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 . Applicant’s amendment filed 1/28/2026 is acknowledged. Claims 1 and 17 have been amended. Claims 2, 6, 8, 13, 21 and 22 have been canceled. Claims 1, 3-5, 7, 9-12, 14-20, 23 and 24 are pending.
All of the amendment and arguments are thoroughly reviewed and considered. Any rejection not reiterated in this action has been withdrawn as being obviated by the amendment of the claims.
This action is made Final.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Previous Rejection
The prior art rejection under 35 USC 103 directed to claims 1-24 as being unpatentable over You in view of Ke and further in view of Cho et al is withdrawn in view of the new ground(s) of rejections necessitated by Applicant’s amendment of the claims.
New Ground(s) of Rejections
THE NEW GROUND(S) OF REJECTIONS WERE NECESSITATED BY APPLICANT’S AMENDMENT OF THE CLAIMS:
Claim Rejections - 35 USC § 103
3. 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.
4. 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.
5. 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.
NOTE* The following are new grounds of rejections necessitated by Applicant's amendments. Although the claims were previously rejected as being anticipated and/or unpatentable over the same reference(s), Applicant's amendments have necessitated the inclusion of new grounds of rejections in this Office action. It is noted that, to the extent that they apply to the present rejection; Applicant's arguments are addressed following the rejection.
6. Claim(s) 1, 3-5, 7, 9-12, 14-20, 23 and 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over You et al {You, used interchangeably herein} (Trends in Biotechnology, vol. 38, no. 6, pages 637-649, Epub date January 2020) in view of Ke (CN 108753941, publication date 11/6/2018, entire translated document) and further in view of Cho et al (US 2018179515, June 2018) (references provided in prior Office action).
Regarding claims 1, 17, 23 and 24, You teaches a nucleic acid amplification system and method of use in ultra-fast PCR systems including isothermal amplification systems, comprising: a reaction space,
a sample, including at least one analyte, placed in the reaction space, wherein the analyte comprises a cell (page 642, third paragraph which teaches detection of miRNA in situ in cells);
a plurality of particles, wherein the plurality of particles are magnetic nanoparticles (page 638, Magnetic NPs),
mixed with the sample, each including:
a body;
at least one enzyme mixed with the sample, wherein the at least one enzyme is a polymerase (page 642 which discuss the avoidance of the nanoparticle absorbing the polymerase in the PCR mixture by adding BSA into the PCR mixture);
at least one energy supply module light source (page 645-646))or laser (page 644-646), providing an external energy to the plurality of particles (pages 638 and 646); at least one temperature equilibrium substance placed in the reaction space, wherein the temperature equilibrium substant is a cooling substance, comprising a nucleic acid amplification solution (640, 642 and 647);
and an operating module that is used to control the plurality of particles in the reaction space (see whole document especially, last paragraph of page 637-638; section entitled “Gold Nanoparticle-based photonic PCR” at page 640-644; and section entitled “Photonic PCR based on other nanomaterials” at page 645; see Figures 2 and 4 highlighted below).
You further teach MNAzyme-based isothermal amplification and wherein the system comprise of the use of MNAzymes, fluorescent probes and target mRNA in silica shell coated on the surface of gold nanorods at page 642, third paragraph. You teaches that this MNAzyme nanosensor detects miRNA in-situ in cells (page 642, third paragraph). You teaches that the photothermal effect of the nanoparticles could be used for cell lysis and extraction of target nucleic acid from prokaryotic or eukaryotic cells (page 647).
PNG
media_image1.png
320
795
media_image1.png
Greyscale
PNG
media_image2.png
308
326
media_image2.png
Greyscale
Further with regards to the operating method of claims 17, 23 and 24, You teaches that not only does system conduct PCR, but also induces cell lysis and extract the intracellular DNA. The amplicon production is quantified in real-time using the colorimetric changes of the AuNR (gold nanorods) using an AuNR-based plasmonic thermocycler intergraded with a microfluidic chip (see Figure 2 and page 642). You teaches the integration of photonic PCR with a microfluidic chip indicates significant potential in digital and multiplex ultrafast PCR (see page 642).
