DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-20 are pending and under consideration in this action.
Priority
The instant application does not claim domestic or foreign benefit, as reflected in the filing receipt mailed 4/22/2022. The filing date of the instant application is the effective filing date of claims 1-20. As such, the effective filing date of claims 1-20 is 4/19/2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 5/20/2022 and 11/1/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS’s have been considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 15 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 recites the limitation “characterizing a relationship between the biopolymer translocation velocity and one or more design parameters” in lines 1-2 of the claim. There is insufficient antecedent basis for this limitation in the claim, since there is no prior mention of this phrase in claim 14, to which this claim depends. For the purpose of compact prosecution, this claim will be interpreted to be dependent on claim 13, which contains the phrase “a biopolymer translocation velocity”; however, correction is respectfully requested.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite mental processes, i.e., concepts performed in the human mind (including observations, evaluations, judgements or opinions) (see MPEP § 2106.04(a)).
Step 1:
In the instant application, claims 1-16 are directed towards a method, claims 17-18 are directed towards a manufacture, and claims 19-20 are directed towards a system, which falls into one of the categories of statutory subject matter (Step 1: YES).
Step 2A, Prong One:
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong One). The following instant claims recite limitations that equate to one or more categories of judicial exceptions:
Claims 1, 17, and 19 recite a mental process (i.e., an evaluation in comparing the fluid response to known properties; see instant specification Para. [0025]) in “characterizing the biopolymer property of the biopolymer in response to the fluid flow velocity and/or the fluid flow pressure”.
Claims 2, 18, and 20 recites a mental process (i.e., an evaluation of the fluid medium, molecule concentration, and dimensional representation) in “wherein the fluid medium is a buffer solution including dye molecules, the molecule concentration over time is a concentration over time of the dye molecules, and the dimensional representation is an optical pattern”.
Claim 3 recites a mental process (i.e., an observation of the fluid channel type) in “wherein the fluid channel is a biopolymer mapping device”.
Claim 4 recites a mental process (i.e., an observation of the fluid channel type) in “wherein the fluid channel is a micro-fluid channel or a nano-fluid channel”.
Claim 5 recites a mental process (i.e., an evaluation of the design parameters or operational conditions to determine responsiveness) in “wherein the dimensional representation is responsive to one or more design parameters of the fluid channel and/or one or more operational conditions of the fluid flow and/or the fluid channel”.
Claim 6 recites a mental process (i.e., an observation and/or evaluation of the design parameters for the fluid channel) in “wherein the one or more design parameters of the fluid channel include a fluid channel size, a presence of one or more pillars within the fluid channel and/or a fluid inlet profile”.
Claim 7 recites a mental process (i.e., an observation and/or evaluation of the operation conditions of the flow or channel) in “wherein the one or more operational conditions of the fluid flow and/or the fluid channel include a salt concentration, an electric field strength, a fluid channel wall charge and/or a fluid channel wall surface treatment”.
Claim 8 recites a mental process (i.e., an evaluation of the size of the biopolymer segments) in “wherein the biopolymer includes biopolymer segments having lengths of less than 1 micron”.
Claim 9 recites a mental process (i.e., an evaluation of the type of machine learning model) in “wherein the machine learning model is a physics-informed neural network model”.
Claim 10 recites a mental process (i.e., an evaluation of the type of biopolymer property) in “wherein the biopolymer property includes a translocation speed, an effective drag, an elastic response, a conformation, a mechanical stiffness, a relaxation time, and/or an effective charge”.
Claim 11 recites a mental process (i.e., an evaluation of the type of biopolymer) in “wherein the biopolymer is DNA, RNA, microRNA, a protein, or a lipid”.
Claim 12 recites a mental process (i.e., an evaluation of the fluid medium, the molecular concentration, and the first/second dye contents and properties) in “wherein the fluid medium is a buffer solution including dye molecules, the molecular concentration over time is a concentration over time of the dye molecules, the dye molecules include a first dye molecule type having a first diffusion property and a second dye molecule type having a second dye molecule type having a second diffusion property different than the first diffusion property”.
