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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April has been entered.
Status of Objections and Rejections
All rejections from the previous office action are maintained.
Examiner’s Notes
Applicant elected Group I, claims 1, 7-9, 11-13, 18-19, 26-30, 32, 41-45, 47-49, drawn to a device for nucleic acid sequencing in the reply filed on August 4, 2025. Based on Applicant’s election, claims 34-40 are withdrawn from further consideration as non-elected claims.
Applicant further elected Species A, drawn to the disintegrator configured to apply chemical hydrolysis, e.g., claims 28 and 37, as requested in the previous Office action sent on June 16, 2025 in the same reply. Based on Applicant’s election, claims 29-30, 32, and 48-49 are withdrawn (claims 29 and 48 directed to Species B and claims 30, 32, and 49 directed to Species C as exemplified in the previous Office action sent on June 16, 2025) from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected Species B-C. Further, claims 9 and 11 belong to Species B that the disintegrator uses a power source to induce electrolysis (PGpub, Fig. 5A; ¶¶40, 69, 125), and they are considered as non-elected Species B. Since Examiner did not include claims 9 and 11 as example claims for Species B in the previous Office action sent on June 16, 2025, Examiner included rejections on claims 9 and 11 in the Office Action sent on August 18, 2015 merely for the purpose of compact prosecution (See Office Action on August 18, 2025, p. 3, para. 1 that explicitly indicated that claims 9 and 11 would be excluded in the further prosecution). Applicant did not argue that claims 9 and 11 are non-elected Species B in its reply, and thus claims 9 and 11 are excluded from consideration as non-elected claims.
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1, 7-8, 12-13, 18, and 41-42 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by So (US 2020/0038868).
Regarding claim 1, So teaches a device for nucleic acid sequencing (¶1), the apparatus comprising:
a substrate (Fig. 10A, 11: the middle layer at the bottom of the microfluidic channel 1010 and the nanofluidic channel 1013; more specifically, Fig. 6B; ¶46: the dielectric layer 607);
a fluidic channel (Fig. 11: the fluidic channel starting from the sample in, through the horizontal microfluidic, then horizontal nanofluidic channel, then vertical channel embedded with a nanopore, then horizontal microfluidic channel to the sample out) having a bottom surface defined by a top side of the substrate (since the dielectric layer 607 on the thin film (including two layers 604 and the middle layer 605) having a nanopore 603, as shown in Fig. 6B, it would have a top side that serves as the bottom of the nanofluidic channel 1013 as shown in Fig. 11);
a disintegrator (Fig. 10A, 11; ¶53: the nanofluidic channel 1013, corresponding to Fig. 14; ¶60: embodiments for straightening the dsDNA; Fig. 14A: dissociation zone 1405) configured to cleave off a portion of a nucleic acid in the fluidic channel (¶25: in dissociation zone 1405, heating causes the DNA to dissociate into short strands of DNA; ¶60: the dissociation can be achieved by heating or enzymes);
a membrane situated on a back side of the substrate (Fig. 6B; ¶46: the thin film may consist of at least three layers comprising two conductive layers 604 sandwiching a dielectric layer 605; here, the thin film is situated on a back side of the dielectric layer 607), the back side of the substrate being distal from the top side of the substrate (Fig. 6B: the back side of the dielectric layer 607, i.e., the bottom side, is distal from the top side of the dielectric layer 607), the membrane comprising a nanopore (Fig. 6B: the nanopore 603 is embedded in the thin film comprising two conductive layers 604 sandwiching a dielectric layer 605) coupled to the fluidic channel at an exit end of the vertical portion of the fluidic channel (Fig. 11: indicating the nanopore at the exit end of the vertical portion);
a first electrode (Fig. 11-12; ¶54: the top driving electrode 1230); and
a second electrode (Fig. 11-12; ¶54: the top driving electrode 1235);
wherein:
the first electrode and the second electrode are situated to apply an electrostatic force on the portion of the nucleic acid to divert the portion of the nucleic acid out of the fluidic channel and through the nanopore (¶54: by alternating the magnitude of the DC biasing voltages is applied to the top and bottom driving electrodes 1230 and 1235, respectively, the molecule under test can be drawn through the nanopore 1225 back and forth multiple times for repeated analyses)
Further, the designation “to apply an electrostatic force on the portion of the nucleic acid to divert the portion of the nucleic acid out of the fluidic channel and through the nanopore” is deemed to be functional limitation in apparatus claims. MPEP 2114 (II). "[A]pparatus claims cover what a device is, not what a device does." Hewlett-Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464, 1469, 15 USPQ2d 1525, 1528 (Fed. Cir. 1990) (emphasis in original). A claim containing a "recitation with respect to the manner in which a claimed apparatus is intended to be employed does not differentiate the claimed apparatus from a prior art apparatus" if the prior art apparatus teaches all the structural limitations of the claim. Ex parte Masham, 2 USPQ2d 1647 (Bd. Pat. App. & Inter. 1987).
