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 .
Response to Amendment
Receipt of Arguments/Remarks filed on 04/08/2026 is acknowledged. Claims 5,7,9-16,18-20,23,26-28,30-40,44-60,63 and 65-67 stand cancelled. Claim 64 was amended. 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 Claims 29,41-43 and 61 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 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.
Withdrawn Rejections
Applicant’s arguments and amendments, see page 7, filed 04/08/2026, with respect to the 35 U.S.C. 101 rejection of claim 64 have been fully considered and are persuasive, due to the amendment to claim 64 to recite “A cell in cell culture”, so that the cell no longer encompasses a cell within a human organism. The 35 U.S.C. 101 rejection of claim 64 has been withdrawn.
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).
Maintained Rejections
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Response to Arguments
Applicant's arguments filed 04/08/2026 have been fully considered but they are not persuasive.
Applicant cites In re Dillon (Anticipation requires the disclosure in a single prior art reference of each element of the claim under consideration), Scripps Clinic & Res. Found. V. Genentech, Inc. (For anticipation, there must be no difference between the claimed invention and the reference disclosure, as viewed by a person of ordinary skill in the art); and Del Mar Engineering Lab v. Physio-Tronics, Inc. (To overcome the defense of anticipation, “it is only necessary for the patentee to show some tangible difference between the invention and the prior art”), on page 7. Applicant argues that Carlson et al. relates to adding an IL2Rg/RAG2 rescue cassette to a line of immunocompromised pig model in which native IL2Rg/RAG2 immune genes were knockout so that the rescued, immunocompetent pig could reproduce better. Applicant argues on page 8 that they disagree with the novelty rejection because claim 1 recites that…an exogenous fusion sequence that is inserted at the locus of an endogenous target gene of the genome, wherein the fusion sequence comprises…(b) a complementation sequence comprising a rescue gene sequence that encodes a rescue gene product that is identical to the endogenous target gene product. Applicant argues that Carlson et al. describe the rescue cassette is integrated into the genome at a conventional safe-harbor locus ROSA (e.g., para. [0007-0009], [0075], [0174], and that Carlson et al. at FIGs 6A and 6B describe that a rescue cassette that expresses RAG2 and IL2Rg was integrated into a conventional safe-harbor locus ROSA, as opposed to a native RAG2 or IL2Rg locus, and thus the rescue cassette product of Carlson et al. is not identical to the endogenous target gene product (ROSA) of the locus into which the rescue cassette is inserted and do not teach insertion of a rescue cassette into the locus of a native gene that the rescue cassette is designed to rescue. Therefore, Carlson et al. is different and do not teach each element of claim 1.
This is not found persuasive. Regarding Applicant’s argument citing In re Dillon, Scripps Clinic & Res. Found. V. Genentech, Inc., and Del Mar Engineering Lab v. Physio-Tronics, Inc., the Examiner maintains that all of the structural limitations of claim 1 are taught by Carlson et al. In the instant case, the preamble of the claim recites a purpose or intended use. The preamble recites the synthetic GSH comprising an exogenous fusion sequence that is inserted at the locus of an endogenous target gene of the genome, which is an intended use or purpose. The body of the claim sets for the required structure of the synthetic GSH comprising an exogenous fusion sequence comprising (a) and (b), and the preamble does not structurally change the exogenous fusion sequence that is claimed. "The patentability of apparatus or composition claims depends on the claimed structure, not on the use or purpose of that structure." Catalina Mktg. Int'l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801,809 (Fed. Cir. 2002). Note: MPEP 2111.02. The Examiner is interpreting the rescue gene sequence of Carlson et al. to meet the limitations of (b) in claim 1 regarding the rescue gene sequence encoding a rescue gene product that is identical to the endogenous target gene product because Carlson et al. teach wherein the rescue genes are homologs to native genes, and is interpreting the native gene to be the endogenous target gene. Therefore, as 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), and that the phrase “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) and teach an HDR template further comprising flanking sequences that provide homology to DNA adjacent to the endogenous allele or the DNA that is to be replaced (0096), all of the structural limitations of instant claim 1 are taught by Carlson et al.
