DETAILED ACTION
The present Office Action is responsive to the Amendment received on January 13, 2026.
Preliminary Remark
Claims 21-23 are new.
Information Disclosure Statement
The IDS received on January 13, 2026 is proper and is being considered by the Examiner. The IDS was received with the fee under 37 CFR 1.17(p).
Claim Rejections - 35 USC § 102
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.
The rejection of claims 1-3, 5-8, 13-17, 19, and 20 under 35 U.S.C. 102(a)(1) as being anticipated by Mir et al. (WO 2010/027870 A2, published March 2010), made in the Office Action mailed on October 17, 2025 is maintained for the reasons of record.
Applicants’ claim amendment and arguments presented in the Amendment received on January 13, 2026 have been carefully considered but they have not been found persuasive for the reasons discussed in the, “Response to Arguments” section below.
The Rejection:
As pointed out in In re Mott, 190 U.S.P.Q. 536 (CCPA 1975), "Claims must be given broadest reasonable construction their language will permit in ex parte prosecution, and applicant who uses broad language runs the risk that others may be able to support the same claim with a different disclosure."
Presently claimed method recites structures of the probes which are broader than the inventive configuration of the inventive probes (i.e., see Fig. 1A), and therefore are subject to the present rejection based on broadest reasonable interpretation.
With regard to claims 1 and 8, Mir et al. teach a method of detecting a target polynucleotide, comprising the steps of:
contacting a sample comprising the target polynucleotide with a set of barcoded probes, wherein the set of barcoded probes comprises (see Figure 6, also “providing T forward preamplification primers to a sample, wherein each forward preamplification primer comprises a different target-specific nucleotide sequence and a set-specific nucleotide tag1, wherein X different forward set-specific nucleotide tags are employed, and X is an integer that is greater than 1”, section [0009]; “every target nucleotide sequence in an assay mixture can be tagged with a distinct sample-specific nucleotide tag, i.e., such that each tagged target nucleotide sequence in the assay mixture bears a sample-specific nucleotide tag having a different nucleotide sequence”, section [0076]; multiplexed, section [0171]);
a first oligonucleotide probe2 comprising a first target hybridization sequence and a first barcode (or tag); a second oligonucleotide probe comprising a second hybridization sequence and a second barcode sequence; and a third oligonucleotide probe comprising a third target hybridization sequence and a third barcode sequence, wherein each target hybridization sequence is designed to specifically bind to a different predetermined sequence of the target polynucleotide (“methods can also be employed to determined DNA … in genomic DNA”, section [0151]3);
sequencing each barcode sequence of the set of barcoded probes (“methods can be employed to prepare nucleic acid samples for further analysis, such as e.g., DNA sequencing”, section [0152]); and
identifying the polynucleotide sample based on the sequenced barcode sequences of the set of barcoded probes (the sequence of the polynucleotide is revealed when sequencing the plurality of the tagged-amplified products).
With regard to claims 2 and 5, the sequencing is by sequencing-by-synthesis “tagged target nucleotide sequences generated as described herein may be analyzed by DNA sequencing … ‘sequencing by synthesis’ … above-described methods for tagging nucleotide sequences can be substituted for ligation, to introduce adaptor sequences”, section [0135]).
With regard to claim 3, the tagged products are also amplified (“encoding reaction comprises separately subjecting each of the S samples to preamplficiation using a distinct set of forward and reverse preamplification primers for each sample to produce preamplified samples”, section [0006]).
With regard to claims 6 and 7, the barcode sequences are between 5-20 or 10 to 16 nucleotides in length (see section [0168], Tag 1, 2, and 3, are longer than 10 nucleotides in length).
With regard to claims 13 and 14, the target polynucleotide is also disclosed as being mRNA (“term nucleic acid includes any form of DNA or RNA … mRNA”, section [0029]), and a sample necessarily comprises a plurality of mRNA molecules.
With regard to claims 15 and 16, the sample comprises cells or tissues (“[n]ucleic acids can be extracted or amplified from cells …”, section [0097]) and cancers (“DNA or RNA useful in the methods described herein can be extracted and/or amplified from any source, including bacteria … particularly humans … plasma, serum, spinal fluid, lymph fluid … or tumors”, section [0097]).
With regard to claims 17 and 20, the artisans teach a single set of 16 tagged-target specific primers (see section [0076]).
With regard to claim 19, the tagged sequence can be common to al probes in the set (“tagged target nucleic acid sequences produced from a given sample can be tagged with a common sample-specific nucleotide tag, i.e., one that has the same nucleotide sequence).
