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 .
DETAILED ACTION
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Status of Claims
Claims 1-4, 6-11, 14-18 and 21-25 are currently pending. Claims 16 and 21-23 have been amended by Applicants’ amendment filed 08-25-2026. No claims have been added or canceled by Applicants’ amendment filed 08-25-2026.
Applicant's election with traverse of Group III, claims 16, 18 and 21-23, directed to an assay method; and the election of Species as follows:
Species (E): wherein in step (c) at least some of the compartments have two or more cells loaded therein, and cell surface protein expression profiles are determined (claim 21), in the reply filed January 30, 2026 was previously acknowledged.
Claims 1-4, 6-11, 14, 15, 17, 24 and 25 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on January 30, 2026.
Claim 18 was previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.
A complete reply to the final rejection must include cancellation of nonelected claims or other appropriate action (37 CFR 1.144) See MPEP § 821.01.
Priority
The present application filed September 14, 2022 is a 371 PCT/US2021/023039, filed March 18, 2021, which claims the benefit of US Provisional Patent Application 62991529, filed March 18, 2020.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed August 25, 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or
objection not specifically addressed below are herein withdrawn.
Specification Objection
The objection to the disclosure is withdrawn because it contains an embedded hyperlink and/or other form of browser-executable code due to Applicant’s amendment of the specification, filed August 25, 2026.
Maintained Objections/Rejections
Claim Rejections - 35 USC § 112(b)
The rejection of claims 16 and 21-23 is maintained under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards
as the invention.
Claim 16 is indefinite for the recitation of the term “the specificity” such as recited in claim 16, line 12. There is insufficient antecedent basis for the term “the specificity” in the claim. Moreover, it is unclear what antibody specificity is being referred to given that there is no step recited of the antibody binding to another component (e.g., cell surface proteins, a handle, barcode, etc.) and, thus, the metes and bounds of the claim cannot be determined. The Examiner suggests that Applicant amend the claim to recite, for example, “identifies a binding specificity of the antibody”.
Claim 16 is indefinite for the recitation of the term “the following nucleotide segments” such as recited in claim 16, line 14. There is insufficient antecedent basis for the term “the following nucleotide segments” in the claim.
Claim 16 is indefinite for the recitation of the term “the binding specificity” such as recited in claim 16, line 20. There is insufficient antecedent basis for the term “the binding specificity” in the claim. Moreover, it is unclear what “binding specificity” of the antibody is identified because claim 16 does not recite a step of antibody binding and, thus, the metes and bounds of the claim cannot be determined. The Examiner suggests that Applicant amend the claim 16, line 12 to recite, for example, “a binding specificity”.
Claim 16 is indefinite for the recitation of the term “the vessel” such as recited in claim 16, lines 24 and 37. There is insufficient antecedent basis for the term “the vessel” in the claim because claim 16, line 2 recites the terms “a plurality of vessels”.
Claim 16 is indefinite for the recitation of the term “the pool barcode segments” such as recited in claim 16, line 28. There is insufficient antecedent basis for the term “the pool barcode segments” in the claim because claim 16, line 23 recites the term “a pool barcode segment”.
Claim 16 is indefinite for the recitation of the term “the staining constructs” such as recited in claim 16, lines 28-29. There is insufficient antecedent basis for the term “the staining constructs” in the claim because claim 16, line 5 recites the terms “a panel of staining constructs”.
Claim 16 is indefinite for the recitation of the term “the same vessel-specific pool barcode sequence” such as recited in claim 16, lines 28-29. There is insufficient antecedent basis for the term “the same vessel-specific pool barcode sequence” in the claim. Moreover, the term is unclear because claim 16 does not recite the presence of “a vessel-specific pool barcode sequence”. The Examiner suggests that Applicant amend the claim to recite, for example, “comprise a vessel-specific pool barcode sequence, wherein each vessel comprises an identical vessel-specific pool barcode sequence”.
Claim 16 is indefinite for the recitation of the term “the vessel-specific pool barcode sequence” such as recited in claim 16, line 30. There is insufficient antecedent basis for the term “the vessel-specific pool barcode sequence” in the claim.
Claim 16 is indefinite for the recitation of the term “at least one staining constructs” such as recited in claim 16, lines 32-33. There is insufficient antecedent basis for the term “at least one staining construct” in the claim because claim 16, line 5 recites the terms “a panel of staining constructs”.
Claim 16 is indefinite for the recitation of the term “staining constructs” such as recited in claim 16, line 35. There is insufficient antecedent basis for the term “staining constructs” in the claim because claim 16, line 5 recites the terms “a panel of staining constructs”.
Claim 16 is indefinite for the recitation of the term “cells” such as recited in claim 16, line 36. There is insufficient antecedent basis for the term “cells” in the claim because claim 16, line 3 recites the term “a plurality of cells”.
Claim 16 is indefinite for the recitation of the term “associated with” in claim 16, lines 36, 51-52 and 69-70 because the term “associated with” is a relative term that renders the claim indefinite. The term “associated with” is not defined by the claim, and the Specification does not provide a standard for ascertaining the requisite amount and/or type of association as compared to some other value that qualifies a stained cell as being “associated with” the vessel-specific pool barcode (e.g., binds to, is in the same vessel as, is located on the same device, etc.), such that one of ordinary skill in the art would not be reasonably appraised of the scope of the invention.
Claims 16 and 23 are indefinite for the recitation of the term “the vessel-specific pool barcode” such as recited in claim 16, lines 37 and 71-72. There is insufficient antecedent basis for the term “the same vessel-specific pool barcode” in the claim.
