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 .
Claims 1-20 are currently pending. Claims 19-20 are withdrawn from consideration as being drawn to a nonelected invention. Claims 1-18 are currently under examination.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-18, drawn to a method for
Detecting interactions between nucleic acid molecules and proteins of interest, in
the reply filed March 13, 2026 is acknowledged.
Claims 10-20 are withdrawn from further consideration to 37 CFR 1.142(b) as being
drawn to a nonelected invention, there being no allowable generic or linking claim. Election was
made without traverse in the reply filed on March 13, 2026, and is acknowledged.
Information Disclosure Statement
The Information Disclosure Statement filed June 23, 2023 been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d)(see Fig. 7E and 10F). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see Page 65, [0168]). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Additionally, The use of the terms Triton®X and Tween® 20 (see Page 52, [0125], Page 56, [0140], Page 57, [0141], Page 58, [0145] and [0147], Page 49, [0147], Page 64, [0167], Page 57, [0144], Page 60, [0152]-[0153]), which are trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1, 6, 15 and 18 are objected to because of the following informalities:
In claim 1, line 6, “antigen binding protein is capable of specifically binding a protein of interest”, should read “antigen binding protein specifically binds to a protein of interest”.
In claim 1, lines 10-11, “a multivalent binding agent comprising two or more binding moieties capable of binding the first ligand”, should read “a multivalent binding agent comprising two or more binding moieties that bind to the first ligand”.
In claim 6, lines 2-3, “said 5' overhang is capable of ligating to a 5' overhang of one or more of a ligation adaptor molecule” should read “said 5' overhang ligates to a 5' overhang of one or more of a ligation adaptor molecule”.
In claim 15, line 3, “a 5' overhang capable of ligation to the 5' overhang of a combinatorial barcode unit”, should read “a 5' overhang ligates to the 5' overhang of a combinatorial barcode unit”.
In claim 18, line 6, “the antigen binding protein is capable of specifically binding a RBP” should read “the antigen binding protein specifically binds to a RBP”.
In claim 18, lines 10-11, “a multivalent binding agent comprising two or more binding moieties capable of binding the first ligand”, should read “a multivalent binding agent comprising two or more binding moieties that bind to the first ligand”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 3, 7-8 and 12 are 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 3 is considered vague and indefinites for the following reasons:
In claim 3, line 7, the “and/or” is unclear and confusing. It is unclear if steps (i) through (iii) are required or alternatively step (iv) is required, or if all of steps (i) through (iv) are subject to the “and/or”?
Claim 3 recites the limitation "the chromatin" in line 5. There is insufficient antecedent basis for this limitation in the claim.
Claim 3 recites the limitation "the nuclei" in line 4. There is insufficient antecedent basis for this limitation in the claim.
Claim 3 recites the limitation "the nuclear pellet" in lines 6-7. There is insufficient antecedent basis for this limitation in the claim.
Claim 7 is considered vague and indefinites for the following reasons:
Claim 7 recites the limitation “the annealed molecules” in line 4. There is insufficient antecedent basis for this limitation in the claim.
Claim 8 is considered vague and indefinites for the following reasons:
Claim 8 recites the limitation “said annealed molecules” in line 5. There is insufficient antecedent basis for this limitation in the claim.
Claim 12 is considered vague and indefinites for the following reasons:
Claim 12 recites the limitation “the binding site” in line 5. There is insufficient antecedent basis for this limitation in the claim.
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 (i.e., changing from AIA to pre-AIA ) 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-17 are rejected under 35 U.S.C. 103 as being unpatentable over Belhocine et al. (U.S. Patent Application Publication US 2019/0361010 A1, published November 28, 2019), in view of Quinodoz et al. (“SPRITE: a genome-wide method for mapping higher-order 3D interactions in the nucleus using combinatorial split-and-pool barcoding. Nat Protoc.;17(1):36-75, published January 10, 2022), cited on the IDS filed June 23, 2023.
