DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Please note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
Applicant’s election without traverse of Group II (claims 23-34, 39, 40, 42-44, and 47) in the reply filed on 8/27/2024 is acknowledged. Claims 1-3, 6-13, 18, 20, 22, 48, 49, and 51-55 remain withdrawn as noted in the Office Action of 2/7/2025.
Claim Status
Claims 1-3, 6-13, 18, 20, 22-25, 27, 29-34, 39-40, 42-44, 48-49, 51-55, and 58-60 are pending. Claims 1-3, 6-13, 18, 20, 22, 48, 49, and 51-55 remain withdrawn as noted in the Office Action of 2/7/2025.
Claims 23-25, 27, 29-34, 39-40, 42-44, and 58-60 are being examined on the merits.
Specification
The objection to the specification for minor informalities is withdrawn in light of Applicant’s amendments to the specification.
Claim Objections
The objections to claims 23-25, 27, 29-34, 39-40, 42-44, and 58-60 are withdrawn in light of Applicant’s amendments to the claims.
Claim Rejections - 35 USC § 112b – Indefiniteness
Withdrawn: The rejection of claims 23-25, 27, 29-34, 39-40, 42-44, and 58-60 under 35 U.S.C. 112(b) as noted in the Office Action of 8/20/2025 are withdrawn in light of Applicant’s amendments to the claims.
New (Necessitated by amendments):
Claim 43 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 43 recites the limitation "the genomic DNA". There is insufficient antecedent basis for this limitation in the claim. The only genomic DNA described in claim 23, from which claim 43 depends, is tagmented genomic DNA fragments. It is unclear if this genomic DNA is being converted via bisulfite conversion prior to tagmentation or if this is being done post-tagmentation.
Claim Rejections - 35 USC § 103
Maintained
Claims 23-25, 27, 29-34, 44, and 58-60 are rejected under 35 U.S.C. 103 as being unpatentable over Pollock (Pollock et al., PNAS; cited on IDS of 11/29/2021) in view of Ingram (Ingram et al., Annual Review of Immunology 2018; cited on IDS of 11/29/2021), Stoeckius (Stoeckius et al., US 20180251825 A1; cited on PTO-892 of 8/20/2025), and Baek (Baek et al., Computational and Structural Biotechnology Journal, June 12, 2020; cited on PTO-892 of 8/20/2025).
Regarding claim 23: Pollock teaches single-cell analysis that includes specific binding of individual cells with an engineered display system (“Fab-phage”) that comprises an engineered display construct comprised of a genetically encoded display molecule (“the Fab is fused to the gene III coat protein on the M13 phagemid within the viral particle” Fig 1A), a genetically encoded affinity molecule (“The selected Fabs are genetically encoded and displayed on a phage particle that packages its specific Fab gene within”, Introduction and Fig 1A), and a genetically encoded sequencing molecule (“the highly variable complementarity determining region (CDR) H3 loop, which represents both the major binding determinant of the encoded Fab and a unique DNA barcode”, Introduction and Fig 1A). Pollock teaches allowing each affinity molecule to specifically bind a target molecule present on the surface of one or more individual cells (Fig 1B) and accessing the engineered display construct(s) in the specifically bound engineered display system(s) and sequencing them (“the bound phage antibodies are propagated, amplified, and subjected to next-generation DNA sequencing to quantify the retained phage antibodies”, Fig 1B). The sequencing performed was a single cell sequencing technique (“Fab-phages were added to a population of cells, and then individual cells were flow-sorted into wells and each was profiled by NGS”, Single-Cell PhaNGS).
Pollock does not teach that the genetically encoded affinity molecule is a nanobody. However, the use of nanobodies in biological applications is known in the art, as taught by Ingram.
Ingram teaches the advantages of using nanobodies for biological applications over the use of antibodies (Abstract).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Pollock to include a nanobody rather than a Fab antibody fragment in the engineered display system. One would be motivated to use a nanobody given the assertion by Ingram that nanobodies “are not constrained by a requirement for heavy chain-light chain pairing” and that the “approximately one-tenth the size of conventional antibodies is also a signature advantage” (1. Introduction). One would have a reasonable expectation of success given that Ingram teaches that “nanobodies can serve in applications similar to those for conventional antibodies” (Abstract).
Pollock in view of Ingram does not teach multi-omic analysis in which the engineered display systems are fixed to the individual cells, accessing cellular polynucleotides within the individual cells, or sequencing the accessed cellular polynucleotides.
