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 .
Preliminary Remark
Mr. Albert Chan was telephoned on November 17, 2025 to obtain a telephonic election on the instant application which was determined to contain two different groups of inventions shown below:
I. Claims 1-16, drawn to a portable device for performing an assay, classified in B01L 7/52.
II. Claims 17-20, drawn to a method of using the product of Group I, classified in C12Q 1/6813.
The telephonic conversation, however, did not end up with an election.
The Office has decided to examine the application as is for the purpose of compact prosecution. Based on this, there is no longer an ODP bar under 35 U.S.C. 121.
Information Disclosure Statement
No IDS has been filed to date of the instant Office communication.
Drawings
The drawings received on March 14, 2023 are acceptable.
Claim Interpretation
Claim 1 has been interpreted to be drawn to a product that does not actively require the presence of any reagents employed in the UCNP-based assay due to the usage of the phrase, “[a] sample chamber for holding a cuvette with a UCNP-based assay and said sample”. The usage of, “for holding a cuvette with a UCNP-based assay and said sample” simply requires a chamber that is able to hold a cuvette.
Consequently, dependent claims which further recite the reagents which is comprised in an UCNP-based assay and sample (i.e., claims 5-10 and 13-16) are also not necessarily required and do not further limit said dependent claims.
The term, “UCNP” is understood in the art as being directed to an acronym for “UpConversion NanoParticles” as evidenced by Ye et al. (below).
The term, “NIR” is also understood in the art as being directed to an acronym for “Near InfraRed” as evidenced by Ye et al.
The term, “TTL” in context of the claim, that is, in context of a wireless technology (see claim 3) has been construed to be directed to acronym for “Transistor-Transistor Logic”.
Claim Objections
Claims 1, 7, 13, 16, and 17 are objected to for containing a period after each sub-step. MPEP 608.01(m) clearly states that each claim begins with a capital letter and ends with a period and that, “[p]eriods may not be used elsewhere in the claims except for abbreviations. Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i)”
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 1-16 are rejected under 35 U.S.C. 103 as being unpatentable over Ye et al. (Small, 2014, vol. 10, no. 12, pages 2390-2397) in view of Silverbrook et al. (US 2011/0312841 A1, published December 22, 2011).
With regard to claim 1, Ye et al. teach a method of detecting a target nucleic acid, wherein the method involves UCNPs (UpConversion NanoParticles) that comprise a capture nucleic acid probe sequence and a AuNP (gold nanoparticles) comprising a target nucleic acid sequence, wherein the presence is determined by FRET which occurs between the UCNPs and the AuNP when bound in proximity (see below representation from Fig. 1 below):
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As seen, UCNP is labeled with a capture (“[c]apture oligonucleotide probe was designed based on the sequence specific for hemaglutin (HA) genes of H7 virus subtypes and conjugated to poly(ethylenimine) (PEI) modified UCNPs”, page 2391, 2nd column); and AuNPs are labeled with a target nucleic acid sequence (“AuNPs were then conjugated to H7 hemaglutinin gene oligonucleotides”, page 2391, 2nd column).
Ye et al. teach that the assay also requires an NIR (Near InfraRed) photons for the upconversion (“[i]t is known that lanthanide-based upconversion nanoparticles (UCNPs) can convert low-energy near-infrared (NIR) photons into visible emission”, page 2391, 1st column, 2nd paragraph) using a CW 980 nm diode laser for excitation and the use of a sensor to detect the fluorescence emission from UCNP-FRET assay (“upconversion LRET spectra were obtained using FLS920P Edinburgh analytical instrument apparatus equipped with CW 980 nm diode laser as an excitation source”, page 2396, 1st column).
Taken together, the method disclosed by Ye et al. employs: i) a chamber in which to perform the LRET assay; ii) an NIR light source (i.e., CW 980 nm diode laser); iii) a sensor for measuring the fluorescence emission from FRET (or LRET) quenching (FLS920P machine); and iv) a microcontroller that determines the emission intensity from the UCNP based assay to produce detection results (as evidenced by Figures 5 and 6).
With regard to claim 2, the sensor of Ye et al. measures the fluorescence at 540 nm (“[o]nce UCNPs-oligo captured AuNPs conjugated with H7 target oligonucleotides, the green UC emission of UCNPs is quenched due to the absorption characteristics of AuNPs at 540 nm”, page 2395, 1st column).
