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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/26/2026 has been entered.
Status of Claims
Claims 12 and 20 are cancelled. Claims 1-11 and 13-19 are pending and under exam.
WITHDRAWN REJECTIONS
Claim Rejections - 35 USC § 101
Claims 1-4, and 11-20 were rejected under 35 U.S.C. 101 because they do not add significantly more to the judicial exception.
The rejection is withdrawn following claim amendments. It is submitted that the step of integrating the transgene adds significantly more to the judicial exception.
Claim Rejections - 35 USC § 112
Claims 1-11, and 13-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth the subject matter which the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the applicant regards as the invention.
The rejection is withdrawn following claim amendments.
Claim Rejections - 35 USC § 103
Claims 1-6 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Pellenz et al (hereinafter "Pellenz"; Hum Gene Ther. 2019 Jul; See PTO-892 of 4/17/2025) in view of Scott-Browne JP et al (hereinafter “Scott-Browne;” Immunity. 2016 Dec 20; See PTO-892).
Claims 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over Pellenz et al (hereinafter "Pellenz"; Hum Gene Ther. 2019 Jul; See PTO-892 of 4/17/2025) in view of Scott-Browne JP et al (hereinafter “Scott-Browne;” Immunity. 2016 Dec 20; See PTO-892) and Rivière et al (hereinafter "Rivière;" Mol Ther. 2017 May 3; See PTO-892 of 4/17/2025).
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Pellenz et al (hereinafter "Pellenz"; Hum Gene Ther. 2019 Jul; See PTO-892 of 4/17/2025) in view of Scott-Browne JP et al (hereinafter “Scott-Browne;” Immunity. 2016 Dec 20; See PTO-892) and Yanez et al (hereinafter "Yanez;" Methods. 2016 May 15; See PTO-892 of 4/17/2025).
Claims 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Pellenz et al (hereinafter "Pellenz"; Hum Gene Ther. 2019 Jul; See PTO-892 of 4/17/2025) in view of Scott-Browne JP et al (hereinafter “Scott-Browne;” Immunity. 2016 Dec 20; See PTO-892) and Corces et al (hereinafter "Corces;" Nat Genet. 2016 Oct; See PTO-892 of 4/17/2025) as applied to claim 13, further in view of Zhao et al (hereinafter "Zhao;" Epigenetics Chromatin. 2019 May 3; See PTO-892 of 4/17/2025).
Claims 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Pellenz et al (hereinafter "Pellenz"; Hum Gene Ther. 2019 Jul; See PTO-892 of 4/17/2025) in view of Scott-Browne JP et al (hereinafter “Scott-Browne;” Immunity. 2016 Dec 20; See PTO-892) and Zhao et al (hereinafter "Zhao;" Epigenetics Chromatin. 2019 May 3; See PTO-892 of 4/17/2025).
The rejections are withdrawn following claim amendments and arguments.
NEW REJECTIONS
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 1-11 and 13-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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 1: The claim recites a step of integrating transgene, However, it is not clear from the wording of the claim if the transgene is inserted in the evaluated locus by performing steps (a)-(f). Claims 2-11 and 13-19 are rejected for their dependency.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 16 are rejected under 35 U.S.C. 103 as being unpatentable over Pellenz et al (hereinafter "Pellenz"; Hum Gene Ther. 2019 Jul; See PTO-892 of 4/17/2025) in view of Scott-Browne JP et al (hereinafter “Scott-Browne;” Immunity. 2016 Dec 20; See PTO-892) further in view of Liu et al (Genome Biol. 2019 Jul 26; hereinafter “Liu;” See PTO-892).
Regarding claim 1: Pellenz identified new sites for targeted transgene insertion that have the potential to serve as new human genomic ‘‘safe harbor’’ sites (SHS). (See Pellenz Abstract). Pellenz disclosed that “the nature of human SHS identified to date, together with a set of desirable general properties for any SHS, have defined the criteria used to assess the SHS potential of additional sites in the human genome.” (See Pellenz p. 815, col. 1, para 2). Pellenz disclosed that “These included plausible criteria from first principles, for example location outside of transcriptional units (claim 1(c)) and ultra-conserved regions (claim 1(d)), and 50–300 kb away from the 5’ ends of genes (claim 1(a)), cancer-related genes (claim 1(b)), and micro RNAs (claim 1(f)). This list was subsequently expanded to include additional, less well-defined criteria such as the exclusion of cell type or lineage-specific essential genes and regulatory RNAs (e.g., long non-coding RNAs) (claim 1(e)) and of cell type–specific, topologically defined nuclear domains (TADs) that have been associated with cancer genes..” (See Pellenz p. 815, col. 1, para 2, also Table 1).
