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 .
Response to Applicant Reply
This office action is in response to Applicant’s reply of 15 July 2026. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance.
Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
This action is made FINAL.
Claim Status
Claims 51-55 and 57-68 are pending and under examination.
Claims 1-50, 56, and 69-70 are canceled.
Withdrawn Objections and Rejections
All objections to the specification in the office action mailed 19 March 2026 are withdrawn in view of the amendment to the specification filed 15 July 2026.
All rejections of claim 56 in the office action mailed 19 March 2026 are withdrawn in view of the cancelation of claim 56 in the amendment to the claims filed 15 July 2026.
Except for the maintained rejections of claims 57, 62, 63, and 65 under 35 U.S.C. 112(b) (see Response to Arguments subsection of the Claim Rejections - 35 U.S.C. 112(b) - Indefiniteness section below), all other rejections under 35 U.S.C. 112(b) in the office action mailed 19 March 2026 are withdrawn in view of the amendment to the claims filed 15 July 2026.
The rejection of claim 62 under 35 U.S.C. 112(d) in the office action mailed 19 March 2026 is withdrawn in view of the amendment to the claims filed 15 July 2026.
The rejections of claims 51-55 and 57-68 under either 35 U.S.C. 102 or 35 U.S.C. 103 are withdrawn in view of the amendment to the claims filed 15 July 2026 (see Response to Arguments subsection of the Claim Rejections - 35 U.S.C. 103 section below). However, a new ground of rejection of these claims is made under 35 U.S.C. 103 as necessitated by the amendment to claim 51.
Claim Objections
Claims 62-63 and 68 are objected to because of the following informalities:
Claim 62 recites “first stand” on line 11, which should read “first strand”.
Claim 63 recites “first stand” on line 11, which should read “first strand”.
Claim 68 recites “enzyme ,wherein” on line 3, which should read “enzyme, wherein”.
Appropriate correction is required.
Claim Interpretation
New - Necessitated by Amendment
Claim 51 recites in step (iii) “(a) where the first part of the polynucleotide has a length above a threshold length” and “(b) where the first part of the polynucleotide has a length below the threshold length” in lines 10-11 and 14-16, each followed by a step that is taken in the respective case. These are clearly contingent limitations, since the steps recited after these phrases are only done in the cases where the length is above or below a threshold length. However, no step is taken if the length assessed in step (ii b) is equal to the threshold length. MPEP §2111.04(II) states: “The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met”. Therefore, because the method can be performed without performing either step (iii)(a) or (iii)(b) in the case that the length is equal to the threshold length, the broadest reasonable interpretation of claim 51 (and claims 52-55 and 57-68 that depend on claim 51) does not require step (iii). Amending either lines 10-11 to read “a length equal to or above a threshold length” or lines 14-16 to read “a length equal to or below the threshold length” would lead to step (iii) being interpreted as a required step because there would no longer be a case where the step is not performed.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
Maintained
Claims 57, 62-63, and 65 are 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.
Regarding claim 57, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The phrase “preferably […] polynucleotide” in lines 2-5 is considered an optional limitation.
Claim 62 recites the limitation "the polynucleotide is single-stranded" in line 3 and “the double-stranded polynucleotide” in line 10. These conflicting limitations render unclear the metes and bounds of the claim. For the purpose of examination, claim 62 is interpreted as requiring that the polynucleotide comprises both single-stranded and double-stranded regions.
Claim 62 recites the limitation "the first strand" in line 10. There is insufficient antecedent basis for this limitation in the claim.
Claim 63 recites the limitation "the polynucleotide binding protein" in line 8. There is insufficient antecedent basis for this limitation in the claim.
Claim 65 recites the limitation "the portion having an oligonucleotide hybridised thereto" in line 4. There is insufficient antecedent basis for this limitation in the claim.
Response to Arguments
Applicant’s arguments, see page 9 of the Remarks, filed 15 July 2026, with respect to the rejection(s) of claim(s) 51-68 under 35 U.S.C. 112(b) have been fully considered and are persuasive in-part.
The arguments are not persuasive with regard to the above maintained rejections of claims 57, 62-63, and 65 because (1) in claim 57, the term “preferably” was not removed, (2) in claim 62, the conflicting limitations that define the polynucleotide as single-stranded and double-stranded are still present, and (3) in claims 62 and 63 the limitations recited in the rejections above still lack antecedent basis. Applicant only argued that the amendment to the claims renders the 112(b) rejections moot without any argument for why the identified limitations do not render the claims indefinite. Therefore, those specific rejections of claims 57, 62-63, and 65 under 35 U.S.C. 112(b) are maintained.
