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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office Action has been withdrawn pursuant to 37 CFR 1.114.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 June 9, 2026 has been entered.
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, 7-9, 11, 13-17, 26, 28, 55, 60-63, 67 and 69-73 are currently pending in the instant application. Claims 1, 7 and 63 have been amended by Applicants’ amendment filed 06-09-2026. Claim 73 has been added by Applicants’ amendment filed 06-09-2026. Claims 57, 59, 64-66, 68 and 70 have been canceled by Applicants’ amendment filed 06-09-2026.
Applicant's election with traverse of Group I, claims 1 and 7-13 (claims 10 and 12, now canceled), directed to a method, and the election of Species as follows:
Species (A): wherein attaching comprises ligating the first oligonucleotide of the plurality of oligonucleotides to the first biological molecule (claim 7);
Species (B): wherein the plurality of oligonucleotides further comprises one or more adaptor sequences (claim 11);
Species (C): wherein the tissue section is a biopsy sample (claim 17); and
Species (D): wherein the first signal sequence is a tag oligonucleotide (claim 28), in the reply filed on September 23, 2019 was previously acknowledged.
Claims 14-18, 26, 28-32, 53 and 54 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.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 September 23, 2019.
Claims 8, 9 and 12 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.
The restriction requirement was deemed proper and was made FINAL.
The claims will be examined insofar as they read on the elected species.
Therefore, claims 1, 7, 11, 13, 55, 60-63, 67, 69 and 71-73 are under consideration to which the following grounds of rejection are applicable.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on January 28, 2026 and June 9, 2026 have been considered. Initialed copies of the IDSs accompany this Office Action.
Priority
The present application, filed September 29, 2017, is a 35 U.S.C. 371 national stage filing of
International Application No. PCT/US16/28118, filed on April 18, 2016, which claims the benefit of claims
the benefit of US Provisional Patent Application 62/149,385, filed April 17, 2015; US Provisional Patent Application 62/148,747, filed April 17, 2015 (now abandoned); and US Provisional Patent Application 62/148,758, filed April 15, 2015.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed June 9, 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.
Maintained Objections/Rejections
Claim Interpretation: the term “coats” such as recited in claim 1 is interpreted to refer to the initiator species being in contact with, partially covered by, and/or entirely covered by the polymer gel.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1, 7, 11, 13, 55, 60-63, 67, 69, 71 and 72 is maintained, and claim 73 is newly rejected, 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.
The rejection of claims 1 and 63 is maintained as being indefinite for the recitation of the term “a surface of the substrate comprises an initiator species” such as recited in claim 1, lines 2, 4 and 12 because the purpose of the initiator species in the method of claims 1 and 63 is completely unclear. Instant claims 1 and 63 recite a surface of a substrate comprising an initiator species, wherein the initiator species can be coated by a polymer gel; however, the initiator species is not recited to bind any other molecule, such that it does not appear have any function or to serve any purpose in the method of claims 1 and 63 and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the terms “the initiator species comprises at least one organosilane comprising at least two distinct surface bonding groups” such as recited in claim 1, lines 4-5 because each organosilane initiator species recited in claim 1 do not comprise two distinct surface bonding groups as recited in claim 1 (e.g., (MeO)3Si comprises three identical –OMe bonding groups). Moreover, when the initiator species actually binds to the surface, all of the bonding groups are will also be the same (e.g., --OH), such that the claim as recited is completely unclear and, thus, the metes and bounds of the claim cannot be determined.
Claims 1 and 63 are indefinite for the recitation of the term “facilitates” such as recited in claim 1, line 9 because the term “facilitates” is relative terms that renders the claim indefinite. The term “facilitates” is not defined by the claim, and the Specification does not provide a standard for ascertaining the requisite amount of facilitation as compared to some other value that qualifies as an “facilitating contact”, such that one of ordinary skill in the art would not be reasonably appraised of the scope of the invention and, thus, the metes and bounds of the claim cannot be determined.
Claims 1, 55, 60, 61 and 63 are indefinite for the recitation of the term “smaller” such as recited in claim 1, line 20 because it is unclear what dimension of the feature is being referred to as being “smaller” (e.g., area, depth, radius, length, height, width, etc.) and, thus, the metes and bounds of the claim cannot be determined. Moreover, the term “smaller” is relative term that renders the claim indefinite. The term “smaller” is not defined by the claim, and the Specification does not provide a standard for ascertaining the requisite radius, area, height, length, width, etc. as compared to some other value that identifies the feature as being “smaller” than 0.5 mm, such that one of ordinary skill in the art would not be reasonably appraised of the scope of the invention and, thus, the metes and bounds of the claim cannot be determined.
Claims 1 and 63 are indefinite for the recitation of the terms “sequencing information” and “location information” such as recited in claim 1, lines 38-39 because claims 1e and 1f do not recite obtaining “sequencing information” and “location information” and, thus, the metes and bounds of the claim cannot be determined.
Claim 7 is indefinite for the recitation of the term “ligating the plurality of oligonucleotides to the plurality of biological molecules” such as recited in claim 7, lines 1-2 because it is unclear how many biological molecules ligate to each oligonucleotide, and whether each oligonucleotide comprises a plurality of biological molecules, whether each oligonucleotide comprises a single biological molecule, whether some oligonucleotides do not ligate to a biological molecule, etc. The instant as-filed Specification does not appear to teach wherein each oligonucleotide comprises a plurality of biological molecules (e.g., the as-filed Specification suggests in Figure 4B that each oligonucleotide binds a single biological molecule) and, thus, the metes and bounds of the claim cannot be determined.
Claim 71 and 72 are indefinite for the recitation of the term “at least three distinct barcode sequences” such as recited in claim 71, lines 1-2. There is insufficient antecedent basis for the term “at least three distinct barcode sequences” in the claim because claim 1, line 16-17 recites that each oligonucleotide comprises “a distinct barcode sequence”. Moreover, instant claim 71 depends from claim 1, and claim 72 depends from instant claim 63, wherein claims 1 and 63 do not recite that each oligonucleotide comprises a plurality of unique or distinct barcodes. Additionally, the as-filed Specification and original claims do not teach that each oligonucleotide comprises a plurality of distinct barcode sequences including three distinct barcodes. Instead, the as-filed Specification teaches that each spatial barcode oligonucleotide will include a unique spatial barcode sequence (paragraphs [0028]; and [0036]; and Figure 5); and that each feature or location on the array includes one distinct barcode sequence (paragraph [0032]) and, thus, the metes and bounds of the claim cannot be determined.