With regard to claim 5, the Office initially notes that the portable device does not actively require the presence of any reagents employed in UCNP-based assay nor sample as discussed above. Notwithstanding this, Ye et al. teaches that the UCNP is modified with a first oligonucleotide probe (i.e., capture probe) that is lanthanide-doped UCNP (see “time-resolved LRET biosensor based on amine-functionalized lanthanide doped NaYF4 UCNPs has been developed …”, page 2391, 1st column, also lanthanide doped UCNP being used in the disclosure as shown in Fig. 1).
With regard to claims 6, 8, 10, 12, 13, and 16, the portable device does not actively require the reagents as recited therein and the excitation and emission elements of Ye et al. would be capable of providing the excitation and emission signals generated from the UCNPs of claims 6, 8, and 10. As well, the assay detection limit (claims 12 and 13) is based on the assay reagents, and because they are not actively required by the claimed device, the portable device of Ye et al. would be capable of achieving the limit should the assay reagents be included.
With regard to claim 7, while the portable device as claimed does not actively require the presence of AuNR, the LRET evidences that the longitudinal absorption overlaps with emission spectra of the UCNP.
With regard to claim 9, while the portable device as claimed does not actively require the presence of AuNP surface modified with a second oligo probe, the AuNP of Ye et al. with a nucleic acid sequence would necessarily have an absorbance overlapping with emission of UCNP surface modified with a first oligo probe (i.e., capture probe) based on the exhibited LRET (see above).
With regard to claims 14 and 15, while the portable device as claimed does not actively require the presence of a target nucleic acid nor any of the UCNPs or AuNPs with probe sequences thereto, the target nucleic acid of Ye et al.’s assay is for an avian influenza virus (or pathogen, see “[a]vian influenza virus (AIV) have become an increased threat … influenza A H7 subtypes are characterized as highly pathogenic avian influenza”, page 2390; “[i]n this work … UCNP-based LRET biosensor has been developed for influenza A H7 subtype detection”, page 2391, 2nd column).
Ye et al. do not explicitly teach that their system of detection employs a portable device configured to contain the analytic sample, with a light source, a sensor, optics with necessary wavelength filters and lens, and a microcontroller that can wireless communicate with a remote controller device (claim 1, in-part), wherein the wireless communication is via Bluetooth, WIFI, or network (claim 3), and that the controlling device is a smartphone, computer, or TTL (claim 4), or that the portable device comprises a housing to prevent external light (claim 11).
Silverbrook et al. teach a well-known practice of providing a portable device which is tailored to assay for any types of assays, routinely involve any combination steps of: i) sample preparation, b) sample extraction; c) sample amplification; and d) detection (sections [0010]-[0014]; also “microfluidic device also has … a probe hybridization section … integrated image sensor obviates the need for an expensive external imaging system and provides … inexpensive integrated solution with low system component that is compact, light and highly portable system … integrated image sensor increases the readout sensitivity …” (section [0325]).
Silverbrook et al. also teach that the wireless network can be employed for communication (section [10356], “cellular radio 21 and wireless network connection 23 are used for communications …”; also “mobile phone reader contains all the test and diagnostic information preloaded. Data can also be loaded or updated via a number of wireless or contact interfaces to enable communication with peripheral devices, computers or online servers …”, section [10361]).
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 Ye et al. with the teachings of Silverbrook et al., thereby arriving at the invention as claimed for the following reasons.
As discussed above, Ye et al. already teach a method which detects the presence of a target pathogen sequence by utilizing an energy transfer which occurs between lanthanide doped UNCP and AuNP, wherein the two are brought in proximity upon binding. While Ye et al. did not teach that their detection method should be engineered to be performed in a portable system, one of ordinary skill in the art before the effective filing date of the claimed invention would have already recognized the well-known advantages provided by fabricating a portable device which is designed to perform the method of Ye et al., allowing for the tests to be done on-site as a point-of-care means, while reducing the costs and time associated with collecting and transporting the collected sample from a site to a clinical laboratory, waiting for the assay result to be completed and communicated back to the site. And given the technological advancement which has occurred as well as the availability of means of such fabrication (as evidenced by Silverbrook et al.), one of ordinary skill in the art would have had a reasonable expectation of success at arriving at a portable device that is designed to perform the assay disclosed by Ye et al., including typical elements, such as a reaction region in which a reaction occurs, an excitation and emission generation/detection means that utilize filters/mirrors (i.e., optics) to allow specific excitation wavelength of light to excite while only allowing a specific emission wavelength of light to flow through for detection while preventing outside interfering light of undesired wavelengths, as well as means of processing the instructions on the device in a wireless manner, all of which would have yielded no more than a predictable outcome of performing the assay on a portable device.
