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
This action is written in response to applicant' s correspondence received November 26, 2025. Claims 1-6 and 8-10 are currently pending.
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 Rejections - 35 USC § 112(b)
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 5 and 6 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 5, Claim 5 recites the donor nucleic acid molecule causes a genetic modification. Claim 1 recites the donor nucleic acid causes a point mutation. It is unclear whether Claim 5 is reciting an additional genetic modification or substitution of the point mutation in Claim 1. A point mutation is a mutation of a single nucleotide and may no longer be a point mutation if multiple mutations exist.
Regarding Claim 6, Claim 6 recites specific genetic mutations but does not clarify Claim 5 to overcome the previous rejection.
Claim Rejections - 35 USC § 112(d)
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 5 and 6 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.
MPEP 608.01(n).III recites, “Following the statute, the test as to whether a claim is a proper dependent claim is that it shall include every limitation of the claim from which it depends and specify a further limitation of the subject matter claimed.”
Regarding Claim 5, Claim 1 recites “generating a donor nucleic acid molecule … to thereby cause a point mutation on the target DNA”, which is interpreted as the donor nucleic acid molecule causes a specific genetic modification called a point mutation. Claim 5 recites “the donor nucleic acid molecule causes a genetic modification on the target DNA”. Genetic modification is genus broader than a point mutation and includes multiple substitutions, deletions and additions. Therefore, Claim 5 fails to further limit the claimed subject matter of Claim 1 and is rejected under 35 USC 112(d).
Regarding Claim 6, Claim 6, dependent on Claim 5, recites additional genetic modifications different from a point mutation and fails to overcome the rejection of Claim 5. Therefore, Claim 6 is rejected under 35 USC 112(d).
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 § 112(a) – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6 and 8-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding Claim 1, the instant specification does not provide a method of gene editing utilizing CRISPR/Cas9 as defined by the instant specification but instead provides a method of negative selection by utilizing CRISPR/Cas9 to kill cells without a point mutation caused by mutagenic oligonucleotides.
Claim Interpretation
Claim 1 recites, “A genome editing method utilizing Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 (CRIPSR/Cas9)”. The instant specification defines “genome editing” as “editing, restoring, modifying, losing and/or altering a gene function by deletion, insertion, substitution, etc. of a nucleic acid molecule by Cas9 cleavage at a target site of the target DNA” (p. 6, lines 15-18). Therefore, Claim 1 is interpreted as a method in which CRISPR/Cas9 performs the genome editing.
Guidance Provided by the Instant Specification
The instant specification teaches a method in which a mutagenic oligonucleotide, or the donor nucleic acid, is inserted into cells to create a point mutation in a target DNA sequence (p. 11, lines 2-10). Then, a gRNA with a mismatch to the original sequence of the target DNA adjacent to the location the point mutation is used in conjunction with CRISPR/Cas9 to cleave cells that failed to incorporate the point mutation (p. 11, lines 6-10; p. 12 lines 3-6). The mechanism by which this invention works is that cells with the point mutation would have two mismatches between the mutated target DNA and gRNA and, CRISPR/Cas9 would fail to cleave the cells. Cells that do not have the point mutation would only have one mismatch, and CRISPR/Cas9 would cleave the DNA of those cells killing those cells (p. 12, lines 3-6). An embodiment of the invention is provided on pages 11, line 18 to page 12, line 2. The instant specification describes the use of CRIPSR/Cas9 for “negative selection” rather than gene editing (p. 12, lines 7-9).
Guidance Provided by the Prior Art
Walquist (Walquist, M. and El-Gewely, M., Encylcopedia of Life Sciences, p. 1-14, January 22, 2018) teaches multiple methods of oligonucleotide mutagenesis on p.3, Table 2 including deoxyuridine incorporation, thionucleotide selection, meythlation and DpnI, unique site elimination, and TA cloning strategy and polymerase chain reaction orientation verification. Walquist teaches CRIPSR may be used with a donor DNA template but does not describe a mutagenic oligonucleotide nor negative selection (p. 11, col. 1-2).
Conclusion
One skilled in the art would not have recognized the inventors in possession of the claimed invention because a gene editing method based on CRISPR/Cas9 is not described in the specification. Instead, gene editing is performed by a mutagenic oligonucleotide, and CRIPSR/Cas9 is used for negative selection to kill cells that failed to incorporate a point mutation. Therefore, Claim 1 is rejected under 35 USC 112(a) for written description.