Therefore, Mir et al. anticipate the invention as claimed.
Response to Arguments:
Applicants traverse the rejection.
Applicants state that each probe of the claim recites that a first and a second target hybridization sequence and that each target hybridization sequence is designed to specifically bind to different predetermined sequences of the target polynucleotide (page 6, Response).
Applicants state that this design-based specificity enables deliberate targeting of a priori known sequences within the sample, such as detecting a gene using multiple distinct barcoded probes of the set to hybridize to different predetermined regions of a target polynucleotide within the sample, wherein sequencing the barcode sequences associated with those designed binding events provides a direct identification scheme to confirm the presence of the target polynucleotide and that the barcodes in connection with probe target biding events allow identification of the target polynucleotide (page 6, Response).
Based on this, Applicants contend that the tag-directed amplification method of Mir does not disclose the structural and functional configuration recited in claim 1, requiring identification based on sequencing of the barcode sequences of the set (pages 6 and 7, Response).
The Office contends that Applicants’ interpretation of the structures of their “barcoded probes” is narrower than that which is construed by the Office.
By “first target hybridization sequence” and “second hybridization sequence” comprised by each barcoded probe, Applicants’ interpretation appears to be that which is depicted as “hybridization pads” in the probes depicted in Fig. 1A and 1B:
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The Office is not projecting that the claims as presently recite requires the stem regions, but simply depicting Applicants’ interpretation of the two target hybridization sequences being separated from each other as shown in these figures.
However, there is nothing in the claim that requires that each of the barcoded probes have two target hybridization sequences. It simply requires that the probe comprise a first and a second target hybridization sequence that is designed to bind a different predetermined sequence of the target polynucleotide.
Such two target specific hybridization sequences can be arbitrarily assigned to Mir’s oligonucleotides, as depicted below:
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As seen, the target specific sequence region can be arbitrarily separated into two different portions with the one portion being assigned a 1st target hybridization sequence and the other portion being assigned 2nd target hybridization sequence, which anneal to separate regions of the same target nucleic acid.
Therefore, Applicants’ argument directed to the structural distinction is not found persuasive.
As to Applicants’ arguments directed to the detection/identification logic that “tags” (or barcode equivalent as construed by the Office) of Mir’s oligonucleotides being directed to identify and facilitate multiplex pooling and selective amplification instead of using them for the purpose of being sequencing and identifying the target based on the barcode itself, the Office respectfully disagrees.
This is because while the claims recite that each barcode is sequenced, the claims do not preclude consideration of the information of the entire product produced by Mir.
That is to say, Mir produces a plurality of amplification products which contain a tagged region, as well as the region which has been amplified from the target. And the entirety of the amplified products is suggested as being sequenced:
“tagged target nucleotide sequences generated as described herein may be analyzed by DNA sequencing … ‘sequencing by synthesis’ … above-described methods for tagging nucleotide sequences can be substituted for ligation, to introduce adaptor sequences”, section [0135], Mir et al.).
Therefore, the sequencing would necessarily reveal not only the target sequence from which the amplification products were produced, but tagged sequences as well, and the information of both would necessarily be employed when sequenced-by-synthesis, revealing the identity of the polynucleotide in the sample.
Therefore, Applicants’ arguments are not found persuasive and the rejection is maintained.
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.
The rejection of claim 4 under 35 U.S.C. 103 as being unpatentable over Mir et al. (WO 2010/027870 A2, published March 2010) in view of Drmanac et al. (WO 2014/145820 A2, published September 2014, cited previously) made in the Office Action mailed on October 17, 2025 is maintained for the reasons of record.
Applicants’ arguments presented in the Amendment received on January 13, 2026 have been carefully considered but they have not been found persuasive for the reasons discussed in the, “Response to Arguments” section below.
The Rejection:
The teachings of Mir et al. have already been discussed above.
Mir et al., while explicitly teaching that the tagged polynucleotides are sequenced, do not explicitly disclose that the barcodes are computationally grouped and sequence reads are based on the co-occurrences of the barcode sequences in the set of barcoded probes (claim 4).
Drmanac et al. teach a well-known means of utilizing barcode/tag sequences to construct a sequencing read:
“computing device can assemble the population of identified bases to provide sequence information for the target nucleic acid … identified bases are assembled into a complete sequence through alignment of overlapping sequences obtained from multiple sequencing cycles performed … by one or more computing devices or computer logic …” (section [0280])
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Mir et al. with the teachings of Drmanac et al., thereby arriving at the invention as claimed for the following reasons.