Claim 13 recites a mental process (i.e., an evaluation of the type of biopolymer property) in “wherein the biopolymer property includes an effective charge of the biopolymer and/or a biopolymer translocation velocity”.
Claim 15 recites a mental process (i.e., an evaluation of the relationship between the translocation velocity and the design parameters) in “characterizing a relationship between the biopolymer translocation velocity and one or more design parameters of the fluid channel and/or one or more operational conditions of the fluid flow and/or the fluid channel”.
These recitations are similar to the concepts of collecting information, and displaying certain results of the collection and analysis is Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)) and comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)) that the courts have identified as concepts that can be practically performed in the human mind.
The abstract ideas recited in the claims are evaluated under the broadest reasonable interpretation (BRI) of the claim limitations when read in light of and consistent with the specification, and are determined to be directed to mental processes that in the simplest embodiments are not too complex to practically perform in the human mind. The instant claims must therefore be examined further to determine whether they integrate the abstract idea into a practical application (Step 2A, Prong One: YES).
Step 2A, Prong Two:
In determining whether a claim is directed to a judicial exception, further examination is performed that analyzes if the claim recites additional elements that when examined as a whole integrates the judicial exception(s) into a practical application (MPEP § 2106.04(d)). A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. The claimed additional elements are analyzed to determine if the abstract idea is integrated into a practical application (MPEP § 2106.04(d)(I)). If the claim contains no additional elements beyond the abstract idea, the claim fails to integrate the abstract idea into a practical application (MPEP § 2106.04(d)(III)). The following claims recite limitations that equate to additional elements:
Claim 1 recites “receiving a dimensional representation of a molecule concentration over time within a fluid flow of a fluid medium flowing through a fluid channel including the biopolymer”; and “predicting a fluid flow velocity and/or a fluid flow pressure of the fluid medium in response to the dimensional representation of the molecule concentration over time within the fluid medium using a machine learning model”.
Claim 14 further recites “controlling a motion of the biopolymer in the fluid channel depending on the biopolymer property of the biopolymer”.
Claim 16 further recites “driving the fluid flow by an external electric field causing migration of ions in the fluid medium”.
Claim 17 recites “a non-transitory computer-readable medium tangibly embodying computer readable instructions for a software program, the software program being executable by a processor of a computing device”; “receiving a dimensional representation of a molecule concentration over time within a fluid flow of a fluid medium flowing through a fluid channel including a biopolymer”; and “predicting a fluid flow velocity and/or a fluid flow pressure of the fluid medium in response to the dimensional representation of the molecule concentration over time within the fluid medium using a machine learning model”.
Claim 19 recites “a computer having a processor for executing computer-readable instructions and a memory for maintaining the computer-executable instructions, the computer-executable instructions when executed by the processor perform functions”; “receiving a dimensional representation of a molecule concentration over time within a fluid flow of a fluid medium flowing through a fluid channel including the biopolymer”; and “predicting a fluid flow velocity and/or a fluid flow pressure of the fluid medium in response to the dimensional representation of the molecule concentration over time within the fluid medium using a machine learning model”.
Regarding the above cited limitations in 1, 14, 16, 17, and 19 of (i) receiving a dimensional representation of a molecule concentration over time within a fluid flow of a fluid medium flowing through a fluid channel including the biopolymer (claims 1, 17, and 19); (ii) predicting a fluid flow velocity and/or a fluid flow pressure of the fluid medium in response to the dimensional representation of the molecule concentration over time within the fluid medium using a machine learning model (claims 1, 17, and 19); (iii) controlling a motion of the biopolymer in the fluid channel depending on the biopolymer property of the biopolymer (claim 14); and (iv) driving the fluid flow by an external electric field causing migration of ions in the fluid medium (claim 16). These limitations equate to insignificant, extra-solution activity of mere data gathering because these limitations gather data before or after the recited judicial exceptions of characterizing the biopolymer property of the biopolymer in response to the fluid flow velocity and/or the fluid flow pressure (see MPEP § 2106.04(d)).