Regarding claim 7, So teaches wherein:
the fluidic channel comprises a horizontal portion and a vertical portion (Fig. 11: the fluidic channel starting from the sample in, through the horizontal microfluidic channel, then horizontal nanofluidic channel, then vertical channel embedded with a nanopore), and
the nanopore is situated at an exit end of the vertical portion of the fluidic channel (Fig. 6B; 11: indicating the nanopore at the exit end of the vertical portion).
Regarding claim 8, So teaches wherein the first electrode is situated along the horizontal portion of the fluidic channel (Fig. 12: indicating the top driving electrode 1230 is along the horizontal direction) and the second electrode is situated on an exit side of the nanopore (Fig. 12: indicating the bottom driving electrode 1235 is on the exit side, i.e., the bottom side, of the nanopore 1225)
Regarding claim 12, So teaches the device further comprising a straightener coupled to or situated in the fluidic channel (Fig. 10A, 11: the microfluidic channel 1010 and the nanofluidic channels 1013 having sample guiding electrodes 1015 in between, which is situated in the horizontal portion of the fluidic channel as shown in Fig. 11; also see Fig. 14A: the left section for straightening the DNA molecule from the chamber 1401 to the channel with guiding electrodes 1404 is deemed to be the straightener).
Regarding claim 13, So teaches wherein the straightener comprises a quasi-two- dimensional structure (e.g., Fig. 14A; ¶25: a DNA pump 1403 defined as a DNA-translocating protein).
Regarding claim 18, So teaches wherein the straightener comprises a three- dimensional structure (e.g., Fig. 14B; ¶26: an array of micro/nanopillars 1407).
Regarding claim 41, So teaches an apparatus for nucleic acid sequencing (¶1), the apparatus comprising:
a substrate (Fig. 11: the middle layer at the bottom of the microfluidic channel 1010 and the nanofluidic channel 1013; more specifically, Fig. 6B; ¶46: the dielectric layer 607);
a fluidic channel (Fig. 11: the fluidic channel starting from the sample in, through the horizontal microfluidic channel, then horizontal nanofluidic channel, then vertical channel embedded with a nanopore, then horizontal microfluidic channel to the sample out) comprising a horizontal portion (Fig. 11: the horizontal channels) and a vertical portion (Fig. 11: the vertical channel embedded with a nanopore), wherein the horizontal portion includes a bottom surface defined by a top side of the substrate (since the dielectric layer 607 on the thin film (including two layers 604 and the middle layer 605) having a nanopore 603, as shown in Fig. 6B, it would have a top side that serves as the bottom of the nanofluidic channel 1013 as shown in Fig. 11);
a straightener coupled to or situated in the horizontal portion of the fluidic channel (Fig. 10A, 11: the microfluidic channel 1010 and the nanofluidic channels 1013 having sample guiding electrodes 1015 in between, which is situated in the horizontal portion of the fluidic channel as shown in Fig. 11; also see Fig. 14A: the left section for straightening the DNA molecule from the chamber 1401 to the channel with guiding electrodes 1404 is deemed to be the straightener);
a disintegrator (Fig. 10A, 11; ¶53: the nanofluidic channel 1013, corresponding to Fig. 14; ¶60: embodiments for straightening the dsDNA; Fig. 14A: dissociation zone 1405) situated in the horizontal portion of the fluidic channel downstream of the straightener (Fig. 14A; ¶60: an embodiment for straightening the DNA; thus, the DNA stretcher of Fig. 14A would be coupled to or situated in the horizontal portion of the fluidic channel), wherein the disintegrator is configured to cleave off a portion of a nucleic acid in the fluidic channel (¶25: in dissociation zone 1405, heating causes the DNA to dissociate into short strands of DNA; ¶60: the dissociation can be achieved by heating or enzymes); and
a membrane situated on a back side of the substrate (Fig. 6B; ¶46: the thin film may consist of at least three layers comprising two conductive layers 604 sandwiching a dielectric layer 605; here, the thin film is situated on a back side of the dielectric layer 607), the back side of the substrate being distal from the top side of the substrate (Fig. 6B: the back side of the dielectric layer 607, i.e., the bottom side, is distal from the top side of the dielectric layer 607), the membrane comprising a nanopore (Fig. 6B: the nanopore 603 is embedded in the thin film comprising two conductive layers 604 sandwiching a dielectric layer 605) coupled to the fluidic channel at an exit end of the vertical portion of the fluidic channel (Fig. 11: indicating the nanopore at the exit end of the vertical portion).
