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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/18/2025 has been entered.
Status of the Claims
Claims 1 – 2, 4, 7 – 8, 10 – 13, 15, 17, 21, 24 – 27, 33 – 34, 36 – 40, 42 – 44, 46, 51, 53 – 54, and 57 – 58 were pending. Claims 1, 8, 10, 24, 26, 36, 44, and 46 were amended, and claims 4, 7, 17, 21, 39 have been canceled. Claims 1 – 2, 8, 10 – 13, 15, 24 – 27, 33 – 34, 36 – 38, 40, 42 – 44, 46, 51, 53 – 54, and 57 – 58 are currently pending and are the subject of this Office Action.
Claim Rejections - 35 USC § 103
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 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.
Previous rejection, withdrawn: claims 1, 2, 4, 7, 8, 10 – 12, 15, 17, 21, 24 – 27, 33, 34, 36 – 38, 40, 42 – 44, 46, 51, 53 – 54, 57, and 58 are rejected under 35 U.S.C. 103 as being unpatentable over ZETSCHE (Zetsche, B. et al. Multiplex gene editing by CRISPR–Cpf1 using a single crRNA array. Nat Biotechnol 35, 31–34 (2017); an IDS reference) in view of HALE (Hale, M. et al. Homology-Directed Recombination for Enhanced Engineering of Chimeric Antigen Receptor T Cells, Molecular Therapy - Methods & Clinical Development, Volume 4, 2017, Pages 192-203; see PTO-892: Notice of References Cited of 05/21/2024).
In view of the claim amendments in the reply of 08/18/2025, this rejection is withdrawn.
Previous rejection, maintained in modified form: claims 1 – 2, 8, 10 – 13, 15, 24 – 27, 33 – 34, 36 – 38, 40, 42 – 44, 46, 51, 53 – 54, and 57 – 58 are rejected under 35 U.S.C. 103 as being unpatentable over ZETSCHE in view of HALE and JARJOUR (WO 2017/156484 A, published 09/14/2017, an IDS reference).
The present application is directed to a method of modifying the genome of a cell comprising introducing to the cell (i) an RNA-guided endonuclease, wherein the RNA-guided endonuclease is Cpf1, or an active fragment thereof, wherein the RNA-guided endonuclease is introduced to the cell as an mRNA by electroporation, and (ii) an Adeno-associated virus (AAV) vector, wherein the AAV vector comprises a sequence that encodes one or more crRNAs, wherein the one or more crRNAs collectively direct the RNA-guided endonuclease to one or more target genes; and wherein the AAV vector further comprises one or more homology-directed repair (HDR) templates, wherein at least one of the HDR templates comprises: (a) a nucleic acid sequence that encodes a chimeric antigen receptor (CAR); (b) one or more nucleic acid sequences collectively homologous to one or more target sites within the one or more target genes; and (c) optionally a nucleic acid sequence that encodes a reporter gene; Filed: April 30, 2021 wherein the RNA-guided endonuclease induces disruption of the target genes and the one or more HDR templates mediate targeted integration of the sequence encoding the CAR, and optionally the reporter gene, at the target site(s).
ZETSCHE is directed to the ability of Cpf1 to process its own CRISPR RNA (crRNA) which can be used to simplify multiplexed genome editing (see abstract).
HALE is directed to gene editing by homology-directed recombination (HDR) which can be used to couple delivery of a therapeutic gene cassette with targeted genomic modifications to generate engineered human T cells with clinically useful profiles. See abstract. HALE also discloses the delivery of anti-CD19 CAR gene into T cells by HDR (see abstract) and that cells were electroporated with nuclease-encoding mRNA (see T Cell Transduction and Gene Editing, p. 200, left column).
