DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
Claims 1-4 and 7-19 are pending and under examination.
35 USC § 112(a) rejections withdrawn
The rejection of claim 19 under 35 U.S.C. 112(a) as failing to comply with the written description requirement are withdrawn in view of Applicant’s amendment to claim 19.
Double Patenting rejections maintained
The rejections of claims 1-4 and 7-19 on the ground of nonstatutory double patenting as being unpatentable over claims 23-33, 38-41 and 43-45 of copending Application No. 14/704551 (US20150247150A1, cited previously) in view of Doudna et al. (US20140068797A1, cited previously) in further view of Smith et al (Stem Cells 26:496-504, 2008) are maintained. The instant application and the copending applicant have a common assignee.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claimed invention is nearly rendered obvious over the claims of the copending application. The copending claims are directed to a composition comprising a S. pyogenes Cas9 and genus of a guide RNA sequence comprising a sequence that is 50 or more nucleotides in length (instant SEQ ID NO:46 comprises a sequence that is more than 50 nucleotides in length). The instant claims are directed to a method of modifying a target sequence in a eukaryotic organism comprised of providing a Cas9 and a guide RNA sequence comprising SEQ ID NO:46. Copending claim 5 limits the Cas9 to be a nickase. Copending claims 9-10 state that Cas9 comprises a nuclear localization sequence.
Regarding the instant embodiment of a guide RNA sequence comprising the sequence of SEQ ID NO:46, “[The specification] may be used to learn the meaning of terms and interpreting the coverage of a claim." In re Basell Poliolefine Italia S.P.A., 89 USPQ2d 1030, 1036 (Fed. Cir. 2008). Thus, the specification is used as a dictionary to determine the meaning of the term guide RNA sequence. Figure 10 of the copending specification disclosed a guide RNA sequence (chiRNA (+85)), which comprises a scaffold sequence that is the same as instant SEQ ID NO:46, is the most effective guide RNA sequence to guide Cas9-mediated DNA modification (figure 10 and paragraph 0177). It would be obvious that the copending claimed composition comprising Cas9 and a genus of guide RNA sequence would include a guide RNA sequence that has been shown to be the best guide RNA sequence that functions with Cas9 to mediate DNA modifications. Further, it would be obvious that the copending claimed composition is used in a method of modifying DNA in eukaryotic since Cas9 is a DNA nuclease. Therefore, it is obvious to a skilled artisan that the claimed composition of Zhang et al. would be used in a method of modifying a target nucleic acid sequence comprising the guide RNA sequence chiRNA (+85), which comprises a scaffold sequence that is the same as instant SEQ ID NO:46. Thus, even though the instant claims recite specificities not explicitly recited by the claims of the reference application/patent, the reference application/patent specification defines the application/patent claims as being directed to species of the instant claims (MPEP 804(II)(B)(2)(a), fifth paragraph; and non-precedential BPAI decision 2018-009106).
The copending application does not teach providing plurality of guide RNA sequences. However, this deficiency is made up in Doudna et al.
Doudna et al. teaches a method of modifying a mouse embryonic stem cell comprised of providing a C. pyogenes Cas9 and a guide RNA sequence (Example 7). Doudna et al. also teaches modifying the DNA of pluripotent stem cells comprised of Cas9 and a guide RNA sequence (paragraphs 0141 and 0142 in particular). Doudna disclose that donor sequences can be introduced as naked nucleic acid, as nucleic acid complexed with an agent such as a liposome or poloxamer, or can be delivered by viruses (e.g., adenovirus, AAV), as described above for nucleic acids encoding a DNA-targeting RNA and/or site-directed modifying polypeptide and/or donor polynucleotide (paragraph 302).Doudna et al. further teaches that providing a plurality of guide RNA sequences (paragraph 0271). Doudna discloses Cas9 (DNA 2.0) was fused with C-terminal SV40 nuclear localization sequences (paragraph 736).
One of ordinary skill in the art at the time the invention was made would have been motivated to modify the method of altering a eukaryotic cell comprising providing a Cas9 and a guide RNA sequence to modify a human stem cell or a pluripotent stem cell comprised of Cas9 of Doudna to form a method of altering a human embryonic stem cell or pluripotent stem cell comprised providing Cas9 and a guide RNA sequence comprising the chiRNA (+85) in order to more effective modify the DNA of a stem cell, because the copending claims are directed to a method of altering DNA comprised of Cas9 and a guide RNA sequence, including a chiRNA (+85), and Doudna et al. teaches modifying a human stem cell or pluripotent stem cell comprising providing a Cas9 and a plurality of guide RNA sequence and showed that Cas9 and a guide RNA sequence effectively modify a human embryonic stem cell. Furthermore, the modified method of altering a stem cell can include providing a plurality of guide RNA sequences, because Doudna also teaches a method of modifying DNA with Cas9 comprised of providing a plurality of guide RNA sequences.
One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success for modifying the copending method of altering a eukaryotic stem cell comprising providing Cas9 and a guide RNA sequence of Zhang et al. to modify a human stem cell or a pluripotent stem cell comprised of Cas9 of Doudna to form a method of modifying a human embryonic stem cell or pluripotent stem cell comprised of Cas9 and a guide RNA sequence comprising the chiRNA (+85) in order to more effective modify the DNA of a stem cell, because the copending claims are directed to a method of altering DNA comprised of Cas9 and a guide RNA sequence, including a chiRNA (+85), and Doudna et al. teaches modifying a human stem cell or pluripotent stem cell comprising a Cas9 and guide RNA sequence and showed that Cas9 and a guide RNA sequence effectively modify a human embryonic stem cell.
Neither the claims of Application No. 14/704551 nor Doudna disclose the limitation “wherein a target nucleic acid sequence of the different target nucleic acid sequences is within an AAVS 1 locus”. However, the AAVS1 locus was well known to be an optimal location for transgene integration at the time this application was filed.