Claim 16 is indefinite for the recitation of the term “one or more staining constructs” such as recited in claim 16, lines 37 and 42. There is insufficient antecedent basis for the term “one or more staining constructs” in the claim because claim 16, line 5 recites the term “a panel of staining constructs”.
Claim 16 is indefinite for the recitation of the term “a cell surface protein” such as recited in claim 16, line 43. There is insufficient antecedent basis for the term “a cell surface protein” in the claim because claim 16, lines 3-4 recite the term “a plurality of cell surface proteins”.
Claim 16 is indefinite for the recitation of the terms “a plurality of droplet oligonucleotides”, “each droplet oligonucleotides” and/or “a droplet barcode” such as recited in claim 16, lines 45-50 because although each of the terms refers to a “droplet”, no droplet is recited in instant claim 16, such that it is unclear: (a) whether the term “droplet” is intended to identify the compartments as being “droplets” (e.g., an aqueous droplet, an oil droplet, an emulsion, etc.); (b) whether the term “compartment” broadly refers to any compartment, and that no droplets are present; and/or (c) whether the compartment itself further comprises a droplet (e.g., a droplet within a well) and, thus, the metes and bounds of the claim cannot be determined.
Claim 16 is indefinite for the recitation of the term “the same droplet barcode” such as recited in claim 16, lines 48-49. There is insufficient antecedent basis for the term “the same droplet barcode” in the claim because claim 16, line 46 recites the term “a droplet barcode”.
Claim 16 is indefinite for the recitation of the terms “the droplet oligonucleotides” and “a droplet oligonucleotide” such as recited in claim 16, lines 49, 50 and 59. There is insufficient antecedent basis for the terms “the droplet oligonucleotides” and “a droplet oligonucleotide” in the claim because claim 16, line 45 recites the term “a plurality of droplet oligonucleotides”.
Claim 16 is indefinite for the recitation of the term “each compartment containing one or more stained cells further comprises a plurality of droplet oligonucleotides” such as recited in claim 16, lines 44-45 because it is unclear whether the compartment also comprises the associated vessel-specific pool barcode recited in claim 16, line 37 and, thus, the metes and bounds of the claim cannot be determined.
Claim 16 is indefinite for the recitation of the term “at least one compartment” such as recited in claim 16, line 51. There is insufficient antecedent basis for the term “at least one compartment” in the claim because claim 16, line 41 recites the terms “compartments”.
Claim 16 is indefinite for the recitation of the term “different vessel-specific pool barcode sequences” such as recited in claim 16, line 52. There is insufficient antecedent basis for the term “different vessel-specific pool barcode sequences” in the claim.
Claim 16 is indefinite for the recitation of the term “producing a plurality of sequence fragment structures” such as recited in claim 16, line 60 because it is unclear how the plurality of sequence fragments are related to any component recited in claim 16(a)-(c) including whether the “plurality of sequence fragment structures” are produced from the capture constructs, produced from stained cells, and/or are produced from components unrelated to the steps recited in claim 16 and, thus, the metes and bounds of the claim cannot be determined.
Claim 16 is indefinite for the recitation of the term “corresponding to” in claim 16, lines 60-61 and 62because the term “corresponding to” is a relative term that renders the claim indefinite. The term “corresponding to” is not defined by the claim, and the Specification does not provide a standard for ascertaining the requisite type, amount and/or method of correspondence as compared to some other value that qualifies sequence fragment structures to ‘correspond to” a combination of barcode sequences, such that one of ordinary skill in the art would not be reasonably appraised of the scope of the invention.
Claim 16 is indefinite for the recitation of the term “individual stained cells” such as recited in claim 16, line 68. There is insufficient antecedent basis for the term “individual stained cells” in the claim because claim 16, line 36 recites the term “stained cells”.
Claim 16 is indefinite for the recitation of the term “the determining comprising resolving” such as recited in claim 16, line 68 because claim 16, line 67 recites that “determining” comprises “determining cell surface expression profiles”, such that “determining” cannot instead comprise resolving those profiles and, thus, the metes and bounds of the claim cannot be determined.
Claim 16 is indefinite for the recitation of the term “different vessel-specific pool barcode sequences” such as recited in claim 16, line 70. There is insufficient antecedent basis for the term “different vessel-specific pool barcode sequences” in the claim.
Claim 16 is indefinite for the recitation of the term “co-encapsulated” such as recited in claim 16, line 70 because none of the steps of claim 16 recite co-encapsulation of any barcode sequences and, thus, the metes and bounds of the claim cannot be determined.
Claim 16 is indefinite for the recitation of the term “at least one compartment” such as recited in claim 16, lines 70-71. There is insufficient antecedent basis for the term “at least one compartment” in the claim because claim 16, line 41 recites the term “compartments”.
Claim 16 is indefinite for the recitation of the term “based on respective combinatorial indexes” such as recited in claim 16, line 71 because it is unclear what happens “based on respective combinatorial indexes”. Moreover, claim 16 does not recite the presence of “combinatorial indexes” and/or a step comprising “combinatorial indexing” such that it is unclear how any step and/or component can be “based on respective combinatorial indexes” and, thus, the metes and bounds of the claim cannot be determined.
Claims 21 and 22 are indefinite for the recitation of the term “at least XX% of the compartments containing stained cells contain two or more stained cells” such as recited in claim 21, lines 1-3 because claim 16(c) recites that stained cells from at least two of the plurality of vessels are combined into compartments, such that each compartment (100%) should inherently comprise two or more stained cells, such that it is unclear how only 30% or 50% of the compartments are recited to comprise “two or more stained cells” and, thus, the metes and bounds of the claim cannot be determined.
