DETAILED ACTION
The amendment filed on 01/22/2026 has been entered.
Claims 1 and 4 were amended in the claim set filed on 01/22/2026.
Applicant's election with traverse of Group I, claims 1-9, drawn to a surface probe-based quantitative PCR detection in the reply filed on 09/23/2025 is acknowledged. Claim 10 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, Group II, drawn to a kit, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 09/23/2025.
Claims 1-9 in the claim set filed on 01/22/2026 are currently under examination.
Response to the Arguments
Objections to the Drawings in the previously mailed non-final have been withdrawn in light of applicants Drawings amendments.
Applicant’s arguments regarding previous rejection(s) of claim(s) 1-9 under 35 U.S.C. 103 have been fully considered but are not persuasive. The 35 U.S.C. 103 rejections documented in the previously mailed non-final have been maintained and revised in light of applicants claim amendments and arguments on Pg. 12-17.
The revised/updated rejections for claims 1-9 are documented below in this Final Office Action are necessitated by claim amendments filed on 01/22/2026.
Priority
This application is the national phase entry of International Application No. PCT/CN2021/082473, filed March 24, 2021, and claims benefit of Chinese Patent Application No. 202010229992.0, filed March 27, 2020. Accordingly, the priority date of instant claims is determined to be March 27, 2020., the filing date of Chinese Patent Application No. 202010229992.0.
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.
Claim(s) 1-7 and 9 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Hassibi et al. (“Hassibi”; Patent App. Pub. US 20170362648 A1, Dec. 21, 2017) in view of Stahlberg et al. (“Stahlberg”; (2016). Simple, multiplexed, PCR-based barcoding of DNA enables sensitive mutation detection in liquid biopsies using sequencing. Nucleic acids research, 44(11), e105.) and Wenz et al. (“Wenz”; Patent App. Pub. US 20040110134 A1, Jun. 10, 2004).
Hassibi discloses “systems for measuring the concentration of multiple nucleic acid sequences in a sample. The nucleic acid sequences in the sample are simultaneously amplified, for example, using polymerase chain reaction (PCR) in the presence of an array of nucleic acid probes. The amount of amplicon corresponding to the multiple nucleic acid sequences can be measured in real-time during or after each cycle using a real-time microarray. The measured amount of amplicon produced can be used to determine the original amount of the nucleic acid sequences in the sample. Also provided herein are biosensor arrays, systems and methods for affinity based assays that are able to simultaneously obtain high quality measurements of the binding characteristics of multiple analytes, and that are able to determine the amounts of those analytes in solution. The invention also provides a fully integrated bioarray for detecting real-time characteristics of affinity-based assays.” (Abstract).
Regarding claim 1 (a), Hassibi teaches a system comprising “an array comprising a solid support having a surface and a plurality of different probes, the different probes immobilized to the surface at different addressable locations, each addressable location comprising a fluorescent moiety” and “detecting the signals from the fluorescent moieties at the addressable locations” (Para. 23). Hassibi teaches a system comprising “the plurality of probes are located on multiple addressable regions on the solid substrate. In some embodiments the solid substrate has about 2…” (Para. 217). Hassibi teaches a system comprising “nucleic acid probes…single stranded nucleic acids” (Para. 134). Thus, Hassibi teaches a system according to the limitations of claim 1 (a).
Regarding claim 1 (b), Hassibi teaches a system comprising “In some embodiments, the amplicon is created using one or more primers that is incorporated into the amplicon.” (Para. 111).
Regarding claim 1 (c), Hassibi teaches a system comprising “one of the primers in a primer pair comprises a quencher” (Para. 21) and “amplified molecules can hybridize with probes, thereby quenching signal from the fluorescent moiety; (c) detecting the signals from the fluorescent moieties at the addressable locations over time; (d) using the signals detected over time to determine the amount of amplified molecules in the fluid; and (e) using the amount of amplified molecules in the fluid to determine the amount of the nucleotide sequences in the sample” ( Para. 23). Thus, Hassibi teaches a system comprising a quenching probe according to the limitations of claim 1 (c).
