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 .
Application Status
The Amendments and Remarks filed 06 January 2026 in response to the Office Action of 31 December 2025 are acknowledged and have been entered. Claims 3-11 and 15-24 are cancelled. Claims 1-2, 12-14, and 25-35 are pending and being examined on the merits.
Priority
The instant application is a CON of PCT US2014/040868 filed on 06/04/2014, which claims priority to US provisional 61/830,787 filed 06/04/2013.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 12-14, and 25-35 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US20140179770A 1, Earliest US priority date is 12 December 2012, cited on the Information Disclosure Statement filed 10/04/2017) in view of Zhang 2 (WO2014093622A2, provisionally filed 5/28/2013) and Joung (US 2014/0295557 A1, provisionally filed 3/15/2013). This rejection is maintained.
Regarding claim 1 and 33, Zhang teaches the use of Cas9 nickases in combination with pairs of guide RNAs to generate DNA double strand breaks with defined overhangs (offset nicks); and when two pairs of guides RNA are used, it is possible to excise an intervening DNA fragment [0867]. Zhang teaches that this CRISPR system provides an effective means for modifying a target polynucleotide [0010]. Zhang teaches that, in general, “CRISPR system" refers collectively to transcripts and other elements involved in the expression of or directing the activity of CRISPR-associated ("Cas") genes [0570]. Zhang teaches that the system includes sequences encoding a Cas gene, a tracr (transactivating CRISPR) sequence (e.g., tracrRNA or an active partial tracrRNA), a tracr-mate sequence (encompassing a "direct repeat" and a tracrRNA-processed partial direct repeat in the context of an endogenous CRISPR system), a guide sequence (also referred to as a "spacer" in the context of an endogenous CRISPR system), or other sequences and transcripts from a CRISPR locus [0570]. Zhang teaches that the CRISPR complex has a wide variety of utility including modifying (e.g., deleting, inserting, translocating, inactivating, activating) a target polynucleotide in a multiplicity of cell types [0010]. Zhang teaches that an exemplary CRISPR complex comprises a CRISPR enzyme complexed with a guide sequence hybridized to a target sequence within the target polynucleotide [0009]. Zhang teaches that the guide sequence is linked to a tracr mate sequence, which in turn hybridizes to a tracr sequence [0574] and that the guide, tracr mate sequence, and tracr sequence are arranged in a 5’ to 3’ orientation (linked by a nucleic acid sequence) [0025]. Zhang teaches the invention provides a method of modifying expression of a polynucleotide in a eukaryotic cell [0583]. Zhang teaches that a guide sequence (spacer sequence) is any polynucleotide sequence having sufficient complementarity with a target polynucleotide sequence to hybridize with the target sequence and direct sequence-specific binding of a CRISPR complex to the target sequence [0535]. Zhang teaches targeted deletion of genes amongst disorders [0249]. Zhang teaches gene delivery of CRISPR Cas system using either viral or nanoparticle delivery wherein the select guide-RNAs targeting genes involved in the disorders are specific to endogenous loci with minimal off-target activity [0766]. Zhang teaches that two or more (more than two) guide RNAs may be encoded into a single CRISPR array to induce simultaneous double-stranded breaks in DNA leading to micro-deletions of affected genes or chromosomal regions [0766] (i.e., preventing the expression of a double stranded DNA target nucleic acid). Zhang teaches that multiple guide RNAs can be used, including 6, 8, 10, 20 guide RNAs (0522, 0862 and 1308 in particular). Zhang teaches that off-target nicking can be accomplished by individual guide RNA, that double stranded break only occur when the target sites are adjacent to each other, and that the double stranded breaks introduced by double nicking are not blunt (offset) (0886). Zhang points to an advantage for fragmenting when Zhang teaches that in NHEJ, DSBs “could” re-ligate in the absence of a repair template, and that multiple DSBs (i.e., fragmenting into separate parts) is exploited to mediate larger deletions in the genome, thereby preventing re-ligation of the DSBs [0898]. Zhang teaches that in multiplex assays several DSBs are induced within the same genome [0910]. Zhang also teaches targeted deletions of larger genomic regions (genes) through concurrent DSBs using guides against two targets within a gene [0695]. Zhang further teaches the method of providing cells with two or more guide RNA and Cas9 protein nickase have reduced off target cleavage and is a more specific method for altering DNA (entire document, specifically note paragraphs 0885 and 0886 in particular).