Regarding Claims 2-6, Claims 2-6 do not recite limitations such that CRISPR/Cas9 would be used for gene editing. Therefore, Claims 2-6 are also rejected under 35 USC 112(a) for written description.
Regarding Claim 8, Claim 8 recites, “A method for increasing genome editing efficiency based in a CRISPR/Cas9 system” and is interpreted to mean a method in which CRISPR/Cas9 performs genome editing. Claim 8 recites the same steps as Claim 1 and is rejected under 35 USC 112(a) for the reasons described above for Claim 1.
Regarding Claim 9, Claim 9 recites, “A method for preparing a subject in which a target DNA is edited in a CRISPR/Cas9 system” and is interpreted to mean a method in which CRISPR/Cas9 edits a target DNA in a subject. Claim 9 recites step (a) and (b) which correspond to Claim 1 steps (b) and (a) and an additional step of (c) contacting the donor nucleic acid molecule and gRNA of steps (a) and (b) into the subject. As described above for Claim 1, the instant specification does not describe a method in which the target DNA in a subject is edited by CRISPR/Cas9, but rather through a mutagenic oligonucleotide. Therefore, Claim 9 is rejected under 35 USC 112(a) for written description.
Regarding Claim 10, Claim 10 does not recite limitations such that CRISPR/Cas9 would be used for gene editing. Therefore, Claim 10 is also rejected under 35 USC 112(a) for written description.
Claim Rejections - 35 USC § 112(a) – Enablement Requirement
Claims 9 and 10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Regarding Claim 9, Claim 9 recites a method for preparing a subject for DNA editing with CRISPR/Cas9 wherein the gRNA and target DNA sequence have two mismatches. The prior art and instant application do not support a method with two mismatches, and both provide evidence that such a method is unpredictable and requires undue experimentation.
The Breadth of the Claims and The Nature of the Invention
Claim 9 recites, “A method for preparing a subject in which a target DNA is edited in a CRISPR/Cas9 system, comprising the steps of: … (c) contacting the donor nucleic acid molecule of step (a) and the guide RNA of step (b) into the subject to be edited, thereby a total of two mismatches occur between the target DNA and the guide RNA sequence to edit the target DNA of the subject”. This is interpreted to mean CRISPR/Cas9 is used to edit the target DNA sequence of a subject in which there are two mismatches between the gRNA and target DNA sequence. Subject is not defined in the instant specification and interpreted as any organism.
The State of the Prior Art, The Level of One of Ordinary Skill, and the Level of Predictability in the Art
The following prior art is cited below: Anderson, E., et. al., Journal of Biotechnology, Vol. 211, p. 56-65, Oct 10, 2015; Zhang, L. et. al., “The effect of sequence mismatches on binding affinity and endonuclease activity are decoupled throughout the Cas9 binding site“, BioRxiv, Posted Aug 15, 2017.
For one skilled in the art, the prior art provides predictable results with one mismatch between the gRNA and the target DNA with the use of CRISPR/Cas9, but two or more mismatches would require experimentation with no reasonable expectation of success. Anderson teaches two consecutive mismatches have little to no activity, and Zhang teaches certain positions may allow for gene editing and increased efficiency, but require experimentation.
Anderson teaches that gene editing with CRISPR/Cas9 is enabled with single mismatches between the gRNA and the target DNA, but only specific double mismatch positions are enabled. Anderson recites, “Consistent with previous results, we observed that single mismatches are fairly well-tolerated, especially in the 5′ PAM-distal end of crRNAs. crRNAs containing mismatches in the seed region, defined here as nucleotides 11–20 of the crRNA, did not exhibit activity, with two minor exceptions: positions 13 and 19 showed detectable activity < 10% relative to the perfect match control. Conclusions from the comprehensive examination of two-base mismatches also agree with published data on selected endogenous off-targets. Namely, consecutive two-base mismatches are generally not active, with the exception of positions 1 and 2” (p. 64, col. 1, para 2) with the use of a CRISPR/Cas9 system. Therefore, Anderson teaches that while single mismatches may work for gene editing with CRISPR/Cas9, two base consecutive mismatches do not work with the exception of position 1 and 2.