Smith disclose that transgene integration at the AAVS1 site in stem cells demonstrated increased expression and stability for the transgene. (page 498, 1st column to page 503, 1st column; Table 1; Abstract)
One of ordinary skill in the art would have been motivated to apply Smith’s disclosure of transgene integration at the AAVS1 site to the claims of Application No. 14/704551 and Doudna’s method of targeting a Cas9 protein to a plurality of
target nucleic acids in a eukaryotic cell comprising providing to the eukaryotic cell a plurality of guide RNA sequences complementary to the plurality of target nucleic acid sequences in the eukaryotic stem cell because Smith disclose that transgene integration at the AAVS1 site in stem cells demonstrated increased expression and stability for the transgene. Thus, the AAVS1 site was known to be a desirable locus for the insertion of the CRISPR-Cas vector system for use in eukaryotic stem cells comprising a plurality of guide RNAs. Doudna disclose that donor sequences can be delivered by an AAV. Absent unexpected results it would have been obvious to have a method of altering a stem cell comprising providing to the eukaryotic stem cell a plurality of guide RNA sequences complementary to the plurality of target nucleic acid sequences in the eukaryotic cell, wherein a target nucleic acid sequence of the plurality of target nucleic acid sequences is within an AAVS 1 locus, and providing to the eukaryotic stem cell a Cas9 protein that interacts with the plurality of guide RNA sequences to form guide RNA/Cas9 protein complexes bound to the plurality of target nucleic acids.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The rejections of claims 1-4 and 7-19 on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 8871445B2, cited previously, in view of Doudna et al. (US20140068797A1, cited previously) in further view of Smith et al (Stem Cells 26:496-504, 2008, cited previously) are maintained. The instant application and U.S. Patent No. 8871445B2 have a common assignee.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claimed invention is anticipated by or nearly rendered obvious over the claims of the patent. The patented claims are directed to a method of altering expression of at least one gen product comprising providing a Cas9 comprising two or more nuclear localization sequences, and a genus of a guide RNA sequence, or a composition comprising said Cas9 and a genus of a guide RNA sequence. The instant claimed method comprise a genus of Cas9 comprising a nuclear localization sequence (claims 51-54), and a guide RNA sequence comprising SEQ ID NO:46.
Regarding the instant embodiment of a guide RNA sequence comprising the sequence of SEQ ID NO:46, “[The specification] may be used to learn the meaning of terms and interpreting the coverage of a claim." In re Basell Poliolefine Italia S.P.A., 89 USPQ2d 1030, 1036 (Fed. Cir. 2008). The specification of the patent disclosed a guide RNA sequence comprising SEQ ID NO:364 (chiRNA (+85)), which comprises a scaffold sequence that is the same as instant SEQ ID NO:46, and demonstrated that it is the best guide RNA sequence to guide Cas9-mediated DNA modification (figures 18 and 19). It would be obvious that the copending claimed method of modifying DNA with Cas9 would include the guide RNA sequence that has been shown to be the best guide RNA sequence that functions with Cas9 to mediate DNA modifications. Therefore, the patented claims of Zhang et al. encompasses a method of altering a stem cell comprising providing a guide RNA sequence comprising SEQ ID NO:364.
Regarding patented claims 1-18, it would be obvious that the patented method is used in a method for altering a stem cell as shown by the claimed methods that are recited in patented claims 1-18. Thus, even though the instant claims recite specificities not explicitly recited by the claims of the reference application/patent, the reference application/patent specification defines the application/patent claims as being directed to species of the instant claims (MPEP 804(II)(B)(2)(a), fifth paragraph; and non-precedential BPAI decision 2018-009106).
The patented claims are silent for providing plurality of guide RNA sequences. However, this deficiency is made up in Doudna et al.
Doudna et al. teaches a method of modifying a mouse embryonic stem cell comprised of providing a Cas9 and a guide RNA sequence (Example 7). Doudna et al. also teaches modifying the DNA of pluripotent stem cells comprised of Cas9 and a guide RNA sequence (paragraphs 0141 and 0142 in particular). . Doudna disclose that donor sequences can be introduced as naked nucleic acid, as nucleic acid complexed with an agent such as a liposome or poloxamer, or can be delivered by viruses (e.g., adenovirus, AAV), as described above for nucleic acids encoding a DNA-targeting RNA and/or site-directed modifying polypeptide and/or donor polynucleotide (paragraph 302). Doudna et al. further teaches that providing a plurality of guide RNA sequences (paragraph 0271). Doudna discloses Cas9 (DNA 2.0) was fused with C-terminal SV40 nuclear localization sequences (paragraph 736).
One of ordinary skill in the art at the time the invention was made would have been motivated to modify the copending method of altering a eukaryotic stem cell comprising providing Cas9 and a guide RNA sequence of Zhang et al. to alter a human stem cell or a pluripotent stem cell comprising providing Cas9 of Doudna to form a method of altering a human stem cell or pluripotent stem cell comprising providing Cas9 and a guide RNA sequence comprising the chiRNA (+85) in order to more effective modify the DNA of a stem cell, because the copending claims are directed to a method of altering DNA comprising providing Cas9 and a guide RNA sequence, including a chiRNA (+85), and Doudna et al. teaches modifying a human stem cell or pluripotent stem cell comprising a Cas9 and guide RNA sequence and showed that Cas9 and a guide RNA sequence effectively modify a human embryonic stem cell. Furthermore, the modified method of altering a stem cell can include providing a plurality of guide RNA sequences, because Doudna also teaches a method of modifying DNA with Cas9 comprised providing a plurality of guide RNA sequences.
One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success for modifying the copending method of altering a eukaryotic cell comprising providing Cas9 and a guide RNA sequence of Zhang et al. to modify a human stem cell or a pluripotent stem cell comprising providing Cas9 of Doudna to form a method of altering a human embryonic stem cell or pluripotent stem cell comprised of Cas9 and a guide RNA sequence comprising the chiRNA (+85) in order to more effective modify the DNA of a stem cell, because the copending claims are directed to a method of altering DNA comprised of Cas9 and a guide RNA sequence, including a chiRNA (+85), and Doudna et al. teaches modifying a human stem cell or pluripotent stem cell comprising a Cas9 and guide RNA sequence and showed that Cas9 and a guide RNA sequence effectively modify a human stem cell.
Neither the claims of U.S. Patent No. 8871445B2 nor Doudna disclose “wherein a target nucleic acid sequence of the different target nucleic acid sequences is within an AAVS 1 locus”. However, the AAVS1 locus was well known to be an optimal location for transgene integration at the time this application was filed.