Regarding claim 2, Zhang teaches a method of modifying a genomic locus by introducing into a cell containing and expressing a double stranded DNA molecule encoding a non-naturally occurring CRISPR-Cas system comprising a Cas protein and two guide RNAs that target a first strand and a second strand of the DNA molecule respectively, wherein the Cas protein and the two guide RNAs do not naturally occur together [0055].
Regarding claim 12, Zhang teaches that the Cas9 nuclease is targeted to genomic DNA.
Regarding claim 13, the teachings of Zhang are discussed above as applied to claim 1 and similarly apply to claim 13. Zhang additionally teaches CRISPR-Cas system directed against viral DNA sequences could allow for targeted disruption and deletion of latent viral genomes even in the absence of ongoing viral production [0828].
Regarding claim 14, the teachings of Zhang are discussed above as applied to claim 2.
Regarding claims 25-30, Zhang teaches that the tracr sequence is more than about 85, or more nucleotides [0521].
Regarding claim 31-32, Zhang teaches that the guide sequence is more than 75, or more nucleotides [0535].
Regarding claim 34, Zhang teaches a tracrRNA-crRNA fusion guide RNA [0090, 0520, Fig. 2A].
Regarding claim 35, Zhang teaches the SpCas9n [0524, 0695, Fig. 4].
Zhang does not specifically teach or suggest a method comprising more than two pairs of guide RNA. Zhang does not teach or suggest providing a cell with more than 2 pairs of guide RNAs that bind to adjacent sites on two different strands which co-localize on the DNA with the Cas9 protein nickase to nick the DNA to generate two or more pairs of offset nicks creating more than two double stranded breaks. Zhang does not teach or suggest that the more than two double stranded breaks cause fragmentation of the DNA target gene, and where the fragmentation causes deletion of the fragmented DNA target gene.
Zhang 2 teaches multiplexed nickases [example 26]. Zhang 2 teaches that the use of Cas9 nickases in combination with pairs of guide RNAs to generate DNA double strand breaks with defined overhangs, thereby teaching using Cas9 nickases to nick DNA to create double stranded breaks [0775]. Zhang teaches that the double strand breaks only occur when the target sites are adjacent to each other [00794]. Zhang 2 teaches when two pairs of guide RNAs are used, it is possible to excise an intervening DNA fragment [0775].
Joung teaches methods for increasing specificity of RNA-guided genome editing, e.g., editing using CRISPR/Cas9 systems, using truncated guide RNAs (tru-gRNAs) [abstract]. Joung teaches vectors that encode more than one gRNA, e.g. 2, 3, 4, 5, or more gRNAs directed to different sites in the same region of the target gene [0060].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the method of Zhang by using of more than two pairs of guide RNAs designed to bind to adjacent sites on two different strands that co-localize on the DNA with the Cas9 protein nickase to nick the DNA target gene to generate two or more pairs of offset nicks creating more than two double stranded breaks. One of ordinary skill would be motivated to make the modification because Zhang and Zhang 2 each teaches the use of pairs of guide RNAs for the purpose of creating multiple offset nicks in order to excise portions of the same genomic DNA. Furthermore, Joung teaches the possibility of encoding many gRNAs on a same vector to target different sites in the same target gene. Zhang’s disclosure of using two pairs of gRNAs to induce several DSBs within the same genome, and up to 20 gRNAs, as discussed above, for the purpose of removing DNA fragments; and Joung’s teaching that you can have many guides expressed from the same vector to target different sited in the same target gene would have motivated one of ordinary skill to use more than two pairs of gRNAs wherein each of the guide RNAs of the pair is complementary to an adjacent sites on two sites on opposite strands of the DNA in conjunction with a Cas9 nickase for the purpose of mediating larger fragment deletions in the genome and minimizing off target cleavage. Additionally, it would be obvious to a skilled artisan that the use of more than two pairs of guide RNAs with a Cas9 protein nickase would cause fragmentation of the DNA target gene wherein the fragmentation would cause deletion of the fragmented DNA target gene given Zhang’s disclosure that targeting DNA with numerous guide-RNAs can result in deletions of the intervening sequences (i.e. fragments) [0828] and Zhang’s 2 disclosure that when two pairs of guide RNAs are used, it is possible to excise an intervening DNA fragment. Furthermore, it would be obvious to a skilled artisan that a targeted deletion of a gene within a genome would prevent its expression as an inherent property of gene deletions. One of ordinary skill would a reasonable expectation of success since both Zhang, Zhang 2, Joung teach using multiple pairs of guide RNAs to excise DNA fragments.
