DETAILED ACTION
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 .
Applicants’ amendment to the claims filed on 7/31/2023 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
Claims 1-4, 7, 9, 12, 14-15, 17, 20, 23, 26, 28, 32, 39, 46, 48, 52, 55 are pending.
Claims 5-6, 8, 10-11, 13, 16, 18-19, 21-22, 24-25, 27, 29-31, 33-38, 40-45, 47, 49-51, 53-54, 56-58 are canceled.
Election/Restrictions
Applicant’s election of Group 1 in the reply filed on 9/16/2025 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 5-6, 8, 10-11, 13, 16, 18-19, 21-22, 24-25, 27, 29-31, 33-38, 40-45, 47, 49-51, 53-54, 56-58 are canceled.
Claims 39, 55 stands withdrawn pursuant to 37 CFR 1.142(b).
Claims 1-4, 7, 9, 12, 14-15, 17, 20, 23, 26, 28, 32, 46, 48, 52 are pending and examined on the merits.
Priority
Acknowledgement is made of this national stage entry of PCT/US21/42949 filed on 7/24/2020, which claims domestic priority to U.S. provisional application 18/017,479, filed on 7/23/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 7/31/2023, 8/5/2024, 9/16/2025 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the Examiner.
Drawings
The Drawings filed on 1/23/2023 are acknowledged and accepted by the Examiner.
Claim Objections
Claim 48 is objected to because of the following informalities: ‘A kit comprising: a container housing an isolated nucleic acid of claim 1.’ Said claim should recite ‘A kit comprising a container housing an isolated nucleic acid of claim 1.’ Appropriate correction is suggested.
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.
Claims 1-4, 7, 9, 12, 17, 20, 26, 28, 32, 46, 48, 52 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gersbach et al (US 2019/0127713 A1, Date Published: May 2, 2019, cited on IDS dated: 7/31/2023) {herein Gersbach} as evidenced by Anthonisen et al (Date Published: 2001, RNA, Examiner cited) {herein Anthonisen} and WP_101454991.1. (Date Published: 23-may-2024, NCBI, Examiner cited) {herein WP_101454991.1). See MPEP 2131.01 regarding multiple reference 102 rejections.
Claims 1-2, 7, 9, 12, 17, 20, 26, 28 are drawn to an isolated nucleic acid comprising a transgene configured to express at least one DNA binding domain fused to at least one transcriptional regulator domain, wherein the DNA binding domain binds to a target gene or a regulatory region of a target gene, wherein the target gene encodes a voltage-gated sodium channel, and wherein the at least one transcriptional regulator domain comprises a TCF4 transactivator, MEF2A transactivator, MEF2C transactivator, MEF2D transactivator, Spl glutamine-rich transactivator, p53 transactivator domain, E2F1 transactivator, MyoD transactivator, MAPK7 transactivator domain, NF1B proline rich transactivator, or RelA transactivator.
Claims 3-4 are drawn to an isolated nucleic acid comprising a transgene configured to express at least one DNA binding domain fused to at least one transcriptional regulator domain, wherein the DNA binding domain binds to a target gene or a regulatory region of a target gene, wherein the target gene encodes a voltage-gated sodium channel, and wherein the transgene comprises a nuclear localization sequence.
Claim 32 is drawn to a recombinant AAV (rAAV) comprising:(i) the isolated nucleic acid of claim 1, and (ii) at least one capsid protein, optionally wherein the AAV capsid protein serotype is selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh8, AAV9, AAV10, AAVrh10, or AAV.PHPB.
Claim 46 is drawn to a composition comprising the isolated nucleic acid of claim 1 and a pharmaceutically acceptable carrier.
Claim 48 is drawn to a kit comprising: a container housing an isolated nucleic acid of claim 1.
Claim 52 is drawn to a host cell comprising the isolated nucleic acid of claim 1, optionally wherein the host cell is a eukaryotic cell.