Claim 73 is indefinite for the recitation of the term “each of the at least two surface bonding groups is (HO)2P=O” such as recited in claim 73, lines 1-2 because the structure recited is at least part of an initiator species (e.g., the surface bonding group is –OH), such that the structure comprises more than the recited surface bonding groups. Moreover, claim 73 depends from instant claim 63, wherein claim 63 recites that the initiator species is an “organo-phosphonic acid”, such the structure recited in claim 73 does not comprise an organic portion, such that it is unclear what the structure actually represents and, thus, the metes and bounds of the claim cannot be determined.
Claims 11, 13 and 62 are indefinite insofar as they ultimately depend from instant claim 1. Claims 67, 69 and 70 are indefinite insofar as they ultimately depend from instant claim 63.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 7, 11, 13, 55, 61, 62 and 71 is maintained under 35 U.S.C. 103 as being unpatentable over Eltoukhy et. al. (hereinafter “Eltoukhy”) (US Patent Application Publication No. 20160046986, filed on September 22, 2015, published February 18, 2016; International Application PCT/US2014/072383, filed December 24, 2014; of record) in view of Rajasekaran et. al. (hereinafter “Rajasekaran”) (US Patent Application No. 20140349888, published November 27, 2014; PCT/US2013/025190, fled February 7, 2013; of record) as evidenced by Holt et al. (hereinafter “Holt”) (Genome Research, 2008, 18, 839-846; of record); and Gunderson et al. (hereinafter “Gunderson”) (US Patent No. 10619204, issued April 14, 2020; PCT/EP2015/076353, filed November 11, 2015; of record); and Illumina (Illumina, 2009, 1-4; of record); and Beckman Coulter (Beckman Coulter, 2000, 1-4; of record).
Regarding claims 1 (in part), 11 and 13, Eltoukhy teaches methods to reduce or combat the errors introduced by the sample preparation and sequencing processes for all molecules that are converted and sequenced (paragraph [0005]). Eltoukhy teaches providing cell free polynucleotides from bodily fluid of (a) a test sample and (b) a control sample; then tagging polynucleotides, wherein the tag includes a source identifier (test or control) and, optionally a further identifier (optionally with duplex tags), such that polynucleotides can be uniquely or non-uniquely tagged (interpreted as contacting a biological sample with spatial barcode array; tagged the same and/or differently; the oligonucleotide has a 5’ end and the biological molecule has a 3’ end; and at least two distinct barcodes, claims 1a, 1d, 63a and 63d) (Figure 8). Eltoukhy teaches a method for detecting and/or quantifying rare deoxyribonucleic acid (DNA) in a heterogeneous population of original DNA fragments, comprising tagging the original DNA fragments in a single reaction including within a single reaction vessel using a library of a plurality of different tags such that >30% or >50% of the fragments are tagged at both ends, wherein the plurality of different tags can be no more than any of 100, 500, 1000, 10,000 or 100,000 different tags (interpreted as at least two distinct tags, claims 1 and 63) (paragraph [0007]). Eltoukhy teaches that a barcode can comprise contiguous or non-contiguous sequences; and at least 1, 2, 3, 4, 5 or more nucleotides (interpreted as barcodes is at most 35 bases, claims 1a and 63a) (paragraph [0121]). Eltoukhy teaches that the invention provides a set of library adaptors that can be used to tag the molecules of interest (e.g., by ligation, hybridization, etc.), wherein the set of library adaptors can comprise plurality of polynucleotide molecules with molecular barcodes including polynucleotide molecules are less than or equal to 80 nucleotide bases in length, wherein the molecular barcodes are at least 4 nucleotide bases in length, and wherein the molecular barcodes are: (a) different from one another and have an edit distance of at least 1 between one another; (b) located at least one nucleotide base away from a terminal end of their respective polynucleotide molecules; (c) optionally, at least one terminal base is identical in all of the polynucleotide molecules; and (d) none of the polynucleotide molecules contains a complete sequencer motif (interpreting the polynucleotide molecules as tagged biological molecules; an edit distance of at least one; ligating; and oligonucleotides comprises adapters, claims 1b, 11 and 63b) (paragraph [0008]). Eltoukhy teaches that a library of polynucleotides comprising a plurality of polynucleotide molecules can also have distinct (with respect to each other) molecular barcode sequences with respect to at least 4, 10, 20, 30, 40, 50 or more nucleic acid bases, wherein the molecular barcode (also "barcode" or "identifier" herein) sequence is a nucleotide sequence that distinguishes one polynucleotide from another (interpreted as distinct barcode sequences including at least four distinct barcode sequences; identifies the oligonucleotide location to within 0.5 microns; and encompassing identifying x and y coordinates on an array, claims 1a, 13, 63a, 70 and 71) (paragraph [0126]). Eltoukhy teaches that a sequencing adaptor can comprise one or more barcodes including a sample barcode, which can comprise a predetermined sequence that can be used to identify the source of the polynucleotides (interpreted as tagged biological molecules, claim 1b and 63b) (paragraph [0137], last ten lines). Eltoukhy teaches analyzing a sample comprising nucleic acids from a subject, wherein the system includes a sequencer, bioinformatic software and internet connection for report analysis by, for example, a hand-held device or desktop computer (interpreted as analyzing sequencing information; generating a gene expression profile; and detecting a target sequence, claims 1c, 1d, 1f, 63c, 63d and 63f) (paragraph [0276]). Eltoukhy teaches a method for detecting copy number variation in a DNA molecule in a biological sample of a subject, comprising: (a) attaching adapters to ends of fragments generated from said DNA molecules in said biological sample of said subject, wherein said adapters tag a 5' end of a strand of an individual fragment among said fragments with a first tag and a 3' end of a complementary strand of said individual fragment with a second tag, thereby providing tagged fragment molecules (interpreted as attaching an oligonucleotide having a 5’ end and a biological molecule has a 3’end, claim 1d and 63d) (pg. 32, col 2, claim 19). Eltoukhy teaches in Figure 9B that the library of adaptors are ligated at both ends of the target polynucleotide molecules to provide a tagged target polynucleotide molecule, wherein the library adaptor is less than or equal to 80 nucleotide bases in length (interpreted as attaching an oligonucleotide having a 5’ end and a biological molecule has a 3’end, claim 1d and 63d) (paragraph [0152], lines 7-11; and Figure 9B). Eltoukhy teaches analyzing the nucleotide