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 .
Status of Claims
Claims 1-20 are pending.
Claims 1-20 are rejected.
Claims 2, 7, 9, 14, 16, and 20 are objected to.
Priority
Applicant’s claim for the benefit of a prior-filed application, Nonprovisional App. No. 16/903,324 filed 16 June 2020 and Provisional App. No. 63/007,266 filed 08 April 2020, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Nonprovisional App. No. 16/903,324 filed 16 June 2020 and Provisional App. No. 63/007,266 filed 08 April 2020, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The disclosures of App. No. ‘324 and ‘266 do not provide support for at least “parsing..to determine putative attributes of the target sequence associated with putative transcription factor (TF) binding sites”, “identifying the putative TF binding sites…”, and “parsing the putative TF binding sites to determine one or more candidate TF binding sites…”.
Accordingly, the effective filing date of the claimed invention is 21 April 2022.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 21 April 2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the list of cited references was considered in full by the examiner.
Drawings
The drawings filed 21 April 2022 are objected to because:
Figures 1-15 fail to comply with 37 1.84(u)(1), which states view numbers must be preceded by the abbreviation "FIG.;
the drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they do not include the following reference sign(s) mentioned in the description: #103 in para. [0047], [0067], [0078], [0080] (it appears #103 should be corrected to be #130 to correspond to the “Candidate Cassette Design Engine 130” in FIG. 1);
the legends in the bottom four plots of Figure 9 are not legible;
FIG. 10 is objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: #1000
Corrected drawing sheets in compliance with 37 CFR 1.121(d) and/or or amendment to the specification to add the reference character(s) are required in reply to the Office action to avoid abandonment of the application. 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. The objection to the drawings will not be held in abeyance.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because:
The abstract includes phrases which can be implied, including “The presence disclosure is drawn to…” in line 1.
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claims 2, 7, 9, 14, 16, and 20 are objected to because of the following informalities:
Claims 2, 7, 9, 14, 16, and 20 recite “…are determined based by mapping..”, which is grammatically incorrect and should read “are determined based on mapping…”.
Appropriate correction is required.
Claim Interpretation
Claims 2-3, 7, 9-10, 14, 16, and 20, recite “historical sequences”. In light of Applicant’s specification at para. [0151], which discusses the historical sequences include genomic sequences that have been analyzed or annotated for their attributes and are included in various databases such as NCBI nucleotide data base, NCBI genome database, UniProt, etc. the term is interpreted to refer to any sequence that has been previously analyzed/characterized.
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.
Claims 3, 9-14, and 16-20 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claims 3 and 10 are indefinite for recitation of “TF protein secondary sequence, TF protein tertiary sequence, TF protein quaternary sequence”. While “TF protein primary sequence” in claims 3 and 10 is understood to the amino acid sequence of the protein, the metes and bounds of a secondary, tertiary, and quaternary sequence of a protein are not clear. It’s not clear if Applicant intends for this to refer to secondary, tertiary, and quaternary structure of a protein (rather than a sequence), or if the secondary, tertiary, and quaternary sequence actually refers to a sequence of a protein. If the latter, it is not clear what sequences of a protein would fall within the metes and bounds of a “secondary sequence”, “tertiary sequence”, or “quaternary sequence”. For purpose of examination, these terms will be interpreted to refer to the structure of a protein.
Claims 3 and 10 are indefinite for recitation of “DNA/chromatin accessibility”. It is unclear if the historical attribute of “DNA/chromatin accessibility” is intended to mean DNA accessibility (e.g. a TF inhibitor blocking DNA) or chromatin accessibility (e.g. DNA packing/organization), or alternatively is intended to mean to just mean chromatin accessibility. Clarification is requested. The term will be interpreted to mean DNA or chromatin accessibility.
Claims 9-14 are indefinite for recitation of “The method of claim 8…”. There is insufficient antecedent basis for this limitation in the claim because claim 8 recites “A non-transitory computer-readable medium comprising instructions…”, but claim 8 is not a method claim. For purpose of examination, claims 9-14 will be interpreted to mean “The non-transitory computer-readable medium of claim 8…”.