With respect to claims 1, 7, 12, 20, 26, 28, 32, 46, 48, 52 Gersbach teaches a pharmaceutical composition in a pharmaceutical carrier comprised of a nucleic acid that encodes a
fusion molecule comprising a sequence comprising a dCas9 molecule fused to a modulator of gene expression (para 0005) and gRNA which targets the fusion molecule to a gene in an amount sufficient to modulate gene expression (para 0006) Said engineered nucleic acid can be engineered to target any genes in mammalian cells (para 0003, 0062, 0168). Said engineered DNA-binding protein is comprised of a dCas9 molecule fused to a modulator of gene expression and gRNA which targets the fusion molecule to the gene of interest (para 0005 and 0006), which can be provided in a kit (para 0174) within a container (para 0421 and 0073). It is well-known by those of average skill in the art that dCas9 is a DNA binding domain. Furthermore, it is well-known by those of average skill in the art that gRNA is a transcriptional regulator. As such, Examiner is interpreting the dCas9 encoding nucleic acid sequence taught by Gersbach to be a DNA binding domain and the gRNA taught by Gersbach to be a transcriptional regulator domain. Regarding the recitation ‘the guide nucleic acid comprises a spacer sequence’ in claim 20 of the instant application, it is known by those of ordinary skill in the art that all gRNA contain a spacer sequence which provides the specificity to guide the Cas molecule to the correct location within the target DNA. As such, Examiner is interpreting the gRNA taught by Gersbach to contain a spacer sequence. Said DNA binding domain and transcriptional regulator domain are fused together by a linker domain (para 0372). In addition, said transcriptional regulator domain can contain a transactivator domain which can be targeted to p53 (para 0333, 0368, 0397, table 3). As such, Examiner is interpreting the transcriptional regulator domain to contain a p53 transactivator domain as Gersbach teaches the up regulation of p53 by dCas9-gRNA (table 3). The nucleic acid contains a promoter operably linked to a polynucleotide encoding the fusion protein (para 0297), of which Examiner is interpreting as being the fusion nucleic acid of the invention. Furthermore, Examiner is interpreting the engineered DNA-binding protein taught by Gersbach to be an isolated transgene fusion of dCas9 and gRNA that is targeted to a gene. Said fusion nucleic acid (dCas9-modular of gene expression-gRNA) result in efficient transgene expression in the liver and heart (para 0181). A gene that the fusion nucleic acid can target is SC1A, of which Gersbach defines as a sodium voltage gated channel (page 27, table 3). Furthermore, Gersbach teaches the gene therapy construct further comprises a first and second AV inverted terminal repeat (ITR) sequence flanking the fusion nucleic acid (para 0167). The ITR sequences may be derived from an adeno-associated virus (para 0219). The minimal elements for AAV integration are the inverted terminal repeat (ITR) sequences and a functional Rep 78/68 protein (para 0226) into a recombinant AAV virion (para 0236). Gersbach further teaches that different AAV capsids may be used, including AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV 9 (para 0303). Cas9 as well as a regulatory element such as a promoter fit within the same viral vector (para 0255). Gersbach further teaches, the present invention incorporates the ITR sequences into a vector for integration to facilitate the integration of the transgene into the host cell genome for sustained transgene expression (para 0226). As such, Examiner is interpreting the dCas9-modular of gene expression-gRNA construct to be a transgene. In order to practice compact prosecution, Examiner is interpreting the recitation ‘optionally wherein the guide nucleic acid comprises a nucleotide sequence of any one of SEQ ID NOs: 83-94’ in claim 20 of the instant application to not be a required limitation of the claim due to the recitation ‘optionally.’ Examiner is interpreting the recitation ‘optionally wherein the promoter is a tissue-specific promoter’ in claim 26 of the instant application to not be a required limitation of the claim due to the recitation ‘optionally.’ In addition, Examiner is interpreting the recitation ‘optionally wherein the linker domain is: (i) a flexible linker; or (ii) a cleavable linker’ in claim 28 of the instant application to not be a required limitation of the claim due to the recitation ‘optionally.’ Furthermore, Examiner is interpreting the recitation ‘optionally wherein the AAV capsid protein serotype is selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh8, AAV9, AAV10, AAVrh10, or AAV.PHPB’ in claim 32 to not be a required limitation of the claim due to the recitation ‘optionally.’ In addition, Examiner is interpreting the recitation ‘optionally wherein the host cell is a eukaryotic cell’ in claim 52 of the instant application as not being a requirement of the claim due to the recitation ‘optionally.’
With respect to claim 2, the fusion molecule further comprises a nuclear localization sequence (para 0033). In order to make the record clear, Examiner is interpreting the recitation ‘optionally wherein the nuclear localization sequence comprises any one of SEQ ID NOs: 135-140’ to not be a requirement of the claim due to the recitation ‘optionally.’
