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 .
Status of the Application
The Amendment filed June 17, 2026 is acknowledged.
Claims 1, 6-8, 19-20 and 24-26 are pending and are being examined on the merits.
Response to Arguments
Applicant’s arguments filed June 17, 2026 have been fully considered.
The following rejections are WITHDRAWN in view of the filing of a terminal disclaimer:
Double patenting rejections
The following rejections are MAINTAINED:
Prior art rejections
Response to arguments regarding prior art rejections
Applicant argues that the prior art rejections should be withdrawn because Drmanac
does not teach an introducer that is configured to mark a 5’-end of a unit and a closure configured to mark a 3’ end of a unit. Applicant further argues that the instantly claimed introducer and closure are structurally and functionally distinct. In contrast, Applicant argues that Drmanac sequence 23 is a single sequence that serves as a binding site for both the forward and reverse primers, and is not two separate sequences (Remarks, pp. 4-5).
The Examiner disagrees. Drmanac sequence 23 is a primer binding site, with two of such sites shown in Fig. 2B top pane. That figure also shows that the corresponding primer binding sites for a pair of PCR primers where the forward primer anneals to the top strand of the concatemer, while the reverse primer anneals to the bottom strand of the concatemer. Thus, even if each iteration of Drmanac sequence 23 in the concatemer has the same nucleotide sequence, the actual PCR primer binding sites are different because the forward primer is annealing to the primer binding site in the top strand of Drmanac sequence 23 and the reverse primer is annealing to the reverse complement of the primer binding site in the top strand. Thus, Drmanac teaches a primer binding site upstream of the target nucleic acid on the top strand (i.e., an introducer) and a primer binding site downstream of the target nucleic acid on the bottom strand (i.e., a closure) that are structurally and functionally distinct. Similarly, in instant claim 1, the introducer and closure are configured to serve as target sequences for the annealing of PCR primers. Thus, in instant claim 1 the introducer and closure are on opposite strands of the concatemer, as in Drmanac.
Applicant argues that the Drmanac sequence 23 is additionally distinguishable from the instantly claimed introducer and closure in that the Drmanac sequence enables PCR amplification of each unit, while in the instant claims, the introducer and the closure additionally define the boundaries of each unit within the multimer. Applicant additionally argues that Drmanac does not disclose computational parsing of units based on boundary-marking sequences (Remarks, pp. 5-6).
It is not clear what Applicant is arguing here. It appears in Drmanac Fig. 2A, middle pane that sequence 23 identifies the boundaries of each unit within the multimer. Further, the instant claims do not require “computational parsing of units”, and thus it is not relevant whether Drmanac makes such a disclosure.
Applicant argues that Drmanac does not teach the instantly claimed identifier because the Drmanac sequences 22a-22d are unique to each position along a DNA fragment, not to the individual molecular copies. In contrast, the claimed identifier has the ability to distinguish one copy of a segment from another copy (Remarks, pp. 6-7).
The Examiner agrees in part and disagrees in part. Applicant’s arguments seem to relate to a claim 1 embodiment where the “multimer comprising multiple units” additionally comprises at least two units with the same target nucleic acid (e.g., target nucleic acid 1 appears in both monomer 1 and monomer 2). It does not. Rather, as noted, the multimer comprises multiple units, but each unit may comprise a different target nucleic acid (e.g., target nucleic acid 1 appears in monomer 1, target nucleic acid 2 appears in monomer 2, and so on). The Examiner agrees that Drmanac does not teach an identifier that is unique for each copy of the nucleic acid segment, if there is more than one copy of the same nucleic acid segment (the former embodiment). However, if none of the nucleic acid segments repeat in the multimer (the latter embodiment), then any unique sequence will meet the requirements of identifier because then the single copy of nucleic acid segment is associated with a unique sequence.
Applicant argues that Tang does not cure the deficiencies of Drmanac (Remarks, pp. 7-9).
The Examiner disagrees with Applicant’s characterizations of the teachings of Drmanac, as noted above, and consequently also disagrees with this argument.
Applicant argues that there would be no motivation to combine Drmanac and Tang in the manner proposed because doing so would “require dismantling the core architectural logic of Drmanac … and grafting onto it elements from Tang that serve a different purpose” (Remarks, pp. 9-10).
The Examiner disagrees. It is not clear why including an additional combinatorial coding element (the Tang index) would “require dismantling the core architectural logic of Drmanac”.
Finally, Applicant argues that Fu does not cure the deficiencies of Drmanac and Tang (Remarks, pp. 10-11).
The Examiner disagrees with Applicant’s characterizations of the teachings of Drmanac and Tang, as noted above, and consequently also disagrees with this argument.
Claim Rejections - 35 USC § 103
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.
Claims 1, 7, 19-20 and 24-26 are rejected under 35 U.S.C. 103 as being unpatentable over Drmanac1 (WO 2014/145820 A2) in view of Tang2 (WO 2016/077313 A1).
Regarding independent claim 1 and dependent claims 7, 19-20 and 24, Drmanac teaches …
A multimer configured to allow sequencing and sequence analysis of at least one nucleic
acid segment, the multimer comprising multiple units, wherein each unit comprises: (a) a segment comprising a target nucleic acid sequence to be sequenced and analyzed (Fig. 2B, top pane; paras. 140-141: individual segments between barcode sequences 22a-22d);
(b) an introducer comprising a nucleic acid sequence that is configured to mark a 5’-end of the unit; a closure comprising a nucleic acid sequence that is configured to mark a 3’-end of the unit, wherein the introducer and the closure are further configured to serve as target sequences for the annealing of primers of a PCR (Fig. 2B; paras. 140-141, 145: primer binding site, 23, marks the 5’ and 3’ end of each segment, as also shown in Fig. 2B middle pane);
and (d) an identifier (1) that is unique for every copy of said nucleic acid segment; (2) that identifies copies of the same target nucleic acid sequence in said nucleic acid segment and (3) whose presence distinguishes errors occurring during at least a second amplification and/or sequencing of said multimer and mutations in said target sequence (Fig. 2B; paras. 79, 86-87, 93, 128, 140-141, 145: unique tag sequence, 22a-22d).