With regard to all other rejections of claims under 35 U.S.C. 112(b) in the office action mailed 19 March 2026, the arguments are persuasive because these rejections have been rendered moot by the amendment to the claims amending the claims to be definite. Therefore, all other rejections of claims under 35 U.S.C. 112(b) that are not maintained have been withdrawn.
Claim Rejections - 35 USC § 103
New or Modified - Necessitated by Amendment
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 51-53, 55, 57, and 68 are rejected under 35 U.S.C. 103 as being unpatentable over Reid et al. (US 2017/0233804, published 17 August 2017), herein Reid, in view of Maglia et al. (US 2018/0364214, published 20 December 2018), herein Maglia.
Regarding claim 51, Reid teaches a method of characterizing a polynucleotide in a sample (“method shown in FIG. 7 of controlling the biochemical analysis system 1 to analyse polymers” [0179], “the polymer may be a polynucleotide” [0100]), the method comprising: (i) contacting a detector with the polynucleotide (“In step C1, the biochemical analysis system 1 is operated by controlling the bias control circuit 30 to apply a bias voltage across the pore 32 of the sensor element 30 that is sufficient to enable translocation of polymer” [0180]); taking measurements as a first part of the polynucleotide moves with respect to the detector under an applied force (“translocation is detected and a measurements start to be taken” [0180]; “Step C2 is performed when a polymer has partially translocated through the nanopore, i.e. during the translocation. At this time, the series of measurements taken from the polymer during the partial translocation is collected for analysis” [0195]; “bias voltage across the pore” [0180] is the applied force); assessing a property of the first part of the polynucleotide based upon the measurements (“In step C3, the chunk of measurements collected in step C2 is analysed. This analysis uses reference data 50 […] The analysis performed in step C3 provides a measure of similarity between (a) the sequence of polymer units of the partially translocated polymer from which measurements have been taken and (b) the one reference sequence” [0196]); where the first part of the polynucleotide has a desired property, controlling the movement of a second part of the polynucleotide with respect to the detector and taking measurements as the second part of the polynucleotide moves with respect to the detector to determine one or more characteristics of the polynucleotide, thereby characterizing the polynucleotide; or (b) where the first part of the polynucleotide does not have the desired property, rejecting the polynucleotide (“In step C4, a decision is made responsive to the measure of similarity determined in step C3 either (a) to reject the polymer being measured, (b) that further measurements are needed to make a decision, or (c) to continue taking measurements until the end of the polymer” [0199]).
However, Reid does not teach that the measurement taken is the determination of a time taken for the first part of the polynucleotide to move with respect to the detector and that the property assessed is the length of the first part of the polynucleotide based upon the time taken and without comparison to reference data. This deficiency is made up for in the teachings of Maglia.
Regarding claim 51, Maglia teaches a method of characterizing a polynucleotide wherein the length of the polynucleotide is assessed (“a method of characterizing a target polynucleotide […] examples of the characteristics of the target polynucleotides that can be determined using the methods described herein include (i) the length of the target polynucleotide” [0017]) based upon the determination of the time taken for the polynucleotide to move with respect to a detector under an applied force without comparison to reference data (“the length of the polynucleotide may be measured for example by determining […] the duration of interaction between the polynucleotide and the pore” [0132]; “measuring, during application of a potential across the nanopore” [0017]). Notably, the assessment of the length of the polynucleotide taught by Maglia does not recite a comparison to reference data in order for the length to be assessed, but rather is derived from the duration of the interaction between the polynucleotide and the detector. Therefore, by substituting Maglia’s determination of the duration of the interaction of the polynucleotide and the detector and assessment of the length based upon the duration for the measurements taken during translocation in the method taught by Reid, the combination of Reid and Maglia teach all claimed required limitations of claim 51 (see Claim Interpretation section above regarding step (iii) of claim 51 being interpreted as a limitation that is not required).
