DETAILED ACTION
Applicant’s response filed 12/8/2025 has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied.
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 1-9 are pending and under consideration in this action.
Priority
The instant application is 371 of PCT/US2020/023283, filed 03/18/2020, which claims priority to U.S. Provisional Application number 62/819,783, filed 03/18/2019, as reflected in the filing receipt mailed 05/23/2025. The claim for domestic benefit for claims 1-9 is acknowledged. As such, the effective filing date of claims 1-9 is 03/18/2019.
Nucleotide and/or Amino Acid Sequence Disclosures
The amended specification to label the corresponding sequence identifiers is acknowledged. The specific deficiencies recited in the Office Action dated 7/14/2025 are withdrawn (Applicant Remarks, Pg. 15).
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 is missing the appropriate semicolon at the end step (b).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
Withdrawn Rejections
The rejection of claims 1-9 under 25 U.S.C 112(b) is withdrawn in view of Applicant’s amendments to the claims filed 12/8/2025 (Applicant’s Remarks, Pg. 15-16).
Maintained Rejections
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 5 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.
This rejection is maintained from the previous office action.
Claim 5 recites the limitation "comprises the step of selecting a formula", in line 3 of the claim. There is insufficient antecedent basis for these limitation in the claim, since there is no prior mention of this phrase in claim 3, to which this claim depends. This rejection can be overcome by amendment of claim 5 to recite "comprises a step of selecting a formula".
Response to arguments under 35 U.S.C 112(b)
Applicant’s arguments filed 12/8/2025 have been fully considered but they are not persuasive.
Applicant argues that claim 5 has been amended to depend on claim 3, instead of claim 2, and the insufficient antecedent basis for the limitation of “comprises the step of selecting a formula” has been overcome (Applicant’s Remarks, Pg. 16). Applicant’s arguments are not persuasive for the following reasons:
In claim 5, “the step of selecting a formula” is a phrase that has not previously been mentioned in claim 3, and therefore lacks antecedent basis. The amendment changing the dependency from claim 2 to 3 does not change the lack of antecedent basis for “the step of selecting a formula”. Therefore, the rejection of claim 5 is maintained.
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 1-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite both (1) mathematical concepts (mathematical relationships, formulas or equations, or mathematical calculations) and (2) mental processes, i.e., concepts performed in the human mind (including observations, evaluations, judgements or opinions) (see MPEP § 2106.04(a)).
Any newly recited portion is necessitated by claim amendment.
Step 1:
In the instant application, claims 1-9 are directed towards a method, 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:
Claim 1 recites a mental process (i.e., an evaluation of changes in conductance) in step (c) of “determining changes in said conductance between adjacent sections of said unknown sequence of double-stranded DNA”, a mental process (i.e., an evaluation of changes to assign a reference character) in step (d) of “assigning reference characters corresponding to said changes in conductance to create a listing”, a mental process (i.e., a comparison of listing to a reference) in step (e) of “matching said listing to said reference map”, and a mental process (i.e., an evaluation of the mapping to determine a sequence) in step (f) of “determining a sequence of said unknown sequence of double-stranded DNA based on said matching of said listing to said reference map”.
Claim 2 recites a mental process (i.e., an observation of the listing contents) in “wherein said reference characters of said reference map and said reference characters of said listings are numerals”.
Claim 3 recites a mental process (i.e., an evaluations of how base pairs align) in step (b) of “determining orientations of said plurality of base pairs relative to a first base pair of said plurality of base pairs”, a mathematical concept in step (c) of “calculating an equivalent conductance of each of said plurality of base pairs of said double-stranded DNA based on said orientations of said plurality of base pairs”, a mathematical concept in step (d) of “calculating system conductances of adjacent sections of double-stranded DNA”, and a mental process (i.e., an evaluation of changes to assign a reference character) in step (e) of “assigning said reference characters of said reference map corresponding to changes in said system conductances in adjacent sections of said double-stranded DNA”.
Claim 4 recites a mathematical concept (i.e., building a matrix) in “further comprising the step of building a matrix comprising said known sequence of said double-stranded DNA and said orientation of said plurality of base pairs”.