Claims 16-20 are indefinite for recitation of “The method of claim 15”. There is insufficient antecedent basis for this limitation in the claim because claim 15 recites “A processing system comprising…”, but claim 15 is not a method. For purpose of examination, claims 16-20 will be interpreted to mean “The system of claim 15…”.
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 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
The Supreme Court has established a two-step framework for this analysis, wherein a claim does not satisfy § 101 if (1) it is “directed to” a patent-ineligible concept, i.e., a law of nature, natural phenomenon, or abstract idea, and (2), if so, the particular elements of the claim, considered “both individually and as an ordered combination,” do not add enough to “transform the nature of the claim into a patent-eligible application.” Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (quoting Alice, 134 S. Ct. at 2355). Applicant is also directed to MPEP 2106.
Step 1: The instantly claimed invention (claims 1, 8, and 15 being representative) is directed to a method, product, and system. Therefore, the instantly claimed invention falls into one of the four statutory categories. [Step 1: YES]
Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
Step 2A, Prong 1: Under the MPEP § 2106.04, the Step 2A (Prong 1) analysis requires determining whether a claim recites an abstract idea, law of nature, or natural phenomenon.
Claims 1, 8, and 15 recite the following steps which fall under the mental processes groupings of abstract ideas:
parsing a target sequence to determine putative attributes of the target sequence associated with putative transcription factor (TF) binding sites;
identifying the putative TF binding sites based on the putative attributes; parsing the putative TF binding sites to determine one or more candidate TF binding sites optimal for editing;
parsing the design library specification to generate proposed modifications to the one or more candidate TF binding sites that would effect the one or more intended attributes of the edited target sequence;
generating an edit specification list comprising the proposed modifications to the one or more candidate TF binding sites; and
assembling a library of candidate editing cassette designs, wherein each candidate editing cassette design comprises at least one of the proposed modifications to effect the one or more intended attributes of the edited target sequence.
The identified claim limitations falls into the group of abstract ideas of mental processes, for the following reasons. In this case, parsing a target sequence to determine putative attributes of the sequence encompasses mentally analyzing a nucleotide sequence and comparing the sequence to historical sequences to infer putative attributes based on respective historical attributes, as discussed in Applicant’s specification at para. [0162]). Identifying putative TF binding sites based on the putative attributes encompasses analyzing the putative attributes of the target sequence to determine if the attributes correspond to a TF binding site, which can b practically performed in the mind. Parsing the design library specification to propose modifications to the one or more candidate TF binding sites can be practically performed in the mind by reading a design library specification and identifying a modification that yields an intended attribute. Generating an edit specification list comprising the proposed modifications amounts to collecting and organizing the proposed modifications identified in the previous step, which can be practically performed in the mind aided by pen and paper. Last, assembling a library of candidate editing cassette designs, each design comprising at least one of the proposed modifications similarly can be practically performed in the mind aided by pen and paper by organizing information related to a candidate editing cassette design (e.g. guide RNA sequence, repair template sequence, etc.) and writing components of each design in a list. Overall, the claims are analogous to a claim to "collecting information, analyzing it, and displaying certain results of the collection and analysis," where the data analysis steps are recited at a high level of generality such that they could practically be performed in the human mind, Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016). Other than reciting these steps are performed by a processor in claims 8 and 15, nothing in the claims precludes the steps from being practically performed in the mind.
Dependent claims XX further recite an abstract idea and/or further limit the abstract idea of claims 1, 8, and 15.
Dependent claims 2-3, 9-10, and 16 further limit the mental process of determining putative attributes to comprise mapping (comparing) sequence data. Dependent claims 4, 11, and 18 further limit the mental process of determining the putative attributes or putative TF binding sites to be performed by machine learning (e.g. linear regression), which encompasses inputting numerical values for attributes into a model to determine a probability of a portion of the target sequence being a TF binding site. Therefore, claims 4, 11, and 17 also recite a mathematical concept, in light of Applicant’s specification at para. [0064] which discloses the machine learning may be a linear regression model. Dependent claims 5, 12, and 18 further limit the mental process of determining one or more candidate TF binding sites. Dependent claims 6, 13, and 19 further limit the mental process of parsing the design library to identify modifications that would affect a desired phenotypic effect or a desired gene expression effect. Dependent claims 7, 14, and 20 further limit the generating of proposed modifications by mapping sequence data (i.e. data comparisons). Therefore, claims 1-20 recite an abstract idea. [Step 2A, Prong 1: YES]
Step 2A: Prong 2: Under the MPEP § 2106.04, the Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. This judicial exception is not integrated into a practical application for the following reasons.
