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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/29/2025 has been entered.
Change in Examiner
The examiner of your application in the PTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Stephanie Sullivan, Art Unit 1635.
Response to Amendment
Receipt of Arguments/Remarks filed on 07/29/2025 is acknowledged. Claims 5,7,9-16,18-20,23,26-28,30-40,44-60,63 and 65-67 were/stand cancelled. Claims 1-4, 6,17,29 and 41 were amended. Claims 69-73 are newly added. Claims 1-4,6,8,17, 21,22,24,25,29,41-43,61,62,64 and 68-73 are pending. Claims 29,41-43 and 61 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/10/2024.
Claims 1-4,6,8,17,21,22,24,25,62,64 and 68-73 are under examination.
Priority
63/413,572 does not provide adequate support under 35 USC 112(a) for instant claims 1-4, 6, 8, 17, 21, 22, 24, 25, 64 and 68. The effective filing date of these claims is considered to be 10/5/2023. The effective filing date of claim 62 is considered to be 10/5/2022. See the final rejection, mailed 01/30/2025.
Response to Arguments
Applicant’s amendments and arguments, see pages 7-10, filed 07/29/2025, with respect to the rejection(s) of claim(s) 1,3,8,17,21,22,24,25,62 and 64 as obvious over Tornabene et al., claims 2,4 and 68 as obvious over Tornabene et al. further in view of Maddalena et al. and GenBank Accession FJ226077, and claim 6 as obvious over Tornabene et al. further in view of Coffin et al. under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendments to the claims adding new limitations. See the new rejections below.
Claim Interpretation
Regarding claim 1, component (a) is interpreted as requiring either 1) a landing sequence comprising at least one cutting sequence, or 2) a transgene sequence encoding a transgene product, or comprising both. The examiner is not interpreting the landing sequence as requiring the transgene sequence because of the and/or, and the landing sequence is not required and may just comprise the transgene sequence for (a).
The phrase “exogenous fusion sequence” in claim 1 is understood to refer to a fusion sequence that is not native to the genome into which it has been inserted. This meaning for “exogenous” is derived from its use in describing transgenes in the instant specification at page 24, lines 11-12.
The instant specification defines the term “landing sequence” or “landing pad” in claim 1, refers to a nucleic acid sequence wherein a transgene sequence could be inserted into, and the nucleic acid sequence is not naturally present at the locus of the endogenous target gene (page 12, lines 8-10).
The instant specification defines the term “cutting sequence” in claim 1 as a nucleic acid sequence capable of being cut by a targeted nuclease, such as a Cas nuclease, and the nucleic acid sequence is not naturally present at the locus of the endogenous target gene (page 10, lines 18-20).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 64 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Based on the broadest reasonable interpretation, claim 64 encompasses a human cell comprising the synthetic GSH of claim 1 that is contained within a human organism, as the cell is not recited to be a non-human cell or an isolated cell.
Claim Rejections - 35 USC § 102
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 1,3,21,22,24,25,62,64,71 and 73 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Carlson et al. (US 20190045761, Published 14 Feb 2019).
Regarding claims 1 and 62, Carlson et al. teach a rescue cassette (exogenous fusion sequence) comprising a germline specific promoter fused to an inducible recombinase; one or more rescue genes wherein the rescue genes are homologs or orthologs to native genes found in livestock animals (complementation sequence comprising a rescue gene sequence) and the cassette is augmented comprising introduction of one or more additional genes into the cassette (paragraph 0187). Carlson et al. teach the phase “rescue cassette” means a nucleic acid sequence having expressed sequences that save a cell or animal from a genomic edit which would otherwise be lethal or cause failure to thrive for animals reared under normal conditions (paragraph 0070). Based on the claim interpretation above regarding component (a) of instant claim 1, Carlson et al. teaches the transgene sequence of (a) as the rescue cassette comprises one or more additional genes in the cassette. Carlson et al. teach homology directed repair, and that an HDR template may further comprise flanking sequences that provide homology to DNA adjacent to the endogenous allele or the DNA that is to be replaced (0096). Therefore, Carlson et al. teach the structure and limitations of claim 1.