Claim 5 recites a mathematical concept and a mental process (i.e., an evaluation of data to select a formula) in “wherein said step of calculating an equivalent conductance of each of said plurality of base pairs of said double-stranded DNA comprises the step of selecting a formula based on said orientations of said plurality of base pairs”.
Claim 6 recites a mental process (i.e., an evaluation of data to determine if conductances are equal) in “wherein said system conductances are equal to a sum of said equivalent conductance of each of said plurality of base pairs within a detection range of said nanoelectrodes”.
Claim 7 recites a mental process (i.e., an evaluation of the width of nanoelectrodes) in “where said detection range of said nanoelectrodes is determined by a width of said nanoelectrodes”.
Claim 8 recites a mathematical concept (i.e., calculated using a noise reduction techniques) in “wherein prior to step (b) noise reduction is performed on said unknown sequence of double-stranded DNA”.
Claim 9 recites a mental process (i.e., an observation of data) in “wherein prior to step (c), said conductance of said unknown sequence of double-stranded DNA is plotted”.
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)), 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)), and organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) that the courts have identified as concepts that can be practically performed in the human mind or mathematical relationships.
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. Additionally, the recited limitations that are identified as judicial exceptions from the mathematical concepts grouping of abstract ideas are abstract ideas irrespective of whether or not the limitations are practical to 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 steps (a) and (b) of “building a reference map comprising reference characters corresponding to a change in conductance measured as a known sequence of double-stranded DNA is translocated through nanoelectrodes of a DNA sequencer” and “determining conductance of an unknown sequence of double-stranded DNA measurement as said unknown sequence of double-stranded DNA is translated through said nanoelectrodes of said DNA sequencer”.
Claim 3 further recites step (a) of “converting a known sequence of single-stranded DNA to said double-stranded DNA comprising a plurality of base pairs”.
Regarding the above cited limitations in claims 1 and 3 of (i) building a reference map comprising reference characters corresponding to a change in conductance measured as a known sequence of double-stranded DNA is translocated through nanoelectrodes of a DNA sequencer, (ii) determining conductance of an unknown sequence of double-stranded DNA measurement as said unknown sequence of double-stranded DNA is translated through said nanoelectrodes of said DNA sequencer, and (iii) converting a known sequence of single-stranded DNA to said double-stranded DNA comprising a plurality of base pairs. 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 determining a sequence of said unknown sequence of double-stranded DNA based on matching of said listing to said reference map (see MPEP § 2106.04(d)). As such, claims 1-9 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 the same additional elements as recited in Step 2A, Prong Two above.
Regarding the above cited limitations in claims 1 and 3 of (i) building a reference map comprising reference characters corresponding to a change in conductance measured as a known sequence of double-stranded DNA is translocated through nanoelectrodes of a DNA sequencer, (ii) determining conductance of an unknown sequence of double-stranded DNA measurement as said unknown sequence of double-stranded DNA is translated through said nanoelectrodes of said DNA sequencer, and (iii) converting a known sequence of single-stranded DNA to said double-stranded DNA comprising a plurality of base pairs. These limitations equate to laboratory techniques that are WURC limitations in the life science arts (see MPEP 2106.05(d)). Analyzing DNA to provide sequence information or detect allelic variants is a WURC limitation in Genetic Techs. Ltd., 818 F.3d at 1377; 118 USPQ2d at 1546. Amplifying and sequencing nucleic acid sequences is a WURC limitation in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014).
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 1-9 are not patent eligible.
Response to Arguments under 35 U.S.C. 101
Applicant’s arguments filed 12/8/2025 have been fully considered but they are not persuasive.
1. Applicant argues that steps (a) and (b) of claim 1 are not extra-solution activities because they are essential steps. Step (a) and (b) of claim 1 are significant limitations and therefore are not merely nominally or tangentially related to the claimed method of DNA base-calling (Applicant’s Remarks Pg. 18-20). Applicant’s arguments are not persuasive for the following reasons:
As described in Step 2A, Prong One above, steps (a) and (b) are merely gathering data for use in the subsequent determination of an unknown sequence of DNA (step (f)). The broadest reasonable interpretation (BRI) of step (a) is gathering conductance data for known sequences to build a reference map, which is used for comparison in steps (e) and (f). The BRI of step (b) is measuring conductance of an unknown DNA sequence, which is used in the analysis disclosed in steps (c)-(f). Steps (a) and (b) are therefore directed to data gathering to perform the functions of collecting the data needed to carry out the abstract ideas (steps (c)-(f)). Data gathering does not impose any meaningful limitation on the abstract idea, or on how the abstract idea is performed. Therefore, data gathering steps (a) and (b) are not sufficient to integrate an abstract idea into a practical application (see MPEP § 2106.05(g)).
