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 .
DETAILED ACTION
Status of Application/Amendment/Claims
Applicant's response filed 02/25/2026 has been considered. Rejections and/or objections not reiterated from the previous office action mailed 12/01/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
With entry of the amendment filed on 02/25/2025, claims 1-29 are pending. Claims 1-15 are currently under examination. Claims 16-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Information Disclosure Statement
The submission of the Information Disclosure Statement on 02/25/2026 is in compliance with 37 CFR 1.97. The information disclosure statements have been considered by the examiner and signed copies have been placed in the file.
Compliance with Sequence Rules
The drawings are objected to because Figures 35, 45, 50 and 60 contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2).
If these sequences are listed in the current Sequence Listing, then the Figures can be amended to include the appropriate SEQ ID NOS. Corrected drawing sheets in compliance with 37 CFR 1.121(d). Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action.
Applicant can also submit a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
A complete response to this office action must correct the defects cited above regarding compliance with the sequence rules and a response to the action on the merits which follows.
The aforementioned instance of failure to comply is not intended as an exhaustive list of all such potential failures to comply in the instant application. Applicants are encouraged to thoroughly review the application to ensure that the entire application is in full compliance with all sequence rules. This requirement will not be held in abeyance.
Claim Rejections - 35 USC § 102 – new based on claim amendment
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 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) 5 and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et al. (US 20190010471) of record cited on 892 mailed 12/01/2025.
Regarding claim 14, Zhang et al. teach an engineered Streptococcus pyogenes Cas9 (SpCas9) nuclease comprising one or more mutations at positions corresponding to K848, R976, H982, K1003 and A1322 of (see 0055-0062, 2003, 0251). (Instantly claimed SEQ ID No. 2 is within Streptococcus pyogenes).
The limitation of “DNA binding cleft” of Claim 1 is defined in the instant specification as the amino acid residues of a Cas protein or variant, or amino acid residues in a region of a Cas protein or variant, which come into contact with DNA, either stably or transiently. "DNA binding cleft" may also be used to refer to residues that may act to stabilize these residues and/or regions.
Zhang et al. teach the mutations are in a region of a Cas protein or variant that which comes into contact with the DNA as illustrated in Figures 15A and three dimensional structure of 15B illustrated below. As shown, the mutations are in a region that is in contact with the DNA and thus meets the instant claim limitations.
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The figure above illustrates mutations that appear inside and outside of the DNA binding cleft (see also 0052-0062 and 0249 for description of Figure and SpCas9 mutations), based on the interpretation above and therefore meets the limitation of modified claim 14.
Regarding amended claim 5, claim 1 recites a single method step of “exposing the cell to an engineered Cas nuclease”. The engineered Cas nuclease taught by Zhang et al. meets the structural limitations of the claimed engineered Cas nuclease as described above. The recitation of limitations of claim 5 would be considered an inherent feature of the step of exposing the cell to an engineered Cas nuclease.
Thus Zhang et al. anticipates claims 5 and 14
Maintained Rejections
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 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.
The rejection of claim(s) 1-13 and 15 under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et al. (US 20190010471) as evidenced by Naka et al. ("Maintenance of genomic integrity in hematopoietic stem cells." International journal of hematology 93.4 (2011): 434-439) and Chauhan et al. ("Altered DNA repair pathway engagement by engineered CRISPR-Cas9 nucleases." Proceedings of the National Academy of Sciences 120.11 (2023)) is maintained for the reasons of record.
Applicant’s arguments are acknowledged but not found persuasive. Applicant argues that Zhang is directed to reducing off-target cleavage and edits, in contrast to the pending application, which is directed to reducing on-target byproduct indels and improving on-target precise edits (homology-directed repair (HDR) based precise editing). Thus, one of ordinary skill reading Zhang would gain no insight as to mutations for reducing on-target byproduct indels and improving on-target precise edits (homology-directed repair (HDR) based precise editing. The Action mistakenly treats these as equivalent because both can be measured via insertion-deletion edits, or "indels." In response and as explained in the rejection, claim 1 recites a single method step of “exposing the cell to an engineered Cas nuclease”. The engineered Cas nuclease taught by Zhang et al. meets the structural limitations of the claimed engineered Cas nuclease as described above. The recitation of limitations “wherein exposure to the engineered Cas nuclease decreases, inhibits, or prevents an indel-producing DNA repair pathway in the cell, and wherein exposure to the engineered Cas nuclease increases one or more precise editing repair pathways within the cell” would be considered an inherent feature of the step of exposing the cell to an engineered Cas nuclease. Furthermore the limitations in claims 3-5 and 13 describing specific editing pathways and the modification of these pathways would also be an inherent function flowing from the single step of exposing the cells to an engineered Cas nuclease” given these pathways are found in cells as evidenced by Chauhan et al.
