filed on 24 Sep. 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claims 7, 11-13, 37-39, and 45-46 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 24 Sep. 2026. PNG media_image1.png 142 206 media_image1.png Greyscale Claim Rejections - 35 USC § 112 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. Claim 1-6, 8-9, and 44 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. In claim 5, the recitation of “preferably” is indefinite because it is not clear if the recitations that follow are required. Claims 1-6, 8-9, and 44 are drawn to an almost unlimited number of variations due to the large number of different chemical substitutions set forth in the claims, such as, wherein Formula I, which has variables A, R1 and R2 which can contain any variety of structures due to the variability, which can encompass various different chemical classes, which all have different structural features and utilities. In certain circumstances, however, a Markush group may be so expansive that persons skilled in the art cannot determine the metes and bounds of the claimed invention. For example, if a claim defines a chemical compound using one or more Markush groups, and that claim encompasses a massive number of distinct alternative members, the claim may be indefinite under 35 U.S.C. 112(b) if one skilled in the art cannot determine its metes and bounds due to an inability to envision all of the compounds defined by the Markush group(s). In such a circumstance, a rejection of the claim for indefiniteness under 35 U.S.C. 112(b) is appropriate. The dependent claims 2-6, 8-9, and 44 fall therewith. Improper Markush Rejection Claims 1-6, 8-9, and 44 are 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 grouping of claimed formula (I) is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons. Instant formula (I) requires the following substituent groups: A is broadly a 6-membered heteroaryl, including all 6 membered heteroaryl containing for example N, S, and O at any position; R1 is broadly a 4- to 7-membered heterocyclyl which is optionally substituted with at least one halo, or a halo C1-C4 alkoxy, or broadly -NH₂; -N(C1-C₄alkyl)₂; or -NH(C₁-C₄alkyl); wherein the C₁-C₄alkyl is optionally substituted with at least one halo or wherein at least one H which is attached to N in -NH₂ or - NH(C₁-C₄alkyl) is replaced by halo, or R2 is broadly any 5-membered or 6-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from -halo, -OH, -CN, -N(C₁-C₄alkyl)₂, -NH(C1-C₄alkyl), -N(haloC1-C₄alkyl)₂, NH(haloC₁-C₄alkyl), haloC₁-C₄alkyl, haloC₁-C₄alkoxy, -C₁-C₄alkoxy, and -C1- C4alkyl. While the compounds defined by the instant Markush groups share the same structural feature as defined by the core PNG media_image2.png 78 83 media_image2.png Greyscale , the compounds do not share a common use such as targeting alpha-synuclein. The instant specification provides binding assay results for about 20 compounds each of containing a pyridin-3-yl ring corresponding ring A. The specification does not teach or suggest that any 6-membered heteroatom substituted ring A including rings comprising one or more of Si, O, S or N would be suitable for targeting alpha-synuclein. The large number of heteroatom rings encompassed by ring A are not known to be functional equivalents in drug discovery. Similarly, regarding instant R2, the specification does not teach or suggest that that any 5- or 6-membered heteroatom substituted ring including rings comprising one or more of Si, O, S or N in combination with ring A would be suitable for targeting alpha-synuclein or share another common use. Merely substituting an alkyl bound F with I or At can change the physical and chemical properties of a compound making the compound unsuitable any biological use due to stability and lipophilicity changes. A 7-membered heterocyclyl having any heteroatom substitution can impose unexpected steric and/or changes that the affect target and off-target binding. Applicants’ attention is directed to the third paragraph of MPEP 803.02 which discloses: “Since the decisions in In re Weber, 580 F.2d 455, 198 USPQ 328 (CCPA 1978) and In re Haas, 580 F.2d 461, 198 USPQ 334 (CCPA 1978), it is improper for the Office to refuse to examine that which Applicants regard as their invention, unless the subject matter in a claim lacks unity of invention. In re Harnisch, 631 F.2d 716, 206 USPQ 300 (CCPA 1980); and Ex parte Hozumi, 3 USPQ2d 1059 (Bd. Pat. App. & Int. 1984). Broadly, unity of invention exists where compounds included within a Markush group (1) share a common utility, and (2) share a substantial structural feature essential to that utility.” In response to this rejection, Applicant should either amend the claim(s) to recite only an individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1) (emphasis provided). 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 dependent claims 2-6, 8-9, and 44 fall therewith. Claim Rejections - 35 USC § 103 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. 