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 .
Applicant’s response of 09/10/2025, including amendments to the specification and replacement drawing sheets, has been received and entered into the application file.
Claims 109, 110, 113, and 114 were amended in the claim set filed 09/10/2025.
Claims 106-118 are pending and under consideration.
Information Disclosure Statement
Receipt of an information disclosure statement on 09/10/2025 is acknowledged. The signed and initialed PTO-1449 has been mailed with this action.
Status of Prior Objections/Rejections
RE: Nucleotide and/or Amino Acid Sequence Disclosures
Figures 4B, 4C, and 4D were previously indicated to include sequences that were not appropriately identified with associated SEQ ID NOs. The replacement drawings filed 09/25/2025 have obviated the basis of the prior objection. The objection of record is hereby withdrawn.
RE: Specification
The specification was previously objected to for referencing the color red in Figure 1, which was not visible in the filed black-and-white drawings. The amendments to the specification have obviated the basis of the prior objection. The objection of record is hereby withdrawn.
RE: Double Patenting
Claims 106-107, 111-112, and 115-117 were previously rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6-8 of U.S. Patent No. 11,491,207 (hereinafter ‘207) in view of Chou et al., 2016 and Kurata et al., 2018, as evidenced by Jiang and Doudna, 2017.
Applicant’s response filed 09/10/2025 has been fully considered but is not persuasive, as there are no arguments presented to overcome the double patenting rejection of record. As set forth in MPEP § 804, only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. An application must not be allowed unless the required compliant terminal disclaimer is filed and/or the withdrawal of nonstatutory double patenting rejection(s) is made of record by the examiner (see 37 CFR § 1.111(b)). Accordingly, the double patenting rejection of record is maintained, as set forth in greater detail below.
RE: Claim Rejections - 35 USC § 112
Claims 109, 110, 113, and 114 were previously rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The amendments to claims 109, 110, 113, and 114 have obviated the basis of the prior rejection. The rejection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 103
►Claims 106-108 and 111 were previously rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/106268 A1 (hereinafter Excision) in view of Chou et al., 2016 and Kurata et al., 2018, as evidenced by Jiang and Doudna, 2017.
Applicant has traversed the rejection of record, asserting that Kurata et al., 2018 targets different sequences within the same gene rather than targeting different sequences in different genes. In response, this is not found persuasive.
While the Examiner acknowledges that the experimental data of Kurata et al., 2018 is drawn to multiplexed gRNAs targeting different sequences within the same gene, the overall disclosure of Kurata et al., 2018 is not limited to multiplexed gRNAs targeting different sequences within the same gene. As cited by Applicant in the remarks filed 09/10/2025, “the reference should be considered in its entirety in the determination of obviousness, not just the portions that seem to support the idea of the combination the examiner wants to make.” Hybritech Inc. v. Monoclonal Antibodies, Inc., 802 F.2s 1367, 1383 (Fed. Cir. 1986) (citing Hodosh v. Block Drug Co., 786 F.2s 1136 (Fed. Cir. 1986)). When considering the entirety of the disclosure of Kurata et al., 2018, it would have been clear to someone of ordinary skill in the art that targeting multiple genes with multiple gRNAs is and has been a known technique in the field and that the disclosure of Kurata et al., 2018 provides a proof-of-principle of the utility of the gRNA arrays taught therein (see page 11, paragraph 3). Per Kurata et al., 2018, CRISPR/Cas9 is known to be amenable to multiplex editing, including editing several different genes by delivering multiple plasmids encoding gRNAs (page 2, paragraph 3). However, these methods are noted to display poor efficiency and significant cytotoxicity (page 2, paragraph 3). The multiplexed gRNA array of Kurata et al., 2018 is disclosed to overcome these obstacles, as editing with the multiplexed gRNA array system taught therein resulted in no obvious toxicity and facilitated higher efficiency of editing (see page 10, paragraph 1-page 11, paragraph 1, as well as Figure 4). Kurata et al., 2018 explicitly acknowledges that they do not present proof of multiple gene modifications, they disclose that the methods taught therein may be applied for modification of multiple genes, going so far as to suggest experimental methodology for researchers to confirm editing of multiple genes in cells supplied with the gRNA array taught therein (page 11, paragraph 3).
Therefore, when considering the entirety of the disclosure of Kurata et al., 2018 (as supported by the case law cited in Applicant’s arguments), the Examiner contends that Kurata et al., 2018 provides sufficient motivation to someone of ordinary skill in the art prior to the effective filing date of the claimed invention to apply the multiplexed gRNA array of Kurata et al., 2018 to targeting multiple genes, as suggested by Kurata et al., 2018, even though Kurata et al., 2018 does not disclose actual practice of the same.
Furthermore, the Examiner notes that Applicant’s assertion that Kurata et al., 2018 discloses editing of the Csy4 gene is not supported by the disclosure of Kurata et al., 2018. The portions of Kurata et al., 2018 cited by Applicant disclose linkage of the Cas9 taught therein to the human codon optimized Pseudomonas aeruginosa Csy4 ribonuclease to process the gRNA array taught therein into individual gRNA units, thereby inducing detectable gene editing at up to 10 target sites (page 7, first full paragraph-as cited by Applicant; see also page 2, paragraph 1 and Figures 1 and 4). Figure 4B lists individual genes that were targeted, none of which are Csy4.