Regarding the above cited limitations in claims 17 and 19 of (v) a non-transitory computer-readable medium tangibly embodying computer readable instructions for a software program, the software program being executable by a processor of a computing device (claim 17); and (vi) a computer having a processor for executing computer-readable instructions and a memory for maintaining the computer-executable instructions, the computer-executable instructions when executed by the processor perform functions (claim 19). These limitations require only a generic computer component, which does not improve computer technology. Therefore, these limitations equate to mere instructions to implement an abstract idea on a generic computer, which the courts have established does not render an abstract idea eligible in Alice Corp. 573 U.S. at 223, 110 USPQ2d at 1983. As such, claims 1-20 are directed to an abstract idea (Step 2A, Prong Two: NO).
Step 2B:
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that equate to well-understood, routine and conventional (WURC) limitations (MPEP § 2106.05(d)). The instant claims recite same additional elements described in Step 2A, Prong Two above.
Regarding the above cited limitations in in claims 17 and 19 of (v) a non-transitory computer-readable medium tangibly embodying computer readable instructions for a software program, the software program being executable by a processor of a computing device (claim 17); and (vi) a computer having a processor for executing computer-readable instructions and a memory for maintaining the computer-executable instructions, the computer-executable instructions when executed by the processor perform functions (claim 19). These limitations equate to instructions to implement an abstract idea on a generic computing environment, which the courts have established does not provide an inventive concept (see MPEP § 2106.05(d) and MPEP § 2106.05(f)).
Regarding the above cited limitations in claims 1, 17, and 19 of (i) receiving a dimensional representation of a molecule concentration over time within a fluid flow of a fluid medium flowing through a fluid channel including the biopolymer. This limitation equates to receiving/transmitting data over a network, which the courts have established as a WURC limitation of a generic computer in buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014).
Regarding the above cited limitations in claims 1, 14, 16, 17, and 19 of (ii) predicting a fluid flow velocity and/or a fluid flow pressure of the fluid medium in response to the dimensional representation of the molecule concentration over time within the fluid medium using a machine learning model (claims 1, 17, and 19); (iii) controlling a motion of the biopolymer in the fluid channel depending on the biopolymer property of the biopolymer (claim 14); and (iv) driving the fluid flow by an external electric field causing migration of ions in the fluid medium (claim 16). These limitations when viewed individually and in combination, are WURC limitations as taught by Zeng et al. (Deep-learning Assisted Extraction of Fluid Velocity from Scalar Signal Transport in a Shallow Microfluidic Channel. arXiv:2112.00385 (2021)) and Zhou et al. (Enhanced nanochannel translocation and localization of genomic DNA molecules using three-dimensional nanofunnels. Nat Commun 8, 807 (2017)). Zeng et al. discloses a deep neural networks assisted scalar image velocimetry (DNN-SIV) method for prediction of fluid velocity in microfluidic channels (Abstract). The method is time dependent and incorporates fluorescent dyes and proteins in the fluid (limitation (ii)) (Pg. 4, Para. 2; (Pg. 3, Para. 3-4; and Pg. 4, Fig. 1). Zhou et al. discloses a method of electrokinetically introducing DNA molecules into a nanochannel, facilitated by incorporating a three-dimensional nanofunnel at the nanochannel entrance. In some cases, DNA molecules are stably trapped and axially positioned within a nanofunnel at sub-threshold electric field strengths (limitation (iii)) (Abstract). Zhou et al. further discloses that the DNA backbone is surrounded by a cloud of uncondensed counterions. The electrostatic force acting on the counterions drives them from the narrow end to the wide end of the nanofunnel (limitation (iv)) (Supplementary Information, Pg. 15, Para. 2).
These additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the instant claims do not amount to significantly more than the judicial exception itself (Step 2B: NO). As such, claims 1-20 are not patent eligible.
Claim Rejections - 35 USC § 103
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.
