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 .
Remarks
In response to communications sent January 22, 2026, claim(s) 1-12 and 14-21 is/are pending in this application; of these claim(s) 1 and 8 is/are in independent form. Claim(s) 13 and 22 is/are cancelled. Claims 8-12, 14, 20, and 21 are withdrawn from consideration.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 22, 2026 has been entered.
Response to Arguments
Applicant’s arguments, see page 7 line 22 to page 8 line 10, filed January 22, 2026, with respect to 1-7 and 16-19 have been fully considered and are persuasive. The rejection of claims 1-7 and 16-19 (sent August 22, 2025) has been withdrawn.
Applicant's arguments filed January 22, 2026 have been fully considered but they are not persuasive. Regarding claim 15, the claim recites a method that is dependent on only elements a) through g) of claim 1 and not the newly entered element i). Note that Applicant’s arguments pertain to element i), the portion that does not limit claim 15.
Applicant’s arguments, see page 8 line 11 to page 12 line 19, filed January 22, 2026, with respect to the rejection(s) of claim(s) 1-7 and 15-19 under 35 U.S.C. § 102 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the combination of references Choi and D’Alessio under 35 U.S.C. § 103.
Claim Interpretation
According to Applicant’s Specification at page 11 lines 14-24 (Para [0082] of Pre-Grant Publication US 2021/0343368 A1), the term "generating" may include generating a computerized implementation “in the computer,” “in the computer software,” “in computer readable format,” etc. Hence, according to the paragraph in Applicant’s Specification, “generating a cell-type specific expression cassette” may refer to an in silico element “without physically producing the corresponding nucleic acid molecule.” This claim interpretation is part of the broadest reasonable interpretation of claims 1 and depend claims 2-7 and 15-19.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 15 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The claim incorporates only steps a) to g) of claim 1 and not steps h) and i) of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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.
Claim 15 falls under at least one of the four categories of patent eligible subject matter, as claim 15 is a process claim.
Claim 15 is rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claim(s) recite(s) the abstract idea of a mental process for almost the entire claim. This judicial exception is not integrated into a practical application because the mental process is merely applied on a general purpose computer during the “generating” step, according to the claim interpretation above.
Claim 15 recites: A computer-implemented method for determining the sequence of a synthetic locus control region (sLCR), comprising the steps a) to g) according to claim 1 (limitations to the mental process).
Claim 15 depends on steps a) to g) of claim 1, which are steps of a mental process:
a) providing a gene expression profile of a cell type of interest (abstract idea, mental process),
b) providing genomic sequence data of said cell type of interest (abstract idea, mental process),
c) selecting a set of signature genes from the gene expression profile, wherein said signature genes are (i) differentially regulated compared to a reference cell type or (ii) selected according to a gene expression level (abstract idea, mental process),
d) identifying genes encoding a transcription factor within the set of signature genes selected in c) (abstract idea, mental process),
e) determining a set of genomic regions from the genomic sequence data, wherein each genomic region comprises a sequence encoding a signature gene identified in c) and additional genomic sequence adjacent to the sequence encoding said signature gene (abstract idea, mental process),
f) identifying multiple genomic sub-regions of comparable and limited size, preferably equal size, within the set of genomic regions determined in e), wherein said genomic sub-regions comprise one or more binding sites for one or more of the transcription factors identified in d) (abstract idea, mental process),
g) selecting a minimal set of genomic sub-regions from those determined in f), wherein the set of genomic sub-regions is selected to comprise transcription factor binding sites for a predetermined percentage of all transcription factors identified in d) (abstract idea, mental process).
Note that steps h) and i) are not claimed in claim 15.
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.
Claim(s) 1-7 and 15-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO-2007025205-A2 (“Choi”) in view of US-20170002319-A1 (“D’Alessio”).