As stated by the Supreme Court in KSR, “[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.”
Therefore, for these reasons, the invention as claimed is deemed prima facie obvious over the cited references.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Tsang et al. (US 2019/0119731 A1, published April 25, 2019) in view of Silverbrook et al. (US 2011/0312841 A1, published December 22, 2011) and Muhr, Verena (URN: NBN:DE: BVB, 2017, vol. 355, pages 75-98).
The present rejection is based on the prior art teaching which renders obvious the inventive concept of the claimed invention, that is, sandwich-based targeting of a target nucleic acid utilizing a first probe comprising UCNP and a second probe comprising AuNP, wherein the two probe anneal to separate regions on the target nucleic acid, and inducing LRET signal.
With regard to claim 1, Tsang et al. teach a method of detecting a target nucleic acid in a sample which is reflected in Figure 3 reproduced below:
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As seen, the method involves: i) UCNPs which comprise oligonucleotide probes (see left-side, also “nanoprobe having one or more first oligonucleotide probes, each complementary to a first segment of said target nucleic acid sequence”, section [0012]; “[c]onjugating said UCNP with polyacrylic acid followed by conjugation with an oligo sequence to obtain the upconversion nanoprobe”, section [0039]); ii) a AuNP comprising oligonucleotide probes (see left-side, also “invention provides a sandwich assay consisting of an upconversion (UC) and a gold (Au) nanoprobe, in which the target recognition is achieved by two segments of DNA oligonucleotide (oligo) hybridization.”, section [0043]; “the upconversion sandwich assay … to increase the specificity and efficiency of the detection … the csUCNPs and oligo modifications are used to form the first probe (P2) but the acid-assisted approached is used to conjugate another segment of oligo probe (P1) on AuNPs”, section [0053]); iii) NIR source (“[e]xposing said mixture to a near infrared wavelength”, section [0013]; and iv) sensor for measuring said fluorescence emission from UCNP-based assay comprising light-to-frequency converter (“measuring the intensity of said luminescence, wherein when said intensity is lower than intensity fluorescence from a control without said target nucleic acid sequence, said sample is shown to contain said nucleic acid sequence”, section [0013]).
With regard to claims 2 and 20, the sensor measures the fluorescence emission around 520-550 nm (see section [0027]).
With regard to claim 5, the UCNP surface modified with a first oligo probe is a lanthanide-doped UCNP (“0.4 mmol of lanthanide acetates (LnAC3) of gadolinium (Gd3+), ytterbium (Yb3+) and erbium (Er3+) were added to a two-necked flask followed by 4 ml of oleic acid (OA) and 6 ml of 1-octadecene (1-ODE) … cyclohexane and ethanol were used to purify and precipitate the oleate UCNPs”, section [0046]).
With regard to claim 6, ligand free UCNP is not actively required (see above rejection and claim interpretation).
With regard to claim 7, the AuNR comprises a longitudinal absorption that overlaps with emission spectra of UCNP as the two result in LRET.
With regard to claim 8, said UCNP surface modified with a first oligo probe is NaGdF4:Yb/Er@ NaGdF4 (see section [0033]).
With regard to claim 9, the AuNP surface modified with a second oligo probe has an absorbance maxima overlapping with emission of said UCNP surface modified with a first oligo probe as the two result in LRET.
With regard to claims 14 and 15, the target is from a pathogen, such as influenza virus (“said nucleic acid sequence is derived from a group consisting of viruses … influenza viruses …”, section [0038]).
Tsang et al. do not explicitly teach that their system of detection employs a portable device configured to contain the analytic sample, with a light source, a sensor, optics with necessary wavelength filters and lens, and a microcontroller that can wireless communicate with a remote controller device (claim 1, in-part), wherein the wireless communication is via Bluetooth, WIFI, or network (claim 3), and that the controlling device is a smartphone, computer, or TTL (claim 4), or that the portable device comprises a housing to prevent external light (claim 11), or a method of using said portable device to detect the target nucleic acid (claim 17), wherein the sample is from nasal swabs, saliva, sputum, etc. (claim 18).
Tsang et al. do not explicitly disclose that the AuNP surface modified with a second probe and the UCNP surface modified probe are spaced less than 10 nm apart after binding to the target nucleic acid sequence (claim 10).