Accordingly, the rejection of record is maintained, as set forth in greater detail below.
►Claim 109 was previously rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/106268 A1 (hereinafter Excision), Chou et al., 2016, and Kurata et al., 2018 as applied to claim 106 above, and further in view of GenBank JF42842.1 (available 08/04/2011).
Applicant has traversed the rejection of record, asserting that Kurata et al., 2018 targets different sequences within the same gene rather than targeting different sequences in different genes. In response, this is not found persuasive.
As set forth in greater detail above, when considering the entirety of the disclosure of Kurata et al., 2018 (as supported by the case law cited in Applicant’s arguments), the Examiner contends that Kurata et al., 2018 provides sufficient motivation to someone of ordinary skill in the art prior to the effective filing date of the claimed invention to apply the multiplexed gRNA array of Kurata et al., 2018 to targeting multiple genes, as suggested by Kurata et al., 2018, even though Kurata et al., 2018 does not disclose actual practice of the same.
Accordingly, the rejection of record is maintained, as set forth in greater detail below.
►Claim 110 was previously rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/106268 A1 (hereinafter Excision), Chou et al., 2016, and Kurata et al., 2018 as applied to claim 106 above, and further in view of GenBank MK728943.1 (available 05/08/2019).
Applicant has traversed the rejection of record, asserting that Kurata et al., 2018 targets different sequences within the same gene rather than targeting different sequences in different genes. In response, this is not found persuasive.
As set forth in greater detail above, when considering the entirety of the disclosure of Kurata et al., 2018 (as supported by the case law cited in Applicant’s arguments), the Examiner contends that Kurata et al., 2018 provides sufficient motivation to someone of ordinary skill in the art prior to the effective filing date of the claimed invention to apply the multiplexed gRNA array of Kurata et al., 2018 to targeting multiple genes, as suggested by Kurata et al., 2018, even though Kurata et al., 2018 does not disclose actual practice of the same.
Accordingly, the rejection of record is maintained, as set forth in greater detail below.
►Claims 112 and 115 were previously rejected under 35 U.S.C. 103 as being unpatentable over Chou et al., 2016 and Kurata et al., 2018, as evidenced by Jiang and Doudna, 2017.
Applicant has traversed the rejection of record, asserting that Kurata et al., 2018 targets different sequences within the same gene rather than targeting different sequences in different genes. In response, this is not found persuasive.
As set forth in greater detail above, when considering the entirety of the disclosure of Kurata et al., 2018 (as supported by the case law cited in Applicant’s arguments), the Examiner contends that Kurata et al., 2018 provides sufficient motivation to someone of ordinary skill in the art prior to the effective filing date of the claimed invention to apply the multiplexed gRNA array of Kurata et al., 2018 to targeting multiple genes, as suggested by Kurata et al., 2018, even though Kurata et al., 2018 does not disclose actual practice of the same.
Accordingly, the rejection of record is maintained, as set forth in greater detail below.
►Claim 113 was previously rejected under 35 U.S.C. 103 as being unpatentable over Chou et al., 2016 and Kurata et al., 2018 as applied to claim 112 above, and further in view of GenBank JF42842.1 (available 08/04/2011).
Applicant has traversed the rejection of record, asserting that Kurata et al., 2018 targets different sequences within the same gene rather than targeting different sequences in different genes. In response, this is not found persuasive.
As set forth in greater detail above, when considering the entirety of the disclosure of Kurata et al., 2018 (as supported by the case law cited in Applicant’s arguments), the Examiner contends that Kurata et al., 2018 provides sufficient motivation to someone of ordinary skill in the art prior to the effective filing date of the claimed invention to apply the multiplexed gRNA array of Kurata et al., 2018 to targeting multiple genes, as suggested by Kurata et al., 2018, even though Kurata et al., 2018 does not disclose actual practice of the same.
Accordingly, the rejection of record is maintained, as set forth in greater detail below.
►Claim 114 was previously rejected under 35 U.S.C. 103 as being unpatentable over Chou et al., 2016 and Kurata et al., 2018 as applied to claim 112 above, and further in view of GenBank HE652130.1 (available 09/30/2013).
Applicant has traversed the rejection of record, asserting that Kurata et al., 2018 targets different sequences within the same gene rather than targeting different sequences in different genes. In response, this is not found persuasive.
As set forth in greater detail above, when considering the entirety of the disclosure of Kurata et al., 2018 (as supported by the case law cited in Applicant’s arguments), the Examiner contends that Kurata et al., 2018 provides sufficient motivation to someone of ordinary skill in the art prior to the effective filing date of the claimed invention to apply the multiplexed gRNA array of Kurata et al., 2018 to targeting multiple genes, as suggested by Kurata et al., 2018, even though Kurata et al., 2018 does not disclose actual practice of the same.
Accordingly, the rejection of record is maintained, as set forth in greater detail below.
