DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. In view of the appeal brief filed on 29 September 2025, PROSECUTION IS HEREBY REOPENED. New grounds of rejection are set forth below.
To avoid abandonment of the application, appellant must exercise one of the following two options:
(1) file a reply under 37 CFR 1.111 (if this Office action is non-final) or a reply under 37 CFR 1.113 (if this Office action is final); or,
(2) initiate a new appeal by filing a notice of appeal under 37 CFR 41.31 followed by an appeal brief under 37 CFR 41.37. The previously paid notice of appeal fee and appeal brief fee can be applied to the new appeal. If, however, the appeal fees set forth in 37 CFR 41.20 have been increased since they were previously paid, then appellant must pay the difference between the increased fees and the amount previously paid.
A Supervisory Patent Examiner (SPE) has approved of reopening prosecution by signing below:
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
Claim Status
3. Claims 1-3, 7, 8, 15, 17, 19, 21, 25, 26 and 121-124 are pending and have been examined herein.
4. All previous grounds of rejection are hereby withdrawn. New grounds of rejection are set forth below.
Claim Objections
5. Claims 1-3, 7, 8, 15, 17, 19, 21, 25, 26 and 121-124 are objected to because of the following informalities:
Claims 1-3, 7, 8, 15, 17, 19, 21, 25, 26 and 121-124 are objected to because the claims recite a step (f) and a step (h) but do not recite a step (g).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) - Indefinite
6. 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, 8, 15, 17, 19, 21, 25, 26 and 124 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.
Claims 1, 8, 15, 17, 19, 21, 25, 26 and 124 are indefinite and confusing over the recitation of “specifically hybridizing the first target nucleic acids to the capture probes of the first population of beads to obtain hybridized first beads comprising first indexes, and hybridizing the second target nucleic acids to the capture probes of the second population of beads to obtain hybridized second beads comprising second indexes.” It is unclear as to how the hybridizing step results in obtaining beads comprising first and second indexes because it is unclear as to the source of the indexes and it is unclear as to what constitutes the indexes. While the claims recite that the indexes are nucleic acids, it is unclear as to whether the target nucleic acids themselves are the indexes or if the first and second polynucleotides comprise target nucleic acids and indexes or if separate nucleic acids are introduced which comprise the first and second indexes. With respect to claim 8, it is further unclear as to how the hybridizing step results in obtaining beads comprising the first or second indexes because the claim appears to encompass methods in which the beads themselves already comprise or have bound thereto first and second indexes.
Double Patenting
7. 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 1-3, 7, 8, 15, 17, 19, 21, 25, 26 and 121-124 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,667,957 (cited in the IDS of 08/07/2023) in view of Steemers et al (WO 2016/061517; cited in the IDS of 03/06/2021) and Frisen (WO 2016162309; cited in the IDS of 08/07/2023).
Although the claims at issue are not identical, they are not patentably distinct from each other because the present claims and the claims of ‘957 both encompass methods for distinguishing a first target nucleic acid from a second target nucleic acid wherein the methods comprise obtaining a first and second population of beads, each of the first and second populations of beads having attached thereto a capture probe for the target polynucleotide, a barcode and a barcode primer binding site (i.e., “primer binding site 3′ of the barcode” in the claims of ‘957); hybridizing the capture probes to the first and second target nucleic acids; distributing the resulting hybridization products on a substrate; extending the capture probes; sequencing barcodes and indexes (attached to the polynucleotides also attached to the beads); and decoding the locations of the barcodes and indexes to identify and distinguish between the first and second target nucleic acids.