As to claim 1, Choi teaches a method for generating a cell-type specific expression cassette (Choi page 30 lines 23-28: generating cis-regulatory modules that are specific to a physiological condition), comprising the steps of:
a) providing a gene expression profile of a cell type of interest (Choi page 4 lines 6-16: “Total RNA or mRNA is extracted from a cell or tissue of the organism and subjected to microarray analysis”),
b) providing genomic sequence data of said cell type of interest (Choi page 4 lines 17-26: “Genomic DNA sequences of the organism are retrieved from one or more genomic DNA database such as, for example, GeneBank or other database”; this is for the purpose of alignment of mRNA to a reference and helps make better use of the mRNA),
c) selecting a set of signature genes from the gene expression profile, wherein said signature genes are (i) differentially regulated compared to a reference cell type or (ii) selected according to a gene expression level (Choi page 4 lines 6-16: “By statistical methodologies, those genes that are differentially expressed are identified by comparison to genes from the same organism not subjected to the one or more condition(s). Tight cluster analysis is performed to generate tight clusters of co-expressed genes”),
d) identifying genes encoding a transcription factor [[ (Choi page 4 lines 6-16: “identification of functional DNA codes (i.e. nucleotide sequences) for condition-specific common cis-regulatory motifs and modules and further identifies their corresponding transcription factors”),
e) determining a set of genomic regions from the genomic sequence data, wherein each genomic region comprises a sequence encoding a signature gene identified in c) and additional genomic sequence adjacent to the sequence encoding said signature gene (Choi page 4 lines 17-26: “ to identify one or more DNA codes of a known motif within the sequences of cis-regulatory regions of co- expressed genes” and “predict potential motifs and modules within the same sequences of cis-regulatory regions”),
f) identifying multiple genomic sub-regions of comparable and limited size (Choi page 4 lines 17-26: “identify common motifs within the cluster”), preferably equal size (this element is interpreted as an optional element and not part of the broadest reasonable interpretation), within the set of genomic regions determined in e), wherein said genomic sub-regions comprise one or more binding sites for one or more of the transcription factors identified in d) (Choi page 4 lines 6-16: “identification of functional DNA codes (i.e. nucleotide sequences) for condition-specific common cis-regulatory motifs and modules and further identifies their corresponding transcription factors”,
g) selecting a minimal set of genomic sub-regions from those determined in f), wherein the set of genomic sub-regions is selected to comprise transcription factor binding sites for a predetermined percentage of all transcription factors identified in d) (Choi page 15 line 33 to page 16 line 8: identification of a set of a smaller number of “common modules” derived from a larger set of “known motifs” involved with transcription factors; see Choi Table 2 on page 23 for “percentages” to determine “common modules” in an example), and
h) generating a cell-type specific expression cassette comprising the set of genomic sub-regions selected in step g) (Choi page 4 lines 17-26: computationally generating “potentially novel motifs” derived from analysis of the sub-regions of the modules; see the claim interpretation section of this office action for the Examiner’s interpretation of the term “generating” based on Applicant’s specification) operably coupled with a reporter or effector gene (Choi page 4 lines 31-34: a “reporter plasmid expression assay”), wherein the genomic sub-regions are configured to regulate the expression of said reporter or effector gene (Choi page 4 lines 31-34: a “reporter plasmid expression assay” where the expression is driven by the identified common motif)
wherein the set of genomic sub-regions selected in step g) forms a synthetic regulatory region comprising 2 to 10 of said genomic sub-regions (Choi page 16 line 35 to page 17 line 3: “reporter genes… fused downstream of one or more putative TF binding site(s)”; hence, Choi teaches 2 TF binding sites, which reads on the claimed “2 to 10 of said genomic regions”; Choi page 27 Table 5 illustrates a module with a plurality of motifs, e.g., at least 2), each comprising 100 bp to 1000 bp (“comprising 100 bp” is interpreted as “at least 100 bp; at least some of the named binding sites in Figure 4 are at least 100 bp), positioned adjacently, without a linker or with a linker sequence of less than 100 bp positioned between two or more of said sub-regions (this element may either be present or not, therefore it is not limiting and does not need to be mapped),
wherein said genomic sub-regions originate from separate and non-adjacent locations in the same genome of said cell type of interest (Choi page 27 Table 5: not only are motifs found for transcription factor binding, but modules of combinations of motifs are analyzed and identified; the modules are different combinations of motifs, hence different module combinations have portions that originate in separate non-adjacent locations, such differences between cluster 2, cluster 10, and cluster 12 in Table 5), and
i) synthesizing, cloning, and/or isolating a nucleic acid molecule comprising the generated cell-type-specific expression cassette of step h) (Choi Para [0164]: cloning a nucleic acid into an inducible promoter system).
