DETAILED ACTION
The Applicant’s response, received 19 February 2026, has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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.
Claims 1-3, 5-15, and 17-20 are rejected.
Claims 4 and 16 are objected to, as noted below.
Allowable Subject Matter
As noted in the Office action mailed 19 November 2025, claims 4 and 16 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Priority
Claims 1-20 are given the benefit of the claim to Provisional Application No. 62/444,656, filed 10 January 2017.
Therefore, the effective filing date of the claimed invention is 10 January 2017.
Terminal Disclaimer
The terminal disclaimer filed on 19 February 2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent 11,100,404 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Claim Interpretation
The claim interpretations in the Office action mailed 19 November 2025 are maintained in view of the Applicant’s amendment and arguments/remarks received 19 February 2026.
Claim 1 recites the limitation “coupled” in line eight. The broadest reasonable interpretation of this limitation encompasses:
connected, either permanently or releasably, whether directly or indirectly through intervening components.
Claims 4 and 16 recite the limitation “wherein the polymerase enzyme molecule is directly conjugated to the electrodes.” The broadest reasonable interpretation of the term “directly conjugated” is interpreted to encompass intervening conjugation chemistry couplings between the enzyme molecule and an electrode, e.g., thiol-gold couplings.
Response to Arguments
The Applicant’s arguments/remarks received 19 February 2026 have been fully considered, but are not persuasive.
The Applicant states on page 6 (para. 2) of the Remarks that while not agreeing or disagreeing with the Office’s description, the Applicant requests that the Office’s construction standard strictly adhere to the broadest reasonable interpretation (BRI) consistent with the specification as defined in §2111 of the MPEP and 37 C.F.R. 1.75(d).
These arguments/remarks are not persuasive, because the claim limitations noted above are given their broadest reasonable interpretations within the context of how a person skilled in the art would understand them.
Claim Objections
The objections to claims 8, 16, and 17 in the Office action mailed 19 November 2025 are withdrawn in view of the Applicant’s amendment received 19 February 2026.
Claim Rejections - 35 USC § 103
As noted in the Office action mailed 19 November 2025, claims 4 and 16 are free of the prior art, because the prior art does not show a polymerase enzyme molecule directly conjugated to a pair of spaced apart electrodes.
The amendment received 19 February 2026 has been fully considered, however after further consideration, the rejection of claims 1, 3, 5-13, 15, 17, 19, and 20 under 35 U.S.C. 103 as being unpatentable over Mansuripur et al. in view of Huang et al. in the Office action mailed 19 November 2025 is maintained in view of the Applicant’s amendment.
The rejection of claims 2, 14, and 18 under 35 U.S.C. 103 as being unpatentable over Mansuripur et al. in view of Huang et al. as applied to claims 1, 3, 5-13, 15, 17, 19, and 20 above, and further in view of Gul et al. in the Office action mailed 19 November 2025 is maintained in view of the Applicant’s amendment received 19 February 2026.
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.
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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 3, 5-13, 15, 17, 19, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Mansuripur et al. (US 2004/0001371, as cited in the Office action mailed 19 November 2025) in view of Huang et al. (US 2015/0017655, as cited in the Information Disclosure Statement (IDS) received 04 April 2021, and as cited in the Office action mailed 19 November 2025).
Regarding independent claims 1, 12, and 17, Mansuripur et al. shows an information storage and retrieval device using macromolecules as storage media (Title); a reading mechanism for converting molecular strands to an electronic signal and a writing mechanism with electro-optical-chemical machinery to create arbitrary sequences of bases, e.g., A, C, G, T molecules for DNA and string them together to form strands of desired length or to modify existing strands to encode the data (para. [0050]). Mansuripur et al. further shows one approach for “writing” comprises a gap between metal electrodes that was spanned by single DNA strands that were attached by hybridization to complementary oligonucleotides anchored to the electrodes (para. [0087]). Regarding the limitation “interpreting the nucleotide sequence through the interaction of the polymerase and the nucleotide sequence,” Mansuripur et al. further shows that as for enzymes that could perform the task of attaching individual nucleic-acid bases to a growing DNA strand, it is well-known that DNA polymerase, reverse transcriptase, and telomerase are enzymes that carry out exactly this task (para. [0071]).
Regarding independent claims 1, 12, and 17, Mansuripur et al. does not show a polymerase enzyme molecule coupled to the electrodes in a molecular electronics circuit.
Regarding independent claims 1, 12, and 17, Huang et al. shows a polymerase enzyme molecule coupled to space apart electrodes in a molecular electronics circuit (Figure 2; and paras. [0022] – [0024]).