In particular, claim 5 of ‘957 recites:
A method for identifying target ligands in an array comprising:
(a) obtaining a substrate having an array of beads distributed on a surface of the substrate, wherein the array of beads comprises a first and a second subpopulation of beads, comprising:
(i) obtaining the first and the second subpopulation of beads, wherein each bead comprises:
a capture probe capable of specifically binding to a target ligand,
a first polynucleotide comprising a barcode, and a primer binding site 3′ of the barcode, wherein the barcode is indicative of the capture probe, and
a second polynucleotide comprising an index and an index primer binding site 3′ of the index, wherein each index of the first subpopulation of beads is different from each index of the second subpopulation of beads;
(ii) specifically binding first target ligands to the capture probes of the first subpopulation of beads in a first reaction volume, and specifically binding second target ligands to the capture probes of the second subpopulation of beads in a second reaction volume; and
(iii) distributing the first and the second subpopulations of beads comprising the specifically bound first and second target ligands on the substrate, thereby obtaining the substrate having an array of beads;
(b) detecting in the array the specifically bound first and second target ligands of the first and the second subpopulations of beads;
(c) sequencing the barcodes of the first and the second subpopulations of beads by hybridizing a plurality of primers to the barcode primer binding sites of the first and the second subpopulations of beads;
and extending the hybridized primers, thereby determining the location of the capture probes of the first and the second subpopulations of beads in the array;
(d) sequencing the indexes of the first and the second subpopulations of beads, thereby determining the locations of the first and the second subpopulations of beads in the array; and
(e) decoding the locations of beads of the array of beads comprising a detected target ligand in the array, thereby identifying target ligands of the first target ligands or of the second target ligands in the array.
Dependent claim 6 of ‘782 specifies that the first and second target ligand is a nucleic acid. Claim 11 recites the method of claim 5 wherein “the capture probes of the first subpopulation of beads comprise different nucleotide sequences from the capture probes of the second subpopulation of beads.”
The claims of ‘782 do not specify the size of the beads and particularly do not recite that the beads are from 1pm to 100um in diameter.
However, Steemers teaches methods for detecting a first and second target nucleic acid using beads having attached thereto a capture probe and a barcode sequence (e.g., p. 14, line 26 to p. 15, line 4; claim 2). Regarding the beads, Steemers (p. 38, lines 5-12) teaches:
“The bead sizes range from nanometers, i.e. about 10 nm, to millimeters in diameter, i.e. 1 mm, with beads from about 0.2 micron to about 200 microns being preferred, and from about 0.5 to about 5 micron being particularly preferred, although in some embodiments smaller or larger beads may be used. In some embodiments, beads can be about 0.1 , 0.2, 0.3, 0.4, 0.5. 0.6, 0.7, 0.8, 0.9, 1 , 1.5, 2, 2.5, 2.8, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, or 200 μιη in diameter.”
Steemers also exemplifies methods wherein the beads are 1 um in diameter (p. 48, lines 4-10).
In view of the teachings of Steemers, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method claimed in ‘782 so as to have specifically used beads that were 1um in diameter or from 0.1 um to 100 um in diameter. One would have been motivated to have done so because Steemers teaches that these are the diameters of beads that are effective for performing methods for capturing target nucleic acids.
The claims of ‘782 also do not specify the length of the barcode and particularly do not recite that the barcode “has a length in a range from 6 to 50 consecutive nucleotides.”
However, Steemers (p. 39, line 29 to p. 40 line 2) teaches that “A barcode can comprise at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more consecutive nucleotides. In some embodiments, a barcode comprises at least about 10, 20, 30, 40, 50, 60, 70 80, 90, 100 or more consecutive nucleotides.” Steemers (p. 40, lines 29-31) exemplifies barcodes that are 8 nucleotides in length.
Accordingly, Steemers teaches that the barcodes are of a length within the presently claimed lengths of 6 to 50 consecutive nucleotides.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method claimed in ‘782 so as to have specifically used barcodes that were of a length of 8 nucleotides or from 8 to 50 nucleotides since Steemers teaches that these are lengths of barcodes that will be effective in methods for identifying the location of a bead based on the barcode sequence attached to the bead.