JARJOUR is directed to genome edited immune effector cell compositions and methods of making the same (see Technical Field, p. 1, lines 17 – 18). JARJOUR discloses a method of editing a TCRa allele in a population of T cells where the donor repair template is incorporated into the TCRa allele by homology directed repair (HDR) (see claim 111) with a Cas nuclease which is Cas9 or Cpf1 (see claim 146). JARJOUR discloses a cell with a nucleic acid comprising a polynucleotide encoding an engineered antigen receptor, inserted into the one or more modified TCRa alleles and that the engineered antigen receptor is a CAR. See claims 2 and 54. Furthermore, JARJOUR teaches improved compositions for adoptive immune effector cell therapies for treatment, prevention, or amelioration of numerous conditions including, but not limited to cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency. See abstract.
According to JARJOUR, crRNA and tracrRNA can engineered into one polynucleotide sequence referred to herein as a "single guide RNA" or "sgRNA". See p. 56, lines 5 – 9. Cas nuclease is introduced into the T cell by mRNA electroporation and an expression cassette encoding a tracrRNA rRNA or sgRNA that binds near the site to be edited in the genome and donor repair template are delivered by transduction with an IDLV lentiviral vector or an AAV vector. See p. 95, lines 10 – 14. It would have one obvious to one having ordinary skill in the art to place the HDR templates and crRNA on the same AAV vector according to the teachings of JARJOUR.
Because ZETSCHE discloses that the endonuclease Cpf1 and crRNA, when introduced into cells via AAV, effectively edit genes, HALE discloses that HDR is an effective method of delivering a CAR gene into T cells, and JARJOUR discloses the electroporation Cpf1 mRNA into cells and the transduction of sgRNA and donor repair template via an AAV vector to deliver a CAR for the treatment, prevention, or amelioration of numerous conditions, it would have been obvious to one having ordinary skill in the art to combine the methods of ZETSCHE, HALE, and JARJOUR to arrive to the method of claims 1 and 36.
Regarding claim 2, ZETSCHE discloses the editing of up to four genes in mammalian cells and three in the mouse brain, simultaneously (see Abstract).
Regarding claim 8, the teachings of HALE are noted above. Furthermore, ZETSCHE discloses the disruption of a gene, that is within the locus of the target gene, as a result of the gene editing method (see p. 32, right column, third paragraph).
Regarding claims 10 and 11, HALE discloses that CARs were targeted to the T cell receptor alpha constant (TRAC) locus by HDR (see abstract).
Regarding claim 12, HALE discloses that the CAR T cells resulting from the disclosed gene editing could be used to treat patients with HIV-associated B cell malignancies (see abstract), and JARJOUR discloses a CAR targeting antigens specific for cancer (see claims 18 and 61).
Regarding claim 13, JARJOUR discloses a bispecific T cell engager molecule (BiTE) that may be a CAR (see claims 3, 25, 26, 54, and 61 – 63).
Regarding claim 15, HALE discloses an anti-CD19 CAR (see abstract).
Regarding claim 24, HALE discloses that the donor templates were delivered via AAV6 (see p. 195, DISCUSSION, first paragraph).
Regarding claim 25, ZETSCHE discloses the transfection of HEK293T cells with DNA outside of the organism (see Cell culture and transfection. and Surveyor nuclease assay for genome modification., p. 35).
Regarding claim 26, ZETSCHE discloses a dual vector system in which RNA-guided endonuclease AsCpf1 (Cpf1 ortholog with activity in mammalian cells, Acidaminococcus Cpf1, p. 31, left column, second paragraph) and CRISPR-Cpf1 array (which encodes the crRNA that directs the RNA-guided endonuclease to the target genes, Figure 2, p. 33; p. 31, right column, last paragraph) were cloned separately into adeno-associated viral vectors (AAVs) that were then transduced into mouse primary cortical neurons or into Human embryonic kidney 293T (HEK293T) cells (see Figure 2, p. 33 and p. 32, right column, third paragraph).
Regarding claim 27, HALE discloses the use of human T cells (see p. 200, Isolation and Culture of Primary Human Cells and Cell Lines, first paragraph).