With respect to claims 3-4, Gersbach teaches engineered DNA-binding proteins that can be engineered to target any genes in mammalian cells (para 0003). Said engineered DNA-binding protein is comprised of a dCas9 molecules fused to a modulator of gene expression and gRNA which targets the fusion molecule to the gene of interest (para 0005 and 0006). It is well-known by those of average skill in the art that dCas9 is a DNA binding domain. Furthermore, it is well-known by those of average skill in the art that gRNA is a transcriptional regulator. As such, Examiner is interpreting the dCas9 taught by Gersbach to be a DNA binding domain and the gRNA taught by Gersbach to be a transcriptional regulator domain. Said transcriptional regulator domain can contain a transactivator domain which can be targeted to p53 (para 0333, 0368, 0397, table 3). As such, Examiner is interpreting the transcriptional regulator domain to contain a p53 transactivator domain as Gersbach teaches the up regulation of p53 by dCas9-gRNA (table 3). Furthermore, Examiner is interpreting the engineered DNA-binding protein taught by Gersbach to be an isolated transgene fusion of dCas9 and gRNA that its targeted to a gene. In addition, Examiner is interpreting the targeting of a gene by the fusion protein to be the same as binding of the fusion nucleotide to the target gene as Gersbach defines said fusion nucleotide as engineered DNA-binding proteins that can be customized to target any gene in mammalian cells (para 0003). Said fusion nucleic acid (dCas9-targeting gene-gRNA) results in efficient transgene expression in the liver and heart (para 0181). Another gene that the fusion nucleic acid can target is SC1A, of which Gersbach defines as a sodium voltage gated channel (page 27, table 3). The fusion molecule further comprises a nuclear localization sequence (para 0033).
With respect to claim 9, Gersbach teaches an RNA stabilizing sequence element to improve the stability of the Cas9/gRNA (0294). Said element is within a target binding region of which the DNA binding domain binds (para 0294). Examiner is interpreting the RNA stabilizing sequence element as an enhancer as it stabilizes the Cas9/gRNA. Evidentiary reference of Anthonisen is cited to demonstrate that RNA stabilizing sequence element is an untranslated region (abstract). As such, Examiner is interpreting the RNA stabilizing sequence element taught by Gersbach to be an untranslated region. In order to practice compact prosecution, Examiner is interpreting the recitation ‘optionally wherein the untranslated region is an enhancer, a promoter, an intron, and/or a repressor’ to not be a required limitation of the claim due to the recitation ‘optionally.’
With respect to claim 17, Gersbach teaches dCas molecules can be derived from Cas5 (para 0259). Evidentiary reference of WP_101454991.1 is cited to demonstrate that SEQ ID NO: 17 is Cas5 (appendix A). As such, Examiner is interpreting the Cas5 taught by Gersbach to be the same as the instant application SEQ ID NO: 17.
For the reasons stated herein, the teachings of Gersbach anticipate claims 1-4, 7, 9, 12, 17, 20, 26, 28, 32, 46, 48, 52.
Claim Rejections - 35 USC § 103
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.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Gersbach et al (US 2019/0127713 A1, Date Published: May 2, 2019, cited on IDS dated: 7/31/2023) {herein Gersbach} in view of Yamakawa et al (JP2018088888A, Date Published: 6/14/2018, Examiner cited) {herein Yamakawa} as evidenced by Anthonisen et al (Date Published: 2001, RNA, Examiner cited) {herein Anthonisen} and WP_101454991.1. (Date Published: 23-may-2024, NCBI, Examiner cited) {herein WP_101454991.1).
Claim 14 is drawn to the isolated nucleic acid of claim 1, wherein the at least one DNA binding domain binds to at least 2 consecutive nucleotides of a nucleic acid sequence set forth in any one of SEQ ID NOs: 3 or 5-7 (claim 14).
The teachings of Gersbach as applied to claims 1-4, 7, 9, 12, 17, 20, 26, 28, 32, 46, 48, 52.
are set forth in the 102a1 rejection above.
However, Gersbach does not teach the product of claim 14, wherein the at least one DNA binding domain binds to at least 2 consecutive nucleotides of a nucleic acid sequence set forth in any one of SEQ ID NOs: 3 or 5-7 (claim 14).
With respect to claims 14, Yamakawa teaches gRNA targeted to the promoter region of the Scn1a gene (Example 1, page 11, para 2). Said nucleotide sequence, upon which the DNA binding domain binds, is SEQ ID NO: 20, which is the same as SEQ ID NO: 3 of the instant application (Appendix B, Example 1, page 11, para 2). It is known by those of average skill in the art that the gRNA binds more than 2 consecutive nucleotides as it is known in the art that two nucleotides would not be insufficient for binding.