sequences with a programmed computer processor to identify one or more genetic variants in the nucleotide sample of the subject including one or more genetic variants are selected from the group consisting of base change(s), insertion(s), repeat(s), deletion(s), copy number variation(s) and transversion(s), wherein the one or more genetic variants include one or more tumor associated genetic alterations (interpreted as generating a gene expression profile; deletions, insertions, or substitutions; using barcodes to target nucleic acid positioning comprising one or more mutations or epigenetic modifications, claims 1e, 1f, 63e and 63f) (paragraph [0027]). Eltoukhy teaches that the substrate can be a bead or planar surface including a surface of a bead for an Illumina flow cell; and that the sample is subjected to proteinase K digestions, DNA is precipitated, and captured on a DNA purification column, where DNAs below 500 bp are selected with Ampure SPRI magnetic bead capture (interpreted as each feature having a size less than 0.5 mm, claims 1 and 63) (paragraphs [0131]; and [0287]), where it is known that SPRI beads are coated with carboxy groups, and have a size of 1 mm as evidenced by Beckman Coulter (pg. 3, first full paragraph). Eltoukhy teaches that the polynucleotides can be amplified including by PCR, and sequenced by massively parallel sequencing to simultaneously sequence any of at least 100, 1000, 10,000, 100,000, 1 million, 100 million, or 1 billion polynucleotide molecules, wherein sequencing methods include high-throughput sequencing, pyrosequencing, sequencing-by-synthesis, single-molecule sequencing, nanopore sequencing, semiconductor sequencing, sequencing-by-ligation, sequencing-by-hybridization, RNA-Seq (Illumina), Digital Gene Expression (Helicos), Next Generation Sequencing, Single Molecule Sequencing by Synthesis (SMSS) (Helicos), massively-parallel sequencing, Clonal Single Molecule Array (Solexa), shotgun sequencing, Maxam-Gilbert or Sanger sequencing, primer walking, sequencing using PacBio, SOLiD, Ion Torrent, or Nanopore platforms (interpreted as encompassing oligonucleotides on an array located in a feature size within 0.5 microns; and amplification and sequencing, claims 1 and 63) (paragraphs [0156]; and [0159]); wherein it is known that the 454 flow cell comprises a fiber optic slide with ~1.6 million 75-piocliter wells; and that in the Illumina system, templates are applied at high density to the flow cells, while Helicos applies templates at very high density as evidenced by Holt (pg. 840, col 1, first full paragraph; and col 2, first full paragraph; and pg 842, col 2, first full paragraph); and it is known that the number of features within a microarray includes about 5,000,000 templates/cm2 or higher as evidenced by Gunderson (col 70, lines 19-20). Eltoukhy teaches that the a sequencing adaptor is adapted to permit a sequencing instrument to sequence a target polynucleotide, wherein the sequencing adaptor comprises a nucleotide sequence that hybridizes or binds to a capture polynucleotide attached to a solid support of a sequencing system such as a flow cell (interpreting sequencing adaptors as tagged oligonucleotides; and interpreting attachment to a flow cell as contacting a biological sample with a spatial barcode array comprising a substrate comprising a plurality of features, claims 1a and 63a) (paragraph [0087]). Eltoukhy teaches that tagged cell-free DNA fragments are amplified by PCR, the amplified fragments are enriched using beads comprising oligonucleotide probes that specifically bind to a group of cancer-associated genes (interpreted as amplification and sequencing; oligonucleotides; a solid support; tagged fragments; generating a gene expression profile; and a target sequence, claims 1c, 1d, 1f, 63c, 63d and 63f) (paragraph [0336]). Eltoukhy teaches that the method comprises quantifying polynucleotides in the sample bearing a nucleotide sequence variant at each of a plurality of genetic loci; determining copy number variation (CNV) at each of the plurality of genetic loci, wherein the CNV indicates a genetic dose of a locus in the disease cell polynucleotides; determining with a programmed computer processor a relative measure of quantity of polynucleotides bearing a sequence variant at a locus per the genetic dose at the locus for each of a plurality of the loci; and comparing the relative measures at each of the plurality of loci, wherein different relative measures is indicative of tumor heterogeneity (interpreted as generating a quantitative gene expression profile; spatial information including obtaining information on the location of biological molecules with in the sample, claims 1g and 63g) (paragraph [0066]). Eltoukhy teaches that sequence reads or consensus sequences can be mapped to one or more selected genetic loci (e.g., as shown step (110), Figure 1), wherein a genetic locus can be, for example, a specific nucleotide position in the genome, a sequence of nucleotides (for example, an open reading frame), a fragment of a chromosome, a whole chromosome, or an entire genome (interpreted as spatial information including obtaining information on the location of biological molecules with in the sample, claims 1g and 63g) (paragraph [0176]). Eltoukhy teaches that a consensus sequence can be generated using any collapsing method disclosed herein, and then the consensus sequence can be mapped to locations in the genome, and reads mapped to a locus can be quantified (e.g., counted) (interpreted as generating a quantitative gene expression profile; spatial information including obtaining information on the location of biological molecules with in the sample, claims 1g and 63g) (paragraph [0178]). Eltoukhy teaches that each of the library adaptors comprises a molecular barcode that is at least 5, 6, 7, 8, 9 and 10 nucleotide bases in length and/or the library adaptors is from 10 nucleotide bases to 80 in length, and that in some cases, at least 1, 2, 3, or 4 terminal bases are identical in all library adaptors (interpreted as encompassing wherein the barcode sequence of 5-35 bases; and comprising an adaptor, claims 1, 11 and 63) (paragraph [0012]). Eltoukhy teaches that the present disclosure can be used to detect genetic variation in non-uniquely tagged initial starting genetic material (e.g., rare DNA) at a concentration that is less than 5% (interpreted as distinct barcodes) (paragraph [0251], lines 1-4). Eltoukhy teaches that a library of polynucleotides comprising a plurality of polynucleotide molecules can also have distinct (with respect to each other) molecular barcode sequences with respect to at least 4, 10, 20, 30, 40, 50 or more nucleic acid bases, wherein the molecular barcode (also "barcode" or "identifier" herein) sequence is a nucleotide sequence that distinguishes one polynucleotide from another (interpreted as distinct barcode sequences encompassing 5-35 bases, claims 1a and 63a) (paragraph [0126]).