However, multi-omic single cell analysis in which a display system is fixed to individual cells, cellular polynucleotides within the cells are accessed and then are subsequently sequenced is known in the art, as taught by Stoeckius.
Stoeckius teaches a method of multi-omic single-cell analysis in which individual cells are isolated into droplets after being bound on the surface by an antibody against a cell surface protein (paragraph [0009, 0015, 0136]). Stoeckius teaches fixation of the individual specifically bound cells (paragraph [0126]). Stoeckius teaches accessing cellular polynucleotides within the individual bound cells (Fig 1C and paragraph [0015]). Stoeckius teaches sequencing the accessed cellular polynucleotides with a single-cell sequencing technique (paragraph [0015 and 0136]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Pollock in view of Ingram with the multi-omic approach of Stoeckius. One would be motivated to access the cellular polynucleotides given the assertion by Stoeckius that this allows “in-depth characterization of single cells by simultaneous measure of gene-expression levels and cell-surface proteins” and “is highly scalable” (paragraph [0136]). One would have a reasonable expectation of success given that Pollock demonstrates successful binding of engineered display systems to surface proteins and single-cell isolation and Stoeckius demonstrates successful integration of surface bound molecule sequencing data with cellular polynucleotide sequencing data.
Pollock in view of Ingram and Stoeckius do not teach tagmenting the genomic DNA within the individual cells. However, tagmentation of genomic DNA in individual cells is known in the art, as taught by Baek.
Baek describes single-cell ATAC-seq, a methodology applied to single cells which involves “the use of hyperactive Tn5 transposase, which simultaneously tags and fragments DNA sequences in open chromatin regions” (also known as “tagmenting”; 1. Introduction).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Pollock in view of Ingram and Stoeckius to employ tagmentation, as taught by Baek. One would be motivated to tagment genomic DNA given the assertion by Baek that tagmenting followed by sequencing allows one to “identify open chromatin regions in the genome” and with single-cell biology allows for “the study of chromatin accessibility at single cell resolution” (1. Introduction). One would have a reasonable expectation of success given that Baek teaches that tagmentation has already been successfully adapted for use in a single-cell context and “can be integrated with single-cell RNA sequencing (scRNA-seq) data and other omics data for multi-omics studies” (1. Introduction).
Regarding claims 24 and 25: Stoeckius teaches generating cDNA copies of cellular RNA and sequencing these cDNA copies (paragraph [0015]).
Regarding claim 27: Stoekcius teaches that accessing the cellular polynucleotides involves lysis of the individual cells (Fig 1C, step 5).
Regarding claim 29: Baek teaches that single-cell ATAC-seq involves tagmentation of genomic DNA (as noted above) and is followed by sequencing of the tagmented genomic DNA (Abstract).
Regarding claim 30: Stoeckius teaches incorporating a cell barcode into the one or more cellular polynucleotides/cDNA copies such that the one or more cellular polynucleotides from the same cell receive the same unique cell barcode (paragraph [0015]).
Regarding claims 31 and 33: Stoeckius teaches incorporating into the one or more cellular polynucleotides one or more barcodes, one or more PCR handles, one or more UMIs by mixing the one or more cellular polynucleotides with an oligonucleotide-adorned bead which comprises one or more barcodes, one or more UMIs, and one or more PCR handles (paragraph [0091] and Figure 1B).
Regarding claim 32: Stoeckius teaches amplifying the one or more cellular polynucleotides/cDNA copies (paragraph [0195-0197]).
Regarding claim 34: Pollock teaches sorting the cells specifically bound with the engineered bacteriophages into individual wells of a 96-well plate (Results - Single-Cell PhaNGS). Stoeckius, as noted above, teaches fixing the cell bound with the display system (conjugated antibody-oligonucleotide construct) prior to sorting, as noted above in the rejection of claim 23.
Regarding claim 44: Stoeckius teaches determining one or more features of the one or more individual cells wherein the features comprise a cellular RNA expression profile and a surface protein expression profile (paragraph [0136]).
Regarding claim 58-59: Stoeckius teaches the one or more features consist of a surface protein expression profile (paragraph [0136]) and Baek teaches that the profile of chromatin accessibility along the genomic DNA region created through tagmentation is assessed in single-cells (Abstract). Rationales and citations for combination of these two modes of assessing individual cellular features is noted above.
Regarding claim 60: Baek teaches scATAC-seq (Abstract).