Claims 25-30 are rejected under 35 U.S.C. 103 as being unpatentable over (US20140179770A 1, Earliest US priority date is 12 December 2012, cited on the Information Disclosure Statement filed 10/04/2017) in view of Zhang 2 (WO2014093622A2, provisionally filed 5/28/2013) and Joung (US 2014/0295557 A1, provisionally filed 3/15/2013), as applied to claims 1, 2, 12-14, and 25-35 above, and further in view of Doudna (US20140068797 A1, of record, filed 3/15/2013). This rejection is maintained.
The teaching of Zhang, Zhang 2, and Joung are described above. The references do not teach or suggest a tracr sequence between 90 and 200 nucleotides.
Zhang teaches that the tracr sequence is more than about 85 or more nucleotides [0521].
Doudna teaches that the length of some natural tracr RNA sequences is 110 nucleotides (entire document, specifically note Table 2 in particular).
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to increase the tracr sequence nucleotide length of the guide RNA of modified Zhang to 110 nucleotides in length to generate a guide RNA comprising a spacer sequence giving Zhang’s disclosure of the tracr sequence being more than 85 nucleotides and Doudna’s teachings that natural tracr sequences are 100 nucleotides in length. This modification would amount to a combination of prior art elements with a reasonable expectation of success since both Zhang and Doudna teach tracr sequences that could encompass 110 nucleotides.
Response to Arguments
Applicant's arguments filed 06 January 2026 have been fully considered but they are not persuasive. Applicants argue that Joung is not directed to methods using nickases, and Joung [0060] provides no direction on the use of more than two pairs of gRNAs with a Cas9 nickase to generate more than two pairs of offset nicks creating more than two double stranded breaks causing fragmentation and deletion of the DNA target gene. Applicants argue that provisional application 61/799,647 makes clear that the reference to a plasmid encoding more than one gRNA is for a method of modulating gene. Applicants argue that one of skill will be led away from the claimed subject matter based on Joung insofar as Joung teaches gene activation using one or more guide RNAs to the region of the transcription start site and, accordingly, teaches against preventing expression by gene deletion. Applicants argue that Joung provides no motivation to modify Zhang alone or in combination with Zhang 2 to arrive at the claimed subject matter and with a reasonable expectation of success, i.e. preventing expression by targeting a gene for fragmentation and deletion using a nickase and more than two pairs of guide RNA, simply because Joung does not teach (1) "methods for increasing specificity of RNA-guided genome editing" as suggested by the Examiner at paragraph 21 of the office action, or (2) that "Joung teach using multiple pairs of guide RNAs to excise DNA fragments" as suggested by the Examiner at paragraph 22 of the office action.
Applicant’s arguments have been considered and are found unpersuasive. First the rejection as discussed above is relied on a combination of Zhang and Zhang 2 and Joung. In response to applicant's arguments against the references individually, 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). Second, applicants’ arguments do not address the merits of the rejection. Joung is relied upon for teaching that vectors that encode more that two pairs of gRNAs can be directed to different sites in the same region of the target gene. While Joung teaches this in the context of transcriptional activation of genes, a skilled artisan would recognize that this feature of using multiple gRNAs to target the same target gene at different locations can be applied to gene editing as well and solely depends on the design of the CRISPR system. Therefore, this teaching would not lead a skilled artisan away from applying these teachings to teachings of Zhang and Zhang 2 to arrive at the claimed subject matter as discussed in the rejection above.
