DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s arguments and amendments to the claims filed on March 12, 2026 have been
received and entered. Claims 1, 16, 38 have been amended, while claims 2-4, 9-15, 17-37, 40, 42-44, 47-48 have been canceled. It is noted that applicant’s response is not fully compliant as status of claims 54 -90 is not listed. For the sake of compact prosecution, claims 54 and 57 remain withdrawn. Applicant should correct the status identifier and list all claims in order to be fully compliant in response to this office action
Claims 1, 5-8, 16, 38-39, 41, 45-46, 49-52 and 53 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claims (1, 2, 5-8, 12, 16, 20, 24, 28, 32, 38-39, 41, 45-46, 49-52 and 53 (group I) in the reply filed on August 15, 2025 was acknowledged.
Claims 54, 57 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention there being no allowable generic or linking claim.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 August 15, 2025.
Claims 1, 5-8, 16, 38-39, 41, 45-46, 49-52 and 53 are under consideration.
Priority
This application is a 371 of PCT/US2021/017950 filed on 02/12/2021, which claims priority from US provisional application 62/975,400 filed on 02/12/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02/27/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Objections
Claim 38 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Maintained-Claim Rejections - 35 USC § 112-in modified form
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 5-8, 16, 39, 41, 45-46, 49-52 and 53 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims encompass enormous genus of (a) a minigene having an alternatively spliced exon and (b) an encoded gene, wherein the minigene comprises, from 5' to 3', Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein Exon 2 is the alternatively spliced exon, and wherein Exon 2 comprises translation initiation regulatory sequences, and wherein Exon 2 comprises a sequence at least 95% identical to the nucleotide sequence of positions 595-653 of SEQ ID NO: 4.. Dependent claims limit the encoded gene encodes a signal peptide, wherein the amino acids encoded by Exon 2 correspond to any sequence of a predicted signal peptide and wherein encoded gene encodes an inhibitory RNA, any therapeutic protein, a Cas9 protein, or a transactivator protein.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it”).
The minigenes described in specification constitute a limited number of species. These species are not representative of all the genes that undergo alternative splicing. Moreover, as the described minigenes are merely fragments of larger genes, such a limited number of species does not provide sufficient description of the modifications necessary in order to create a claimed minigene from any other genes which undergo alternative splicing. The specification contemplates minigene comprises fewer than 2000, fewer than 1900, fewer than 1800, fewer than 1700, fewer than 1600, fewer than 1500, fewer than 1400, fewer than 1300, fewer than 1200, fewer than 1100, fewer than 1000, fewer than 900, fewer than 800, fewer than 700, fewer than 600 or fewer than 500 nucleotides (see para. 15 of the specification). Further, specification discloses in presence of the splice modifier drug, the second exon is included in an mRNA product of the nucleic acid, and in the absent of said splice modifier drug, said exon is not included in an mRNA product of the nucleic acid. In some aspects, the splicing modifier drug is LMI070 or RG7800/RG7619 (see para. 22).