Claims 39-40 are rejected under 35 U.S.C. 103 as being unpatentable over Pollock (Pollock et al., PNAS; cited on IDS of 11/29/2021) in view of Ingram (Ingram et al., Annual Review of Immunology 2018; cited on IDS of 11/29/2021), Stoeckius (Stoeckius et al., US 20180251825 A1; cited on PTO-892 of 8/20/2025), and Baek (Baek et al., Computational and Structural Biotechnology Journal, June 12, 2020; cited on PTO-892 of 8/20/2025) as applied to claims 23-25, 27, 29-34, 44, and 58-60 above, and further in view of Vickovic (Vickovic et al., Nature Methods 2019; cited on PTO-892 of 9/24/2024).
The teachings of Pollock in view of Ingram, Stoeckius, and Baek are detailed above. Relevant to the instantly rejected claims, Pollock in view of Ingram, Stoeckius, and Baek teach mixing the one or more cellular polynucleotides with oligonucleotide-adorned beads.
Pollock in view of Ingram, Stoeckius, and Baek do not teach that the oligonucleotide-adorned beads are present on a surface of the substrate or container and are arranged in an ordered array, wherein each oligonucleotide-adorned bead has a unique barcode corresponding to the x,y coordinate of the oligonucleotide-adorned bead in the array. They also do not teach depositing, on the ordered array, a tissue section comprising the one or more individual cells.
However, creation of ordered arrays consisting of oligonucleotide-adorned beads with unique barcodes corresponding to x,y coordinates of each bead in the array and depositing tissue sections onto said arrays is known in the art, as taught by Vickovic.
Vickovic teaches a high-definition spatial transcriptiomics method in which RNA from tissue sections is captured on spatially barcoded bead arrays (Abstract). Vickovic teaches creating an ordered array in which each bead is adorned with oligonucleotide capture probes that have barcode sequences (x,y) barcodes denoting their spatial position on the array (Fig 1a). Vickovic then teaches depositing on this ordered array, a tissue section that comprises one or more individual cells (Fig 1a).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Pollock in view of Ingram, Stoeckius, and Baek to construct an ordered array with the barcoded beads and apply a tissue section to said beads. One would be motivated to perform this operation given the assertion by Vickovic that this methodology allows for spatially resolving feature information of individual cells within a tissue (pg 987, col 1). This allows for in situ spatial information at high resolution and “will improve understanding of tissue organizing and function in health and disease” (pg 989, col 2). One would have a reasonable expectation of success given that Vickovic teaches that this method is readily adaptable to inclusion in other analysis pipeline because it “relies on robust and commoditized tissue, molecular, bead-array and imaging modular tasks” (pg 989, col 2).
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Pollock (Pollock et al., PNAS; cited on IDS of 11/29/2021) in view of Ingram (Ingram et al., Annual Review of Immunology 2018; cited on IDS of 11/29/2021), Stoeckius (Stoeckius et al., US 20180251825 A1; cited on PTO-892 of 8/20/2025), and Baek (Baek et al., Computational and Structural Biotechnology Journal, June 12, 2020; cited on PTO-892 of 8/20/2025) as applied to claims 23-25, 27, 29-34, 44, and 58-60 above, and further in view of Chen (Chen et al., Cell August 20, 2020; cited on PTO-892 of 8/20/2025).
The teachings of Pollock in view of Ingram, Stoeckius, and Baek are detailed above. Relevant to the instantly rejected claims, Pollock in view of Ingram, Stoeckius, and Baek teach applying a tissue section to a spatially barcoded, ordered bead array for multi-omic analysis.
Pollock in view of Ingram, Stoeckius, and Baek do not teach performing in situ sequencing within the applied tissue section. However, performing barcoded in situ sequencing on intact tissue section applied to ordered arrays is known in the art, as taught by Chen.
Chen teaches performing spatially barcoded transcriptomics combined with in situ sequencing (Introduction, paragraph 3 and Fig 1a).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Pollock in view of Ingram, Stoeckius, and Baek to perform in situ sequencing as taught by Chen. One would be motivated to do so given the assertion by Chen that in situ sequencing allows for “visualiz[ing] hundreds of selected transcripts with cellular resolution” (Introduction, paragraph 3). One would have a reasonable expectation of success given that Chen successfully performs in situ sequencing using capture probes (similar to those adorning the beads in the methodology taught by Pollock in view of Ingram, Stoeckius, and Baek) that are spatially barcoded (the barcode corresponds to the coordinates of the probe on the array).