Additionally, steps (a) and (b) are data gathering steps using routine laboratory elements. The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity (see MPEP 2106.05(d)(II)): determining the level of a biomarker in blood by any means (Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017)); and detecting DNA or enzymes in a sample (Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017)). This argument is thus not persuasive.
2. Applicant argues that the Examiner must also consider whether the limitation amounts to necessary data gathering and outputting (i.e., all uses of the recited judicial exception require such data gathering or data output). MPEP 2106.05(g). Step (a) of a building a reference map comprising reference characters corresponding to a change in conductance is much more than conventional data gathering and the Examiner has cited no evidence showing otherwise. This also establishes that step (a) of claim 1 is not an insignificant, extra-solution activity (Applicant’s Remarks, Pg. 20). Applicant’s arguments are not persuasive for the following reasons:
As described in the arguments directly above, the BRI of step (a) is gathering conductance data for known sequences to build a reference map, which is used for comparison in steps (e) and (f). Step (a) is directed to data gathering because it is merely correlating measured conductance data with any reference character to create a map. Step (a) does not impose any further limitations on the types of reference characters or the structure of the generated reference map. As such, step (a) does not impose any meaningful limit on the abstract idea or on how the abstract idea is performed. Therefore, step (a) is an insignificant, extra-solution activity of mere data gathering and this argument is thus not persuasive.
3. Applicant argues that under Step 2B, the Examiner must determine whether steps (a) and (b) of claim 1 (i.e., the additional elements) amount to significantly more than the judicial exception itself. The same insignificant extra-solution activities discussed in Step 2A, Prong Two, are also relevant in Step 2A, but the additional consideration of "whether the extra-solution limitation is well known" must also be evaluated. Step (a) of claim 1 is not disclosed in the cited references, and therefore the limitation is step (a) are not well-known and therefore not an insignificant, extra-solution activity. Accordingly, the additional element of step (a) of claim 1 amounts to significantly more than the judicial exception and the claims are patent eligible subject matter under Step 2B (Applicant’s Remarks, Pg. 20-21). Applicant’s arguments are not persuasive for the following reasons:
The references cited in the 102/103 rejections (Gundlach, Carlsen, Tung, and Balan) were not relied upon in Step 2B. Step (a) of “building a reference map comprising reference characters corresponding to a change in conductance measured as a known sequence of double-stranded DNA is translocated through nanoelectrodes of a DNA sequencer” is considered a WURC limitation in the life science arts. The BRI of step (a) is an analysis of the gathered conductance data for known sequences to build a reference map. As described in the arguments directly above, step (a) is a routine laboratory element. The courts have recognized the following laboratory technique as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity (see MPEP 2106.05(d)(II)): analyzing DNA to provide sequence information or detect allelic variants, which is a WURC limitation in Genetic Techs. Ltd., 818 F.3d at 1377; 118 USPQ2d at 1546 (see MPEP § 2106.05(d)). This argument is thus not persuasive.
Though not relied upon for the 101 rejection, Examiner notes that Gundlach does teach step (a) as described in the Response to Arguments under 102 section below.
Claim Rejections - 35 USC § 102
Maintained Rejections
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 4, and 9 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Gundlach et al. (U.S. Patent Application Publication 2015/0132745 A1; published 5/14/2015; previously cited).
This rejection is maintained from the previous office action.