Regarding claim 52, the combination of Reid and Maglia teach a method according to claim 51 as discussed above, and Reid further teaches the method wherein the first part of the polynucleotide does not have the desired property, then the method is repeated with further polynucleotides of the sample until a polynucleotide having a first part with the desired property is identified (“If the decision made in step C4 is (a) to reject the polymer being measured, then the method proceeds to step C5 wherein the biochemical analysis system 1 is controlled to reject the polymer, so that measurements can be taken from a further polymer” [0200]; “After ejection such ejection in step C5, the method returns to step C1” [0202]). Examiner further notes that because claim 52 only limits steps taken in the case when the length of the first part of the polynucleotide is below the threshold length, as discussed with regard to step (iii) of claim 51 in the Claim Interpretation section above, the limitation in claim 52 is not a required limitation.
Regarding claim 53, the combination of Reid and Maglia teach a method according to claim 51 as discussed above, and Reid further teaches the method wherein the detector is a nanopore and wherein step (ii a) comprises allowing the first part of the polynucleotide to translocate through the nanopore under the applied potential (“Step C2 is performed when a polymer has partially translocated through the nanopore, i.e. during the translocation” [0195]).
Regarding claim 55, the combination of Reid and Maglia teach a method according to claim 51 as discussed above, and Reid further teaches the method wherein determining one or more characteristics of the polynucleotide comprises determining the sequence of the polynucleotide (“(c) to continue taking measurements until the end of the polymer” [0199]; “Examples of various applications of the method shown in FIG. 7, and more generally in accordance with the first aspect of the present invention, will now be described” [0323]; “retained in the nanopore and sequenced in its entirety” [0326] describing the measurement taken in an example when a polymer is retained instead of rejected).
Regarding claim 57, the combination of Reid and Maglia teach a method according to claim 51 as discussed above, and Maglia further teaches the method wherein an adapter is attached to one or both ends of the polynucleotide prior to step (i) (“the polynucleotide may be double stranded. If the polynucleotide is double stranded, the method may further comprises before the contacting step ligating a hairpin adaptor to one end of the polynucleotide” [0162]). The remaining limitations of claim 57 (“preferably […] polynucleotide” claim 57 lines 2-5) are in a “preferably” clause and therefore are interpreted as optional.
Regarding claim 68, the combination of Reid and Maglia teach a method according to claim 51 as discussed above, and both Reid and Maglia each further teach the method wherein in step (ii a) the movement of the polynucleotide with respect to the detector is governed by an ultra-fast polynucleotide-handling enzyme, wherein the ultra-fast polynucleotide handling enzyme is a FtsK, SpoIIIE, phi29, AddAb, or RecBCD enzyme (“Where the polymer is a polynucleotide there are a number of methods proposed for controlling the rate of translocation including use of polynucleotide binding enzymes” Reid [0134]; “The enzyme is preferably derived from a Phi29 DNA polymerase” Reid [0138]; “the rate of translocation of the double stranded DNA analyte may be controlled by a double stranded DNA translocase such as FtsK” Maglia [0074]; “a RecD helicase” Maglia [0074]).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to perform the simple substitution of the length of a polynucleotide taught by Maglia for the sequence taught by Reid as the characteristic of the polynucleotide used to determine whether to reject or further characterize a polynucleotide. One of ordinary skill in the art would be able to substitute one analysis (the analysis of duration of interaction taught by Maglia) for another analysis (the analysis of sequence taught by Reid) that both are calculated from fundamentally the same measurements (measurements of ion flow through the nanopore: “measuring, during application of a potential across the nanopore, ion flow through the modified ClyA nanopore” Maglia [0017]; “measurements of the ion current flowing through the pore” Reid [0133]). One of ordinary skill in the art would have a reasonable expectation of success because both methods are applied to the characterization of polynucleotides translocating through a nanopore and both methods are based on similar measurements of ion flow through the nanopore. Therefore, the invention as a whole of claims 51-53, 55, 57, and 68 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Claims 54 and 61-63 are rejected under 35 U.S.C. 103 as being unpatentable over Reid et al. (US 2017/0233804, published 17 August 2017), herein Reid, in view of Maglia et al. (US 2018/0364214, published 20 December 2018), herein Maglia, as applied to claims 51-53, 55, 57, and 68 above, and further in view of Rand (US 2018/0030525, published 1 February 2018).
Regarding claim 61, the combination of Reid and Maglia teach a method according to claim 51 as discussed above. However, Reid does not teach that step (i) comprises contacting the detector with a leader sequence at the first end of the polynucleotide and the polynucleotide binding protein is stalled at a second end of the polynucleotide or on an adapter attached to the second end of the polynucleotide; and b) the first part of the polynucleotide is the part between the leader sequence and the polynucleotide binding protein and the second part of the polynucleotide is the same as the first part of the polynucleotide; and c) the polynucleotide binding protein is orientated on the polynucleotide such that the polynucleotide binding protein controls the movement of the second part of the polynucleotide with respect to the detector against the applied force. This deficiency is made up for in the teachings of Rand.