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over Pollock (Pollock et al., PNAS; cited on IDS of 11/29/2021) in view of Ingram (Ingram et al., Annual Review of Immunology 2018; cited on IDS of 11/29/2021), Stoeckius (Stoeckius et al., US 20180251825 A1; cited on PTO-892 of 8/20/2025), and Baek (Baek et al., Computational and Structural Biotechnology Journal, June 12, 2020; cited on PTO-892 of 8/20/2025) as applied to claims 23-25, 27, 29-34, 44, and 58-60 above, and further in view of Spektor (Spektor et al., Genome Research 2019; cited on PTO-892 of 8/20/2025).
The teachings of Pollock in view of Ingram, Stoeckius, and Baek are detailed above. Relevant to the instantly rejected claims, Pollock in view of Ingram, Stoeckius, and Baek teach a method of multi-omic single cell analysis in which multiple features of individual cells can be measured and associated together (such as cell surface protein expression, mRNA expression, and/or epigenetic information such as chromatin accessibility).
Pollock in view of Ingram, Stoeckius, and Baek do not teach converting unmethylated cytosines to uracil in the genomic DNA via bisulfite conversion prior to sequencing the genomic DNA or portion thereof. However, converting unmethylated cytosines to uracil in the genomic DNA via bisulfite conversion prior to sequencing the genomic DNA or portion thereof is known in the art, as taught by Spektor.
Spektor teaches a modification of ATAC-seq in which, prior to sequencing, unmethylated cytosines are converted to uracils via bisulfite conversion (Fig 1).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Pollock in view of Ingram, Stoeckius, and Baek to perform bisulfite conversion prior to sequencing, as taught by Spektor. One would be motivated to perform this conversion given the assertion by Spektor that this allows assessment of the methylation state of the DNA (Abstract). One would have a reasonable expectation of success given that Spektor successfully integrates the bisulfite conversion and sequencing protocol with the tagmentation and ATAC-seq protocol as taught by Baek.
Response to Remarks
In the Remarks of 11/20/2025 pgs 16-21, Applicant traverses the rejection of all claims under 35 USC 103. Applicant's arguments have been fully considered but they are not deemed persuasive for the following reasons.
Applicant argues on page 16-17 of Remarks that Pollock does not sequence cellular RNA or DNA and therefore does not teach a multi-omic approach and additionally does not teach the use of nanobodies or tagmentation of genomic DNA. In response to applicant's arguments against the references individually, 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).
Applicant next argues on page 17 of Remarks that Ingram “does not suggest that nanobodies may be directly substituted for Fab fragments in the specific, genetically encoded phage display architecture of Pollock, which are certainly not ‘conventional antibodies’” and that this type of substitution would “necessitate substantial redesign of the phage display vector, signal sequences, linkers, sequencing adapters, expression conditions, and validation” which “would not have been routine or conventional at the time of Pollock’s publication in 2018”. Applicant does not provide evidence to support the claim that this would not have been routine or conventional at the time of Pollock’s publication in 2018. While Ingram mentions the phrase “conventional antibodies”, Ingram also notes that “conventional antibodies can be shrunk to smaller formats” (Introduction, paragraph 3), much like single-chain variable fragments (ScFvs) or, in the case of Pollock, Fab fragments.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references of Ingram and Pollock (page 17 of Remarks), the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See 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), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Ingram teaches several distinct advantages of nanobodies in relation to antibodies (as cited above). While Ingram does not specifically note the application of nanobodies to phage-sequencing systems, those of skill in the art would recognize the advantages of adapting nanobodies for use in the phage system as taught by Pollock, rather than use antibodies. Additionally, as noted above, Ingram teaches that conventional antibodies can also be shrunk into fragments of antibodies for various applications.
