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, 4, 7, 10, 14, 20, 27, 31-32, 34, 40-42, 44, 46, 48, 64, 67, 69, 74, 97-100, 103, 105, 107- 108, 112-113 and 119-120 are pending in the instant application. Acknowledgment is made of Applicant’s amendments filed September 4, 2026.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1, 4, 7, 10, 14, 20, 27, 31-32, 34, 40, 99, 100, 103 and 119-120, drawn to a compound of Formula (I) and a composition thereof, and Group V, claims 105, 107 and 108, drawn to a method of forming a complex comprising a component of a spliceosome, a nucleic acid and a compound of Formula (I), (II), (III) or (IV) and a method of altering the conformation of a nucleic acid comprising contacting the nucleic acid with a compound of Formula (I), (II), (III) or (IV) in the supplemental response filed on September 4, 2026 is acknowledged.
Claims 112 and 113 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 2-(6-(3-(tert-butylamino)pyrrolidin-1-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol:
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(page 61, specification, Table 1, ex. 101) in the reply filed on August 10, 2026 is acknowledged. Upon performing the search of prior art Examiner detected compounds related to non-elected species, compound of Formula (II). Hence, the examination will expand to include non-elected species, compound of Formula (II).
Claims 74 and 97 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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, 4, 7, 10, 14, 20, 27, 31-32, 34, 40 - 42, 44, 46, 48, 64, 67, 69, 98 - 100, 103, 105, 107, 108 and 119-120 are under consideration in the present office action, as related to the elected species (compound of ex. 101) and expanded species (compound of Formula (II).
Priority
The present application is a 371 of PCT/US2022/075712, filed August 2022, and claims the benefits of priority to the U.S. Provisional Application No. 63/238,697, filed on August 30, 2021; U.S. Provisional Application No. 63/238,405, filed on August 30, 2021; U.S. Provisional Application No. 63/283, 145, filed on November 24, 2021; U.S. Provisional Application No. 63/325,503, filed on March 30, 2022; and U.S. Provisional Application No. 63/325,511, 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 119 and 120 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.
The claims recite “A composition for use in treating a disease or disorder…” which suggests a product composition comprising a compound of Formula (I – IV) and treating with the compound of Formula (I – IV) a disease or disorder. Thus, it is unclear if the claims are intended to encompass a composition comprising compound of Formula (I – IV) which has an intended use in the disclosed method of treating a disease or disorder or if the claims are intended to encompass a method of treating a disease or disorder comprising the compound of Formula (I – IV). The claims as written can be interpreted as both a product and a method of using the product.
In the instant office action, in the interest of compact prosecution, for the purposes of applying art, the claims have been construed as a composition comprising compound of Formula (I – IV), wherein the method of application of said composition is an intended use of the claimed composition.
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, 4, 7, 10, 14, 20, 27, 31-32, 34, 40 - 42, 44, 46, 48, 64, 67, 69, 98 - 100, 103, 105, 107, 108 and 119-120 are rejected under 35 U.S.C. 103 as being unpatentable over Bhattacharyya et al (WO 2018/232039 A1, cited in IDS, filed 02/09/2024, hereinafter Bhattacharyya).
Regarding claims 1, 4, 7, 10, 14, 20, 27, 31-32, 34, 40 - 42, 44, 46, 48, 64, 67, 69, 98 - 100, 103 and 119-120, drawn to a compound of genus Formula I:
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, such as compound of Formula (I-c):
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where A is heteroaryl optionally substituted with one or more R¹, R¹ is independently hydrogen, C₁-C₆-alkyl; such as ring A is:
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,
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; L is absent, C₁-C₆-alkyl, C₂-C₆-alkenyl, -O-, -C(O)-, -N(R³)-; X is C(R⁵) or N; each R⁴ᵃ and R⁴ᵇ is independently hydrogen or C1-C₆-alkyl; R⁶ is C1-C6-alkyl, cyano, -ORA(e.g. -OH); fragment
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is e.g.:
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. Instant claims are also directed to a compound or Formula (II):
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, where A is heteroaryl optionally substituted with one or more R¹, R¹ is independently hydrogen, C₁-C₆-alkyl, such as ring A is:
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,
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,
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; ring
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is e.g.