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to apply the teachings of Gersbach et al of a pharmaceutical composition in a pharmaceutical carrier comprised of engineered DNA-binding proteins that can be engineered to target any gene in mammalian cells (para 0003, 0062, 0168), wherein said engineered DNA-binding protein is comprised of a dCas9 molecule fused to a modulator of gene expression and gRNA which targets the fusion molecule to the gene (para 0005 and 0006), which can be provided in a kit (para 0174) within a container (para 0421 and 0073) or combine the teachings of Yamakawa because Yamakawa teaches gRNA targeted to the promoter region of the Scn1a gene (Example 1, page 11, para 2). Said nucleotide sequence, upon which the DNA binding domain binds, is SEQ ID NO: 20, which is the same as SEQ ID NO: 3 of the instant application (Appendix B, Example 1, page 11, para 2).
One of ordinary skill in the art would be motivated to either use the teachings of Gersbach et al. by itself or combine the teachings of Yamakawa because Yamakawa provides the motivation for Gersbach to bind to SEQ ID NO: 20 (instant application SEQ ID NO: 3) since the target specificity of the selected sequence is a sequence that does not perfectly match other regions in the human or mouse genomic sequence (Yamakawa: page 11, para 3), thereby reducing the likelihood of off-targeting. Furthermore, there is not a homologous nucleotide sequence of more than 17 bp consecutive, the number of homologous partial sequences is small, and even if the homologous partial sequence was 17 bp or less, the sequence not located at the 3 '- side end is selected (Yamakawa: page 11, para 3). One of ordinary skill in the art knowing the benefit of accurately targeting DNA utilizing CRISPR/Cas based on the teachings of Gersbach and Yamakawa would have a reasonable expectation of success that utilizing SEQ ID No: 20, taught by Yamkawa, would result in better targeting of the Scn1a gene, thereby resulting in a better targeting molecule and reduced mistargeting.
One of skill in the art would have a reasonable expectation of success to make and use the claimed targeting sequence of SEQ ID NO: 3 (SEQ ID NO: 20: Yamakawa) for the targeting of the Scn1a gene because Yamakawa provides the basic targeting sequence of SEQ ID NO: 30 (instant application SEQ ID NO: 3) and its uses and methods of making it. Gersbach provides the teaching of a transgene comprising CRISPR/Cas9 and gRNA for the targeting of Scn1a. Therefore there would be a reasonable expectation of success to arrive at the above invention. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Gersbach et al (US 2019/0127713 A1, Date Published: May 2, 2019, cited on IDS dated: 7/31/2023) {herein Gersbach} in view of Liu et al (WO2018/204764 A1, Date Published: 8/11/2018, Examiner cited) {herein Liu} as evidenced by Anthonisen et al (Date Published: 2001, RNA, Examiner cited) {herein Anthonisen} and WP_101454991.1. (Date Published: 23-may-2024, NCBI, Examiner cited) {herein WP_101454991.1).
Claim 23 is drawn to the isolated nucleic acid of claim 1, wherein the at least one transcriptional regulator domain is encoded by the amino acid sequence set forth in any one of SEQ ID NOs: 122-134.
The teachings of Gersbach as applied to claims 1-4, 7, 9, 12, 17, 20, 26, 28, 32, 46, 48, 52.
are set forth in the 102a1 rejection above.
With respect to claim 23, Gersbash teaches inhibiting the myostatic signaling pathway is a potential method for treating skeletal muscle degradation.
However, Gersbash does not teach the method of claim 23, wherein the at least one transcriptional regulator domain is encoded by the amino acid sequence set forth in any one of SEQ ID NOs: 122-134 (claim 23).
With respect to claim 23, Liu teaches SEQ ID NO: 16193, which is the same as instant application SEQ ID NO: 125 (appendix C). Said SEQ ID allows for the identification and targeted modulation of gene signaling networks by targeting the genomic signaling center (para 0010, appendix C).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to apply the teachings of Gersbach et al of a pharmaceutical composition in a pharmaceutical carrier comprised of engineered DNA-binding proteins that can be engineered to target any gene in mammalian cells (para 0003, 0062, 0168), wherein said engineered DNA-binding protein is comprised of a dCas9 molecule fused to a modulator of gene expression and gRNA which targets the fusion molecule to the gene (para 0005 and 0006), which can be provided in a kit (para 0174) within a container (para 0421 and 0073) or combine the teachings of Liu which teaches SEQ ID NO: 16193 (instant application SEQ ID NO: 125, appendix C), which allows for the identification and targeted modulation of gene signaling networks by targeting the genomic signaling center (para 0010, appendix C).