Smith disclose that transgene integration at the AAVS1 site in stem cells demonstrated increased expression and stability for the transgene. (page 498, 1st column to page 503, 1st column; Table 1;Abstract).
One of ordinary skill in the art would have been motivated to apply Smith’s disclosure of transgene integration at the AAVS1 site to the claims of U.S. Patent No. 8871445B2 and Doudna’s method of targeting a Cas9 protein to a plurality of target nucleic acids in a eukaryotic stem cell comprising providing to the eukaryotic stem cell a plurality of guide RNA sequences complementary to the plurality of target nucleic acid sequences in the eukaryotic cell because Smith disclose that transgene integration at the AAVS1 site demonstrated increased expression and stability for the transgene in stem cells. Thus, the AAVS1 site was known to be a desirable locus for the insertion of the CRISPR-Cas vector system for use in eukaryotic stem cells comprising a plurality of guide RNAs. Doudna disclose that donor sequences can be delivered by an AAV. Absent unexpected results it would have been obvious to have a method of altering a stem cell comprising targeting a Cas9 protein to a plurality of target nucleic acids in a eukaryotic cell comprising providing to the stem cell a plurality of guide RNA sequences complementary to the plurality of target nucleic acid sequences in the eukaryotic cell, wherein a target nucleic acid sequence of the plurality of target nucleic acid sequences is within an AAVS 1 locus, and providing to the stem cell a Cas9 protein that interacts with the plurality of guide RNA sequences to form guide RNA/Cas9 protein complexes bound to the plurality of target nucleic acids.
The rejections of claims 1-4 and 7-19 on the ground of nonstatutory double patenting as being unpatentable over claims 1-21, 29 and 30 of U.S. Patent No. 8906616B2, cited previously, in view of Doudna et al. (US20140068797A1, cited previously) in further view of Smith et al (Stem Cells 26:496-504, 2008, cited previously) are maintained. The instant application and U.S. Patent No. 8906616B2 have a common assignee.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claimed invention is anticipated by or nearly rendered obvious over the claims of the patent. The patented claims are directed to a an engineered composition comprising a CRISPR having a guide RNA polynucleotide sequence (claims 1-28) and method for genome engineering introducing the engineered composition comprising a Cas9 and a genus of a guide RNA sequence (claims 29 and 30). The instant claimed method of altering a stem cell comprising providing a Cas9 comprising a nuclear localization sequence and a guide RNA sequence comprising SEQ ID NO:46.
Regarding the instant embodiment of a guide RNA sequence comprising the sequence of SEQ ID NO:46, “[The specification] may be used to learn the meaning of terms and interpreting the coverage of a claim." In re Basell Poliolefine Italia S.P.A., 89 USPQ2d 1030, 1036 (Fed. Cir. 2008). Thus, the specification is used as a dictionary to determine the meaning of the term guide RNA sequence. The specification of the patent disclosed a guide RNA sequence comprising SEQ ID NO:153 (chiRNA (+85)), which is comprised of 85 nucleotides wild type S. pyogenes Cas9 tracrRNA (figure 10; example 4). Guide RNA sequence comprising SEQ ID NO:153 has the same scaffold sequence that is the same as instant SEQ ID NO:46. Furthermore, Zhang et al. demonstrated that it is the best guide RNA sequence to guide Cas9-mediated DNA modification (figures 10 and 11). Therefore, patented claims 29 and 30 encompasses a method of modifying a target nucleic acid sequence comprising a guide RNA sequence comprising SEQ ID NO:153.
Regarding patented claims 1-28, it would be obvious that the patented composition is used in a method for altering a stem cell as shown by the claimed methods that are recited in patented claims 29 and 30. The specification is used as a dictionary to determine the meaning of the term “at least nucleotides 1-85 of the corresponding wild type S. pyogenes Cas9 tracRNA”. The specification of the patent disclosed a guide RNA sequence comprising SEQ ID NO:153, which is comprised of 85 nucleotides wild type S. pyogenes Cas9 tracRNA (figure 10; example 4). Guide RNA sequence comprising SEQ ID NO:153 has the same scaffold sequence that is the same as instant SEQ ID NO:46.
Thus, even though the instant claims recite specificities not explicitly recited by the claims of the reference application/patent, the reference application/patent specification defines the application/patent claims as being directed to species of the instant claims (MPEP 804(II)(B)(2)(a), fifth paragraph; and non-precedential BPAI decision 2018-009106).
The patented claims are silent that the eukaryotic cell is a stem cell, and providing plurality of guide RNA sequences. However, this deficiency is made up in Doudna et al.
Doudna et al. teaches a method of modifying a mouse embryonic stem cell comprised of providing a Cas9 and a guide RNA sequence (Example 7). Doudna et al. also teaches modifying the DNA of pluripotent stem cells comprised of Cas9 and a guide RNA sequence (paragraphs 0141 and 0142 in particular). Doudna disclose that donor sequences can be introduced as naked nucleic acid, as nucleic acid complexed with an agent such as a liposome or poloxamer, or can be delivered by viruses (e.g., adenovirus, AAV), as described above for nucleic acids encoding a DNA-targeting RNA and/or site-directed modifying polypeptide and/or donor polynucleotide (paragraph 302). Doudna et al. further teaches that providing a plurality of guide RNA sequences (paragraph 0271). Doudna discloses Cas9 (DNA 2.0) was fused with C-terminal SV40 nuclear localization sequences (paragraph 736).
One of ordinary skill in the art at the time the invention was made would have been motivated to modify the copending method of altering a eukaryotic cell comprising providing Cas9 and a guide RNA sequence of Zhang et al. to modify a human stem cell or a pluripotent stem cell comprised of Cas9 of Doudna to form a method of modifying a human embryonic stem cell or pluripotent stem cell comprising providing Cas9 and a guide RNA sequence comprising the chiRNA (+85) in order to more effective modify the DNA of a stem cell, because the copending claims are directed to a method of altering DNA comprised of Cas9 and a guide RNA sequence, including a chiRNA (+85), and Doudna et al. teaches modifying a human stem cell or pluripotent stem cell comprising a Cas9 and guide RNA sequence and showed that Cas9 and a guide RNA sequence effectively modify a human embryonic stem cell. Furthermore, the modified method of altering a stem cell can include providing a plurality of guide RNA sequences, because Doudna also teaches a method of modifying DNA with Cas9 comprised of providing a plurality of guide RNA sequences.