Regarding claim 61, Rand teaches a method of characterizing a polynucleotide using a nanopore detector (“method for analyzing properties of a target portion polynucleotide using a nanopore in a membrane separating a cis fluid area from a trans fluid area” [0018]) comprising contacting a detector with the polynucleotide (“adding to the cis fluid side a polynucleotide to be analyzed” [0018]), wherein the polynucleotide comprises a leader sequence at one end of the polynucleotide (“FIG.3 […] 310 on the other side of the folded sequence, showing an enzyme displacement sequence; and adjacent to that is a thread threading sequence 314” [0059]; FIG. 3, 310 and 314 together are equivalent to the claimed leader sequence) and a polynucleotide binding protein is stalled at another end of the polynucleotide (“FIG. 3 […] 304 showing a folded sequence (e.g. GQ) adjacent to the strand of interest; 306 showing an enzyme binding sequence”; FIG. 3; “if the folded portion 304 is in place, the enzyme will bind to the strand, but will not move forward past the folded portion, when it is folded” [0062]), the part of the polynucleotide that is characterized first is the part between the leader sequence and the polynucleotide binding protein and the part of the polynucleotide that is characterized second is the same as the part of the polynucleotide that is characterized first, and the polynucleotide binding protein is orientated on the polynucleotide such that the polynucleotide binding protein controls the movement of the second part of the polynucleotide with respect to the detector against the applied force (“The enzyme ratchets the DNA against the voltage, allowing sequencing of the strand as it passes through the nanopore, and the GQ refolds behind the helicase […] the electric potential pulls the strand to the starting position at the GQ and the read starts over” [0058], by having the read start over, the same part is characterized again, so the first and second parts characterized are the same; see FIG. 1 and [0058] in its entirety for full cycle and its ability to repeat).
Regarding claim 62, the limitation of lines 4-6 of claim 62 regarding the leader sequence are a broader version of the limitation regarding the leader sequence in lines 2-3 of claim 61 since it includes the alternative that the leader sequence is comprise din an adapter attached to the first end of the polynucleotide, the limitation of lines 7-8 of claim 62 regarding the stalled polynucleotide binding protein is equivalent to the limitation regarding the stalled polynucleotide binding protein of lines 3-5 of claim 61, the limitation of lines 10-12 of claim 62 is a narrower version of the limitation in lines 6-8 of claim 62 since it specifies that the polynucleotide is double-stranded (interpreted as requiring it to have a double-stranded region, see 35 U.S.C. 112(b) rejection of claim 62 above), and the limitation of lines 14-16 of claim 62 is equivalent to the limitation of lines 9-11 of claim 61. Therefore, claim 62 differs from claim 61 in that it contains the further limitations that the polynucleotide is single-stranded and is double-stranded (interpreted as requiring it to have a single-stranded region and a double-stranded region, see 35 U.S.C. 112(b) rejection of claim 62 above). The combination of Reid, Maglia, and Rand teach all of the limitations of claim 61 as discussed with regard to claim 61 above, and Rand further teaches that the polynucleotide is single-stranded and double-stranded (see Figure 1A and Figure 3 having both single- and double-stranded regions, also paragraphs [0059-0061]).
Regarding claim 63, Reid teaches a method of characterizing a polynucleotide wherein the polynucleotide is double stranded (“The polynucleotide may […] be double-stranded” [0101]).
Regarding claim 63, Maglia teaches a method of characterizing a polynucleotide wherein the polynucleotide is double stranded (“the target polynucleotide can be […] double-stranded” [0018]), comprises a leader sequence (“attaching to the polynucleotide a leader sequence which preferentially threads into the pore” [0164]) and a hairpin adapter connecting the two strands (“a target double stranded polynucleotide is provided with a hairpin loop adaptor at one end and the method comprises contacting the polynucleotide with any one of the modified ClyA nanopores described herein such that both strands of the polynucleotide move through the pore” [0163]). As the leader sequence is taught to thread into the pore and the hairpin adapter to link the translocation of one strand to the following translocation of the other strand, the relationship of the leader to the hairpin adapter is that the leader is at a first end of a first strand and the hairpin adapter connects a second end of the first strand to a first end of a second strand.