Regarding claim 42, So teaches wherein the straightener comprises a plurality of pillars (Fig. 14B; ¶26: an array of micro/nano-pillars 1407).
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over So in view of Gumbercht (US 2016/0153105).
Regarding claim 19, So discloses all limitations of claim 18. So further teaches the three-dimensional structure comprises a funnel packed with an array of micro/nanopillars 1407 (Fig. 14B; ¶26). So does not disclose a plurality of spheres.
However, Gumbercht teaches a nanopore for sequencing a biopolymer, such as a nucleic acid or a protein (¶2). A better control of the translocation speed of the nucleic acid strands may be expected as a result of a packing of nanoparticles 16, 16’ (e.g., Fig. 2A; ¶76), which are spheres.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified So by substituting the micro/nanopillars within the funnel-shaped DNA straightening channel with packed nanoparticles as taught by Gumbercht because the translocated biopolymer through the nanopore would be straightened and the substitution of one known element, i.e., packed spheres, for another, i.e., the packed micro/nanopillars would yield nothing more than predictable results. MPEP 2141(III)(B).
Claim(s) 26-28, 45 and 47 is/are rejected under 35 U.S.C. 103 as being unpatentable over So in view of Soper (US 2021/0268503).
Regarding claims 26, 28 and 45, 47, So discloses all limitations of claims 1 and 41, respectively, but fails to teach wherein the disintegrator comprises a catalytic moiety embedded in the fluidic channel (claims 26, 45) or wherein the disintegrator is configured to apply chemical hydrolysis (claims 28, 47).
However, Soper teaches nanopores used to detect and/or analyze analyte(s) following processing by the sample processing region (¶5). In the sample processing region, the sample handling include chemical modification (e.g., ligase, cleavage, polymerase, and/or chemical derivatization/hybridization) of an analyte of interest (¶5). For cleavage, a cleaving enzyme is immobilized to the support structure within the sample processing region (¶9). An example of the cleaving enzyme is an exonuclease (¶9). An exonuclease encompasses any enzyme capable of catalyzing the hydrolysis of a single nucleotide from the end of a DNA or RNA molecules (¶97).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified So by incorporating a catalytic moiety, e.g., a cleaving enzyme exonuclease for cleaving DNA/RNA molecules by hydrolysis, as taught by Soper because the cleaving enzyme is suitable for cleaving DNA/RNA molecules as an alternative for dissociation of the molecules. Here, the substitution is obvious because the use of a cleavage enzyme instead of the use of heating to dissociating DNA/RNA molecules would yield nothing more than predictable results. MPEP 2141(III)(B). Further, applying a known technique to a known device ready for improvement to yield predictable results is prima facie obvious. MPEP 2141(III)(D).
Regarding claim 27, So and Soper disclose all limitations of claim 26. So does not disclose wherein the catalytic moiety comprises a divalent cation.
However, Soper teaches the cleaving enzyme may require activation, e.g., Mg2+ contained in the buffer (¶91), which is a divalent cation
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified So by incorporating a catalytic moiety, e.g., a cleaving enzyme activated by a divalent cation (Mg2+) for cleaving DNA/RNA molecules, as taught by Soper because the divalent cation (Mg2+) would activate the cleaving enzyme to enable the cleavage (¶91). Here, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results. MPEP 2143(I)(A).
Claim(s) 43-44 is/are rejected under 35 U.S.C. 103 as being unpatentable over So in view of Wang (C. Wang, Clog-Free Translocation Of Long DNA In Nanofluidic Pillar Arrays And 30 NM Wide Channels: A Fabrication And Hydrodynamic Study, 18th International Conference on Miniaturized Systems for Chemistry and Life Sciences October 26-30, 2014, San Antonio, Texas, USA; pp. 1347-49).
Regarding claim 43, So discloses all limitations of claim 42, but fails to teach wherein a dimension of a first pillar of the plurality of pillars is a first value, and a corresponding dimension of a second pillar of the plurality of pillars is a second value, wherein the second value is larger than the first value.
However, Wang teaches a nanofluidic devices comprising diamond-shaped nanopillars through which long DNAs are successfully translocating and the translocation speed can be tuned ([Abstract]). The nanopillars have different dimensions so that pillar gaps are progressively reduced, functioning as cascaded microchannels and nanochannels to prestretch the DNA (Fig. 2; p. 1348, para. 1). Thus, Wang teaches the dimension of a second pillar (Fig. 2(b): pillar 1 having a dimension of 6.35 µm) is larger than the dimension of a first pillar (Fig. 2(b): pillar 2 having a dimension of 3.25 µm).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified So by adjusting the pillars’ dimensions into two different values as taught by Wang because such dimensions would successfully translocate long DNAs with tunable translocation speed ([Abstract]) and the reduced nanochannel dimensions would enable nearly 100% stretching of DNA (p. 1348, para. 1). Here, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results. MPEP 2143(I)(A).