One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success for modifying the copending method of altering a stem comprising providing Cas9 and a guide RNA sequence of Zhang et al. to modify a human stem cell or a pluripotent stem cell comprised of Cas9 of Doudna to form a method of altering a stem cell comprising providing Cas9 and a plurality of guide RNA sequence a human stem cell comprised of Cas9 and a guide RNA sequence comprising the chiRNA (+85) in order to more effective modify the DNA of a stem cell, because the copending claims are directed to a method of altering DNA comprising providing Cas9 and a guide RNA sequence, including a chiRNA (+85), and Doudna et al. teaches modifying a human stem cell or pluripotent stem cell comprising a Cas9 and a plurality of guide RNA sequence and showed that Cas9 and a guide RNA sequence effectively modify a human embryonic stem cell.
Neither the claims of U.S. Patent No. 8906616B2 nor Doudna disclose “wherein a target nucleic acid sequence of the different target nucleic acid sequences is within an AAVS 1 locus”. However, the AAVS1 locus was well known to be an optimal location for transgene integration at the time this application was filed.
Smith disclose that transgene integration at the AAVS1 site in stem cells demonstrated increased expression and stability for the transgene. (page 498, 1st column to page 503, 1st column; Table 1;Abstract)
One of ordinary skill in the art would have been motivated to apply Smith’s disclosure of transgene integration at the AAVS1 site to the claims of U.S. Patent No. 8906616B2 and Doudna’s method of altering a stem cell comprising targeting a Cas9 protein to a plurality of target nucleic acids in a eukaryotic cell comprising providing to the eukaryotic cell a plurality of guide RNA sequences complementary to the plurality of target nucleic acid sequences in the eukaryotic cell because Smith disclose that transgene integration at the AAVS1 site demonstrated increased expression and stability for the transgene. Thus, the AAVS1 site was known to be a desirable locus for the insertion of the CRISPR-Cas vector system for use in eukaryotic stem cells comprising a plurality of guide RNAs. Doudna disclose that donor sequences can be delivered by an AAV. Absent unexpected results it would have been obvious to have a method of targeting a Cas9 protein to a plurality of target nucleic acids in a eukaryotic cell comprising providing to the eukaryotic cell a plurality of guide RNA sequences complementary to the plurality of target nucleic acid sequences in the eukaryotic stem cell, wherein a target nucleic acid sequence of the plurality of target nucleic acid sequences is within an AAVS 1 locus, and providing to the eukaryotic stem cell a Cas9 protein that interacts with the plurality of guide RNA sequences to form guide RNA/Cas9 protein complexes bound to the plurality of target nucleic acids.
The rejections of claims 1-4 and 7-19 on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 8932814B2, cited previously, in view of Doudna et al. (US20140068797A1, cited previously) in further view of Smith et al (Stem Cells 26:496-504, 2008, cited previously) are maintained. The instant application and U.S. Patent No. 8932814B2 have a common assignee.
The reference Chen et al (US 2016/0017366, published January 21, 2016, effective filing date December 6, 2012, IDS) has been removed as art in view of Applicant’s Declaration under 37 USC §1.131 by each of the inventors Prashant Mali, George Church, and Luhan Yang evidencing reduction to practice of the claimed invention at least as early as before the December 6, 2012 filing date of the Chen provisional application.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claimed invention is nearly rendered obvious over the claims of the patent. The patented claims are directed to a method of altering expression of a gene product comprising proving a Cas9 comprising a mutation in the catalytic domain and a nuclear localization sequence, and a genus of a guide RNA sequence, or a composition comprising said Cas9 and a genus of a guide RNA sequence. The instant claimed method comprising a genus of Cas9 and a nuclear localization sequence and a guide RNA sequence comprising SEQ ID NO:46. The instant claimed method comprising a genus of Cas9 encompasses a Cas9 mutant.
Regarding the instant embodiment of a guide RNA sequence comprising the sequence of SEQ ID NO:46, “[The specification] may be used to learn the meaning of terms and interpreting the coverage of a claim." In re Basell Poliolefine Italia S.P.A., 89 USPQ2d 1030, 1036 (Fed. Cir. 2008). Thus, the specification is used as a dictionary to determine the meaning of the term guide RNA sequences. The specification of the patent disclosed a guide RNA sequence comprising SEQ ID NO:366 (chiRNA(+85), which comprises a scaffold sequence that is the same as instant SEQ ID NO:46, and demonstrated that it is the best guide RNA sequence to guide Cas9-mediated DNA modification (figures 18 and 19). It would be obvious that the copending claimed method of altering a stem cell comprising providing Cas9 would include the guide RNA sequence that has been shown to be the best guide RNA sequence that functions with Cas9 to mediate DNA modifications. Therefore, the patented claims of Zhang et al. encompass a method of altering a stem cell comprising providing a guide RNA sequence comprising SEQ ID NO:366.
Regarding patented claims 13, 25, 26 and 30, it would be obvious that the patented composition is used in a method for modifying a target nucleic acid as shown by the claimed methods that are recited in patented claims 1-12, 14-24, 28 and 29.
Thus, even though the instant claims recite specificities not explicitly recited by the claims of the reference application/patent, the reference application/patent specification defines the application/patent claims as being directed to species of the instant claims (MPEP 804(II)(B)(2)(a), fifth paragraph; and non-precedential BPAI decision 2018-009106).
The patented claims are silent that the eukaryotic cell is a stem cell, and providing plurality of guide RNA sequences. However, this deficiency is made up in Doudna et al.
Doudna et al. teaches a method of modifying a mouse embryonic stem cell comprised of providing a Cas9 and a guide RNA sequence (Example 7). Doudna et al. also teaches modifying the DNA of pluripotent stem cells comprised of Cas9 and a guide RNA sequence (paragraphs 0141 and 0142 in particular). . Doudna disclose that donor sequences can be introduced as naked nucleic acid, as nucleic acid complexed with an agent such as a liposome or poloxamer, or can be delivered by viruses (e.g., adenovirus, AAV), as described above for nucleic acids encoding a DNA-targeting RNA and/or site-directed modifying polypeptide and/or donor polynucleotide (paragraph 302). Doudna et al. further teaches that providing a plurality of guide RNA sequences (paragraph 0271). Doudna discloses Cas9 (DNA 2.0) was fused with C-terminal SV40 nuclear localization sequences (paragraph 736).