Regarding claim 33, HALE discloses that the cells are in a buffer (see T Cell Transduction and Gene Editing, p. 200). According to the present specification, "pharmaceutically acceptable" is meant to be a material that is not biologically or otherwise undesirable (see p. 25, lines 21- 25).
Regarding claim 33, JARJOUR discloses pharmaceutical T cell compositions comprising genome edited T cells comprising one or more modified and/or non-functional TCRa alleles and that express one or more immunosuppressive signal dampers, flip receptors, engineered TCRs, CARs, Darics, or other therapeutic polypeptides (see p. 135, lines 4 – 8).
Regarding claims 34 and 57, HALE discloses that CAR T cells produced using this method have possible utility for use in HIV+ lymphoma patients, where simultaneous CCR5 disruption could protect therapeutic cells from HIV infection and as an off-the-shelf therapy, where CAR+TCR− cells could be produced from an allogeneic donor (see DISCUSSION, see p. 195, first paragraph – p. 196, first paragraph), suggesting the cells may be isolated from the subject having HIV-associated lymphoma prior to introduction to the cells.
Regarding claim 34, JARJOUR discloses the administration of a therapeutically effective amount of a genetically modified therapeutic cell that varies according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the genome edited immune effector cells to elicit a desired response in the individual (see p. 35, lines 6 – 9).
Regarding claim 36, as discussed above, ZETSCHE discloses a method of genetically modifying a cell using the RNA-guided endonuclease Cpf1 and AAV vectors encoding crRNA wherein the crRNAs collectively direct the Cpf1 to edit target genes. JARJOUR discloses the use of HDR templates encoding a CAR with a homologous sequence to the target site (see claim 110) in order to edit T cells that may be used to treat numerous conditions including, but not limited to cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency (see Abstract). Because ZETSCHE discloses that the RNA-guided endonuclease Cpf1 and crRNA effectively edit multiple genes when introduced to the cell via AAV vectors and JARJOUR discloses that HDR is an effective method of delivering a CAR gene into cells, it would have been obvious to one having ordinary skill in the art to combine the methods of ZETSCHE and JARJOUR in order to modify the genome of a cell to encode a CAR.
Regarding claims 37 and 38, HALE discloses the disruption of CCR5 by HDR delivery of anti-CD19- or anti-BCMA-CAR expression cassettes into the CCR5 locus (see p. 192, right column, last paragraph).
Regarding claim 40, HALE discloses that CARs were targeted to the T cell receptor alpha constant (TRAC) locus by HDR (see abstract).
Regarding claim 42 - 44, HALE discloses the generation of CCR5-deficient CD19 CAR T cells for therapy of HIV-associated lymphoma (see p. 199, left column, third paragraph), which is a non-Hodgkin’s lymphoma.
Regarding claim 46, HALE discloses a CAR targeting CD19 (see abstract).
Regarding claim 51, ZETSCHE discloses the RNA-guided endonuclease LbCpf1 (see Figure 1, p. 32).
Regarding claims 53 and 54, HALE discloses that the genetically modified cell is a T cell includes CD4+ T cells (see Figure 5C, p. 198). Also, JARJOUR discloses that the T cells include thymocytes, naive T lymphocytes, immature T lymphocytes, mature T lymphocytes, resting T lymphocytes, or activated T lymphocytes. A T cell can be a T helper (Th) cell, for example a T helper 1 (Thl) or a T helper 2 (Th2) cell. The T cell can be a helper T cell (HTL; CD4+ T cell) CD4+ T cell, a cytotoxic T cell (CTL; CD8+ T cell), a tumor infiltrating cytotoxic T cell (TIL; CD8+ T cell), CD4+CD8+ T cell, CD4 CD8" T cell, or any other subset of T cells. In one embodiment, the T cell is an NKT cell. Other illustrative populations of T cells suitable for use in particular embodiments include naive T cells and memory T cells (see p. 31, lines 8 – 16).