Regarding claim 1, Belhocine teaches a method for detecting interactions between nucleic acid molecules and proteins of interest (Pages 1-3, [0009]-[0010] and Pages 4-6, [0014]-[0016]). Belhocine teaches a pool of barcoded detection particles (Pages 1-3, [0009]-[0010], Page 32, [0321], Page 45, [0401], Page , [0441], Pages 51-52, [0472] and Pages 141-142, [0970]) Belhocine teaches each barcoded detection particle comprises a particle associated with an antigen-binding protein and a plurality of barcoding oligonucleotides (Page 48, [0418]-[0419], Pages 48-49, [0422]-[0425], Pages 140-141, [0966] and Fig. 20). Belhocine teaches the antigen binding protein is capable of specifically binding a protein of interest (Pages 48-49, [0418]-[0425]). Belhocine teaches plurality of barcoding oligonucleotides comprise a first ligand, wherein the particle comprises a second ligand (Page 6, [0017], Page 36, [0353]-[0355], Page 48, [0418] and [0421] and Page 52, [0443]). Belhocine teaches the plurality of barcoding oligonucleotides are associated with the particle via a multivalent binding agent comprising two or more binding moieties capable of binding the first ligand and/or the second ligand (Page 6, [0017], Page 36, [0353]-[0355], Page 48, [0418] and [0421] and Page 52, [0443]). Belhocine teaches each barcoding oligonucleotide comprises a capture barcode, wherein the capture barcode is a unique sequence specific to the antigen-binding protein associated with the particle to which the barcoding oligonucleotide is associated with (Pages 4-6, [0013]-[0015], Page 7, [0018], Page 34, [0337], Page 37, [0361]-[0362], Page 39, [0373] Pages 48-49, [0418]-[0425] and Pages 49-50, [0432]). Belhocine teaches two or more barcoded detection particles of the pool of barcoded detection particles differ from each other with respect to the antigen-binding protein associated with the particle (Page 48, [0419]-[0422]). Belhocine teaches lysing a sample comprising a plurality of cells to generate a cell lysate (Page 6, [0015], Page 18, [0209], Page 26, [0275] and Page 58, [0469]). Belhocine teaches the cells comprise nucleic acid molecules suspected of being associated with proteins of interest (Pages 1-2, [0009], Page 160, [1059] and Page 161, [1064]). Belhocine teaches contacting the cell lysate, or a product thereof, with the pool of barcoded detection particles to form a plurality of detection complexes (Page 6, [0015], Pages 1-3, [0009]-[0010], Page 18, [0209], Page 32, [0321], Page 45, [0401], Page 51, [0441], Pages 58-59, [0472] and Pages 141-142, [0970]). Belhocine teaches a barcoded detection particle, a captured protein of interest, and captured nucleic acid molecule(s) associated with the captured protein of interest (Page 34, [0337], Pages 1-2, [0009], Page 160, [1059], Page 161, [1064], Pages 4-6, [0013]-[0015], Page 7, [0018], Page 34, [0337], Page 37, [0361]-[0362], Page 39, [0373] Pages 48-49, [0418]-[0425] and Pages 49-50, [0432]). Belhocine teaches two or more iterations of split-and-pool barcoding (Pages 1-3, [0009]-[0010], Page 32, [0321], Page 45, [0401], Page 51, [0441], Pages 58-59, [0472], Pages 141-142, [0970] and Page 145, [0986]-[0987]). Belhocine teaches randomly distributing the plurality of detection complexes into a plurality of partitions (Page 82, [0584]). Belhocine teaches in the plurality of partitions, combinatorially barcoding captured nucleic acid molecules and barcoding oligonucleotides, or products thereof, with a combinatorial barcode unit (Pages 141-142, [0970]-[0972] and Page 160, [1060]-[1061]). Belhocine teaches within each partition, the captured nucleic acid molecules and barcoding oligonucleotides are barcoded with the same combinatorial barcode unit, wherein captured nucleic acid molecules and barcoding oligonucleotides of different partitions receive different combinatorial barcode units from each other, and captured nucleic acid molecules and barcoding oligonucleotides of the same detection complex will assort together in a partition of the plurality of partitions (Pages 141-142, [0970]-[0972] and Page 160, [1059]-[1061]). Belhocine teaches pooling the detection complexes from the plurality of partitions, and two or more iterations of split-and-pool barcoding (Pages 1-3, [0009]-[0010], Page 32, [0321], Page 45, [0401], Page 51, [0441], Pages 58-59, [0472], Pages 141-142, [0970] and Page 145, [0986]-[0987]). Belhocine teaches combinatorially barcoded captured nucleic acid molecule and each combinatorially barcoded barcoding oligonucleotide comprises a combinatorial barcode comprising two or more combinatorial barcode units, obtaining sequence information of the combinatorially barcoded captured nucleic acid molecules and the combinatorially barcoded barcoding oligonucleotides, or products thereof, as well as detecting interactions between captured nucleic acid molecules and proteins of interest based on the sequence information (Pages 141-142, [0970]-[0972] and Page 160-161, [1059]-[1064]).