►Claims 116-118 were previously rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/106268 A1 (hereinafter Excision) in view of Chou et al., 2016, Kurata et al., 2018, and Lau and Suh, 2017.
Applicant has traversed the rejection of record, asserting that Kurata et al., 2018 targets different sequences within the same gene rather than targeting different sequences in different genes. In response, this is not found persuasive.
As set forth in greater detail above, when considering the entirety of the disclosure of Kurata et al., 2018 (as supported by the case law cited in Applicant’s arguments), the Examiner contends that Kurata et al., 2018 provides sufficient motivation to someone of ordinary skill in the art prior to the effective filing date of the claimed invention to apply the multiplexed gRNA array of Kurata et al., 2018 to targeting multiple genes, as suggested by Kurata et al., 2018, even though Kurata et al., 2018 does not disclose actual practice of the same.
Accordingly, the rejection of record is maintained, as set forth in greater detail below.
New/Maintained Grounds of Rejection
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 106-107, 111-112, and 115-117 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6-8 of U.S. Patent No. 11,491,207 (hereinafter ‘207) in view of Chou et al., 2016 (of record) and Kurata et al., 2018 (of record), as evidenced by Jiang and Doudna, 2017 (of record).
With regard to instant claims 106-107, which recite “a composition comprising: (a) a Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated endonuclease or a nucleic acid sequence encoding the CRISPR-associated endonuclease; (b) a first guide RNA (gRNA) or a nucleic acid sequence encoding the first gRNA, the first gRNA being complementary to a first target nucleic acid sequence within a non-coding control region (NCCR) of a JC virus (JCV) genome; and (c) a second gRNA or a nucleic acid sequence encoding the second gRNA being complementary to a second target nucleic acid sequence within a T antigen gene of the JCV genome,” said composition “further comprising a third gRNA or a nucleic acid sequence encoding the third gRNA, the third gRNA being complementary to a third target nucleic acid sequence within a VP gene of the JCV genome,” claim 6 of ‘207 recites a pharmaceutical composition that comprises “a) a CRISPR associated endonuclease Cas9 or a nucleic acid sequence encoding the CRISPR associated endonuclease Cas9; b) a first guide RNA (gRNA) or a nucleic acid sequence encoding the first gRNA, the first gRNA being complementary to a first target sequence within the VP1 gene of a JC virus (JCV); and c) a second gRNA or a nucleic acid sequence encoding the second gRNA, the second guide RNA being complementary to a second target sequence within the T-antigen gene of the JCV.” Thus, claim 6 of ‘207 discloses each and every limitation of instant claims 106 and 107, with the exception of an additional gRNA targeting a NCCR of a JCV genome, as in instant claim 106.
However, Chou et al., 2016 discloses gRNAs separately targeting the VP1 capsid gene and the NCCR of the JCV (or JCPyV, as acronymized in Chou et all, 2016) genome with CRISPR-Cas9, resulting in significant inhibition of virus replication and viral protein expression both prior to or following JCV infection (abstract; table 1; figures 1, 3, and 5). As depicted in figures 1, 3, and 5, CRISPR-Cas9 complexed with gRNAs separately targeting the VP1 capsid gene and the NCCR of the JCV genome successfully inhibited virus replication and viral protein expression. Thus, Chou et al., 2016 teaches that a gRNA targeting either the NCCR or the VP1 capsid gene of the JCV genome for disruption via CRISPR-Cas9 reduces virus replication and viral protein expression.
Additionally, Kurata et al., 2018 discloses a single gRNA array transcript that delivers up to 10 gRNAs to facilitate multiplexed genomic engineering (abstract; page 11, paragraph 3). Per Kurata et al, 2018, “the ability to delivery multiple gRNAs simultaneously makes [the] CRISPR/Cas9 system highly amenable to multiplex genome editing” (page 2, paragraph 3). Thus, Kurata et al., 2018 teaches that CRISPR/Cas9 is amenable to targeting multiple sequences with multiple gRNAs, all within a single editing composition. As noted by Applicant, Kurata et al., 2018 only reduces this system to practice to target single genes (see Figure 4). However, Kurata et al., 2018 explicitly suggests applying the system taught therein to editing multiple genes at once.
As set forth above, when considering the entirety of the disclosure of Kurata et al., 2018, it would have been clear to someone of ordinary skill in the art that targeting multiple genes with multiple gRNAs is and has been a known technique in the field and that the disclosure of Kurata et al., 2018 provides a proof-of-principle of the utility of the gRNA arrays taught therein (see page 11, paragraph 3). Per Kurata et al., 2018, CRISPR/Cas9 is known to be amenable to multiplex editing, including editing several different genes by delivering multiple plasmids encoding gRNAs (page 2, paragraph 3). However, these methods are noted to display poor efficiency and significant cytotoxicity (page 2, paragraph 3). The multiplexed gRNA array of Kurata et al., 2018 is disclosed to overcome these obstacles, as editing with the multiplexed gRNA array system taught therein resulted in no obvious toxicity and facilitated higher efficiency of editing (see page 10, paragraph 1-page 11, paragraph 1, as well as Figure 4). Kurata et al., 2018 explicitly acknowledges that they do not present proof of multiple gene modifications, they disclose that the methods taught therein may be applied for modification of multiple genes, going so far as to suggest experimental methodology for researchers to confirm editing of multiple genes in cells supplied with the gRNA array taught therein (page 11, paragraph 3).