Carlson et al. teach each and every limitation of the structure required by the instant claimed synthetic GSH comprising an exogenous fusion sequence recited in (a) and (b), and therefore the 35 U.S.C. 102 rejection is maintained for claims 1,3,21,22,24,25,62,64,71 and 73.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Response to Arguments
Applicant's arguments filed 04/08/2026 have been fully considered but they are not persuasive.
Applicant cites MPEP 2143 on page 8 regarding establishing a prima facie case of obviousness, and states they disagree with the obviousness rejection because the primary reference, Carlson et al. is different as discussed above and George et al. does not cure the deficiency of Carlson et al. Applicant argues on page 9 that George et al. relates to design of exogenous landing pad(s) designed to receive donor nucleic acids and cites various paragraphs of George et al. pertaining to landing pads, and again states that Carlson et al. and George et al., singly or combined do not teach or suggest all of the claim elements wherein…an exogenous fusion sequence that is inserted at the locus of an endogenous target gene of the genome, wherein the fusion sequence comprises…(b) a complementation sequence comprising a rescue gene sequence that encodes a rescue gene product that is identical to the endogenous target gene product.
This is not found persuasive. Applicant’s main argument to the 103 rejection pertains to Carlson et al. as explained above by Applicant and has been responded to above by the Examiner regarding the interpretation of the claim and how the reference teaches the structural limitations of the claims. The further citations in George et al. that Applicant provides pertain to teachings of the landing pads in George et al., but Applicant does not explain how these citations are intended to argue that George does not teach the limitations regarding a landing sequence comprising at least one cutting sequence based on the support provided by the Examiner in the rejection. The examiner responded to the arguments regarding Carlson et al. above, and maintains that as explained above, Carlson et al. teaches the structural limitations of (a) and (b), with George et al. providing the support for the cutting sequence in the landing sequence for (a) 1).
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.
Response to Arguments
Applicant's arguments filed 04/08/2026 have been fully considered but they are not persuasive.
Applicant argues on page 10 that they disagree with the rejection for the reasons discussed above and Lundberg et al. fail to cure the defect of Carlson et al. and George et al. Applicant states what Lundberg relates to and that the wild type ATXN1 gene insertion encodes a wild type product that is not identical to the endogenous mutated target gene product, and that Lundberg et al. and the other cited references singly or combined do not teach or suggested all of the claim limitations.
This is not found persuasive. Applicant’s main argument to the 103 rejection pertains to Carlson et al. as explained above by Applicant and has been responded to above by the Examiner regarding the interpretation of the claim and how the reference teaches the structural limitations of the claims. Lundberg et al. was cited for teaching the additional limitations in claims 4 and 8 as explained in the 103 rejection above not taught by Carlson et al. or George et al. The 103 rejection is maintained.
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.
Response to Arguments
Applicant's arguments filed 04/08/2026 have been fully considered but they are not persuasive.
Applicant argues on pages 10-11 that they disagree with the rejection for the reasons discussed above and that Adolfi et al. fail to cure the defect of the other cited references as discussed above. Applicant argues that Adolfi mentioned a recoded portion of kh gene in the context of mosquito gene drive and differs by at least two aspects, the first being the Adolfi et al. rescue gene sequence appears to encode only a portion of the gene product which is not identical to a full-length product, and second, the recoded portion of kh gene sequence in Adolfi et al. was integrated into an engineered non-endogenous gene locus that comprises exogenous elements such as Cas9 and gRNA (see Fig 1) for gene drive, which is not an endogenous target gene locus.
This is not found persuasive. Applicant’s main argument to the 103 rejection pertains to Carlson et al. as explained above by Applicant and has been responded to above by the Examiner regarding the interpretation of the claim and how the reference teaches the structural limitations of the claims. Adolfi et al. was cited for teaching the motivation that the genome is an insect genome in claim 72, as the combination of Carlson et al., George et al., and Lundberg et al. already was established as teaching the limitations of claims 1 and 4. The 103 rejection is maintained.
Conclusion
Claims 1-4,6,8,17,21,22,24,25,62,64 and 68-73 are rejected.
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.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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