Regarding claim 2, Belhocine teaches the pool of barcoded detection particles comprises at least about 2 to about 500 barcoded detection particles that differ from each other with respect to the antigen-binding protein and barcoding oligonucleotide associated with the particle (Page 25, [0265], Pages 27-28, [0283]-[0284], Page 48, [0419]-[0422], Page 49, [0426], Pages 50-51, [0437], Page 51, [0440], and Example 9).
Regarding claim 3, Belhocine teaches adding a crosslinking agent to the plurality of cells prior to the lysis step; or adding a crosslinking agent to the cell lysate (Page 17, [0204], Page 18, [0209] and Page 20, [0226]-[0227]). Belhocine teaches isolation of the nuclei of the plurality of cells (Page 34, [0337]). Belhocine teaches fragmentation of the chromatin of the plurality of cells, wherein fragmentation comprises enzymatic chromatin fragmentation (Pages 4-5, [0014] and Page 10, [0099]).
Regarding claim 4, Belhocine teaches processing at least one end of the captured nucleic acid molecule(s) to enable ligation of said captured nucleic acid molecule(s) to a ligation adaptor molecule and said processing comprises phosphorylation, and/or dA-tailing as well as ligating a ligation adaptor molecule to the captured nucleic acid molecule(s) (Page 13, [0179], Page 36, [0352], Page 45, [0399], Page 118, [0820] and Page 137-138, [0955]).
Regarding claim 5, Belhocine teaches the interactions between the nucleic acid molecule and the protein of interest as discussed above.
Regarding claim 6, Belhocine teaches each combinatorial barcode unit comprises: at least one 5' overhang, and wherein said 5' overhang is capable of ligating to a 5' overhang of one or more of a ligation adaptor molecule, a combinatorial barcode unit, or a terminal tag and a modified 5' phosphate group (Page 45, [0396]-[0397] and [0399] and Page 142, [0972]).
Regarding claim 7, Belhocine teaches the combinatorial barcoding step comprises: annealing the 5' overhang of a barcoding oligonucleotide, a ligation adaptor molecule, or a combinatorial barcode unit, to the 5' overhang of a combinatorial barcode unit and ligating the annealed molecules (Page 45, [0396]-[0397] and [0399] and Page 142, [0972]-[0973]).
Regarding claim 8, Belhocine teaches the two or more iterations of split-and-pool barcoding (Pages 1-3, [0009]-[0010], Page 32, [0321], Page 45, [0401], Page 51, [0441], Pages 58-59, [0472], Pages 141-142, [0970] and Page 145, [0986]-[0987]). Belhocine teaches annealing a terminal tag to each captured nucleic acid molecule and each barcoding oligonucleotide and ligating said annealed molecules (Page 70, [0520]-[0521], Page 72, [0533], Page 126, [0875], Page 141, [0969] and Page 142-143, [0973]-[0974]).
Regarding claim 9, Belhocine teaches the multivalent binding agent, the first ligand, the second ligand, and/or at least one of the two or more binding moieties is a biotin moiety and/or an avidin moiety (Page 6, [0017], Page 36, [0353]-[0355], Page 48, [0418] and [0421] and Page 52, [0443]).
Regarding claim 10, Belhocine teaches obtaining sequence information comprises: obtaining sequencing data comprising a plurality of sequencing reads of the combinatorially barcoded captured nucleic acid molecules and the combinatorially barcoded barcoding oligonucleotides, or products thereof (Page 13, [0180], Page 7, [0018], Pages 84-85, [0596], Pages 141-142, [0970]-[0972] and Page 160, [1059]-[1061]). Belhocine teaches each of the plurality of sequencing reads of the combinatorially barcoded captured nucleic acid molecules, or products thereof, comprise a combinatorial barcode sequence, and a captured nucleic acid molecule sequence (Pages 141-142, [0970]-[0972]). Belhocine teaches each of the plurality of sequencing reads of the combinatorially barcoded barcoding oligonucleotides, or products thereof, comprise a combinatorial barcode sequence, and a capture barcode sequence (Pages 1-3, [0009], Pages 4-5, [0013]-[0014] and Pages 141-142, [0970]-[0972]).
