DETAILED ACTION
Status of the Claims
Claims 1-7, 9-21, and 23 are currently pending and examined herein.
Claim 1 has been amended.
Claim 23 is new.
Claims 8 and 22 have been cancelled by Applicant.
The following Office Action is in response to Applicant’s communication dated 01/28/2026. Rejection(s) and/or objection(s) not reiterated from previous office actions are hereby withdrawn. The following rejection(s) and/or objection(s) are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/02/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Modified Claim Rejections – 35 U.S.C. 103(a)
Necessitated by Amendments
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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 factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Bell et al. and Abate et al.
Claims 1, 8-18, 21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Bell et al. (U.S. 10,725,027 B2, cited in IDS of 09/15/2025, of record) in view of Abate et al. (WO 2019/139650, of record).
Regarding claim 1(in part), Bell discloses a method for screening a DNA-encoded library using a cellular assay comprising single cells, for example, as per col. 64, lines 30-41:
Disclosed herein, in some embodiments, are compositions, methods, and systems useful in the analysis of multiple analytes in a single cell or cell population. Examples of analytes include, without limitation, DNA (e.g., genomic DNA or cDNA), epigenetic information (e.g., accessible chromatin, DNA methylation), RNA (e.g., mRNA, CRISPR guide RNAs), synthetic oligonucleotides (e.g., DNA transgenes), and proteins (e.g., intracellular proteins, cell surface proteins, nuclear membrane proteins, extracellular matrix proteins). In some embodiments, the compositions, methods, and systems disclosed herein identify the cell that the analytes originated from.
Regarding claim 1(in part), Bell further discloses binding cells with DELs comprising small molecules linked to DNA tags (e.g., termed “labelling agents”, which may be a small molecule and can comprise a “reporter oligonucleotide” that identifies the small molecule, as per col. 89, lines 10-55),
wherein the DNA tag comprises a DEL barcode sequence flanked by a capture moiety, wherein the barcode sequence is unique to the small molecule of the DEL (e.g., as per col. 89 and as per col. 78-79, similar to Fig. 10B but with a small molecule rather than an antibody),
wherein the DELs are not particle bound (e.g., “[t]hese reporter oligonucleotides may be directly coupled to the labelling agent” as per col. 89, lines 48-50);
combining the DEL-bound cells and template particles comprising covalently linked capture oligos to create a plurality of partitions (e.g., in partitions that comprise a cell, lysing reagents, and a bead or particle comprising “capture oligonucleotides”, as per col. 78-79),
wherein the capture moiety of the DNA tag of the DEL is complementary to the capture oligos (e.g., as per col. 78-79, col. 89, and similar to Fig. 10B but with a small molecule rather than an antibody),
wherein a substantial number of the partitions contain a single one of the cells and a single one of the template particles (e.g., as per col. 78-79);
lysing the cells inside the partitions to release mRNA and the DNA tags (e.g., “[t]he partition also comprises cell [and] lysis agents that aid in releasing nucleic acids from the cell” as per col. 79, lines 6-8); and
barcoding, with the capture oligos covalently linked to the template particles, the released mRNA and the released DNA tags inside the partitions for single cell analysis (e.g., barcoding of the mRNA and the “reporter oligonucleotides” of the labelling agent, as per col. 77-79).
However, Bell is silent regarding the explicit limitations of combining, in a tube containing a first fluid, the DEL-bound cells, and template particles comprising capture oligos, adding a second fluid immiscible with the first fluid to the tube, and shearing the fluids to create a plurality of partitions, near simultaneously, inside the tube, as set forth in claim 1.
Similar to Bell, the Abate reference is interested in forming emulsion droplets each comprising a cell and a particle useful for performing RNA-seq methods (e.g., as per [00178]-[00179]). Abate discloses a method termed “particle-templated emulsification” (or PTE) that encapsulates target particles of interest into emulsion droplets without requiring the use of a microfluidic device (e.g., as per [0004]), comprising combining first fluid that includes a plurality of target particles with a second, immiscible fluid to provide a second mixture, and shearing the second mixture such that a plurality of the monodisperse template particles are encapsulated in a plurality of monodisperse droplets in the second fluid, thereby providing a plurality of monodisperse droplets including the first fluid, one of the monodisperse template particles, and one of the plurality of target particles (e.g., as per [0005]-[0007] and/or Fig. 2). Abate describes, in at least one embodiment, that this PTE method can create single-cell emulsions “simultaneously” as the mixture is subject to shearing (e.g., as per [00276]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to utilize methods of generating monodisperse emulsions by shearing fluids taught by Abate in the method for screening DNA-encoded libraries with single cells as taught in Bell. One of ordinary skill in the art would have been motivated to do so since Abate teaches that such emulsion partitioning does not require the use of specialized microfluidic devices and that it scales better than microfluidic methods since large volumes and/or large number of particles and partitions can be processed near simultaneously (e.g., as per [0004] and/or [00261]-[00262]).