Claim 23 is indefinite for the recitation of the term “a single compound barcode” in claim 23, line 2 because claim 23 depends from instant claim 16, wherein claim 16 does not recite the presence of a compound, and it is unclear how or why the vessel-specific pool barcode and the antibody barcode can comprise portions of a compound barcode and, thus, the metes and bounds of the claim cannot be determined. Applicant is reminded that although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26USPQ2d 1057 (Fed. Cir. 1993).
Claim Rejections - 35 USC § 112(d)
The rejection of claims 23 is maintained under 35 U.S.C. 112(d) 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.
Claim 23 recites (in part): “wherein the vessel-specific pool barcode and the antibody barcode are respective portions of a single compound” in lines 1-2 because claim 23 depends from instant claim 16, wherein claim 16 does not recite the presence of a compound. Thus, claim 23 is an improper dependent claim 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.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 103
Please note: the references have been modified slightly in response to Applicant’s amendments and arguments, filed August 25, 2026.
The rejection of claims 16 and 21-23 is maintained under 35 U.S.C. 103 as being unpatentable over Engreitz et al. (hereinafter “Engreitz”) (US Patent No. 11549135, issued January 10, 2023; previously published March 19, 2020; effective filing date September 14, 2018; of record) in view of Stoeckius et. al. (hereinafter “Stoeckius”) (Genome Biology, 2018, 19(224), 1-12; of record) as evidenced by Regev et al. (hereinafter “Regev”) (International Application WO2016040476, published March 17, 2016); and Weitz et al. (hereinafter “Weitz”) (International Application WO2016168584, published October 20, 2016); and Macosko et al. (hereinafter “Macosko”) (Cell, 2015, 161, 1202-1214).
Regarding claim 16 (in part), Engreitz teaches that compositions comprise an antibody-tagged oligonucleotide, including an origin specific barcode handle sequence, a first primer handle sequence, a second primer handle sequence, and a target binding region, wherein the composition can include an adapter sequence, a unique molecular identifier (UMI), and a poly-A sequence, such that methods for simultaneously measuring target oligonucleotides and protein in single cells generally involve delivering a mixture of the composition to a population of cells and encapsulating individual cells in an individual discrete volume comprising PCR primers on a bead, where the individual discrete volume can be suspended in a reverse transcription mixture and the nucleotide sequence of the origin specific barcode handle sequence can be detected, thereby assigning the target oligonucleotide and protein of interest to a specific individual discrete volume, while maintaining information about sample origin of the target oligonucleotide (interpreting discrete volumes as a plurality of vessels comprising cells, handle-tagged antibodies as staining constructs; a handle oligonucleotide attached to an antibody; barcode or UMI as identifying specificity of the antibi; and antibody specific for a cell surface protein, claim 16(i-a)-(iv-a)) (Abstract). Engreitz teaches methods for visualizing nucleic acids including direct fluorescence hybridization, wherein the oligonucleotide is single-stranded or double-stranded DNA, RNA, or a synthetic oligonucleotide; and wherein the synthetic oligonucleotide is a peptide nucleic acid; and the target binding region is sequence specific (interpreted as an antibody specific for a cell surface protein, claim 16(iii-a)) (col 3, lines 7-14). Engreitz teaches delivering one or more ligation dependent probes to the cells (interpreted as pool oligonucleotides), wherein the one or more ligation dependent probe comprise (i) sequences that bind in proximate locations on a target RNA, and (ii) the first primer handle sequence, the second primer handle sequence, or both; linking the bound proximity probes; amplifying the oligonucleotide of the composition and the linked ligation dependent probes using barcoded PCR primers, wherein the barcode is incorporated into each resulting amplicon, and quantifying target protein abundance and/or determining target protein localization based at least in part on sequencing of amplicons (interpreting the ligation-dependent probes as pool oligonucleotides comprising a handle complement segment; a capture complement segment; an antibody barcode complement segment; a pool barcode complement segment; loading stained cells, and sequencing, claim 16(viii-a), 16(c) and 16(e)) (col 3, lines 22-33). Engreitz teaches delivering a mixture of any of the compositions described herein to the oligonucleotide protein complexes, encapsulating complexes in an individual discrete volume (interpreted as a compartment/droplet), wherein the individual discrete volume comprises PCR primers on a bead, suspending the individual discrete volume in a reverse transcription mixture, and detecting the nucleotide sequence of the origin specific barcode sequence, thereby assigning the target oligonucleotide and protein of interest to a specific individual discrete volume, while maintaining information about sample origin of the target oligonucleotide (interpreted as a barcoded antibody annealed to a barcoded primer/handled oligonucleotide, comprising a volume/vessel-specific barcode, claim 16) (col 4, lines 25-35). Engreitz teaches that the invention provides a method for quantifying protein in individual molecule complexes comprising fixing a population of cells, lysing the cells, and encapsulating the resulting individual molecule complexes with any of the compositions described herein in an individual discrete volume (interpreted as combining the contents of all or some of the plurality of vessels, claim 16(b)) (col 5, lines 8-13). Engreitz teaches that the oligonucleotide tag can be used to encode identifying information about the binding specificity of a protein binding molecule and/or enable amplification and detection of said target protein (interpreted as a sequence that identifies the binding specificity of the antibody, claim 16(iv-a) and (vii-a)) (col 9, lines 27-30). Engreitz teaches that some examples of nucleic acids include the probes disclosed herein, wherein the oligonucleotide tag can range from approximately 30 to 300 nucleotides in length, and can comprise one or more of the following elements; an origin specific barcode, a first primer handle sequence, a second primer handle sequence, a target binding region, and an adapter, such that these elements can be directly adjacent to another or separated by a spacer sequence; and/or they can be ordered in any combination 5' to 3' (interpreted as segments position between v-a and vi-a, claim 16(viii-a)) (col 15, lines 14-23). Engreitz teaches that a "primer" as used herein refers to short nucleic acid molecules, which can be