The sequences of all minigene, other than the other than the minigenes comprising exons of SF3B3 comprising the SEQ IDNO: 4 (fig. 1 and 3C), encompassed within the genus of minigene having an alternatively spliced exon sequences have not been disclosed. Based upon the prior art there is expected to be sequence variation among the species of sequences of minigene having an alternatively spliced exon. The specification has provided the sequences of the SF3B3 minigene (SEQ ID NO: 4, 13-15). The specification however has not disclosed the sequences of any of the other minigene sequences having an alternatively spliced exon as embraced by the claims. There is no evidence on the record of a relationship between the structures of the nucleic acid molecules of any of the embraced minigene having an alternatively spliced exon that would provide any reliable information about the structure of other minigene sequence within the genus showing contemplated biological activity. There is no evidence on the record that embraced SF3B3 as set forth in SEQ ID NO: 4 had known structural relationships to each other; the art indicated that there is variation between sequences of various minigenes. Further, claims read on exon 2 comprising any sequence comprising 90% sequence identity to nucleotides 595-653 of SEQ ID NO:4. However, before effective filing date of instant invention, Cooper (Methods, 2005, 37, 331-340) states “specific nucleotide changes affect splicing efficiency and to define elements required for responsiveness to cell type and specific splicing regulators. First, the context of the exon within the minigene influences basal recognition in a way that cannot be predicted. The flanking exons and their adjacent intronic segments can influence the basal recognition of the alternative exon under study. Further, a mutation that affect splicing of an exon in one context might not affect splicing in another context, and in particular, not in the context of the full-length pre-mRNA. Therefore, it is possible that splicing “elements” defined by mapping within a minigene context might have no consequence in the context of the full-length pre-mRNA expressed under its own promoter” (see page 339, col. 2, para. 1). Lin (Front. Genet. 2021, 12:701652, 1-12) compared full-length gene-splicing assay in two different minigene assay for 20+2T>C splice site variant. Lin reported many variants that produced wild type transcript in full length assay did not so in the minigene (see abstract). Lin emphasizes the importance of sequence context in regulating splicing of various genetic variants on splicing. (abstract) (emphasis added). In a recent study, Canson (npj Genomic Medicine, 2025, 10:37, 1-11) provides evidence for the role of spatial constraints and regulatory elements in variant-induced splicing impacts. Canson teaches even intronic deletions outside the consensus splice motifs can have severe consequences and should be considered for splicing assays (see page 8, col. 2, para. 2). The guidance provided in the specification is limited to three intronic regions rich in silencing sequences that could repress splicing in the absence of the drug were identified downstream of the pseudoexon. To test their impact on drug-induced control, SF3B3-on-reporter cassettes containing the full intron sequence (SF3B3int; FIG. 11E), intron fragments rich in silencer sequences (SF3B3il (FIG. 118), SF3B3i2 (FIG. 11G), and SF3B3i3 (FIG. 11H)), or an intron fragment less enriched for intronic silencer sequences (SF3B3i4 (FIG. 11I) were generated (FIG. 31). In the instant case, the 5% sequence variant or even a single nucleotide variant could disrupt exonic/intronic splicing enhancer/silencer elements (ESE or ESS). Hence, a construct comprising a minigene comprising nucleotide sequence of SEQ ID NO: 4 (SF3B3) as species of minigene showing contemplated biological activity could only be demonstrated possessed by the applicant before the effective filing date of the instant application. Regarding the transgene fused and operably linked to the minigene, the disclosure provides descriptions of the transgene encoding a therapeutic protein, an inhibitory RNA, or a Cas9 protein (claims 1, 41, 51). However, the breadth of the definition of a “therapeutic protein” is unclear, in view of the teachings of the specification. Furthermore, the genus of “therapeutic protein” would not reasonably encompass proteins with no known or conjectured therapeutic application for the genus of minigene embraced by the independent claim. The breadth of claim 1 encompasses a nucleic acid construct wherein the transgene comprises a minigene and an encoded gene which is not therapeutic or a trans activator. Given this, the disclosure fails to describe the full breadth of the genus of encoded gene claimed in claim 1. The claimed invention as a whole is not adequately described if the claims require essential or critical elements which are not adequately described in the specification and which is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641, 1646 (1998).
In the instant case, the claimed embodiments of genus of minigene having an alternatively spliced exon, other than the SEQ ID NO: 4 that are less than 1300 nucleotide in length that exhibits the contemplated biological activity encompassed within the genus of minigene lack a written description. The specification fails to describe what minigene having an alternatively spliced exon fall into this genus. The skilled artisan cannot envision the detailed chemical structure of the encompassed minigene having contemplated biological activity, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. The applicant has failed to fully describe the limits of the genus of “therapeutic proteins”, or a representative number of species thereof, and has failed to describe transgenes which encode proteins that are not therapeutic or transactivator proteins. The applicant has also failed to describe representative numbers of species of the genera of minigenes which undergo alternative splicing. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481, 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
In view of the above considerations, one of skill in the art would not recognize that applicant was in possession of the necessary common features or attributes possessed by member of the genus of minigene having alternative splicing exon, other than the SB3F3 as set forth in SEQ ID NO: 4. Moreover, the art has recognized that there would be variation among the species of the genus of minigene sequences. Therefore, Applicant was not in possession of the genus of minigene sequences having the contemplated biological activity as encompassed by the claims. University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that to fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention."