However, Choi does not teach that the transcription factors identified in step d) are within the set of signature genes selected in step c).
Nevertheless, D’Alessio teaches the identification of master transcription factors by identifying top transcription factors within a set of tissue-specific genes. (D’Alessio Figure 1B on the right lists particular transcription factors within a set of genes; see also Para [0036] of D’Alessio, which recites: “Tissue and cell types are arranged on the x-axis and clustered according to anatomical groups, represented by the colored bar at the top. Genes are arranged on the y-axis. Blue dashes represent candidate master transcription factors in a cell type. Clusters of candidate master transcription factors in cell types representing an anatomical group are boxed. Representative genes are listed on the side.”)
Choi and D’Alessio are in the same field of bioinformatics. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Choi to include the teachings of D’Alessio because “master transcription factors” can cause trans-differentiation (See D’Alessio). There would be a reasonable expectation of success because master transcription factors often control the expression patterns of the genes who expression they control; thus the master transcription factors have correlated expression with groups of genes that they control.
As to claim 2, Choi in view of D’Alessio teaches the method for generating an expression cassette according to claim 1, wherein the gene expression profile comprises expression levels of genes in the cell type of interest (Choi page 4 lines 6-16: “genes that are differentially expressed are identified by comparison to genes from the same organism not subjected to the one or more condition(s)”), and according to step c) (i) a gene expression profile of a reference cell type is provided (Choi page 4 lines 6-16: “Tight cluster analysis is performed to generate tight clusters of co-expressed genes”, comprising expression levels of genes in the reference cell type (Choi page 4 lines 6-16: “genes from the same organism not subjected to the one or more condition(s)”, and differentially regulated signature genes are selected by identifying genes that are up- or down-regulated compared to the expression levels in the reference cell type (Choi page 4 lines 6-16: “genes that are differentially expressed are identified by comparison to genes from the same organism not subjected to the one or more condition(s)”), or according to step c) (ii) the genes of the cell type of interest are ranked according to their gene expression level and signature genes are selected based on expression of a predetermined level or a predetermined number of signature genes (this element is claimed in the alternative and does not need to be mapped).
As to claim 3, Choi in view of D’Alessio teaches the method for generating an expression cassette according to claim 1, wherein the predetermined percentage of transcription factors covered is 30% or more (Choi Table 2 on page 23 for percentages that are above 30%).
As to claim 4, Choi in view of D’Alessio teaches the method for generating an expression cassette according to claim 1, wherein the genomic regions determined in e) correspond to genomic sequences of topological associating domains that contain the differentially regulated gene (Choi page 4 lines 17-26: “ one or more DNA codes of a known motif within the sequences of cis-regulatory regions of co-expressed genes” and “predict potential motifs and modules within the same sequences of cis-regulatory regions”).
As to claim 5, Choi in view of D’Alessio teaches the method for generating an expression cassette according to claim 1, wherein the identifying genomic sub-regions of equal size in step f) is performed by a sliding window algorithm of the genomic regions determined in e), wherein the window has a length of 500 bp to 5000 bp, and the sliding step has a length of 100 bp to 1000 bp (Choi page 4 lines 17-26: identify motifs using TRANSPLORER analysis, which uses a positional weight matrix having various parameters).