Regarding claim 3, Carlson et al. teach the rescue cassette is augmented comprising introduction of one or more additional genes into the cassette (paragraph 0187), and that a promoter driving expression of the transgene can be either ubiquitous or tissue-specific (paragraph 0112). Carlson et al. does not teach wherein the additional genes (transgene sequence) encode a fluorescent protein product, and therefore teaches the limitations of claim 3.
Regarding claim 21, Carlson et al. teach rescue cassettes comprising RAG2 and IL2Rg each driven by their native promoters (paragraph 0169), and therefore teaches the rescue gene sequence encodes a protein (RAG2, IL2Rg).
Regarding claim 22, Carlson et al. teach the exogenous nucleic acid encodes a polypeptide (paragraph 0113).
Regarding claim 24, Carlson et al. does not teach that the exogenous fusion sequence comprises a transgene sequence that encodes a Cas nuclease product or a gRNA product. Carlson et al. teach the cassette is augmented comprising introduction of one or more additional genes into the cassette (paragraph 0187), but does not teach that the additional genes (transgenes) encode a Cas nuclease product or gRNA product. Therefore, the limitations of claim 24 are met.
Regarding claim 25, Carlson et al. teach “safe harbor” or “safe harbor locus” refers to a site in a genome in which a gene or nucleotide sequence can be introduced without interrupting a native gene function and which is transcriptionally active, and examples include the ROSA26 locus in mice and AAVS1 locus in humans (paragraph 0075).
Regarding claim 64, Carlson et al. teach a cell having introduced therein the cassette (paragraph 0192), and a livestock animal comprising in its genome the rescue cassette (paragraph 0201).
Regarding claims 71 and 73, Carlson et al. teach the rescue cassette comprises one or more rescue genes and the cassette is augmented comprising introduction of one or more additional genes into the cassette (paragraph 0187). Therefore, Carlson et al. teaches the rescue genes and additional genes in the cassette, and which would be two separate products. Carlson et al. does not teach that the landing sequence encodes a transgene product that is a fluorescent protein product, and therefore teaches the limitations of claim 73.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3,6,17,21,22,24,25,62,64,68-71 and 73 are rejected under 35 U.S.C. 103 as being unpatentable over Carlson et al. (US 20190045761, Published 14 Feb 2019) in view of George et al. (US 20190144887, Published 16 May 2019).
Regarding claims 1 and 68, Carlson et al. teach a rescue cassette (exogenous fusion sequence) comprising a germline specific promoter fused to an inducible recombinase; one or more rescue genes wherein the rescue genes are homologs or orthologs to native genes found in livestock animals (complementation sequence comprising a rescue gene sequence) and further comprising a landing pad (Paragraph 0186). Carlson et al. teach the term “landing pad” as a known nucleic acid sequence inserted into genome which optimizes the further insertion of exogenous DNA (paragraph 0076), and that the genes expressed in the cassette can be augmented or increased by making use of a landing pad included in the cassette used to introduce one or more rescue genes into the cassette to create new lines or models, and in these cases native genes are also edited to create knockouts or disease alleles that are then rescued by the genes added to the augmented rescue cassette (paragraph 0007). Carlson et al. teach the phase “rescue cassette” means a nucleic acid sequence having expressed sequences that save a cell or animal from a genomic edit which would otherwise be lethal or cause failure to thrive for animals reared under normal conditions (paragraph 0070). Carlson et al. teach homology directed repair, and that an HDR template may further comprise flanking sequences that provide homology to DNA adjacent to the endogenous allele or the DNA that is to be replaced (0096).
Carlson et al. does not explicitly teach that the landing sequence comprises at least one cutting sequence.
However, George et al. cures the deficiencies of Carlson et al. George et al. teach compositions and methods that minimize re-customization of exogenous donor nucleic acids for integration into the host cell’s genome, and that a host cell’s genome is modified to comprise a landing pad which can be used to further facilitate integration of exogenous donor nucleic acids comprising standardized homology sequences. The landing pad comprises landing pad homology sequences which are capable of homologously recombining with the standardized homology sequences of the exogenous nucleic acids (paragraph 0006). George et al. teach each landing pad further comprises a nuclease target sequence positioned between an upstream landing pad homology sequence and a downstream landing pad homology sequence, and that the nuclease target sequence comprises a nucleotide sequence that is recognized and cleavable by a site-specific nuclease (paragraphs 0007,0063). Therefore, George et al. teach that the landing sequence comprises a cutting sequence, and in addition teaches flanking sequences (the upstream and downstream landing pad homology sequences).
