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 .
Status of Claims
Claim 12 is cancelled. Claims 1-11 and 13-19 are pending and under exam.
WITHDRAWN REJECTIONS AND OBJECTIONS
Claim Objections
Objections are withdrawn following correction of informal matters.
Claim Rejections - 35 USC § 112
Claims 2-5, and 12-13 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.
Claims 2 and 3 were rejected for reciting “cleavage efficiency” of at least about 90% or 95%.
This rejection is withdrawn following applicant’s amendments that the cleavage efficiency is determined by analysis of sequencing data. It is also acknowledged that [0100] of the specification taught “[a]nalysis of PCR amplicon sequencing data for cleavage efficiency determination was performed using CRISPresso online tool for the deep sequencing data and the ICE online tool (Synthego) for the Sanger sequencing data.” It is submitted that a person of ordinary skill in the art would be able to measure cleavage efficiency using the method disclosed in the specification.
Claim 5 recites “measuring expression of a transgene.” However, it is unclear how the transgene expression is measured.
This rejection is withdrawn. This rejection is withdrawn following Applicant’s arguments. It is noted that measurement of expressions of transgenes are routine in the art.
Claim 12 requires determining chromatin accessibility.
This rejection is withdrawn. This rejection is withdrawn following Applicant’s arguments. It is noted that chromatin accessibility is a routinely used term in the art.
The term “detectable” in claim 5 is a relative term which renders the claim indefinite.
The rejection is withdrawn following Applicant’s argument and amendments.
Claim Rejections - 35 USC § 102
Claims 1-3, and 5-6 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pellenz et al (hereinafter "Pellenz"; Hum Gene Ther. 2019 Jul; See PTO-892).
The rejection is withdrawn following claim amendments to indicate that the genomic safe harbor is identified by comparing the chromatin accessibility of the loci in the activated state of a T-cell 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 about 90% of the plurality of loci in both the resting and activated states of the cell. This limitation is not explicitly stated in Pellenz.
MAINTAINED REJECTIONS (ADAPTED FOR AMENDED CLAIMS)
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-4, and 11-20 are rejected under 35 U.S.C. 101 because they do not add significantly more to the judicial exception.
The claims have been analyzed for eligibility in accordance with their broadest reasonable interpretation.
Regarding claim 1: The claim is directed to a method of identifying a safe harbor locus in a genome.
The claim is directed to a method, which is a statutory category of invention (Step 1: YES).
The claim is then analyzed to determine whether it is directed to any judicial exception. The claim recites screening the genome for certain conditions (recited in claim1a-1f), and identifying the locus as a genomic safe harbor locus. This describes a correlation or relationship between the presence of naturally occurring patterns in a genome and its characteristic as a genomic safe harbor. This limitation sets forth a judicial exception, because this type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo). Additionally, as indicated, methods of prediction can be performed by mental steps or basic critical thinking, which are types of activities that have been found by the courts to represent abstract ideas (e.g., the mental comparison in Ambry Genetics, or the diagnosing an abnormal condition by performing clinical tests and thinking about the results in Grams). Thus, the claim recites at least one exception, which may be termed a law of nature, an abstract idea, or both. (Step 2A prong 1: YES). For purposes of this rejection, analysis will be focused on the law of nature judicial exception.
The claim is then analyzed to determine if additional elements integrates the judicial exception into a practical application. The claim recites no additional elements and is limited to predicting identifying or selecting the locus as a genomic safe harbor based on detection of the patterns recited in claim 1a-1f and steps of comparing accessibility in activated and rested state of a T-cell. (Step 2A prong 2: NO). Therefore, the claim is directed to a law of nature judicial exception.
The claim is analyzed to determine if it adds additional elements that amount to significantly more beyond generally linking the use of judicial exception to technological environment. The claim recites “identifying the locus as genomic safe harbor if” certain conditions are met. When recited at this high level of generality, there is no meaningful limitation, such as a particular or unconventional machine or a transformation of a particular article, in this step that distinguishes it from well-understood, routine, and conventional data gathering activity engaged in by scientists prior to applicant’s invention. Therefore, there are no additional elements that add significantly more to the judicial exception (Step 2B: NO).
The claim is patent ineligible.
Regarding claims 2-4: The measuring cleavage efficiency does not seek to add significantly more to the judicial exception of “identifying.” As such, the analysis for claims 2-4 are the same as for claim 1. The additional details in claims 2-4 do not change the analysis.
Regarding claim 11: The analysis for claim 11 is the same as for claim 1. The additional details in claim 11 do not change the analysis i.e. analyzing the locus comprises a pseudogene does not add significantly more to the judicial exception of “identifying.”
Regarding claim 13-20: The analysis for claims 13-20 is the same as for claim 1. The additional details in claims 12-20 do not change the analysis i.e. analyzing the locus comprises a pseudogene does not add significantly more to the judicial exception of “identifying.”
Response to claim amendments and arguments: Applicant contended that “claim 1 has been amended to specify "method for identifying a genomic safe harbor (GSH) and integrating a transgene" and "selecting a locus as a GSH for integrating the transgene". Applicant contends that the claims recite additional elements which integrate a practical application to the judicial exception under Step 2A, prong 2.” Applicant’s arguments have been fully considered but are not persuasive.
It is submitted that selection or identifying a naturally occurring phenomenon or property as such is not considered to add an inventive concept. As such it is still maintained that the claim fails the 32 U.S.C 101 analysis at Step 2A prong 2.
NEW REJECTIONS, NECESSITATED BY AMENDMENT
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.
Amended claim 1 recites a method of identifying a GSH and integrating a transgene into T-cell by performing methods (i)-(iii); and a selecting a locus as GSH by performing methods (iv)-(v). It is not clear what methods need to be performed for identifying GSH. Appropriate clarification is required. Claims 2-11 and 13-19 are rejected for their dependency on claim 1.
Claim 2 as currently worded recites:
2. The method of claim 1, further comprising (vi) delivering a gene editing system to the isolated cell and measuring cleavage efficiency of a gene editing system through the analysis of sequencing data and selecting a locus as a GSH if the cleavage efficiency of the gene editing system at the locus is at least about 90 %.
As emphasized above, the claim recites “a gene editing system” two times. The second iteration of “gene editing system” should be prefaced with “the.” Claim 3 is rejected for its 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).
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 about 90% of the plurality of loci in both the resting and activated states of the cell,” as required by the Applicant 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).
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.
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, 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).
Regarding claims 7-10: The teachings of Pellenz in view of Scott-Browne 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).
Regarding claim 11: The teachings of Pellenz in view of Scott-Browne 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).
Regarding claim 13: The teachings of Pellenz in view of Scott-Browne 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).
Regarding claim 14: 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 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).
Regarding claim 17: The teachings of Pellenz in view of Scott-Browne 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.
Conclusion
No claim is 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.
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/JAGAMYA NMN VIJAYARAGHAVAN/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633