Regarding claim 7, Eltoukhy teaches high-efficiency DNA tagging (>80%) is performed by blunt-end repair and ligation with 8 different octamers with overloaded hairpin adaptors (interpreting blunt-end repair and ligation as including phosphorylation of the oligonucleotide, claim 7) (paragraph [0289]). Eltoukhy teaches that a polynucleotide can include one or more subunits selected from a group including adenosine (interpreted as encompassing adenylation, claim 7) (paragraph [0082], lines 1-4). Eltoukhy teaches that a sequence adaptor can be a polynucleotide that comprises a sequence that hybridizes to one or more sequencing adaptors or primers, wherein the sequencing adaptor can comprise a sequence that hybridizes to a solid support, such as a flow cell sequence; and that the term "flow cell sequence" refers to a sequence that permits hybridization to a substrate, for example, by way of a primer attached to the substrate, wherein the substrate can be bead or a planar surface (interpreting beads etc. as a solid support; and interpreting the planar surface as a flat surface, claim 63a) (paragraph [0131]).
Regarding claims 55, 60 and 61, Eltoukhy teaches that the polynucleotides can be amplified including by PCR, and sequenced by massively parallel sequencing to simultaneously sequence any of at least 100, 1000, 10,000, 100,000, 1 million, 100 million, or 1 billion polynucleotide molecules, wherein sequencing methods include high-throughput sequencing, pyrosequencing, sequencing-by-synthesis, single-molecule sequencing, nanopore sequencing, semiconductor sequencing, sequencing-by-ligation, sequencing-by-hybridization, RNA-Seq (Illumina), Digital Gene Expression (Helicos), Next Generation Sequencing, Single Molecule Sequencing by Synthesis (SMSS) (Helicos), massively-parallel sequencing, Clonal Single Molecule Array (Solexa), shotgun sequencing, Maxam-Gilbert or Sanger sequencing, primer walking, sequencing using PacBio, SOLiD, Ion Torrent, or Nanopore platforms (interpreted as encompassing oligonucleotides on an array located in a feature size within 0.5 microns, 0.4 microns, 0.2 microns, and 0.1 microns; and amplification and sequencing, claims 1, 55, 60, 61 and 63) (paragraphs [0156]; and [0159]); wherein the feature size for Solexa sequencing is 1.0 microns to submicron levels as evidenced by Illumina (pg. 3, col 2, Data Density); and wherein it is known that the 454 flow cell comprises a fiber optic slide with ~1.6 million 75-piocliter wells; and that in the Illumina system, templates are applied at high density to the flow cells, while Helicos applies templates at very high density as evidenced by Holt (pg. 840, col 1, first full paragraph; and col 2, first full paragraph; and pg 842, col 2, first full paragraph); and it is known that the number of features within a microarray includes about 5,000,000 templates/cm2 or higher as evidenced by Gunderson (col 70, lines 19-20). Eltoukhy teaches that a library of polynucleotides comprising a plurality of polynucleotide molecules can have an edit distance of at least one, wherein in some cases the plurality of polynucleotide molecules can have an edit distance of at least 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or more; and the edit distance can be a Hamming distance (interpreted as including an edit distance of 4, claims 1a, and 63a) (paragraph [0130]). Eltoukhy teaches that DNA fragments, comprising tagging the original DNA fragments in a single reaction including within a single reaction vessel using a library of a plurality of different tags such that >30%or >50% of the fragments are tagged at both ends, wherein the plurality of different tags (interpreted as barcode sequences for each oligonucleotide are different, claims 1 and 63) (paragraph [0008]).
Regarding claims 62, Eltoukhy teaches that sequencing adaptor can further comprise a sequence hybridizing to a solid support including a planar surface, such as a flow cell sequence (interpreted as a solid support; and a flat surface, claims 62 and 67, in part) (paragraphs [0131]; and [0137], lines 4-6). Eltoukhy teaches that selective enrichment can be performed using a solid support (e.g., beads), wherein the beads can comprise probes (e.g., oligonucleotides) specifically hybridizing to certain sequences (interpreted as a solid support, claim 62) (paragraph [0213], lines 4-6).
Regarding claim 71, Eltoukhy teaches that the molecular barcodes are located at least 10 nucleotide base away from a terminal end of an adapter, wherein the plurality of library adapters includes at least 2, 4, 6, 8, 10, 20, 30, 40 or 50 different molecular barcodes, or from 2-100, 4-80, 6-60 or 8-40 different molecular barcodes (interpreted as each oligonucleotide comprising an adaptor, and at least three distinct barcode sequences, claims 1 and 71) (paragraph [0013]). Eltoukhy teaches that a library of polynucleotides comprising a plurality of polynucleotide molecules can also have distinct (with respect to each other) molecular barcode sequences (interpreted as distinct barcode sequences, claims 71 and 72) (paragraph [0126]).
Eltoukhy does not specifically exemplify the initiator species comprising at least two distinct surface bonding groups (claim 1, in part).