Regarding claims 5, 13, and 19, Mansuripur et al. further shows a device and method for the storage and retrieval of arbitrary sequences of binary information (para. [0012]).
Regarding claim 6, Mansuripur et al. further shows the information is encoded in long strands of biological or non-biological molecules such as artificial DNA, RNA or other synthetic molecules that form a macromolecule (Abstract).
Regarding claim 7, Mansuripur et al. further shows adding redundancy for error correction (para. [0047]).
Regarding claims 8 and 10, Mansuripur et al. further shows using CMOS processing (i.e., the semiconductor technology used in integrated circuits) and chemical synthesis technologies used to synthesize the molecules (para. [0019]).
Regarding claim 20, Mansuripur et al. further shows that DNA consists of four bases which can be used to represent 2-bit sequences in a quaternary system (para. [0013]).
Mansuripur et al. does not show the polymerase enzyme molecule is coupled to each electrode by two arm molecules, one attached to each electrode, wherein the arm molecules are conjugated to two distinct sites on the polymerase enzyme (claims 3 and 15); the measurable electrical parameter of the sensor is modulated by enzymatic activity of the polymerase enzyme molecule (claim 9); or the molecular electronics sensor further comprises a gate electrode adjacent the spaced apart electrodes (claim 11).
Regarding dependent claims 3 and 15, Huang et al. further shows a protein transistor for providing conductance readings by holding a polymerase during synthesis of a new strand (Figure 2; and para. [0022]); spaced apart electrodes with a source electrode 11, a drain electrode 12, and a gate electrode 13, gold nanoparticles 20 and 30, and a DNA polymerase 60 connected to antibody molecules which are connected to the gold nanoparticles located at the edges of the electrodes (paras. [0023], [0024], & [0025]).
Regarding claim 9, Huang et al. further shows that single-molecule sequencing can be achieved by monitoring the conductance of a polymerase during the synthesis of a growing DNA strand (para. [0037]).
Regarding claim 11, Huang et al. further shows spaced apart electrodes with a source electrode 11, a drain electrode 12, and a gate electrode 13 (Figure 2; and para. [0023]).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method shown by Mansuripur et al. by incorporating methods for conjugating a polymerase to the electrodes using intervening components (e.g., molecular arms, e.g., antibody molecules) to achieve single-molecule sequencing, as shown by Huang et al., and discussed above. One of ordinary skill in the art would have been motivated to combine the methods of Mansuripur et al. with the methods of Huang et al., because Huang et al. shows a method for connecting a polymerase to a protein transistor using molecular arms allowing for the direct measurement of the electrical conductivity of the polymerase, and that is suitable for sequencing complex nucleic acids (Abstract). This modification would have had a reasonable expectation of success given that both Mansuripur et al. and Huang et al. disclose sequencing methods for achieving single-base molecular resolution.
Claims 2, 14, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Mansuripur et al. in view of Huang et al. as applied to claims 1, 3, 5-13, 15, 17, 19, and 20 above, and further in view of Gul et al. (Biosensors, 2016, Vol. 6, No. 29, pp. 1-19, as cited in the Office action mailed 19 November 2025).
Mansuripur et al. in view of Huang et al. as applied to claims 1, 3, 5-13, 15, 17, 19, and 20 above, does not show the polymerase enzyme molecule is coupled to each electrode by a single bridge molecule attached to and connecting the electrodes, wherein the polymerase enzyme is conjugated to the bridge molecule (claims 2, 4, and 18).
Gul et al. shows single molecule bioelectronics and their application to amplification-free measurement of DNA lengths (Title); and further shows the operation of single-enzyme transistors made using single-walled carbon nanotubes that transduce the motions and catalytic activity of a single protein into an electronic signal for real-time monitoring of the protein’s activity (Abstract), and further shows as one example of a nanocircuit technique, using the Klenow Fragment of DNA polymerase I as it catalytically processes single-stranded DNA templates with single-base sensitivity (Abstract). Gul et al. further shows the Klenow Fragment (i.e., a polymerase enzyme probe molecule) as being coupled to spaced apart electrodes in a molecular electronics circuit (Figure 1(a)).