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R2 is hydrogen; each R⁴ᵃ and R⁴ᵇ is independently hydrogen or C1-C₆-alkyl; R⁶ is C1-C6-alkyl, cyano, -ORA (e.g. -OH); fragment
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is e.g.:
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. Exemplary compounds of Formula (I) and (II) are:
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and
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. Instant claims are further drawn to a pharmaceutical composition comprising a compound of Formula (I) and (II) and a pharmaceutically acceptable excipient, where the compound (i) alters a target nucleic acid or (ii) binds to 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, e.g., as determined by qPCR.
Bhattacharyya teaches the compound of Formula (Ia):
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, where X is a bond; A is aryl or heteroaryl such as
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,
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,
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,
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R1a is halogen, hydroxyl, cyano, C1-4alkyl, amino, C1-4alkyl-amino, heteroaryl having 1, 2, or 3 heteroatom ring members selected from N, O, and S. “Heteroaryl” is defined as a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with one or more heteroatoms, such as an O, S or N atom (e.g.: pyrrolyl, pyridinyl) (pages 310-311, [00254]). Ring B is heterocyclyl, where “heterocyclyl” is defined as a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced with a heteroatom, such as an O, S or N (e.g.: pyrrolidinyl, piperidinyl) (page 311,[00255]). Ring B is optionally substituted with R4, where R4 is halogen, C1-4alkyl, amino, C1-4alkyl-amino (page 192, [00199]). Exemplary structures of ring B are:
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,
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(pages 197 – 198). Although ring B taught by Bhattacharyya is not identical to the instantly claimed fragment
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, it is the positional isomer (different point of attachment to the pyridazine ring). Thus, since ring B of Bhattacharyya is structurally similar to the instantly claimed fragment
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, it presumably possesses similar properties and therefore an obvious variant. According to MPEP 2144.09: Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or 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. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Examples of compounds taught by Bhattacharyya:
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(page 222, [00223]),
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(page 208, [00208]). Compounds taught by Bhattacharyya act as splicing modifier compounds and serve to define nascent exons by increasing the binding affinity of the pre-mRNA splicing machinery to the iREMS sequence (page 4,[0007]), where an effective amount of a compound of Formula (I) is an amount effective to increase or decrease the amount of an alternative splice variant of an RNA transcript of gene (page 344, [00399]). Bhattacharyya further teaches splicing analysis, where reads were counted for different exons annotated or not annotated but identified from RNA-seq. for each exon. A Percent-Spliced-In (PSI) value was calculated using the percent of average read number supporting the inclusion of the exon among all reads supporting either the inclusion or the exclusion of an exon. PSI differences between two samples were compared and Fisher’s Exact Test was used to determine statistical significance. A PSI increase of >5% and P-value <0.01 was used to select statistically significant intronic exons being included by the compound (page 442, [00564]). the amount of RNA transcripts is measured by RT-qPCR (page 339, [00383]). Bhattacharyya also teaches pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, excipient or diluent.
Thus, since Bhattacharyya teaches compounds of the same functionality and similar chemical structure as instantly claimed compounds, 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 make various structural analogs by selecting and combining known structural elements, to arrive at claimed compounds. The one of ordinary skills would be motivated to do so in search of an active agent, possessing similar or better pharmaceutical properties for treatment of disease or disorder associated with expression of an aberrant quantity of gene product or of an aberrant gene product with the reasonable expectation of success.
Regarding claims 105, 107 and 108, drawn to a method of forming a complex comprising a component of a spliceosome, a nucleic acid and a compound of Formula (I) or (II) and a method of altering the conformation of a nucleic acid comprising contacting the nucleic acid with a compound of Formula (I) or (II).
Bhattacharyya teaches methods for modifying RNA splicing in order to prevent and/or treat a disease in which the modulation (e.g., increase or decrease) in the expression RNA isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS. The methods comprise administering to a subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I). The method taught by Bhattacharyya describes the action of molecules of compounds of Formula (I) as follow: the small molecules according to the Formula (I) initiate the assembly of a splicing-competent spliceosome around a weak or incompletely defined exon (i.e., a nascent iExon) (page 4, [0007]).
Thus, Bhattacharyya teaches the same method to be practiced with the compounds of similar structure, thereby rendering 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.
Conclusion
Claims 1, 4, 7, 10, 14, 20, 27, 31-32, 34, 40 - 42, 44, 46, 48, 64, 67, 69, 98 - 100, 103, 105, 107, 108 and 119-120 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.
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/E.V.V./ Examiner, Art Unit 1691
/SAVITHA M RAO/ Primary Examiner, Art Unit 1691
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