Regarding claims 1 (in part), Rajasekaran teaches formulations, substrates and arrays, and methods for identifying peptide sequences useful for diagnosis and treatment of disorders, wherein substrates and arrays comprise a porous layer for synthesis and attachment of polymers or biomolecules (interpreted as substrates and arrays, claims 1 and 63) (Abstract). Rajasekaran teaches that the uses of such an array include, but are not limited to, diagnostic microbiology, including the detection and identification of pathogens, investigation of anti-microbial resistance, epidemiological strain typing, investigation of oncogenes, analysis of microbial infections using host genomic expression, and polymorphism profiles; as well as, determining binding specificity of a plurality of antibodies to one or more features of the array; and imaging an intensity profile (interpreted as generated a gene expression profile, claim 1) (paragraphs [0003]; [0050]; and [0348]). Rajasekaran teaches peptide arrays with distinct analyte-detecting regions or probes can be assembled on a single substrate (paragraph [0005]). Rajasekaran teaches an array of features attached to a surface at positionally-defined locations (interpreted as an array of features on a solid support having an x and y location, claims 1 and 63) (paragraph [0014]). Rajasekaran teaches that the method includes producing an array of features, comprising: obtaining a surface; attaching the features to the surface, the features each comprising a collection of peptide chains of determinable sequence and intended length, wherein within an individual feature, the fraction of peptide chains within the collection having the intended length is characterized by an average coupling efficiency for each coupling step of at least 98% (interpreted as features on a surface or solid support, claims 1 and 63) (paragraph [0021]). Rajasekaran teaches that substrates can be surfaced derivatized in a semiconductor module as explained in US Patent Application 2010/0240555, herein incorporated by reference in its entirety, for all purposed, wherein surface derivatization is a method wherein an amino silane group is added to the substrate so that free amino groups are available for coupling a biomolecule (interpreted as encompassing organosilanes for coupling biomolecules; and binding biomolecules, claims 1 and 63) (paragraph [0228]). Rajasekaran teaches that the wafer surface is derivatized using aminopropyl triethoxysilane (APTES) (interpreted as comprising at least two surface bonding groups; and (EtO)3Si, claims 1 and 63) (paragraph [0283]). Rajasekaran teaches wafer fabrication, silane deposition is generally needed to promote the chemical adhesion of an organic compound (photoresist) to a non-organic substrate (wafer), wherein the silane acts as a sort of "bridge," with properties that will bond to both the photoresist and wafer surface including hexamethyldisilizane (HMDS) (interpreted as an organosilane initiator species, claim 66) (paragraph [0217], lines 8-14). Rajasekaran teaches that the plurality of pillars are present at a density of greater than 10,000/cm2; that the surface area of each pillar is 1 mm2; distance between the surface of each pillar and the lower surface of the layer is 2,000-7,000 angstroms; and the center of each pillar is at least 2,000 angstroms from the center of any other pillar (interpreted as encompassing less than 0.5 microns to 0.1 microns, claims 55, 60 and 61) (paragraphs [0023]; and [0034]).
Regarding claims 67, 69 and 70, Rajasekaran teaches that porous layers are permeable, polymeric materials of porous structure which have a functional group native to the constituent polymer or which is introduced to the porous layer for attachment of the first peptide building block, wherein the polymeric material includes polyacrylamides, wherein the porous layer can range from 0.01 microns to about 1,000 microns (interpreted as polyacrylamide polymer, claims 67 and 70) (paragraph [0199]). Rajasekaran teaches that Figures 2A and 2B illustrate a derivatized surface (e.g., a surface derivatized wafer) with a linker molecule attached is spun coat with a photoactive formulation (photoresist) as described herein, wherein the resist thickness can be 100 nm to 200 nm to enable better photoacid diffusion; and the spin speed can be modified to achieve the desired thickness of the resist (interpreted as a coating including a sub-200 nm coating of a polymer including polyacrylamide, claim 67) (paragraph [0238]; and Figure 2). Rajasekaran teaches in Figure 2F, a cap film solution coat is applied on the wafer to prevent the unreacted amino groups on the substrate from reacting with the next coupling molecule (interpreted as coating with polymer, claims 67, 69 and 70) (paragraph [0247], lines 1-3; and Figure 2F). Rajasekaran teaches that a substrate can include a gelatinous form of a water soluble polymer in contact with the surface or at least one of said pillars; and that surface materials include, for example, silicon, bio-compatible polymers such as poly(methyl methacrylate) (PMMA) and polydimethylsiloxane (PDMS), glass, and silicon dioxide (interpreted as a polymer gel including PDMS or polyacrylamide gel coating the initiator species, claims 67, 69 and 70) (paragraphs [0194]; and [0204]).
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 preparing a substrate for use as a high density arrays as exemplified by Rajasekaran, it would have been prima facie obvious before the effective filing date of the claimed invention to modify the method of efficiently and differentially tagging DNA fragments, and reducing errors introduced by sample preparation and sequencing processes as disclosed by Eltoukhy to include the methods of producing high density peptide and polypeptide arrays including through the use of photoactive formulations as taught by Rajasekaran with a reasonable expectation of success in producing a substrate binding assay having significantly improved tagging, coupling efficiency, performance, and/or processability; and/or in using the improved array substrates and efficient tagging methods for the accurate detection and quantification of polynucleotides including for the early detection, monitoring, and treatment of diseases such as cancer; as well as, in reducing sequencing noise, amplification bias and/or in reducing redundancy in sequencing reads to provide for the efficient and accurate detection of rare sequence variants.
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 remarks filed June 9, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) although the APTES taught by Rajasekaran discloses two distinct surface binding groups, it does not teach the surface bonding group selected from MeO3Si, (MeO)3Si, (EtO)3Si, (AcO)3Si, (Me2N)3Si, and (HO)3Si (Applicant Remarks, pg. 13, fifth and sixth full paragraphs).
Regarding (a), 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). Additionally, MPEP § 2112.01(I) states that,
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 although the APTES taught by Rajasekaran discloses two distinct surface binding groups, it does not teach the surface bonding group selected from MeO3Si, (MeO)3Si, (EtO)3Si, (AcO)3Si, (Me2N)3Si, and (HO)3Si, is not found persuasive. As an initial matter, the surface bonding groups present in each of the silane structure recited in claim 1 do not comprise at least two distinct surface bonding groups. All of the surface bonding groups in each of the molecules as recited in instant claim 1 are identical (e.g., -OMe, or -OAc, or -Me, etc.). Applicant cannot have it both ways, the initiator species cannot have two distinct surface bonding groups, and be one of the structures illustrated in instant claim 1. The combined references teach all of the limitations of the claims. Thus, the claims remain rejected.