Response to arguments
Applicant disagree with the rejection arguing base claim has been amended to recite the sequence of one of the alternatively spliced minigene exons disclosed in the application. Applicants’ arguments have been fully considered, but are not found persuasive.
As an initial matter, to the extent applicant’s argument pertains to claim 38, the argument is found persuasive, therefore, previous rejection of claim 38 is hereby withdrawn.
In response, it is noted that claims encompasses a genus of (a) a minigene having an alternatively spliced exon and (b) an encoded gene, wherein the minigene comprises, from 5' to 3', Exon 1, Intron 1, Exon 2, Intron 2, and Exon 3, wherein Exon 2 is the alternatively spliced exon, and wherein Exon 2 comprises translation initiation regulatory sequences, and wherein Exon 2 comprises a sequence at least 95% identical to the nucleotide sequence of positions 595-653 of SEQ ID NO: 4. The specification contemplates minigene comprises fewer than 2000, fewer than 1900, fewer than 1800, fewer than 1700, fewer than 1600, fewer than 1500, fewer than 1400, fewer than 1300, fewer than 1200, fewer than 1100, fewer than 1000, fewer than 900, fewer than 800, fewer than 700, fewer than 600 or fewer than 500 nucleotides (see para. 15 of the specification). The sequences of all minigene variant containing exon 2 sequence having at least 95% identical to the nucleotide sequence of positions 595-653 of SEQ ID NO: 4 and adjacent intron and exon, other than the other than the minigenes comprising exons of SF3B3 comprising the SEQ IDNO: 4 (fig. 1 and 3C), encompassed within the genus of minigene having an alternatively spliced exon sequences have not been disclosed. It is emphasized that the surrounding introns (97-594 and 654-1153 of SEQ ID NO: 4) are critical to regulate splicing, allowing for controlled exon inclusion or skipping. As stated in previous office action, art teaches Cooper (Methods, 2005, 37, 331-340) explicitly states “the flanking exons and their adjacent intronic segments can influence the basal recognition of the alternative exon under study”. Lin reported many variants that produced wild type transcript in full length assay did not do so in the minigene (see abstract). Lin emphasizes the importance of sequence context in regulating splicing of various genetic variants on splicing. (abstract) (emphasis added). In a recent study, Canson (npj Genomic Medicine, 2025, 10:37, 1-11) provides evidence for the role of spatial constraints and regulatory elements in variant-induced splicing impacts. Canson teaches even intronic deletions outside the consensus splice motifs can have severe consequences and should be considered for splicing assays (see page 8, col. 2, para. 2).
The guidance provided in the specification is limited to three intronic regions rich in silencing sequences that could repress splicing in the absence of the drug were identified downstream of the pseudoexon. To test their impact on drug-induced control, SF3B3-on-reporter cassettes containing the full intron sequence (SF3B3int; FIG. 11E), intron fragments rich in silencer sequences (SF3B3il (FIG. 118), SF3B3i2 (FIG. 11G), and SF3B3i3 (FIG. 11H)), or an intron fragment less enriched for intronic silencer sequences (SF3B3i4 (FIG. 11I) were generated (FIG. 31). In the instant case, the 5% sequence variant or even a single nucleotide variant could disrupt exonic/intronic splicing enhancer/silencer elements (ESE or ESS) (emphasis added). Hence, a construct comprising a minigene comprising nucleotide sequence of SEQ ID NO: 4 (SF3B3) as species of minigene showing contemplated biological activity could only be demonstrated possessed by the applicant before the effective filing date of the instant application. Regarding the transgene fused and operably linked to the minigene, the disclosure provides descriptions of the transgene encoding a therapeutic protein, an inhibitory RNA, or a Cas9 protein (claims 1, 41, 51). Further, the breadth of the definition of a “therapeutic protein” is unclear, in view of the teachings of the specification. Furthermore, the genus of “therapeutic protein” would not reasonably encompass proteins with no known or conjectured therapeutic application for the genus of minigene embraced by the independent claim.
