COMPOUNDS AND METHODS FOR MODULATING SPLICING

§103 §112 §DP

DETAILED ACTION This office action is in response to applicant’s filing dated September 4, 2026. 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 . Status of claims Claims 1, 5, 7, 13, 20, 22, 28, 35, 44, 46, 51, 56, 58, 65-66, 70, 86, 100, 111, 121, 125, 140, 157, 171-174, 177, 181 and 186-187 are pending in the instant application. Election/Restrictions Applicant’s election without traverse of Group I, claims 1, 5, 7, 13, 20, 22, 28, 35, 44, 46, 51, 56, 58, 65, 173, 174 and 177, drawn to a compound of Formula (I) and Group IV, claim 181, drawn to a method of altering the conformation of a nucleic acid, comprising contacting the nucleic acid with a compound of Formula (I), (II) or (III) in the reply filed on September 4, 2026 is acknowledged. Claims 66, 70, 86, 100, 111, 121, 125, 140, 157, 171, 172, 186 and 187 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 4, 2026. Applicant’s election without traverse of (1R,3s,5 S)-N-(6-(5-fluoro-4-(1H-pyrazol-4-yl)benzo[d]thiazol-7-yl)pyridazin-3 -yl)-8-azabicyclo[3.2.1]octan-3-amine: PNG media_image1.png 92 249 media_image1.png Greyscale (compound 339, Table 1) as a single species of compound of formula (I) in the reply filed on August 10, 2026 is acknowledged. Claims 22 and 58 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 August 10, 2026. Claims 1, 5, 7, 13, 20, 28, 35, 44, 46, 51, 56, 65, 173, 174, 177 and 181 are under consideration in the present office action as related the elected inventions of Groups I and IV and the elected species, compound 339. Priority The present application is a 371 of PCT/US2022/075702, filed August 30, 2022 and claims the benefits of priority to U.S. Provisional Application No. 63/238,409, filed on August 30, 2021; U.S. Provisional Application No. 63/238,414, filed on August 30, 2021; and U.S. Provisional Application No. 63/325,502, filed on March 30, 2022. Information Disclosure Statement The information disclosure statements (IDS) submitted on 02/29/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. 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. Claims 44, 177 and 181 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. Claims 44, 177 and 181, recite the term “e.g.” which is equivalent to the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). 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. Claims 1, 5, 7, 13, 20, 28, 35, 44, 46, 51, 56, 65, 173, 174, 177 and 181 are rejected under 35 U.S.C. 103 as being unpatentable over Luzzio et al (WO 2019/028440 A1, cited in IDS, filed 02/29/2024, hereinafter Luzzio). Regarding claims 1, 5, 7, 13, 20, 28, 35, 44, 46, 51, 56, 65, 173, drawn to a compound of Formula (I): PNG media_image2.png 106 228 media_image2.png Greyscale , such as a compound of Formula (I-a): PNG media_image3.png 108 234 media_image3.png Greyscale , where wherein L is -N(R3)- (R3 is H or C1-C6 alkyl); A and B is independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, e.g.: A is PNG media_image4.png 200 400 media_image4.png Greyscale , B is PNG media_image5.png 51 69 media_image5.png Greyscale , fragment PNG media_image6.png 117 99 media_image6.png Greyscale is PNG media_image7.png 100 184 media_image7.png Greyscale or PNG media_image8.png 116 96 media_image8.png Greyscale , R5c is H, C1-C6 alkyl; R7 is C1-C6 alkyl or halogen, n is 0-2. One of the exemplary compounds of Formula (I-a) is PNG media_image1.png 92 249 media_image1.png Greyscale (compound 339, Table 1). The compounds of genus formula (I) are capable of modulating nucleic acid splicing. Instant claims are further drawn to a pharmaceutical composition comprising compound (I) and a pharmaceutically acceptable excipient. Luzzio teaches small molecule splicing modulators (SMSMs) of formula (IV): PNG media_image9.png 200 400 media_image9.png Greyscale (page 71, [0435]), where fragment PNG media_image10.png 200 400 media_image10.png Greyscale ; X is -NR3-, R3 is H or e.g. -CH3; fragment PNG media_image11.png 200 400 media_image11.png Greyscale is PNG media_image12.png 62 113 media_image12.png Greyscale , Q is PNG media_image13.png 60 146 media_image13.png Greyscale or PNG media_image14.png 78 126 media_image14.png Greyscale , RB is halogen, C1-6 alkyl or heteroaryl, m is 1-3 (pages 71 – 72 and 80-81). Luzzio defines “heteroaryl” as an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, such as pyrazolyl (page 27, [0263]. Thus, Luzzio teaches all the structural elements equivalent to the instantly claimed compounds. Luzzio further teaches a pharmaceutical composition where the SMSMs are mixed with one or more other chemical components such as carriers or excipients (page 190, [0578]). Thus, since Luzzio teaches a compound that acts as a nucleic acid splicing modulator where all the structural elements of the molecule are equivalent of those of instant claims, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to select and combine structural elements of the molecule, taught by prior art, and make various structural analogs acting as nucleic acid splicing modulators, to arrive at claimed compounds. The one of ordinary skills would be motivated to do so in search of an active agent, which is capable of modulating nucleic acid splicing and having improved desired properties, with the reasonable expectation of success. Regarding claims 174 and 177, drawn to a compound