Applicant next argues that “The combination of references fails to teach or suggest performing multi-omics analysis using an engineered display system” (pg 18 of Remarks). Applicant notes that Stoeckius “teaches a synthetic, chemically conjugated antibody-oligonucleotide system, in which antibodies are covalently linked to short DNA barcodes that are sequenced in parallel with cellular mRNA after fixation after fixation and lysis” and states that “a person of ordinary skill would have recognized that merging these two fundamentally different systems would require substantial re-engineering”. However, the chemically conjugated antibody-oligonucleotide system, which Stoeckius does indeed teach, is merely a single method of measuring the expression of membrane proteins on the surface of a cell to obtain proteomic data. Pollock in view of Ingram present an alternative method of measuring protein expression on the surface of cells with a nanobody phage system, and there is no indication or evidence provided that would suggest that this method of cellular labeling would not be compatible with the system of Stoeckius, which is being using in this context as motivation for combining cell-surface labeling with cellular polynucleotide sequencing. Applicant asserts that “it would necessitate transforming Pollock’s phage-displayed genetic constructs into reagents compatible with single-cell RNA-sequencing workflows”, but this is not necessarily true. Those of skill in the art would be motivated to combine Pollock and Stoeckius to produce multi-omic data, as noted above, which the advantage of Pollock’s method being the use of nanobody based bacteriophage labeling for an “inexpensive method for proteomics using NGS” (Pollock, Abstract). Those of skill in the art would additionally be able to recognize that parallel methods could be performed, both replication of the bacteriophage as taught by Pollock followed by NGS and reverse transcription of the mRNA followed by sequencing, as taught by Stoeckius and claimed in the instant application (see claims 24 and 25). Neither method is mutually exclusive.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning (pg 19 of Remarks), it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, Pollock in view of Ingram teach an engineered bacteriophage with a nanobody as the genetically engineered affinity molecule, and teach performing next-generation sequencing on said genetically encoded affinity molecule for purposes of proteomic analysis of single cells. Stoeckius teaches simultaneous proteomic and cellular polynucleotide analysis, albeit one which uses a different proteomic analysis method. However, Stoeckius uses a single cell polynucleotide analysis method, and teaches the advantage of combining proteomic and nucleotide analysis together in a single cell context, as described above.
Applicant next argues that “The combination of references fails to teach or suggest performing tagmentation of genomic DNA in cells or nuclei fixed with specifically bound engineered display systems” (pg 19-20 of Remarks). Applicant argues on page 19 of Remarks that “Baek does not teach or suggest performing tagmentation within cells bound by an engineered genetically encoded display system, nor does it involve any sequencing of a genetically encoded construct”. In response to applicant's arguments against the references individually, 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). Applicant further argues that the present system performs tagmentation after fixing and binding of a genetically encoded display system to the cell or nucleus (pg 19 of Remarks), but there is no indication that the method of Baek would not be applicable to the cellular polynucleotides (genomic DNA) that are released from single cells whether a display system was bound to the cell or nucleus or not.
Applicant argues that the “Examiner’s rationale substitutes Bake’s unrelated chromatin-profiling method into an engineered molecular assay without any teaching or motivation in the art to do so” (pg 20 of Remarks). The teaching or motivation, as supplied above, is that this information can be integrated into a multi-omic system to provide further information about genomic DNA, specifically regarding open chromatin information. Pollock, Ingram, and Stoeckius provide rationale for linking genomic and proteomic information, Baek teaches a method of determining a specific type of information that can be integrated and supply further information to that determined by Pollock, Ingram, and Stoeckius. Applicant argues that “a person of ordinary skill in the art would not have been motivated to modify Pollock’s phage-based display and Stoeckius’s antibody-oligo conjugation methods with Baek’s single-nucleus ATAC-seq procedure” because it “operates on fixed or permeabilized nuclei under conditions optimizes for transposase access to chromatin, not for preserving phage particles or engineered display constructs”, meaning that integrating this procedure into Pollock’s or Stoeckius’s workflow would “risk degradation of display constructs and loss of the binding information they encode” (pg 20 of Remarks). No evidence has been provided by Applicant to indicate that the optimized conditions for transposase would case degradation of display constructs. Furthermore, Applicant acknowledges that Baek presents an optimized procedure. Therefore, it is clear that the procedure can be optimized by one skilled in the art for the desired purpose/aim of the methodology, such as incorporation into a multi-omic system.
Applicant next argues that Baek “does not teach tagmentation as part of a multi-omic workflow involving sequencing of both genomic and engineered construct nucleic acids” (pg 20 of Remarks). In response to applicant's arguments against the references individually, 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).
Applicant argues that Examiner’s proposed combination constitutes an impermissible hindsight in combining Baek with the teachings of Pollock, Ingram, and Stoeckius (pg 20 of Remarks). In the instant case, all aspects of the invention are known by those in the art, as evidenced by Pollock in view of Ingram, Stoeckius, and Baek, with rationales for combining said references provided above.
Applicant argues that Vickovic, Chen, and Spektor fail to dure the deficiencies of the combination of Pollock, Ingram, Stoeckius, and Baek and therefore dependent the dependent claims are patentable over the cited references. However, the arguments against Pollock, Ingram, Stoeckius, and Baek as they apply to independent claim 23 were not deemed persuasive as detailed above.