Dependent claims 2-7, 9-14, and 16-20 do not recite any elements in addition to the judicial exception.
The additional elements of claims1, 8, and 15 include:
receiving a design library specification comprising one or more intended attributes of an edited target sequence (claims 1, 8, and 15);
a non-transitory computer-readable medium (claim 8); and
a memory and a processor (claim 15).
A memory, processor, and receiving data are generic computer components and/or functions. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See MPEP 2106.05(f).
Further regarding receiving a design library specification, the limitation only serves to gather necessary data for use by the abstract idea to generate proposed modifications, which amounts to insignificant extra-solution activity and does not integrate the judicial exception into a practical application. See MPEP 2106.05(g).
Therefore, the additionally recited elements merely invoke computers as a tool and amount to insignificant extra-solution activity and, as such, the claims as a whole do no integrate the abstract idea into practical application. Thus, claims 1-20 are directed to an abstract idea. [Step 2A, Prong 2: NO]
Step 2B: In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP § 2106.05.
The claims do not include any additional steps appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception for the following reasons.
Dependent claims 2-7, 9-14, and 16-20 do not recite any elements in addition to the judicial exception.
The additional elements of claims1, 8, and 15 include:
receiving a design library specification comprising one or more intended attributes of an edited target sequence (claims 1, 8, and 15);
a non-transitory computer-readable medium (claim 8); and
a memory and a processor (claim 15).
A memory, processor, and receiving data are conventional computer components and/or functions. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not provide significantly more. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
Therefore, taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself. [Step 2B: NO]
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to an abstract idea without significantly more. For additional guidance, applicant is directed generally to applicant is directed generally to the MPEP § 2106.
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.
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 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Halweg-Edwards (2021) in view of Meysman (2011).
Cited references:
Halweg-Edwards et al., WO2021207541 A1; and
Meysman et al., Use of structural DNA properties for the prediction of transcription-factor binding sites in Escherichia coli, 2011, 39(2), pg. 1-11.
Regarding claims 1, 8, and 15, Halweg-Edwards discloses a method for designing gene editing cassettes, a non-transitory computer-readable medium with executable instructions for carrying out the method, and a system comprising a memory and processor configured to execute the method (Abstract; [0009]-[0010]), wherein the method comprises the following steps:
Halweg-Edwards discloses selecting a target sequence as the portion of the genome to be edited ([0047]-[0050]). Halweg-Edwards discloses the target sequence can be a transcription factor binding site ([00107]).
Halweg-Edwards discloses receiving an input design library specification comprising a set of candidate cassette designs (i.e. a design library specification) for each unique edit specification of edit specifications obtained from a customer or user ([0039]; [0041]; Figure 1), wherein each edit specification comprises attributes/features of the edit sequences, comprising TFBSs as discussed above, requested by the user (i.e. the specification comprising one or more intended attributes of an edited target sequence) ([0044]; [0051], e.g. annotation object of target sequence includes biological activity of annotated feature).
Halweg-Edwards discloses parsing the design library specification to generate a top ranked candidate design based on the expected biological activity, such as formation of proteins, of the edited sequence (i.e. an intended attribute of the edited sequence) ([0039]; [0056], e.g. biological activity of candidate cassette design [0058]-[0060]; [0107]). Each selected candidate design comprises an edit specification ([0041]), identified as having the expected biological activity, such that each selected design is considered a proposed modification of the target sequence/TFBS that effects the intended attribute(s). Halweg-Edwards discloses that some received edit specifications result in no cassette designs ([0046]), demonstrating the design library specification is parsed and only a subset of the received edit specifications may be proposed.
Halweg-Edwards discloses generating a candidate design library of selected design candidates that includes an edit specification of the selected designs (i.e. an edit specification list comprising the proposed modifications to the target sequence/TFBS) ([0041]; [0066]).