Regarding claim 3, You teaches the nucleic acid amplification system of claim 1, wherein the at least one temperature equilibrium substance is a cooling substance (see page 642, second paragraph, figure 3).
PNG
media_image3.png
428
852
media_image3.png
Greyscale
Regarding claim 4 You teaches the nucleic acid amplification system of claim 1, wherein the at least one analyte comprises at least one cell (see page 642, third paragraph).
Regarding claim 8, You teaches wherein the specific tag comprises a fluorescent group (page 642, third paragraph).
Regarding claim 9, You teaches the nucleic acid amplification system of claim 1, wherein the at least one enzyme is a polymerase (see pages 642 and 644, first full paragraph).
Regarding claim 10, You teaches wherein PCR which inherently encompasses the use of DNA polymerase is performed (see abstract).
Regarding claim 12, You teaches the nucleic acid amplification system of claim 1, wherein the energy supply module comprises a laser transmitter, a light-emitting diode or magnetic field (See e.g., Figures).
Regarding claim 14, You teaches the nucleic acid amplification system of claim 1, wherein the operating module comprises a magnetic component (see page 638 and Figures).
Regarding claim 15, You teaches nucleic acid amplification system of claim 14, wherein the magnetic component serves as the operating module, and the plurality of particles comprises a plurality of magnetic particles (see page 638 and Figures).
Regarding claims 1, 3-5, 7, 9-12, 14-20, 23 and 24, You does not expressly teach using in the system and method a first and second ligand, wherein the first ligand functionalized on the body matches at least one analyte and at least one second ligand functionalized on the body, wherein the at least one first ligand comprises an antibody, an aptamer, an oligonucleotide or a combination therein and wherein the at least one second ligand is a single-strand nucleic acid sequence and includes a tag, the at least one second ligand is configured to capture a biological substance released from the analyte and is configured to perform a nucleic acid amplification reaction with the biological substance, and the tag comprises a fluorescent group or a nucleic acid tag. You also does not teach wherein the analyte comprises cell-free nucleic acid.
Regarding claims 1, 3-5, 7, 9-12, 14-20, 23 and 24, Ke et al teaches magnetic double-labeled beads and preparation methods and applications thereof. Ke teach wherein the at least one first ligand functionalized on the body matches the at least one analyte and at least one second ligand functionalized on the body comprises a specific tag in order to generate a weight signal, wherein the at least one analyte comprises a microorganism, or virus (see claims, abstract and pages 2-6).
Ke teaches that wherein the at least one first ligand or the at least one second ligand comprises a capture antibody and further wherein the ligand are functionalized on the body through a stabilizing structure wherein the structure comprises a contact inhibition coating (see Abstract, claims and pages 2-6).
Ke et al teach wherein the second ligand comprises of a fluorescence detection probe for detecting a specific nucleic acid fragment and amplification primers for amplification (see claims 4-7). Ke further teaches wherein the magnetic nanoparticle bead solution comprises steps of purifying the sample to remove impurities and concentrating the solution by centrifugation (operating module) (see claims and pages 5-6). Ke teaches wherein qPCR assay is performed and the polymerase is DNA polymerase (pages 3-5).
While You and Ke teaches various aspects of the instant invention, they do not teach wherein the biological sample comprise of cell-free nucleic acid which is use to in diagnostic methods for cancer.
Regarding claims 1, 3-5, 7, 9-12, 14-20, 23 and 24, Cho et al teach magnetic nanostructure for detecting and isolating cell-free that includes a cationic polymer and a magnetic nanoparticle-containing conductive polymer. Cho et al teach that the magnetic nanostructure for detecting and isolating cfDNA can significantly improve detection and extraction efficiencies of DNA present in a urine, CFS, blood plasma, or blood sample, and exhibits an enhanced sensitivity. Cho addition teach that the magnetic nanostructure used for detecting and isolating cfDNA can additionally be used for extracting DNA for use in a genetic mutation diagnosis service as well as for an early cancer diagnosis and cancer treatment (abstract). Cho et al teach combining the technique with PCR techniques ([0058], [0097]-[0098] and [0121]).