Regarding claim 57, JARJOUR discloses that the method of treating a subject diagnosed with a cancer comprises removing immune effector cells from the subject, editing the genome of said immune effector cells and producing a population of genome edited immune effector cells, and administering the population of genome edited immune effector cells to the same subject. In a preferred embodiment, the immune effector cells comprise T cells (see p. 148, lines 8 – 12).
Regarding claim 58, HALE discloses that cells isolated from healthy donors prior to introduction to the cells (see Isolation and Culture of Primary Human Cells and Cell Lines, p. 200, first paragraph).
Claims 1, 8, 10 – 13, 15, 24 – 27, 33 – 34, 36 – 38, 40, 42 – 44, 46, 53 – 54, and 57 are rejected under 35 U.S.C. 103 as being unpatentable over JARJOUR.
JARJOUR is directed to genome edited immune effector cell compositions and methods of making the same (see Technical Field, p. 1, lines 17 – 18). JARJOUR discloses a method of editing a TCRa allele in a population of T cells where the donor repair template is incorporated into the TCRa allele by homology directed repair (HDR) (see claim 111) with a Cas nuclease which is Cas9 or Cpf1 (see claim 146). JARJOUR discloses a cell with a nucleic acid comprising a polynucleotide encoding an engineered antigen receptor, inserted into the one or more modified TCRa alleles and that the engineered antigen receptor is a CAR. See claims 2 and 54.
According to JARJOUR, crRNA and tracrRNA can engineered into one polynucleotide sequence referred to herein as a "single guide RNA" or "sgRNA". See p. 56, lines 5 – 9. Cas nuclease is introduced into the T cell by mRNA electroporation and an expression cassette encoding a tracrRNA rRNA or sgRNA that binds near the site to be edited in the genome and donor repair template are delivered by transduction with an IDLV lentiviral vector or an AAV vector. See p. 95, lines 10 – 14. It would have one having ordinary skill in the art to place the HDR templates and crRNA on the same AAV vector according to the teachings of JARJOUR.
Overall, JARJOUR’s disclosure of the electroporation Cpf1 mRNA into cells and the transduction of sgRNA and donor repair template via an AAV vector to deliver a CAR renders a method of modifying the genome of claim 1 obvious.
Regarding claim 8, 10 – 11, and 40, because the invention being described as a knockout, knock-in genomic modification (abstract of the specification) and TCR is described as being knocked out (FIG 2I of the specification), TRAC is assumed to be a TCR locus. JARJOUR discloses TCR disruption and the transgene being knocked into the TCRa locus. See BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS, p. 21 and Figs. 1A and 2A.
Regarding claim 12, 15, 36, 42, 43, and 46, JARJOUR discloses that the CAR binds CD19 or CD22, which are cancer antigens and teaches compositions for adoptive immune effector cell therapies for treatment, prevention, or amelioration of numerous conditions including, but not limited to cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency. See claim 61, p. 74, lines 4 – 7, and abstract.
Regarding claim 13, JARJOUR discloses a bispecific T cell engager molecule (BiTE) that may be a CAR. See claims 3, 25, 26, 54, and 61 – 63.
Regarding claim 24, JARJOUR discloses recombinant adeno-associated viral vector (rAAV) that has a serotype selected from the group consisting of: AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV 8, AAV9, and AAV 10. See claims 119 and 120.
Regarding claim 25, JARJOUR teaches that “ex vivo" procedures involve living cells or tissues taken from an organism and cultured or modulated in a laboratory apparatus, usually under sterile conditions, and typically for a few hours or up to about 24 hours, but including up to 48 or 72 hours, depending on the circumstances. In certain embodiments, such tissues or cells can be collected and frozen, and later thawed for ex vivo treatment. See p. 32, line 11 – 14.
Regarding claim 26, JARJOUR discloses that Cas nuclease is introduced into the T cell by mRNA electroporation and an expression cassette encoding a tracrRNA rRNA or sgRNA that binds near the site to be edited in the genome and donor repair template are delivered by transduction with an IDLV lentiviral vector or an AAV vector. See p. 95, lines 10 – 14.
