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 .
DETAILED ACTION
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on November 03, 2025. Claims 1, 9, 18-20, 24-25, 30, 62-63, and 65 are presently amended. Claims 6-8, 10-12, 14-16, 21-23, 26-29, 31-40, 42-49, 51-56, 58-61, 64, and 66-71 were previously canceled.
Election/Restrictions
Applicant's election without traverse of Group I, claims 1-5, 9, 13, 17-20, 24-25, 30, 41, 50, and 57, drawn to a nucleic acid molecule comprising a minigene linked to a transgene encoding a protein of interest was previously acknowledged.
In addition, Applicants’ election without traverse of the following species was previously acknowledged:
(A) Protease cleavage site: SEQ ID NO: 39.
(B) Second exon: SEQ ID NO: 80.
(C) Nucleic acid molecule: both (i) one or more GAA repeats and (ii) a Kozak sequence.
(D) Minigene: SEQ ID NO: 94.
Claims 62-63 and 65 were previously withdrawn from further consideration, pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions. The requirement for restriction between Groups I-III was previously made FINAL.
Therefore, claims 1-5, 9, 13, 17-20, 24-25, 30, 41, 50, and 57 are currently under examination.
Priority
The present application is a 35 U.S.C. 371 national stage filing of the International
Application No. PCT/IB2020/057038, filed July 24, 2020. Applicants’ claims benefit of a prior filed application parent provisional application 63/013,283, filed on April 21, 2020, and 62/878,514, filed July 25, 2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c).
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 112 as follows:
The later-filed application must be an application for a patent for an invention that is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. Specifically, the instant claim 30 is drawn to the elected species SEQ ID NO: 94 introduced on April 21, 2020 is not supported by the earlier specification filed July 25, 2019. Neither is their support for SEQ ID NO: 98, found in claim 20. Should the applicant disagree, the applicant is encouraged to point out with particularity by page and line number where such support might exist in each intervening document. In order to properly claim priority, the support for each of the claim limitations must exist in each of the intervening documents.
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Applicant states disclosures of shorter versions of SEQ ID NO: 71 supports SEQ ID NO: 94, but a sequence alignment does not support this claim, see below. The same applies for SEQ ID NO: 98 in claim 20. Neither of these were disclosed.
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Thus, the earliest possible priority for the instant application is April 21, 2020.
Response to Applicants’ arguments as they apply to the Priority
Applicant points to Page 22, 3rd paragraph for support for the sequence identified as SEQ ID NO: 94. This is not persuasive because no such support is found here. Additionally, there is no support identified for claimed SEQ ID NO: 98, found in claim 20. In order to properly claim priority, the support for each of the claim limitations must exist in each of the intervening documents. Applicant is again encouraged to point out with particularity by page and line number where such support might exist
Withdrawn- Claim Objections
In view of Applicants’ amendment to claims 9, 18, 19, 20, and 30, removing “e.g., consists of,” the objections to improper form are moot and have been withdrawn.
Withdrawn- Improper Markush Grouping Rejection
In view of Applicants’ amendment to claim 19, reciting that “the second exon comprises a sequence selected from the group consisting of” the improper Markush grouping rejection has been withdrawn.
Withdrawn- Claim Rejections - 35 USC § 112(b)
In view of Applicants’ amendment to claim 1, amending the claim to recite “the nucleic acid molecule,” the rejection of claim 1 under 35 U.S.C. 112(b) has been withdrawn.
In view of Applicants’ amendment to claims 9, 18-20, 24, 25, and 30, removing the exemplary phrase “e.g.,” the rejection of claims 9, 18-20, 24, 25, and 30 under 35 U.S.C. 112(b) have been withdrawn.