Therefore, when considering the entirety of the disclosure of Kurata et al., 2018 (as supported by the case law cited in Applicant’s arguments), the Examiner contends that Kurata et al., 2018 provides sufficient motivation to someone of ordinary skill in the art prior to the effective filing date of the claimed invention to apply the multiplexed gRNA array of Kurata et al., 2018 to targeting multiple genes, as suggested by Kurata et al., 2018, even though Kurata et al., 2018 does not disclose actual practice of the same.
Therefore, given the success in inhibiting virus replication and viral protein expression by targeting the NCCR of the JCV genome with CRISPR-Cas9 machinery, as disclosed in Chou et al., 2016, as well as the efficacy of multiplexing gRNAs to target multiple genes with separate gRNAs simultaneously, as disclosed in Kurata et al., 2018, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition of ‘207 to further comprise a gRNA targeting the NCCR of the JCV genome to predictably produce an effective JCV-editing composition comprising a CRISPR-associated endonuclease such as type II endonuclease Cas9, as well as gRNAs targeting the NCCR, T antigen gene and/or a VP gene (i.e. VP1) of the JCV genome. One would have been motivated to make such a modification in order to receive the expected benefit of producing an effective JCV-editing composition targeting multiple JCV genes to eliminate JCV from host cells.
With regard to instant claims 111 and 115, which recite “the CRISPR-associated endonuclease is a Type II Cas endonuclease,” claim 6 of ‘207 recites a pharmaceutical composition that comprises “a) a CRISPR associated endonuclease Cas9 or a nucleic acid sequence encoding CRISPR associated endonuclease Cas9…”. As reviewed in Jiang and Doudna, 2017, Cas9 is a type II DNA endonuclease employed by type II CRISPR systems (page 509, paragraph 2). Thus, claim 6 of ‘207 is considered to read on the instantly claimed “Type II Cas endonuclease,” as evidenced by Jiang and Doudna, 2017.
With regard to instant claim 112, which recites “a composition comprising: (a) a Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated endonuclease or a nucleic acid sequence encoding the CRISPR-associated endonuclease; (b) a first guide RNA (gRNA) or a nucleic acid sequence encoding the first gRNA, the first gRNA being complementary to a first target nucleic acid sequence within a non-coding control region (NCCR) of a JC virus (JCV) genome; and (c) a second gRNA or a nucleic acid sequence encoding the second gRNA being complementary to a second target nucleic acid sequence within a VP gene of the JCV genome,” claim 6 of ‘207 recites a pharmaceutical composition that comprises “a) a CRISPR associated endonuclease Cas9 or a nucleic acid sequence encoding the CRISPR associated endonuclease Cas9; b) a first guide RNA (gRNA) or a nucleic acid sequence encoding the first gRNA, the first gRNA being complementary to a first target sequence within the VP1 gene of a JC virus (JCV); and c) a second gRNA or a nucleic acid sequence encoding the second gRNA, the second guide RNA being complementary to a second target sequence within the T-antigen gene of the JCV.” Thus, claim 6 of ‘207 discloses each and every limitation of instant claim 112, with the exception of a gRNA targeting a NCCR of a JCV genome, as in instant claim 112.
However, as set forth above, Chou et al., 2016 discloses gRNAs separately targeting the VP1 capsid gene and the NCCR of the JCV (or JCPyV, as acronymized in Chou et all, 2016) genome with CRISPR-Cas9, resulting in significant inhibition of virus replication and viral protein expression both prior to or following JCV infection (abstract; table 1; figures 1, 3, and 5). As depicted in figures 1, 3, and 5, CRISPR-Cas9 complexed with gRNAs separately targeting the VP1 capsid gene and the NCCR of the JCV genome successfully inhibited virus replication and viral protein expression. Thus, Chou et al., 2016 teaches that a gRNA targeting either the NCCR or the VP1 capsid gene of the JCV genome for disruption via CRISPR-Cas9 reduces virus replication and viral protein expression.
Therefore, given the success in inhibiting virus replication and viral protein expression by targeting the NCCR of the JCV genome with CRISPR-Cas9 machinery, as disclosed in Chou et al., 2016, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition of ‘207 to comprise a gRNA targeting the NCCR of the JCV genome to predictably produce an effective JCV-editing composition comprising a CRISPR-associated endonuclease such as type II endonuclease Cas9, as well as gRNAs targeting the NCCR and a T antigen gene or a VP gene (i.e. VP1) of the JCV genome. One would have been motivated to make such a modification in order to receive the expected benefit of producing an effective JCV-editing composition targeting multiple JCV genes to eliminate JCV from host cells.