Regarding claim 44, So and Wang disclose all limitations of claim 43. Since So teaches the dissociation zone is downstream of the straightening zone (So, Fig. 14A), and Wang teaches the DNA molecules translocate through pillar 1, pillar 2, pillar ¾, and then into the nano-channels (Fig. 2; p. 1348, para. 1). Thus, the combined So and Wang would necessarily result in the first pillar (Fig. 2: pillar 2) being closer to the downstream disintegrator than the second pillar (Fig. 2: pillar 1), i.e., a less distance.
Response to Arguments
Applicant’s arguments have been considered but are unpersuasive.
Applicant argues So does not teach a substrate and a membrane situated on a back side of the substrate and having a nanopore (Response, pp. 9-10; also see pp. 12-14 for claim 41). Applicant argues the thin film itself constitutes the nanopore membrane (p. 10, para. 3), and the dielectric layer 605 cannot be read as the substrate (p. 11, para. 1). Examiner notes, in the instant rejection, that the dielectric layer 607 is read as the substrate, and the thin film consisting of two conductive layers 604 sandwiching a dielectric layer 605 (Fig. 6B; ¶46) is read as the membrane with a nanopore embedded in.
Applicant argues So does not disclose that the first electrode and the second electrode are situated to apply an electrostatic force on the portion of the nucleic acid to divert the portion of the nucleic acid out of the fluidic channel and through the nanopore (pp. 11-12). First, this limitation does not explicitly recite the locations on which the two electrodes are situated, but merely recites the function of these two electrodes based on their locations. Examiner suggest further amending the claim to specify their locations. Second, So is relied on to teach a first electrode (Fig. 12A: top driving electrode 1230) and a second electrode (Fig. 12: bottom driving electrode 1235). By alternating the magnitude of the DC biasing voltages is applied to the top and bottom driving electrodes 1230 and 1235, respectively, the molecule under test can be drawn through the nanopore 122.5 back and forth multiple times for repeated analyses (So, ¶54), which is better to anticipate the limitation “situated to apply an electrostatic force on the portion of the nucleic acid to divert the portion of the nucleic acid out of the fluidic channel and through the nanopore.”
Applicant argues So discloses the structure associated with straightening DN A in separate embodiments (e.g., So, Fig. 14A, ¶60) in pp. 15-16. This argument is unpersuasive. These teaching are not separate embodiments exclusive to each other. Instead, Fig. 10A and 11 show the microfluidic channel 1010, the sample guiding electrodes 1015, and the nanofluidic channel 1013 (corresponding to Fig. 14, ¶60: embodiments for straightening the dsDNA), and measurement chambers 1030 (Fig. 10A, corresponding to the right portion with a nanopore in Fig. 11 and unshown downstream portion in Fig. 14A). Thus, the straightening and dissociation are both located in the horizontal portion and the nanopore is located in the vertical portion.
In response to Applicant’s arguments regarding Gumbercht (pp. 17-19), Examiner notes that Gumbercht provides an alternative structure, using nanospheres, to stretch nucleic acid strands, in a better controllable way (e.g., Fig. 2A: ¶76), and thus would motivate one of ordinary skill in the art to substitute the micro/nanopillars of So with the nanospheres as taught by Gumbercht because they are pertinent to the same issue and the substitution would not yield unexpected or surprising results. MPEP 2141(III)(B).
Similarly, in response to Applicant’s arguments regarding Soper (pp. 19-21), Examiner notes that So teaches the methods of dissociation include heating or enzymes (So, ¶60), which indicates they are two alternative approaches to obtain the same results. In addition, Soper teaches using an exonuclease enzyme for cutting a single nucleotide from the end of DNA molecules by hydrolysis (Soper, ¶97) in the presence of Mg2+ (¶91) before passing through nanopores (Fig. 5B). Thus, the teachings of So and Soper would motivate one of ordinary skill in the art to substitute the heating method of So with the hydrolysis method using an enzyme as taught by Soper because they are pertinent to the same issue and the substitution would not yield unexpected or surprising results. MPEP 2141(III)(B).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAITLYN M SUN whose telephone number is (571)272-6788. The examiner can normally be reached on M-F: 8:30am - 5:30pm.
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/C. SUN/Primary Examiner, Art Unit 1795
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