Withdrawn- Claim Rejections - 35 USC § 103
In view of Applicants amendment to the instant claims, clarifying the scope of the claims removing language such as e.g (for example), the rejection under 35 U.S.C. 103 to claims 1-5, 9, 13, 17-20, 24-25, 41, 50, and 57 as being unpatentable over Collin et al. (WO 2016/034680 A1, published March 10, 2016), in view of Bhattacharyya et al. (US 11,608,501 B2, prior published December 20, 2018), and further in view of Bonnemann et al. (US 11,655,470 B2, prior published January 11, 2018). Further evidenced by Roebroek et al. (EMBO J. 1993 May;12(5):1853-70.), Kota et al. (J Gen Physiol. 2018 Aug 6;150(8):1179-1187. Epub 2018 Jul 6.), Kozak (Cell. 1986 Jan 31;44(2):283-92.), Blanco et al. (Biotechnol Bioeng. 2020 Jul;117(7):1946-1960. Epub 2020 Apr 21.) has been withdrawn. Applicants’ arguments are moot in view of the withdrawn rejection.
New Claim Objections
Claim 2 is objected to because of the following informality: “absense” is incorrected spelled. Applicant may obviate the objection by correcting the spelling to “absence”.
Claim 50 is objected to under 37 CFR 1.75 as being in improper form because a
dependent claim should refer to a precedent claim. See MPEP § 608.01(n). Claim 50 is alternatively dependent on claims 1 or claim 16, however claim 16 is presently canceled. Applicant may obviate the objection amending the claim to remove dependence on canceled claim 16.
Claim 57 is objected to under 37 CFR 1.75(c) as being in improper form because
multiple dependent claims should refer to other claims in the alternative only. See MPEP §
608.01(n). Specifically, claim 57 is alternatively dependent upon claim 1, claim 41, and claim 50; however, claim 50 is multiply dependent on claims 1 and 16. Additionally, claim 16 is presently canceled.
Claim Interpretation
Limitations recited as optional are interpreted as not required, and thus nonlimiting.
New Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, 17-18, 24-25, 41, 50, and 57 are rejected under 35 U.S.C. 102(a)(1)
as being anticipated by Monteys et al. (Regulated control of gene therapies with a drug induced switch; bioRxiv 2020.02.21.956664). Amendments such as the removal of “e.g., consists of” change the scope and limitations of the claims. This is a new rejection necessitated by amendment of the claims in the response filed November 03, 2025.
Regarding claim 1, Monteys discloses a method to finely control protein expression via a drug inducible switch (pg. 3, para. 2). Monteys discloses a nucleic acid construct comprising a drug-responsive splicing cassette (Xon) that functions as a portable minigene element controlling expression of a linked transgene encoding a protein of interest. The construct disclosed by Monteys includes a conditionally included cassette exon, flanked by intronic sequences and constitutive exons, thereby forming a three-exon/two-intron minigene structure (pg. 4, para. 1-2; Fig. 1; pg. 14, para. 1; Fig. 3; pg. 15, para. 2). Monteys further discloses minigene cassettes configured with flanking exons and an inducible exon, or pseudoexon, where inclusion is inducible by LMI070, with exon exclusion yielding no productive translation and exon inclusion yielding translation of the linked reporter/payload (pg. 4, para. 1-2; pg. 14, para. 1; pg. 5, para. 2-3; Fig. 3; pg. 15-16, bridging para.). Thus, Monteys discloses the claimed nucleic acid architecture and the functional requirement that in the presence of splice modulator the exon is included and in the absences is excluded.
Regarding claims 2-4, dependent on claim 1, Monteys discloses that translation is controlled by splice state, and exon exclusion yields premature stop/no translation, whereas drug-induced exon inclusion permits translation of the linked coding sequence (pg. 4, para. 1; pg. 14, para. 1; Fig. 1). Monteys also teaches placing a Kozak sequence and AUG start codon within the drug-induced exon in order for translation to be initiated only upon LMI070-induced exon inclusion (pg. 5, para. 3; pg. 15, para 2; Fig. 3). Hence, Monteys discloses the codon/frame-dependent translation-control limitations.