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 factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1-11 and 13-20 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al. (Enhanced nanochannel translocation and localization of genomic DNA molecules using three-dimensional nanofunnels. Nat Commun 8, 807 (2017); published 10/9/2017) in view of Zeng et al. (Deep-learning Assisted Extraction of Fluid Velocity from Scalar Signal Transport in a Shallow Microfluidic Channel. arXiv:2112.00385 (2021). DOI: 10.48550/arXiv.2112.00385; published 12/1/2021; provided in the IDS dated 11/1/2023).
Regarding claim 1, Zhou et al. teaches a method to precisely control and understand the transport of single DNA molecules through a nanoscale channel. Individual DNA molecules are imaged as they attempt to overcome the entropic barrier to nanochannel entry through nanofunnels with various shapes. Theoretical modeling of this behavior reveals the pushing and pulling forces that result in up to a 30-fold reduction in the threshold electric field needed to initiate nanochannel entry (i.e., a computational method for characterizing a biopolymer property of a biopolymer) (Abstract). Zhou et al. further teaches the measurement of DNA molecules within a three-dimensional nanofunnel in Fig. 2. The figure shows representative images recording the position and conformation of a λ-phage DNA molecule at various time points as it is electrokinetically driven from right to left through a nanofunnel and into the associated nanochannel. The top panel is a bright-field image showing the position of the nanofunnel and nanochannel and the voltage polarity applied across the nanofunnel–nanochannel device. The numbered frames (1–5) are fluorescence images of the DNA molecule stained with an intercalating dye recorded at the indicated time points. Image analysis determined the positions of the molecule’s leading (x0) and trailing (xN) ends at each time point (i.e., receiving a dimensional representation of a molecule concentration over time within a fluid flow of a fluid medium flowing through a fluid channel including the biopolymer) (Pg. 3, Fig. 2). Zhou et al. further teaches the velocity profiles around a DNA molecule stalled/trapped in bulk solution and around a stalled/trapped DNA molecule under confinement in a nanofunnel in Supplementary Fig. 6 (i.e., in response to the fluid flow velocity) (Supplementary Information, Pg. 6, Supp. Fig. 6). Zhou et al. further teaches the DNA conformation (position, length, and packing density) associated with trapped molecules (Pg. 5, Fig. 4b/c) as well as the calculated relative free energies at different nanochannel electric field strengths of a DNA molecule as a function of its leading end position within the nanofunnel–nanochannel (i.e., characterizing the biopolymer property of the biopolymer in response to the fluid flow velocity) (Pg. 3, Fig. 2c).
Regarding claims 2, 18, and 20, Zhou et al. teaches that lambda-phage DNA (Promega) or T4-phage DNA (Nippon Gene) in 2X TBE was stained with the intercalating dye, YOYO-1, at a base-pair: dye ratio of 5:1. Solutions containing 0.5 ng/μL of DNA (16 pM for λ-phage and 4.6 pM for T4-phage) also contained 4% β-mercaptoethanol to limit photo-induced damage and 2% polyvinylpyrrolidone to reduce electro-osmotic flow within the channels (i.e., wherein the fluid medium is a buffer solution including dye molecules) (Pg. 6, Col. 2, Para. 3). Zhou et al. further teaches representative images recording the position and conformation of a λ-phage DNA molecule at various time points through a nanofunnel and into the associated nanochannel. The numbered frames in Fig. 2 are fluorescence images of the DNA molecule stained with an intercalating dye recorded at the indicated time points. Image analysis determined the positions of the molecule’s leading (x0) and trailing (xN) ends at each time point (i.e., the molecule concentration over time is a concentration over time of the dye molecules, and the dimensional representation is an optical pattern) (Pg. 3, Fig. 2).
Regarding claim 3, Zhou et al. teaches representative images recording the position and conformation of a λ-phage DNA molecule at various time points through a nanofunnel and into the associated nanochannel (i.e., wherein the fluid channel is a biopolymer mapping device) (Pg. 3, Fig. 2).
Regarding claim 4, Zhou et al. teaches the transport of single DNA molecules through nanochannels (i.e., wherein the fluid channel is a nanofluid channel) (Abstract).
