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 .
Notice of Pre-AIA or AIA Status
This action is written in response to applicant’s correspondence received 24 September 2025. Claims 1 and 3-38 are currently pending. Claims 16-17, 21-23, and 34-38 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 1, 3-15, 18-20, and 24-33 are examined herein. The restriction requirement mailed 11 February 2025 is still deemed proper. Applicant's elected Group I without traverse in the reply filed 11 April 2025.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Interpretation
Regarding the newly amended limitation “wherein at least one of the two or more Cas proteins is catalytically active” present in amended claim 1, it is noted that the instant specification teaches that the system could be used to induce the cleavage of a genomic locus of interest in a cell via the use of Cas enzymes that are nucleases or nickases ([0297]). Therefore, the claimed “catalytically active” Cas protein is interpreted as encompassing a Cas protein that has been engineered to be a nickase.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 9-18 and 38 are 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.
Regarding claim 9, claim 1 (i.e., the claim from which claim 9 ultimately depends on) recites that at least one of the two or more Cas proteins is catalytically inactive while claim 9 recites that the first and second Cas protein are both catalytically inactive. Thus, it is unclear if the system of claim 9 requires a catalytically active Cas protein or if the system of claim 9 only comprises catalytically inactive Cas proteins.
Regarding claims 10-18 and 38, as the claims are ultimately dependent on claim 9 and do not rectify the 35 USC 112(b) rejection above, the claims are also rejected under 35 USC 112(b).
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 9 and 32 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claim 9, claim 1 (i.e., the claim from which claim 9 ultimately depends on) recites that at least one of the two or more Cas proteins is catalytically inactive while claim 9 recites that the first and second Cas protein are both catalytically inactive. Thus, claim 9 does not include all of the limitations of the claim from which it depends because claim 1 requires at least one Cas protein with catalytic activity.
Regarding claim 32, the claim further claims that the organism is a non-human animal. However, claims 30-31, the claims from which claim 32 ultimately depends, claim a non-human organism (see claim 30), wherein the organism is an animal (see claim 31). Thus, claim 32 does not further limit the subject matter of claim 31. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 3-6, and 9-13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Adli (Nature communications 9.1 (2018): 1911).
Regarding claim 1, Adli is drawn to a study concerned with CRISPR Cas9 toolkits for genome editing (Abstract). Adli teaches the use of a CRISPR-Cas targeting system that comprises two tandem nickase Cas9 proteins (i.e., at least one of the two proteins is catalytically active) and two sgRNAs that can target the nickases to a genomic locus of interest to induce a base edit (i.e., at least one guide molecule that is capable of forming a complex with at least one Cas protein and redirects site specific binding to a target sequence) (pg. 5).
Regarding claims 3-6, Adli teaches that CRISPR Cas9 proteins comprise two catalytic domains, an HNH and RuvC domain, that act together to mediate DNA double-strand breaks (pg. 6). Adli teaches that nickase Cas9s are generated by mutating the domains, cleavage activity is lost such that the proteins can be utilized as nickases (pg. 6).
Regarding claim 9, the indefinite claim limitations discussed above are interpreted as requiring that both tandem Cas proteins are catalytically inactive (i.e., neither of the Cas proteins have catalytic activity). Adli teaches that the tandem Cas9 proteins can be dCas9 proteins (i.e., catalytically inactive Cas proteins that comprise an inactive RuvC domain) (pg. 5; see FIG. 3).
Regarding claims 10-13, Adli teaches that two tandem dCas9 proteins can complex with one another, via an allosteric interaction between a protein dimer (i.e., a first and second functional domain that is activated upon allosteric interaction between the dCas9 proteins), in order to effect change in a target nucleic acid (pg. 5; see Fig. 3).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 7-8 and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Adli (Nature communications 9.1 (2018): 1911) as applied to claims 1, 3-6, and 9-13 above, and further in view of Konermann (PG Pub No. WO 2015/089486 A2, cited in the IDS filed 12 December 2022).
Regarding claims 14-15, Adli anticipates claims 1, 3-6, and 9-13 as described above.
Adli does not teach or suggest that the first Cas protein acts as a nickase on a first strand of a dsDNA polynucleotide and the second Cas protein acts as a nickase on a second strand of the dsDNA polynucleotide (Claim 7). Adli does not teach or suggest that the first and second Cas proteins allosterically interact upon target recognition to coordinate nicking of the first and second strands of the dsDNA polynucleotide (Claims 8 and 19).
However, one of ordinary skill in the art would have considered the teachings of Konermann as both references are common fields of endeavor pertaining to the use of CRISPR-Cas systems (Abstract).