One of ordinary skill in the art at the time the invention was made would have been motivated to modify the copending method of altering a stem cell comprising providing Cas9 and a guide RNA sequence of Zhang et al. to modify a human stem cell or a pluripotent stem cell comprised of Cas9 of Doudna to form a method of modifying a human embryonic stem cell or pluripotent stem cell comprising providing Cas9 and a guide RNA sequence comprising the chiRNA (+85) in order to more effective modify the DNA of a stem cell, because the copending claims are directed to a method of altering DNA comprised of Cas9 and a guide RNA sequence, including a chiRNA (+85), and Doudna et al. teaches modifying a human stem cell or pluripotent stem cell comprising a Cas9 and guide RNA sequence and showed that Cas9 and a guide RNA sequence effectively modify a human embryonic stem cell. Furthermore, the modified method of altering a stem cell can include providing a plurality of guide RNA sequences, because Doudna also teaches a method of modifying DNA with Cas9 comprised of providing a plurality of guide RNA sequences.
One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success for modifying the copending method of altering a stem cell comprising providing Cas9 and a guide RNA sequence of Zhang et al. to modify a human stem cell or a pluripotent stem cell comprised of Cas9 of Doudna to form a method of altering a stem cell or pluripotent stem cell comprising providing Cas9 and a guide RNA sequence comprising the chiRNA (+85) in order to more effective modify the DNA of a stem cell, because the copending claims are directed to a method of altering DNA comprised of Cas9 and a guide RNA sequence, including a chiRNA (+85), and Doudna et al. teaches modifying a human stem cell or pluripotent stem cell comprising a Cas9 and guide RNA sequence and showed that Cas9 and a guide RNA sequence effectively modify a human embryonic stem cell.
Neither the claims of U.S. Patent No. 8932814B2 nor Doudna disclose “wherein a target nucleic acid sequence of the different target nucleic acid sequences is within an AAVS 1 locus”. However, the AAVS1 locus was well known to be an optimal location for transgene integration at the time this application was filed.
Smith disclose that transgene integration at the AAVS1 site in stem cells demonstrated increased expression and stability for the transgene. (page 498, 1st column to page 503, 1st column; Table 1;Abstract)
One of ordinary skill in the art would have been motivated to apply Smith’s disclosure of transgene integration at the AAVS1 site to the claims of U.S. Patent No. 8932814B2 and Doudna’s method of targeting a Cas9 protein to a plurality of target nucleic acids in a eukaryotic cell comprising providing to the eukaryotic cell a plurality of guide RNA sequences complementary to the plurality of target nucleic acid sequences in the eukaryotic cell because Smith disclose that transgene integration at the AAVS1 site demonstrated increased expression and stability for the transgene. Thus, the AAVS1 site was known to be a desirable locus for the insertion of the CRISPR-Cas vector system for use in eukaryotic cells comprising a plurality of guide RNAs. Doudna disclose that donor sequences can be delivered by an AAV. Absent unexpected results it would have been obvious to have a method of altering a stem cell comprising targeting a Cas9 protein to a plurality of target nucleic acids in a eukaryotic stem cell comprising providing to the eukaryotic stem cell a plurality of guide RNA sequences complementary to the plurality of target nucleic acid sequences in the eukaryotic stem cell, wherein a target nucleic acid sequence of the plurality of target nucleic acid sequences is within an AAVS 1 locus, and providing to the eukaryotic stem cell a Cas9 protein that interacts with the plurality of guide RNA sequences to form guide RNA/Cas9 protein complexes bound to the plurality of target nucleic acids.
A.
Applicant argues that the claims of Zhang patents (US Patent Nos. 8932814, 8871445, and 8906616) and copending applications (application numbers 14/104837, and 14/704551) recite a general term for guide RNA sequence, and not a specific guide RNA sequence comprising the sequence of SEQ ID NO:46 as required by the instant claims. Applicant argues that it is inappropriate to look to the specification of the Zhang patents or applications to determine the species of guide RNA sequences that are encompassed by a general recitation of a guide RNA sequence in the claims of the Zhang patents or applications.
Applicant further argued that the instant claims are distinct from In re Basell, because the specific species that is being disputed in the instant application is not already defined by the claim terms in the Zhang patents or applications. Applicant argues that the Zhang claims are to be understood according to their plain meaning consistent with the specification. Applicant argues that only if the patentee expressly defined a claim term, can the specification be used as a dictionary. Applicant argues that Zhang did not expressly define the term guide RNA.
In re Basell at 1378 does state that "a patent's disclosure may be used to determine whether an application claim is merely an obvious variation of an invention in a patent," i.e., what the patent claims. Applicant argues that it is clear that In re Basell and BPAI 2018-009106 focus on what is disclosed and claimed in the reference patent. Applicant argues that a sequence corresponding to SEQ ID NO:46 is not disclosed and claimed by Zhang. The Zhang claims recite the genus term guide RNA, which Applicant asserts is readily understood by those of skill in the art based on plain meaning. Applicant argues that the Zhang guide RNA term may be interpreted as being overly broad in view of the limited examples in the specification, but it cannot be interpreted as expressly reciting any particular guide RNA species disclosed in the specification for purposes of being compared to Applicant's claims. Applicant argues that the interpretation of the Zhang claims asserted by the Examiner for purposes of determining
obviousness-type double patenting, i.e. a guide RNA including a sequence corresponding to SEQ ID N0:46, is incorrect under In re Basell, and amounts to incorporating a limitation into the claim that is simply not there to begin with.
Applicant argues that Zhang never provides a dictionary definition that the genus term guide RNA must also comprise any particular guide RNA species. Applicant argues that the Examiner inserts an "obviousness" analysis into the claim interpretation analysis, i.e. one of skill would find it obvious that the genus term guide RNA includes the disclosed species within its scope. Applicant argues that that this understanding of scope reached by the Examiner confirms Applicant's position that the term guide RNA is truly a genus which is not restricted to any particular species. Applicant argues that only finds disclosure of Applicant's SEQ ID N0:46 within the Zhang specification and uses that disclosure combined with Zhang's claims to render a conclusion of obviousness.