Regarding dependent claims 2, 14, and 18, Gul et al. shows the Klenow Fragment (i.e., a polymerase enzyme probe molecule) as being coupled to a single bridge molecule (i.e., the single-walled carbon nanotube) that connects the spaced apart electrodes in a molecular electronics circuit (Figure 1(a)).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method shown by Mansuripur et al. in view of Huang et al. as applied to claims 1, 3, 5-13, 15, 17, 19, and 20 above, by incorporating methods for using single-enzyme transistors made using a single-walled carbon nanotube (i.e., a single bridge molecule connecting the electrodes) as shown by Gul et al., and discussed above. One of ordinary skill in the art would have been motivated to combine the methods of Mansuripur et al. in view of Huang et al. as applied to claims 1, 3, 5-13, 15, 17, 19, and 20 above, with the methods of Gul et al., because Gul et al. shows that such single-enzyme transistors can be used to transduce the motions and catalytic activity of a single protein (i.e., the Klenow Fragment polymerase) into an electronic signal for real-time monitoring of the protein’s activity, e.g., catalytically processing single-stranded DNA templates. This modification would have had a reasonable expectation of success given that Mansuripur et al. in view of Huang et al. as applied to claims 1, 3, 5-13, 15, 17, 19, and 20 above, discloses methods that require detecting individual bases or a collection of bases directly from a molecular strand in order to read out encoded data, and Gul et al. discloses using a polymerase coupled to a single-walled carbon nanotube (i.e., a single bridge molecule connecting the electrodes) for catalytically processing single-stranded DNA templates, wherein the fidelity of DNA polymerases makes them a key component in many DNA sequencing techniques due to their single-base sensitivity; and further reasonable expectation of success because a single-walled carbon nanotube is used in biosensors because of high strength, flexibility, and conductivity, which allows for measurements to extend for many more minutes and the ability to resolve individual nucleotide incorporation for many more events.
Response to Arguments
The Applicant’s arguments/remarks received 19 February 2026 have been fully considered, but are not persuasive.
The Applicant summarizes aspects of the MPEP regarding obviousness rejections on page 6 (bottom) and page 7 (top) of the Remarks, and provides a brief summary of Mansuripur (i.e., primary reference) on page 7 (para. 2) and states that the base detection mechanism in Mansuripur is fundamentally passive and does not require a polymerase-mediated electrochemical interaction as recited in each of the independent claims. The Applicant further provides a brief summary of Huang (i.e., secondary reference) and states (para. 3) that base detection in Huang is achieved by monitoring enzyme-mediated biochemical interactions during controlled nucleotide incorporation, rather than by the physical translocation of a strand through a pore, and further states (para. 4) that modifying Mansuripur in view of Huang would require fundamental changes to the primary reference that are neither contemplated by Mansuripur nor evidenced in a manner that would suggest success. The Applicant further states that Mansuripur is directed to passive physical detection (i.e., ionic current blockade or tunneling probe detection) and data is written via one of several mechanisms which produce a DNA strand in which data is synthesized base-by-base, and further states on page 8 (para. 2) that the read mechanisms disclosed in Mansuripur rely on proximity detection of the electromagnetic field generated by each base of the strand, and as the strand passes through the nanopore, each base partially blocks ionic current, causing a fluctuation corresponding to the specific base under detection. The Applicant further states that Mansuripur contemplates a passive, non-enzymatic read mechanism, whereas in contrast, modifying Mansuripur in view of Huang requires changing the read mechanism to an active mechanism in which a base interacts with an enzyme. The Applicant further states that there is no evidence in the cited references to suggest this proposed change would be functional, and thus, the asserted obviousness is, at best, an “obvious-to-try” argument unsupported by extrinsic evidence of efficacy. The Applicant further states (para. 3) that moreover, the proposed modification of Mansuripur in view of Huang would require changing the transport means contemplated by the primary reference, and that specifically, Mansuripur’s transport mechanism would have to be modified to accommodate a polymerase positioned at the strand, a primer-template complex, and a suitable environment for controlled nucleotide incorporation, and that the latter is a highly unpredictable environment requiring extensive modification and experimentation. The Applicant further states that this is more than a simple substitution of a sequencing-by-incorporation system into a nanopore detection system; it is a change in the principle of operation. The Applicant further states that the Office has provided no explanation or reasoning as to why such a substitution would be desirable, feasible, or successful, and (para. 4) for at least these reasons, a prima facie case of obviousness has not been made.
These arguments are not persuasive, because first, with regard to the Applicant’s argument that the base detection mechanism in Mansuripur is fundamentally passive and does not require a polymerase-mediated electrochemical interaction as recited in each of the independent claims, it is noted in response that Mansuripur et al. shows that as for enzymes that could perform the task of attaching individual nucleic-acid bases to a growing DNA strand, it is well-known that DNA polymerase, reverse transcriptase, and telomerase are enzymes that carry out exactly this task (para. [0071]).