With regard to instant claims 116-117, which recite “an adeno-associated virus (AAV) vector comprising a nucleic acid encoding: (a) a Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated endonuclease; (b) a first guide RNA (gRNA) complementary to a first target nucleic acid sequence within a non-coding control region (NCCR) of a JC virus (JCV) genome; and (c) a second gRNA complementary to a second target nucleic acid sequence within a T antigen gene of the JCV genome,” said vector “further comprising a third gRNA complementary to a third target nucleic acid sequence within a VP gene of the JCV genome,” as set forth above, claim 6 of ‘207, in view of Chou et al., 2016 and Kurata et al., 2018, discloses each and every limitation of the instantly claimed CRISPR editing composition (i.e. the endonuclease and the gRNAs targeting the NCCR, a T antigen gene, and a VP gene of the JCV genome). However, these disclosures do not address the AAV vector of instant claims 116-117.
Claims 7 and 8 of ‘207 recite “the CRISPR-associated endonuclease Cas9, the first guide RNA, and the second guide RNA are encoded by a same expression vector,” said “expression vector [being] selected from the group consisting of lentiviral vectors, adenovirus vectors, adeno-associated virus vectors, vesicular stomatitis virus (VSV) vectors, pox virus vectors, and retroviral vectors.” Thus, claims 7 and 8 of ‘207 disclose encoding the JCV-editing composition (addressed above) into an AAV vector, as in instant claims 116-117.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 106-108 and 111 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/106268 A1 (hereinafter Excision; of record) in view of Chou et al., 2016 (of record) and Kurata et al., 2018 (of record), as evidenced by Jiang and Doudna, 2017 (of record).
With regard to claim 106, which recites “a composition comprising: (a) a Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated endonuclease…; (b) a first guide RNA (gRNA)…complementary to a…nucleic acid sequence within a non-coding control region (NCCR) of a JC virus (JCV) genome; and (c) a second gRNA…complementary to a…nucleic acid sequence within a T antigen gene of the JCV genome,” Excision discloses compositions to eliminate John Cunningham Virus (JCV) from host cells, said compositions comprising a CRISPR-associated endonuclease and a gRNA complementary to a target sequence in the polyoma virus (abstract). Excision specifically discloses “at least one…gRNA…complementary to…the large T antigen (T-Ag) gene of the JCV DNA” (paragraph [00010]). Collectively, these disclosures from Excision read on the instantly claimed composition comprising a CRISPR-associated nuclease and a “gRNA…complementary to a…nucleic acid sequence within a T antigen gene of the JCV genome.” However, Excision does not disclose the instantly claimed gRNA targeting the NCCR of the JCV genome. Additionally, while Excision discloses “at least one” gRNA (paragraph [0010]), they do not explicitly disclose the inclusion or utility of multiple gRNAs, as instantly claimed. These instant claim limitations are disclosed in Chou et al., 2016 and Kurata et al., 2018, as set forth below.
Chou et al., 2016 discloses gRNAs separately targeting the VP1 capsid gene and the NCCR of the JCV (or JCPyV, as acronymized in Chou et all, 2016) genome with CRISPR-Cas9, resulting in significant inhibition of virus replication and viral protein expression both prior to or following JCV infection (abstract; table 1; figures 1, 3, and 5). As depicted in figures 1, 3, and 5, CRISPR-Cas9 complexed with gRNAs separately targeting the VP1 capsid gene and the NCCR of the JCV genome successfully inhibited virus replication and viral protein expression. Thus, Chou et al., 2016 teaches that a gRNA targeting either the NCCR or the VP1 capsid gene of the JCV genome for disruption via CRISPR-Cas9 reduces virus replication and viral protein expression. However, like Excision, Chou et al., 2016 discloses targeting the JCV genome with only one gRNA.
Kurata et al., 2018 discloses a single gRNA array transcript that delivers up to 10 gRNAs to facilitate multiplexed genomic engineering (abstract; page 11, paragraph 3). Per Kurata et al, 2018, “the ability to delivery multiple gRNAs simultaneously makes [the] CRISPR/Cas9 system highly amenable to multiplex genome editing” (page 2, paragraph 3). Thus, Kurata et al., 2018 teaches that CRISPR/Cas9 is amenable to targeting multiple sequences with multiple gRNAs, all within a single editing composition. As noted by Applicant, Kurata et al., 2018 only reduces this system to practice to target single genes (see Figure 4). However, Kurata et al., 2018 explicitly suggests applying the system taught therein to editing multiple genes at once.
As set forth above, when considering the entirety of the disclosure of Kurata et al., 2018, it would have been clear to someone of ordinary skill in the art that targeting multiple genes with multiple gRNAs is and has been a known technique in the field and that the disclosure of Kurata et al., 2018 provides a proof-of-principle of the utility of the gRNA arrays taught therein (see page 11, paragraph 3). Per Kurata et al., 2018, CRISPR/Cas9 is known to be amenable to multiplex editing, including editing several different genes by delivering multiple plasmids encoding gRNAs (page 2, paragraph 3). However, these methods are noted to display poor efficiency and significant cytotoxicity (page 2, paragraph 3). The multiplexed gRNA array of Kurata et al., 2018 is disclosed to overcome these obstacles, as editing with the multiplexed gRNA array system taught therein resulted in no obvious toxicity and facilitated higher efficiency of editing (see page 10, paragraph 1-page 11, paragraph 1, as well as Figure 4). Kurata et al., 2018 explicitly acknowledges that they do not present proof of multiple gene modifications, they disclose that the methods taught therein may be applied for modification of multiple genes, going so far as to suggest experimental methodology for researchers to confirm editing of multiple genes in cells supplied with the gRNA array taught therein (page 11, paragraph 3).