As discussed above, Mir et al. explicitly teach that the tagged nucleic acid molecules should be sequenced using any of commercially available sequencing platforms:
“If desired, tagged target nucleotide sequences generated as described herein may be analyzed by DNA sequencing … provide a high throughput automated sequencing” (section [0136])
One of ordinary skill in the art would have recognized that in sequencing, the tagged sequences of the amplified products should also be sequenced in order to identify and group the multiple sequence reads that comprise a tagged sequence which originated from the same target nucleic acid, or the same sample, so as to construct a sequence of the target nucleic acid specific to that target nucleic acid and/or sample. And doing so utilizing a computerized means have been well-known in the art with multiple commercially available platforms, such as 454® and Solexa®, as alluded to by Mir et al. (see section [0136]).
For these reasons, the invention as claimed is deemed prima facie obvious over the cited references.
Response to Arguments:
Applicants traverse the rejection.
Applicants contend that Mir does not teach or suggest co-occurrence grouping logic because the “tag” sequences of Mir are used for the purposes of sample identity and multiplex pooling, not for “cooperative barcode set whose co-occurrence is computationally grouped to associated multiple reads with a target polynucleotide (page 9, Response).
Applicants also contend that even where Mir contemplates sequencing tagged nucleic acid molecules, the artisans do not disclose computationally grouping sequencing reads on co-occurrence of barcode sequences from a set of barcoded probes as recited in claim 4 (page 9, Response).
Applicants further state that while Drmanac was relied upon for the computational feature of the claim, the artisans fail to teach an alignment step based on the co-occurrence of barcode sequences, nor does the Office provide a persuasive rationale to modify Mir in the manner required by claim 4 (page 10, Response).
These arguments have been considered but have not been found persuasive.
As discussed above, Mir explicitly teach that their amplification products can either be detected via PCR or by sequencing means that employ sequencing-by-synthesis reaction:
“If desired, tagged target nucleotide sequences generated as described herein may be analyzed by DNA sequencing … rely on ‘sequencing by synthesis’” (section [0135])
As also acknowledged by Applicants, the amplification products of Mir can be utilized for the purpose of pooling the samples, wherein the tags of the amplified products can be analyzed to determine the identity of the sequences:
“methods are provided for detecting a plurality of target nucleic acids … in a plurality of samples … providing S samples that will be mixed together (i.e., pooled) prior to assay, where S is an integer greater than 1. Each of these samples is separately subjected to an encoding reaction that produces a set of T tagged target nucleotide sequences, wherein each nucleotide tag encodes information about the identity and/or sample source of a particular target nucleic acid” (section [0071])
Because the amplification products produced from Mir would necessarily comprise the tag sequence specific to the samples, which are pooled together, when performing sequencing-by-synthesis, the sequence read products would necessarily comprise sample-specific tags which are sequenced and grouped together for identifying the source of the sequence. This is an inherent feature of using tags, such as sample specific tags well-established in the art.
Applicants’ arguments are not found persuasive therefore.
The rejection of claims 9-12 and 18 under 35 U.S.C. 103 as being unpatentable over Mir et al. (WO 2010/027870 A2, published March 2010) in view of Pasetto et al. (Cancer Immunol. Res., September 2016, vol. 4, no. 9, pages 734-743, cited previously) and Ignatius et al. (Journal of Thoracic Oncology, April 2014, vol. 9, no. 4, pages 549-553, cited previously), made in the Office Action mailed on October 17, 2025 is maintained for the reasons of record.
Applicants’ arguments presented in the Amendment received on January 13, 2026 have been carefully considered but they have not been found persuasive for the reasons discussed in the, “Response to Arguments” section below.
The Rejection:
The teachings of Mir et al. have already been discussed above.
Mir et al. specifically alludes testing the types of samples which may be implicated with clinically relevant phenotypes:
“DNA or RNA useful in the methods described herein can be extracted and/or amplified from any source, including bacteria … particularly humans … plasma, serum, spinal fluid, lymph fluid … or tumors” (section [0097])
Mir et al. do not explicitly teach all types of genes which should be targeted, such as those listed in claims 9-12 and 18.
Pasetto et al. evidence a well-known practice of targeting and sequencing TCR genes:
“we describe a sequence-based search for germline polymorphism in the vriable (V) gene segments of the human TCRA/D locus … germline variations TCR genes could influence an individual’s immune response, and may also contribute to susceptibility to diseases and such autoimmunity” (Abstract)
Ignatius et al. evidence a well-known practice of sequencing genes such as ALK (“we identified a novel acquired secondary ALK mutation … in NSCL patient …”, page 549, 2nd column).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Mir et al. with the teachings of Pasetto et al. and Ignatius et al., thereby arriving at the invention as claimed for the following reasons.