One of ordinary skill in the art would be motivated to either use the teachings of Gersbach et al. by itself or combine the teachings of Liu because Liu provides the motivation for Gersbach to utilize the transcriptional domain encoded by instant application SEQ ID NO: 125 (Liu SEQ ID NO: 16193), because Liu teaches said domain allows for the identification and targeted modulation of gene signaling networks, therefore would allow for the targeted inhibition of the myostatic signaling pathway, taught by Gersbash. Furthermore, said transcriptional regulator domain would allow for the identification and location of occupancy-dependent signaling centers (ODSCs), and methods and compositions for altering the binding profile of the ODSC (para 0003) and unidentified targets for disease (para 0003). Thereby, resulting in better control of gene expression. One of ordinary skill in the art knowing the benefit of a transcriptional regulator domain (instant application SEQ ID No: 125) for modulating gene expression utilizing CRISPR/Cas based on the teachings of Gersbach and Liu would have a reasonable expectation of success because Liu teaches said transcriptional regulator domain (Liu SEQ ID NO: 16193; instant application SEQ ID NO: 125) is multifunctional since it allows for the identification, targeted modulation of gene signaling and targeting inhibition of gene expression. Thereby, resulting in a CRISPR/Cas system that can be utilized for multiple instances of gene targeting.
One of skill in the art would have a reasonable expectation of success to make and use the claimed transcriptional regulatory domain of SEQ ID NO: 125 of modulating gene expression by the CRISPR/Cas system gene because Liu provides the teaching of SEQ ID NO: 16193 (instant application SEQ ID NO: 125, appendix C) that allows for the identification and targeted modulation of gene signaling networks by targeting the genomic signaling center (para 0010, appendix C) and its uses and methods of making it. Gersbach provides the teaching of a transgene comprising CRISPR/Cas9 and gRNA for the targeting of Scn1a. Therefore there would be a reasonable expectation of success to arrive at the above invention. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
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 1-4, 7, 9, 12, 14-15, 17, 20, 23, 26, 28, 32, 46, 48, 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 7, 9, 13, 18, 32, 48, 79, 81, 85 of Co-pending Patent Application No. 17/433,269 in view of Gersbash et al (US Patent Application No. 2019/0127713 A1, Date Published: May 2, 2019, cited on IDS dated 7/31/2023) {herein Gersbash}. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are drawn to an isolated nucleic acid comprising a transgene configured to express at least one DNA binding domain fused to at least one transcriptional regulator domain, wherein the DNA binding domain binds to a target gene or a regulatory region of a target gene, wherein the target gene encodes a voltage-gated sodium channel.
The instant application claims 1, 23, 28 are not patentably distinct from claim 1 of ‘296 because claim 1 of ‘296 recites ‘an isolated nucleic acid comprising a transgene configured to express at least one DNA binding domain fused to at least one transcriptional regulator domain, wherein the DNA binding domain binds to a target gene or a regulatory region of a target gene, and wherein the target gene encodes a voltage-gated sodium channel, and wherein the at least one transcriptional regulator domain is encoded by the nucleic acid sequence set forth in SEQ ID NO: 47 and/or the at least one transcriptional regulator domain is encoded by the amino acid sequence set forth in SEQ ID NO: 48,’ which is not patentably distinct from the instant application claims 1, 23, 28 (see appendix D below).
The instant application claim 9 is not patentably distinct from claim 4 of ‘296 because claim 9 of ‘296 recites ‘the isolated nucleic acid of claim 1, wherein the at least one DNA binding domain binds (i) to an untranslated region of the target gene and/or (ii) between 2-2000 bp upstream or between 2-2000 bp downstream of a regulatory region of the target gene,’ which is not patentably distinct from the instant application claim 9.
The instant application claim 12 is not patentably distinct from claim 7 of ‘296 because claim 7 of ‘296 recites ‘the isolated nucleic acid of claim 1, wherein the at least one DNA binding domain encodes a zinc finger protein (ZFP), transcription-activator like effectors (TALE), a dCas protein, and/or a homeodomain,’ which is not patentably distinct from the instant application claims 12.
The instant application claim 14 is not patentably distinct from claim 8 of ‘296 because claim 8 of ‘296 recites ‘the isolated nucleic acid of claim 1, wherein the at least one DNA binding domain binds to a nucleic acid sequence set forth in any one of SEQ ID NOs: 5-7,’ which is not patentably distinct from the instant application claim 14 (See Appendix G below).