Zhang specifically teaches the use of Cas9 nickases in combination with a pair of guide RNAs to excise intervening DNA fragments (i.e., fragmenting) by creating multiple DSBs [0867], Zhang also discloses the use of Cas9 nickases and multiple guide RNAs to excise DNA fragments from genomes. In particular, Zhang explicitly teaches that two or more guide RNAs (to include more than two pairs) can be used to induce simultaneous DSBs in DNA leading to microdeletions as discussed above. Zhang teaches the use of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or more guide sequences [0522]. Additionally, Zhang 2 teaches the use of pairs of guide RNAs to excide DNA fragments. Joung teaches that is possible to design one vector to include 2, 3, 4, 5, or more gRNAs directed to different sites in the same region of the target gene, thereby teaching that there is no need to introduce more than one gRNA encoding vector into the cell. Therefore, a skilled artisan equipped with these teachings would have motivation to use more than two guides RNAs along with a nickase to create more than two DSBs along the same gene, thereby fragmenting the gene for fragment deletion as a method for genomic deletion.
Furthermore, Applicant has not provided any objective, factually supported evidence to the contrary. Applicants have provided only arguments of counsel, and arguments of counsel cannot take the place of factually supported objective evidence. See, e.g., In re Huang, 100 F.3d 135,139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Applicants have not provided evidence supporting the fact that a skilled artisan could not be successful in combining the references as rejected above and use more than two pairs of guide RNAs with a Cas9 protein nickase to cause fragmentation of the DNA target gene wherein the fragmentation would cause deletion of the fragmented DNA target gene given Zhang's disclosure that targeting DNA with numerous guide-RNAs can result in deletions of the intervening sequences (i.e., fragments) and Zhang's 2 disclosure that when two pairs of guide RNAs are used, it is possible to excise an intervening DNA fragment.
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 Langi, 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 §§ 706.02(1)(1) - 706.02(1)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-l.isp.
Claims 1, 2, 12-14, and 25-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of US10435708 in view of Zhang (US20140179770A 1, Earliest US priority date is 12 December 2012, cited on the Information Disclosure Statement filed 10/04/2017), Zhang 2 (WO2014093622A2, provisionally filed 5/28/2013), Joung (US 2014/0295557 A1, provisionally filed 3/15/2013), and Doudna (US20140068797 A1, of record, filed 3/15/2013).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claimed invention is obvious over the claims of the patent. The patented claims teach all the limitations of the instant claims except, a method comprising more than 2 pairs of guide RNA sequences and a Cas9 nickase to create more than two double stranded breaks in the same DNA target nucleic acid resulting in deletion of fragmented double stranded DNA target nucleic acids. The teachings of Zhang, Zhang 2, Joung and Doudna are discussed in the rejection and obviousness rationale above.
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the patented claims to include the use of more than two pairs of guide RNAs as claimed. One of ordinary skill would be motivated to make the modification because Zhang teaches the use of multiple guide RNAs for the purpose of creating multiple offset nicks in order to excise portions of the same genomic DNA. Zhang’s disclosure of using both two pairs of gRNAs to induce several DSBs within the same genome, and up to 20 gRNAs, as discussed above, for the purpose of removing DNA fragments would have motivated one of ordinary skill to use more than two pairs of gRNAs wherein each of the guide RNAs of the pair is complementary to an adjacent sites on two sites on opposite strands of the DNA in conjunction with a Cas9 nickase for the purpose of mediating larger deletions in the genome and minimizing off target cleavage. Joung also teaches vectors that encode more than one gRNA, e.g. 2, 3, 4, 5, or more gRNAs directed to different sites in the same region of the target gene. Additionally, it would be obvious to a skilled artisan that the use of more than two pairs of guide RNAs with a Cas9 protein nickase would cause fragmentation of the DNA target gene wherein the fragmentation would cause deletion of the fragmented DNA target gene given Zhang’s disclosure that targeting DNA with numerous guide-RNAs can result in deletions of the intervening sequences (i.e. fragments) [0828] and Zhang’s 2 disclosure that when two pairs of guide RNAs are used, it is possible to excise an intervening DNA fragment. Furthermore, it would be obvious to a skilled artisan that a targeted deletion of a gene within a genome would prevent its expression as an inherent property of gene deletions. One of ordinary skill would a reasonable expectation of success since both Zhang and Zhang 2 teach using multiple pairs of guide RNAs to excise DNA fragments.