Regarding claim 63, Rand teaches a method of characterizing a polynucleotide wherein a polynucleotide binding protein is stalled at the end of a strand of polynucleotide that will translocate through a nanopore wherein it is on the opposite end of the strand as a leader/threading sequence (“FIG. 3 […] 304 showing a folded sequence (e.g. GQ) adjacent to the strand of interest; 306 showing an enzyme binding sequence”; FIG. 3; “if the folded portion 304 is in place, the enzyme will bind to the strand, but will not move forward past the folded portion, when it is folded” [0062]; FIG. 3, threading sequence 314 and enzyme binding sequence 306 are opposite, portion of interest to be sequenced 302 between them), wherein the first part of the polynucleotide comprises (i) the part of the first strand between the leader sequence and the hairpin adapter, (ii) the hairpin adapter, and (iii) the part of the second strand between the hairpin adapter and the polynucleotide binding protein; and the second part of the polynucleotide is the same as the first part of the polynucleotide; and wherein the polynucleotide binding protein is orientated on the polynucleotide such that the polynucleotide binding protein controls the movement of the second part of the polynucleotide with respect to the detector against the applied force (“The enzyme ratchets the DNA against the voltage, allowing sequencing of the strand as it passes through the nanopore, and the GQ refolds behind the helicase […] the electric potential pulls the strand to the starting position at the GQ and the read starts over” [0058], by having the read start over, the same part is characterized again and includes the hairpin, so the first and second parts characterized are the same; see FIG. 1 and [0058] in its entirety for full cycle and its ability to repeat). Therefore, in combination with the teachings of Reid and Maglia discussed in the two paragraphs above, Rand teaches the polynucleotide binding protein stalled at the second end of the second strand, since that is the end that is opposite to the end with the leader sequence due to the hairpin adapter connecting the two strands.
Regarding claim 54, Rand teaches a method of characterizing a polynucleotide as discussed with regard to claims 61-63 above wherein the polynucleotide is a double-stranded polynucleotide comprising a first strand connected to a second strand by a hairpin or hairpin adapter, wherein prior to step (i) a polynucleotide binding protein is bound to and/or stalled at the hairpin or hairpin adapter (“the present inventive method comprises the use of an enzyme blocking sequence in a polynucleotide region that contains at least one hairpin turn. In certain aspects, the present method comprises a blocking sequence is a G-quadruplex” [0020]).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to combine the method of characterizing a polynucleotide taught by Reid with the method of characterizing a polynucleotide taught by Rand in view of the advantages taught Reid and Rand for each method. One of ordinary skill in the art would recognize that Rand’s method, while providing “the advantage of removing stochastic undesired enzyme behavior by comparing reads of the same molecule” (Rand [0049]), requires a longer time to repeatedly characterize a molecule instead of characterizing it just once, so they would be motivated to combine it with methods that reduce the time taken, which Reid provides by rejecting undesired polynucleotides before characterizing their full length. One of ordinary skill in the art would have a reasonable expectation of success because both methods are modifications of the same general method of nanopore sequencing and because the sequencing of a target strand multiple times as taught by Rand would not impair the ability for the polynucleotide to be rejected as taught by Reid or vice versa. The first cycle of sequencing in Rand would constitute the initial measurement of a sequence to compare with a reference sequence as taught by Reid. Therefore, the invention as a whole of claims 54 and 61-63 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Claims 58-60 and 64-67 are rejected under 35 U.S.C. 103 as being unpatentable over Reid et al. (US 2017/0233804, published 17 August 2017), herein Reid, in view of Maglia et al. (US 2018/0364214, published 20 December 2018), herein Maglia, as applied to claims 51-53, 55, 57, and 68 above, and further in view of Clarke et al. (in IDS filed 27 March 2023)(WO 2018/100370, published 7 June 2018), herein Clarke.
Regarding claim 58, the combination of Reid and Maglia teach a method according to claim 51 as discussed above. Additionally, Reid teaches their method possesses the advantage of improved speed and efficiency by reducing the amount of wasted data acquisition spent on polymers/polynucleotides that are not of interest (“The method potentially provides a significantly faster time to result wherein continued measurement is carried out only on those polymers determined to be of interest and those determined to be not of interest are rejected. This advantage of reducing the amount of wasted data acquisition is particularly significant in applications where a large amount of data acquisition is required” [0011]). However, neither Reid nor Maglia teach that prior to step (i) a polynucleotide binding protein capable of controlling the movement of the polynucleotide is stalled on the polynucleotide or on an adaptor attached to the polynucleotide. This deficiency is made up for in the teachings of Clarke.