Regarding claim 1, Gundlach et al. teaches a method to efficiently analyze polymer characteristics using nanopore-based assays. Specifically disclosed is a method for generating reference signals for polymer analysis in a nanopore system, wherein the nanopore system has a multi-subunit output resolution (Abstract). Gundlach et al. further teaches that the polymer is single stranded or double stranded DNA (i.e., a method of DNA-base calling and a known sequence of double stranded DNA) (Para. [0014] and claim 16). Gundlach et al. further teaches that the method comprises translocating a reference sequence through a nanopore to generate a plurality of reference output signals, wherein each possible multi-subunit sequence that can determine an output signal only appears once in the reference sequence (i.e., a known sequence is translocated). The output signals are compiled into a reference map for nanopore analysis of an analyte polymer (i.e., building a reference map comprising reference characters) (Abstract and claim 1). Gundlach et al. further teaches that nanopore systems also incorporate structural elements to apply a voltage across the nanopore-bearing membrane or film. For example, the system can include a pair of drive electrodes that drive current through the nanopores (i.e., translocated through nanoelectrodes) (Para. [0031]). Gundlach et al. further teaches that various assay conditions might fluctuate, changing conductance and causing a variation in the calibration constant. Such changing conditions can include temperature, applied voltage, salinity of the conductive media, nanopore shape, etc. (i.e., corresponding to a change in conductance) (Para. [0044]). Gundlach et al. further teaches that for sequence analysis of unknown DNA, the patterns of current levels obtained from nanopore-based analysis systems need to be related to a known sequence. The observed current signals for each iterative movement of a nucleotide subunit were determined by a plurality of nucleotides residing at that time in the pore constriction zone (i.e., determining conductance of an unknown sequence of double-stranded DNA measured as said unknown sequence of double-stranded DNA is translated through said nanoelectrodes of said DNA sequencer) (Para. [0064]). Gundlach et al. further teaches that for DNA, it has been demonstrated that several nucleotides affect the ion current. In the case of using a preferred nanopore, MspA mutant M2-NNN, it was demonstrated that four nucleotides are involved in controlling the ion current when the DNA is held from the cis side and 180 mV is applied. When the DNA is moved through the pore in single nucleotide steps, a succession of quadromer generated current values best describes the ion current trace (i.e., determining changes in said conductance between adjacent sections of said unknown sequence of double-stranded DNA) (Para. [0055]). Gundlach et al. further teaches that to efficiently generate the reference library, the 256 current values for all possible DNA quadromers were measured. Specifically, a De Bruijn sequence was generated, resulting in a circular or cyclical sequence with the shortest possible sequence because each quadromer only appears once. In the linearized form, the De Bruijn sequence results in a reference sequence that is only 259 (i.e., kn+n-1 or 256+4-1) nucleotides long, and contains all possible quadromers in a contiguous orientation (i.e., assigning reference characters corresponding to said changes in conductance to create a listing) (Para. [0065]). Gundlach et al. further teaches that the reference map can thereafter be used to determine characteristics of an unknown analyte polymer. Output signals obtained from an analyte polymer are compared to a reference map, where the analyte polymer is the same type of polymer as the reference polymer or reference sequence (i.e., matching said listing to said reference map) (Para. [0046] and claim 19). Gundlach et al. further teaches that when a matching output signal is found, the particular reference multi-subunit sequence is determined to have resided in the nanopore at that specific time of measurement. As a series of sequences are correlated to a series of output signals in the analyte polymer trace, the characteristics of the polymer (e.g., the sequence) can be reconstructed (i.e., determining a sequence of said unknown sequence of double-stranded DNA based on said matching of said listing to said reference map) (Para. [0048]).
Regarding claim 2, Gundlach et al. teaches that the reference sequence is a De Bruijn sequence B represented by B(k,n), where k is the number of potential polymer subunit identities and wherein n is the number of contiguous poly subunits that correspond to the resolution of the nanopore system. The De Bruijn sequence can be generated by taking a Hamiltonian path of an n-dimensional graph of k subunit identities, taking a Eulerian cycle of a (n-1)-dimensional graph over k subunit identities, using finite fields analysis, or concatenating all possible Lyndon words whose length divides by n (i.e., wherein said reference characters of said reference map and said reference characters of said listing are numerals) (Para. [0010]).