New Objections/Rejections
Claim Objection
Claims 1, 55, 60, 61 and 63 are objected to because of the following informalities: Claims 1, 55, 60, 61 and 63 recites the term "mm”, where an abbreviation should be spelled out in the first encounter of the claims.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
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.
Claims 71-73 are rejected 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 71 and 72 recite (in part) “wherein each oligonucleotide comprises at least three distinct barcode sequences” in lines 1-2, wherein claim 71 depends from instant claim 1, and claim 72 depends from instant claim 63, such that claims 1 and 63 do not recite that each oligonucleotide comprises a plurality of unique or distinct barcode Thus, claim 71 and 72 are improper dependent claims 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 73 recites (in part): “wherein each of the at least two surface bonding groups is (H0)2P(=O)” in lines 1-2, wherein claim 73 depends from instant claim 63, wherein claim 63 recites that the initiator species is an “organo-phosphonic acid”, such that the structure recited in claim 73 does not recite a surface bonding group alone, and it does not comprise an organic portion. Thus, claim 73 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
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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 7, 11, 13, 55, 60-63, 67, 69 and 71-73 are rejected under 35 U.S.C. 103 as being unpatentable over Frisen et al. (hereinafter “Frisen”) (US Patent Application 20140066318, published March 6, 2014) in view of Torras et. al. (hereinafter “Torras”) (The Journal of Physical Chemistry C, 2014, 118, 17724-17736); and further in view of Eltoukhy et. al. (hereinafter “Eltoukhy”) (US Patent Application Publication No. 20160046986, filed on September 22, 2015, published February 18, 2016; International Application PCT/US2014/072383, filed December 24, 2014; of record)
Regarding claims 1 (in part) and 63 (in part), Frisen teaches the localized spatial detection-determination-analysis means that the RNA or DNA can be localized to its native position within a cell or tissue in the tissue sample (interpreted as spatial detection, claims 1 and 63) (paragraph [0048], lines 8-11). Frisen teaches methods and products for the localized or spatial detection of nucleic acids in a tissue sample comprising: (a) providing an array comprising a substrate on which multiple species of capture probes are directly or indirectly immobilized such that each species occupies a distinct position on the array and is oriented to have a free 3’ end to enable the probe to function as a reverse transcriptase (RT) primer, wherein each species of capture probe comprises a nucleic acid molecule with a 5’ to 3’ comprising: (i) a positional domain that corresponds to the position of the capture probe on the array, and (ii) a capture domain, wherein capture probes include “barcoded” oligo-dT probes; (b) contacting the array with a tissue sample such that the position of a capture probe on the array can be correlated with a position in the tissue sample, allowing the nucleic acids of the tissue sample to hybridize to the capture domain in said capture probes (interpreting an spatial array comprising uniquely barcoded oligonucleotides; and indicative of the location of features on the array, claims 1 and 63); (c) generating DNA molecules from the captured nucleic acid molecules of the tissue sample using the capture probes as extension or ligation primers, wherein the ligated DNA molecules are tagged by virtue of the positional domain (interpreted as binding oligonucleotides to biological molecules claims 1c and 63c); (d) optionally generating a complementary strand of tagged DNA (cDNA) and/or optionally amplifying the tagged DNA (interpreting as amplifying, claims 1d and 63d); (e) releasing at least part of the tagged DNA molecules and/or their complements or amplicons from the surface of the array, wherein said released molecules includes the positional domain or a complement thereof; and (f) directly or indirectly analyzing the sequence of the released molecules such as by sequencing including high-throughput sequencing (interpreted as sequencing, claims 1e and 63e) (Abstract; and paragraphs [0034]-[0043]; [0066], lines 9-11; and [0325]). Frisen teaches that the method relates to a quantitative and/or qualitative method for analyzing the distribution, location or expression of genomic sequences in a tissue sample, wherein spatial expression or distribution or location pattern within the tissue sample is retained, such that the methods result in a global and spatial profile of all transcripts in the tissue sample (interpreted as determining a location of the biological molecule in the sample, claims 1e and 63e) (paragraph [0002], lines 4-8; and [0034], lines 3-5).