Regarding claim 11, Belhocine teaches for each unique capture barcode sequence, which indicates a captured protein of interest, identifying the captured nucleic acid molecule sequence of sequencing reads sharing a capture barcode sequence (Pages 1-3, [0009]-[0010], Page 4-5, [0012]-[0014], Page 7, [0018], Page 13, [0175], Pages 14-15, [0187], Page 27, [0279] and Page 34, [0337]).
Regarding claim 12, Belhocine teaches determining the binding site of a captured protein of interest on associated captured nucleic acid molecule sequence(s) (Page 15, [0189] and Page 76, [0555]). Belhocine teaches aligning captured nucleic acid molecule sequence(s) to a reference genome (Page 128, [0884]).
Regarding claim 13, Belhocine teaches the nucleic acid molecules are selected from the group comprising double-stranded DNA, single-stranded DNA, microRNA (miRNA), messenger RNA (mRNA), long non-coding RNA (lncRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), Piwi-interacting RNA (piRNA), interfering RNA (siRNA), antisense RNA (aRNA), transfer messenger RNA (tmRNA), tRNA-derived small RNA (tsRNA), rDNA-derived small RNA (srRNA), ribozyme, viral RNA, single-stranded RNA, double-stranded RNA, or any combination thereof (Page 57, [0461]-[0462]).
Regarding claim 14, Belhocine teaches detecting interactions between nucleic acid molecules and proteins of interest comprises detecting interactions between nucleic acid molecules and at least about 2 to about 500 different proteins of interest (Page 25, [0265], Pages 27-28, [0283]-[0284], Page 48, [0419]-[0422], Page 49, [0426], Pages 50-51, [0437], Page 51, [0440], and Example 9).
Regarding claim 15, Belhocine teaches the 5' end of the barcoding oligonucleotide comprises a modified phosphate group and/or a 5' overhang capable of ligation to the 5' overhang of a combinatorial barcode unit (Page 45, [0396]-[0397] and [0399] and Page 142, [0972]). Belhocine teaches the barcoding oligonucleotide comprises a unique molecular identifier (UMI) (Page 141-142, [0969]-[0971]). Belhocine teaches the barcoding oligonucleotide comprises a universal library sequence, wherein the universal library sequence comprises a sequence complementary to at least a portion of a sequencing primer (Page 27, [0282], Pages 72-73, [0533]-[0543] and Page 141, [0969]). , Belhocine teaches the barcoding oligonucleotide further comprises a 3' spacer sequence (Page 13, [0179], Page 45, [0396], Page 77, [0561] and Page 136, [0983]).
Regarding claim 16, Belhocine teaches the protein of interest may be an intracellular protein or a histone protein (which encompasses all of the listed proteins listed; Page 3, [0010], Pages 4-5, [0014], Page 86, [0601] and Page 94, [0663]).
Regarding claim 17, Belhocine teaches the antigen binding protein comprises an antibody, an antibody fragment, an scFv, a Fv, a Fab, a (Fab')2, a single domain antibody (SDAB), a VH or VL domain, a camelid VHH domain, a Fab, a Fab', a F(ab')2, a Fv, a scFv, a dsFv, a diabody, a triabody, a tetrabody, a multispecific antibody formed from antibody fragments, a single-domain antibody (sdAb), a single chain comprising cantiomplementary scFvs (tandem scFvs) or bispecific tandem scFvs, an Fv construct, a disulfide-linked Fv, a dual variable domain immunoglobulin (DVD-Ig) binding protein or a nanobody, an aptamer, an affibody, an affilin, an affitin, an affimer, an alphabody, an anticalin, an avimer, a DARPin, a Fynomer, a Kunitz domain peptide, a monobody, or any combination thereof, and/or is not conjugated to an oligonucleotide (Page 15, [0189], Page 36, [0355] and Fig. 20).