Regarding claim 17-18, dependent on claim 1, Monteys discloses that the drug-responsive splicing modulator or pseudoexons share a strong 3’ motif corresponding to the U1 RNA binding sequence targeted by LMI070 (pg. 5, para. 2-3). Additionally, Monteys discloses LMI070 as a small molecule splicing modulator used to induce inclusion of the switch exon or pseudoexon (pg. 4-5; pg. 15, para. 2-3).
Regarding claims 24-25, Monteys discloses the utility of a Kozak sequence to control translation (pg. 5, para. 3; pg. 15, para. 2). Additionally, Monteys discloses engineering and screening of exon/intron sequence context to tune background splicing and inducibility, including identifying and modifying silencer/enhancer elements and intronic fragments to modulate splicing behavior (pg. 6, para. 1-3).
Regarding claim 41, 50, and 57, Monteys discloses the utility of expression plasmids and promoters driving the cassette, AAV vectors, and HEK293 cells (pg. 7, para. 2-3).
New Claim Rejections - 35 USC § 103
Claims 1-5, 9, 13, 17-20, 24-25, 30, 41, 50, and 57 are rejected under 35 U.S.C. 103 as being unpatentable over Monteys et al. (Regulated control of gene therapies with a drug induced switch; bioRxiv 2020.02.21.956664) in view of Chng et al. (MAbs
. 2015;7(2):403-12.), and Bhattacharyya et al. (US 11,608,501 B2, prior published December 20, 2018). This is a new rejection necessitated by Applicants’ amendments to the claims in the response filed on November 03, 2025.
Regarding claim 1, Monteys discloses a method to finely control protein expression via a drug inducible switch (pg. 3, para. 2). Monteys discloses a nucleic acid construct comprising a drug-responsive splicing cassette (Xon) that functions as a portable minigene element controlling expression of a linked transgene encoding a protein of interest. The construct disclosed by Monteys includes a conditionally included cassette exon, flanked by intronic sequences and constitutive exons, thereby forming a three-exon/two-intron minigene structure (pg. 4, para. 1-2; Fig. 1; pg. 14, para. 1; Fig. 3; pg. 15, para. 2). Monteys further discloses minigene cassettes configured with flanking exons and an inducible exon, or pseudoexon, where inclusion is inducible by LMI070, with exon exclusion yielding no productive translation and exon inclusion yielding translation of the linked reporter/payload (pg. 4, para. 1-2; pg. 14, para. 1; pg. 5, para. 2-3; Fig. 3; pg. 15-16, bridging para.). Thus, Monteys discloses the claimed nucleic acid architecture and the functional requirement that in the presence of splice modulator the exon is included and in the absences is excluded.
Regarding claims 2-4, Monteys discloses that translation is controlled by splice state, and exon exclusion yields premature stop/no translation, whereas drug-induced exon inclusion permits translation of the linked coding sequence (pg. 4, para. 1; pg. 14, para. 1; Fig. 1). Monteys also teaches placing a Kozak sequence and AUG start codon within the drug-induced exon in order for translation to be initiated only upon LMI070-induced exon inclusion (pg. 5, para. 3; pg. 15, para 2; Fig. 3). Hence, Monteys discloses the codon/frame-dependent translation-control limitations.
Regarding claims 5 and 9, claim 5.a)/b) and recitations after the first clause in claim 9, such as the RNRR cleavage site are optional limitations. Monteys teaches a drug-inducible splicing modulator switch comprising an engineered minigene cassette that controls expression of a downstream transgene encoding a protein of interest in response to the splice modulator LMI070 (pg. 4, para. 1; pg. 5, para. 3; pg. 15, para. 2). Regarding the minigene and the transgene comprising a protease cleavage site, although Monteys does not explicitly teach a protease furin cleavage site within the switch cassette, Monteys does teach modular gene-expression constructs for controlled protein expression in mammalian cells and viral vectors (pg. 7, para. 2-3).