The instant application claim 15 is not patentably distinct from claim 9 of ‘296 because claim 9 of ‘296 recites ‘the isolated nucleic acid of claim 1, wherein the at least one DNA binding domain is a zinc finger protein comprising a recognition helix encoded by a nucleic acid having a sequence set forth in any one of SEQ ID NOs: 11-16, 23-28, or 35-40,’ which is not patentably distinct from the instant application claim 15 (see appendix E below).
The instant application claim 17 is not patentably distinct from claim 13 of ‘296 because claim 13 of ‘296 recites ‘the isolated nucleic acid of claim 1, wherein the at least one DNA binding domain is a zinc finger protein comprising the amino acid sequence set forth in any one of SEQ ID NOs: 17-22, 29-34, or 41-46,’ which is not patentably distinct from the instant application claims 17 (see appendix F below).
The instant application claim 20 is not patentably distinct from claim 18 of ‘296 because claim 18 of ‘296 recites ‘the isolated nucleic acid of claim 17, wherein the guide nucleic acid comprises a spacer sequence that targets SCNIA,’ which is not patentably distinct from the instant application claim 20.
The instant application claim 32 are not patentably distinct from claim 32 of ‘296 because claim 32 of ‘296 recites ‘a recombinant AAV (rAAV) comprising:(i) the isolated nucleic acid of claim 1 and (ii) at least one capsid protein,’ which is not patentably distinct from the instant application claims 32.
The instant application claim 46 is not patentably distinct from claim 79 of ‘296 because claim 79 of ‘296 recites ‘a composition comprising the isolated nucleic acid of claim 1 and a pharmaceutically acceptable carrier,’ which is not patentably distinct from the instant application claim 46.
The instant application claim 48 is not patentably distinct from claim 81 of ‘296 because claim 81 of ‘296 recites’ A kit comprising a container housing the isolated nucleic acid of claim 1,‘ which is not patentably distinct from the instant application claim 48.
The instant application claim 52 is not patentably distinct from claim 85 of ‘296 because claim 85 of ‘296 recites ‘a host cell comprising the isolated nucleic acid of claim 1, optionally wherein the host cell is a eukaryotic cell,’ which is not patentably distinct from the instant application claim 52.
However, the claims of ‘296 do not recite the product of claim 2, wherein the transgene further comprises a nuclear localization sequence, optionally wherein the nuclear localization sequence comprises any one of SEQ ID NOs: 135-140 (Instant Application claim 2). An isolated nucleic acid comprising a transgene configured to express at least one DNA binding domain fused to at least one transcriptional regulator domain, wherein the DNA binding domain binds to a target gene or a regulatory region of a target gene, wherein the target gene encodes a voltage-gated sodium channel, and wherein the transgene comprises a nuclear localization sequence (claim 3). The product of claim 4, wherein the at least one transcriptional regulator domain comprises a VPR transactivator, Rta transactivator, p65 transactivator, Hsf1 transactivator, TCF4 transactivator, MEF2A transactivator, MEF2C transactivator, MEF2D transactivator, Spl glutamine-rich transactivator, p53 transactivator domain, E2F1 transactivator, MyoD transactivator, MAPK7 transactivator domain, NF1B proline rich transactivator, or RelA transactivator (claim 4). The product of claim 7, wherein the transgene is flanked by inverted terminal repeats (ITRs) derived from adeno-associated virus (AAV) (claim 7). The product of claim 26, wherein the transgene is operably linked to a promoter, optionally wherein the promoter is a tissue-specific promoter (claim 26).
With respect to claim 2, the fusion molecule further comprises a nuclear localization sequence (para 0033 and Appendix D).
With respect to claims 3-4, Gersbach teaches a pharmaceutical composition in a pharmaceutical carrier comprised of a nucleic acid that encodes a fusion molecule comprising a sequence comprising a dCas9 molecule fused to a modulator of gene expression (para 0005) and gRNA which targets the fusion molecule to a gene in an amount sufficient to modulate gene expression (para 0006) Said engineered nucleic acid can be engineered to target any genes in mammalian cells (para 0003). Said engineered DNA-binding protein is comprised of a dCas9 molecules fused to a modulator of gene expression and gRNA which targets the fusion molecule to the gene (para 0005 and 0006). It is well-known by those of average skill in the art that dCas9 is a DNA binding domain. Furthermore, it is well-known by those of average skill in the art that gRNA is a transcriptional regulator. As such, Examiner is interpreting the dCas9 taught by Gersbach to be a DNA binding domain and the gRNA taught by Gersbach to be a transcriptional regulator domain. Said transcriptional regulator domain can contain a transactivator domain which can be targeted to p53 (para 0333, 0368, 0397, table 3). As such, Examiner is interpreting the transcriptional regulator domain to contain a p53 transactivator domain as Gersbach teaches the up regulation of p53 by dCas9-gRNA (table 3). Furthermore, Examiner is interpreting the engineered DNA-binding protein taught by Gersbach to be an isolated transgene fusion of dCas9 and gRNA that its targeted to a gene. In addition, Examiner is interpreting the targeting of a gene by the fusion protein to be the same as binding of the fusion nucleotide to the target gene as Gersbash defines said fusion nucleotide as engineered DNA-binding proteins that can be customized to target any gene in mammalian cells (para 0003). Said fusion nucleic acid (dCas9-targeting gene-gRNA) results in efficient transgene expression in the liver and heart (para 0181). Another gene that the fusion nucleic acid can target is SC1A, of which Gersbach defines as a sodium voltage gated channel (page 27, table 3). The fusion molecule further comprises a nuclear localization sequence (para 0033).