Tsang et al. do not explicitly teach the limit of detection as being about 1 fg/mL (claim 12), or 11 fM (claim 13), or targeting a viral gene from nucleocapsid ORF1a or ORF1b (claim 16) or that the detection is achieved after 5 to 20 minutes after placing the sample into the device (claim 19)
Silverbrook et al. teach a well-known practice of providing a portable device which is tailored to assay for any types of assays, routinely involve any combination steps of: i) sample preparation, b) sample extraction; c) sample amplification; and d) detection (sections [0010]-[0014]; also “microfluidic device also has … a probe hybridization section … integrated image sensor obviates the need for an expensive external imaging system and provides … inexpensive integrated solution with low system component that is compact, light and highly portable system … integrated image sensor increases the readout sensitivity …” (section [0325]).
Silverbrook et al. also teach that the wireless network can be employed for communication (section [10356], “cellular radio 21 and wireless network connection 23 are used for communications …”; also “mobile phone reader contains all the test and diagnostic information preloaded. Data can also be loaded or updated via a number of wireless or contact interfaces to enable communication with peripheral devices, computers or online servers …”, section [10361]).
Muhr teaches a well-known fact that for energy transfer to occur between donor and acceptor, their separation distance should be within 10 nm:
“Due to its strong dependence on the distance between donor and acceptor, which has to be below 10 nm” (page 77)
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 Tsang et al. with the teachings of Silverbrook et al. and Muhr, thereby arriving at the invention as claimed for the following reasons.
As discussed above, Tsang et al. already teach a method which detects the presence of a target pathogen sequence by utilizing an energy transfer which occurs between lanthanide doped UNCP and AuNP, wherein the two probes are brought in proximity upon binding of the same pathogenic target nucleic acid sequence. While Tsang et al. did not teach that their detection method should be engineered to be performed in a portable system, one of ordinary skill in the art before the effective filing date of the claimed invention would have already recognized the well-known advantages provided by fabricating a portable device which is designed to perform the method of Tsang et al., allowing for the tests to be done on-site as a point-of-care means, while reducing the costs and time associated with collecting and transporting the collected sample from a site to a clinical laboratory, waiting for the assay result to be completed and communicated back to the site. And given the technological advancement which has occurred as well as the availability of means of such fabrication (as evidenced by Silverbrook et al.), one of ordinary skill in the art would have had a reasonable expectation of success at arriving at a portable device that is designed to perform the assay disclosed by Tsang et al., including typical elements, such as a reaction region in which a reaction occurs, an excitation and emission generation/detection means that utilize filters/mirrors (i.e., optics) to allow specific excitation wavelength of light to excite while only allowing a specific emission wavelength of light to flow through for detection while preventing outside interfering light of undesired wavelengths, as well as means of processing the instructions on the device in a wireless manner, all of which would have yielded no more than a predictable outcome of performing the assay on a portable device.
With regard to the sample being nasal swab, sputum, etc., assaying for sample from which influenza is detected as well as the targeting genes which specifically identify their presence, such as their nucleocapsid encoding genes, ORF1a/1b genees, etc., would have been an obvious conclusion held by the ordinarily skilled artisan assaying types of samples which are known and routinely examined and targeting conventionally targeted gene regions for the pathogens.
As stated by the Supreme Court in KSR, “[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.”
As to the time it takes for the assay to complete, while Tsang et al. explicitly disclosed a range of 0.5-2 hrs (“influenza subtype virus oligos are added to the hybridization medium with the probes for 0.5-2 h followed by the readout process”, section [0052]) which is roughly 30 minutes to 2 hours, the Office contends that the reduction in assay time would have been achievable by routine optimization of assay conditions involving the probe sequences, incubation time, and detection parameters.
Lastly, with regard to the sensitivity achieved, Tsang et al. state that assays such as ELISA having a limit of detection in the nanomolar range (10-9) are considered relatively low (“procedures of ELISA are laborious and the limit of detection is relatively low (nanomolar range)”, section [0003]) and state alludes that their method fulfills the need for “sensitive and quick diagnostic assays”, section [0003]).
Given that the assay disclosed by Tsang et al. employs the same types of assay configuration, one of ordinary skill in the art would have been capable of achieving the requisite sensitivity of detection in the ranges of femtomolar in target in a portable device based on optimization based on the teachings of Tsang et al., absent evidence to the contrary.
Therefore, for these reasons, the invention as claimed is deemed prima facie obvious over the cited references.
Conclusion
No claims are allowed.
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 November 18, 2025
/YJK/