Konermann is drawn towards an invention concerned with CRISPR-Cas systems and methods of using the systems (Abstract). Konermann teaches the use of two guide nucleic acids that can be utilized to direct two Cas9 nickases to sense and antisense strands of a target nucleic acid of interest such that the target nucleic acid is nicked and NHEJ is induced (i.e., the two Cas nickases allosterically interact to nick a direct and second strand of a dsDNA molecule) ([00336]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the guide nucleic acid molecules of Aldi for guide nucleic acids that target two nickase to sense and antisense strands of a target nucleic acid of interest such that they can allosterically interact to nick a target dsDNA molecule, as described by Konermann. A person of ordinary skill in the art would have been motivated to do so in order to induce NHEJ at a target dsDNA region of interest. A person of ordinary skill in the art would have had a reasonable expectation of success because both Adli and Konermann teach the use of two Cas9 nickases that can be targeted to target nucleic acids of interest via the use of guide nucleic acids.
Claim(s) 14-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Adli (Nature communications 9.1 (2018): 1911) as applied to claims 1, 3-6, and 9-13 above, and further in view of Stynen (Microbiology and molecular biology reviews 76.2 (2012): 331-382).
Regarding claims 14-15, Adli anticipates claims 1, 3-6, and 9-13 as described above.
Adli does not teach or suggest that the functional domain is a nucleotide deaminase (Claims 14-15).
However, one of ordinary skill in the art would have considered the teachings of Stynen as both references are common fields of endeavor pertaining to the use of proteins dimers.
Stynen is drawn towards a study concerned with protein-protein interactions utilizing a yeast two-hybrid system (Abstract). Stynen teaches the use of a split yeast cytosine deaminase that comprises two monomers that can each be fused to different proteins such that the monomers can form a dimer (i.e., allosterically interact) and form a functional deaminase complex between the two different proteins (i.e., form a functional domain comprising a nucleotide deaminase) (pg. 352).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the protein dimer described by Adli for a nucleotide deaminase dimer, as described by Stynen. A person of ordinary skill in the art would have been motivated to do so in order to deaminate cytosines of interests at target nucleic acids via the use of the targeted dCas9 molecules. A person of ordinary skill in the art would have had a reasonable expectation of success because Adli teaches the use of a protein dimer that can be fused to two different dCas9 proteins and Stynen teaches the use of a split cytosine deaminase dimer that can be fused to two different proteins.
Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Adli (Nature communications 9.1 (2018): 1911) as applied to claims 1, 3-6, and 9-13 above, and further in view of Amoutzias (Trends in biochemical sciences 33.5 (2008): 220-229).
Regarding claim 18, Adli anticipates claims 1, 3-6, and 9-13 as described above.
Adli does not teach or suggest that the first portion and the second portion comprise a split transcription protein (Claim 18).
However, one of ordinary skill in the art would have considered the teachings of Amoutzias as both references are common fields of endeavor pertaining to the use of proteins dimers.
Amoutzias is drawn towards a review study concerned with dimerization of eukaryotic transcription factors (Abstract). Amoutzias teaches the use of multiple different homotypic transcription factors (i.e., TFs), including bHLH, bZIP, NR, MADS-box, HD-ZIP NF-κB, and STATs, that can form dimers (pg. 221). Amoutzias teaches that TF families that can combine in homotypic and dimeric protein complexes create a large number of TF dimers with distinct properties, equaling or even exceeding the actual number of sequence-specific TF genes in a genome (pg. 227-228).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the protein dimer described by Adli for a split transcription factor dimer, as described by Amoutzias. A person of ordinary skill in the art would have been motivated to do so in order to utilize unique protein dimer systems that can comprise distinct properties resulting from the large amount of possible combinations of transcription factors. A person of ordinary skill in the art would have had a reasonable expectation of success because Adli teaches the use of a protein dimer that can be fused to two different dCas9 proteins and Stynen teaches the use of a split transcription dimer.
Claim(s) 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Adli (Nature communications 9.1 (2018): 1911) as applied to claims 1, 3-6, and 9-13 above, and further in view of Tóth (Biology direct 11 (2016): 1-14).
Regarding claim 20, Adli anticipates claims 1, 3-6, and 9-13 as described above.
Adli does not teach or suggest the use of a Cas12a protein (Claim 20).
However, one of ordinary skill in the art would have considered the teachings of Tóth as both references are common fields of endeavor pertaining to the use of CRISPR enzymes.
Tóth is drawn to a study concerned with Cpf1 nucleases (i.e., Cas12a nucleases) (Abstract). Tóth teaches that Cpf1 is a known CRISPR nuclease that is an equally or more effective tool than the most frequently used orthogonal Cas9 counterparts of SpCas9 (pg. 1). Tóth teaches that AsCpf1 proteins can be mutated such that the protein becomes a nickase (pg. 2).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute at least one nickase Cas9 protein of Adli for a nickase AsCpf1 protein, as described by Tóth. A person of ordinary skill in the art would have been motivated to do so in order to utilize an alternative CRISPR protein that is known in the art to be a more effective tool for gene editing when compared to Cas9. A person of ordinary skill in the art would have had a reasonable expectation of success because both Aldi and Tóth teaches the use of CRISPR proteins that can be converted to nickases and used in tandem.