Regarding claim 58, Clarke teaches a method of characterizing a polynucleotide wherein prior to contacting a detector with the polynucleotide a polynucleotide binding protein capable of controlling the movement of the polynucleotide is stalled on the polynucleotide or on an adapter attached to the polynucleotide (“In some embodiments, the adaptor described herein can comprise one or more spacers to prevent pre-bound polynucleotide binding protein (e.g., a polynucleotide unwinding enzyme) from moving along and unwinding a double stranded polynucleotide. These spacers prevent further movement of the polynucleotide binding protein (e.g., a polynucleotide unwinding enzyme) until the polynucleotide binding protein (e.g., a polynucleotide unwinding enzyme) is located at the pore and a potential difference is applied across the pore. The additional force provided by the potential difference pushes the polynucleotide binding protein (e.g., a polynucleotide unwinding enzyme) over the spacers and allows it to unwind and control movement of the polynucleotide through the nanopore” page 47 line 30 - page 48 line 3).
Regarding claim 59, the combination of Reid, Maglia, and Clarke teach a method according to claim 58 as discussed above, and Reid further teaches a method wherein in step (ii a) the first part of the polynucleotide moves freely with respect to the detector in a first direction relative to the applied force, and in step (iii) the polynucleotide binding protein controls the movement of the second part of the polynucleotide with respect to the detector in a second direction relative to the applied force (“In order to allow measurements to be taken as the polymer translocates through the pore 32, the rate of translocation can be controlled by a polymer binding moiety […] Where the polymer is a polynucleotide there are a number of methods proposed for controlling the rate of translocation including use of polynucleotide binding enzymes” [0134] teaches a polynucleotide binding protein controlling the movement; the additional limitations in step (ii a) of a first direction and step (iii) of a second direction do not further limit claim 51 as these directions are not defined in relation to each other and therefore could be the same or any different directions).
Regarding claim 60, Clarke teaches a method of characterizing a polynucleotide wherein a detector is contacted with a first end of the polynucleotide or an adapter attached to the first end of the polynucleotide and a polynucleotide binding protein is bound to a second end of the polynucleotide or to an adapter attached to the second end of the polynucleotide (“In some embodiments, an adaptor is attached to one or both of the two ends of the double-stranded polynucleotide […] In some embodiments, a polynucleotide unwinding enzyme is prebound to one or each of both adaptors” page 5 lines 17-18 and 27-28; Figure 2A, in the leftmost frame polynucleotide binding proteins are attached to each end of the polynucleotide and in the second frame one of the ends is contacted with and translocating through a nanopore detector).
Regarding claim 64, Clarke teaches a method of characterizing a polynucleotide wherein the polynucleotide comprises a portion which is complementary to a tag sequence, wherein the tag sequence is attached to the detector (“a nanopore with a capture polynucleotide conjugated to an outer rim of the nanopore […] binding the capture sequence of the adaptor that is attached to the second strand to the tag (e.g., a capture polynucleotide)” page 13 lines 4-7, Figures 9 and 10).
Regarding claim 65, Clarke teaches a method of characterizing a polynucleotide wherein the polynucleotide comprises a portion which is complementary to a tag sequence; wherein the polynucleotide is double stranded, comprising a first strand and a second strand; wherein the portion which is complementary to a tag sequence is a portion of the first strand of the polynucleotide; and wherein the portion having an oligonucleotide hybridized thereto (interpreted as referring to a portion of the polynucleotide being hybridized to the tag sequence) is a portion of the first strand of the polynucleotide and wherein the second strand hybridizes to the tag sequence as the first strand moves with respect to the detector (“A system for characterizing a polynucleotide […] at least one nucleic acid having sequence complementarity with a portion of the adaptor. […] An adaptor may be attached at each of two ends of the polynucleotide, wherein each adaptor comprises a duplex stem and a first single strand extending from the duplex stem. The first single strand of one adaptor may be contiguous with the template strand and the first single strand of the other adaptor may be contiguous with the complement strand” page 7 line 3 - page 8 line 5, the at least one nucleic acid having sequence complementarity with a portion of the adapter is the tag sequence; Figure 10).