The rationale to do so is based on the combination yielding no more than a predictable outcome, as discussed in KSR, wherein the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.”
Similarly, applying the method of tagging, amplifying and sequencing locations on which clinically relevant information is derived from, such as cancer-related, immunity-related genes, would have been an obvious application of the method disclosed by Mir et al., yielding no more than the predictable outcome of producing sequencing constructs that are tagged with unique sequences that are used to compile the sequence of the target nucleic acid or identify other related types of information, such as the source of sample from which the target nucleic acids are isolated.
Therefore, the invention as claimed is deemed prima facie obvious over the cited references.
Response to Arguments:
Applicants traverse the rejection.
Applicants’ arguments stem from the architecture of the probes which have already been responded to above as being unpersuasive. Based on this, as there exists a general motivation in the art to assay for genes/markers which have been implicated with human conditions, evidenced by Pasetto and Ignatius, targeting them via the method of Mir would have been an obvious application.
Rejection – New Grounds, Necessitated by Amendment
Claims 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Mir et al. (WO 2010/027870 A2, published March 2010) in view of Comstock et al. (US 2015/0065358 A1, published March 5, 2015).
The teachings of Mir et al. have already been discussed above.
While Mir et al. suggest that the amplified products can be sequenced by means such as sequencing-by-synthesis, the artisans do not explicitly teach the well-known steps of incorporating labeled nucleotides or analogs and detecting the incorporated labeled nucleotides during a sequencing reaction (claims 21 and 22), as well as performing a sequencing reaction for two different samples (claim 23).
Comstock et al. teach a well-known means of sequencing-by-synthesis, wherein labeled nucleotides are incorporated into a template strand:
“sequencing reaction begins by introducing DNA polymerase and a fluorescently labeled nucleotide … the polymerase incorporates the labeled nucleotides to the primer in a template directed manner … templates that have directed incorporation of the fluorescently labeled nucleotide are discerned by imaging the flow cell surface” (section [0083])
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed inventio to combine the teachings of Mir et al. with the teachings of Comstock et al., thereby arriving at the invention as claimed because Mir et al. already teach that the amplified products comprising the sample-specific tags can be sequenced by means such as sequencing-by-synthesis, which, as demonstrated by Comstock et al., generates sequence signals by annealing a primer to the template and incorporation and detection of labeled nucleotides. In order for the sequence reads from other sample sources (i.e., first sample and a second sample) to be distinguished from each other (as Mir et al. already teaches pooling the amplified products from different sources for assaying), one of ordinary skill in the art would have been motivated to sequence the sample-specific tag regions of the amplified products during the sequencing reaction, and group the sequence reads by the sample-specific tags in the sequencing reactions.
Comstock et al. also teach the use computational means to group the sequence reads from the same sources:
“[v]erification of the integrity of each of the plurality of source samples is accomplished by first grouping sequence tags associated with identical index sequences to associate the genomic marker sequences and distinguish sequences belonging to each of the libraries made from genomic molecules of a plurality of samples” (section [0095])
Therefore, grouping the sequence reads according to their sample source from which amplification products were generated according to Mir et al. would have been an obvious application.
Therefore, the invention as claimed is deemed prima facie obvious over the cited references.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Inquiries
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7:30 a.m. to 4:00 p.m (M-F). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782.
Papers related to this application may be submitted to Art Unit 1681 by facsimile transmission. The faxing of such papers must conform with the notice published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 CFR 1.6(d)). NOTE: If applicant does submit a paper by FAX, the original copy should be retained by applicant or applicant’s representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED, so as to avoid the processing of duplicate papers in the Office. All official documents must be sent to the Official Tech Center Fax number: (571) 273-8300. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 April 2, 2026
/YJK/
1 Applicants usage of the term, “barcode” is indistinguishable from the term, “tag” used by Mir et al. as both comprise a unique sequence for identification; also see, “term, ‘nucleotide tag’ is used herein to refer to a predetermined nucleotide sequence that is added to a target nucleotide sequence … tag can encode an item of information about the target nucleotide sequence”, section [0047].
2 The term, “probe” does not distinguish itself over the term, “primer” as used by Mir et al. as both are directed to an oligonucleotide sequence that anneals to a complementary sequence.
3 Genomic DNA necessarily contains multiple genes and multiple target-specific primers would anneal to their respective target genes/sites of a single molecule.
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