It is noted that Pellenz taught the importance of structure accessibility as an important criteria for identifying genomic safe harbor. For example, Pellenz taught assessment of in vivo accessibility of new target sites “by determining their cleavage sensitivity and ability to be edited by different nuclease/repair template combinations.” (See Pellenz, p. 822, col. 2, para 2). Pellenz in fact taught identification of loci based on chromatin accessibility “The in vivo cleavage sensitivity of several potential SHS was subsequently assessed in 293T cells by co-expressing the mCreI homing endonuclease together with the TREX2 3′ to 5′ exonuclease, followed by site amplification and mCreI cleavage versus mock-transfected control cells. Three representative new sites were extensively analyzed in this way: SHS231, a unique chromosome 4 site that was the most highly scored for SHS potential; SHS229, a chromosome 2 site that was the sole newly identified site with perfect nucleotide sequence identity to a highly cleavage-sensitive mCreI site variant; and SHS253, the chromosome 2–specific member of the small family of six identical target-site sequences represented once each on six different chromosomes” (See Pellenz, p. 818, col. 1, para 2).
Pellenz did not teach or suggest “comparing the chromatin accessibility of the loci in the activated state to the chromatin accessibility of the loci in a resting state, and selecting a locus as a GSH for integrating the transgene, if the locus has higher chromatin accessibility than 90% of the plurality of loci in both the resting and activated states of the cell,” as required by the Applicants amendments.
Scott-Browne taught that the chromatin structure of T-cells is different in the rested state versus activated states. (See Scott-Browne Abstract). Scott-Browne mapped accessible regulatory elements by ATAC-seq in naive, effector, memory and exhausted CD8+ T cells from mice with acute or chronic LCMV infection [and] identified dynamic changes in chromatin accessibility in CD8+ T cells, with clusters of regions with shared accessibility profiles between different subsets.” (See Scott Browne p. 2, last para). Scott-Browne further pointed out that they “assessed chromatin accessibility changes during in vivo responses to acute viral infection by comparing naive, effector and memory CD8+ T cells. Of the 45,489 regions that were accessible in any of these subsets, more than 12,000 were differentially-accessible when comparing naive and effector T cells” (See Scott Browne p. 4, last para).
Liu taught that “CRISPR/Cas9 system is unable to edit all targetable genomic sites with full efficiency in vivo. We show that Cas9-mediated editing is more efficient in open chromatin regions than in closed chromatin regions” (See Liu Abstract). Liu also taught that “Cas9 editing in rice is more efficient in open chromatin regions than in closed chromatin regions. Pairwise comparisons of indel frequencies at pairs of sgRNA-targeted sites in open and closed chromatin regions, respectively.” (See Liu Fig. 2). As such Liu taught that chromatin accessibility is a parameter that affects genome editing efficiency, such that increased chromatin accessibility improves editing outcomes.
To ensure robust and durable transgene expression, it would have been obvious for a person of ordinary skill in the art to choose a site that remains accessible across the physiologically relevant states of T cells. The person would understand that if a locus is accessible in both states, it is more likely to function as a stable GSH for long-term expression.
It is noted that none of the references teach choice of a locus that has higher chromatin accessibility than about 90% of the plurality of loci in both the resting and activated states of the cell. However, Pellenz used mCreI cleavage as test of accessibility (See Pellenz, p. 817, col. 1, last para; supplementary table S1). Pellenz used the chromatin accessibility assay (by “co-expressing the mCreI homing endonuclease together with the TREX2 3’ to 5’ exonuclease, followed by site amplification and mCreI cleavage versus mock-transfected control cells.” – see Pellenz p. 818, col. 1, 2nd para) to arrive at three new sites: SHS231, SHS229 and SHS253 containing open chromatin. As such Pellenz taught that higher accessibility, the better for SHS for integration of a transgene. Further, Liu explicitly taught that accessibility directly affected editing efficiencies.
A person of ordinary skill in the art would understand that, among a set of candidate loci, selecting the locus with higher chromatin accessibility is a predictable and routine optimization to improve the probability of successful gene integration.