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. Claim(s) 1-6, 8-10, and 44 is/are rejected under 35 U.S.C. 103 as being unpatentable over Molette et al. (WO 2017/153601 A1; published 14 Sep. 2017; see IDS filed on 7 Aug. 2024), in view of Devasthale et al. (WO 2010/047956 A1; published 29 Apr. 2010; see IDS filed on 9 May 2024). Molette et al. teach bicyclic compounds for diagnosis and therapy (see title). Molette et al. teach Parkinson’s disease (PD) (see abstract). Molette et al. teach that the invention relates to compounds of formula (I) PNG media_image3.png 93 340 media_image3.png Greyscale (pg.40) and formula (II) PNG media_image4.png 162 257 media_image4.png Greyscale (pg. 58). Molette et al. teach hit enrichment through scaffold hopping (see international search report, pg. 3). Molette et al. teach core substitutions (pg. 49). Molette et al. teach that radionuclides such as 18F can be attached at any position (pg. 65). Molette et al. teach compound 90 PNG media_image5.png 60 168 media_image5.png Greyscale (pg. 133; table 9, staining of Syn aggregates on PD sections,++ (good); staining of Aβ on PD sections, - (no)), compound 129 PNG media_image6.png 83 227 media_image6.png Greyscale (pg. 153; table 9, staining of Syn aggregates on PD sections,++ (good); staining of Aβ on PD sections, +++ (strong)), and compound 99 PNG media_image7.png 82 225 media_image7.png Greyscale (pg. 117; table 9, staining of Syn aggregates on PD sections,++ (good); staining of Aβ on PD sections, +/- (weak)). (The last compounds reads in part on a compound of instant formula (I) wherein A=pyridyl (6-membered heteroaryl); X=N; R1=piperidinyl (6-membered heterocyclyl) substituted with F (halo)= PNG media_image8.png 85 162 media_image8.png Greyscale , R1a=F; and R2=thiazolyl (5-membered heteroaryl)= PNG media_image9.png 103 164 media_image9.png Greyscale , s=0) Molette et al. teach a test kit for detection and diagnosis of a disorder associated with alpha-synuclein aggregates, wherein the test kit comprises a compound and optionally comprises a container for at least one of the compounds and instructions for using the least one compound and kit comprising a sealed vial containing at least one compound (pg. 191). Molette et al. teach a diagnostic composition comprising a compound and pharmaceutically acceptable carrier, diluent, adjuvant and/or excipient (pg. 18). Molette et al. do not teach a claimed compound comprising the core of formula I PNG media_image10.png 122 156 media_image10.png Greyscale or the elected species PNG media_image1.png 142 206 media_image1.png Greyscale . Devasthale et al. teach that the azolopyrrolone melanin concentrating hormone receptor-1 antagonists (see title). Devasthale et al. teach Parkinson’s disease (PD) ([0057], [0059]). Devasthale et al. teach prior art prior art compounds of formula A PNG media_image11.png 107 313 media_image11.png Greyscale ([0008]). Devasthale et al. teach that the bicyclic core ring PNG media_image12.png 120 125 media_image12.png Greyscale will preferably include PNG media_image13.png 118 127 media_image13.png Greyscale or PNG media_image14.png 115 132 media_image14.png Greyscale ([0014]). The preferred PNG media_image15.png 99 166 media_image15.png Greyscale groups include PNG media_image16.png 70 266 media_image16.png Greyscale ([0019]). Devasthale et al. teach isotopically labeled compounds ([00114]). Devasthale et al. teach the example 55 compound PNG media_image17.png 100 397 media_image17.png Greyscale (pg. 131). Devasthale et al. teach pharmaceutical compositions including a compound of formula I and at least one pharmaceutically acceptable diluent or carrier ([0030]). It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compositions of Molette et al. (compound 99 and pharmaceutical compositions thereof comprising a pharmaceutically acceptable carrier and test kits comprising the compounds of the invention) by substituting the bicyclic core of compound 99 with the bicyclic dihydropyrrolopyrazol-6-one core in Devasthale et al. as taught by Molette et al. and Devasthale et al. because the core substitution would have been expected to provide equivalent bicyclic core and compound advantageously capable of staining α-synuclein and detecting PD whereby advantageously expanding on the discovery of a synuclein diagnostic agent Homologs are prima facie obvious due to a general expectation of similar properties. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify the compound made obvious by Molette et al. and Devasthale et al. so that the fluoro-substituted piperidinyl is fluoro-substituted pyrrolidinyl to arrive at the elected species as taught by Molette et al. and Devasthale et al. because it would have been expected to provide a functionally equivalent compound advantageously capable of targeting synuclein and detecting PD. 