Regarding claim 4, Gundlach et al. teaches that in a linearized form, the De Bruijn sequence results in a reference sequence that is only 259 nucleotides long and contains all possible quadromers in a contiguous orientation (i.e., the matrix comprises said orientation of said plurality of base pairs) (Para. [0065]). The linear reference sequence design with the De Bruijn sequence was separated into eight distinct segments, which were used as design templates for the synthesis of the reference oligonucleotide constructs (i.e., the matrix comprises said known sequence of said double stranded DNA) (Para. [0066]). Furthermore, each reference oligonucleotide construct was generated with an additional overlap sequence to assist continuity between the signals generated from each reference oligonucleotide construct and to provide that every possible quadromer was presented in a contiguous sequence (i.e., building a matrix comprising said known sequence of said double-stranded DNA) (Para. [0067]).
Regarding claim 9, Gundlach et al. teaches that in practice, a trace obtained for an analyte polymer can be generated in a nanopore system. Each output signal can be compared to the reference map (i.e., said conductance of said unknown sequence of double-stranded DNA is plotted) (Para. [0048]).
Therefore, Gundlach et al. teaches all the limitations in claims 1-2, 4, and 9.
Response to Arguments under 35 U.S.C. 102
Applicant’s arguments filed 12/8/2025 have been fully considered but they are not persuasive.
1. Applicant argues that for step (a), the cited excerpt from paragraph [0044] that "various assay conditions might fluctuate from assay to assay" and "changing conductance caus[es] a variation in the calibration constant" does not disclose the "corresponding to a change in conductance measured as a known sequence of double-stranded DNA is translocated through nanoelectrodes of a DNA sequencer” (Applicant’s Remarks, Pg. 16). Applicant’s arguments are not persuasive for the following reasons:
Gundlach et al. (see Para. [0025]) discloses that “a polymer in a nanopore will generate a unique output signal, such as a current level, that is determined by a single, monomeric subunit of the polymer residing in the pore at each iterative translocation step”. When viewed in combination with “various assay conditions might fluctuate, changing conductance and causing a variation in the calibration constant”, as disclosed by Gundlach et al. in Para. [0044], Gundlach discloses that iterative current / conductance measurements are recorded as a polymer translocates through a nanopore. As disclosed in the rejection above, Gundlach et al. also discloses the translocation of known sequences of DNA through nanoelectrodes (see Para. [0014], [0031], and claim 16). Therefore, under BRI, Gundlach et al. does disclose “corresponding to a change in conductance measured as a known sequence of double-stranded DNA is translocated through nanoelectrodes of a DNA sequencer” as disclosed in instant claim 1. This argument is thus not persuasive.
2. Applicant argues that for step (d), the Examiner cites paragraph [0065] of Gundlach as disclosing step (d), but the Applicant respectfully disagrees because paragraph [0065] does not disclose use of changes in conductance to create a listing (Applicant’s Remarks, Pg. 17). Applicant’s arguments are not persuasive for the following reasons:
Applicant does not provide any arguments regarding why the cited paragraph does not disclose use of changes in conductance to create a listing. Examiner respectfully submits Gundlach et al. does teach step (d). Specifically, Gundlach et al. (see Para. [0065]) discloses the measurement of current / changes in conductance for exemplary DNA quadromers translocating through a nanopore to generate a reference library. The generated current/conductance is therefore correlated to a specific quadromer sequence (i.e., assigning a reference character). While, Gundlach et al. does not use the term “listing”, under BRI, “listing” can correspond to any form of output, and therefore, the compilation of output sequences from different quadromers translocating through the pore falls under the BRI of “create a listing”.
As further support that Gundlach et al. teaches step (d), Gundlach et al. (see Para. [0046]) discloses that the reference library can be used to determine characteristics of an unknown analyte polymer in a nanopore. Gundlach et al. further discloses (see Para. [0047]) that the characteristics ascertained from an analyte polymer can be a sequence pattern that does not provide a primary sequence but merely provides a unique and recognizable pattern of subunit structures, such as a "fingerprint." In this regard, the term "fingerprint" is used to refer to sufficient structural or sequence data that can be used to determine whether two polymers are different or whether they are likely the same. When viewed together, Gundlach et al. discloses the assignment of reference characters (e.g., sequences or fingerprints) corresponding to a change in conductance to create an output listing. Therefore, Gundlach et al. teaches step (d) of “assigning reference characters corresponding to said changes in conductance to create a listing”. This argument is thus not persuasive.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The 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 3, 5, and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Gundlach et al., as applied to claims 1-2, 4, and 9 above, and further in view of Carlsen et al. (Interpreting the Conductance Blockades of DNA Translocations through Solid-State Nanopores. ACS Nano. 8(5): 4754-4760 (2014); published 4/23/2014; previously cited).