It would have been obvious to a person of ordinary skill in the art, guided by the teachings of Pellenz and Liu, to screen multiple candidate loci and preferentially choose those exhibiting higher accessibility such as 90%. As such this is a straightforward optimization to maximize editing efficiency and stable expression of an inserted transgene. Based on the disclosure of Pellenz it is submitted that determination of level of accessibility would be readily determinable by one having ordinary skill in the art by routine experimentation (e.g., mCreI cleavage, TREX2 enhancement, PCR quantification). Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05. Therefore, ranking candidate loci by accessibility and selecting the most accessible site constitutes an obvious optimization of the method taught by Pellenz.
Regarding claims 2-4: Pellenz disclosed integration of CRISPR/Cas9 in SHS231 locus. (See Pellenz, p. 819, col. 1, 1st para). Pellenz taught that “[t]he highest efficiency of homology-directed repair can in most instances be promoted by incorporating >200 bp of perfect DNA sequence identity between a SHS and donor repair template arms.” (See Pellenz p. 826, col. 1, last para). A person of ordinary skill in the art, armed with Pellenz, would have understood that gene-editing efficiency at a locus is a predictable function of accessibility and would have been motivated to select those loci expected to yield the highest editing efficiency for purposes of transgene insertion, expression stability, and reproducibility. The art also routinely optimized gene-editing system parameters (e.g., nuclease choice, guide design, donor template configuration, delivery method) to improve integration efficiency at any given locus. Therefore, once Pellenz teaches that accessibility correlates with editing efficiency and identifies a highly accessible locus such as SHS231 as preferred for genome engineering, it would have been an obvious matter of design choice and routine optimization to select a locus based on achieving a high editing efficiency threshold, including the claimed threshold of “greater than 90%” or “greater than 95%” as required by claim 5
Regarding claim 5-6: Pellenz disclosed expression of a puromycin transgene in the identified safe harbor locus, as detected by spectrophotometry or crystal violet staining. (See Pellenz Figure 3B-D)
Regarding claim 16: Pellenz did not specifically teach selecting a locus as a GSH if the locus has higher is located at a distance of up to about 250 kb from at least one gene that is activated and expressed in both resting and activated states of a cell as required by the claim. However, it is noted that Pellenz taught that a safe harbor locus should be > 50 kb away from any 5’ gene end (See Pellenz table 1).
Based on the disclosure of Pellenz it is submitted that determination of appropriate distance from a gene would be readily determinable by one having ordinary skill in the art by routine experimentation. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05. Pellenz taught that a SHS should be located outside of transcriptional units and ultra-conserved regions, and 50–300 kb away from the 5’ ends of genes. It would have been obvious for a skilled artisan to arrive at the claimed distance from a gene that is expressed in both resting and activated states of a cell.
Claims 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over Pellenz et al (hereinafter "Pellenz"; Hum Gene Ther. 2019 Jul; See PTO-892 of 4/17/2025) in view of Scott-Browne JP et al (hereinafter “Scott-Browne;” Immunity. 2016 Dec 20; See PTO-892) and Rivière et al (hereinafter "Rivière;" Mol Ther. 2017 May 3; See PTO-892 of 4/17/2025) further in view of Liu et al (Genome Biol. 2019 Jul 26; hereinafter “Liu;” See PTO-892).
Regarding claims 7-10: The teachings of Pellenz in view of Scott-Browne and Liu are set forth above. Pellenz does not explicitly teach expression of a T-cell receptor or the molecules recited by the claims for the required number of days in claim 10. It is noted that Pellenz taught expression of a puromycin gene (See Figure 2B-D) and GFP (See Figure 4A). A person of ordinary skill, in reading Pellenz, would have recognized the desirability of expression of chimeric receptors, which are useful in various therapeutics in place of GFP or puromycin taught by Pellenz. For example, Rivière taught that chimeric antigen receptors (CARs) are synthetic receptors that target T cells to a chosen antigen and reprogram T cell function, metabolism, and persistence” (See Rivière, Pg. 1117, col.1, 2nd para). Thus, it would have been obvious to a person of ordinary skill in the art to try to insert CARs and TCRs as particularly for providing therapeutic potential It has been held that "a person with ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense." See KSR International Co. v Teleflex, Inc. 82 USPQ2d 1385 at 1390. It is noted that Pellenz taught that the transgenes (for example GFP) inserted in a safe harbor locus can express stably for 45 days. (See Pellenz, p. 824, col.1, para 3). As such, the person would have expected the functional expression of the transgene of interest for at least 45 days as taught by Pellenz.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Pellenz et al (hereinafter "Pellenz"; Hum Gene Ther. 2019 Jul; See PTO-892 of 4/17/2025) in view of Scott-Browne JP et al (hereinafter “Scott-Browne;” Immunity. 2016 Dec 20; See PTO-892) and Yanez et al (hereinafter "Yanez;" Methods. 2016 May 15; See PTO-892 of 4/17/2025) further in view of Liu et al (Genome Biol. 2019 Jul 26; hereinafter “Liu;” See PTO-892).