Further, regarding the identifier, Drmanac teaches that the barcode sequences (Fig. 2B; paras. 140-141, 145: unique tag sequence, 22a-22d) are unique for each copy of the segment. As can also be seen in Fig. 2B (middle pane), identifiers 22a and 22b are both attached to the first segment (one at each end), while 22b and 22c are attached to the second segment, and so on. Since each barcode sequence is unique, then the combination of 22a and 22b is also unique as to the first segment, as is the combination of 22b and 22c as to the second segment, and so on. Thus, each of 22a-22d can be considered a partial identifier, and collectively they can be considered multiple partial identifiers, wherein one partial identifier is attached to one side of the segment and the other partial identifier is attached to the other side of the segment. Finally, Drmanac teaches that each barcode sequence is any length sufficient to provide a population of different tags, including 10-20 nucleotides (para. 124-125). Finally, these unique sequences, e.g., 22a plus 22b, are capable of identifying copies of the same target nucleic acid sequence in said nucleic acid segment, and whose presence can be used distinguish errors occurring during at least a second amplification and/or sequencing of said multimer and mutations in said target sequence.
Finally, regarding the index, Drmanac generally teaches adding an index sequence to each target segment (e.g., para. 145 and Fig. 3: barcode (22) serves as an identifier for each segment of the target nucleic acid, thus could be used as a sample index), but does not teach an embodiment where an index sequence is attached to each unit of a monomer in a concatemer. However, Tang teaches an index comprising a nucleic acid sequence that is unique to an origin of the segment in a concatemer and identifies the source of the sequence of the segment (para. 53).
Prior to the effective filing date of the instant invention, it would have been prima facie
obvious to modify the Drmanac multimer with the Tang index sequences. Drmanac teaches that associating an index sequence with each target segment is useful for downstream sequence assembly, while Tang teaches attaching an index sequence to each monomer in a concatemer. The ordinary artisan would have been motivated to include the index sequence with each monomer of the Drmanac concatemer with the expectation that doing so would result in the advantage of a concatemer which, when used in, e.g., long read sequencing, would result in sequencing data that is readily aligned and analyzed. There would also have been an expectation that such a concatemer would increase the throughput and efficiency of sequencing, as samples from different sources could be pooled and analyzed at once, while still generating data that can be matched to the original sample source. The ordinary artisan would have had an expectation of success as the modification of nucleic acids by adding indices, identifiers, or other barcodes is well-known in the art, and because Drmanac teaches the use of such index sequences in other embodiments.
Regarding dependent claims 25-26, Drmanac additionally teaches that at least some of the units differ in the sequence of their segments (Figs. 2A-B; paras. 20-21: e.g., the segments are from adjacent regions of the same target nucleic acid), while Tang teaches that at least some of the units have identical sequences (paras. 53-55).
Claims 6 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Drmanac (WO 2014/145820 A2) in view of Tang (WO 2016/077313 A1) as applied to claim 1 above, and further in view of Fu3 (US Patent App. Pub. No. 2016/0289740).
Fu teaches combinatorial coding of nucleic acids to increase sequencing throughput.
Regarding dependent claims 6 and 8, as noted above, Drmanac teaches that various
barcodes can be split into multiple partial barcodes (e.g., Fig. 2B: 22a-22d). Drmanac also teaches that splitting barcodes into multiple partial barcodes is advantageous because such combinatorial barcoding “provides a larger repertoire of possible barcodes while reducing the number of full-size barcodes that need to be generated” (para. 126). Tang specifically teaches a sample index that is unique to the origin of the segment. Further, Fu also teaches that identifiers/indices/barcodes can be split into multiple, partial identifiers/indices/barcodes and that each partial sequence can be attached on either side of the segment, or on both sides (paras. 11, 13, 99). Fu also teaches that combinatorial coding of nucleic acids increases sequencing throughput (paras. 3, 6). Further, regarding claim 6, Fu teaches that the identifier/index/barcode can have varying lengths from 1 nucleotide to 300 nucleotides (para. 64). Fu does not teach any particular length for the partial identifiers/indices/barcodes however the ordinary artisan would be able to optimize to arrive at the length of at least 6 nucleotides.
Prior to the effective filing date of the instant invention, it would have been prima facie
obvious to further modify the modified Drmanac multimer, discussed above, to optimize the length of the barcodes/indices/identifiers. The ordinary artisan would have been motivated to optimize the length of the partial barcodes/indices/identifiers through routine experimentation in order to customize the assay as needed. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05 (II)(A). The ordinary artisan would have had an expectation of success as the modification of nucleic acids by adding indices, identifiers, or other barcodes is well-known in the art, and because Fu provides direction on how to do so.
Conclusion
Claims 1, 6-8, 19-20 and 24-26 are being examined and are rejected. No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROLYN GREENE whose telephone number is (571)272-3240. The examiner can normally be reached M-Th 7:30-5:30 EST.
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/CAROLYN L GREENE/Primary Examiner, Art Unit 1681
1 Drmanac was cited in the PTO-892 Notice of References Cited mailed March 17, 2026.
2 Tang was cited in the PTO-892 Notice of References Cited mailed March 17, 2026.
3 Fu was cited in the Information Disclosure Statement submitted May 12, 2021.
Prosecution Insights