Applicant’s argument that the O.A. mistakenly treats the teachings of Zhang and the instantly claimed invention as equivalent is incorrect. Examination of the claims does not need to consider the reason for Zhang et al. teaching editing of a HBB genome in Hematopoietic Stem Cells (HSCs) comprising exposing the cells to an sgRNA and an engineered SpCas9 comprising mutations (K848A), K1003A and R1060A) (see Example) and comparing this to a SpCas9 nuclease without mutations that were exposed to cells. Zhang et al. The engineered Cas nuclease taught by Zhang et al. meets the structural limitations of the claimed engineered Cas nuclease as described above and therefore the method of Zhang et al. anticipates the instantly claimed method.
Applicant further argues Zhang does not measure or provide any data on on-target by products. Zhang only describes that certain mutations lead to reduced off-target indels (R783, K810, R832, R859, K968, K1047, R1060) as shown in Figures 1, 2A, and 3. Critically, these same residues show no reduction in on-target byproduct indels. In response, the data on on-target by products is not a claim limitation that needed to be considered. As stated previously, because the engineered Cas nuclease taught by Zhang et al. meets the structural limitations of the claimed engineered Cas nuclease as described above and therefore the method of Zhang et al. anticipates the instantly claimed method.
Applicant concludes that Zhang does not directly or inherently predict, anticipate, or render obvious the pending claims. As stated previously, because the engineered Cas nuclease taught by Zhang et al. meets the structural limitations of the claimed engineered Cas nuclease as described above and therefore the method of Zhang et al. anticipates the instantly claimed method. The rejection is therefore maintained.
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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.
The rejection of claims 1-15 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph is maintained for reasons of record.
Applicant argues the specification provides a roadmap for practicing the technology. For example, the specification teaches that different Cas9 structures were known to produce different double strand break structures upon cutting of the DNA, citing Figure 8. See Par. [0232]. Furthermore, the specification teaches that double strand break structure is known to be able to influence DNA repair mechanisms. The specification accordingly teaches that alterations were therefore made to the binding cleft of SpCas9 to change the structure of the double-stranded breaks as a starting point. The specification further teaches that 14 mutations were made to basic or polar residues to change them to alanine. This argument does not provide enablement for methods of editing a genome in a cell comprising exposing a cell to a CRISPR-Cas system comprising any Cas nucleases having any mutation or any mutation at positions corresponds to one or more positions in claim 8 wherein the exposure decreases, inhibits or prevents an indel-producing DNA repair pathway in a cell or increase one or more any precise editing repair pathway within the cell as compared to a reference Cas nuclease without mutation or having different mutations.
As state previously, the patent and non-patent literature describes engineered SpCas9 nucleases comprising mutations was capable of editing a HBB genome in Hematopoietic Stem Cells (HSCs) (see Zhang et al. cited above in the 103 rejection (see 0055-0062, 2003 and 0434) and further teach editing of the VEGFA gene or the EXM1.3 using the CRISPR system comprising modified engineered SpCas9 nuclease wherein %Indel formation was affected (see Figures 2A and 2B), however a review of the prior art does not provide a correlation between exposing cells to a SpCas9 comprising mutations (as in claims 33 and 34 of Zhang et al.) and decreasing, inhibiting or preventing any indel-producing DNA pathway or increasing one more precise editing repair pathways as instantly claimed.
Applicant further argues the specification teaches in Example 3 that the R976A mutation produced the greatest change in repair pathway frequency and the largest drop in total editing activity, perhaps because it is located at one end of the nontarget cleft near where the substrate DNA strands separate. Therefore, the specification teaches that the R976 mutation might regulate repair pathway frequencies while also controlling total activity. The specification further taught that mutating residues near A976 to Arginine might rescue activity without reverting to changes to repair pathway frequence, so that six residues in the R976A-K1003A variant were mutated to produce a set of triple, quadruple, and quintuple mutants in Table 6 and Figure 16. Table 7 also provided a list of multi-mutant sequences for testing.
In response, describing several different mutations and illustrating a mutation with the greatest change in repair pathway frequency does not provide enablement for
methods of editing a genome in a cell comprising exposing a cell to a CRISPR-Cas system comprising any Cas or Cas9 nucleases having any mutation or any mutation at positions corresponding to one or more positions in claim 8 such that the exposure decreases, inhibits or prevents an indel-producing DNA repair pathway in a cell or increase one or more any precise editing repair pathway within the cell.
The standard of an enabling disclosure is not the ability to make and test if the invention works, or providing a detailed roadmap as argued by Applicant, but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant invention suggests exposing the cell to any Cas nuclease having any mutation or any of the claimed mutations wherein the exposure decreases, inhibits or prevents an indel-producing DNA repair pathway in a cell or increase one or more any precise editing repair pathway within the cell.
The prior art is undeveloped for the role engineered Cas nucleases comprising one or more mutations, from the broad genus of Case nucleases, plays in decreasing, inhibiting or preventing any indel-producing DNA pathway or increasing one more precise editing repair pathways. The specification does not provide sufficient guidance to enable the claimed invention and without further guidance, one of skill in the art would have to practice a substantia amount of trial and error experimentation to practice the instantly claimed invention. Thus the rejection is maintained.