Regarding claim 11: The teachings of Pellenz in view of Scott-Browne and Liu are stated above. Pellenz did not teach or suggest a pseudogene as a safe-harbor locus. However, Yanez taught that pseudogene loci may be used as safe-harbors for transgene integration. In particular, Yanez taught pointed out GULOP HPRT1 and CLYBL loci as potential sites. Yanez particularly pointed out that CLYBL locus conferred 10 times greater transgene expression. As such, a person of ordinary skill in the art would have been motivated to.
Thus, it would have been obvious to a person of ordinary skill in the art to try to insert a transgene into a pseudogene locus such as CLYBL locus for transgene expression. It has been held that "a person with ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense." See KSR International Co. v Teleflex, Inc. 82 USPQ2d 1385 at 1390.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Pellenz et al (hereinafter "Pellenz"; Hum Gene Ther. 2019 Jul; See PTO-892 of 4/17/2025) in view of Scott-Browne JP et al (hereinafter “Scott-Browne;” Immunity. 2016 Dec 20; See PTO-892) and Corces et al (hereinafter "Corces;" Nat Genet. 2016 Oct; See PTO-892 of 4/17/2025) further in view of Liu et al (Genome Biol. 2019 Jul 26; hereinafter “Liu;” See PTO-892).
Regarding claim 13: The teachings of Pellenz in view of Scott-Browne and Liu are stated above. Pellenz did not teach or suggest use of ATAC-seq for determining accessibility of a chromatin structure. However, Corces taught that the Assay for Transposase Accessible Chromatin using sequencing (ATAC-seq), as “a method capable of measuring chromatin accessibility” (See Corces, p. 2, last paragraph). It is noted that Pellenz taught that using nuclease digestion as a measure of accessibility (See Pellenz, p. 817, col. 1, last para). As such it would have been obvious for a person of ordinary skill in the art to have used the method taught by Corces in place of the method taught by Pellenz. It would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute one method (ATAC-seq peak) for accessing chromatin accessibility in place of the method taught by Pellenz. One of ordinary skill in the art would recognize this as simply substituting one method for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Claims 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Pellenz et al (hereinafter "Pellenz"; Hum Gene Ther. 2019 Jul; See PTO-892 of 4/17/2025) in view of Scott-Browne JP et al (hereinafter “Scott-Browne;” Immunity. 2016 Dec 20; See PTO-892) and Corces et al (hereinafter "Corces;" Nat Genet. 2016 Oct; See PTO-892 of 4/17/2025) as applied to claim 13, further in view of Zhao et al (hereinafter "Zhao;" Epigenetics Chromatin. 2019 May 3; See PTO-892 of 4/17/2025) further in view of Liu et al (Genome Biol. 2019 Jul 26; hereinafter “Liu;” See PTO-892).
Regarding claim 14: The teachings of Pellenz in view of Scott-Browne and Liu are stated above. Pellenz did not teach or suggest that a region should be a GSH if the locus is located at a distance of about 5kb from an ATAC-seq peak. It is noted again that Pellenz taught that structure accessibility was an important consideration in site-scoring criteria for a potential human SHS (Safe harbor site) (See Pellenz Table 1, p. 817, col. 1, paragraph 1). Zhao used ATAC-seq, to investigate dynamics of chromatin changes during mouse lens fibers and epithelium differentiation. Zhao taught that ATAC-seq peak is able to predict open (i.e. accessible) regions within 5kb of an ATAC-seq peak region. (See Zhao p. 2, col. 1, para 1; Figure 1f; p. 4, col. 2, para 2). A person of ordinary skill in the art would easily comprehend that based on the teachings of Pellenz, and in view of the teachings of Zhao, ATAC-seq peak about 5 kb from an open genomic region, and can be used to predict accessible chromatin regions, which in view of teachings of Pellenz could be used as safe harbor if the conditions in claim 1 are met. The person would also be motivated to use ATAC-seq peak to determine the accessible regions of the genome in view of teachings of Zhao.