Halweg-Edwards assembles the candidate design library including the edit specification of the selected designs ([0066]).
Regarding claims 6, 13, and 19, Halweg-Edwards further discloses the intended attributes may include reconstructing variants to represent a particular disease state (i.e. a desired phenotypic effect) or changing the gene expression regulation for a particular gene or sets of genes (i.e. a desired gene expression effect achieved by editing) ([00107]).
Regarding claims 7, 14, and 20, Halweg-Edwards discloses the parsing the design library specification to generate a top ranked candidate design based on the expected biological activity of the edited sequence (i.e. generating the proposed modifications) ([0039]; [0058]-[0060]; [0107]), comprises using alignment-based metrics from multiple sequence alignment of the target sequence and structured RNA regulatory elements (i.e. historical sequences) to conserve secondary structure ([0055]; [0078[).
Halweg-Edwards does not disclose the following limitations:
Regarding claims 1, 8, and 15, Halweg-Edwards does not disclose the process of identifying the one or more candidate TF binding sites, including : parsing the target sequence to determine putative attributes of the target sequence associated with putative transcription factor (TF) binding sites; identifying the putative TF binding sites based on the putative attributes; and parsing the putative TF binding sites to determine one or more candidate TF binding sites optimal for editing.
Regarding claims 2-3, 9-10, and 16, Halweg-Edwards further does not disclose the putative attributes are determined by mapping sequence data of the target sequence to a historical sequence(s), wherein the historical sequence(s) comprises one or more of: DNA secondary structure, DNA tertiary structure.
Regarding claims 4, 11, and 17, Halweg-Edwards further does not disclose the putative TF binding sites are determined using machine learning.
Regarding claims 5, 12, and 18, Halweg-Edwards further does not disclose the one or more candidate TF binding sites are determined based on positions of the putative TF binding sites.
However, regarding claims 1-4, 9-11, and 15-18, Meysman discloses a method for predicting transcription-factor binding sites (TFBS) (Abstract), which comprises parsing a target sequence to determine attributes of TFBS, including a sequence and structural properties (Figure 1; pg. 2, col. 1, para. 3 to col.2 , para. 2 and pg. 2, col. 3, para. 3 to pg. 3, col. 1, para. 1), as recited in claims 1, 8, and 15. Meysman discloses determining the putative attributes comprises mapping the sequence of the target sequence to structural scales, including B-DNA twist and propellar twist (i.e. DNA secondary structure) determined from experimental data such as x-ray crystallography and modeling of DNA structure (i.e. historical attribute data) (pg. 2, col. 1, para. 3-4; Table 1), as recited in claims 2-3, 9-10, and 16.
Meysman discloses predicting TFBSs (i.e. putative TF binding sites) based on inputting the determined attributes into a trained machine learning model (i.e. wherein the putative TF binding sites are determined using machine learning) (Figure 1; pg. 2, col. 2, para. 2, e.g. inputs include plain sequence information and structural profiles; pg. 6, col. 1, para. 2; pg. 3, col. 1, para. 3 and col. 2, para. 2; pg. 4, col. 2, para. 1, e.g. a supervised classifier), as recited in independent claims 1, 8, and 15 and dependent claims 4, 11, and 17.
Meysman further discloses identifying the highest ranked TFBS predictions from the set of TFBS predictions and validating the highest ranked TFBS (i.e. parsing the putative TFBSs to identify one or more candidate TFBSs) (pg. 6, col. 2, para. 2), as recited in claims 1, 8, and 15. Meysman discloses the ranking is performed by evaluating whether a co-regulated gene set is enriched in high-scoring binding sites predicted by the model (pg. 3, col. 2, para. 3 to pg. 4, col. 1 para. 1), demonstrating the one or more candidate TFBSs are determined based on the positions of the putative TFBs being within the genes, as recited in claims 5, 12, and 18.