Regarding claim 1, Hassibi teaches a system wherein “Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects” (Para. 43). Hassibi also teaches “While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention.” (Para. 395). Thus, these claim elements were known in the art and one of skill in the art could have combined these elements with other known elements with no change in their respective functions.
However, Hassibi does not teach explicitly teach the following limitations of claim 1 (b): wherein (i) the first primer has a structure of Formula I and (ii) the second primer has a structure of Formula II.
Regarding the limitations of claim 1 (b) (i): first primer
Stahlberg discloses “Detection of cell-free DNA in liquid biopsies offers great potential for use in non-invasive prenatal testing and as a cancer biomarker. Fetal and tumor DNA fractions however can be extremely low in these samples and ultra-sensitive methods are required for their detection. Here, we report an extremely simple and fast method for introduction of barcodes into DNA libraries made from 5 ng of DNA. Barcoded adapter primers are designed with an oligonucleotide hairpin structure to protect the molecular barcodes during the first rounds of polymerase chain reaction (PCR) and prevent them from participating in mis-priming events. Our approach enables high-level multiplexing and next-generation sequencing library construction with flexible library content. We show that uniform libraries of 1-, 5-, 13- and 31-plex can be generated. Utilizing the barcodes to generate consensus reads for each original DNA molecule reduces background sequencing noise and allows detection of variant alleles below 0.1% frequency in clonal cell line DNA and in cell-free plasma DNA. Thus, our approach bridges the gap between the highly sensitive but specific capabilities of digital PCR, which only allows a limited number of variants to be analyzed, with the broad target capability of next-generation sequencing which traditionally lacks the sensitivity to detect rare variants.” (Abstract).
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Regarding claim 1 (b), Stahlberg teaches a system comprising “universal hairpin structure that protects the barcode and adapter sequences from spurious interaction, while leaving the target portion of the primer available for hybridization during the first steps of library construction” (Pg. 3, Col. 1, Results, Para.1; Figure 1A see below). Thus, Stahlberg teaches a system comprising a first primer that has a structure of Formula I, wherein the first primer contains a hairpin structure, the Tai region in Tbi -Tai at the 3' end is complementary to the Tai' region at the 5' end;
Regarding the limitations of claim 1 (b) (ii): second primer
Wenz discloses “methods and kits for quantitating target nucleic acid sequences using coupled ligation and amplification. The invention also relates to methods, reagents, and kits that employ addressable-support specific portions.” (Abstract).
Regarding claim 1 (b), Wenz teaches a system comprising “the probe set comprises (a) at least one first probe, comprising a first target-specific portion, and (b) at least one second probe, comprising a second target-specific portion and a 3' primer-specific portion” (Para. 6). Wenz also teaches “universal primers, universal primer sets” (Para. 150). Thus, Wenz teaches a system comprising a second primer that has a structure of Formula II.
Hassibi, Stahlberg and Wenz are considered to be analogous to the claimed invention because they are in the same field of nucleic acid detection. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the surface probe-based quantitative PCR detection system as taught by Hassibi to incorporate the first primer according to the limitations claim 1 (b) as taught by Stahlberg and the second primer according to the limitation of claim 1 (b) as taught by Wenz and provide universal probe chip-based multiplexed quantitative PCR detection system. Doing so would enhance signal sensitivity and allow for identification and quantification of nucleic acids in a nucleic acid detection system.
The teachings of Hassibi, Stahlberg and Wenz are documented above in the rejection of claim 1 under 35 U.S.C. 103. Claim 2-7 and 9 depend on claim 1.
Regarding claims 2-3, Hassibi teaches a system wherein “A target DNA analyte is introduced in the system at time zero and quenching (reduction of signal) occurs upon hybridization” (Para. 62; Figure 17). Hassibi teaches a system wherein” decrease in the fluorescent signal with time from the probes is measured in real-time to determine the rate of binding of the amplicon to the probe which is used to determine the amount of amplicon in solution” (Para. 84) The MPEP recites
Regarding claim 4, as stated in claim 1, Stahlberg teaches a system wherein “universal hairpin structure that protects the barcode and adapter sequences from spurious interaction, while leaving the target portion of the primer available for hybridization during the first steps of library construction” (Pg. 3, Col. 1, Results, Para.1; Figure 1A see above). Thus, Stahlberg teaches Formula V.