Regarding claim 15: The teachings of Pellenz in view of Scott-Browne are stated above. Pellenz did not teach or suggest that a region should be a GSH if the ATAC-seq peak is present in both resting and activated states of a cell as required by the claim. It is noted that Pellenz taught that the GSH region should be in an open chromatin (See Pellenz Table 1; p. 817, col. 1, paragraph 2). Zhao taught that the existence of an ATAC-seq peak indicated the presence of an open chromatin (See Zhao, p. 11, para 1). As such one of ordinary skill in the art would have expected to locate a GSH if the ATAC-seq peak is present in both resting and activated states of a cell, given the teachings of Pellenz in view of the teachings of Zhao.
Claims 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Pellenz et al (hereinafter "Pellenz"; Hum Gene Ther. 2019 Jul; See PTO-892 of 4/17/2025) in view of Scott-Browne JP et al (hereinafter “Scott-Browne;” Immunity. 2016 Dec 20; See PTO-892) and Zhao et al (hereinafter "Zhao;" Epigenetics Chromatin. 2019 May 3; See PTO-892 of 4/17/2025) further in view of Liu et al (Genome Biol. 2019 Jul 26; hereinafter “Liu;” See PTO-892).
Regarding claim 17: The teachings of Pellenz in view of Scott-Browne and Liu are set forth above. It is noted again that Pellenz taught that structure accessibility was an important consideration in site-scoring criteria for a potential human SHS (Safe harbor site) (See Pellenz Table 1, p. 817, col. 1, paragraph 1). Scott-Browne taught that chromatin structure in rested and activated T-cells are different. Pellenz did not specifically teach ATAC peaks on both sides of a locus. Zhao taught that ATAC-seq peak on both sides of a locus are indicative of open chromatin. (See Zhao Figure 7 a, b)
Regarding claims 18: The teachings of Pellenz in view of Scott-Browne are set forth above. Pellenz did not specifically teach selecting a locus as a GSH if the locus has higher is located at a distance of up to about 250 kb from at least one gene that is activated and expressed in both resting and activated states of a cell as required by the claim. However, it is noted that Pellenz taught that a safe harbor locus should be > 50 kb away from any 5’ gene end (See Pellenz table 1).
Based on the disclosure of Pellenz it is submitted that determination of appropriate distance from a gene for a locus to be characterized as safe harbor would be readily determinable by one having ordinary skill in the art by routine experimentation. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05. Pellenz taught that a SHS should be located outside of transcriptional units and ultra-conserved regions, and 50–300 kb away from the 5’ ends of genes. It would have been obvious for a skilled artisan to arrive at the claimed distance from a gene that is expressed in both resting and activated states of a cell.
Regarding claim 19: The teachings of Pellenz are stated above. Pellenz did not teach or suggest that a region should be a GSH if the ATAC-seq peak is present in both resting and activated states of a cell as required by the claim. It is noted that Pellenz taught that the GSH region should be in an open chromatin (See Pellenz Table 1; p. 817, col. 1, paragraph 2). Zhao taught that the existence of an ATAC-seq peak indicated the presence of an open chromatin (See Zhao, p. 11, para 1). As such one of ordinary skill in the art would have expected to locate a GSH if the ATAC-seq peak is present in both resting and activated states of a cell, given the teachings of Pellenz in view of the teachings of Zhao.
Response to Arguments: Applicants argued that Examiner’s reasoning of routine optimization of the claim limitation directed to preferential choosing of loci exhibiting higher accessibility such as 90% accessibility amounts to impermissible hindsight/speculation. Applicants arguments are not persuasive. Scott-Browne taught that chromatin accessibility is not static, but varies across T-cell differentiation states. A person of ordinary skill in the art would reasonably understand that such variability introduces instability in gene expression or integration outcomes when selecting genomic loci.
In view of Liu’s teaching that higher chromatin accessibility improves genome editing efficiency, it would have been obvious to select loci that remain accessible across relevant physiological states to ensure consistent transgene expression. Accordingly, the combination suggests selecting loci with favorable accessibility characteristics across multiple cellular states. It is also pointed out that chromatin accessibility is measurable, quantifiable, and routinely assessed using well-known assays such as ATAC-seq or nuclease sensitivity. Optimization of such known measurable parameters including selection of highly accessible loci is considered routine experimentation. Neither has the Applicant provided evidence of any unexpected results, criticality or improved performance associated with the claimed greater than 90% chromatin accessibility threshold in either resting or activated T cell states. In the absence of such evidence, the claimed threshold represents an unpatentable optimizable result-effective variable, namely chromatin accessibility, which the prior art establishes as influencing genome editing efficiency.
Conclusion
No claim is allowed.
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/JAGAMYA NMN VIJAYARAGHAVAN/ Examiner, Art Unit 1633
/EVELYN Y PYLA/ Primary Examiner, Art Unit 1633
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