One of ordinary skill in the art would also have had a reasonable expectation of success for creating a plurality of partitions as taught by Abate, since Abate specifically teaches that their emulsion-shearing method is appropriate for creating droplet partitions for single-cells followed by lysing and processing of nucleic acids within the individual droplets, for example, in assays such as RNA-seq (e.g., as per [0005]-[0007], [0010], and/or [00178]-[00179]).
Regarding claim 9, Bell teaches the above method, wherein the small molecule comprises a drug candidate against a cell surface receptor (e.g., “a small molecule compound may be a small molecule drug” as per col. 306, lines 3-4).
Regarding claim 10, Bell teaches the above method, wherein the oligos of the template particles comprise one or more of barcodes, primer binding sequences, or molecular binders for capturing mRNA or DNA tags released from cells (e.g., as per col. 238-239 and/or Fig. 10).
Regarding claim 11, Bell teaches the above method, wherein at least a portion of the oligos comprise molecular binders comprising poly-T capture sequences (e.g., as per col. 238-239 and/or Fig. 10).
Regarding claim 12, Bell teaches the above method, further comprising amplifying the barcoded mRNA and DNA tags released by the cells to generate amplicons (e.g., as per col. 97).
Regarding claim 13, Bell teaches the above method, wherein amplifying is performed with gene specific primers to thereby amplify mRNA associated with genes of interest (e.g., “primer sequences useful in any of the various operations for attaching barcode sequences and/or amplification reactions may comprise gene specific sequences which target genes or regions of genes” as per col. 66, lines 56-59).
Regarding claim 14, Bell teaches the above method, wherein the genes of interest comprise genes involved in gene expression pathways that are associated with drug candidates (e.g., “[a] high-throughput screening may be a screening that identifies active compounds, antibodies, or genes that modulate a particular biomolecular pathway” as per col. 305, lines 10-12).
Regarding claim 15, Bell teaches the above method, further comprising sequencing the amplicons to produce a plurality of sequence reads (e.g., as per col. 97).
Regarding claim 16, Bell teaches the above method, wherein the sequence reads comprise sequence information linking the small molecules of DELs with transcriptional output of corresponding single cells.
Regarding claim 17, Bell teaches the above method, further comprising washing the cells after binding (e.g., “[f]ollowing incubation, the cells may be washed to remove unbound labelling agents” as per col. 92, lines 18-19)
Regarding claim 18, Bell teaches the above method, wherein the small molecules bind to surface receptors of the cells (e.g., as per col. 89).
Regarding claim 21, Bell teaches the above method, wherein the DELs target cell type specific proteins (e.g., as per col. 89).
Regarding claim 23, Bell teaches the above method, wherein the method further comprises: breaking the partitions; and reverse transcribing the released barcoded mRNA to form cDNA outside of the partitions (e.g., as per col. 79 and/or the mRNA may be barcoded before reverse transcription as per col. 82 and shown in Fig. 10F).
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Response to Arguments
The 01/28/2026 remarks argue: not all elements are taught.
Applicant's arguments have been fully considered but they are not persuasive for at least the following reasons.
Specifically, the remarks assert that the prior art cited by the examiner in the Non-final Office Action of 9/28/2025 “fails to teach or suggest all of the claim features of amended independent claim 1 and the claims that depend therefrom.” In response, it is noted that the rejection has been altered to the extent necessary to render the claims obvious, as detailed herein.
Bell et al., Abate et al., and Chen et al.
Claims 1-7, 9-18, 21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Bell et al. (U.S. 10,725,027 B2, cited in IDS of 09/15/2025, of record) in view of Abate et al. (WO 2019/139650, of record), and further in view of Chen et al. (A method for estimating binding affinity from primary DEL selection data., Biochemical and Biophysical Research Communications, Vol. 533, 249-255, 2020, of record).