For additional limitations of the instant claims, see the additional teachings of the patented claims. To the extent that there are limitations that are not provided for by the patented claims, the teachings of Zhang, Zhang 2, Joung, and Doudna are discussed above. It would have been obvious to have modified the subject matter of the patented claims to arrive at the subject matter of the instant claims for substantially the same reasons as discussed above in view of the teachings of these references.
Claims 1, 2, 12-14, and 25-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4-6 of U.S. Patent No. 10787684 in view of Zhang (US20140179770A 1, Earliest US priority date is 12 December 2012, cited on the Information Disclosure Statement filed 10/04/2017), Zhang 2 (WO2014093622A2, provisionally filed 5/28/2013), Joung (US 2014/0295557 A1, provisionally filed 3/15/2013), and Doudna (US20140068797 A1, of record, filed 3/15/2013).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claimed invention is obvious over the claims of the patent. The patented claims teach all the limitations of the instant claims except, a method comprising more than 2 pairs of guide RNA sequences and a Cas9 nickase to create more than two double stranded breaks in the same DNA target nucleic acid resulting in deletion of fragmented double stranded DNA target nucleic acids. The teachings of Zhang, Zhang 2, Joung and Doudnaare discussed in the rejection and obviousness rationale above.
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the patented claims to include the use of more than two pairs of guide RNAs as claimed. One of ordinary skill would be motivated to make the modification because Zhang teaches the use of multiple guide RNAs for the purpose of creating multiple offset nicks in order to excise portions of the same genomic DNA. Zhang’s disclosure of using both two pairs of gRNAs to induce several DSBs within the same genome, and up to 20 gRNAs, as discussed above, for the purpose of removing DNA fragments would have motivated one of ordinary skill to use more than two pairs of gRNAs wherein each of the guide RNAs of the pair is complementary to an adjacent sites on two sites on opposite strands of the DNA in conjunction with a Cas9 nickase for the purpose of mediating larger deletions in the genome and minimizing off target cleavage. Joung also teaches vectors that encode more than one gRNA, e.g. 2, 3, 4, 5, or more gRNAs directed to different sites in the same region of the target gene. Additionally, it would be obvious to a skilled artisan that the use of more than two pairs of guide RNAs with a Cas9 protein nickase would cause fragmentation of the DNA target gene wherein the fragmentation would cause deletion of the fragmented DNA target gene given Zhang’s disclosure that targeting DNA with numerous guide-RNAs can result in deletions of the intervening sequences (i.e. fragments) [0828] and Zhang’s 2 disclosure that when two pairs of guide RNAs are used, it is possible to excise an intervening DNA fragment. Furthermore, it would be obvious to a skilled artisan that a targeted deletion of a gene within a genome would prevent its expression as an inherent property of gene deletions. One of ordinary skill would a reasonable expectation of success since both Zhang and Zhang 2 teach using multiple pairs of guide RNAs to excise DNA fragments.
For additional limitations of the instant claims, see the additional teachings of the patented claims. To the extent that there are limitations that are not provided for by the patented claims, the teachings of Zhang, Zhang 2, Joung, and Doudna are discussed above. It would have been obvious to have modified the subject matter of the patented claims to arrive at the subject matter of the instant claims for substantially the same reasons as discussed above in view of the teachings of these references.