Meysman further discloses the method allows for the prediction of novel binding sites that were validated experimentally, and results in improved classification of transcription factor binding sites that can be used for large scale screening of TF binding sites (Abstract; pg. 2, col. 1, para. 2; pg. 8, col. 1, para. 2-3 and col. 2, para. 3).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the method of Halweg-Edwards to have determined the one or more candidate TFBSs according to the method of Meysman discussed above, thus arriving at the claimed invention. One of ordinary skill in the art would have been motivated to combine the methods of Halweg-Edwards and Meysman, in order to accurately predict novel TFBSs (Meysman: Abstract, pg. 8, col. 1, para. 1-2), thus identifying gene editing targets for changing the expression regulation for a gene or set of genes, as shown by Halweg-Edwards ([00107]). This modification would have had a reasonable expectation of success given the gene editing method of TFBSs of Halweg-Edwards can be applied to a binding site identified by Meysman.
Therefore, the invention is prima facie obvious.
Examiner Comment:
The prior art reference Halweg-Edwards was published within one year of the effective filing date of the claimed invention, and shared inventors in common with the instant Application. However, it is not readily apparent that the publication is an inventor-originated disclosure due to the presence of additional authors in Halweg-Edwards. Therefore, the prior art reference is currently prior art under AIA 35 U.S.C. 102(a)(1). Applicant is directed to MPEP 2153.01 for showing that a grace period inventor-originated public disclosure is not prior art under AIA 35 U.S.C. 102(a)(1) because the AIA 35 U.S.C. 102(b)(1)(A) exception applies.
In in the interest of compact prosecution, an alternative 103 rejection over Zamft in view of Meysman is provide below.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Zamft (2021) in view of Meysman (2011).
Cited references:
Zamft et al., US 2022/0301658 A1, effectively filed 19 March 2021; and
Meysman et al., Use of structural DNA properties for the prediction of transcription-factor binding sites in Escherichia coli, 2011, 39(2), pg. 1-11.
Regarding claims 1, 8, and 15, Zamft discloses a method for recommending genome edits conductive to a desired phenotype, a non-transitory computer-readable medium for executing the method, and a system comprising a memory and processor configured to carry out the method (Abstract; [0012]-[0013]), wherein the method comprises the following steps:
Zamft discloses receiving a set of candidate gene targets (i.e. a target sequence), from which an ideal gene expression profile is generated from (FIG. 8; [0077]). Zamft further discloses the edits may be made to a binding site of a transcription factor to module the effect of expression on a target gene ([0073]), demonstrating the candidate genes comprises TF binding sites.
Zamft discloses receiving a desired phenotype and ideal gene expression profiles for the desired phenotype corresponding to an edited target sequence (i.e. a design library specification comprising intended attributes of an edited target sequence) ([0007];[0053]; [0058]; FIG. 1).
Zamft discloses analyzing the ideal gene expression profiles (i.e. the design library specification) to make recommended gene edits for upregulating or downregulating a particular gene to achieve an ideal gene expression for the given phenotype (i.e. proposed modifications that would effect the intended attributes of the edited sequence) ([0011]; [0059] FIG. 1; FIG. 7, e.g. ).
Zamft discloses generating a list comprising the proposed modifications to the particular gene ([0065]; [0072], e.g. recommendation module determines where to make edits that will modulate the gene expression; FIG. 6, e.g. see “Suggestions: list”; FIG. 7, e.g. gene edit recommendation 775).
Zamft further discloses generating DNA sequences, including synthetic guide RNAs (gRNAs) (i.e. a library of candidate editing cassette designs) from information from output generated from the gene edit model and manual design from experts and facilitates the recommended edits (i.e. comprising the proposed modifications to effect the intended attributes ([0068]; [0070]; FIG. 7, e.g. library design system)
Regarding claims 6, 13, and 19, Zamft further discloses the intended attributes include a desired gene expression achieved by editing (FIG. 1; [0070], e.g. ideal gene expression profiles).
Regarding claims 7, 14, and 20, Zamft further discloses the recommended gene edits are determined by mapping input expression data (i.e. sequence data of the target sequence, consistent with instant claim 3 stating the sequence data can be expression data) to corresponding genes in a hidden layer of an neural network trained on gene expression profiles of phenotype ground truths (i.e. sequence data of historical sequences) ([0041]) [0083]-[0084]; FIG. 2A). Thus the neural network maps, or correlates, the input gene expression data to expression data of historical sequences is interpreted to read on the claims, in light of Applicant’s specification at para. [0172]) which states the proposed modifications are determined based on mappings, or correlations, between the target and historical sequence data ([0172]), supporting the interpretation of mapping to be synonymous with correlating.