Regarding claim 27, JARJOUR teaches that the cell is a hematopoietic, immune effector, or T cell, and that the immune effector cell may be an NK cell. See p. 15, lines 24 – 29 and p. 31, lines 5 – 7.
Regarding claim 33, JARJOUR discloses pharmaceutical T cell compositions comprising genome edited T cells comprising one or more modified and/or non-functional TCRa alleles and that express one or more immunosuppressive signal dampers, flip receptors, engineered TCRs, CARs, Darics, or other therapeutic polypeptides (see p. 135, lines 4 – 8).
Regarding claim 34, JARJOUR discloses the administration of a therapeutically effective amount of a genetically modified therapeutic cell that varies according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the genome edited immune effector cells to elicit a desired response in the individual (see p. 35, lines 6 – 9).
Regarding claim 36, JARJOUR discloses the use of HDR templates encoding a CAR with a homologous sequence to the target site (see claim 110) in order to edit T cells that may be used to treat numerous conditions including, but not limited to cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency (see Abstract).
Regarding claims 37 and 38, JARJOUR discloses a CAR transgene knocked into the TCRa locus. See p. 24. Lines 19 – 20.
Regarding claims 44, JARJOUR discloses cancers such as CLL, ALL, and AML. See p. 142, lines 21 – 26.
Regarding claims 53 and 54, JARJOUR discloses that the T cells include thymocytes, naive T lymphocytes, immature T lymphocytes, mature T lymphocytes, resting T lymphocytes, or activated T lymphocytes. A T cell can be a T helper (Th) cell, for example a T helper 1 (Thl) or a T helper 2 (Th2) cell. The T cell can be a helper T cell (HTL; CD4+ T cell) CD4+ T cell, a cytotoxic T cell (CTL; CD8+ T cell), a tumor infiltrating cytotoxic T cell (TIL; CD8+ T cell), CD4+CD8+ T cell, CD4 CD8" T cell, or any other subset of T cells. In one embodiment, the T cell is an NKT cell. Other illustrative populations of T cells suitable for use in particular embodiments include naive T cells and memory T cells (see p. 31, lines 8 – 16).
Regarding claim 57, JARJOUR discloses that the method of treating a subject diagnosed with a cancer comprises removing immune effector cells from the subject, editing the genome of said immune effector cells and producing a population of genome edited immune effector cells, and administering the population of genome edited immune effector cells to the same subject. In a preferred embodiment, the immune effector cells comprise T cells (see p. 148, lines 8 – 12).
Response to Arguments
On page 12, second paragraph under the heading “The Differences between the Claims and the Cited Art”, of the reply of 08/18/2025, Applicant argues that “Zetsche fails to teach or suggest engineering of immune cells at all.” Applicant’s argument has been fully considered but not found persuasive because independent claims 1 and 36 do not specify a specific cell type and thus ZETSCHE reads on the claims. Furthermore, HALE and JARJOUR teaches genetic engineering of immune cells as discussed above and of record.
Applicant further argues that “Zetsche does not teach or suggest introduction of any functional genes to a cell for any purpose. In contrast, Zetsche is only concerned with knock-out of a gene(s). Thus, Zetsche does not hint or suggest introduction of a CAR (or any other gene) to a cell, much less a T cell, for any purpose. Zetsche does not hint or suggest homology-directed repair (HDR) for any purpose. Rather, Zetsche describes Cpfl-based genetic modification is sufficient for genomic modification on its own. In essence, Zetsche describes little more than the Cpf1 nuclease itself. Accordingly, Zetsche does not teach or suggest an HDR template for directing the introduction of a CAR (or any other gene) to disrupt expression of a targeted gene, nor does Zetsche contemplate the benefits or goals of any such system.” Applicant’s arguments have been considered but not found persuasive because ZETSCHE discloses an endonuclease that is used with CRISPR and that is efficient in genome editing. HALE and JARJOUR each teaches that genome editing may be used to knock out endogenous TCR and deliver CAR genes.