Frisen teaches that in standard microarrays, the probes are attached to a solid surface or substrate by a covalent bond to a chemical matrix, e.g. epoxy-silane, amino-silane, lysine, polyacrylamide etc., wherein the substrate typically is a glass, plastic or silicon chip or slide, although other microarray platforms are known, such as microscopic beads (interpreting polyacrylamide as a polymer matrix that coats the surface; and epoxysilane/aminosilane as initiator species, claims 1b and 63b) (paragraph [0070]). Frisen teaches that cells can be captured in a matrix (for example a gel matrix e.g., agar, agarose, etc.) and can then be sectioned in a conventional way (interpreted as an array comprising a polymer gel that facilitates contact with the biological sample, claims 1b and 63b) (paragraph [0125]). Frisen teaches that the method comprising a substrate on which multiple species of capture probes are directly or indirectly immobilized such that each species are directly or indirectly immobilized such hat each species occupies a distinct position on the array and is oriented to have a free 3’ end to enable said probe to function as a reverse transcriptase (RT) primer (paragraph [0049]). Frisen teaches that the capture domain can be selected or designed for the selective capture of mRNA, wherein this can be on the basis of hybridization to the poly-A tail of mRNA, such that the capture domain comprises a poly-T DNA oligonucleotide, which is capable of hybridizing to the poly-A tail of mRNA (paragraph [0091]). Frisen teaches using microarrays with immobilized DNA oligos (oligonucleotides) carrying spatial labeling tag sequences (positional domains), wherein each feature of oligos of the microarray carries (1) a unique labeling tag (positional domain); and (2) capture sequence (capture domain), such that keeping track of where which labeling tag is geographically placed on the array surface makes it possible to extract positional information in two dimensions from each labeling tag (paragraph [0433]). Frisen teaches that a “species” of capture probe is defined with reference to its positional domain; a single species of capture probe will have the same positional domain (paragraph [0096], lines 4-6). Frisen teaches that the capture domain of the capture probe comprises or consists of deoxyribonucleotides (dNTPs), wherein the capture domain comprises a nucleotide sequence that is capable of hybridizing to nucleic acid such as RNA present in cells of the tissue sample contacted with the array (interpreted as the oligonucleotide binding biological molecules in the sample, claims 1 b and 63b) (paragraphs [0086]; and [0090]). Frisen teaches that DNA is amplified inside water droplets in an oil solution (emulsion PCR); and the sequencing machine contains picoliter volume wells containing a single bead and sequencing enzymes (interpreted as sequencing in compartments, claim 1e and 63e) (paragraph [0187]). Frisen teaches that the resultant data can be correlated to images of the original tissue samples including sections through so-called barcode sequences (or ID tags, defined herein as positional domains) incorporated into the arrayed nucleic acid probes (interpreted as determining a location; and generating a quantitative gene expression profile using the sequencing and location information, claims 1g and 63g) (paragraph [0066], lines 11-15). Frisen teaches that the fluorescent marker probes aid in the orientation of the resulting image after tissue visualization, making it possible to combine the image with the resulting expression profiles for individual capture probe “tag” (positional domain) sequences obtained after sequencing (interpreted as determining a location; and generating a quantitative gene expression profile using the sequencing and location information, claims 1g and 63g) (paragraph [378]).
Regarding claim 7, Frisen teaches that ligation requires that the 5’ end to be ligated is phosphorylated, such that the 5’ end of the added linker, namely the end which is to be ligated to the capture probe will be phosphorylated (interpreted as phosphorylating the 5’ end; and ligating, claim 7) (paragraph [0284], lines 7-11).
Regarding claim 11, Frisen teaches that it can be advantageous to block the capture probes prior to contacting the tissue sample with the array, wherein the nucleic acid in the tissues sample (e.g., fragmented genomic DNA) can be modified such that it can be captured by the capture probe, wherein an adaptor sequence comprising a binding domain capable of binding to the capture domain of the capture probe can be added to the end of the nucleic acid (e.g., fragmented genomic DNA) (interpreted as adding adaptors sequences, claim 11) (paragraph [0137], lines 1-13).
Regarding claim 69, Frisen teaches that in standard microarrays, the probes are attached to a solid surface or substrate by a covalent bond to a chemical matrix, e.g. epoxy-silane, amino-silane, lysine, polyacrylamide etc., wherein the substrate typically is a glass, plastic or silicon chip or slide, although other microarray platforms are known, such as microscopic beads (interpreting polyacrylamide as a polymer matrix that coats the surface, claim 69) (paragraph [0070]).
Regarding claim 13, Frisen teaches reverse transcription (RT) primers, which comprise also unique positional tags (domains), to be arrayed on an object substrate, such as a glass slide, to generate an “array”, wherein the unique positional tags correspond to the location of the RT primers on the array (the features of the array)(interpreted as providing x/y coordinates on the barcode array, claim 13) (paragraph [0021], lines 2-7). Frisen teaches that each feature of oligos of the microarray carries a (1) a unique labeling tag (positional domain) and (2) a capture sequence (capture domain); and that keeping track of where which labeling tag is geographically placed on the array surface makes it possible to extract positional information in two dimensions from each labeling tag (interpreted as a plurality of tags; and x-y coordinates, claims 70 and 71) (paragraph [0433]).
Regarding claims 55, 60 and 61, Frisen teaches that a number of standard arrays are commercially available and both the number and size of the features can be varied, such that the arrangement of the features can be altered to correspond to the size and/or density of the cells present in different tissues or organisms, wherein Nimblegen arrays are available with up to 2.1 million features, or 4.2 million features can be preferred for tissue samples from an animal or fungus; and commercial arrays are also available or known for use in the context of sequence analysis and in particular in the context of NGS technologies, where such arrays can also be used as the array surface in the context of the present invention e.g. an Illumina bead array (interpreted as including features smaller than 0.1 mm, claims 55, 60 and 61) (paragraph [0078]).
Regarding claims 62, 67 and 69, Frisen teaches that in standard microarrays, the probes are attached to a solid surface or substrate by a covalent bond to a chemical matrix, e.g. epoxy-silane, amino-silane, lysine, polyacrylamide, etc., wherein the substrate typically is a glass, plastic or silicon chip or slide, although other microarray platforms are known, such as microscopic beads (interpreted as a solid support; include a polymer matrix gel such as agarose; and a polyacrylamide gel, claims 62 and 69) (paragraph [0070]). Frisen teaches that cells can be captured in a matrix (for example a gel matrix e.g., agar, agarose, etc.) and can then be sectioned in a conventional way (interpreted as an array comprising a polymer gel that facilitates contact with the biological sample, claims 67 and 69) (paragraph [0125]).
Regarding claims 71 and 72, Frisen teaches that the RT primers comprise unique positional tags (domains) arrayed on an object substrate such as a glass slide (interpreted as a plurality of tags, claims 70 and 71) (paragraph [0021], lines 2-5). Frisen teaches that the positional domain of each species of capture probe contains a unique barcode sequence that can be generated using a random sequence generator (interpreted as a plurality of tags, claims 70 and 71) (paragraph [0100]). Frisen teaches that each feature of oligos of the microarray carries a (1) a unique labeling tag (positional domain) and (2) a capture sequence (capture domain); and that keeping track of where which labeling tag is geographically placed on the array surface makes it possible to extract positional information in two dimensions from each labeling tag (interpreted as a plurality of tags; and x-y coordinates, claims 70 and 71) (paragraph [0433]).
Frisen does not specifically exemplify an initiator species with two distinct surface groups; and an edit distance of 4 (claim 1, in part); an initiator species comprising organo-phosphonic acid comprising two surface bonding groups (claim 63, in part); and the phosphonic acid surface bonding groups suggested in claim 73 (claim 73).