Therefore, when considering the entirety of the disclosure of Kurata et al., 2018 (as supported by the case law cited in Applicant’s arguments), the Examiner contends that Kurata et al., 2018 provides sufficient motivation to someone of ordinary skill in the art prior to the effective filing date of the claimed invention to apply the multiplexed gRNA array of Kurata et al., 2018 to targeting multiple genes, as suggested by Kurata et al., 2018, even though Kurata et al., 2018 does not disclose actual practice of the same.
With regard to claim 107, which recites “the composition of claim 106, further compris[es] a third gRNA…complementary to a…target nucleic acid sequence within a VP gene of the JCV genome,” Chou et al., 2016 discloses gRNAs targeting the VP1 capsid gene of the JCV (or JCPyV, as acronymized in Chou et all, 2016) genome with CRISPR-Cas9, resulting in significant inhibition of virus replication and viral protein expression both prior to or following JCV infection (abstract; table 1; figures 1, 3, and 5), as set forth above. The targeting of the VP1 capsid gene of the JCV genome for disruption with CRISPR-Cas9 via gRNAs, as disclosed in Chou et al., 2016 reads on the instantly claimed third gRNA targeting “a VP gene of the JCV genome.”
With regard to claim 108, which recites “the composition of claim 106, wherein the T antigen gene is a Large T antigen gene,” Excision discloses “at least one…gRNA…complementary to…the large T antigen (T-Ag) gene of the JCV DNA” (paragraph [00010]), as set forth above. The targeting of the large T antigen gene of the JCV genome, as disclosed in Excision, reads on the instantly claimed targeted “Large T antigen gene.”
With regard to claim 111, which recites “the composition of claim 106, wherein the CRISPR-associated endonuclease is a Type II Cas endonuclease,” Excision, Chou et al., 2016, and Kurata et al., 2018 all disclose the utility and applicability of genome editing with at least CRISPR/Cas9, as set forth above. As reviewed in Jiang and Doudna, 2017, Cas9 is a type II DNA endonuclease employed by type II CRISPR systems (page 509, paragraph 2). Thus, the disclosures of Excision, Chou et al., 2016, and Kurata et al., 2018 are considered to read on the instantly claimed “Type II Cas endonuclease,” as evidenced by Jiang and Doudna, 2017.
Given that Excision discloses compositions to eliminate JCV from host cells, said compositions comprising a CRISPR-associated endonuclease and at least one gRNA complementary to the large T antigen gene of the JCV genome, Chou et al., 2016 discloses gRNAs targeting VP1 and the NCCR of the JCV genome for CRISPR-Cas9 editing, and that Kurata et al., 2018 discloses the efficacy of multiplexing gRNAs and motivates targeting multiple genes with a single CRISPR system using the multiplexed gRNA array taught therein, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition of Excision to comprise multiple gRNAs (as disclosed in Kurata et al., 2018) targeting the VP1 gene and the NCCR of the JCV genome (as disclosed in Chou et al., 2016) to predictably produce an effective JCV-editing composition comprising a CRISPR-associated endonuclease such as type II endonuclease Cas9, as well as gRNAs targeting the NCCR, T antigen gene (i.e. large T antigen) and/or a VP gene (i.e. VP1) of the JCV genome. One would have been motivated to make such a modification in order to receive the expected benefit of producing an effective JCV-editing composition targeting multiple JCV genes to eliminate JCV from host cells.
Claim 109 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/106268 A1 (hereinafter Excision; of record), Chou et al., 2016 (of record), and Kurata et al., 2018 (of record) as applied to claim 106 above, and further in view of GenBank JF42842.1 (available 08/04/2011; of record).
The combined disclosures of WO 2018/106268 A1 (hereinafter Excision), Chou et al., 2016, and Kurata et al., 2018 are described above and applied as before. However, these disclosures do not teach the first target nucleic acid sequence identity of instant claim 109.
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With regard to claim 109, which recites “the composition of claim 106, wherein the first target nucleic acid sequence comprises a sequence comprising at least...90% sequence identity to SEQ ID NO: 2,” SEQ ID NO 2 aligns with GenBank JF425842.1, which corresponds to “JC polyomavirus isolate JCV176RRC-01 control region, partial sequence.” The JCV control region of GenBank JF425842.1 reads on the instantly claimed first target of the JCV NCCR. This alignment is shown below:
Thus, the sequence of GenBank JF425842.1, which corresponds to “JC polyomavirus isolate JCV176RRC-01 control region, partial sequence” “comprises a sequence comprising at least…90% sequence identity to SEQ ID NO: 2,” as instantly claimed.