Furthermore, before the effective filing date, the ordinary artisan would have found it obvious to include a protease cleavage site between linked coding regions, as taught by Monteys, to permit predictable post-translational processing or separation of encoded polypeptides. The ordinary artisan would have recognized the prior art taught the incorporation of protease-cleavable linker sequences, including those cleaved by furin, between functional domains in recombinant expression constructs, further in view of Chng. Chng teaches inserting furin recognition sites between linked coding sequences in mammalian expression constructs to enable proteolytic processing and separation of encoded proteins following translation (Abstract; Fig. 1; pg. 404, column 1-2 bridging para.; pg. 406, column 1, para. 2-3). Hence, the ordinary artisan would have found it obvious to incorporate a protease cleavage site, including a furin cleavage site, between the minigene and transgene of Monteys’ construct to obtain predictable proteolytic processing of the encoded proteins while maintaining the drug-inducible splicing control mechanism, as taught by Monteys, with a reasonable expectation of success.
Regarding claim 13, Monteys does not expressly teach that the minigene and the transgene comprise a self-cleaving peptide.
However, Chng additionally teaches recombinant expression constructs in which linked coding sequences are separated by self-cleaving 2A peptides which mediate ribosomal skipping during translation to produce separate polypeptides from a single open reading frame. Chng further explains that such self-cleaving peptides are routinely incorporated into mammalian expression constructs to enable efficient coexpression and separation of encoded proteins. Hence, the ordinary artisan would have found it obvious to incorporate a self-cleaving peptide between coding regions of the construct, as taught by Monteys, in order to produce predictable translational separation of encoded polypeptides while maintaining the drug-inducible splicing control mechanism, with a reasonable expectation of success (pg. 404, column 1, para. 2; pg. 406, column 1, para. 2).
Regarding claim 17-18, dependent on claim 1, Monteys discloses that the drug-responsive splicing modulator or pseudoexons share a strong 3’ motif corresponding to the U1 RNA binding sequence targeted by LMI070 (pg. 5, para. 2-3). Additionally, Monteys discloses LMI070 as a small molecule splicing modulator used to induce inclusion of the switch exon or pseudoexon (pg. 4-5; pg. 15, para. 2-3).
Regarding claim 19-20, Monteys teaches constructing switch cassettes from LMI070 responsive pseudoexons discovered by RNA-Seq and validated, such as SF3B3, BENC1, C12orf4, PDXDC2, etc., and utilizing them as inducible exons in engineered minigene cassettes controlling luciferase/eGFP expression (Fig. 2; pg. 14-15, bridging para.). Monteys teaches the same class of LMI070 responsive exons used as the switch exon, and the identification of LMI070 induced pseudoexons and their associated LMI070 binding motifs using RNA-Seq analysis along with functional validation (Fig. 2; pg. 4, para. 2; pg. 5, para 2-3). Monteys teaches that responsive pseudoexons share a characteristic U1-dependent binding sequence motif, including sequences such as AGAGTAAGAC, AGAGTAAGGC, AGAGTATAGT, AGAGTAAGAA, AGAGTAAGAA, AGAGTAGGAT, AGAGTAGGTG, AGAGTAAGCA, AGAGTAAGAA, AGAGTAGGCC (pg. 5, para. 2; Fig. 2). These motifs define a consensus AGAGT(A/G)AG sequence context that mediated drug dependent splice site recognition.
Hence, Monteys teaches fragments or variants having at least 90-99% identity, and the claimed sequences represent motif-like regions closely matching the LMI070-responsive consensus, including regions such as and CAGAGAGACG in SEQ ID NO: 4, which preserve the AGAG core motif characteristic of LMI070 responsive splicing elements (pg.5, para. 2; Fig. 2). In view of Monteys’ teaching that drug responsive exons can be identified and engineered based on these binding motifs, the ordinary artisan would have been motivated to design or select exon sequences containing the same or closely related AGAG-based motif elements to achieve LMI070-inducible exon inclusion. Furthermore, the ordinary artisan would have been motivated to screen for and optimize responsive exon sequences derived from endogenous loci and utilize them as inducible exon cassettes controlling reporter expression, in view of Monteys teaching of selective screening (pg. 6, para. 3; Fig. 3). The ordinary artisan would have found it obvious to employ sequences with the appropriate motif conferring LMI070 responsive splicing as the inducible exon in the minigene construct, as taught by Monteys, with a reasonable expectation of success.