Regarding claim 5, Zhou et al. teaches that the residence time changes at various nanochannel electric field strengths, E, in three different nanofunnels (defined by α = 0.78, α = 0.45, and α = 0) (Pg. 4, Fig. 3). Zhou et al. further teaches that the residence time is determined using the leading edge of the DNA measured from the fluorescence images (i.e., wherein the dimensional representation is responsive to one or more design parameters of the fluid channel) (Pg. 3, Fig. 2). Zhou et al. further teaches that the position of a molecule’s leading end within a nanofunnel measured at three different nanochannel electric field strengths: 77.5 V/cm, 54.3 V/cm, and 15.5 V/cm (i.e., wherein the dimensional representation is responsive to one or more operational conditions of the fluid channel) (Pg. 3, Fig. 2).
Regarding claim 6, Zhou et al. teaches that the field-dependent residence times were measured in nanofunnels with comparable dimensions but different shapes, as well as for DNA entry into a nanochannel without an incorporated nanofunnel. The nanofunnel shape was defined using the following equation:
y
x
≈
z
x
=
D
x
x
D
α
, where
y
x
and
z
x
are the funnel width and depth, respectively, at position
x
>
0
along the funnel’s longitudinal axis,
D
is the widest dimension of the nanofunnel, and
x
D
is the nanofunnel length. In this study,
D
= 1.6 ± 0.1 μm,
x
D
= 21.5 ± 0.2 μm, and the nanochannel width and depth were each 120 ± 15 nm. Residence time measurements were performed in nanofunnels defined by
α
values of 0, 0.45, and 0.78, whereas supplementary experiments were conducted in nanofunnels with
α
values of 1.46 and 1.89 (i.e., wherein the one or more design parameters of the fluid channel include a fluid inlet profile) (Pg. 4, Col. 1, Para. 2).
Regarding claim 7, Zhou et al. teaches that the position of a molecule's leading end within a nanofunnel was measured at three different nanochannel electric field strengths: 77.5V/cm, 54.3 V/cm, and 15.5 V/cm (i.e., wherein the one or more operational conditions of the fluid flow and/or the fluid channel include an electric field strength) (Pg. 3, Fig. 2).
Regarding claim 8, Zhou et al. teaches that data were collected using stained λ-phage (48.5 kbp) and T4-phage (165.6 kbp) DNA molecules. The molecule can be segmented into a 3000-bp segment or smaller (i.e., wherein the biopolymer includes biopolymer segments having lengths of less than 1 micron) (Pg. 4, Fig. 3).
Regarding claim 10, Zhou et al. teaches that the molecule's elasticity that resists its stretching is another contributor to the entropic force that was included in the calculations (i.e., wherein the biopolymer property includes an elastic response) (Pg. 7, Col. 1, Para. 2). Zhou et al. further teaches a schematic representation of the DNA conformation (position, length, and packing density) associated with different operating conditions (i.e., wherein the biopolymer property includes a conformation) (Pg. 5, Fig. 4). Zhou et al. further teaches that extrapolation of the experimental electric field data results in the characteristic threshold electric field strength, E0 (normalized to the threshold electric field strength measured in the absence of a nanofunnel E0 (no funnel)) for three nanofunnels.
τ
0
= 6 ms corresponds to the Zimm relaxation time of the leading portion (~3000 bp) of the nanofunnel-confined molecule (i.e., wherein the biopolymer property includes a relaxation time) (Pg. 4, Fig. 3).
Regarding claim 11, Zhou et al. teaches the transport of single DNA molecules through nanochannels (i.e., wherein the biopolymer is DNA) (Abstract).
Regarding claim 13, Zhou et al. teaches that in the model of DNA trapping, the electro-osmotic flow due to the surface charges on the walls of the device as a reduction in the effective charge on the DNA molecule (i.e., wherein the biopolymer property includes an effective charge of the biopolymer) (Supplementary Information, Pg. 18, Para. 1). Zhou et al. further teaches that DNA molecules are stably trapped and axially positioned within a nanofunnel at sub-threshold electric field strengths (i.e., the translocation velocity is reduced when trapping the molecules; wherein the biopolymer property includes a biopolymer translocation velocity) (Abstract).