Given that Excision, Chou et al., 2016, and Kurata et al., 2018, when combined, disclose an effective JCV-editing composition comprising a CRISPR-associated endonuclease such as type II endonuclease Cas9 (per Jiang and Doudna, 2017), as well as gRNAs targeting the NCCR, T antigen gene (i.e. large T antigen) and/or a VP gene (i.e. VP1) of the JCV genome, as set forth above, and that GenBank JF425842.1 discloses the JCV non-coding control region sequence (this sequence comprising a sequence comprising at least 90% sequence identity to SEQ ID NO: 2), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the JCV-editing composition set forth above to target the NCCR sequence disclosed in GenBank JF425842.1 to predictably target and edit the NCCR of the JCV genome. One would have been motivated to make such a modification in order to receive the expected benefit of producing an effective JCV-editing composition targeting at least the JCV NCCR sequence to eliminate JCV from host cells.
Claim 110 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/106268 A1 (hereinafter Excision; of record), Chou et al., 2016 (of record), and Kurata et al., 2018 (of record) as applied to claim 106 above, and further in view of GenBank MK728943.1 (available 05/08/2019; of record).
The combined disclosures of WO 2018/106268 A1 (hereinafter Excision), Chou et al., 2016, and Kurata et al., 2018 are described above and applied as before. However, these disclosures do not teach the second target nucleic acid PAM sequence identity of instant claim 110.
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With regard to claim 110, which recites “the composition of claim 106, wherein the second target nucleic acid sequence comprises a sequence comprising at least…90% sequence identity to SEQ ID NO: 7,” SEQ ID NO 7 aligns with GenBank MK728943.1, which corresponds to “JC polyomavirus isolate NB14 large T antigen and small T antigen genes, partial cds.” The large T antigen and small T antigen genes of GenBank MK728943.1 read on the instantly claimed second target of a JCV T antigen gene. This alignment is shown below:
Thus, the sequence of GenBank MK728943.1, which corresponds to “JC polyomavirus isolate NB14 large T antigen and small T antigen genes, partial cds” “comprises a sequence comprising at least…90% sequence identity to SEQ ID NO: 7,” as instantly claimed.
Given that Excision, Chou et al., 2016, and Kurata et al., 2018, when combined, disclose an effective JCV-editing composition comprising a CRISPR-associated endonuclease such as type II endonuclease Cas9 (per Jiang and Doudna, 2017), as well as gRNAs targeting the NCCR, T antigen gene (i.e. large T antigen) and/or a VP gene (i.e. VP1) of the JCV genome, as set forth above, and that GenBank MK728943.1 discloses the JCV large T antigen and small T antigen gene sequence (this sequence comprising a sequence comprising at least 90% sequence identity to SEQ ID NO: 7), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the JCV-editing composition set forth above to target the JCV large T antigen and small T antigen gene sequence disclosed in GenBank MK728943.1 to predictably target and edit a T antigen gene of the JCV genome. One would have been motivated to make such a modification in order to receive the expected benefit of producing an effective JCV-editing composition targeting at least a JCV T antigen gene sequence to eliminate JCV from host cells.
Claims 112 and 115 are rejected under 35 U.S.C. 103 as being unpatentable over Chou et al., 2016 (of record) and Kurata et al., 2018 (of record), as evidenced by Jiang and Doudna, 2017 (of record).
With regard to claim 112, which recites “a composition comprising: (a) a Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated endonuclease…; (b) a first guide RNA (gRNA)…complementary to a…nucleic acid sequence within a non-coding control region (NCCR) of a JC virus (JCV) genome; and (c) a second gRNA…complementary to a…nucleic acid sequence within a VP gene of the JCV genome,” Chou et al., 2018 discloses gRNAs separately targeting the VP1 capsid gene and the NCCR of the JCV (or JCPyV, as acronymized in Chou et all, 2016) genome with CRISPR-Cas9, resulting in significant inhibition of virus replication and viral protein expression both prior to or following JCV infection (abstract; table 1; figures 1, 3, and 5), as set forth above. However, Chou et al., 2016 does not disclose targeting multiple JCV genes with multiple gRNAs simultaneously.
However, as set forth above, Kurata et al., 2018 discloses a single gRNA array transcript that delivers up to 10 gRNAs to facilitate multiplexed genomic engineering (abstract; page 11, paragraph 3). Per Kurata et al, 2018, “the ability to delivery multiple gRNAs simultaneously makes [the] CRISPR/Cas9 system highly amenable to multiplex genome editing” (page 2, paragraph 3).
As noted by Applicant, Kurata et al., 2018 only reduces this system to practice to target single genes (see Figure 4). However, Kurata et al., 2018 explicitly suggests applying the system taught therein to editing multiple genes at once.