Claim(s) 24-32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Adli (Nature communications 9.1 (2018): 1911) as applied to claims 1, 3-6, and 9-13 above, and further in view of Lone (Genetics research international 2018.1 (2018): 3797214).
Regarding claims 24-32, Adli anticipates claims 1, 3-6, and 9-13 as described above. Adli further teaches that AAV vectors are attractive therapeutic delivery vehicles for Cas9 (pg. 9).
Adli does not teach or suggest the use of a polynucleotide that encodes one or more components of the system of claim 1 (Claim 24). Adli does not teach or suggest that one or more regions of the polynucleotide is codon optimized for expression in a eukaryotic cell (Claim 25). Adli does not teach or suggest the use of a vector comprising the polynucleotide encoding one or more components of the system (Claim 26). Adli does not teach or suggest the use of a vector system comprising two or more vectors (Claim 27). Adli does not teach or suggest the use of a modified isolated cell comprising the polynucleotide of claim 24 (Claim 28) or a eukaryotic cell comprising the polynucleotide (Claim 29). Adli does not teach or suggest the use of a non-human organism comprising one or more cells of claim 28 (Claim 30) selected from an animal (Claim 31) or a non-human animal (Claim 32).
However, one of ordinary skill in the art would have considered the teachings of Lone as both references are common fields of endeavor pertaining to the study and use of Cas9 proteins.
Lone is drawn to a study concerned with CRISPR Cas9 systems (Abstract). Lone teaches the use of a polynucleotide that encodes Cas9 and is codon-optimized for expression in mammalian cells (pg. 3). Lone teaches that AAVs can be utilized to encode Cas9 and successfully deliver the Cas9 protein to target cells (pg. 9). Lone teaches that multiple AAVs can be utilized to deliver two different Cas9 proteins (pg. 9). Lone teaches that CRISPR/Cas9 systems can be delivered to cultured cells (i.e., a modified isolated cell) (pg. 10; see Figure 7). Lone teaches that utilizing AAVs to deliver Cas9 to target living cells is favored for gene delivery in vivo because the AAV is associated with minor immune responses and little pathogenesis (pg. 9).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the system of Adli such that a vector system comprising codon optimized polynucleotides that encode one or more components of the system and can be delivered to isolated or living non-human organisms is utilized, as described by Lone. A person of ordinary skill in the art would have been motivated to do so in order to utilize a known delivery method of Cas9 to mammalian cells via a method known to be associated with minor immune responses and little pathogenesis. A person of ordinary skill in the art would have had a reasonable expectation of success because both Adli and Lone are drawn towards studies concerned with the use of Cas9 proteins for expression in target cells.
Claim(s) 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Adli (Nature communications 9.1 (2018): 1911) in view of Lone (Genetics research international 2018.1 (2018): 3797214) as applied to claims 24-32 above, and further in view of Liu (Acta pharmaceutica sinica B 7.3 (2017): 292-302).
Regarding claim 33, Adli in view of Lone renders obvious claims 24-33 as described above.
Adli in view of Lone does not teach or suggest the use of a plant cell (Claim 33).
However, one of ordinary skill in the art would have considered the teachings of Liu as both references are common fields of endeavor pertaining to the use of CRISPR enzymes.
Liu is drawn to a study concerned with the utilization of CRISPR/Cas9 proteins in plant cells (Abstract). Liu teaches the use of a plant codon-optimized Cas9 (pg. 294). Liu teaches that Cas9 was known to be able to be utilized in plant cells in order to edit target nucleic acids in the plant cells (pg. 297). Liu teaches that utilizing Cas9 editing in plant cells can be advantageous in developing plants that have increased yield and desirable traits (pg. 299).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the non-human animal cell of Adli in view of Lone with a plant cell, as described by Liu. A person of ordinary skill in the art would have been motivated to do so in order to develop plants that have increased yield and desirable traits. A person of ordinary skill in the art would have had a reasonable expectation of success because both Liu and Adli in view of Lone teach the use of functional CRISPR Cas systems in target cells.
Response to Arguments
Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Applicant alleges that the two tandem dCas9 proteins of Aldi comprise two catalytically inactive Cas proteins. Applicant alleges that the previously pending 35 USC 103 rejections of record are improper as Aldi does not teach or suggest that at least one of the Cas proteins is catalytically active.
This argument is not found persuasive because Adli teaches the use of a CRISPR-Cas targeting system that comprises two tandem nickase Cas9 proteins (i.e., at least one of the two Cas proteins is catalytically active) and two sgRNAs that can target the nickases to a genomic locus of interest to induce a base edit (i.e., at least one guide molecule that is capable of forming a complex with at least one Cas protein and redirects site specific binding to a target sequence) (pg. 5). Thus, Aldi anticipates claims 1, 3-6, and 9-13 as currently amended.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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