Bell in view of Abate is relied on as above, however, the references are silent as to some limitations of claims 2-7.
Claim 2 recites comprising pre-screening candidate DELs in a binding assay and selecting the DELs used for cell binding. Bell et al. and Abate et al. are silent to a pre-screening method of candidate DELs in a binding assay by selecting the DELs used for cell binding.
Chen et al. (pg. 250, 2.2. Multiple round selections and compound retention, column 1, paragraph 3, lines 1-4) discloses that several cycles of affinity selection (pre-screening of candidate DELs in a binding assay), commonly referred to as a “round”, are usually conducted during a DEL selection experiment, where library molecules recovered at the end of one round (pre-screening) of selection are used as input for the subsequent selection round.
Claim 3 recites that the binding assay comprises: combining a plurality of candidate DELs with targets; enriching candidate DELs bound with targets; and identifying a subset of the enriched candidate DELs for single cell analysis. Bell et al. and Abate et al. are silent to a binding assay comprising: combining a plurality of candidate DELs with targets, enriching candidate DELs bound with targets, and identifying a subset of the enriched candidate DELs for single cell analysis.
Chen et al. (pg. 249, Introduction, column 1, paragraph 1, lines 5-8) discloses that affinity selection is a binding assay where a target (typically a protein) is equilibrated with the DEL library, and compounds that bind to the target are retained while molecules that do not bind to the target are removed. Chen et al. (pg. 251, 3.1. DNA sequence counts and decisions on hit resynthesis, column 1, paragraph 1, lines 1-4) discloses that after the final round of affinity selection, the selection population is amplified and sequenced and in most DEL selection experiments, enriched compounds with a range of counts are available for additional studies.
Claim 4 recites that the subset comprises a portion of the enriched candidate DELs having a higher target binding affinity than a second portion of the enriched candidate DELs. Bell et al. and Abate et al. are silent to the subset comprising a portion of enriched candidate DELs having a higher target binding affinity than a second portion of enriched candidate DELs.
Chen et al. (pg. 249, Introduction, column 1, paragraph 1, lines 8-12) discloses that DNA sequence analysis is used to identify enriched molecules in the selected population and the sequence population is translated into chemical structures, and enriched compounds are chosen for off-DNA synthesis and characterization of binding and activity. Chen et al. (pg. 249, abstract, lines 2-3) further discloses that ideally higher affinity ligands will have higher counts than weaker affinity ligands (second portion of enriched candidate DELs).
Claim 5 recites identifying the subset comprises sequencing DNA tags corresponding with the enriched candidate DELs to generate sequence reads. Bell et al. and Abate et al. are silent to identifying the subset comprising sequencing DNA tags corresponding with enriched candidate DELs to generate sequence reads.
Chen et al. (pg. 249, abstract, lines 1-3) discloses that DEL selections are binding assays conducted with mixtures of chemically diverse DNA-tagged ligands and a screening target and DEL selections use DNA sequence counts to measure target binding.
Claim 6 recites further comprising quantifying the sequence reads of DELs to assess binding affinities, wherein a greater number of unique reads correlates to a higher binding affinity. Bell et al. and Abate et al. are silent to quantifying sequence reads of DELs to assess binding affinities, wherein a greater number of unique reads correlates to a higher binding affinity.
Chen et al. (pg. 249, abstract, lines 2-3) further discloses that DEL selections use DNA sequence counts to measure target binding, where ideally higher affinity ligands will have higher counts than weaker affinity ligands. Chen et al. (pg. 249, Introduction, paragraph 2, lines 1-3) disclose that DNA sequence counts are the basis of quantitative analysis of DEL selection data and DEL DNA is the analyte that provides a quantifiable signal for ligand binding affinity in the affinity selection assay. Ideally, sequence count will correlate with compound affinity, as the fraction of a DEL ligand that is retained during affinity selection is a function of the concentration of the target and affinity of the ligand to that target according to Chen et al. (pg. 249, Introduction, paragraph 2, lines 4-7). Chen et al. (pg. 251, Fig. 3, lines 3-4) further discloses compounds with higher sequence counts are often chosen for follow up studies, as DNA sequence count is the signal in the affinity selection assay.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to utilize methods of estimating binding affinity from DEL selections and performing several cycles of affinity selection as taught by Chen et al. because it would be advantageous for improved screening of DNA-encoded libraries with single cells linked to DNA tags as taught by Bell et al. One of ordinary skill in the art would have been motivated to use DNA sequence counts from enriched compounds because it would assist in obtaining a higher binding affinity once a DEL library is equilibrated with a target according to Chen et al. (pg. 252, 3.4. Interpreting sequence counts in multi-round selection experiments, column 2, paragraph 1, lines 1-3).