Regarding claim 2, Carlson et al. teach embodiments of the rescue cassette without a transgene sequence encoding a transgene product (paragraph 0186).
Regarding claims 3 and 62, Carlson et al. teach the rescue cassette is augmented comprising introduction of one or more additional genes into the cassette (paragraph 0187), and that a promoter driving expression of the transgene can be either ubiquitous or tissue-specific (paragraph 0112). The additional gene(s) is interpreted as the transgene sequence. Carlson et al. does not teach wherein the additional genes (transgene sequence) encode a fluorescent protein product.
Regarding claim 6, Carlson et al. teach one or more rescue genes wherein the rescue genes are homologs or orthologs to native genes found in livestock animals, and wherein the genes in the cassette are under the control of their native promoter (paragraphs 0169, 0186).
Regarding claim 17, Carlson et al. teach additional regulatory regions that may be useful in nucleic acid constructs include translation control sequences (e.g., IRES) which may increase expression by affecting transcription, stability of the mRNA, translational efficiency, or the like, and such regulatory regions can be included in a nucleic acid construct as desired to obtain optimal expression of the nucleic acids in the cell(s) (paragraph 0110).
Regarding claim 21, Carlson et al. teach rescue cassettes comprising RAG2 and IL2Rg each driven by their native promoters (paragraph 0169), and therefore teaches the rescue gene sequence encodes a protein (RAG2, IL2Rg).
Regarding claim 22, Carlson et al. teach the exogenous nucleic acid encodes a polypeptide (paragraph 0113).
Regarding claim 24, Carlson et al. does not teach that the exogenous fusion sequence comprises a transgene sequence that encodes a Cas nuclease product or a gRNA product. Carlson et al. teach the cassette is augmented comprising introduction of one or more additional genes into the cassette (paragraph 0187), but does not teach that the additional genes (transgenes) encode a Cas nuclease product or gRNA product. Therefore, the limitations of claim 24 are met.
Regarding claim 25, Carlson et al. teach “safe harbor” or “safe harbor locus” refers to a site in a genome in which a gene or nucleotide sequence can be introduced without interrupting a native gene function and which is transcriptionally active, and examples include the ROSA26 locus in mice and AAVS1 locus in humans (paragraph 0075).
Regarding claim 64, Carlson et al. teach a cell having introduced therein the cassette (paragraph 0192), and a livestock animal comprising in its genome the rescue cassette (paragraph 0201).
Regarding claim 69, Carlson et al. teach a rescue cassette comprising one or more rescue genes wherein the rescue genes are homologs or orthologs to native genes found in livestock animals (complementation sequence comprising a rescue gene sequence) and further comprising a landing pad (paragraph 0186) and teaches flanking sequences that provide homology to DNA adjacent to the endogenous allele or the DNA that is to be replaced (0096).
Carlson et al. does not teach the specific arrangement from 5’ to 3’ of a first flanking sequence, the complementation sequence, the landing sequence or the transgene sequence and a second flanking sequence.
However, George et al. teaches the arrangement of the landing pad being a nuclease target sequence positioned between an upstream landing pad homology sequence and a downstream landing pad homology sequence, and the nuclease target sequence is recognized and cleavable by a site-specific nuclease (paragraph 0007).
Regarding claim 70, Carlson et al. teach nucleic acid sequences can be operably linked to regulatory regions such as promoters (paragraph 0108). Carlson et al. does not teach the specific arrangement of the promoter sequence being downstream of the complementation sequence and upstream of the landing sequence. However, Carlson does teach that regulatory regions, including promoters, can be included in a nucleic acid construct as desired to obtain optimal expression of the nucleic acids in the cell(s) (paragraph 0110).