Claims 1, 2, 12-14, and 25-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over allowed claims 1-11, 17, and 22-27 of US Patent 11597949B2 in view of Zhang (US20140179770A 1, Earliest US priority date is 12 December 2012, cited on the Information Disclosure Statement filed 10/04/2017), Zhang 2 (WO2014093622A2, provisionally filed 5/28/2013), Joung (US 2014/0295557 A1, provisionally filed 3/15/2013), and Doudna (US20140068797 A1, of record, filed 3/15/2013).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claimed invention is obvious over the claims of the US Patent. The patented claims teach all the limitations of the instant claims except, a method comprising more than 2 pairs of guide RNA sequences and a Cas9 nickase to create more than two double stranded breaks in the same DNA target nucleic acid resulting in deletion of fragmented double stranded DNA target nucleic acids. The teachings of Zhang, Zhang 2, Joung and Doudnaare discussed in the rejection and obviousness rationale above.
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the patented claims to include the use of more than two pairs of guide RNAs as claimed. One of ordinary skill would be motivated to make the modification because Zhang teaches the use of multiple guide RNAs for the purpose of creating multiple offset nicks in order to excise portions of the same genomic DNA. Zhang’s disclosure of using both two pairs of gRNAs to induce several DSBs within the same genome, and up to 20 gRNAs, as discussed above, for the purpose of removing DNA fragments would have motivated one of ordinary skill to use more than two pairs of gRNAs wherein each of the guide RNAs of the pair is complementary to an adjacent sites on two sites on opposite strands of the DNA in conjunction with a Cas9 nickase for the purpose of mediating larger deletions in the genome and minimizing off target cleavage. Joung also teaches vectors that encode more than one gRNA, e.g. 2, 3, 4, 5, or more gRNAs directed to different sites in the same region of the target gene. Additionally, it would be obvious to a skilled artisan that the use of more than two pairs of guide RNAs with a Cas9 protein nickase would cause fragmentation of the DNA target gene wherein the fragmentation would cause deletion of the fragmented DNA target gene given Zhang’s disclosure that targeting DNA with numerous guide-RNAs can result in deletions of the intervening sequences (i.e. fragments) [0828] and Zhang’s 2 disclosure that when two pairs of guide RNAs are used, it is possible to excise an intervening DNA fragment. Furthermore, it would be obvious to a skilled artisan that a targeted deletion of a gene within a genome would prevent its expression as an inherent property of gene deletions. One of ordinary skill would a reasonable expectation of success since both Zhang and Zhang 2 teach using multiple pairs of guide RNAs to excise DNA fragments.
For additional limitations of the instant claims, see the additional teachings of the patented claims. To the extent that there are limitations that are not provided for by the patented claims, the teachings of Zhang, Zhang 2, Joung, and Doudna are discussed above. It would have been obvious to have modified the subject matter of the patented claims to arrive at the subject matter of the instant claims for substantially the same reasons as discussed above in view of the teachings of these references.
Claims 1, 2, 12-14, and 25-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, and 8-12 of copending Application No. 15/230025 in view of Zhang (US20140179770A 1, Earliest US priority date is 12 December 2012, cited on the Information Disclosure Statement filed 10/04/2017), Zhang 2 (WO2014093622A2, provisionally filed 5/28/2013), Joung (US 2014/0295557 A1, provisionally filed 3/15/2013), and Doudna (US20140068797 A1, of record, filed 3/15/2013). 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 obvious over the claims of the copending application. The copending claims teach all the limitations of the instant claims except, a method comprising more than 2 pairs of guide RNA sequences and a Cas9 nickase to create more than two double stranded breaks in the same DNA target nucleic acid resulting in deletion of fragmented double stranded DNA target nucleic acids. The teachings of Zhang, Zhang 2, Joung and Doudnaare discussed in the rejection and obviousness rationale above.