Applicant argues that while the genus term guide RNA includes within its scope species of guide RNA described in the specification, the claim term guide RNA is not defined by the species described in the specification, such that the species can be inserted into the
Zhang claims or otherwise substituted for the term guide RNA
Applicant argues that based on the broad disclosure in the priority application 61/736,527 of the Zhang ODP references one of skill will readily understand that the claimed "guide RNA" does not require nor motivate any specific sequence. Applicant argues that all such guide RNA need have is a guide sequence, a tracr sequence and a tracr mate sequence. Applicant argues that while the specification can be used to understand the scope of the term guide RNA as including described species within its scope, the species cannot be used to limit the scope of the term guide RNA to any particular species, or be used as motivation to one of skill to select any particular species, including that claimed by Applicant. Applicant argues that when this happens, the specification is being used as prior art, which is prohibited under In re Kaplan.
2111.
Applicant argues the term "guide RNA" used by Zhang has not been given any special definition in the specification limiting the term to species described therein or directing one of skill to any particular species described therein. Applicant argues that the term "guide RNA" would be understood by one of skill as a genus and not as a listing of species, even though one of skill understands that examples of guide RNA
sequences are present in the specification. By choosing the term "guide RNA," Zhang clearly intended to claim a guide RNA broader than the species identified in the specification, and without direction to any particular species described in the specification or not. Applicant argues that had Zhang intended to claim a specific guide RNA sequence, he would have done so. Applicant argues that the Zhang term guide RNA is a genus and is not intended to be limited to certain species identified in the specification or that such a genus term can be interpreted to provide direction to one of skill to any particular species identified in the specification.
Applicant argues that the Examiner has effectively lifted a specific guide RNA sequence from the Zhang specifications and firmly placed it within the Zhang claims to change the broadest reasonable plain meaning of the claimed guide RNA from a genus to a species.
Applicant respectfully submits that the previously-filed Declaration of Kirin Musunuru dated April 10, 2019 at paragraphs 91-102 demonstrates the unexpectedly superior performance of the guide RNA with SEQ ID NO:46. Certainly, the declaration is sufficient to rebut the obviousness portion of the ODP rejection, when comparing the ODP reference claimed "guide RNA" to applicant's claimed guide RNA with the scaffold sequence.
Applicant’s arguments have been considered but are not persuasive. The issue is whether the generic recitation of a guide RNA sequence in the claims of the Zhang patents and applications include a disclosed specific guide RNA sequence labeled as chiRNA (+85), even though none of the claims in the Zhang patents and application explicitly recite a specific guide RNA sequence. First, in the US Patent No. 8906616, claim 8 does limit the guide RNA sequence of the patented composition comprising a Cas9 and a guide RNA sequence to comprise at least nucleotide 1-85 of wild type A. pyogenes Cas9 tracrRNA. According to the specification of US Patent No. 8906616, the guide RNA sequence comprising SEQ ID NO:153, which includes the scaffold sequence that is the same as instant SEQ ID NO:46, comprises nucleotide 1-85 of wild type A. pyogenes Cas9 tracrRNA (figure 10; example 4).
In addition, regarding the other Zhang patents (US Patent Nos. 8932814 and 8871445) and copending application (application number 14/704551), Examiner agreed that when reading the claims of the Zhang patents and applications, a skilled artisan would not envision the guide RNA sequence comprising the same sequence as instant SEQ ID NO:46. However, In re Basell (page 6) does states:
While we stated in Kaplan that it is impermissible to treat a "patent disclosure as
though it were prior art" in a double patenting inquiry, we further reaffirmed the holding in In re Vogel, 57 C.C.P.A. 920, 422 F.2d 438 (CCPA 1970), that certain instances may exist where a patent's disclosure may be used. Kaplan, 789 F.2d at 1580. Indeed, our predecessor court stated that a patent's disclosure may be used to determine whether an application claim is merely an obvious variation of an invention claimed in a patent. Vogel, 422 F.2d at 441-12. The court stated that the disclosure may be used to learn the meaning of terms and in "interpreting the coverage of [a] claim." Id. at 441. It may also be used to answer the question whether claims merely define an obvious variation of what is earlier disclosed and claimed. The court stated that the disclosure "sets forth at least one tangible embodiment within the claim, and it is less difficult and more meaningful to judge whether [something] has been modified [*1379] in an obvious manner." Id. at 442. The court further stated that "use of the disclosure is not in contravention of the cases forbidding itsuse as prior art, nor is it applying the patent as a reference under 35 U.S.C. § 103, since only the disclosure of the invention claimed in the patent may be examined." Id.
The specification of Zhang et al. disclosed that the chiRNA (+85) guide RNA or guide sequence (same sequence as instant guide RNA sequence comprising the sequence of SEQ ID NO:46) is the best guide RNA sequence for guiding Cas9-mediated DNA modification. In re Kaplan, the Federal Circuit does find that the specification cannot be used to determine coverage of the claims. The Courts of Appeals in Appeal 2013-008619 (12/335235) compared the use of In re Kaplan and In re Basell for ODP analysis, and found that that the specification can be used to determine the species that is covered by a claimed subgenus. The Courts of Appeals noted that in In re Kaplan, “that the process using a mixture of tetraglyme and sulfolane was the joint invention of Kaplan and Walker, not Kaplan alone. Id. at 1575. It was disclosed in Kaplan’s application practicing the claimed process. The court held that [i]n effect, what the board did was to use a disclosure of appellants’ own joint invention which had been incorporated in the Kaplan sole disclosure to show that their invention was but an obvious variation of Kaplan’s claimed invention. That amounts to using an applicant’s invention disclosure ... as prior art against him. That is impermissible” (page 8-9). The Court of Appeals also noted that In re Kaplan, the relevant section of the speciation that “the relevant example in the disclosure of the Kaplan patent could not properly be treated as a disclosed species of the more generic process claimed by Kaplan, since Kaplan (alone) did not invent it; rather, it was the invention of Kaplan and Walker” (page 9). In In re Kaplan, it was explicated stated that the relevant embodiment was invented by both Kaplan and Walker. In contrast to the instant case, Zhang et al. does not explicitly or implicitly state that he did not invent chiRNA (+85) guide RNA and demonstrated that it is the most effective guide RNA sequence for guiding Cas9-mediated gene editing (figures 18 and 19). The Courts of Appeals in Appeal 2013-008619 (12/335235) further states that “[[T]]the Federal Circuit has reaffirmed the use of a patent’s specification, as described in Vogel, in analyzing obviousness-type double patenting. See In re Basell Poliolefme Italia S.P.A., 547 F.3d 1371, 1378—79 (Fed. Cir. 2008). The Basell court held that “the PTO had good basis for its conclusion that the claims of the ’987 patent rendered obvious the claims of the ’687 patent and that the latter claims are invalid for obviousness-type double patenting” because “the specification of the ’987 patent itself refers to ethylene, propylene, butene, and other olefins which indicates that those olefins were intended to fall within the meaning of the claims.” Basell, 547 F.3d at 1378. The court held that the Board’s use of the earlier patent’s specification in that case was consistent with Vogel” (pages 7-8).