Regarding claim 66, Clarke teaches a method of characterizing a polynucleotide wherein prior to contacting a detector with the polynucleotide a polynucleotide binding protein is stalled on the polynucleotide and wherein there is a step comprising the destalling of the polynucleotide binding protein (“In some embodiments, the adaptor described herein can comprise one or more spacers to prevent pre-bound polynucleotide binding protein (e.g., a polynucleotide unwinding enzyme) from moving along and unwinding a double stranded polynucleotide. These spacers prevent further movement of the polynucleotide binding protein (e.g., a polynucleotide unwinding enzyme) until the polynucleotide binding protein (e.g., a polynucleotide unwinding enzyme) is located at the pore and a potential difference is applied across the pore. The additional force provided by the potential difference pushes the polynucleotide binding protein (e.g., a polynucleotide unwinding enzyme) over the spacers and allows it to unwind and control movement of the polynucleotide through the nanopore” page 47 line 30 - page 48 line 3).
Regarding claim 67, Clarke teaches a method of characterizing a polynucleotide wherein prior to contacting a detector with the polynucleotide a polynucleotide binding protein is stalled on the polynucleotide, wherein there is a step comprising the destalling of the polynucleotide binding protein, and wherein destalling the polynucleotide binding protein comprises applying a destalling force to the polynucleotide wherein said destalling force is of opposite direction to the force applied in the step of taking measurements as a first part of the polynucleotide is translocated through a nanopore under an applied force (“In some embodiments, the adaptor described herein can comprise one or more spacers to prevent pre-bound polynucleotide binding protein (e.g., a polynucleotide unwinding enzyme) from moving along and unwinding a double stranded polynucleotide. These spacers prevent further movement of the polynucleotide binding protein (e.g., a polynucleotide unwinding enzyme) until the polynucleotide binding protein (e.g., a polynucleotide unwinding enzyme) is located at the pore and a potential difference is applied across the pore. The additional force provided by the potential difference pushes the polynucleotide binding protein (e.g., a polynucleotide unwinding enzyme) over the spacers and allows it to unwind and control movement of the polynucleotide through the nanopore” page 47 line 30 - page 48 line 3; Figure 2A, in the second panel to the left the leftmost binding protein is stalled on the second strand/part while the first strand/part is translocated through the nanopore under an applied force indicated by the downward arrow, in the fourth panel to the left the binding protein has been destalled, which the quoted text describes as involving the binding protein being pushed over the spacers, which in the figure is the upward direction).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to combine the method of characterizing a polynucleotide taught by the combination of Reid and Maglia with the method of characterizing a polynucleotide taught by Clarke in view of the advantages taught Reid and Clarke for each method. One of ordinary skill in the art would recognize that Clarke’s method, while providing the advantage of higher confidence observations, requires a longer time to characterize both strands instead of just one, so they would be motivated to combine it with methods that reduce the time taken, which Reid provides by rejecting undesired polynucleotides before characterizing their full length. One of ordinary skill in the art would have a reasonable expectation of success because both methods are modifications of the same general method of nanopore sequencing and because the sequencing of a template strand and then its complement as taught by Clarke would not impair the ability for the polynucleotide to be rejected as taught by Reid or vice versa. Therefore, the invention as a whole of claims 58-60, and 64-67 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Response to Arguments
Applicant’s arguments, see page 10 of the Remarks, filed 15 July 2026, with respect to the rejection(s) of claim(s) 51-53, 55, 59, 62, and 68 under 35 U.S.C. 102 as anticipated by Reid have been fully considered and are persuasive because the independent claim 51 has been amended to recite “determining a time taken for a first part of the polynucleotide to move with respect to the detector under an applied force” and “assessing length of the first part of the polynucleotide based upon the time taken for the first part of the polynucleotide to move with respect to the detector under the applied force and without comparison to reference data”, which are not taught by Reid. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection of claims 51-53, 55, and 68 under 35 U.S.C. 103 is made over Reid in view of Maglia, a new ground of rejection of claim 59 under 35 U.S.C. 103 is made over Reid in view of Maglia in further view of Clarke, and a new ground of rejection of claim 62 is made over Reid in view of Maglia in further view of Rand. These new grounds of rejections are necessitated by the amendment to the independent claim 51 to recite the above identified limitations. Note that the scope of amended claim 51 differs from claim 56 in the claims filed 7 August 2023 because amended claim 51 requires assessing the length without comparison to reference data and also no longer requires the limitations of step (iii) as discussed in the Claim Interpretation section above.
