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
Pursuant to a preliminary amendment filed May 7, 2026 claims 1-3, 7, 8, 10, 11, 14, 17, 27-29, 31, 33, 34, 36, 37, 40, 43, 53 and 55 are currently pending in the instant application.
Response to Election/Restriction
Applicant's election of Group I without traverse, claims 1-3, 5, 7, 8, 10, 11, 14, 17 and 53, directed to a method of single cell analysis; and the election of Species with traverse as follows:
Species (A): wherein the capture agent is configured to couple to a cell surface molecule (claim 3); and
Species (B), further comprising (d) sequencing the barcoded nucleic acid molecule (claim 53), in the reply filed May 7, 2026 is acknowledged.
Claims 27-29, 31, 33, 34, 36, 37, 40, 43 and 55 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 7, 10, 11, and 17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on May 7, 2026.
Response to Traversals:
The traversal of is on the grounds that: (a) the dependent claims at issue merely add limitations to the independent claim and do not define separate species in any meaningful sense. Each dependent claim narrows the same invention rather than presenting an alternative embodiment requiring a distinct search or examination effort (Applicant Remarks, pg. 7, second full paragraph).
Regarding (a), MPEP 806.04(f) states that where two or more species are claimed, a requirement for restriction to a single species may be proper if the species are mutually exclusive. Claims to different species are mutually exclusive if one claim recites limitations disclosed for a first species but not a second, while a second claim recites limitations disclosed only for the second species and not the first. (e.g., the claims must not overlap in scope). In the Requirement for Election/Restriction mailed March 10, 2026, Species (B) required an election with regard to the method of claim 1 further comprising an additional component and/or an additional step including: wherein the reporter nucleic acid molecule further comprises a second reporter agent (claim 10); or wherein the labelled cell further comprises a second reporter agent (claim 11); or wherein the partition further comprises a second barcode nucleic acid molecule (claim 14); or wherein the labelled cell further comprises a plurality of nucleic acid analytes (claim 17); or further comprising (d) sequencing the barcoded nucleic acid molecule (claim 53). Each of the species is mutually exclusive; and the claims to each species do not overlap in scope. Moreover, there is a serious burden on the Office to search completely different components, structures, structural features, and/or process steps used for single cell analysis. Thus, the restriction is proper.
The restriction requirement is still deemed proper and is therefore made FINAL.
The claims will be examined insofar as they read on the elected species.
Therefore, claims 1-3, 8 and 53 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed February 2, 2023 is a CON of 35 U.S.C. 371 national stage filing of International Application PCT/US2154035, filed October 8, 2021, which claims the benefit US Provisional Patent Application 63090137, filed October 9, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on October 25, 2024 has been considered. An initialed copy of the IDS accompanies this Office Action.
Claim Objections/Rejections
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 8 and 53 are 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.
Claim 1 is indefinite for the recitation of the terms “the labelled cell comprises a complex” such as recited in claim 1, lines 4-5 because it is unclear what the labelled cell actually comprises given that claim 1, lines 2-3 recites that “contacting an antibody-secreting cell with a reporter agent comprising a reporter nucleic acid molecule to provide a labelled cell”; while lines 4-7 appear to indicate that the labelled cell comprises something different (e.g., a capture agent, secreted antibody, and reporter agent) and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the terms “the cell” such as recited in claim 1, line 5. There is insufficient antecedent basis for the term “the cell” in the claim because claim 1, lines 1-3 recite the terms “single cell”, “antibody-secreting cell”, and “a labelled cell.’ Moreover, it is unclear which cell the term “the cell” is referring to and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “generating a barcoded nucleic acid molecule from a barcode nucleic acid molecule of the plurality of barcode nucleic acid molecules” such as recited in claim 1, lines 11-12 because the term is confusing and unclear regarding how a barcoded nucleic acid molecule is generated from a barcoded nucleic acid molecule and, thus, the metes and bounds of the claim cannot be determined.
Claim 2 is indefinite for the recitation of the term “B-cell lineage” such as recited in claim 2, line 2 because the term “B-cell lineage’ describes a developmental pathway of B lymphocytes, such that it does not describe a type of B-cell and, thus, the metes and bounds of the claim cannot be determined.