Regarding claims 71 and 73, Carlson et al. teach the rescue cassette comprises one or more rescue genes and the cassette is augmented comprising introduction of one or more additional genes into the cassette (paragraph 0187). Therefore, Carlson et al. teaches the rescue genes and additional genes in the cassette, and which would be two separate products. Carlson et al. does not teach that the landing sequence encodes a transgene product that is a fluorescent protein product, and therefore teaches the limitations of claim 73.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have modified the rescue cassette of Carlson et al. with the teachings regarding the cutting sequence of George et al. with a reasonable expectation of success. There would be a reasonable expectation of success, because both Carlson et al. and George et al. teach landing pads. One of ordinary skill in the art would have been motivated to provide at least one cutting sequence in the landing pad sequence of the rescue cassette of Carlson et al. because George et al. teach compositions and methods that minimize re-customization of exogenous donor nucleic acids for integration into the host cell’s genome and a landing pad can be used to further facilitate integration of exogenous donor nucleic acids comprising standardized homology sequences and that each landing pad further comprises a nuclease target sequence positioned between an upstream landing pad homology sequence and a downstream landing pad homology sequence, and that the nuclease target sequence comprises a nucleotide sequence that is recognized and cleavable by a site-specific nuclease (paragraphs 0007,0063) and would make obvious the limitations of claims 1-3,6,21,22,24,25,62,64,68,71 and 73.
It would be obvious that the rescue cassette of Carlson et al. modified with the teachings regarding the cutting sequence of George et al. would comprise an IRES sequence between the complementation sequence and the transgene sequence or the landing sequence, or that the rescue cassette of Carlson et al. modified with the cutting sequence of George et al. would further comprise a promoter sequence downstream of the complementation sequence and upstream of the landing sequence with a reasonable expectation of success. An ordinary artisan would have been motivated to do so based on the teachings of Carlson et al. that additional regulatory regions that may be useful in nucleic acid constructs include translation control sequences (e.g., IRES) which may increase expression by affecting transcription, stability of the mRNA, translational efficiency, or the like, and such regulatory regions can be included in a nucleic acid construct as desired to obtain optimal expression of the nucleic acids in the cell(s) (paragraph 0110) and nucleic acid sequences can be operably linked to regulatory regions such as promoters (paragraph 0108). An ordinary artisan could use the teachings of Carlson et al. regarding the IRES and promoter regulatory regions and place in a nucleic acid construct in a way as to achieve optimal expression of the nucleic acid(s).
Accordingly, the limitations of claims 17 and 70 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would be obvious to provide the arrangement of 5’ to 3’ of a first flanking sequence, the complementation sequence, the landing sequence or the transgene sequence and second flanking sequence as in claim 69 based on the combined teachings of Carlson et al. and George et al. with a reasonable expectation of success. One of ordinary skill in the art would be motivated to do so because Carlson et al. teach a rescue cassette comprising one or more rescue genes wherein the rescue genes are homologs or orthologs to native genes found in livestock animals and further comprising a landing pad (paragraph 0186) and teaches flanking sequences that provide homology to DNA adjacent to the endogenous allele or the DNA and George et al. teaches the arrangement of the landing pad being a nuclease target sequence positioned between an upstream landing pad homology sequence and a downstream landing pad homology sequence, and the nuclease target sequence is recognized and cleavable by a site-specific nuclease (paragraph 0007). An ordinary artisan would only have to insert the rescue gene sequence of Carlson et al. between the upstream landing pad homology sequence and the nuclease target sequence in the landing pad of George et al. to arrive at the arrangement of claim 69 and could do so with a reasonable expectation of success in order to optimize the expression of the complementation sequence.
Accordingly, the limitations of claim 69 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 4 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Carlson et al. and George et al. as applied to claims 1-3,6,17,21,22,24,25,62,64,68-71 and 73 above, and further in view of Lundberg et al. (US 20220047722, Published 17 Feb. 2022).
The teachings of Carlson et al. and George et al. as applicable to claims 1-3,6,17,21,22,24,25,62,64,68-71 and 73 are described above.
Regarding claim 8, Carlson et al. do teach the term nucleic acid refers to both RNA and DNA, including cDNA (paragraph 0118).
Carlson et al. and George et al. do not teach wherein the landing sequence comprises two or more unique cutting sequences and one or more filler sequences, wherein the locus of the endogenous target gene has no sequence having 100% identity to the unique cutting sequences, wherein each of the two or more unique cutting sequences comprise a PAM sequence and a gRNA related sequence, each of the two or more unique cutting sequences are separated by a filler sequence that has a length of at least 100 nt, and the filler sequence is homologous to a sequence at the locus of the endogenous target gene. Carlson et al. and George et al. do not explicitly teach wherein the rescue gene sequence comprises a cDNA sequence that does not comprise an altered codon(s) relative to the native encoding sequence of the endogenous target gene.