Claim 7 recites that the DNA tags comprise a barcode and primer binding sequences. Regarding claim 7, Bell et al. (Figure 37) illustrates that DNA tags linked to small molecules comprise a barcode (e.g., “[i]n some aspects, these reporter oligonucleotides may comprise nucleic acid barcode sequences that permit identification of the labelling agent which the reporter oligonucleotide is coupled to” as per col. 89, lines 26-29)
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Response to Arguments
The 01/28/2026 remarks argue: not all elements are taught.
Applicant's arguments have been fully considered but they are not persuasive for at least the following reasons.
Specifically, the remarks assert that the prior art cited by the examiner in the Non-final Office Action of 9/28/2025 “fails to teach or suggest all of the claim features of amended independent claim 1 and the claims that depend therefrom.” In response, it is noted that the rejection has been altered to the extent necessary to render the claims obvious, as detailed herein.
Bell et al., Abate et al., and Cai et al.
Claims 1, 9-21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Bell et al. (U.S. 10,725,027 B2, cited in IDS of 09/15/2025, of record) in view of Abate et al. (WO 2019/139650, of record), and further in view of Cai et al. (Selection of DNA-Encoded Libraries to Protein Targets within and on Living Cells, Journal of the American Chemical Society, 141, 17057-17061, 2019, of record).
Bell in view of Abate is relied on as above, however, the references are silent as to some limitations of claims 19-20.
Claim 19 recites that binding involves integrating at least a portion of the DELs inside the cells. Bell et al. and Abate et al. are silent to methods of binding involving integrating at least a portion of DELs inside the cells.
Regarding claim 19, Cai et al. (pg. 17057, abstract, lines 7-9) discloses methods of using a cyclic cell-penetrating peptide appended to DNA-encoded libraries for delivery across a cell membrane to access targets within a cell.
Claim 20 recites that the DELs further comprise cell-penetrating ligands. Bell et al. and Abate et al. are silent to methods of the DELs further comprising cell-penetrating ligands.
Regarding claim 20, Cai et al. (pg. 17057, column 1, paragraph 2, lines 22-25) disclose trapping the transient interaction of DEL ligands to the target, cross-linking can give improved enrichment of ligands over nonligands, particularly for low affinity binders or with protein targets at low concentration. Cai et al. (pg. 17057, column 2, paragraph 2, lines 18-20) discloses that upon cytosolic delivery of the DEL, the binding event between a protein and a DNA-linked ligand enables a covalent bond to be formed between the protein and DNA by affinity labeling. Cai et al. (pg. 17057, column 2, paragraph 2, lines 13-16 and Scheme 1) further discloses a conjugated DNA-linked molecule to a cyclic cell-penetrating peptide to produce an enriched ligand.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to utilize methods of selecting targets bound to cell-penetrating ligands within live cells using DNA-encoded small molecule libraries against protein targets within and on living cells as taught by Cai et al. in the methods of Bell et al. in view of Abate et al. because it would be advantageous for improved enrichment of DEL ligands to a target through DEL screenings with single cells as taught by Bell et al. One of ordinary skill in the art would have been further motivated to use conjugated DNA-linked molecules to a cyclic, cell-penetrating peptide because it would produce an enriched ligand for assessing target binding affinity in screened DNA encoded libraries with cells according to Cai et al. (pg. 17057, Introduction, column 2, paragraph 2, lines 2-5).
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Response to Arguments
The 01/28/2026 remarks argue: not all elements are taught.
Applicant's arguments have been fully considered but they are not persuasive for at least the following reasons.
Specifically, the remarks assert that the prior art cited by the examiner in the Non-final Office Action of 9/28/2025 “fails to teach or suggest all of the claim features of amended independent claim 1 and the claims that depend therefrom.” In response, it is noted that the rejection has been altered to the extent necessary to render the claims obvious, as detailed herein.
Conclusion
No claims are 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 extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEREMY FLINDERS whose telephone number is (571)270-1022. The examiner can normally be reached M-F 10-6:00 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Heather Calamita can be reached on (571)272-2876. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEREMY C FLINDERS/Primary Examiner, Art Unit 1684
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