Claim 8 is indefinite for the recitation of the term “configured to couple to the secreted antibody or antigen binding fragment thereof” such as recited in claim 8, lines 1-2 because claim 8 depends from instant claim 1, wherein claim 1 recites that the secreted antibody forms a complex with the reporter agent, while claim 8 recites that the reporter agent is only “configured to couple” the secreted antibody, such that there is no indication that it does, in fact, couple to the secreted antibody and, thus, the metes and bounds of the claim cannot be determined.
Claim 53 is indefinite for the recitation of the terms “is analyzed”, “secreting an antibody”, “capable of binding the reporter agent”, and “via detection of the reporter sequence” such as recited in claim 53, lines 3-4 because claim 53 depends from instant claim 1, wherein claim 1 does not recite analyzing the antibody-secreting ell, that the antibody-secreting ell secrets an antibody, that the antibody is only capable of binding the reporter agent; and/or the detection of a reporter sequence and, thus, the metes and bounds of the claim cannot be determined.
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.
Claim 53 is 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 53 recites (in part): “further comprising: d) sequencing the barcoded nucleic acid molecule, wherein the antibody secreting cell is analyzed as secreting an antibody capable of binding the reporter agent via detection of the reporter sequence” in lines 1-4 because claim 53 depends from instant claim 1, wherein claim 1 does not recite analyzing the antibody-secreting ell, that the antibody-secreting ell secrets an antibody, that the antibody is only capable of binding the reporter agent; and/or the detection of a reporter sequence. Thus, claim 53 is an improper dependent claims for failing to further limit the subject matter of the claim upon which they depend, or for failing to include all the limitations of the claim upon which they 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 § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 8 and 53 are rejected under 35 U.S.C. 102(a1)/102(a2) as being anticipated by Belgrader et al. (hereinafter “Belgrader”) (US Patent No. 10323278, issued June 18, 2019; also US Patent Application Publication No. 20180179591, published June 28, 2018).
Regarding claims 1 and 53, Belgrader teaches compositions, methods, systems, and devices for polynucleotide processing (Abstract). Belgrader teaches that the method comprises: (a) providing a partition comprising a cell and at least one labelling agent that is (i) capable of binding to a cell surface feature of the cell and (ii) is coupled to a reporter oligonucleotide comprising a nucleic acid barcode sequence that permits identification of the at least one labelling agent; (b) in the partition, synthesizing a nucleic acid molecule comprising at least a portion of the nucleic acid barcode sequence or a complement thereof; and (c) subjecting the nucleic acid molecule to sequencing to identify the labelling agent or the cell, wherein the reporter oligonucleotide comprises a unique molecular identification (UMI) sequence (interpreted as a partition comprising the reporter oligonucleotide-reporter nucleic acid molecule-reporter agent; the cell as an antibody secreting cell; and the UMI as the label; and the barcode as the partition-specific barcode; and sequencing, claims 1 and 53) (col 1, lines 60-67; and col 2, lines 1-5 and 49-50). Belgrader teaches that the at least one labelling agent is selected from the group comprising of an antibody, an antibody fragment, a cell surface receptor binding molecule, a receptor ligand, a small molecule, a bi-specific antibody, a bi-specific T-cell engager, a T-cell receptor engager, a B-cell receptor engager, a pro-body, an aptamer, a monobody, an affimer, a darpin, a protein scaffold, an antigen, an antigen presenting particle, and a major histocompatibility complex (MHC); and the cell surface feature is selected from the group comprising a receptor, an antigen, a surface protein, a transmembrane protein, a glycoprotein, an engineered T-cell receptor, a B-cell receptor, etc. (interpreted as the complex comprising: interpreting the cell surface feature to comprise the secreted surface protein/antibody; interpreting the cell surface receptor binding molecule as the capture agent; interpreting the labelling agent as the reporter agent, claim 1) (col 2, lines 56-67; and col 3, lines 1-6). Belgrader teaches that the fragments from the nucleic acids of a given cell will share the same barcode sequence because each fragment is coded as to its partition of origin (interpreted as a partition-specific barcode, claim 1) (col 43, lines 4-6). Belgrader teaches that the B cell receptor, or BCR, is a molecule found on the surface of B cells, wherein the antigen binding portion of a BCR is composed of a membrane-bound antibody that, like most antibodies (e.g., immunoglobulins), has a unique and randomly determined antigen-binding site, such that the antigen binding portion of a BCR includes