Regarding claims 1 (in part) and 63 (in part), Torras teaches the importance in using inorganic−organic hybrid materials to protect metal surface or to serve as intermediate adhesion promoter layer for further coating deposition in order to elucidate the mechanism of silane deposition onto aluminum surface, in the presence of organophosphonic acid as adhesion promoter and using experimental and theoretical techniques, such that transparent thin films of layered inorganic−organic composites were prepared by the sol−gel synthesis of tetraethylorthosilicate and vinyltrimethoxysilane in the presence of 1,2-diaminoethanetetrakis-methylenephosphonic acid, wherein the inorganic−organic coating was characterized by FTIR and XPS spectroscopies; and density functional theory was employed to evaluate three simplified molecules, orthosilicic acid (Si(OH)4), methylphosphonic acid (MePA), and Si(OH)3OMePA (interpreted as organosilanes comprising at least two distinct surface bonding groups; and organophophonic acid including comprising (HO)2P=O, claims 1, 63 and 73) (Abstract). Torras teaches that phosphonic groups act as adhesion promoters for TEOSVTMS deposition onto aluminum surface, creating a homogeneous and thin coating, compared to the irregular and thick layer of samples obtained in absence of phosphonic molecules, wherein experimental results proved that silanol groups are mainly located outside the hybrid organic−inorganic film, whereas phosphorus and siloxane rings are found close to the metal surface, such that the synergistic combination of MePA and Si(OH)4 chemisorbed on a γ-AlOOH (010) surface contributes to the successful formation of both stable linkages to the Al surface through monodentate and bidentate coordination sites and highly favored hydrogen bonds between the P=O and HO−Si-O groups; thus, the phosphonic group presence on the surface of boehmite enhances the stability of silane deposition by creating stronger interactions with the aluminum surface, improving coating adhesion and allowing the formation of a more compact and homogeneous protective layer (interpreted as organosilanes comprising at least two distinct surface bonding groups; and organo-phosphonic acid including comprising (HO)2P=O, claims 1, 63 and 73) (pg. 17734, col 2, Conclusions; and pg. 17735, col 1, first partial paragraph).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of spatial transcriptomics for determining the location of biological molecules such as mRNA in a tissue sample as exemplified by Frisen to include orthosilicic acid, methyl phosphonic acid, and Si(OH)3OMePA to prepare inorganic-organic composite materials as disclosed by Torras with a reasonable expectation of success in producing transparent thin-film as a substrate coating comprising layered inorganic-organic composites; and/or in producing a multi-functional transparent thin-film substrate composite that improves substrate coating adhesion and forms a protective layer on a substrate surface.
The combined references of Frisen and Torras do not specifically exemplify an edit distance of 4 (claim 1, in part).
Regarding claim 1 (in part), Eltoukhy teaches methods to reduce or combat the errors introduced by the sample preparation and sequencing processes for all molecules that are converted and sequenced (paragraph [0005]). Eltoukhy teaches providing cell free polynucleotides from bodily fluid of (a) a test sample and (b) a control sample; then tagging polynucleotides, wherein the tag includes a source identifier (test or control) and, optionally a further identifier (optionally with duplex tags), such that polynucleotides can be uniquely or non-uniquely tagged (interpreted as contacting a biological sample with spatial barcode array; tagged the same and/or differently; the oligonucleotide has a 5’ end and the biological molecule has a 3’ end; and at least two distinct barcodes, claims 1a, 1d, 63a and 63d) (Figure 8). Eltoukhy teaches a method for detecting and/or quantifying rare deoxyribonucleic acid (DNA) in a heterogeneous population of original DNA fragments, comprising tagging the original DNA fragments in a single reaction including within a single reaction vessel using a library of a plurality of different tags such that >30% or >50% of the fragments are tagged at both ends, wherein the plurality of different tags can be no more than any of 100, 500, 1000, 10,000 or 100,000 different tags (interpreted as at least two distinct tags, claims 1 and 63) (paragraph [0007]). Eltoukhy teaches that a barcode can comprise contiguous or non-contiguous sequences; and at least 1, 2, 3, 4, 5 or more nucleotides (interpreted as barcodes is at most 35 bases, claims 1a and 63a) (paragraph [0121]). Eltoukhy teaches that a library of polynucleotides comprising a plurality of polynucleotide molecules can have an edit distance of at least one, wherein in some cases the plurality of polynucleotide molecules can have an edit distance of at least 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or more; and the edit distance can be a Hamming distance (interpreted as including an edit distance of 4, claims 1a, and 63a) (paragraph [0130]). Eltoukhy teaches that DNA fragments, comprising tagging the original DNA fragments in a single reaction including within a single reaction vessel using a library of a plurality of different tags such that >30%or >50% of the fragments are tagged at both ends, wherein the plurality of different tags (interpreted as barcode sequences for each oligonucleotide are different, claims 1 and 63) (paragraph [0008]).
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 reducing errors introduced by sample preparation and sequencing as exemplified by Eltoukhy, it would have been prima facie obvious for one of ordinary skill in the art at the time the invention was made to modify the methods for the spatial detection of captured nucleic acids in a biological sample such as a tissue sample using uniquely barcoded probes as exemplified by Frisen; and the method of preparing inorganic-organic composite surfaces including surfaces comprising orthosilicic acid, methyl phosphonic acid, and Si(OH)3OMePA as disclosed by Torras to include molecular barcodes having a minimum edit distance of 1-10 as taught by Eltoukhy with a reasonable expectation of success in producing substrate surfaces comprising multi-functional transparent thin-film composites that form a protective layer on a substrate surface and improves substrate coating adhesion; in reducing experimental noise, sequencing errors, amplification bias and/or sequencing read redundancy; in allowing for the efficient and accurate detection of rare sequence variants; and/or in increasing the ability to specifically determine the location of the polynucleotide within a biological sample.
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.
Conclusion
Claims 1, 7, 11, 13, 55, 60-63, 67, 69 and 71-73 are rejected.
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/AMY M BUNKER/Primary Examiner, Art Unit 1684
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