As set forth above, when considering the entirety of the disclosure of Kurata et al., 2018, it would have been clear to someone of ordinary skill in the art that targeting multiple genes with multiple gRNAs is and has been a known technique in the field and that the disclosure of Kurata et al., 2018 provides a proof-of-principle of the utility of the gRNA arrays taught therein (see page 11, paragraph 3). Per Kurata et al., 2018, CRISPR/Cas9 is known to be amenable to multiplex editing, including editing several different genes by delivering multiple plasmids encoding gRNAs (page 2, paragraph 3). However, these methods are noted to display poor efficiency and significant cytotoxicity (page 2, paragraph 3). The multiplexed gRNA array of Kurata et al., 2018 is disclosed to overcome these obstacles, as editing with the multiplexed gRNA array system taught therein resulted in no obvious toxicity and facilitated higher efficiency of editing (see page 10, paragraph 1-page 11, paragraph 1, as well as Figure 4). Kurata et al., 2018 explicitly acknowledges that they do not present proof of multiple gene modifications, they disclose that the methods taught therein may be applied for modification of multiple genes, going so far as to suggest experimental methodology for researchers to confirm editing of multiple genes in cells supplied with the gRNA array taught therein (page 11, paragraph 3).
Therefore, when considering the entirety of the disclosure of Kurata et al., 2018 (as supported by the case law cited in Applicant’s arguments), the Examiner contends that Kurata et al., 2018 provides sufficient motivation to someone of ordinary skill in the art prior to the effective filing date of the claimed invention to apply the multiplexed gRNA array of Kurata et al., 2018 to targeting multiple genes, as suggested by Kurata et al., 2018, even though Kurata et al., 2018 does not disclose actual practice of the same. Thus, Kurata et al., 2018 teaches that CRISPR/Cas9 is amenable to targeting multiple sequences with multiple gRNAs, all within a single editing composition.
With regard to claim 115, which recites “the composition of claim 112, wherein the CRISPR-associated endonuclease is a Type II Cas endonuclease,” Chou et al., 2016 and Kurata et al., 2018 all disclose the utility and applicability of genome editing with at least CRISPR/Cas9, as set forth above. As reviewed in Jiang and Doudna, 2017, Cas9 is a type II DNA endonuclease employed by type II CRISPR systems (page 509, paragraph 2). Thus, the disclosures of Chou et al., 2016 and Kurata et al., 2018 are considered to read on the instantly claimed “Type II Cas endonuclease,” as evidenced by Jiang and Doudna, 2017.
Given that Chou et al., 2016 discloses gRNAs targeting VP1 and the NCCR of the JCV genome for CRISPR-Cas9 editing, and that Kurata et al., 2018 discloses the efficacy of multiplexing gRNAs to target multiple genes with a single CRISPR system, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the CRISPR-Cas9 system disclosed in Chou et al., 2016 to target both the VP1 gene (a VP gene) and the NCCR of the JCV genome simultaneously, as disclosed in Kurata et al., 2018 (which discloses the efficacy of multiplexing gRNAs and motivates targeting multiple genes with a single CRISPR system using the multiplexed gRNA array taught therein) to predictably produce an effective JCV-editing composition comprising a CRISPR-associated endonuclease such as type II endonuclease Cas9, as well as gRNAs targeting the NCCR and a VP gene (i.e. VP1) of the JCV genome. One would have been motivated to make such a modification in order to receive the expected benefit of producing an effective JCV-editing composition targeting multiple JCV genes to eliminate JCV from host cells.
Claim 113 is rejected under 35 U.S.C. 103 as being unpatentable over Chou et al., 2016 (of record) and Kurata et al., 2018 (of record) as applied to claim 112 above, and further in view of GenBank JF42842.1 (available 08/04/2011; of record).
The combined disclosures of Chou et al., 2016 and Kurata et al., 2018 are described above and applied as before. However, these disclosures do not teach the first target nucleic acid sequence identity of instant claim 113.
With regard to claim 113, which recites “the composition of claim 112, wherein the first target nucleic acid sequence comprises a sequence comprising at least...90% sequence identity to SEQ ID NO: 2,” SEQ ID NO 2 aligns with GenBank JF425842.1, which corresponds to “JC polyomavirus isolate JCV176RRC-01 control region, partial sequence.” The JCV control region of GenBank JF425842.1 reads on the instantly claimed first target of the JCV NCCR. This alignment is shown below:
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Thus, the sequence of GenBank JF425842.1, which corresponds to “JC polyomavirus isolate JCV176RRC-01 control region, partial sequence” “comprises a sequence comprising at least…90% sequence identity to SEQ ID NO: 2,” as instantly claimed.
Given that Chou et al., 2016 and Kurata et al., 2018, when combined, disclose an effective JCV-editing composition comprising a CRISPR-associated endonuclease such as type II endonuclease Cas9 (per Jiang and Doudna, 2017), as well as gRNAs targeting the NCCR, and a VP gene (i.e. VP1) of the JCV genome, as set forth above, and that GenBank JF425842.1 discloses the JCV non-coding control region sequence (this sequence comprising a sequence comprising at least 90% sequence identity to SEQ ID NO: 2), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the JCV-editing composition set forth above to target the NCCR sequence disclosed in GenBank JF425842.1 to predictably target and edit the NCCR of the JCV genome. One would have been motivated to make such a modification in order to receive the expected benefit of producing an effective JCV-editing composition targeting at least the JCV NCCR sequence to eliminate JCV from host cells.
Claim 114 is rejected under 35 U.S.C. 103 as being unpatentable over Chou et al., 2016 (of record) and Kurata et al., 2018 (of record) as applied to claim 112 above, and further in view of GenBank HE652130.1 (available 09/30/2013; of record).