However, before the effective filing date, Lundberg et al. teach one or more gRNA or one or more sgRNA can comprise a spacer sequence that is complementary to a DNA sequence within or near the ATXN1 gene (paragraph 0025). Lundberg et al. teach in genome-targeting nucleic acids, a spacer extension sequence can modify activity, provide stability and/or provide a location for modifications of a genome-targeting nucleic acid, and a spacer extension sequence can modify on- or off- target activity or specificity (paragraph 0128). Lundberg et al. teach the spacer extension sequence can have more than 100 up to 7000 or more nucleotides (paragraph 0128). Lundberg et al. teach the target nucleic acid in a Type II CRISPR system is referred to as a protospacer adjacent motif (PAM), and in nature the PAM is essential to facilitate binding of a site-directed polypeptide (e.g. Cas9) to the target nucleic acid (paragraph 0073). Lundberg et al. teach that in a CRISPR/Cas system herein, the spacer sequence can be designed to hybridize to a target nucleic acid that is located 5’ of the PAM of the Cas9 enzyme used in the system, the spacer may perfectly match the target sequence, and that each Cas9 enzyme has a particular PAM sequence that it recognizes in target DNA (paragraph 0131). Lundberg et al. teach the specificity of targeting is driven by a 20 or 24 nucleotide sequence in the guide RNA that undergoes Watson-Crick base-pairing with the target DNA (plus an additional 2 bases in the adjacent NAG or NGG PAM sequence in the case of Cas9 from S. pyogenes) (paragraph 0399).
Lundberg et al. teach using genome editing by correction of mutant or defective sequences to a wild-type sequence which restores structure or function to a gene or its gene product (paragraph 0066), and also teach DNA sequences can be knocked-in and may include an entire gene or any portion or fragment of the gene, and that cDNA encoding the wild-type protein may be inserted into the genome of the cell carrying a mutant gene (paragraph 0067). Lundberg et al. specifically teaches disrupting or deleting the mutant ATXN1 gene and inserting a wild-type ATXN1 gene, a cDNA or a minigene (comprised of one or more exons and optionally one or more introns, including natural or synthetic introns) into the ATXN1 gene locus or a safe harbor locus (paragraph 0077), which can be achieved by delivering into the cell one or more CRISPR endonucleases, a pair of gRNAs targeting upstream and downstream of or in the first and last exon and/or intron of the ATXN1 gene and a donor DNA that contains the desired sequence and homology arms flanking regions of the target locus (paragraph 0082). Lundberg et al. teach that a full length cDNA can be knocked into any safe harbor locus (paragraph 0257).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to provide the rescue cassette of Carlson et al. and George et al. with a landing sequence comprising two or more unique cutting sequences each comprising a PAM sequence and gRNA related sequence, each of the two or more unique cutting sequences separated by a filler sequence having a length of at least 100 nt, and being homologous to a sequence at the locus of the endogenous target gene, based on the teachings of Lundberg et al. One of ordinary skill in the art would have been motivated to provide a landing sequence with multiple cutting sequences each comprising a PAM and gRNA because Lundberg et al. teach the target nucleic acid in a Type II CRISPR system is referred to as a protospacer adjacent motif (PAM), and in nature the PAM is essential to facilitate binding of a site-directed polypeptide (e.g. Cas9) to the target nucleic acid (paragraph 0073) and that each Cas9 enzyme has a particular PAM sequence that it recognizes in target DNA (paragraph 0131). Lundberg et al. teach the specificity of targeting is driven by a 20 or 24 nucleotide sequence in the guide RNA that undergoes Watson-Crick base-pairing with the target DNA (plus an additional 2 bases in the adjacent NAG or NGG PAM sequence in the case of Cas9 from S. pyogenes) (paragraph 0399). One of ordinary skill in the art would have been motivated to provide a spacer sequence of at least 100 nt to separate the cutting sequences because Lundberg et al. teach a spacer extension sequence can modify activity, provide stability and/or provide a location for modifications of a genome-targeting nucleic acid, and a spacer extension sequence can modify on- or off- target activity or specificity (paragraph 0128), and the spacer extension sequence can have more than 100 up to 7000 or more nucleotides (paragraph 0128), and would make obvious the limitations of claim 4.