annealed to a complementary nucleic acid molecule by nucleic acid hybridization to form a hybrid between the primer and the nucleic acid strand (interpreting the handle oligonucleotide to be annealed to the handle complement segment, claim 16(v-a)) (col 17, lines 60-65). Engreitz teaches that in array-based methods, single-stranded DNA is annealed to beads and amplified via EmPCR (interpreting the handle oligonucleotide to be annealed to the handle complement segment, claim 16(v-a)) (col 26, lines 63-64). Engreitz teaches that the invention can comprise amplifying the target nucleic acid sequence including amplification by polymerase chain reaction (PCR), in which a sample is contacted with a pair of oligonucleotide primers under conditions that allow for the hybridization of the primers to a nucleic acid template in the sample, such that the primers are extended under suitable conditions, dissociated from the template, re-annealed, extended, and dissociated to amplify the number of copies of the nucleic acid, wherein this cycle can be repeated; and the product of amplification can be characterized by such techniques as electrophoresis, restriction endonuclease cleavage patterns, oligonucleotide hybridization or ligation, and/or nucleic acid sequencing (interpreted as loading a PCR compartment; interpreting primers as droplet oligonucleotides comprising a capture segment; interpreting sequencing as producing sequence fragment structures and determining sequences of the droplet barcode, claims 16(d) and 16(e)) (col 28, lines 18-30). Engreitz teaches that the method can comprise admixing the population of cells with monomers of a polymerizable hydrogel and polymerizing the gel in an oil emulsion under conditions that allow covalent anchoring of nucleic acids and/or proteins to the hydrogel; and that an emulsion can be achieved by a variety of methods known in the art (see, for example, US 2006/0078888, of which paragraphs [0139]-[0143] are incorporated by reference herein) (interpreting hydrogels and emulsions as compartments and/or droplets, claim 16) (col 31, lines 8-17). Engreitz teaches that the hydrogel can comprise primer pairs comprising releasable linkers, wherein the primers are barcoded using combinatorial indexing, and wherein barcoded primer are incorporated into DNA or cDNA amplicons by the amplification step (interpreted as loading a PCR compartment; interpreting primers as droplet oligonucleotides comprising a capture segment and droplet barcodes; and interpreting forming amplicons as producing sequence fragment structures, claim 16(e)) (col 32, lines 4-8). Engreitz teaches that the invention involves high-throughput single-cell RNA-seq and/or targeted nucleic acid profiling (for example, sequencing, quantitative reverse transcription polymerase chain reaction, and the like) where the RNAs from different cells are tagged individually, allowing a single library to be created while retaining the cell identity of each read. In this regard reference is made to Macosko et al., 2015, "Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets" Cell 161, 1202-1214; International patent application number PCT/US2015/049178, published as WO2016/040476 on Mar. 17, 2016; Klein et al., 2015, "Droplet Barcoding for Single-Cell Transcriptomics Applied to Embryonic Stem Cells" Cell 161, 1187-1201; International patent application number PCT /US2016/027734, published as WO2016168584Al on Oct. 20, 2016; Zheng, et al., 2016, "Haplotyping germline and cancer genomes with high-throughput linked-read sequencing" Nature Biotechnology 34, 303-311; Zheng, et al., 2017, "Massively parallel digital transcriptional profiling of single cells" Nat. Commun. 8, 14049 doi:10.1038/ncomms14049; International
patent publication number WO 2014210353 A2; Zilionis, et al., 2017, "Single-cell barcoding and sequencing using droplet microfluidics" Nat Protoc. January; 12(1):44-73; Cao et al., 2017, "Comprehensive single cell transcriptional profiling of a multicellular organism by combinatorial indexing" bioRxiv preprint first posted online Feb. 2, 2017, doi:dx.doi.org/10.1101/104844; and Rosenberg et al., 2017, "Scaling single cell transcriptomics through split pool barcoding" bioRxiv preprint first posted online Feb. 2, 2017, doi: dx.doi.org/10.1101/105163, all the contents and disclosure of each of which are herein incorporated by reference in their entirety (interpreted as encompassing determining from sequencing cell surface protein expression profiles for individual stained cell including resolving respective cell surface protein expression profiles for the at least two stained cells associated with different vessel-specific pool barcode sequences and co-encapsulated in at least one compartment based on combinatorial indexes, claim 16) (col 27, lines 10-42), wherein systems and methods for manipulating droplets within a high throughput microfluidic system is known in the art, where the RNA of each cell with a ‘cell barcode’ unique to that cell/drop, measure the expression level of each RNA with sequencing, and then use the cell barcodes to determine which cell each RNA molecule came from; and Figure shows a microfluid droplet (10) encapsulates a differentiated cell (not shown in the figure), wherein the cell is lysed and its mRNA (20) is hybridized onto a capture bead containing barcoded oligo dT primers on the surface (30) (40), all inside the droplet, such that the barcode is covalently attached to the capture bead, wherein since all of the mRNA from any given cell is uniquely barcoded, a single library is sequenced and then computationally resolved to determine which mRNAs came from which cells, such that through a single sequencing run, tens of thousands (or more) of distinguishable transcriptomes can be simultaneously obtained as evidenced by Regev (interpreted as resolving expression profiles for stained cells associated with different vessel-specific barcodes) (WO2016040476, paragraphs [0005]; and [00108]); wherein the 3' end of a barcoded primer is terminated with a poly-T sequences that may be used to capture cellular mRNA for whole transcriptome profiling, wherein the resulting library combining all cells can optionally be enriched using PCR-based methods or using hybridization capture-based methods (such as Agilent Sure Select), e.g., to allow sequencing of only a sub-set of genes of interest; and/or where the 3' end of the barcoded primers can terminate with a random DNA sequence that can be used to capture the RNA in the cell as evidenced by Weitz (pg. 12, lines 22-28); and wherein drop-seq, a strategy for quickly profiling thousands of individual cells by separating them into nanoliter-sized aqueous droplets, associating a different barcode with each cell’s RNAs, and sequencing them all together, wherein drop-seq analyzes mRNA transcripts from thousands of individual cells simultaneously while remembering transcripts’ cell of origin is known in the art as evidenced by Macosko (Abstract).