This rejection is maintained from the previous office action.
Regarding claim 3, Gundlach et al. teaches that the DNA polymerase pulls the single strand DNA through the nanopores as it incorporates dNTPs to extend the double stranded portion using the single stranded DNA as a template (i.e., converting a known sequence of single-stranded DNA to said double stranded DNA comprising a plurality of base pairs) (Para. [0021]). Gundlach et al. further teaches that in linearized form the De Bruijn sequence results in a reference sequence that is only 259 nucleotides long and contains all possible quadromers in a contiguous orientation (i.e., determining orientations of said plurality of base pairs relative to the first base pair of said plurality of base pairs) (Para. [0065]). Each reference oligonucleotide construct was generated with an additional overlap sequence to assist continuity between the signals generated from each reference oligonucleotide construct (i.e., calculating an equivalent conductance based on said orientations of the plurality of base pairs) and to provide that every possible quadromer was presented in a contiguous sequence (Para. [0067]). Gundlach et al. further teaches that the observed current signals for each iterative movement of a nucleotide subunit were determined by a plurality of nucleotides residing at that time in the pore constriction zone (i.e., calculating an equivalent conductance of each of said plurality of base pairs of said double stranded DNA) (Para. [0064]). Gundlach et al. further teaches a method comprising translocating a reference sequence through a nanopore to generate a plurality of reference output signals. The output signals are ion current through the nanopore and compiled into a reference map for analysis (i.e., the output signals are changes in said conductances in adjacent sections of said double stranded DNA as it is translocated through the pore, and the output signals are associated with sequence reference characters assigned in the reference map) (Abstract and claims 1-2).
Gundlach et al., as applied to claims 1-2, 4, and 9 above, does not teach calculating system conductances of adjacent sections of double stranded DNA; wherein said step of calculating an equivalent conductance of each of said plurality of base pairs of said double stranded DNA comprises the step of selecting a formula based on said orientations of said plurality of base pairs; and wherein said system conductances are equal to a sum of said equivalent conductance of each of said plurality of base pairs within a detection range of said nanoelectrodes.
Regarding claim 3, Carlsen et al. teaches a method of interpreting conductance of DNA translocation through solid state nanopores (Title). Carlsen et al. further teaches that in order to describe the conductance, they used a model in which the nanopore sensing region is composed of three relevant sections: the interior of the nanopore itself and two access regions on either side. The conductance of each access region can be expressed simply as:
G
0
,
a
c
c
=
2
σ
d
p
, where
d
p
is nanopore diameter and
σ
is the conductivity of the solution, defined as
μ
c
a
t
i
o
n
+
μ
a
n
i
o
n
n
e
. Here, n is the number density (proportional to the concentration) of the ionic species, e is the elementary charge, and
μ
c
a
t
i
o
n
and
μ
a
n
i
o
n
are the electrophoretic mobilities of the cation and anion, respectively. The conductance of the pore is:
G
0
,
p
o
r
e
=
π
d
p
2
4
L
e
f
f
(
σ
+
4
S
μ
c
a
t
i
o
n
d
p
)
, where
L
e
f
f
is the effective thickness of the membrane and S is the surface charge density of the nanopore walls. Because the conductances are in series, the total open-pore conductance of the system can be written as:
G
0
,
t
o
t
a
l
=
(
1
G
0
,
p
o
r
e
+
2
G
0
,
a
c
c
)
-
1
(Pg. 4755, Col. 1, Para. 2 – Pg. 4756, Col. 1, Para. 2). Carlsen et al. further teaches the typical conductance trace measured for a 3 kbp double stranded DNA using a 4.5 nm thick, 3.4 nm diameter solid state nanopore (i.e., calculating system conductances of adjacent sections of said double stranded DNA as the DNA moves through the nanopore) (Pg. 4755, Fig. 1).