Zhang teaches that gene editing with CRISPR/Cas9 is enabled with certain combinations of double mismatches between the gRNA and the target DNA but require experimentation. Zhang recites, “First, as has been observed previously, it is clear that mismatches in the PAM-distal region impair enzymatic activity while affinity is unaffected. … Second, and perhaps most strikingly, mismatches within the PAM-proximal region of protospacer, while they decrease affinity, actually enhance enzymatic activity. Importantly, adjacent mismatches within this region decrease binding synergistically, while enhancing activity less than additively” (p. 12, para 1). Zhang further recites, “Mismatch activation is particularly prominent between positions 6 and 9 of the PAM-proximal region … Although not observed as consistently, this phenomenon was nonetheless most prominent in same region (positions ~5-10)” (p. 12, para 2).” Therefore, Zhang teaches that two mismatches in certain positions may allow for CRISPR/Cas9 gene editing, but the results are not consistent and require experimentation.
The Amount of Direction Provided by the Inventor and The Existence of Working Examples
The instant specification teaches methods utilizing CRIPSR/Cas9 comprising generating one or two mismatches between the target DNA and the guide RNA sequence in E. coli. The instant specification recites in Example 3-1 (p. 21, line 20 - p.22, line 5), “ when a guide RNA plasmid having a single mismatched sequence at base 505 of the galK gene was used, the editing efficiency was about 95%. On the other hand, when there was a single mismatch at base 503, the editing efficiency was reduced to 36%. In addition, when a guide RNA plasmid having a double mismatched sequence at bases 505 and 506 of the galK gene was used, the editing efficiency was about 86%. On the other hand, when there was a double mismatched sequence at bases 502 and 503 … the editing efficiency could not be calculated. The reason was that when there was the double mismatched sequence at base 502 and 503, the guide RNA did not recognize a galK target gene…”. This is a method with one or two mismatches between the target DNA and the guide RNA sequence.
In Example 3-2 (p. 23, lines 1-12), the specification teaches, “the editing efficiency was 84% when a single mismatch was present at base 579 … and 82% when a mismatched sequence was present at base 577”. The specification teaches that a double mismatch failed to edit the target gene: “the double mismatched sequences … did not recognize the galK target gene”. Example 3-2 concludes, “for the double mismatched sgRNA, no white colonies were observed…, which indicated that a Cas9/double mismatched sgRNA complex could not recognize a non-edited target”. This is also a method with one or two mismatches between the target DNA and the guide RNA sequence.
In Example 5 (p. 24, line 8 – p. 26, line 17), the specification teaches a method gene editing using a single mismatch: “four guide RNAs per target site were prepared to include different three mismatched sequences in nucleotide 12 of the guide RNA” (p. 24, lines 15-16). The example continues, “mutation introduction was successful in 42 of the 192 electroporations”. This is also a method with one or two mismatches between the target DNA and the guide RNA sequence with a uncertain chance of success.
Therefore, the instant specification provides support for two mismatches adjacent to the site of point mutation of the target gene, but the results are variable.
The Quantity of Experimentation Needed
The instant specification and prior art provide evidence against the use of two or more mismatches between the gRNA and the target DNA for DNA editing with CRISPR/Cas9. For a 20 nt length gRNA, one skilled in the art would have test over a thousand variants for two or more base pairs. It would not be predictable whether the variants would edit the target DNA or edit the target DNA more efficiently.
Conclusion
The prior art and instant specification provide support for one mismatch between the gRNA and the target DNA for DNA editing with CRISPR/Cas9. However for more than one mismatch, the prior art teaches against most combinations of multiple mismatches, and although a few may work, they require experimentation and are not predictable. The instant specification recites mixed success with two mismatches. It would require undue experimentation for one of ordinary skill in the art to use CRISPR/Cas9 with a gRNA with more than one mismatch with respect to the target DNA because they would need to test thousands of mismatches with no predictability of success.
Therefore, Claim 9 is rejected under 35 USC 112(a) under the enablement requirement.
Regarding Claim 10, Claim 10 recites the additional limitation of an antibiotic-resistant selection marker. This limitation does not overcome the enablement rejection with respect to two mismatches between the gRNA and target DNA sequence. Therefore, Claim 10 is rejected under 35 USC 112(a) under enablement.
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.
Claims 1-6 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Anderson, E., et. al., Journal of Biotechnology, Vol. 211, p. 56-65, October 10, 2015 and Walquist, M. and El-Gewely, M., Encylcopedia of Life Sciences, p. 1-14, January 22, 2018.
Regarding Claim 1, Anderson teaches (a) generating a gRNA with a complementary sequence to a target DNA sequence with one mismatched nucleotide: “First we synthesized crRNAs containing a single disruptive transversion mismatch to the DNA target” (p. 62, col. 1). Anderson teaches the crRNA was used with tracrRNA (p.57, 2.2-2.3). Anderson teaches that single mismatches allow for cleavage by CRISPR/Cas9 while two mismatches have low efficiency: “Their results demonstrated that, in general, single mismatches are well-tolerated at the 5’ end of the sgRNA” (p. 57, col. 1); “less than 5% of crRNAs with two mismatches to their target are effective in gene editing” (p. 56, Abstract).