Regarding claims 5-6, Hassibi teaches “primers of the invention are usually short, chemically synthesized DNA molecules with a length about 10 to about 30 bases... and the sequence of the primers are complementary to the beginning and the end of the DNA fragment to be amplified” (Para. 189). Thus, Hassibi suggests the lengths of Tai and Tbi according to claims 5 and 6.
Regarding claim 7, Hassibi teaches a system wherein “Probes can be attached covalently to the solid surface of the substrate (but non-covalent attachment methods can also be used)” (Para. 205). Hassibi teaches Figure 10 wherein the surface probe has a capture region and is attached to a support through a linker group. (Fig. 10). Thus, Hassibi teaches a system wherein the microarray surface probe has the structure of Formula IV according to claim 7.
Regarding claim 9, Hassibi teaches a system wherein “a method comprising; performing a nucleic acid amplification on two or more nucleotide sequences to produce two or more amplicons in a fluid wherein the array comprises a solid surface with a plurality of nucleic acid probes at independently addressable locations; and measuring the hybridization of the amplicons to the two or more nucleic acid probes while the fluid is in contact with the array to obtain an amplicon hybridization measurement. In some embodiments the invention further comprises using the amplicon hybridization measurement to determine the concentration of the amplicons in the fluid. In some embodiments the invention further comprises using the amplicon hybridization measurement to determine the original amount of nucleotide sequences” (Para. 15). Thus, Hassibi teaches a method for performing a quantitative detection according to claim 9.
Response to Arguments
Applicant' s arguments filed 01/22/2026 (Pg.10-14) with respect to claim 1-7 and 9 have been considered but are not persuasive. To clarify some instances argued in the response filed 01/22/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “Applicant respectfully traverses the rejection to the extent it may be applied to the claims as presently amended. "[O]bviousness requires a suggestion of all limitations in a claim."1 The Office must explain why a skilled artisan would have had some apparent reason to modify a known system taught in the art in a way to arrive at the claimed system.2 The Office's rejection is unsupported for at least the following reasons.” (Pg. 10)
Response: In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Hassibi teaches a system wherein “Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects” (Para. 43). Hassibi also teaches “While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention.” (Para. 395). Thus, these claim elements were known in the art and one of skill in the art could have combined these elements with other known elements cited by other prior art with no change in their respective functions.
Furthermore, Hassibi, Stahlberg and Wenz are considered to be analogous to the claimed invention because they are in the same field of nucleic acid detection. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the surface probe-based quantitative PCR detection system as taught by Hassibi to incorporate the first primer according to the limitations claim 1 (b) as taught by Stahlberg and the second primer according to the limitation of claim 1 (b) as taught by Wenz and provide universal probe chip-based multiplexed quantitative PCR detection system. Doing so would enhance signal sensitivity and allow for identification and quantification of nucleic acids in a nucleic acid detection system.