As to claim 6, Choi in view of D’Alessio teaches the method for generating an expression cassette according to according to claim 1, wherein the selection of a set of genomic sub-regions in g) is performed by calculating for each genomic sub-region identified in f): an enrichment of binding sites for the transcription factors according to d) in the genomic sequence data (Choi Table 2 on page 23: high “percentages” to determine “common modules” in an example), and a score for the diversity of transcription factors for which binding sites are present (Choi page 24 lines 6-16: diverse location scores for transcription factor motifs were analyzed), wherein the genomic sub-regions are ranked according to the cumulative percentage of transcription factors for which binding sites are present (Choi page 24 lines 6-16: ranking the frequency of common motifs), and wherein a minimal set of genomic sub-regions is selected to comprise binding sites for a predetermined percentage of all transcription factors identified in d) (Choi page 15 line 33 to page 16 line 8: identification of a set of a smaller number of “common modules” derived from a larger set of “known motifs” involved with transcription factors).
As to claim 7, Choi in view of D’Alessio teaches a cell-type specific reporter vector in the form of a nucleic acid molecule, comprising cell-type specific expression cassette generated by the method according to claim 1 (Choi page 4 lines 17-26: computationally generating “potentially novel motifs” derived from analysis of the sub-regions of the modules; Note regarding claim interpretation: According to Applicant’s Specification at page 11 lines 14-24, the term "generating" may include generating a computerized implementation “in the computer,” “in the computer software,” “in computer readable format,” etc. Hence, according to the paragraph in Applicant’s Specification, “generating a cell-type specific expression cassette” may refer to an in silico element “without physically producing the corresponding nucleic acid molecule.”).
As to claim 15, Choi in view of D’Alessio teaches a computer-implemented method for determining the sequence of a synthetic locus control region (sLCR), comprising the steps a) to g) according to claim 1 (Applicant’s Specification at page 1 lines 4-10 describes a synthetic locus control region as a synonym for synthetic cis regulatory DNA; see Choi page 30 lines 23-28: generating cis-regulatory modules).
As to claim 16, Choi in view of D’Alessio teaches the method according to claim 1, wherein the minimal set of genomic sub-regions comprises 2 to 10 genomic sub-regions, from those determined in step f) of claim 1 (Choi Table 5 on page 27 indicates motifs involving clusters of genes involving 2 genes contributing to the subregions of the motif derived from the 2 genes).
As to claim 17, Choi in view of D’Alessio teaches the method according to claim 2, wherein differentially regulated signature genes are 3- to 10-fold upregulated in the cell type of interest (Choi page 19 lines 18-37: differentially regulated signature genes that were significantly upregulated, i.e. filtering out less significant values such as 1.5-fold changes), or wherein the signature genes selected based on expression of a predetermined level or a predetermined number of signature genes are the 100 to 1000 most highly expressed, or 100 to 1000 most lowly expressed genes in the cell type of interest (these elements are claimed in the alternative and not need to be mapped).
As to claim 18, Choi in view of D’Alessio teaches the method according to claim 4, wherein the topological associating domain corresponds to a genomic sequence between two CTFC-binding sites located outside the coding region of and including the signature genes (Choi page 4 lines 17-26: “one or more DNA codes of a known motif within the sequences of cis-regulatory regions of co-expressed genes” and “predict potential motifs and modules within the same sequences of cis-regulatory regions”; the Examiner argues that cis-regulator regions contain are between CTFC-binding sites and outside of the coding regions of the relevant genes).
As to claim 19, Choi in view of D’Alessio teaches the method according to claim 5, wherein the window has a length of 700 bp to 2000 bp or 800 bp to 1200 bp, and the sliding step has a length of 120 bp to 300 bp or 130 bp to 170 bp (Choi page 4 lines 17-26: identify motifs using TRANSPLORER analysis, which uses a positional weight matrix having various parameters).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US 20060160108 A1: “Populations Of Reporter Sequences And Methods Of Their Use”
US 20190024118 A1: pertinence is the transgene expression using multiple regulatory elements
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/JESSE P FRUMKIN/Primary Examiner, Art Unit 1685 February 25, 2026