Anderson does not teach (b) generating a donor nucleic acid molecule.
Walquist teaches (b) generating a donor nucleic acid molecule that complementarily binds to the target DNA and introduces one mismatched nucleotide into the target DNA to thereby cause a point mutation on the target DNA: “Site-directed mutations are most commonly designed in a synthetic oligonucleotide referred to as the mutagenic oligonucleotide. The mutagenic oligonucleotide sequence is identical to the parental DNA sequence with the exception of one or more nucleotides” (p. 2, col. 2).
It would have been obvious to one skilled in the art before the effective filing date to perform a combination of prior art elements with the teachings of Anderson and Walquist to create the method of Claim 1 wherein a total of two mismatches are generated between the target DNA and gRNA, in which one mismatch is generated by the introduction of a point mutation in the target DNA and one mismatch is generated through the construction of the gRNA. Anderson teaches generating the gRNA of (a), Walquist teaches the donor nucleic acid of (b), and each element performs the same function together as steps (a) and (b) are independent steps. One skilled in the art would have found the results predictable because Anderson successfully generated the sgRNA, and Walquist teaches multiple methods for generating the donor nucleic acid. One would be motivated do so because Anderson teaches two mismatches have a high likelihood of not being cleaved by CRISPR/Cas9, while one mismatch have a high likelihood of being cleaved by CRISPR/Cas9. Therefore, Claim 1 is obvious over Anderson and Walquist.
Regarding Claim 2, Anderson teaches a dual RNA comprising a crRNA and tracrRNA (p.57, 2.2-2.3). Therefore, Claim 2 is obvious over Anderson and Walquist.
Regarding Claim 3, Anderson teaches the target DNA comprises a complementary sequence to the crRNA and a PAM: “… direct Cas9 to the target location for cleavage based on sequence complementarity to the crRNA as well as proximity of the DNA target to a protospacer adjacent motif (PAM)” (p. 56, col. 2). Therefore, Claim 3 is obvious over Anderson and Walquist.
Regarding Claim 4, Anderson does not teach a single or double stranded donor nucleic acid molecule. Walquist teaches a single or double stranded donor nucleic acid molecule (p. 4, Thionucleotide selection-based method). Therefore, Claim 4 is obvious over Anderson and Walquist.
Regarding Claims 5 and 6, Claim 5 and 6 are rejected under 35 USC 112(b) and 35 USC 112(d). Since Claims 5 and 6 fails to further limit Claim 1, Claims 5 and 6 are obvious over Anderson and Walquist as described above for Claim 1.
Regarding Claim 8, the preamble of Claim 8 recites a method for increasing gene editing efficiency utilizing a CRISPR/Cas9 system which is interpreted to mean the method utilizing CRISPR/Cas9 to target cells without gene editing for cleavage. Claim 8 recites a method identical to Claim 1 with no additional limitations. Therefore, Claim 8 is obvious over Anderson and Walquist as described above for Claim 1.
Applicant’s Arguments – 35 USC § 102
Applicant argues “’Introducing a single point mutation in the target DNA’” is both the technical problem that the present invention seeks to solve and as essential technical feature of the present invention”. This argument is not persuasive because Chen teaches introducing a single point mutation into a target DNA as described above for Claim 1. The applicant discusses the use of CRIPSR/Cas9 for “negative selection”, but “negative selection” does not appear in the claims and is not part of a step of the claimed invention.
Applicant argues, “Zhang has a technical feature of reducing ‘off-target effects’…”. This argument is not persuasive as Claim 1 is rejected as being obvious over Chen and Walquist.
Applicant argues, “There is a significant difference in the purpose of introducing mismatches into the gRNA”. This argument is not persuasive because the intended purpose is not present in the claims. The method of Claim 1 is defined by steps (a) and (b), and the preamble recites the claim for use with a CRIPSR/Cas9 system. The purpose of the mismatches as argued and present in the specification, which is for negative selection, does not appear in the claimed invention and is not a step within the method of Claim 1.
Conclusion
No claims are allowed.
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 Krishna Nuggehalli Ravindra whose telephone number is (571)272-2758. The examiner can normally be reached M-Th, alternate F, 8a-5p 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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/K.N.R./Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636