Moreover, Bhattacharyya teaches methods for modulating RNA splicing used for producing mature mRNA transcript comprising iExon and modulating the amount of mature mRNA transcript produced by pre-mRNA transcript. The methods taught utilize artificial gene constructs and are used for preventing and treating a disease associated with the aberrant expression of a product of a gene by modulating protein production, including those utilizing SNX7 (Abstract; claims 1, 2, 9, 12, and 14)). Bhattacharyya teaches the SNX7 gene sequence SEQ ID NO: 4021, which is 100% identical to the claimed SEQ ID NO: 80 as a gene or RNA transcript transcribed from a gene (Table 25, row 8).
Specifically, Bhattacharyya teaches, alternative configurations corresponding to the subject matter claimed, such as transcripts comprising SNX7, two exons and an intron, splice sites, branch points, and splicing modification elements (columns 347-390)
Before the effective filing date of the instant application, the ordinary artisan would have found it obvious to have simply substituted the known SEQ ID NO: 4021, as taught by Bhattacharyya, as an exon component in the genetic constructs taught by Monteys, to obtain predictable result of the minigene construct with a reasonable expectation of success, since Bhattacharyya provides express motivation for the incorporation of the SNX7 element in transcripts for modifying RNA splicing, and specific analogous, such as configurations comprising exons and introns.
Regarding claims 24-25, Monteys discloses the utility of a Kozak sequence to control translation (pg. 5, para. 3; pg. 15, para. 2). Additionally, Monteys discloses engineering and screening of exon/intron sequence context to tune background splicing and inducibility, including identifying and modifying silencer/enhancer elements and intronic fragments to modulate splicing behavior (pg. 6, para. 1-3).
Regarding claim 30, Monteys teaches identifying LMI070 responsive pseudoexons through RNA-Seq discovery and validation, cloning minimal intervening sequences, and iteratively engineering exon/intron context to optimize inducibility versus baseline or background splicing (pg. 12, para. 2; Fig 2-4). Thus, prior to the effective filing date of the instant application, it would have been obvious for the ordinary artisan to have arrived at a particular sequence variants or functional fragments of the minigene through routine sequence optimization and screening, in view of the teachings of Monteys, to obtain predictable improvements in performance, such as reduced background and increased fold induction.
Regarding claim 41, 50, and 57, Monteys discloses the utility of expression plasmids and promoters driving the cassette, AAV vectors, and HEK293 cells (pg. 7, para. 2-3).
Response to Applicants’ arguments as they apply to the rejection of Claims 1-5, 9, 13, 17-20, 24-25, 41, 50, and 57 under 35 USC § 103
Applicant's arguments filed November 03, 2025, have been fully considered but they are not persuasive.
At pages 11-15 of the remarks filed on November 03, 2025, Applicants essentially argue the following:
Applicants present arguments traversing the rejection based on Collin, in view of Bhattacharyya, and Bonnemann. The crux of applicants’ arguments is the previously cited referenced did not disclose or suggest a minigene comprising a second exon having a splice-modulator binding sequence that is included in mRNA in the presence of a splice modulator and excluded in its absence, and that the cited art related instead to mutation-driven aberrant splicing events.
Applicant’s arguments with respect to claims 1-5, 9, 13, 17-20, 24-25, 41, 50, and 57 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. Newly cited Monteys discloses an engineered drug-inducible exon cassette used as generalizable switch to control expression of a downstream transgene, where exon inclusion occurs in the presence of the splice modulator LMI070, and exon exclusion occurs in its absence. Thus, Monteys directly addresses the structural and functional limitations emphasized in Applicant’s arguments.
Conclusion
Claims 1-5, 9, 13, 17-20, 24-25, 30, 41, 50, and 57 are rejected. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/J.D.L./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633