Regarding claim 18, Belhocine teaches a method for detecting interactions between ribonucleic acid molecules and RNA- binding proteins (RBPs) (Page 75, [0546] and Page 37, [0361]—Page 38, [0368]). Belhocine teaches providing a pool of barcoded detection particles (Pages 1-3, [0009]-[0010], Page 32, [0321], Page 45, [0401], Page , [0441], Pages 51-52, [0472] and Pages 141-142, [0970]). Belhocine teaches each barcoded detection particle comprises a particle associated with an antigen-binding protein and a plurality of barcoding oligonucleotides (Page 48, [0418]-[0419], Pages 48-49, [0422]-[0425], Pages 140-141, [0966] and Fig. 20). Belhocine teaches the antigen binding protein is capable of specifically binding a RBP (Page 75, [0546] and Page 37, [0361]—Page 38, [0368]). Belhocine teaches plurality of barcoding oligonucleotides comprise a first ligand, wherein the particle comprises a second ligand (Page 6, [0017], Page 36, [0353]-[0355], Page 48, [0418] and [0421] and Page 52, [0443]). Belhocine teaches the plurality of barcoding oligonucleotides are associated with the particle via a multivalent binding agent comprising two or more binding moieties capable of binding the first ligand and/or the second ligand (Page 6, [0017], Page 36, [0353]-[0355], Page 48, [0418] and [0421] and Page 52, [0443]). Belhocine teaches each barcoding oligonucleotide comprises a capture barcode, wherein the capture barcode is a unique sequence specific to the antigen-binding protein associated with the particle to which the barcoding oligonucleotide is associated with (Pages 4-6, [0013]-[0015], Page 7, [0018], Page 34, [0337], Page 37, [0361]-[0362], Page 39, [0373] Pages 48-49, [0418]-[0425] and Pages 49-50, [0432]). Belhocine teaches two or more barcoded detection particles of the pool of barcoded detection particles differ from each other with respect to the antigen-binding protein associated with the particle (Page 48, [0419]-[0422]). Belhocine teaches lysing a sample comprising a plurality of cells to generate a cell lysate (Page 6, [0015], Page 18, [0209], Page 26, [0275] and Page 58, [0469]). Belhocine teaches the cells comprise ribonucleic acid molecules suspected of being associated with RBPs (Page 75, [0546] and Page 37, [0361]—Page 38, [0368]). Belhocine teaches contacting the cell lysate, or a product thereof, with the pool of barcoded detection particles to form a plurality of detection complexes (Page 6, [0015], Pages 1-3, [0009]-[0010], Page 18, [0209], Page 32, [0321], Page 45, [0401], Page 51, [0441], Pages 58-59, [0472] and Pages 141-142, [0970]). Belhocine teaches each of the plurality of detection complexes comprises a barcoded detection particle, a captured RBP, and captured ribonucleic acid molecule(s) associated with the captured RBP (Page 34, [0337], Pages 1-2, [0009], Page 160, [1059], Page 161, [1064], Pages 4-6, [0013]-[0015], Page 7, [0018], Page 34, [0337], Page 37-38, [0361]-[0368], Page 39, [0373] Pages 48-49, [0418]-[0425] , Pages 49-50, [0432], and Page 75, [0546]). Belhocine teaches converting the captured ribonucleic acid molecule(s) to complementary DNA (cDNA) molecules (Pages 5-6, [0015] and Page 142, [0973]). Belhocine teaches two or more iterations of split-and-pool barcoding (Pages 1-3, [0009]-[0010], Page 32, [0321], Page 45, [0401], Page 51, [0441], Pages 58-59, [0472], Pages 141-142, [0970] and Page 145, [0986]-[0987]). Belhocine teaches each iteration comprises randomly distributing the plurality of detection complexes into a plurality of partitions (Page 82, [0584]). Belhocine teaches in the plurality of partitions, combinatorially barcoding cDNA molecules and barcoding oligonucleotides, or products thereof, with a combinatorial barcode unit, wherein within each partition, the cDNA molecules and barcoding oligonucleotides are barcoded with the same combinatorial barcode unit (Pages 141-142, [0970]-[0974] and Page 160, [1060]-[1061]). Belhocine teaches cDNA molecules and barcoding oligonucleotides of different partitions receive different combinatorial barcode units from each other, and wherein cDNA molecules and barcoding oligonucleotides of the same detection complex will assort together in a partition of the plurality of partitions (Pages 141-142, [0970]-[0974] and Page 160, [1060]-[1061]). Belhocine teaches pooling the detection complexes from the plurality of partitions, and said two or more iterations of split-and-pool barcoding (Pages 1-3, [0009]-[0010], Page 32, [0321], Page 45, [0401], Page 51, [0441], Pages 58-59, [0472], Pages 141-142, [0970] and Page 145, [0986]-[0987]). Belhocine teaches each combinatorially barcoded cDNA molecule and each combinatorially barcoded barcoding oligonucleotide comprises a combinatorial barcode comprising two or more combinatorial barcode units, obtaining sequence information of the combinatorially barcoded cDNA molecules and the combinatorially barcoded barcoding oligonucleotides, or products thereof, and detecting interactions between captured ribonucleic acid molecules and RBPs based on the sequence information (Page 75, [0546], Page 37, [0361]—Page 38, [0368], Pages 141-142, [0970]-[0974] and Page 160-161, [1059]-[1064]).