Regarding claim 5, Carlsen et al. teaches the method of calculating system conductances as described in claim 3 above. Carlsen et al. further teaches two cases with different double stranded DNA (dsDNA) orientations. In case 1, the dsDNA is positioned coaxially with the mouth of the pore such that it interacts with only a single access region. In this case, the total change in conductance is expressed as:
Δ
G
c
a
s
e
1
=
(
1
G
0
,
p
o
r
e
+
1
G
0
,
a
c
c
+
1
G
0
,
a
c
c
,
D
N
A
)
-
1
-
G
0
,
t
o
t
a
l
. In case 2, the dsDNA is present in all three regions of the system, and the total expected conductance change is
Δ
G
c
a
s
e
2
=
(
1
G
p
o
r
e
,
D
N
A
+
2
G
a
c
c
,
D
N
A
)
-
1
-
G
0
,
t
o
t
a
l
(i.e., wherein the step of calculating an equivalent conductance of each of said plurality of base pairs of said double-stranded DNA comprises the step of selecting a formula based on said orientations of said plurality of base pairs) (Pg. 4756, Col. 1, Para. 4 – Col. 2, Para. 1).
Regarding claim 6, Carlsen et al. teaches that for case 2, described above for claim 5, where the DNA is located in the pore and in the two sensing regions, the expected change in conductance is
Δ
G
c
a
s
e
2
=
(
1
G
p
o
r
e
,
D
N
A
+
2
G
a
c
c
,
D
N
A
)
-
1
-
G
0
,
t
o
t
a
l
. The first term shows that the conductance of the plurality of base pairs in the pore is the sum of the pore region and the two sensing regions (i.e., wherein said system conductances are equal to a sum of said equivalent conductance of each of said plurality of base pairs within a detection range of said nanoelectrodes) (Pg. 4759, Col. 2, Para. 1).
Therefore, regarding claims 3, 5, and 6, 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 DNA sequencing using nanopore-based assays of Gundlach et al. with the teachings of Carlsen et al. because the model accurately describes the experimentally measured conductance levels, and provides a possible explanation for the observed voltage dependence (Carlsen et al., Pg. 4758, Col. 2, Para. 2). One of ordinary skill in the art would be able to combine the teachings of Gundlach et al. with Carlsen 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 measuring conductance of DNA in nanopores. Therefore, regarding claims 3, 5, and 6, the instant invention is prima facie obvious (MPEP § 2142).
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Gundlach et al., as applied to claims 1-2, 4, and 9 above, and further in view of Tung et al. (U.S. Patent Application Publication 2017/0152134; published 6/1/2017; previously cited).
This rejection is maintained from the previous office action.
Gundlach et al., as applied to claims 1-2, 4, and 9 above, does not teach wherein said detection range of said nanoelectrodes is determined by a width of the said nanoelectrodes.
Regarding claim 7, Tung et al. teaches that since the internucleotide spacing is only about 0.34 nm for single stranded DNA, the nanoelectrodes must be fabricated on the sub-nanometer scale in order to achieve single nucleotide detection (i.e., wherein said detection range of said nanoelectrodes is determined by a width of said nanoelectrodes) (Para. [0017]).
Therefore, regarding claim 7, 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 DNA sequencing using nanopore-based assays of Gundlach et al. with the teachings of Tung et al. because the nanochannel system achieves rapid DNA sequencing without the use of lengthy sample pre-treatment or DNA replication that is currently used by other DNA sequencing techniques. The system is also much faster and more cost-effective (Tung et al., Para [0020]). One of ordinary skill in the art would be able to combine the teachings of Gundlach et al. with Tung 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 sequencing DNA in nanopores. Therefore, regarding claim 7, the instant invention is prima facie obvious (MPEP § 2142).
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Gundlach et al., as applied to claims 1-2, 4, and 9 above, and further in view of Balan et al. (Improving Signal-to-Noise Performance for DNA Translocation in Solid-State Nanopores at MHz Bandwidths. Nano Letters. 14(12): 7215-7220 (2014); published 11/21/2014; previously cited).
This rejection is maintained from the previous office action.
Gundlach et al., as applied to claims 1-2, 4, and 9 above, does not teach wherein prior to step (b), noise reduction is performed on said unknown sequence of double-stranded DNA.