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the copending claims to include the use of more than two pairs of guide RNAs as claimed. One of ordinary skill would be motivated to make the modification because Zhang teaches the use of multiple guide RNAs for the purpose of creating multiple offset nicks in order to excise portions of the same genomic DNA. Zhang’s disclosure of using both two pairs of gRNAs to induce several DSBs within the same genome, and up to 20 gRNAs, as discussed above, for the purpose of removing DNA fragments would have motivated one of ordinary skill to use more than two pairs of gRNAs wherein each of the guide RNAs of the pair is complementary to an adjacent sites on two sites on opposite strands of the DNA in conjunction with a Cas9 nickase for the purpose of mediating larger deletions in the genome and minimizing off target cleavage. Joung also teaches vectors that encode more than one gRNA, e.g. 2, 3, 4, 5, or more gRNAs directed to different sites in the same region of the target gene. Additionally, it would be obvious to a skilled artisan that the use of more than two pairs of guide RNAs with a Cas9 protein nickase would cause fragmentation of the DNA target gene wherein the fragmentation would cause deletion of the fragmented DNA target gene given Zhang’s disclosure that targeting DNA with numerous guide-RNAs can result in deletions of the intervening sequences (i.e. fragments) [0828] and Zhang’s 2 disclosure that when two pairs of guide RNAs are used, it is possible to excise an intervening DNA fragment. Furthermore, it would be obvious to a skilled artisan that a targeted deletion of a gene within a genome would prevent its expression as an inherent property of gene deletions. One of ordinary skill would a reasonable expectation of success since both Zhang and Zhang 2 teach using multiple pairs of guide RNAs to excise DNA fragments.
For additional limitations of the instant claims, see the additional teachings of the patented claims. To the extent that there are limitations that are not provided for by the patented claims, the teachings of Zhang, Zhang 2, Joung, and Doudna are discussed above. It would have been obvious to have modified the subject matter of the patented claims to arrive at the subject matter of the instant claims for substantially the same reasons as discussed above in view of the teachings of these references.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 2, 12-14, and 25-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of US Patent No. 11365429B2 in view of Zhang (US20140179770A 1, Earliest US priority date is 12 December 2012, cited on the Information Disclosure Statement filed 10/04/2017), Zhang 2 (WO2014093622A2, provisionally filed 5/28/2013), Joung (US 2014/0295557 A1, provisionally filed 3/15/2013), and Doudna (US20140068797 A1, of record, filed 3/15/2013).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claimed invention is obvious over the claims of the patent. The patented claims teach all the limitations of the instant claims except, a method comprising more than 2 pairs of guide RNA sequences and a Cas9 nickase to create more than two double stranded breaks in the same DNA target nucleic acid resulting in deletion of fragmented double stranded DNA target nucleic acids. The teachings of Zhang, Zhang 2, Joung and Doudnaare discussed in the rejection and obviousness rationale above.
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the patented claims to include the use of more than two pairs of guide RNAs as claimed. One of ordinary skill would be motivated to make the modification because Zhang teaches the use of multiple guide RNAs for the purpose of creating multiple offset nicks in order to excise portions of the same genomic DNA. Zhang’s disclosure of using both two pairs of gRNAs to induce several DSBs within the same genome, and up to 20 gRNAs, as discussed above, for the purpose of removing DNA fragments would have motivated one of ordinary skill to use more than two pairs of gRNAs wherein each of the guide RNAs of the pair is complementary to an adjacent sites on two sites on opposite strands of the DNA in conjunction with a Cas9 nickase for the purpose of mediating larger deletions in the genome and minimizing off target cleavage. Joung also teaches vectors that encode more than one gRNA, e.g. 2, 3, 4, 5, or more gRNAs directed to different sites in the same region of the target gene. Additionally, it would be obvious to a skilled artisan that the use of more than two pairs of guide RNAs with a Cas9 protein nickase would cause fragmentation of the DNA target gene wherein the fragmentation would cause deletion of the fragmented DNA target gene given Zhang’s disclosure that targeting DNA with numerous guide-RNAs can result in deletions of the intervening sequences (i.e. fragments) [0828] and Zhang’s 2 disclosure that when two pairs of guide RNAs are used, it is possible to excise an intervening DNA fragment. Furthermore, it would be obvious to a skilled artisan that a targeted deletion of a gene within a genome would prevent its expression as an inherent property of gene deletions. One of ordinary skill would a reasonable expectation of success since both Zhang and Zhang 2 teach using multiple pairs of guide RNAs to excise DNA fragments.