Regarding claims 21 and 22, Engreitz teaches delivering a mixture of any of the compositions described herein to a population of cells including encapsulating individual cells in an individual discrete volume, which can comprise PCR primers on a bead, such that the individual discrete volume can be suspended in a reverse transcription mixture and the nucleotide sequence of the origin specific barcode sequence can be detected, thereby assigning the target oligonucleotide and protein of interest to a specific individual discrete volume (interpreting a population of cells in a mixture, and discrete volumes suspended in RT mixture as compartments having two or more cells loaded therein, claims 21 and 22) (col 2, lines 3-12). Engreitz teaches that the method can comprise admixing the population of cells with monomers of a polymerizable hydrogel and polymerizing the gel in an oil emulsion under conditions that allow covalent anchoring of nucleic acids and/or proteins to the hydrogel, wherein individual cells are encapsulated in the individual discrete volume; and the emulsions can then be broken to release the individual discrete volume (interpreted as combining the contents of the plurality of vessels), where the oligonucleotide-tagged protein binding molecules can then be added, either before or after hydrogel polymerization, PCR can be performed in the individual discrete volumes, wherein cell-barcoded amplicons are generated, and the resulting amplicons can be sequenced (interpreting admixing a population of cells, and cells in an emulsion including within a PCR or sequencer as a compartment having two or more cells loaded therein, claims 21 and 22) (col 2, lines 41-53). Engreitz teaches the cells or population of cells can be obtained from a biological sample, wherein the biological sample can be obtained from a subject suffering from a disease (interpreting a biological sample and a subject as compartments comprising two or more cells, claims 21 and 22) (col 23, lines 64-66).
Regarding claim 23, Engreitz teaches that unique molecular identifiers (UMIs) can be used, for example, to normalize samples for variable amplification efficiency including featuring a solid or semisolid support (for example a hydrogel bead), to which nucleic acid barcodes such as a plurality of barcodes sharing the same sequence are attached, each of the barcodes can be further coupled to a unique molecular identifier, such that every barcode on the particular solid or semisolid support receives a distinct unique molecule identifier, wherein the unique molecular identifier can then be transferred to a target molecule with the associated barcode, such that the target molecule receives not only a nucleic acid barcode, but also an identifier unique among the identifiers originating from that solid or semisolid support (interpreting UMIs and/or barcodes that are the same as a compound barcode, claim 23) (col 17, lines 9-23).
Engreitz does not specifically exemplify determining distribution of cell surface proteins on individual cells (claim 16, in part).
Regarding claim 16 (in part), Stoeckius teaches cell hashing, where oligo-tagged antibodies against ubiquitously expressed surface proteins uniquely label cells from distinct samples, which can be subsequently pooled, such that by sequencing these tags alongside the cellular transcriptome, each cell can be assigned to its original sample, robustly identify cross-sample multiplets, and “super-load” commercial droplet-based systems for significant cost reduction, wherein a complementary genetic approach was used to validate the approach and demonstrate how hashing can generalize the benefits of single cell multiplexing to diverse samples and experimental designs (Abstract). Stoeckius teaches that recent developments have demonstrated how sample multiplexing can simultaneously overcome multiple challenges, such as the demuxlet algorithm, which enables the pooling of samples with distinct genotypes together into a single scRNA-seq experiment, such that here, the sample-specific genetic polymorphisms serve as a fingerprint for the sample of origin and therefore can be used to assign each cell to an individual after sequencing; and this workflow also enables the detection of multiplets originating from two individuals, reducing non-identifiable multiplets at a rate that is directly proportional to the number of multiplexed samples (pg. 1, col 2, last partial paragraph). Stoeckius teaches that CITE-seq was recently introduced, where oligonucleotide-tagged antibodies are used to convert the detection of cell surface proteins into a sequenceable readout alongside scRNA-seq, wherein a defined set of oligo-tagged antibodies against ubiquitous surface proteins could uniquely label different experimental samples, which enabled the pooling of these together and use the barcoded antibody signal as a fingerprint for reliable demultiplexing (pg. 2, col 1, first full paragraph, lines 1-9). Stoeckius teaches that by labeling and pooling eight human PBMC samples and running them simultaneously in a single droplet based scRNAseq run, cell hashtags allow for robust sample multiplexing, confident multiplet identification, and discrimination of low-quality cells from ambient RNA; and “super-loading” of commercial scRNA-seq platforms to substantially reduce costs, this strategy represents a generalizable approach for multiplet identification and multiplexing that can be tailored to any biological sample or experimental design (pg. 2, col 1, first full paragraph, lines 14-24). Stoeckius teaches in Figure 1, sample multiplexing using DNA-barcoded antibodies; (a) a schematic overview of sample multiplexing by cell hashing, wherein cells from different samples are incubated with DNA-barcoded antibodies recognizing ubiquitous cell surface proteins; and distinct barcodes (referred to as hashtag-oligos, HTO) on the antibodies allow pooling of multiple samples into one scRNA-seq experiment, such that after sequencing, cells can be assigned to their sample of origin based on HTO levels (“Methods” section); (b) representative scatter plot showing raw counts for HTO A and HTO B across all cell barcodes, where both axes are clipped at 99.9% quantiles to exclude visual outliers; (c) heatmap of scaled (z-scores) normalized