membrane-bound immunoglobulin molecule of one isotype (e.g., IgD, IgM, IgA, IgG, or IgE); and when a B cell is activated by its first encounter with a cognate antigen, the cell proliferates and differentiates to generate a population of antibody-secreting plasma B cells and memory B cells (interpreting B cell receptor on the surface of B cells as capture agents and cell surface molecules; and B cells as antibody-secreting cells, claims 1 and 2) (col 49, lines 26-36). Belgrader teaches that the given partition comprises the cell or one or more components of the cell, such that when the given partition comprises a single cell, the first nucleic acid molecule or the second nucleic molecule comprises a third barcode sequence derived from a third nucleic acid molecule, wherein the third nucleic acid molecule is coupled to a labelling agent capable of binding to a cell surface feature of a cell (interpreting the cell as a partition; interpreting the first and second barcode as a partition-specific barcode; and the third barcode as a cell label, claim 1) (col 5, lines 58-67). Belgrader teaches that the given partition is a droplet among a plurality of droplets or a well among a plurality of wells, wherein the first nucleic acid barcode sequence and the second nucleic barcode sequence are identical (interpreting droplets and wells as partitions; and interpreting the first and second barcodes as partition-specific barcodes, claim 1) (col 8, lines 6-10). Belgrader teaches that
the reporter oligonucleotides can be selected to provide barcoded products that are already sized, and otherwise configured to be analyzed on a sequencing system (interpreted as analyzed by detecting the reporter sequence, claim 53) (col76, lines 32-35).
Regarding claim 2, Belgrader teaches generating a population of antibody-secreting plasma B cells and memory B cells (interpreted as antibody secreting cells of a B-cell lineage, claim 2) (col 49, lines 34-36).
Regarding claims 3 and 8, Belgrader teaches that the method comprises: (a) providing a partition comprising a cell and at least one labelling agent including an antibody, cell surface binding molecule, antigen, etc. (interpreted as a capture agent), wherein the at least one labelling agent is (i) capable of binding to a cell surface feature of the cell, wherein cell surface features include a surface protein, antigen, antigen fragment, etc. (interpreted as a secreted antibody); and (ii) is coupled to a reporter oligonucleotide comprising a nucleic acid barcode sequence that permits identification of the at least one labelling agent (interpreted as a capture agent configure to couple to a cell surface molecule; and the reporter agent is configure to couple to the secreted antibody or antigen, claims 3 and 8) (col 1, lines 60-66; and col 2, lines 56-64).
Belgrader meets all the limitations of the claims and, therefore, anticipates the claimed invention.
Claims 1-3, 8 and 53 are rejected under 35 U.S.C. 102(a1)/102(a2) as being anticipated by Mikkelsen et al. (hereinafter “Mikkelsen”) (US Patent Application No. 20180105808, published April 19, 2018).
Regarding claim 1, Mikkelsen teaches methods, compositions and systems for analyzing individual cells or cell populations through a partitioned analysis of contents of individual cells or cell populations, such as cancer cells and cells of the immune system (Abstract, lines 1-5). Mikkelsen teaches that the B cell receptor, or BCR, is a molecule found on the surface of B cells, wherein the antigen binding portion of a BCR is composed of a membrane-bound antibody that, like most antibodies (e.g., immunoglobulins), has a unique and randomly determined antigen-binding site, such that the antigen binding portion of a BCR includes membrane-bound immunoglobulin molecule of one isotype (e.g., IgD, IgM, IgA, IgG, or IgE); and when a B cell is activated by its first encounter with a cognate antigen, the cell proliferates and differentiates to generate a population of antibody-secreting plasma B cells and memory B cells (interpreting B cell receptor on the surface of B cells as capture agents and cell surface molecules; and B cells as antibody-secreting cells, claims 1 and 2) (paragraph [0209]). Mikkelsen teaches that the methods can be used to characterize cell features, such that the methods can be used to attach reporter molecules to these cell features, that when partitioned as described above, can be barcoded and analyzed, e.g., using DNA sequencing technologies, to ascertain the presence, and in some cases, relative abundance or quantity of such cell features within an individual cell or population of cells (interpreted as contacting an antibody-secreting cell with a reporter nucleic acid to form a labeled cell; barcoded; analyzed; partitioned; and sequencing, claims 1 and 53) (paragraph [0194]). Mikkelsen teaches the amplification of the cell’s nucleic acids is carried out until the barcoded overlapping fragments within the partition constitute at least 1x coverage of the particular portion of all of the cell’s genome (interpreted as amplification) (paragraph [0189], lines 1-4).