For additional limitations of the instant claims, see the additional teachings of the patented claims. To the extent that there are limitations that are not provided for by the patented claims, the teachings of Zhang, Zhang 2, Joung, and Doudna are discussed above. It would have been obvious to have modified the subject matter of the patented claims to arrive at the subject matter of the instant claims for substantially the same reasons as discussed above in view of the teachings of these references.
Claims 1, 2, 12-14, and 25-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 14, 52, 54, and 61 of US Patent No. 11359211B2 in view of Zhang (US20140179770A 1, Earliest US priority date is 12 December 2012, cited on the Information Disclosure Statement filed 10/04/2017), Zhang 2 (WO2014093622A2, provisionally filed 5/28/2013), Joung (US 2014/0295557 A1, provisionally filed 3/15/2013), and Doudna (US20140068797 A1, of record, filed 3/15/2013).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claimed invention is obvious over the claims of the patent. The patented claims teach all the limitations of the instant claims except, a method comprising more than 2 pairs of guide RNA sequences and a Cas9 nickase to create more than two double stranded breaks in the same DNA target nucleic acid resulting in deletion of fragmented double stranded DNA target nucleic acids. The teachings of Zhang, Zhang 2, Joung and Doudnaare discussed in the rejection and obviousness rationale above.
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the patented claims to include the use of more than two pairs of guide RNAs as claimed. One of ordinary skill would be motivated to make the modification because Zhang teaches the use of multiple guide RNAs for the purpose of creating multiple offset nicks in order to excise portions of the same genomic DNA. Zhang’s disclosure of using both two pairs of gRNAs to induce several DSBs within the same genome, and up to 20 gRNAs, as discussed above, for the purpose of removing DNA fragments would have motivated one of ordinary skill to use more than two pairs of gRNAs wherein each of the guide RNAs of the pair is complementary to an adjacent sites on two sites on opposite strands of the DNA in conjunction with a Cas9 nickase for the purpose of mediating larger deletions in the genome and minimizing off target cleavage. Joung also teaches vectors that encode more than one gRNA, e.g. 2, 3, 4, 5, or more gRNAs directed to different sites in the same region of the target gene. Additionally, it would be obvious to a skilled artisan that the use of more than two pairs of guide RNAs with a Cas9 protein nickase would cause fragmentation of the DNA target gene wherein the fragmentation would cause deletion of the fragmented DNA target gene given Zhang’s disclosure that targeting DNA with numerous guide-RNAs can result in deletions of the intervening sequences (i.e. fragments) [0828] and Zhang’s 2 disclosure that when two pairs of guide RNAs are used, it is possible to excise an intervening DNA fragment. Furthermore, it would be obvious to a skilled artisan that a targeted deletion of a gene within a genome would prevent its expression as an inherent property of gene deletions. One of ordinary skill would a reasonable expectation of success since both Zhang and Zhang 2 teach using multiple pairs of guide RNAs to excise DNA fragments.
For additional limitations of the instant claims, see the additional teachings of the patented claims. To the extent that there are limitations that are not provided for by the patented claims, the teachings of Zhang, Zhang 2, Joung, and Doudna are discussed above. It would have been obvious to have modified the subject matter of the patented claims to arrive at the subject matter of the instant claims for substantially the same reasons as discussed above in view of the teachings of these references.
Response to Arguments
Applicants argue that the present claims are not obvious over Zhang, Zhang 2, Joung and Doudna and therefore the claims of the patent and applications are patentably distinct from the present claims. Applicants’ arguments have been considered and found not persuasive for the same reasons discussed above. Therefore, the nonstatutory double patenting rejections above are maintained.
Conclusion
No claims are allowed.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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