Additionally, while the claims of ‘782 recite sequencing the barcodes and indexes, the claims of ‘782 do not recite the limitation of the present claims of “(f) sequencing the barcodes and the indexes in the array of beads in the presence of labeled nucleotides.”
However, Frisen (p. 23, lines 17-23) teaches:
“Sequencing techniques, such as sequencing-by-synthesis (SBS) techniques, are a particularly useful method for determining barcode sequences. SBS can be carried out as follows. To initiate a first SBS cycle, one or more labeled nucleotides, DNA polymerase, SBS primers etc., can be contacted with one or more features on a solid support (e.g. feature(s) where nucleic acid probes are attached to the solid support). Those features where SBS primer extension causes a labeled nucleotide to be incorporated can be detected.”
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method claimed in ‘782 so as to have performed the extension reaction as part of a method of sequencing and to have incorporated labeled nucleotides into the extended products. One would have been motivated to have done so because Frisen teaches that this is a conventional method for performing sequencing to accomplish the objective of determining barcode sequences.
The claims of ‘782 also do not recite randomly distributing the hybridized beads at a discrete location on the array to obtain an array of beads having no more than one bead at each discrete site.
However, Frisen teaches randomly distributing the beads on a support such that each discrete location, such as a well, on the support can accommodate no more than a single bead (p. 18, lines 3-9).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have distributed the beads at discrete sites so that a single bead is at each discrete side, as taught by Frisen, in order to accomplish the objective of the methods claimed in ‘782 of identifying the first and second target nucleic acids, and barcodes and indexes associated therewith.
Regarding present claims 2, 3, 7 and 121-123, the claims of ‘782 do not recite that the first and second polynucleotides include a first and second index, respectively, which are incorporated into the polynucleotides by tagmenting with a plurality of transposomes and further include first and second index primer binding sites that becomes part of the extended capture probe, or wherein tagmenting comprises adding adaptors that comprise first and second indexes.
However, Steemers (p. 13, line 30 to p. 14, line 1) teaches “methods of tagmenting (fragmenting and tagging) target nucleic acid on a solid support for the construction of a tagmented target nucleic acid library.” It is stated that the method disclosed therein can be used to prepare a library of barcoded / index coded DNA fragments using transposomes to fragment target DNA and incorporate adaptor sequences that include a barcode / index (e.g., p. 20, line 19 to p. 21, line 14) and provides the advantage that the methods can be used to derive contiguity or assembly/phasing information (p. 14, lines 3-5). Steemers (p. 21 lines 4-14) states:
“In one aspect, the present invention relate to methods and compositions to derive contiguity information by means of capturing contiguously-linked, transposed, target nucleic acid onto a solid support. In some embodiments, contiguity preserving transposition (CPT) is carried out on the DNA, but the DNA is kept intact (CPT-DNA), thus making contiguously linked libraries. Contiguity information can be preserved by the use of transposase to maintain the association of template nucleic acid fragments adjacent in the target nucleic acid. The CPT DNA can be captured by hybridization of complimentary oligonucleotides having unique indexes or barcodes and immobilized on solid support, e.g., beads (Figure 29B). In some embodiments, the oligonucleotide immobilized on the solid support may further comprise primer binding sites, unique molecular indices (UMI), in addition to barcodes.”
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method claimed in ‘782 so as to have incorporated indexes into the first and second polynucleotides using the tagmenting process of Steemers. One would have been motivated to have done so for the benefits set forth by Steemers that tagmenting fragments the target DNA into contiguous fragments that can be used to derive assembly/phasing information and incorporates a detectable tag / index / barcode into the target nucleic acid to aid in the identification of the target nucleic acid.
Regarding present claim 8, as discussed above, claim 5 of ‘782 recites that the first and second subpopulation of beads comprise “a second polynucleotide comprising an index and an index primer binding site 3′ of the index, wherein each index of the first subpopulation of beads is different from each index of the second subpopulation of beads.”