Regarding claim 14, Zhou et al. teaches that stable DNA can be trapped in a nanofunnel using applied electric fields (Pg. 5, Col. 1, Para. 1). Zhou et al. further teaches that at the lowest field strengths, the molecule is weakly trapped and thermal fluctuations are larger and highly correlated as the molecule fluctuates as a whole along the longitudinal nanofunnel axis. At higher electric fields, the correlations between fluctuations of the ends are reduced as compression of the leading sections of the molecule suppresses the fluctuations of this end, whereas the less constrained trailing end of the molecule is freer to fluctuate (i.e., controlling a motion of the biopolymer in the fluid channel depending on the biopolymer property of the biopolymer) (Pg. 5, Col. 2, Para. 1).
Regarding claim 15, Zhou et al. teaches that stable DNA can be trapped in a nanofunnel using applied electric fields. For example, measured values of various combinations of end coordinates for a T4-phage DNA molecule trapped at the representative nanochannel electric fields of 8 V/cm and 21 V/cm are shown in Fig. 4b and c, respectively (i.e., the biopolymer translocation velocity is reduced with certain applied electric fields; characterizing a relationship between the biopolymer translocation velocity and one or more operational conditions of the fluid flow and/or the fluid channel) (Pg. 5, Col. 1, Para. 1-2, and Pg. 5, Fig. 4).
Regarding claim 16, Zhou et al. teaches that by incorporating a three-dimensional nanofunnel at the nanochannel entrance, DNA can be more efficiently introduced into the nanochannel without an increase in the nanochannel electric field (i.e., driving the fluid flow by an external electric field) (Pg. 2, Col. 2, Para. 2). Zhou et al. further teaches that the DNA backbone is further surrounded by a cloud of uncondensed counterions (cations) localized within the double layer, delimited by the Debye length of the solution. The electrostatic force acting on the counterions drives them from the narrow end to the wide end of the nanofunnel, in the direction opposite to the force acting on the polyanionic DNA molecule (i.e., causing migration of ions in the fluid medium) (Supplementary Information, Pg. 15, Para. 2).
Regarding claim 17, Zhou et al. teaches the limitations of receiving a dimensional representation of a molecule concentration over time within a fluid flow of a fluid medium flowing through a fluid channel including a biopolymer and characterizing a biopolymer property of the biopolymer in response to the fluid flow velocity and/or the fluid flow pressure as described for claim 1 above. Zhou et al. further teaches that images recording DNA position were analyzed using an automated program written in MATLAB to extract the location of the molecule's ends at each time point (i.e., a non-transitory computer-readable medium tangibly embodying computer readable instructions for a software program, the software program being executable by a processor of a computing device to provide operations) (Pg. 6, Col. 2, Para. 7).
Regarding claim 19, Zhou et al. teaches the limitations of receiving a dimensional representation of a molecule concentration over time within a fluid flow of a fluid medium flowing through a fluid channel including a biopolymer and characterizing a biopolymer property of the biopolymer in response to the fluid flow velocity and/or the fluid flow pressure as described for claim 1 above. Zhou et al. further teaches that images recording DNA position were analyzed using an automated program written in MATLAB to extract the location of the molecule's ends at each time point (i.e., on a computer; a computer having a processor for executing computer-readable instructions and a memory for maintaining the computer-executable instructions, the computer-executable instructions when executed by the processor perform functions) (Pg. 6, Col. 2, Para. 7).
Zhou et al. does not teach predicting a fluid flow velocity and/or a fluid flow pressure of the fluid medium in response to the dimensional representation of the molecule concentration over time within the fluid medium using a machine learning model; and wherein the machine learning model is a physics-informed neural network model.