Written Description
The rejection of claims 1-15 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 is maintained for the reasons of record.
Applicant’s arguments are acknowledged but not found persuasive. The claims are drawn to a genus of engineered Cas nucleases and DNA repair pathways with the function of editing a genome in a cell, decreasing or increasing or preventing an indel-producing DNA pathway and increasing one or more precise editing repair pathways with a cell. Applicant argues the specification describes efficient editing of a genome in a cell by exposing the cell to an engineered Cas nuclease, which inhibits an indel-producing pathways and increases a precise editing repair pathway in the cell... and the engineered Cas nuclease can comprise one or more mutations of an amino acid residue inside, outside, or a mixture of both inside and outside of the DNA binding cleft of the nuclease. In response, describing an single type of engineered Streptococcus (S. pyogenes) Cas9 nuclease with mutations at the claimed residues (claim 8 and Table 7) and describing the engineered Cas9 nucleases as having increased editing of the Homology-directed repair (HDR) pathway comprising mutations (Example 3) and further describing a quadruple mutant engineered Cas9 nuclease comprising mutations at positions S55, R976, K1003 and T1314 (vCas) as capable of suppressing NHEJ deletions and insertions and favoring repair pathways that use homologous sequences such as HDR and MMEJ (see 0245) does not provide a description of the entire genus claimed.
The specification and claims do not indicate what distinguishing characteristics of the Streptococcus (S. pyogenes) Cas9 nuclease with mutations described in the specification that are concisely shared by the members of the broad genus of Cas nucleases comprising any mutation and any editing repair pathway with a cell that would convey to one of skill in the art that this Cas9 nuclease exposed to any editing pathway represents the entire genus. A review of the specification shows that it provides no description or guidance that would allow one of skill to distinguish the functional species of the recited structural genus from the non-functional members without empirical determination.
As sated previously, the prior art of Koonin et al. ("Diversity, classification and evolution of CRISPR-Cas systems." Current opinion in microbiology 37 (2017): 67-78) teach there are numerous different Cas proteins from numerous different organisms (see Figure 1). Koonin et al. illustrates each has different structures based on the different class systems (see Figure 1 and Figure 3). The prior art of Ceccaldi et al. ("Repair pathway choices and consequences at the double-strand break." Trends in cell biology 26.1 (2016): 52-64)) describes different DNA repair pathways such as homologous recombination (HR) and classical nonhomologous end joining (C-NHEJ). In addition, alternative error-prone DSB repair pathways, namely alternative end joining (alt-EJ) and single-strand annealing (SSA) (see abstract page 52).
The written description requirement for a genus may be satisfied through sufficient description of a representative number of species by relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties or by functional characteristics coupled with a known or disclosed correlation between functional and structure. It is clear from the prior art that there are many different Cas9 molecules and repair pathways and Applicant has not described a representative number of species by relevant, identifying characteristics.
Applicant further argues the specification further describes that the engineered Cas nuclease can have the same or greater activity than a reference Cas nuclease without mutation. The engineered Cas nuclease can comprise an amino acid sequence selected from the group consisting of SEQ ID NOs: 3-13. In response, Applicant is arguing that the Streptococcus (S. pyogenes) Cas9 nuclease with mutations described in the specification is a functional characteristic that correlates to the entire genus of Cas proteins such that they would have possession of the entire genus. The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163.
Thus the specification and claims lack written description because it is clear that Applicant did not have possession of every Cas protein with any mutation or mutations as in claim 8 and did not have possession of Cas proteins had the function of decreasing, inhibiting or preventing an indel-producing DNA repair pathway or increased one more precise editing repair pathways.
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521,222 USPQ 369,372-372 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed, had possession of the entire scope of the claimed invention.
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).
706.07(a) Final Rejection, When Proper on Second Action [R-07.2015]
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Second or any subsequent actions on the merits shall be final, except where the examiner introduces a new ground of rejection that is neither necessitated by applicant’s amendment of the claims, nor based on information submitted in an information disclosure statement filed during the period set forth in 37 CFR 1.97(c) with the fee set forth in 37 CFR 1.17(p). Where information is submitted in an information disclosure statement during the period set forth in 37 CFR 1.97(c) with a fee, the examiner may use the information submitted, e.g., a printed publication or evidence of public use, and make the next Office action final whether or not the claims have been amended, provided that no other new ground of rejection which was not necessitated by amendment to the claims is introduced by the examiner. See MPEP § 609.04(b).
Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY CHONG at 571-272-3111. The examiner can normally be reached Monday thru Friday 9-5 pm.
If attempts to reach the examiner by telephone are unsuccessful please contact the SPE for 1636 Neil Hammell at 571-272-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KIMBERLY CHONG/Primary Examiner, Art Unit 1636