of formula (I), where the compound is capable of altering a target nucleic acid, binding to a target nucleic acid or stabilizing a target nucleic acid, and where the compound increases splicing at splice site on a target nucleic acid, by about 0.5% to 95%, or more, or the compound decreases splicing at splice site on a target nucleic acid, by about 0.5% to 95%, or more, as determined by qPCR. Luzzio teaches small molecule splicing modulators (SMSMs) of formula (IV) (see the structure above) wherein splicing modulators bind to a target RNA (page 195, [0603]), and wherein the SMSMs modulate splicing at a splice site sequence of a pre-mRNA and wherein a total amount of the mRNA is increased at least about 10% compared to the total amount of the mRNA encoding the target protein or functional RNA produced in control cells (page 11, [0077]), or wherein the SMSMs modulate splicing at a splice site sequence of a pre-mRNA, and wherein a total amount of the mRNA and/or the functional RNA is at least 10% lower than the total amount of the mRNA and/or the functional RNA in control cells (page 11, [0078]). Luzzio teaches that the levels of various mRNA targets of the SMSMs were determined by performing qPCR (page 380, [01073]). The value “about 10%” of increased total amount of the mRNA compared to the total amount of the mRNA encoding the target protein or functional RNA produced in control cells after contacting with splicing modulators (SMSMs), as well as “10% lower” than the total amount of the mRNA, or the functional RNA in control cells fall within the claimed ranges (see above). MPEP 2144.05 states: In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Regarding claim 181, drawn to a method of altering the conformation of a nucleic acid comprising contacting the nucleic acid with a compound of Formula (I). Luzzio teaches the method where binding of an SMSM to a polynucleotide or a splicing complex component decreases conformational stability of a splice site sequence, or binding of an SMSM to a polynucleotide increases conformational stability of a splice site sequence (page 267, [0711]). Thus, Luzzio teaches the same methos to be practiced with the compounds of the same or similar structure, thereby rendering the instantly claimed method obvious. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary. 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, 5, 7, 13, 20, 28, 35, 44, 46, 51, 56, 65, 173, 174, 177 and 181 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 5, 7, 8, 10, 14, 19, 25, 28, 31, 32, 33, 34, 36, 37, 40, 44 of copending Application No. 17/802,702 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claims are directed to a compound of Formula (I): PNG media_image2.png 106 228 media_image2.png Greyscale , such as a compound of Formula (I-a): PNG media_image3.png 108 234 media_image3.png Greyscale , where wherein L is -N(R3)- (R3 is H); A and B is independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, e.g.: A is PNG media_image4.png 200 400 media_image4.png Greyscale , B is PNG media_image5.png 51 69 media_image5.png Greyscale , fragment PNG media_image6.png 117 99 media_image6.png Greyscale is PNG media_image7.png 100 184 media_image7.png Greyscale or PNG media_image8.png 116 96 media_image8.png Greyscale , R5c is H, C1-C6 alkyl; R7 is C1-C6 alkyl or halogen, n is 0-2. One of the exemplary compounds of Formula (I-a) is PNG media_image1.png 92 249 media_image1.png Greyscale (compound 339, Table 1). The compounds of genus formula (I) are capable of modulating nucleic acid splicing. Instant claims are further drawn to a pharmaceutical composition comprising compound I and a pharmaceutically acceptable excipient. Copending claims are directed to a compound of Formula (I-d): PNG media_image15.png 106 241 media_image15.png Greyscale , such as a compound of formula (I-e): PNG media_image16.png 110 233 media_image16.png Greyscale , where A is PNG media_image4.png 200 400 media_image4.png Greyscale , B is PNG media_image5.png 51 69 media_image5.png Greyscale , fragment PNG media_image17.png 107 91 media_image17.png Greyscale is PNG media_image18.png 95 95 media_image18.png Greyscale or PNG media_image19.png 109 92 media_image19.png Greyscale . the exemplary compounds of Formula (I-d) are: PNG media_image20.png 73 244 media_image20.png Greyscale or PNG media_image21.png 80 229 media_image21.png Greyscale The compounds of genus formula (I-d) are capable of modulating nucleic acid splicing. Instant claims are further drawn to a pharmaceutical composition comprising compound I-d and a pharmaceutically acceptable excipient. Thus, copending claims are directed to a compounds of the same functionality and the same or similar structure. Therefore, compounds and methods of copending claims would anticipate instantly claimed compounds and methods. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Conclusion Claims 1, 5, 7, 13, 20, 28, 35, 44, 46, 51, 56, 65, 173, 174, 177 and 181 are rejected. No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELENA V VISHNYAKOVA whose telephone number is (571)272-3781. The examiner can normally be reached 7:30am - 5pm ET. 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. 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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. /E.V.V./Examiner, Art Unit 1691 /SAVITHA M RAO/Primary Examiner, Art Unit 1691