With respect to claim 7, Gersbach teaches the gene therapy construct further comprises a first and second AV inverted terminal repeat (ITR) sequence flanking the fusion nucleic acid (para 0167). The ITR sequences may be derived from an adeno-associated virus (para 0219).The minimal elements for AAV integration are the inverted terminal repeat (ITR) sequences and a functional Rep 78/68 protein (para 0226) into a recombinant AAV virion (para 0236). Gersbash further teaches that different AAV capsids may be used, including AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV 9 (para 0303).
With respect to claim 26, Gersbach teaches the nucleic acid contains a promoter operably linked to a polynucleotide encoding the fusion protein (para 0297), of which Examiner is interpreting as being the fusion nucleic acid of the invention.
Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to combine the recitations of ‘269, which recites ‘an isolated nucleic acid comprising a transgene configured to express at least one DNA binding domain fused to at least one transcriptional regulator domain, wherein the DNA binding domain binds to a target gene or a regulatory region of a target gene, wherein the target gene encodes a voltage-gated sodium channel, and wherein the at least one transcriptional regulator domain is encoded by the nucleic acid sequence set forth in SEQ ID NO: 47 and/or the at least one transcriptional regulator domain is encoded by the amino acid sequence set forth in SEQ ID NO: 48’ and the teaching of Gersbach which teaches a transgene, operably linked to a promoter (para 0297) comprised of Cas9/gRNA wherein Cas9 has a nuclear localization sequence (para 0287), a transcriptional regulator domain comprised of a p53 activator domain (para 0333, 0368, 0397, table 3) and is flanked by inverted terminal repeats derived from AAV (para 0167).
One of ordinary skill in the art would have had a reasonable expectation of success and a reasonable level of predictability to combine the recitations of the ‘269 and Gersbach because Gersbach acknowledges that the nuclear localization sequence enables trafficking of the transgene into the cell nucleus (para 0519) thereby allowing for better targeting of the molecule. Furthermore, Gersbach acknowledges that operably linking the transgene to a promoter allows for directed expression within cells of an individual or mammal to which the nucleic acid is administered (0194). In addition, a transcriptional regulator domain comprised of a p53 activator domain will allow for the specific targeting of the cancer related molecule. Furthermore, by flanking the transgene with AAV inverted terminal repeats that are derived from AAV, the transgene can be rescued, replicated and efficiently packaged within an AAV virion or particle (para 0219), thereby resulting in efficient and effective transfection. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Status of the Claims
Claims 5-6, 8, 10-11, 13, 16, 18-19, 21-22, 24-25, 27, 29-31, 33-38, 40-45, 47, 49-51, 53-54, 56-58 are canceled.
Claims 39, 55 stands withdrawn pursuant to 37 CFR 1.142(b).
Claims 1-4, 7, 9, 12, 14-15, 17, 20, 23, 26, 28, 32, 46, 48, 52 are pending.
Claims 1-4, 7, 9, 12, 14-15, 17, 20, 23, 26, 28, 32, 46, 48, 52 are rejected.
No claims are in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERICA NICOLE JONES-FOSTER whose telephone number is (571)270-0360. The examiner can normally be reached mf 7:30a - 4:30p.