HTO values based on our classifications, wherein multiplets express more than one HTO; and negative populations contain HEK293T and mouse NIH-3T3 cells that were spiked into the experiments as negative controls; (d) tSNE embedding of the HTO dataset, wherein cells are colored and labeled based on our classifications; eight singlet clusters and all 28 cross-sample doublet clusters are clearly present; (e) distribution of RNA UMIs per cell barcode in cells that were characterized as singlets (red), multiplets (violet) or negatives (grey); (f) transcriptome-based clustering of single-cell expression profiles reveals distinct immune cell populations interspersed across donors. B, B cells; T, T cells; NK, natural killer cells; mono, monocytes; DC, dendritic cells, wherein cells are colored based on their HTO classification (donor ID), as in (d) (interpreted as protein expression profiles; and interpreting (a), (d), (e) and (f) as determining the distribution of cell surface proteins on each cell, claim 16) (pg. 3, Figure 1). Stoeckius teaches that UMI distributions of each classification group indicated that only barcodes classified as doublets by both techniques exhibited a positive shift in transcriptomic complexity (Figure 2d) (pg. 4, col 2, first full paragraph, lines 7-11; and Figure 2d). Figure 1 is shown below:
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Stoeckius teaches that Figure 2(b) illustrates count distribution of the most highly expressed HTO for groups of concordant and discordant singlets, wherein both groups have identical classification strength based on cell hashing (pg. 5, Figure 2). Figures 2b and 2d are shown below:
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It is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of uniquely labeling expressed cell surface proteins as exemplified by Stoeckius, 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 modify the method of simultaneously measuring cell proteins and/or target oligonucleotides in single cells via combinatorial indexing with oligonucleotide-tagged proteins comprising an antibody bound to an oligonucleotide handle, which can comprise one or more of a barcode, barcoded primer handle sequences, UMIs, cell-barcoded amplicons, and/or poly-A sequences within a gel or emulsion as disclosed by Engreitz to include the method of cell hashing following a combination of Cite-seq and scRNA-seq as taught by Stoeckius with a reasonable expectation of success in simultaneously uniquely labeling and analyzing ubiquitous cell surface proteins including surface protein expression within pooled cell samples from multiple subjects in a single droplet-based scRNA-seq run; in identifying low-quality cells; and/or in substantially reducing assay costs, while providing a generalizable approach that can be tailored to any biological sample or experimental design.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly
rejected under 35 USC §103(a) as obvious over the art.
Response to Arguments
Applicant’s arguments filed August 25, 2026 have been fully considered but they are not persuasive. Applicants essentially asserts: (a) Engreitz and Stoeckius do not disclose the arrangement recited in amended claim 16, in which an antibody bears a handle oligonucleotide and a separate pool oligonucleotide anneals to the handle oligonucleotide while carrying the recited antibody barcode and vessel-specific pool barcode segments; and nothing in the disclosure teaches annealing a ligation-dependent probe to the handle oligonucleotide of a handle-tagged antibody, or each of the various segments (Applicant Remarks, pgs. 16-18, Section A); (b) the references do not disclose resolving respective cell surface protein expression profiles for those co-encapsulated cells based on respective combinatorial indexes comprising the antibody barcode, vessel-specific pool barcode, and droplet barcode; and Stoeckius identifies cross-sample multiplets and excludes their mixed profiles from downstream single-cell analysis, such that Stoeckius does not resolve the mixed antibody derived-tag counts into respective (Applicant Remarks, pgs. 18-19, Section B); and (c) performing an Engreitz or CITE-seq analysis in parallel with Cell Hashing, that approach would not produce a pool oligonucleotide annealed both to an antibody handle and to a droplet oligonucleotide. It also would not place the antibody barcode, vessel specific pool barcode, and droplet barcode into the claimed sequence-fragment architecture (Applicant Remarks, pgs., 19-20, Section C).
Regarding (a), it is noted that none of the references has to teach each and every claim limitation. If they did, this would have been anticipation and not an obviousness-type rejection. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Additionally, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26USPQ2d 1057 (Fed. Cir. 1993). Moreover, as noted in MPEP 2112.01(I),
where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Applicant’s assertion that the references do not disclose an antibody that bears a handle oligonucleotide and a separate pool oligonucleotide anneals to the handle oligonucleotide while carrying the recited antibody barcode and vessel-specific pool barcode segments; and nothing in the disclosure teaches annealing a ligation-dependent probe to the handle oligonucleotide of a handle-tagged antibody; or each of the various segments, is not found persuasive. As an initial matter, instant claim 16 is broadly recited, and comprises limitations are indefinite and unclear as noted in the 35 USC 112(b) rejections discussed supra. Instant claim 16 does not recite a step of “annealing” handle complement segment to a handle oligonucleotide of a handle-tagged antibody. Instead, claim 16 recites the term “annealed to”, which uses past tense to describe an existing structural feature. For example -
“wherein each pool oligonucleotide comprises the following nucleotide segments: a handle complement segment complementary to, and annealed to, the handle oligonucleotide” in lines 14-17 (e.g., base paired)
The Examiner contends that the combined references teach all of the limitations of the claims. For example -
Engreitz teaches:
Figure 1 shows an antibody comprising an antibody barcode (Figure 1).