Zamft does not disclose the following limitations:
Regarding claims 1, 8, and 15, Zamft does not disclose the process of identifying the one or more candidate TF binding sites, including : parsing the target sequence to determine putative attributes of the target sequence associated with putative transcription factor (TF) binding sites; identifying the putative TF binding sites based on the putative attributes; and parsing the putative TF binding sites to determine one or more candidate TF binding sites optimal for editing.
Regarding claims 2-3, 9-10, and 16, Zamft further does not disclose the putative attributes are determined by mapping sequence data of the target sequence to a historical sequence(s), wherein the historical sequence(s) comprises one or more of: DNA secondary structure, DNA tertiary structure.
Regarding claims 4, 11, and 17, Zamft further does not disclose the putative TF binding sites are determined using machine learning.
Regarding claims 5, 12, and 18, Zamft further does not disclose the one or more candidate TF binding sites are determined based on positions of the putative TF binding sites.
However, regarding claims 1-4, 9-11, and 15-18, Meysman discloses a method for predicting transcription-factor binding sites (TFBS) (Abstract), which comprises parsing a target sequence to determine attributes of TFBS, including a sequence and structural properties (Figure 1; pg. 2, col. 1, para. 3 to col.2 , para. 2 and pg. 2, col. 3, para. 3 to pg. 3, col. 1, para. 1), as recited in claims 1, 8, and 15. Meysman discloses determining the putative attributes comprises mapping the sequence of the target sequence to structural scales, including B-DNA twist and propellar twist (i.e. DNA secondary structure) determined from experimental data such as x-ray crystallography and modeling of DNA structure (i.e. historical attribute data) (pg. 2, col. 1, para. 3-4; Table 1), as recited in claims 2-3, 9-10, and 16.
Meysman discloses predicting TFBSs (i.e. putative TF binding sites) based on inputting the determined attributes into a trained machine learning model (i.e. wherein the putative TF binding sites are determined using machine learning) (Figure 1; pg. 2, col. 2, para. 2, e.g. inputs include plain sequence information and structural profiles; pg. 6, col. 1, para. 2; pg. 3, col. 1, para. 3 and col. 2, para. 2; pg. 4, col. 2, para. 1, e.g. a supervised classifier), as recited in independent claims 1, 8, and 15 and dependent claims 4, 11, and 17.
Meysman further discloses identifying the highest ranked TFBS predictions from the set of TFBS predictions and validating the highest ranked TFBS (i.e. parsing the putative TFBSs to identify one or more candidate TFBSs) (pg. 6, col. 2, para. 2), as recited in claims 1, 8, and 15. Meysman discloses the ranking is performed by evaluating whether a co-regulated gene set is enriched in high-scoring binding sites predicted by the model (pg. 3, col. 2, para. 3 to pg. 4, col. 1 para. 1), demonstrating the one or more candidate TFBSs are determined based on the positions of the putative TFBs being within the genes, as recited in claims 5, 12, and 18.
Meysman further discloses the method allows for the prediction of novel binding sites that were validated experimentally, and results in improved classification of transcription factor binding sites that can be used for large scale screening of TF binding sites (Abstract; pg. 2, col. 1, para. 2; pg. 8, col. 1, para. 2-3 and col. 2, para. 3).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the method of Zamft to have determined the one or more candidate TFBSs according to the method of Meysman discussed above, thus arriving at the claimed invention. One of ordinary skill in the art would have been motivated to combine the methods of Zamft and Meysman, in order to accurately predict novel TFBSs (Meysman: Abstract, pg. 8, col. 1, para. 1-2), thus identifying gene editing targets for changing the expression regulation for a gene, as shown by Zamft ([0073]). This modification would have had a reasonable expectation of success given the gene editing method on TFBs of Zamft can be applied to a TF binding site identified by Meysman.
Therefore, the invention is prima facie obvious.
Conclusion
No claims are allowed.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685