Therefore, the rejection of the claims under 35 USC 103, as outlined above, are maintained.
Double Patenting
Maintained
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Copending Application No. 17/393,994
Claims 23-25, 27, 29-34, 44, and 58-60 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 3, 12, 27, 44, 46, and 61 of copending Application No. 17/393,994 in view of Pollock (Pollock et al., PNAS; cited on IDS of 11/29/2021), Ingram (Ingram et al., Annual Review of Immunology 2018; cited on IDS of 11/29/2021), Stoeckius (Stoeckius et al., US 20180251825 A1; cited on PTO-892 of 8/20/2025), and Baek (Baek et al., Computational and Structural Biotechnology Journal, June 12, 2020; cited on PTO-892 of 8/20/2025) based on citations and rationales provided above.
Although the claims are not identical, they are not patentably distinct from each other because both sets of claims are drawn to the same limitations. Any additional limitations of the ‘994 claims are encompassed by the open claim language “comprising” found in the instant claims.
Regarding claim 23: ‘994 teaches a multi-omic single cell analysis in which cells are bound with barcoded antibody epitopes. ‘994 does not teach that the recognition molecules are an engineered display system. However, use of engineered display systems for binding specific epitopes on a cell surface and which contain barcodes is known in the art, as taught by Pollock.
Pollock teaches single-cell analysis that includes specific binding of individual cells with an engineered display system (“Fab-phage”) that comprises an engineered display construct comprised of a genetically encoded display molecule (“the Fab is fused to the gene III coast protein on the M13 phagemid within the viral particle” Fig 1A), a genetically encoded affinity molecule (“The selected Fabs are genetically encoded and displayed on a phage particle that packages its specific Fab gene within”, Introduction and Fig 1A), and a genetically encoded sequencing molecule (“the highly variable complementarity determining region (CDR) H3 loop, which represents both the major binding determinant of the encoded Fab and a unique DNA barcode”, Introduction and Fig 1A). Pollock teaches allowing each affinity molecule to specifically bind a target molecule present on the surface of one or more individual cells (Fig 1B) and accessing the engineered display construct(s) in the specifically bound engineered display system(s) and sequencing them (“the bound phage antibodies are propagated, amplified, and subjected to next-generation DNA sequencing to quantify the retained phage antibodies”, Fig 1B). The sequencing performed was a single cell sequencing technique (“Fab-phages were added to a population of cells, and then individual cells were flow-sorted into wells and each was profiled by NGS”, Single-Cell PhaNGS).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of ‘994 with that taught by Pollock. One would be motivated to do so given the assertion by Pollock that the use of engineered display constructs (such as the Fab-Phage), allows for “simultaneous profiling of hundreds of cell-surface targets on cells…at low cost and without the need for chemical conjugation to purified antibodies” (Significance). One would have a reasonable expectation of success given that Pollock demonstrates successful use of the Fab-phages in a single-cell analysis format. Pollock does not teach that the affinity molecule is a nanobody, but usage of antibodies rather than Fab fragments for epitope recognition was known in the art as taught by Ingram and as detailed in the rejections above.
Claims 39-40, and 42-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 3, 12, 27, 44, 46, and 61 of copending Application No. 17/393,994 in view of Pollock (Pollock et al., PNAS; cited on IDS of 11/29/2021), Ingram (Ingram et al., Annual Review of Immunology 2018; cited on IDS of 11/29/2021), Stoeckius (Stoeckius et al., US 20180251825 A1; cited on PTO-892 of 8/20/2025), and Baek (Baek et al., Computational and Structural Biotechnology Journal, June 12, 2020; cited on PTO-892 of 8/20/2025) and further in view of Vickovic (Vickovic et al., Nature Methods 2019; cited on PTO-892 of 9/24/2024), Chen (Chen et al., Cell August 20, 2020; cited on PTO-892 of 8/20/2025), and Spektor (Spektor et al., Genome Research 2019; cited on PTO-892 of 8/20/2025) based on citations and rationales provided above.
This is a provisional nonstatutory double patenting rejection.
Response to Remarks
Applicant has traversed the double patenting rejections on the grounds that the combination of Pollock, Ingram, Stoeckius, Baek, Vickovic, Chen, and Spektor fail to teach all elements of independent claim 23. However, the arguments were not deemed persuasive (as explained above), thus the double patenting rejections are maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any 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.
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/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683