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, Manjunath Rao can be reached at 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERICA NICOLE JONES-FOSTER/Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656
Appendix A
WP_101454991.1 (Cas5/CasD) vs Instant Application SEQ ID NO: SEQ ID NO: 17
Query Match 100.0%; Score 35; Length 264;
Best Local Similarity 100.0%;
Matches 7; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QRGNLVR 7
|||||||
Db 65 QRGNLVR 71
Appendix B
Instant Application SEQ ID NO: 3 vs Yamakawa SEQ ID NO: 20
Query Match 100.0%; Score 130; Length 800;
Best Local Similarity 100.0%;
Matches 130; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TTTTTTTTTTTTTTTTTGAAACAAGCTATTTGCTGATTTGTATTAGGTACCATAGAGTGA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 561 TTTTTTTTTTTTTTTTTGAAACAAGCTATTTGCTGATTTGTATTAGGTACCATAGAGTGA 620
Qy 61 GGCGAGGATGAAGCCGAGAGGATACTGCAGAGGTCTCTGGTGCATGTGTGTATGTGTGCG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 621 GGCGAGGATGAAGCCGAGAGGATACTGCAGAGGTCTCTGGTGCATGTGTGTATGTGTGCG 680
Qy 121 TTTGTGTGTG 130
||||||||||
Db 681 TTTGTGTGTG 690
Appendix C
Liu et al (WO2018204764-A1) SEQ ID NO: 16193 vs Instant Application SEQ ID NO: 125
Query Match 100.0%; Score 61; Length 327;
Best Local Similarity 100.0%;
Matches 13; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 SVSEDVDLLLNQR 13
|||||||||||||
Db 143 SVSEDVDLLLNQR 155
Appendix D for Double Patenting Rejection
Instant Application 18352719 (SEQ ID NO: 133) vs Reference Application 17433269 (SEQ ID NO: 48)
Query Match 100.0%; Score 1351; DB 1; Length 523;
Best Local Similarity 100.0%;
Matches 260; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QYLPDTDDRHRIEEKRKRTYETFKSIMKKSPFSGPTDPRPPPRRIAVPSRSSASVPKPAP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 68 QYLPDTDDRHRIEEKRKRTYETFKSIMKKSPFSGPTDPRPPPRRIAVPSRSSASVPKPAP 127
Qy 61 QPYPFTSSLSTINYDEFPTMVFPSGQISQASALAPAPPQVLPQAPAPAPAPAMVSALAQA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 128 QPYPFTSSLSTINYDEFPTMVFPSGQISQASALAPAPPQVLPQAPAPAPAPAMVSALAQA 187
Qy 121 PAPVPVLAPGPPQAVAPPAPKPTQAGEGTLSEALLQLQFDDEDLGALLGNSTDPAVFTDL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 188 PAPVPVLAPGPPQAVAPPAPKPTQAGEGTLSEALLQLQFDDEDLGALLGNSTDPAVFTDL 247
Qy 181 ASVDNSEFQQLLNQGIPVAPHTTEPMLMEYPEAITRLVTGAQRPPDPAPAPLGAPGLPNG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 248 ASVDNSEFQQLLNQGIPVAPHTTEPMLMEYPEAITRLVTGAQRPPDPAPAPLGAPGLPNG 307
Qy 241 LLSGDEDFSSIADMDFSALL 260
||||||||||||||||||||
Db 308 LLSGDEDFSSIADMDFSALL 327
Appendix E for Double Patenting Rejection
Instant Application 18352719 (SEQ ID NO: 11) vs Reference Application 17433269 (SEQ ID NO: 11)
Query Match 100.0%; Score 21; DB 1; Length 21;
Best Local Similarity 100.0%;
Matches 21; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CAGCGGGGAAACCTGGTGAGG 21
|||||||||||||||||||||
Db 1 CAGCGGGGAAACCTGGTGAGG 21
Appendix F for Double Patenting Rejection
Instant Application 18352719 (SEQ ID NO: 17) vs Reference Application 17433269 (SEQ ID NO: 17)
Query Match 100.0%; Score 35; DB 1; Length 7;
Best Local Similarity 100.0%;
Matches 7; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QRGNLVR 7
|||||||
Db 1 QRGNLVR 7
Appendix G for Double Patenting Rejection
Instant Application 18352719 (SEQ ID NO: 5) vs Reference Application 17433269 (SEQ ID NO: 5)
Query Match 100.0%; Score 18; DB 1; Length 18;
Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GAGTGAGGCGAGGATGAA 18
||||||||||||||||||
Db 1 GAGTGAGGCGAGGATGAA 18
Appendix H
Instant Application SEQ ID NO: 11 vs SEQ ID NO:
Query Match 100.0%; Score 21; Length 84;
Best Local Similarity 100.0%;
Matches 21; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CAGCGGGGAAACCTGGTGAGG 21
|||||||||||||||||||||
Db 34 CAGCGGGGAAACCTGGTGAGG 54