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 1-6, 8-10, and 44 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12,552,800 B2, in view of Devasthale et al. (WO 2010/047956 A1; published 29 Apr. 2010; see IDS filed on 9 May 2024). Claims 1-21 of U.S. Patent No. 12,552,800 B2 claim the compound PNG media_image18.png 121 223 media_image18.png Greyscale and a diagnostic composition comprising a pharmaceutically acceptable carrier and methods of imaging alpha synuclein aggregates and a disease such as PD and a test kit for the detection and/or diagnosis of a disease, disorder or abnormality associated with alpha-synuclein wherein the test kit comprising at least one compound of formula (I). Claims 1-21 of U.S. Patent No. 12,552,800 B2 do not claim the elected species PNG media_image1.png 142 206 media_image1.png Greyscale having the dihydropyrrolopyrazol-6-one core. Devasthale et al. teach as discussed above. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of claims 1-21 of U.S. Patent No. 12,552,800 B2 by substituting the dihydropyrrolopyrazol-4-one core with the bicyclic dihydropyrrolopyrazol-6-one core to arrive at the elected species as taught by Devasthale et al. because that core would have been expected to provide an equivalent compound and test kit advantageously enabling a compound suitable for targeting synuclein and diagnosis of PD. Claims 1-6, 8-10, and 44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7, 9-10, 12-13, 17, 25, 36, 38-39, 41, and 43-44 of copending Application No. 18/708,694, in view of Molette et al. (WO 2017/153601 A1; published 14 Sep. 2017; see IDS filed on 7 Aug. 2024) and Devasthale et al. (WO 2010/047956 A1; published 29 Apr. 2010; see IDS filed on 9 May 2024). This is a provisional nonstatutory double patenting rejection. Claims 1-4, 7, 9-10, 12-13, 17, 25, 36, 38-39, 41, and 43-44 of copending Application No. 18/708,694 claim the compounds PNG media_image19.png 119 151 media_image19.png Greyscale and PNG media_image20.png 124 151 media_image20.png Greyscale and a diagnostic composition comprising a pharmaceutically acceptable carrier and a method of imaging synuclein and detecting PD and a test kit for diagnosing and detecting a disease. Claims 1-4, 7, 9-10, 12-13, 17, 25, 36, 38-39, 41, and 43-44 of copending Application No. 18/708,694 do not claim the elected species PNG media_image1.png 142 206 media_image1.png Greyscale having the dihydropyrrolopyrazol-6-one core and a pyridinyl ring. Molette et al. teach as discussed above. Devasthale et al. teach as discussed above. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the above compounds of claims 1-4, 7, 9-10, 12-13, 17, 25, 36, 38-39, 41, and 43-44 of copending Application No. 18/708,694 by substituting the dihydropyrrolopyrazol-4-one core with the bicyclic dihydropyrrolopyrazol-6-one core and by substituting the pyridazinyl and pyrazinyl rings with a pyridinyl ring to arrive at the elected species as taught by Molette et al. and Devasthale et al. because that core and pyridinyl ring would have been expected to provide an equivalent compound advantageously enabling a compound and test kit suitable for targeting synuclein and diagnosis of PD. Claims 1-6, 8-10, and 44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 8-9, 11-13, 15-16, 18, 29, 38-39, and 41-44 of copending Application No. 18/709,187, in view of Devasthale et al. (WO 2010/047956 A1; published 29 Apr. 2010; see IDS filed on 9 May 2024). This is a provisional nonstatutory double patenting rejection. Claims 1-4, 6, 8-9, 11-13, 15-16, 18, 29, 38-39, and 41-44 of copending Application No. 18/709,187 claim the compounds PNG media_image21.png 132 233 media_image21.png Greyscale and a diagnostic composition comprising a pharmaceutically acceptable carrier and a diagnostic method for detecting PD and a test kit for detecting and/or diagnosing a disease associated with synuclein wherein the kit comprises a compound of claim 1. Claims 1-4, 6, 8-9, 11-13, 15-16, 18, 29, 38-39, and 41-44 of copending Application No. 18/709,187 do not claim the elected species PNG media_image1.png 142 206 media_image1.png Greyscale having the dihydropyrrolopyrazol-6-one core. Devasthale et al. teach as discussed above. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of claims 1-4, 6, 8-9, 11-13, 15-16, 18, 29, 38-39, and 41-44 of copending Application No. 18/709,187 by substituting the bicyclic core with the bicyclic dihydropyrrolopyrazol-6-one core to arrive at the elected species as taught by Devasthale et al. because that core would have been expected to provide an equivalent compound and test kit advantageously enabling a compound suitable for targeting synuclein and diagnosis of PD. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN R DONOHUE whose telephone number is (571)270-7441. The examiner can normally be reached on Monday - Friday, 8:00 - 5:00 EST. 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, Michael Hartley can be reached on (571)272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618 /SEAN R. DONOHUE/ Examiner, Art Unit 1618