Second, with regard to the Applicant’s argument that base detection in Huang is achieved by monitoring enzyme-mediated biochemical interactions during controlled nucleotide incorporation, rather than by the physical translocation of a strand through a pore, and further states (para. 4) that modifying Mansuripur in view of Huang would require fundamental changes to the primary reference that are neither contemplated by Mansuripur nor evidenced in a manner that would suggest success, it is noted in response that Huang et al. at least shows that an alternative third-generation technology is the nanopore sequencing technology, which uses a special protein to perforate nanopores in a membrane, and which identifies the sequence of nucleotides (T, C, G, and A) of a DNA molecule by measuring the modulations in the ionic current across a synthetic or biological pore while the DNA molecule is driven through it under an applied potential, and this technique has been used to read DNA at single-nucleotide resolution by using a particular DNA polymerase to control the rate of DNA translocation through the pore (para. [0007]). Thus, as noted in the motivation statement in the above rejection, one of ordinary skill in the art would have been motivated to combine the methods of Mansuripur et al. with the methods of Huang et al., because Huang et al. shows a method for connecting a polymerase to a protein transistor using molecular arms allowing for the direct measurement of the electrical conductivity of the polymerase, and that is suitable for sequencing complex nucleic acids, and that this modification would have had a reasonable expectation of success given that both Mansuripur et al. and Huang et al. disclose sequencing methods for achieving single-base molecular resolution (e.g., nanopore sequencing).
Third, with regard to the Applicant’s argument that Mansuripur is directed to passive physical detection (i.e., ionic current blockade or tunneling probe detection) and data is written via one of several mechanisms which produce a DNA strand in which data is synthesized base-by-base, and further states on page 8 (para. 2) that the read mechanisms disclosed in Mansuripur rely on proximity detection of the electromagnetic field generated by each base of the strand, and as the strand passes through the nanopore, each base partially blocks ionic current, causing a fluctuation corresponding to the specific base under detection, it is noted in response that the combination of references is applied to show that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method shown by Mansuripur et al. by incorporating methods for conjugating a polymerase to the electrodes using intervening components (e.g., molecular arms, e.g., antibody molecules) to achieve single-molecule sequencing, as shown by Huang et al., and discussed above.
Fourth, with regard to the Applicant’s argument that Mansuripur contemplates a passive, non-enzymatic read mechanism, whereas in contrast, modifying Mansuripur in view of Huang requires changing the read mechanism to an active mechanism in which a base interacts with an enzyme. The Applicant further states that there is no evidence in the cited references to suggest this proposed change would be functional, and thus, the asserted obviousness is, at best, an “obvious-to-try” argument unsupported by extrinsic evidence of efficacy, it is noted in response that XXX
Fifth, with regard to the Applicant’s argument that the proposed modification of Mansuripur in view of Huang would require changing the transport means contemplated by the primary reference, and that specifically, Mansuripur’s transport mechanism would have to be modified to accommodate a polymerase positioned at the strand, a primer-template complex, and a suitable environment for controlled nucleotide incorporation, and that the latter is a highly unpredictable environment requiring extensive modification and experimentation. The Applicant further states that this is more than a simple substitution of a sequencing-by-incorporation system into a nanopore detection system; it is a change in the principle of operation. The Applicant further states that the Office has provided no explanation or reasoning as to why such a substitution would be desirable, feasible, or successful, it is noted that Mansuripur et al. shows that as for enzymes that could perform the task of attaching individual nucleic-acid bases to a growing DNA strand, it is well-known that DNA polymerase, reverse transcriptase, and telomerase are enzymes that carry out exactly this task (para. [0071]).
Double Patenting
The rejection of claims 1, 2, 5, 6, 7, 9, 11, 12, 13, 14, 17, 18, 19, and 20 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, and 19 of U.S. Patent No. 11,100,404 B2 in view of Gul et al. in the Office action mailed 19 November 2025 is withdrawn in view of the Terminal Disclaimer received 19 February 2026.
The rejection of claims 3 and 15 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, and 19 of U.S. Patent No. 11,100,404 B2 in view of Huang et al. in the Office action mailed 19 November 2025 is withdrawn in view of the Terminal Disclaimer received 19 February 2026.
The rejection of claims 8 and 10 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, and 19 of U.S. Patent No. 11,100,404 B2 in view of Mansuripur et al. in view of Huang et al. in the Office action mailed 19 November 2025 is withdrawn in view of the Terminal Disclaimer received 19 February 2026.
Conclusion
No claims are allowed.
Claims 4 and 16 are free of the prior art, as noted above.
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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/S.W.B./Examiner, Art Unit 1687
/Joseph Woitach/Primary Examiner, Art Unit 1687
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