In addition, the proper used of the specification to determine the coverage of a generic term in a claim is further highlighted in the non-precedential BPAI decision 2018-009106 (14/434818). The BPAI found that “the court adhered to the principle articulated in Basell that "a patent's disclosure may be used to determine whether an application claim is merely an obvious variation of an invention claimed in a patent." Basell, 547 F.3d at 1378. Similarly, we find that here the Examiner properly consulted the disclosure of the '207 Patent in reaching the determination that the claims to an anti-
PSMA antibody comprising a SEQ ID NO: 1 is no more than an obvious variation of the
already patented anti-CD25 antibody conjugate” (page 9). Contrary to Applicant’s assertion that a recitation of an anti-PSMA antibody is limited to a finite number of antibodies and the state of the art would permit a skilled
artisan to pick the specific anti-PSMA antibody that is recited in the 14/434818
application, it is well accepted in the antibody art that there is no structure function
relation between an antibody epitope (i.e. binding to PSMA) and antibody. Thus, a skill
artisan would pick the specific antibody comprising the sequences of SEQ ID NOs:31
and 38 or 39 of the 207 Patent as the preferred anti-PSMA antibody that is included in
the general recitation of an anti-PSMA is because the disclosure of the patent showed
that this specific anti-PSMA antibody has therapeutic potential. The BPAI also states
that “[[T]]the description of the antibody in the 207 Patent disclosure includes SEQ ID NOS.31 and 38 or 39, which are the same amino acid sequences recited in rejected
claims 130 and 131. The obviousness of an amino acid sequence can be determined
based on whether there is reasonable expectation of success of obtaining it using
known and conventional techniques. Kubin, 56 1 F. 3d at 1360-6 1. The '207 patent
claims are presumptively fully enabled, and thus it would have been obvious to one of
ordinary skill in art at the time of the invention to have identified the claimed variable
chain amino acid sequences of the anti-PSMA antibody of patented claim 5 using
conventional technology. One of ordinary skill in the art would have had reason to do
so because the patented antibodies are described in the '207 Patent as useful
therapeutic agents (at col. 2, 11. 25-63) and, as found by the Examiner, are described in
the '207 Patent as the amino sequences which define the variable regions of the
patented antibody conjugate” (pages 10-11). The BPAI concluded that it is permissive
to go to the specification to determine the specific species that are covered by the term
“anti-PSMA antibody” to determine the coverage of the patented claims of US9889207B2, since the disclosure of the ‘207 Patent demonstrated that the anti-
PSMA antibody comprising the amino acid sequences of SEQ ID NOs:31 and 38 or 39
is a useful therapeutic agent. Thus, it would be obvious that the patented claims include
the species of anti-PSMA antibody comprising the amino acid sequences of SEQ ID
NOs:31 and 38 or 39.
Similar to the instant claims, the guide RNA of the Zhang patented or copending
claims include the chiRNA (+85) guide RNA, because the disclosure of the Zhang
patents or copending applications demonstrated that the chiRNA (+85) guide RNA sequence would be a species of guide RNA that is included in the recited genus of
guide RNA sequence. Recently, the non-precedential BPAI decision 2019-004191 (14/200652) find that it is impermissible to use the reference specification to determine the obvious variant of a claimed genus, rather than a specific meaning of a term (page 7). In this appeal, the BPAI concluded that claims directed to an anti-CD3 antibody comprising the SEQ ID NOs:411, 413, 417, 420, 425 and 433 does not have an ODP over claims that recite a heterodimeric antibody comprising a genus of anti-CD3 scFv even when the specification of the reference application disclosed a heterodimeric antibody comprising an anti-CD3 scFv comprising the same CDR sequences as SEQ ID NOs:411, 413, 417, 420, 425 and 433. BPAI states that “a generic expression does not render obvious all of the species that it encompasses,” but emphasized that the claims at issue in Basell Poliofine“ are both generic and specific to each other in interchangeable ways, involving the same groups of species.” (page 9). It is noted that the reference applications of the BPAI 2019-004191 disclosed a heterodimeric antibody comprising an anti-CD3 scFv comprising CDR sequences that are the same as the sequences of SEQ ID NOs:411, 413, 417, 420, 425 and 433 that are being claimed in the application of 14/200542, but the reference applications do not demonstrate that this specific heterodimeric antibody is functionally better than other species, nor present data that the that this heterodimeric antibody is the preferred heterodimeric antibody that is encompassed by the general recitation of a heterodimeric antibody comprising a CD3 scFv. Therefore, the reference applications do not disclosed data that would permit a skilled artisan to pick the species of heterodimeric antibody comprising an anti-CD3 scFv comprising the same sequences that are the same as the SEQ ID NOs:411, 413, 417, 420, 425 and 433 that is being claimed in the 14/200542 application.