Cho et al teach at paragraph [0086] As shown in FIGS. 1A and 1B, a magnetic nanostructure including polyethyleneimine (PEI), which is a cationic polymer, conjugated onto a surface thereof was prepared. One surface of an AAO template was coated with a gold (Au) layer (about 150 nm thick) for 600 seconds at 5×10.sup.−3 mbar and 50 mA using the Q150T Modular Coating System. All electrochemical experiments were carried out on an Au-coated AAO template by using the BioLogic SP-150 potentiostat/galvanostat equipped with a platinum wire counter electrode and an Ag/AgCl (3.0 M NaCl type) reference electrode. In order to induce the attachment of magnetic nanoparticles (MNPs, 5 μg/ml, diameter: 10 nm) on the Au-coated AAO disk to prepare PEI/mPpy NWs, MNPs were prepared and were allowed to penetrate into pores of AAO through the application of suitable suction at room temperature (RT). 0.01 M poly(4-styrene sulfonic acid), a 0.01 M pyrrole solution containing 1 mg/ml biotin, and seven minutes of chronoamperometry at 1.0 V (vs. Ag/AgCl) were applied into the pores of the AAO template to perform electrochemical deposition. The AAO template thus processed was washed several times with distilled water, dipped in a 2 M sodium hydroxide (NaOH) solution for three hours, and then was put in Bioruptor® UCD-200 for sonication to obtain free-standing polypyrrole (Ppy) nanowires (free-standing Ppy NWs) doped with MNPs and biotin molecules. Then, 30 mM N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) and 6 mM N-hydroxysuccinimide (NHS) were added to the resulting Ppy NWs prepared above to activate a carboxylic acid group (—COOH). Subsequently, the Ppy NWs were then incubated with streptavidin (10 μg/ml) for 45 minutes and were washed with distilled water. Then, the Ppy NWs labeled with streptavidin were put in a PEI solution containing biotin added thereinto, maintained additionally for one hour at room temperature, washed with water, and then were subjected to magnetic separation using a magnetic field.
The PEI/mPpy NWs were dispersed in deionized water and stored at room temperature until use. With the above preparation method being used, individual Ppy NWs were released from the AAO template after the AAO template selectively dissolved, and cationic branched PEI (25 kDa) was additionally conjugated to the Ppy NWs through a biotin-streptavidin interaction.
PNG
media_image4.png
606
497
media_image4.png
Greyscale
PNG
media_image5.png
682
528
media_image5.png
Greyscale
It would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the claimed invention to have been motivated to have combined the teachings of You, Ke and Cho to encompass magnetic nanostructures for isolation, extraction and analysis of cell-free nucleic acid via PCR as taught by the combined teachings of You, Ke and Cho because all of the prior art of similar scope and combining the teachings of Ke and Cho with You would not negatively alter or modify results of performing a photothermal nanomaterial-based PCR assay to detecting a desired analyte. The ordinary artisan would have been motivated to do so for the benefit of improved detection and extraction efficiencies as well as enhanced sensitivity and speed in cancer detection.
Response to Arguments
Applicant’s Traversal
7. Applicant traverses the rejections on the following grounds:
(a) Applicant summarized the Examiner’s rejection and acknowledges the Examiner’s comment that You does not expressly teach particles functionalized with both a first ligand and a second ligand on the same body, nor does You teach that the first ligand matches the analyte while a second ligand is concurrently present on the particle. Applicant states that You does not disclose an analyte comprising cell free nucleic acid.
(b) Applicant summarizes the claims as amended and states that You, Ke and Cho fail to teach generating a reaction temperature for performing photothermal lysis and nucleic acid amplification by the plurality of particles.
(c) Applicant states that You does not teach the second ligand and particle surface nucleic acid amplification. Applicant states that You does not teach the solid phase nucleic acid amplification on dual functionalized solid phase carriers, the magnetothermal effect of magnetic nanoparticles under an alternating magnetic field and controllable amplicon manipulation via an operating module.