Belhocine does not explicitly teach or suggest each combinatorial barcode unit corresponds to an iteration of split-and-pool barcoding. Belhocine does not teach or suggest the protein of interest is specifically H3K27ac. Belhocine does not teach or suggest a probability of the interaction between the nucleic acid molecule and the protein of interest as being bona fide is proportional to the number of iterations of split-and-pool barcoding.
Quinodoz teaches mapping of interactions within the nucleus of DNA, RNA and protein molecules (Abstract). Quinodoz teaches using SPRITE tags (barcodes) through an iterative split-pool barcoding method (Abstract). Quinodoz teaches because all molecules in a cross-linked complex are covalently attached, they will sort together throughout each round of split-and-pool and will obtain the same series of SPRITE tags, which we refer to as a barcode which are sequenced, and all reads sharing identical barcodes are matched to reconstruct interactions (Abstract). Quinodoz teaches the protein of interest is H3K27ac (Fig. 5). Quinodoz teaches each combinatorial barcode unit corresponds to an iteration of split-and-pool barcoding (Abstract, Page 3, Last Paragraph, Page 4, Second Paragraph, Page 7, Last Paragraph—Page 8, Second Paragraph, Page 32, Last Paragraph, Page 65, Last Paragraph—Page 66, First Paragraph). Quinodoz teaches beaded molecules used in the spilt pool analysis (Page 8, Third Paragraph). Quinodoz teaches determining protein interaction using biotin (Page 2, Second Paragraph, Page 5, First—Fourth Paragraph). Quinodoz teaches using adaptors, a 5’overhang, 5’ phosphate, da-tailing, ligation and terminal tags (Page 40 First Paragraph—Page 41, Second Paragraph). Quinodoz teaches probability of the interaction between the nucleic acid molecule and the protein of interest as being bona fide is proportional to the number of iterations of split-and-pool barcoding (Page 8, Third Paragraph, Page 58, Second Paragraph and Fig. 4). Quinodoz teaches using these methods allows for improved sequencing quality scores for barcode identification, measures higher-order spatial interactions to create global/combinatorial spatial maps of DNA, RNA and/or protein (Page 4, Last Two Paragraphs—Page 5, Fourth Paragraph).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the invention to modify the teachings of Belhocine with the teachings of Quinodoz to use a split-pool barcoding process where each combinatorial barcode unit corresponds to an iteration of split-and-pool barcoding. This would allow for improved sequencing quality scores for barcode identification, measures higher-order spatial interactions to create global/combinatorial spatial maps of DNA, RNA and/or protein as taught by Quinodoz (Page 4, Last Two Paragraphs—Page 5, Fourth Paragraph).
Double Patenting
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.
Claims 1, 5-8 and 17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 9-14 and 16-17 of U.S. Patent No. 11,078,480. Although the claims at issue are not identical, they are not patentably distinct from each other because while the preambles are slightly different, it appears that the steps of the claims are identical, so it would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to perform a method providing a of detecting an interaction between a macromolecule and an interaction partner or perform a method for detecting interactions between nucleic acid molecules and proteins of interest using those same steps. Therefore, the claims are not deemed to be patentably distinct.
Conclusion
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/JESSICA D PARISI/Examiner, Art Unit 1684
/HEATHER CALAMITA/Supervisory Patent Examiner, Art Unit 1684
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