Applicants’ argument: “the artisan would understand that the presently claimed systems employ a barcode-mediated model, in which an independent barcode index sequence (Pi) is introduced. The capture region (Si) of the surface probe on the chip is unrelated and not complementary to the target sequence. Instead, the capture region (Si) is designed to be complementary to Pi.” (Pg. 11)
Response: In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., , the capture region (Si) is designed to be complementary to Pi.) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicants’ argument: “Applicant submits that the Office's position is unsupported, at least because the Office overlooks technical obstacles posed to achieve such a combination… the hairpin in Stahlberg aims for "isolating and protecting" the non-target barcode sequence, while the presently recited hairpin "integrates and optimizes" the target-recognition sequence itself to enhance reaction specificity. Given such differences, there is no evidence on the record, or adduced by the Office, that a skilled artisan would have been directed to apply Stahlberg's hairpin design to Hassibi's system to improve the PCR specificity, let alone arriving at the presently claimed design.” (Pg. 12)
Response: In response to applicant's argument stated above, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Furthermore, In response to applicant's argument that “the hairpin in Stahlberg aims for "isolating and protecting" the non-target barcode sequence, while the presently recited hairpin "integrates and optimizes" the target-recognition sequence itself to enhance reaction specificity”, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Applicants’ argument: “none of the cited references teaches or suggests the "barcode-mediated" universal chip architecture of the presently claimed detection system. No prior art suggests changing the complementary target of the surface probe from the "target sequence" to a target-independent "universal barcode sequence (Pi)" and designing a corresponding primer system incorporating Pi and a specific hairpin structure for this purpose.” (Pg. 15)
Response: In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Furthermore,
Applicants’ argument: “The Office appears to be picking and choosing among elements of the cited references to create a certain combination of elements (e.g., Stahlberg's hairpin primer and Wenz's universal primer design). Such picking and choosing using the framework of the claims relies upon impermissible hindsight.” (Pg. 15)
Response: In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Claim(s) 8 is rejected under 35 U.S.C. 103 as being unpatentable over Hassibi et al. (“Hassibi”; Patent App. Pub. US 20170362648 A1, Dec. 21, 2017) in view of Stahlberg et al. (“Stahlberg”; (2016). Simple, multiplexed, PCR-based barcoding of DNA enables sensitive mutation detection in liquid biopsies using sequencing. Nucleic acids research, 44(11), e105.) and Wenz et al. (“Wenz”; Patent App. Pub. US 20040110134 A1, Jun. 10, 2004), as applied to claims 1-7 and 9 and further in view of Abate et al. (“Abate”; Patent App. Pub. AU 2016215304 A1, Aug. 10, 2017),
The teachings of Hassibi, Stahlberg and Wenz are documented above in the rejection of claims 1-7 and 9 under 35 U.S.C. 103. Claim 8 depends on claim 1. Hassibi, Stahlberg and Wenz do not explicitly teach the limitations of claim 8.
Abate discloses “Microfluidic methods for barcoding nucleic acid target molecules to be analyzed, e.g., via nucleic acid sequencing techniques, are provided. Also provided are microfluidic, droplet-based methods of preparing nucleic acid barcodes for use in various barcoding applications. The methods described herein facilitate high-throughput sequencing of nucleic acid target molecules as well as single cell and single virus genomic, transcriptomic, and/or proteomic analysis/profiling. Systems and devices for practicing the subject methods are also provided.” (Abstract).
Regarding claim 8, Abate teaches a system wherein “nucleic acid barcode sequences and UMIs can be used to identify PCR products via sequencing and correct for amplification bias as needed. In addition to detection via sequencing of barcode containing nucleic acids, various non-barcode based detection methods may be utilized in connection with the disclosed methods” (Para. 315). Abate teaches a system wherein “a special set of primers may be used in which the 5' primer has a quencher dye and the 3' primer has a fluorescent dye. These dyes can be arranged anywhere on the primers, either on the ends or in the middles. Because the primers are complementary, they will exist as duplexes in solution” (Para. 316) Thus, Abate teaches a system wherein the quenching probe has a structure of Formula III.
Hassibi, Stahlberg, Wenz and Abate are considered to be analogous to the claimed invention because they are in the same field of nucleic acid detection. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the surface probe-based quantitative PCR detection system as taught by Hassibi, Stahlberg and Wenz to incorporate the quencher probe according to claim 8 as taught by Abate and provide surface probe-based quantitative PCR detection system wherein the quencher probe comprises a marker probe. Doing so would allow for identification and quantification of nucleic acids in a nucleic acid detection system.
Response to Arguments
Applicant' s argument filed 01/22/2026 (Pg.14-15) with respect to claim 8 has been considered but is not persuasive. Arguments against Hassibi, Stahlberg and Wenz on Pg. 10-14 are not persuasive as discussed above.
Conclusion of Response to Arguments
In view of the amendments, revised rejections and the above responses to arguments are documented in this Final Office Action. No claims are in condition for allowance.
Conclusion
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 KENDRA R VANN-OJUEKAIYE whose telephone number is (571)270-7529. The examiner can normally be reached M-F 9:00 AM- 5:00 PM.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682