In contrast, the specification of the reference patent of the BPAI 2018-009106 (14/434818) and the specifications of the reference Zhang patents and applications do disclosed data that the species in questions is functionally better. The disclosure of the Zhang patents and applications show that the chiRNA (+85) guide RNA is best guide RNA to be used with Cas9 to mediated alterations of DNA. Thus, it would be obvious for the skilled artisan to pick the chiRNA (+85) guide RNA to guide Cas9 to mediate alterations on a target DNA sequence. Thus, even though the instant claims recite specificities not explicitly recited by the claims of the reference application/patent, the reference application/patent specification defines the application/patent claims as being directed to species of the instant claims (MPEP 804(II)(B)(2)(a), fifth paragraph, In re Basell, and non-precedential decisions in Appeal 2013-008619 (12/335235) and 2018-009106 (14/434818). Therefore, instant claims reciting guide RNA sequence comprising the SEQ ID NO:46 is an obvious variation of the patented or copending claims of Zhang et al. since the specification of the Zhang patents and applications disclosed the chiRNA (+85) guide RNA sequence and demonstrated that it is the best guide RNA sequence for guiding Cas9 to mediated cleavage of double stranded DNA.
In response to Applicant’s argument that the Examiner has effectively lifted a specific guide RNA sequence from the Zhang specifications and firmly placed it within the Zhang claims to change the broadest reasonable plain meaning of the claimed guide RNA from a genus to a species, the claimed gRNA scaffold sequence is not just one of many species of gRNA guide sequences. Zhang discloses that the gRNA scaffold sequence having the nucleic acid sequence of SEQ ID N0:46 is the most effective guide RNA sequence for guiding Cas9-mediated gene editing (figures 18 and 19).
In response to Applicant’s argument that the previously-filed Declaration of Kirin Musunuru dated April 10, 2019 at paragraphs 91-102 demonstrates the unexpectedly superior performance of the guide RNA with SEQ ID NO:46, the Declaration just supports Zhang’s disclosure that the gRNA scaffold sequence having the nucleic acid sequence of SEQ ID N0:46 is the most effective guide RNA sequence for guiding Cas9-mediated gene editing.
In response to Applicant’s argument that the figure in the Zhang patents and applications that demonstrate that the guide RNA sequence labeled as chiRNA (+85) is the best guide RNA for guiding Cas9-mediated gene editing was filed in March, almost 4 months after the earliest priority of the instant application, Applicant is reminded that the disclosures of the provisional documents is not relevant for ODP analysis, but rather the disclosure as a whole at the time of filing is considered. In this instant, the Zhang specifications on figures 18 and 19 disclosed the use of the chiRNA (+85) guide RNA sequence and demonstrated that it is the best guide RNA sequence for guiding Cas9 to mediated cleavage of double stranded DNA. Therefore, it would be obvious the genus of guide RNA as recited in patented method or copending methods in the Zhang patents or applications, respectively would include chiRNA (+85) guide RNA sequence as a species.
In response to Applicant’s argument that there is no evidence to demonstrate that Applicant's claimed SEQ ID NO:46 is an obvious modification of the Zhang genus term guide RNA and that to find otherwise is also to prohibit the patenting of a species within a genus when the species manifests unexpected properties or produces unexpected results, as discussed previously, Zhang discloses that the gRNA scaffold sequence having the nucleic acid sequence of SEQ ID N0:46 is the most effective guide RNA sequence for guiding Cas9-mediated gene editing (figures 18 and 19).
In response to Applicant’s argument that by choosing the term "guide RNA," Zhang clearly intended to claim a guide RNA broader than the species identified in the specification, and without direction to any particular species described in the specification or not, as discussed previously, Zhang discloses that the gRNA scaffold sequence having the nucleic acid sequence of SEQ ID N0:46 is the most effective guide RNA sequence for guiding Cas9-mediated gene editing (figures 18 and 19).
Furthermore, it is not clear the relevance of USSN 16/906,580 and USSN 16/938,110. They don’t appear to be in the continuity data map for 14/701,912 and were filed after the filing date of the present case.
B.
Applicant argues that the Examiner states that "the AAVS1 locus was well known to be an optimal location for trans gene integration at the time this application was filed." Applicant argues that the Examiner's statement is based on hindsight in view of Applicant's specification. Applicant argues that nothing in Zhang or Doudna points to the AAVS 1 locus out of many possible targets within the human genome. Applicant argues that the Examiner has identified no reason based on the Zhang claims and Doudna why one of skill would have selected the AAVSI locus, as opposed to any other location within the genome. Applicant argues that the Examiner has cherry picked the Smith prior art that uses a very different system and has alleged motivation based solely on impermissible hindsight reconstruction. Applicant argues that the Examiner has failed to demonstrated motivation to modify the claims of Zhang, and therefore has failed to demonstrate a prima facie case of obviousness.
Applicant’s arguments have been considered but are not persuasive. In response to Appellants’ argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As discussed above, there is ample motivation to combine the references independent of the inherent feature. Absent unexpected results as to why this particular site-directed insertion site would have it, as discussed above it would have been obvious to use the AAVS1 insertion site as described by Smith. Smith disclose that transgene integration at the AAVS1 site demonstrated increased expression and stability for the transgene.
In response to Applicant’s argument that nothing in Zhang or Doudna points to the AAVS 1 locus out of many possible targets within the human genome one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Smith disclose a viral vector delivery system for inserting transgenes within the genome of a stem cell. Smith disclose that transgene integration at the AAVS1 site in stem cells demonstrated increased expression and stability for the transgene.
In response to Applicant’s argument that the Examiner has failed to demonstrated motivation to modify the claims of Zhang, one of ordinary skill in the art would have been motivated to apply Smith’s disclosure of transgene integration at the AAVS1 site to the claims of Application No. 14/704551 and Doudna’s method of targeting a Cas9 protein to a plurality of target nucleic acids in a eukaryotic cell comprising providing to the eukaryotic cell a plurality of guide RNA sequences complementary to the plurality of target nucleic acid sequences in the eukaryotic cell because Smith disclose that transgene integration at the AAVS1 site demonstrated increased expression and stability for the transgene. Thus, the AAVS1 site was known to be a desirable locus for the insertion of the CRISPR-Cas vector system for use in eukaryotic cells comprising a plurality of guide RNAs.
Summary
Claims 1-4 and 7-19 stand 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 extension fee 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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/MARK HALVORSON/Primary Examiner, Art Unit 1646
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