(d) Applicant states that Ke does not teach that the double-labeled beads participate in any heat generation through photothermal or magnetothermal effects, nor that they perform in situ thermally lysis or nucleic acid amplification on the bead surfaces,
(e) Applicant states that based on Ke, the significant difference is that the detection mode for nucleic acid amplification as described by Ke, the processes of thermolysis and nucleic acid amplification need an additional PCR machine to perform the overall detection procedures. Applicant state states that contrary to the teaching of Ke, the present application discloses that nucleic acid amplification is generated by solid phase NAAT or solid phase LAMP and the signal read out of nucleic acid amplification are converted from solid phase carriers. Applicant states that Cho et al does not remedy the fundamental deficiencies of You and Ke which fails to discloses the dual ligand configuration and the particle surface amplification mechanism recited in the claim 1 or dependent claims.
Examiner’s Response
8. All of the Applicant’s amendment and arguments have been thoroughly reviewed and considered but are not found persuasive for the reasons that follows:
i. Regarding Applicant’s arguments at (a) – (e), the examiner acknowledges Applicant’s arguments but respectfully disagree because the arguments are not commensurate fully in scope with the claims as currently written. Firstly, the claims comprise of open language which do not exclude additional components or operational modules or detection modes. Secondly, applicant argues components which are taught by the combination of the cited prior art and not the references individually and finally, applicant argues intended use limitations and/or functional limitations of components of the system that is claimed.
MPEP 2114 states “While features of an apparatus/system may be recited either structurally or functionally, claims directed to an apparatus must be distinguished from the prior art in terms of structure rather than function. >In re Schreiber, 128 F.3d 1473, 1477-78, 44 USPQ2d 1429, 1431-32 (Fed. Cir. 1997) (The absence of a disclosure in a prior art reference relating to function did not defeat the Board’s finding of anticipation of claimed apparatus because the limitations at issue were found to be inherent in the prior art reference); see also In re Swinehart, 439 F.2d 210, 212-13, 169 USPQ 226, 228-29 (CCPA 1971); In re Danly, 263 F.2d 844, 847, 120 USPQ 528, 531 (CCPA 1959). “[A]pparatus claims cover what a device is, not what a device does.” Hewlett-Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464, 1469, 15 USPQ2d 1525, 1528 (Fed. Cir. 1990).
In this case, the claims recite alternative limitations in the recitation of “OR” which does not require the specific of both limitations to be recited by the prior art. Nonetheless, You meets the limitation of providing an external energy to the plurality of particles and states that photothermal effect of the nanoparticles could be used for cell lysis and extraction of target nucleic acid from prokaryotic or eukaryotic cells along with PCR (see cited prior art). Thus, You provide sufficient evidence that the function upon which Applicant relies can be performed by the combination of cited prior art.
ii. With regards to Applicant arguments that the combination of the cited prior art does not teach dual-labeled configuration and particle-surface amplification mechanism, and controllable amplicon manipulation as instantly claimed in the claim 1, the examiner respectfully disagree as the secondary teachings of Ke provides the teaching of dual label ligand configuration as broadly recited by the claims and the claims do not require a particle surface amplification mechanism. It is further noted that while applicant points to multiple additional embodiments claimed to not be taught by the cited prior art, those features upon which applicant relies are not expressly recited in the rejected claim(s). Applicant is reminded that 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).
Finally, Attention is directed to KSR Int’l Co. v. Teleflex Inc. (550 U.S. 398, 127 S. Ct. 1727 (2007)) where the Supreme Court determined that “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103 (KSR, 550 U.S. at 398, 82 USPQ2d at 1397).” The Supreme Court also determined that “[t]he combination of familiar elements according to known methods is likely to be obvious when the combination does no more than yield predictable results (KSR, 550 U.S. at 398, 82 USPQ2d at 1395).” The examiner maintains that the combination of the cited prior art of You in view of Ke and further in view of Cho et al meets the claims as broadly written. Applicant’s arguments are not found persuasive to overcome the103 rejection recited above.
Conclusion
9. N0 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.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CYNTHIA B WILDER whose telephone number is (571)272-0791. The examiner can normally be reached Flexible.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, GARY BENZION can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CYNTHIA B WILDER/Primary Examiner, Art Unit 1681