It would have been obvious to one of ordinary skill in the art before the effective filing date, that the rescue gene sequence in the rescue cassette of Carlson et al. and George et al. comprise a cDNA sequence that does not comprise an altered codon(s) relative to the native encoding sequence of the endogenous target gene, based on the teachings of Lundberg et al. There would be a reasonable expectation of success because Lundberg et al. also pertains to introducing wild-type genes into a safe harbor locus. One of ordinary skill in the art would have been motivated to provide a rescue gene sequence as a cDNA sequence that does not comprise an altered codon in order to restore function of the gene, because Lunderberg et al. teach using genome editing by correction of a mutant or defective sequences to a wild-type sequence which restores structure or function to a gene or its gene product (paragraph 0066), and also teach DNA sequences can be knocked-in and may include an entire gene or any portion or fragment of the gene, and that cDNA encoding the wild-type protein may be inserted into the genome of the cell carrying a mutant gene (paragraph 0067). Lundberg et al. specifically teaches disrupting or deleting the mutant ATXN1 gene and inserting a wild-type ATXN1 gene or a cDNA into the ATXN1 gene locus or a safe harbor locus, and would make obvious the limitations of claim 8.
Accordingly, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 72 is rejected under 35 U.S.C. 103 as being unpatentable over Carlson et al., George et al., and Lundberg et al. as applied to claims 4 and 8 above, and further in view of Adolfi et al. (Nat Commun. 3 Nov 2020; 11:5553), cited on an IDS.
The teachings of Carlson et al., George et al., and Lundberg et al. as applicable to claims 4 and 8 are described above.
Carlson et al., George et al., and Lundberg et al. do not teach wherein the genome is an insect genome.
However, before the effective filing date, Adolfi et al. teach that Cas9/gRNA mediated gene-drive systems have advanced development of genetic technologies for controlling vector-borne pathogen transmission, including population suppression approaches, genetic analogues of insecticidal techniques that reduce the number of insect vectors, and population modification approaches which interfere with competence to transmit pathogens (Abstract). Adolfi et al. teach a recoded gene-drive rescue system for population modification of the malaria vector, Anopheles stephensi, that relieves the load in females caused by integration of the drive into the kynurenine hydroxylase gene by rescuing its function (Abstract). Adolfi et al. teach a gene drive Reckh, which targets the haplosufficient gene kh, required for adult female survival and reproduction in An. stephensi following a blood meal, and provides a recoded portion of the gene that rescues its function. In doing so, individuals that carry a copy of the drive are functionally protected and comparably as fit as their WT counterparts, while nonfunctional resistant alleles are eliminated owing to the reduced survival and impaired reproductive capacity in white-eyed homozygous and mosaic heterozygous females (Discussion page 7, right column).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the rescue cassette of Carlson et al., George et al., and Lundberg et al. for insertion into an insect genome, based on the teachings of Adolfi et al. There would be a reasonable expectation of success, because Carlson et al. and Adolfi et al. pertain to gene rescue and Carlson et al. teach rescue genes in livestock animals, and Lundberg et al. and Adolfi et al. both utilize Cas9/CRISPR. One of ordinary skill in the art would have been motivated to modify the rescue cassette of Carlson et al., George et al., and Lundberg et al. for insertion into an insect genome because Adolfi et al. teach a recoded gene-drive rescue system for population modification of the malaria vector, Anopheles stephensi, that relieves the load in females caused by integration of the drive into the kynurenine hydroxylase gene by rescuing its function (Abstract) and that the gene drive Reckh, which targets the haplosufficient gene kh, required for adult female survival and reproduction in An. stephensi following a blood meal, and provides a recoded portion of the gene that rescues its function. In doing so, individuals that carry a copy of the drive are functionally protected and comparably as fit as their WT counterparts, while nonfunctional resistant alleles are eliminated owing to the reduced survival and impaired reproductive capacity in white-eyed homozygous and mosaic heterozygous females (Discussion page 7, right column).
Accordingly, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Claims 1-4,6,8,17,21,22,24,25,62,64 and 68-73 are rejected.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636