Mikkelsen teaches that Figure 5 shows a population of cells, represented by cells 502 and 504 are incubated with a library of cell surface associated reagents, e.g., antibodies, cell surface binding proteins, ligands or the like (interpreted as secreted antibodies and capture agents), where each different type of binding group includes an associated nucleic acid reporter molecule that is associated with it (interpreted as reporter agents), shown as ligands and associated reporter molecules 506, 508, 510 and 512 (with the reporter molecules being indicated by the differently shaded circles), wherein the cell expresses the surface features that are bound by the library (interpreted as secreted antibodies), such that the ligands and their associated reporter molecules can become associated or coupled with the cell surface (interpreted as forming the complex); and the individual cells are then partitioned into separate partitions, e.g., droplets 514 and 516, along with their associated ligand/reporter molecules, as well as an individual barcode oligonucleotide bead as described elsewhere herein e.g., beads 522 and 524, respectively; and the barcoded oligonucleotides are released from the beads and used to attach the barcode sequence the reporter molecules present within each partition with a barcode that is common to a given partition, but which varies widely among different partitions (interpreted as partitioning and a partition-specific barcode), such that in the example, the reporter molecules that associate with cell 502 in partition 514 are barcoded with barcode sequence 518, while the reporter molecules associated with cell 504 in partition 516 are barcoded with barcode 520, such that as a result, one is provided with a library of oligonucleotides that reflects the surface ligands of the cell, as reflected by the reporter molecule, but which is substantially attributable to an individual cell by virtue of a common barcode sequence, allowing a single cell level profiling of the surface characteristics of the cell (interpreted as a cell; a complex comprising a capture agent, secreted antibody or antigen, and a reporter agent; partitions/emulsions; and partition/emulsion-specific barcodes, claim 1) (paragraph [0197]). Figure 5 is shown below:
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Regarding claim 2, Mikkelsen teaches generating a population of antibody-secreting plasma B cells and memory B cells (interpreted as antibody secreting cells of a B-cell lineage, claim 2) (paragraph [0209], lines 10-11).
Regarding claim 3, Mikkelsen teaches a library of antibodies, antibody fragments, or other molecules having a binding affinity to the cell surface proteins or antigens (or other cell features) for which the cell is to be characterized ( also referred to herein as cell surface feature binding groups) (interpreted as a capture agent configured to couple to a cell surface molecule, claims 1 and 3) (paragraph [0279], lines 7-11). Mikkelsen teaches that the methods can be used to characterize cell features, such that the methods can be used to attach reporter molecules to these cell features, that when partitioned as described above, can be barcoded and analyzed, e.g., using DNA sequencing technologies, to ascertain the presence, and in some cases, relative abundance or quantity of such cell features within an individual cell or population of cells (interpreting surface features as capture agents configure to couple, claims 1 and 3) (paragraph [0194]).
Regarding claim 8, Mikkelsen teaches that the methods can be used to characterize cell features, such that the methods can be used to attach reporter molecules to these cell features, that when partitioned as described above, can be barcoded and analyzed, e.g., using DNA sequencing technologies, to ascertain the presence, and in some cases, relative abundance or quantity of such cell features within an individual cell or population of cells (interpreted as a reporter agent configured to couple to a secreted antibody or antigen, claims 1 and 8) (paragraph [0194]).
Regarding claim 53, Mikkelsen teaches that all of the fragments from multiple different partitions can then be pooled for sequencing on high throughput sequencers as described herein, where the pooled fragments comprise a large number of fragments derived from the nucleic acids of different cells or small cell populations, but where the fragments from the nucleic acids of a given cell will share the same barcode sequence because each fragment is coded as to its partition of origin, and consequently its single cell or small population of cells, the sequence of that fragment can be attributed back to that cell or those cells based upon the presence of the barcode (interpreted as sequencing the barcoded nucleic acid molecules, claim 53) (paragraph [0190], lines 1-11).
Mikkelsen meets all the limitations of the claims and, therefore, anticipates the claimed invention.
Conclusion
Claims 1-3, 8 and 53 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M BUNKER whose telephone number is (313) 446-4833. The examiner can normally be reached on Monday-Friday (6am-2:30pm).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Heather Calamita can be reached on (571) 272-2876. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
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/AMY M BUNKER/Primary Examiner, Art Unit 1684
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