On page 13, first paragraph of the reply, Applicant argues that “[n]othing in Zetsche could lead one of skill in the art to predict or assess why or how the use of a Cpfl-based genetic manipulation system for HDR-based engineering of CAR T cells to knock-out one or more different genes in the same T cell using a single vector-based system could achieve the unexpectedly high knock-out efficiency of 66.5%, much less to simultaneously knock-out one or more T cell exhaustion markers, such as PD-1, TIGIT and LAG3, as demonstrated according to Applicant’s methods.” Applicant’s arguments have been fully considered but not found persuasive because ZETSCHE clearly “show[s] that the ability of Cpf1 to process its own CRISPR RNA (crRNA) can be used to simplify multiplexed genome editing. Using a single customized CRISPR array, [ZETSCHE’s method] edit[s] up to four genes in mammalian cells and three in the mouse brain, simultaneously” (see abstract), and JARJOUR teaches that a CRISPR/Cas system may be used for HDR-based engineering of CAR T cells as discussed above. Furthermore HALE discloses the previous development of “a TRAC megaTAL with high on-target versus off-target cutting (NHEJ) rates that resulted in efficient knock down of TCR surface expression in primary human T cells.34” which is detailed in HALE’s reference #34: BOISSEL (Boissel S., et al. megaTALs: a rare-cleaving nuclease architecture for therapeutic genome engineering. Nucleic Acids Res. 2014;42:2591–2601; see PTO-892). BOISSEL discloses “ rates of TCRα gene disruption consistently exceeding 70%” (see p. 2597, right column, third paragraph). Thus, HALE via BOISSEL renders a TCR knock-out efficiency of 66.5% obvious.
As Applicant noted on page 14, second paragraph, HALE does not anticipate the method of claim 1, but ZETSCHE in view of HALE and JARJOUR or JARJOUR renders the method of the present claims obvious as discussed above.
On page 15, Applicant points to HALE’s reference of Sather et al. to show the differences between the present claims and the method of HALE. The rejections above and of record detail the differences between the claimed method and HALE. However, HALE, in combination with the teachings of ZETSCHE and JARJOUR, renders the claimed method obvious. HALE shows how genome editing may be used to produce CAR-T cells.
On page 16, Applicant argues that “[n]othing in Hale and Zetsche could lead the skilled person to develop the same simultaneous knock out of one or more T cell exhaustion markers, such as PD-1, TIGIT and LAG3 according to Applicant’s methods.” However, the present claims do not require simultaneous knock out of one or more T cell exhaustion markers, such as PD-1, TIGIT and LAG3 and thus, ZETSCHE in view of HALE and JARJOUR or JARJOUR renders the present claims obvious.
On page 17, Applicant argues that “Jarjour requires a two-vector approach, whereby a nuclease and an HDR cassette are incorporated separately into a population of cells. Nothing in the conventional HDR-based methodologies of Jarjour could lead one of ordinary skill in the art to contemplate that, or establish how, a crRNA array specific for one or more user-defined target genes could selectively knock out a multiplicity of target genes for insertion of a CAR. Nor does Jarjour teach or suggest the same concept or goal thereof.” Applicant’s argument has been considered but not found persuasive because the suggestions of JARJOUR on the delivery of the nuclease, templates, and guide RNAs can lead one having ordinary skill in the art to contemplate the HDR template and crRNA genes on one vector. Furthermore, independent claims 1 and 36 do not require a crRNA array. Nonetheless, ZETSCHE teaches the use of a crRNA array with CRISPR/Cpf1 system.
Conclusion
Claims 1 – 2, 8, 10 – 13, 15, 24 – 27, 33 – 34, 36 – 38, 40, 42 – 44, 46, 51, 53 – 54, and 57 – 58 are rejected.
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/ESTELLA M. GUSTILO/Examiner, Art Unit 1646
/PETER J REDDIG/Primary Examiner, Art Unit 1646