Regarding present claim 15, the claims of ‘782 do not specifically state that the first and second target nucleic acids are from different nucleic acid samples. However, claim 14 of ‘782 recites “the first and second target ligands are obtained from different subjects.” Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have specifically performed the method claimed in ‘782 using different nucleic acid samples to achieve the objective set forth in claim 14 therein of identifying nucleic acids from different subjects present in different samples.
Regarding present claim 17, claim 5 of ‘782 recites that the first and second beads each have a capture probe and each have a barcode wherein the barcode is indicative of the capture probe. Accordingly, claim 5 of ‘782 suggests using barcodes in which the barcode attached to the first bead is different from the barcode attached to the second bead so that the capture probe associated with the first and second beads can be distinguished from one another.
Regarding present claim 19, the claims of ‘782 do not specifically recite that the barcode primer binding sites are the same. However, the claims of ‘782 do recite that each bead has attached thereto a barcode and a barcode primer site. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have performed the method claimed in ‘782 using barcode primer binding sites that are the same since this would have allowed for the use of a single primer to sequence each of the barcodes.
Regarding present claim 21, claims 6-7 and 9 of ‘782 recite that the beads are contacted with a polymerase to extend and sequence of the capture probes.
Regarding present claims 25 and 124, claim 5 of ‘782 recites “(ii) specifically binding first target ligands to the capture probes of the first subpopulation of beads in a first reaction volume, and specifically binding second target ligands to the capture probes of the second subpopulation of beads in a second reaction volume.” Accordingly, the method claimed in ‘782 is one in which the hybridizing step is performed in solution and includes hybridizing in a first volume the first target nucleic acids to the first capture probes and hybridizing in a second volume the second target nucleic acids to the second capture probes.
Regarding present claim 26, claim 20 of ‘782 recites that the array is a flow cell.
8. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Frisen et al (WO2016162309; cited in the IDS and discussed above) teaches a method for spatially tagging nucleic acids in a biological specimen. Frisen (p. 1, line 33 to p. 2 line 10) states:
“The method can include the steps of (a) attaching different nucleic acid probes to a solid support to produce randomly located probes on the solid support, wherein the different nucleic acid probes each includes a barcode sequence, and wherein each of the randomly located probes includes different barcode sequences from other randomly located probes on the solid support; (b) performing a nucleic acid detection reaction on the solid support to determine the barcode sequences of the randomly located probes on the solid support; (c) contacting a biological specimen with the solid support that has the randomly located probes; (d) hybridizing the randomly located probes to target nucleic acids from portions of the biological specimen that are proximal to the randomly located probes; and (e) extending the randomly located probes to produce extended probes that include the barcode sequences and sequences from the target nucleic acids, thereby spatially tagging the nucleic acids of the biological specimen.”
Frisen teaches that in step (b) the barcodes can be detected / decoded on the solid support by: (i) performing a “decoder probe hybridization reaction” on the solid support (p. 42, lines 8-21) or (ii) by amplifying the capture probes by extension of the nucleic acid primers to produce nucleic acid clusters having copies of the barcode sequence and target capture sequence at the randomly located positions on the solid support and then sequencing the amplification products to identify the barcode sequences (p. 39, line 23 to p. 40 line 8).
It is disclosed that “a solid support used in a method set forth herein can include an array of beads, wherein different nucleic acid probes are attached to different beads in the array.”
Frisen does not teach or suggest the presently claimed methods wherein the first and second plurality of polynucleotides comprising the first and second target nucleic acids are in solution and the step of hybridizing the target nucleic acids to the capture probes is performed prior to randomly distributing the resulting hybridized first beads and hybridized second beads on a surface of a substrate comprising an array of discrete sites, to obtain an array of beads having no more than a single bead at each discrete site.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARLA J MYERS whose telephone number is (571)272-0747. The examiner can normally be reached M-Th 6:30-5:00 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached on 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682
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