Regarding claims 1, 17, and 19, Zheng et al. teaches a method to predict fluid velocity in a microfluidic channel using a deep neural networks assisted scaler image velocimetry (DNN-SIV) (Abstract). Zheng et al. further teaches that the predicted velocity is time dependent (Pg. 4, Para. 2). Zeng et al. further teaches that the model can use a representative shape of a microchannel, as shown in Fig. 1. The channel can also include fluorescent dyes or fluorescent protein molecules (i.e., predicting a fluid flow velocity of the fluid medium in response to the dimensional representation of the molecule concentration over time within the fluid medium using a machine learning model) (Pg. 3, Para. 3-4 and Pg. 4, Fig. 1).
Regarding claim 9, Zeng et al. teaches that the deep neural networks assisted scalar image velocimetry (DNN-SIV) is built on physics-informed neural networks and residual neural networks that integrate data of scalar field and physics laws (i.e., wherein the machine learning model is a physics-informed neural network model) (Abstract).
Therefore, regarding claims 1-11 and 13-20, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of analyzing DNA translocation through nanochannels of Zhou et al. with the machine learning algorithm to predict fluid velocity of Zeng et al. because the algorithm of Zeng et al. is more stable, efficient, and allows for real-time flow visualization (Zeng et al., Abstract and Pg. 11, Para. 2). One of ordinary skill in the art would be able to combine the teachings of Zhou et al. with Zeng et al. with reasonable expectation of success due to the same nature of the problem to be solved, since both are drawn towards a method for analyzing fluid flow in channels. Therefore, regarding claims 1-11 and 13-20, the instant invention is prima facie obvious (MPEP § 2142).
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al. in view of Zeng et al. as applied to claims 1-11 and 13-20 above, and further in view of Benninger et al. (Fluorescence-lifetime imaging of DNA-dye interactions within continuous-flow microfluidic systems. Angew Chem Int Ed Engl. 246(13): 2228-2231 (2007); published 3/9/2007).
Regarding claim 12, Zhou et al. teaches the limitations of wherein the fluid medium is a buffer solution including dye molecules, and the molecular concentration over time is a concentration over time of the dye molecules as described for claim 2 above. Zhou et al. further teaches that the intercalating dye is YOYO-1 (Pg. 6, Col. 2, Para. 3). Though not explicitly stated by Zhou et al., it is obvious to one of ordinary skill in the art that the YOYO-1 dye is a molecule with diffusion properties (i.e., a first dye molecule type having a first diffusion property).
Zhou et al. in view of Zeng et al., as applied to claims 1-11 and 13-20 above, does not teach a second dye molecule type having a second dye molecule type having a second diffusion property different than the first diffusion property.
Regarding claim 12, Benninger teaches the intercalating dye Hoechst 33258 (H33258) in microfluidic systems (i.e., a second dye molecule type) (Pg. 2228, Col. 2, Para. 2). Benninger et al. further teaches that free H33258 molecules are diffusing throughout the DNA and are then depleted as they bind to DNA. At a residence time of 7.2 s, the mean interdiffusion distance of free H33258 molecules in aqueous solution is approximately 46 mm (based on a diffusion coefficient of D ≈ 300 μm/s2), which results in nearly complete diffusion across the 50 mm wide channel (i.e., a second dye type molecule having a second diffusion property different than the first diffusion property) (Pg. 2230, Col. 2, Para. 1).
Therefore, regarding claim 12, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of analyzing DNA translocation through nanochannels of Zhou et al. in view of Zeng et al. with the dye used by Benninger et al. because the method of Benninger et al. provides an ideal platform for studying the temporal variation in fluorescence kinetics during and after DNA–dye binding with improved resolution (Benninger et al., Pg. 2228, Col. 2, Para. 2 and Pg. 2231, Col. 2, Para. 3). One of ordinary skill in the art would be able to combine the teachings of Zhou et al. in view of Zeng et al. with Benninger et al. with reasonable expectation of success due to the same nature of the problem to be solved, since both are drawn towards analyzing DNA in channels. Therefore, regarding claim 12, the instant invention is prima facie obvious (MPEP § 2142).
Conclusion
No claims allowed.
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/D.P.S./Examiner, Art Unit 1687
/Karlheinz R. Skowronek/Supervisory Patent Examiner, Art Unit 1687