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants' arguments are not compelling and do not overcome the rejection of record.
Withdrawn-Claim Rejections - 35 USC § 102
Claims 1, 6-7, 39, 41, 45-46, 52 and 53 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Beibel et al (WO/2021/014428, EFD 07/25/2019, IDS) . In view of Applicants’ amendment of base claim 1, introducing the limitation of claim 16 that is not taught by Beibel, the previous rejection is rendered moot and hereby withdrawn.
Withdrawn-Claim Rejections - 35 USC § 103
Claims 1, 2, 5-7, 12, 39, 41, 45-46, 52 and 53 were rejected under 35 U.S.C. 103 as being unpatentable over Beibel et al (WO/2021/014428, EFD 07/25/2019), Paushkin et al (US20110086833, dated 4/14/20211), Bhattacharya et al (WO2018/098446, dated 5/31/2018, IDS) in view of. Palacino (Nature Chemical Biology, 2015, 511-517, IDS). In view of Applicants’ amendment of base claim 1, introducing the limitation of claim 16 that is not taught by Beibel, the previous rejection is rendered moot and hereby withdrawn.
Claims 1 and 8 were rejected under 35 U.S.C. 103 as being unpatentable over Beibel et al (WO/2021/014428, EFD 07/25/2019), and further in view of Cardoso et al (Molecular and Cellular Endocrinology 332 (2011) 228–233). The rejection is withdrawn for the reasons discussed above.
Claims 1, 49-51 were rejected under 35 U.S.C. 103 as being unpatentable over Beibel et al (WO/2021/014428, EFD 07/25/2019, IDS), Paushkin et al (US20110086833, dated 4/14/20211), Bhattacharya et al (WO2018/098446, dated 5/31/2018, IDS ) as evidenced by Palacino (Nature Chemical Biology, 2015, 511-517, IDS) as applied above and Vogel (Gene Therapy, 2004, 157-165, IDS) as evidenced by Stieger et al (Advanced Drug Delivery Reviews, 61, 7-8, 2009, 527-541, IDS). The rejection is withdrawn for the reasons discussed above.
Withdrawn-Double Patenting
Claims 1-2, 5-7, 12, 39, 41, 45-46, 49-52, and 53 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3, 9, 12, 14-16, 23-24, 40-41, 48, 94-96 of copending Application No. 17265302 in view of Paushkin et al (US20110086833). In view of Applicants’ amendment of base claim 1, introducing the limitation of claim 16 that is not taught by Beibel, the previous rejection is rendered moot and hereby withdrawn.
Claims 1-2, 5-8, 12, 16, 20, 24, 28, 32, 39, 41, 45-46, 49-52 and 53 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 11-12, 15-17, 23, 31, 34-35, 36 and 30 of copending Application No. 18865836 in view of Paushkin et al (US20110086833). The claims in 836 have been amended to exclude SF3B3 minigene and therefore, previous is rendered moot and hereby withdrawn.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Davidson et al (WO/2020/033473, IDS) teaches chimeric transactivator minigenes, where the alternative splicing of the minigene determines whether a transactivator is expressed. Expression of the transactivator results in the transcription of a target gene that is under the control of a designer promoter sequence. The reference is no applied as prior because of 102(b)(2) (A) and 102(b)(2)(c) exceptions.
Demoyen (US20190000946, dated 1/3/2019) teaches a second exon comprising translation initiation regulatory sequences comprising of a CMV promoter and start of exon 1, a HTLV-1 R sequence which contains the 5' splice acceptor site, a synthetic 3' acceptor site based on the rabbit j3-globin intron, an exon 2 splicing enhancer comprising a serine-arginine rich (SR) protein binding site to improve RNA export and an exon 2 Kozak sequence upstream of the start codon for the gene of interest (see para. 210) .
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANOOP K. SINGH whose telephone number is (571)272-3306. The examiner can normally be reached Monday-Friday, 8AM-5PM.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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