Regarding claim 8, Balan et al. teaches that by reducing the nanopore chip capacitance to the 1-5 pF range by adding thick insulating layers to the chip surface, they were able to transition to a regime in which input-referred current noise (∼117−150 pArms at 1 MHz in 1 M KCl solution) is dominated by the effects of the input capacitance amplifier itself. The signal-to-noise ratios ranged from 15 to 20 at 1 MHz for double stranded DNA translocations through nanopores with diameters from 4 to 8 nm with applied voltages from 200 to 800 mV (i.e., noise reduction is performed on said unknown sequence of double-stranded DNA) (Abstract).
Therefore, regarding claim 8, 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 DNA sequencing using nanopore-based assays of Gundlach et al. with the teachings of Balan et al. because reducing chip and amplifier capacitances will be essential to further bandwidth enhancements of nanopore measurements. Improved measurement capabilities will have the potential to complement or displace approaches which slow down translocation in DNA sequencing applications, paving the way for human genome sequencing in sub 1 hr. timeframes (Balan et al., Pg 7219, Col. 2, Para. 2). One of ordinary skill in the art would be able to combine the teachings of Gundlach et al. with Balan 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 sequencing DNA in nanopores. Therefore, regarding claim 8, the instant invention is prima facie obvious (MPEP § 2142).
Response to Arguments under 35 U.S.C. 103
Applicant’s arguments filed 12/8/2025 have been fully considered but they are not persuasive.
1. Applicant argues that the Examiner has rejected claims 3 and 5-6 under 35 U.S.C. 103 as being unpatentable over Gundlach and further in view of the Carlsen article ("Carlsen"). Claims 3 and 5-6 contain all of the limitations of claim 1. Gundlach does not teach or suggest all of the limitations of claim 1 for the reasons discussed above, and Carlsen does not teach or suggest all of the limitations missing in Gundlach. Claims 3 and 5-6 therefore are allowable over Gundlach and Carlsen for the same reasons as claim 1 (Applicant’s Remarks, Pg. 17). Applicant’s arguments are not persuasive for the following reasons:
As described in the Response to Arguments under 35 U.S.C. 102 above, Gundlach does teach all of the limitations in claim 1. Since Applicant did not provide any further arguments regarding the rejection of claims 3 and 5-6 over Gundlach in view of Carlsen, this rejection is maintained.
2. Applicant argues that the Examiner has rejected claim 7 under 35 U.S.C. 103 as being unpatentable over Gundlach and further in view of U.S. Published Patent Application No. 2017/0152134 to Tung. Claim 7 contains all of the limitations of claim 1. Gundlach does not teach or suggest all of the limitations of claim 1 for the reasons discussed above, and Tung does not teach or suggest all of the limitations missing in Gundlach. Claim 7 therefore is allowable over Gundlach and Tung for the same reasons as claim 1 (Applicant’s Remarks, Pg. 17-18). Applicant’s arguments are not persuasive for the following reasons:
As described in the Response to Arguments under 35 U.S.C. 102 above, Gundlach does teach all of the limitations in claim 1. Since Applicant did not provide any further arguments regarding the rejection of claim 7 over Gundlach in view of Tung, this rejection is maintained.
3. Applicant argues that the Examiner has rejected claim 8 under 35 U.S.C. 103 as being unpatentable over Gundlach and further in view of the Balan article ("Balan"). Claim 8 contains all of the limitations of claim 1. Gundlach does not teach or suggest all of the limitations of claim 1 for the reasons discussed above, and Balan does not teach or suggest all of the limitations missing in Gundlach. Claim 8 therefore is allowable over Gundlach and Balan for the same reasons as claim 1 (Applicant’s Remarks, Pg. 17). Applicant’s arguments are not persuasive for the following reasons:
As described in the Response to Arguments under 35 U.S.C. 102 above, Gundlach does teach all of the limitations in claim 1. Since Applicant did not provide any further arguments regarding the rejection of claim 8 over Gundlach in view of Balan, this rejection is maintained.
Conclusion
No claims allowed.
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.
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/D.P.S./Examiner, Art Unit 1687
/Lori A. Clow/Primary Examiner, Art Unit 1687