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Delivering a mixture of any of the compositions described herein (e.g., including cells) to the oligonucleotide protein complexes, and encapsulating complexes in an individual discrete volume (interpreted as a compartment/droplet).
The individual discrete volume comprises PCR primers on a bead, and detecting the nucleotide sequence of the origin specific barcode sequence, thereby assigning the target oligonucleotide and protein of interest (e.g., the antibody) to a specific individual discrete volume, while maintaining information about sample origin of the target oligonucleotide (interpreted as a barcoded antibody annealed to a barcoded primer/handled oligonucleotide, comprising a volume/vessel-specific barcode; the origin-specific barcode is a vessel-specific pool barcode, claim 16) (col 4, lines 25-35).
PCR can be performed in the individual discrete volumes, wherein cell-barcoded amplicons are generated (interpreting PCR as annealing the pool oligonucleotide to the antibody handle, claim 16) (col 3, lines 50-51).
The cells are mixed with a mixture of padlock probes that hybridize to the PCR handles on the DNA-tagged antibodies (interpreting padlock probes as pool oligonucleotides as a handle complement segment as complementary to, and annealed to (base paired to), the handle oligonucleotide, claim 16) (col 43, lines 25-27).
A barcode receiving adapter can be attached to a polypeptide target molecule (interpreting the target molecule attached to a barcode receiving adaptor as a pool oligonucleotide, claim 16) (col 16, lines 26-27).
A barcode receiving adapter is a molecule configured to accept or receive a nucleic acid barcode, such as an origin-specific nucleic acid barcode, which is capable of hybridizing to a given barcode (for example, an origin-specific barcode), such as via a sequence complementary to a portion or the entirety of the nucleic acid barcode (interpreting the antibody barcode as a capture complement segment; and an antibody barcode segment, claim 16) (col 16, lines 10-18).
A barcode receiving adapter can be used to identify a particular condition related to one or more target molecules, such as a cell of origin or a discreet volume of origin (interpreting the barcode receiving adapter as the vessel-specific pool barcode, claim 16) (col 16, lines 30-33).
Stoeckius teaches:
DNA barcoded antibodies comprising distinct barcodes known as hashtag-oligos (HTO), such that after sequencing, the cells can be assigned to their sample of origin based on the HTO levels (interpreted as barcoded antibodies, and interpreting hashtag-oligos as pool oligonucleotides; and where the barcode identifies the vessel/droplet, claim 16) (pg. 3, Figure 1a).
The combined references of Engreitz and Stoeckius teach all of the limitations of the claims. Thus, the claims remain rejected.
Regarding (b), Applicant’s assertion that the Engreitz and Stoeckius do not disclose resolving respective cell surface protein expression profiles for those co-encapsulated cells based on respective combinatorial indexes comprising the antibody barcode, vessel-specific pool barcode, and droplet barcode, is not found persuasive. As an initial matter, instant claim 16 recites:
“(f) determining from the sequencing in (e) respective cell surface protein expression profiles for individual stained cells, the determining comprising resolving respective cell surface protein expression profiles for the at least two stained cells associated with different vessel-specific pool barcode sequences and co-encapsulated in the at least one compartment based on respective combinatorial indexes comprising the antibody barcode, the vessel-specific pool barcode, and the droplet barcode” in lines 67-72.
Thus, instant claim 16 does not recite resolving mixed antibody-derived-tag counts into respective, usable cell surface protein expression profiles for co-encapsulated cells. The Examiner asserts that the combined references teach all of the limitations of the claims, including:
Engreitz teaches:
The invention involves high-throughput single-cell RNA-seq and/or targeted nucleic acid profiling (for example, sequencing, quantitative reverse transcription polymerase chain reaction, and the like) where the RNAs from different cells are tagged individually, allowing a single library to be created while retaining the cell identity of each read. In this regard reference is made to Macosko et al., 2015, "Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets" Cell 161, 1202-1214; International patent application number PCT/US2015/049178, published as WO2016/040476 on Mar. 17, 2016; Klein et al., 2015, "Droplet Barcoding for Single-Cell Transcriptomics Applied to Embryonic Stem Cells" Cell 161, 1187-1201; International patent application number PCT/US2016/027734, published as WO2016168584A1 on Oct. 20, 2016; Zheng, et al., 2016, "Haplotyping germline and cancer genomes with high-throughput linked-read sequencing" Nature Biotechnology 34, 303-311; Zheng, et al., 2017, "Massively parallel digital transcriptional profiling of single cells" Nat. Commun. 8, 14049 doi:10.1038/ncomms14049; International patent publication number WO 2014210353 A2; Zilionis, et al., 2017, "Single-cell barcoding and sequencing using droplet microfluidics" Nat Protoc. January; 12(1):44-73; Cao et al., 2017, "Comprehensive single cell transcriptional profiling of a multicellular organism by combinatorial indexing" bioRxiv preprint first posted online Feb. 2, 2017, doi:dx.doi.org/10.1101/104844; and Rosenberg et al., 2017, "Scaling single cell transcriptomics through split pool barcoding" bioRxiv preprint first posted online Feb. 2, 2017, doi:dx.doi.org/10.1101/105163, all the contents and disclosure of each of which are herein incorporated by reference in their entirety (interpreted as encompassing determining from sequencing cell surface protein expression profiles for individual stained cell including resolving respective cell surface protein expression profiles for the at least two stained cells associated with different vessel-specific pool barcode sequences and co-encapsulated in at least one compartment based on combinatorial indexes, claim 16) (col 27, lines 10-42);
wherein systems and methods for manipulating droplets within a high throughput microfluidic system is known in the art, where the RNA of each cell with a ‘cell barcode’ unique to that cell/drop, measure the expression level of each RNA with sequencing, and then use the cell barcodes to determine which cell each RNA molecule came from; and Figure shows a microfluid droplet (10) encapsulates a differentiated cell (not shown in the figure), wherein the cell is lysed and its mRNA (20) is hybridized onto a capture bead containing barcoded oligo dT primers on the surface (30) (40), all inside the droplet, such that the barcode is covalently attached to the capture bead, wherein since all of the mRNA from any given cell is uniquely barcoded, a single library is sequenced and then computationally resolved to determine which mRNAs came from which cells, such that through a single sequencing run, tens of thousands (or more) of distinguishable transcriptomes can be simultaneously obtained as evidenced by Regev (interpreted as resolving expression profiles for stained cells associated with different vessel-specific barcodes) (WO2016040476, paragraphs [0005]; and [00108]); and
wherein the 3' end of a barcoded primer is terminated with a poly-T sequences that may be used to capture cellular mRNA for whole transcriptome profiling, wherein the resulting library combining all cells can optionally be enriched using PCR-based methods or using hybridization capture-based methods (such as Agilent Sure Select), e.g., to allow sequencing of only a sub-set of genes of interest; and/or where the 3' end of the barcoded primers can terminate with a random DNA sequence that can be used to capture the RNA in the cell as evidenced by Weitz (pg. 12, lines 22-28).