Applicant’s arguments, see page 11 of the Remarks, filed 15 July 2026, with respect to the rejection(s) of claim(s) 54, 57-58, 60, and 64-67 under 35 U.S.C. 103 as obvious over Reid in view of Clarke have been fully considered and are persuasive because the independent claim 51 that these claims depend upon has been amended with the limitations identified in the paragraph above regarding the 35 U.S.C. 102 rejection over Reid, which are not taught by either Reid or Clarke. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection of claim 57 under 35 U.S.C. 103 is made over Reid in view of Maglia, a new ground of rejection of claim 54 under 35 U.S.C. 103 is made over Reid in view of Maglia in further view of Rand, and a new ground of rejection of claims 58, 60, and 64-67 under 35 U.S.C. 103 is made over Reid in view of Maglia in view of Clarke. These new grounds of rejections are necessitated by the amendment to the independent claim 51 to recite the above identified limitations.
Applicant’s arguments, see pages 11-12 of the Remarks, filed 15 July 2026, with respect to the rejection(s) of claim(s) 61 under 35 U.S.C. 103 as obvious over Reid in view of Rand have been fully considered and are persuasive because the independent claim 51 that this claim depends upon has been amended with the limitations identified in the paragraph above regarding the 35 U.S.C. 102 rejection over Reid, which are not taught by either Reid or Rand. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection of claim 61 under 35 U.S.C. 103 is made over Reid in view of Maglia in further view of Rand. This new ground of rejection is necessitated by the amendment to the independent claim 51 to recite the above identified limitations.
Applicant’s arguments, see pages 12-13 of the Remarks, filed 15 July 2026, with respect to the rejection(s) of claim(s) 56 and 63 under 35 U.S.C. 103 as obvious over Reid in view of Rand further in view of Maglia have been fully considered and are persuasive in-part. The argument that the rejection of claim 56 is moot because claim 56 has been canceled is persuasive. The argument that the combination of references does not disclose or suggest each claim element because of the amendment to claim 51 upon which claim 63 depends is not persuasive. Firstly, the assessment of length of a polynucleotide based upon how long it takes for the polynucleotide to move with respect to a nanopore as taught by Maglia does not require comparison to reference data, so in combination with Reid’s teaching of assessing a characteristic of a first part of a polynucleotide (in the case of Reid this characteristic is the sequence) a method comprising all of steps (i), (ii a), and (ii b) is taught. The amendment of step (iii) of claim 51 does not overcome this, since step (iii) is not required for the method to be performed and therefore is not a required limitation, as discussed in the Claim Interpretation section above. Applicant’s argument on page 13 that “the mere disclosure in paragraph [0132] of Maglia that polynucleotide length is a feature that can be characterized using nanopores is not sufficient to have given a person of ordinary skill in the art a reason to have modified the disclosure of Reid to arrive at the claimed invention” is also not persuasive. MPEP §2143(I)(B) states: “The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art”. This rationale does not require a specific reason to be taught to perform the modification, but rather simply that two elements (the characteristic of length and the characteristic of sequence) could be substituted as the characteristic assessed in the method and that the results of the substitution would be predictable. As both are characteristics able to be measured by translocating a portion of a polynucleotide through a nanopore and can be used to make a decision on whether to reject or continue characterizing the polynucleotide, the result of the substitution is predictable. Therefore, this argument is not persuasive. Note that the modifications to the rejection of claim 63 (both the claim itself and claim 51 on which it depends) are necessitated by the amendment to the independent claim 51 to recite the above identified limitations and the amendment of claim 63 to remove the word “optionally”.
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Sage Science (“Nanopore Sequencers Give Optimal Results with BluePippin Size Selection” https://sagescience.com/blog/nanopore-sequencers-give-optimal-results-with-bluepippin-size-selection/ posted 1 November 2016) discloses that it is desirable in long-read sequencing methods such as methods of sequencing using nanopores to select polynucleotides greater than a threshold length for sequencing in order to maximize the read lengths. While step (iii) of claim 51 as currently amended is not a required limitation, this teaching would make step (iii) of claim 51 obvious when combined with the teachings of Reid and Maglia if it were amended such that it would be interpreted as a required limitation.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/JEFFREY BELLAH/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