wherein drop-seq, a strategy for quickly profiling thousands of individual cells by separating them into nanoliter-sized aqueous droplets, associating a different barcode with each cell’s RNAs, and sequencing them all together, wherein drop-seq analyzes mRNA transcripts from thousands of individual cells simultaneously while remembering transcripts’ cell of origin is known in the art as evidenced by Macosko (Abstract).
wherein characterizing cellular diversity, but current methods use custom microfluidics or microwells to compartmentalize single cells, limiting scalability and widespread adoption, wherein Split Pool Ligation-based Transcriptome sequencing (SPLiT-seq), a scRNA-seq method that labels the cellular origin of RNA through combinatorial indexing; and that SPLiT-seq workflow begins with an in situ reverse transcription = reaction that converts RNA to cDNA within formaldehyde fixed cells in suspension, wherein the cells are then subjected to a combinatorial indexing procedure consisting of several split-ligate-pool rounds, such that to initiate the first round of indexing, cells are randomly distributed into a 96 well plate, with each well containing a unique DNA barcode is known in the art as evidenced by Rosenberg (Abstract; and pg. 2, second full paragraph).
Stoeckius teaches
A multiplexing strategy that enables pooling across donors but also the simultaneous profiling of multiple experimental conditions, which is widely applicable to the simultaneous profiling of diverse environmental and genetic perturbations (interpreted as resolving expression profiles, claim 16) (pg. 5, col 2, first full paragraph).
Transcriptome-based clustering of single-cell expression profiles reveals distinct immune cell populations interspersed across donors. (B) B cells; T, T cells; NK, natural killer cells; mono, monocytes; DC, dendritic cells, wherein cells are colored based on their HTO classification (donor ID), as in (d) (interpreted as resolving expression profiles, claim 16) (pg. 3, Figure 1a).
The combined references of Engreitz and Stoeckius teach all of the limitations of the claims. Thus, the claims remain rejected.
Regarding (c), Applicant’s assertion that amended claim 16 recites more than detecting a multiplet; and that performing an Engreitz or CITE-seq analysis in parallel with Cell Hashing, that approach would not produce a pool oligonucleotide annealed both to an antibody handle and to a droplet oligonucleotide. It also would not place the antibody barcode, vessel specific pool barcode, and droplet barcode into the claimed sequence-fragment architecture, is not found persuasive. As an initial matter, instant claim 16 does not recite “detecting a multiplet”. Moreover, MPEP 2144(I) states:
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning).
Please see the Examiner responses to Applicant’s arguments regarding the teachings of Engreitz and Stoeckius supra, as well as, the teachings of Engreitz and Stoeckius. Additionally, the Examiner has not suggested performing cite-seq analysis in parallel with cell hashing as argued by Applicant. Applicants are reminded that the motivation for combining the teachings of the prior art may be different from Applicants’ motivation to make the disclosed compositions. The fact that applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). The Office has provided motivation for modifying the method of simultaneously measuring cell proteins and/or target oligonucleotides in single cells via combinatorial indexing with oligonucleotide-tagged proteins comprising an antibody bound to an oligonucleotide handle, which can comprise one or more of a barcode, barcoded primer handle sequences droplet as disclosed by Engreitz to include the method of cell hashing following a combination of cite-seq and scRNA-seq as taught by Stoeckius to simultaneously unique label and analyze ubiquitous cell surface proteins including surface protein expression within pooled cell samples from multiple subjects in a single droplet-based scRNA-seq run; and providing a generalizable approach that can be tailored to any biological sample or experimental design. Thus, the claim remain rejected.
New Objections/Rejections
Claim Objections
Claims 16 is objected to because of the following informalities: Claim 16, line 39 recites a mixture of pronouns including “the” and “said” within each claim, such that for consistency, a single pronoun reciting either “the” or “said” should be used.
Appropriate correction is required.
Conclusion
Claims 16 and 21-23 is rejected.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M BUNKER whose telephone number is (313) 446-4833. The examiner can normally be reached on Monday-Friday (6am-2:30pm).
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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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/AMY M BUNKER/Primary Examiner, Art Unit 1684
