DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
The Response filed April 13, 2026 is acknowledged.
Claims 1-3, 7, 9, 11, 15-19, 22, 24, 28-29, 31-32, 36-38 and new claim 99 are pending and are being examined on the merits.
Response to Arguments
Applicant’s arguments filed April 13, 2026 have been fully considered.
The following objections and rejections are WITHDRAWN in view of Applicant’s arguments and amendments to the specification and claims:
Objection to the Specification – cross reference to related applications
Objection to the Specification – trademarks
Objections to claims 1, 22 and 37
Rejection of claims 9 and 18-19 under 35 USC § 112(b), indefiniteness
Rejection of claims 17 and 36 under 35 USC § 112(b), lack of antecedent basis
The following rejections are MAINTAINED:
Prior art rejections
Response to arguments regarding prior art rejections
Applicant argues that the prior art rejections should be withdrawn because the cited art does not teach or suggest all of the limitations of, in particular, independent claim 1. Specifically, Applicant argues that Drmanac does not teach methods in which DNA circles are formed from DNA for RCR after attaching a support surface (Remarks, p. 12).
The Examiner disagrees. Claim 1 does not recite attaching DNA circles to a surface. Claim 1 merely recites bringing a nucleic acid sequence into contact with a surface “under conditions that are sufficient to” couple the nucleic acid to the surface. Claim 1 does not clearly require that the DNA circles are then actually coupled to the surface. Further, claim 1 does not recite the order or timing of steps (a) or (b), nor does it prohibit step (b) from occurring simultaneously with step (a). Further, Applicant has not provided an explanation as to why the cited portions of Drmanac (Non-Final Office Action, p. 7) do not teach forming DNA circles after attaching to a solid support. In particular, paras. 126-129 describe attaching a biotinylated adapter to the target DNA sequence which is then attached to a streptavidin support, circularizing the structure, and then amplifying the DNA circles by RCA. Applicant does cite para. 34 as describing an embodiment where DNA circles are formed prior to attaching to a surface. However, para. 34 was not cited in the Office Action as teaching the limitations recited in instant claim 1 steps (a) and (b).
Applicant additionally states …
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(Remarks, p. 12).
Applicant does not provide any argument or explanation as to the basis of such an assertion, and it is not clear to the Examiner what point Applicant is trying to make with this statement. To the extent that Applicant is arguing that nucleotide hybridization is not a “nucleotide … binding reaction”, the Examiner cannot find any definition of “binding reaction” in the specification at all1, much less one that would distinguish the cited teaching in Drmanac.
Applicant additionally argues that the instantly claimed invention provides unexpected results in terms of reduced reaction time and more consistent polony densities, as compared to the Drmanac embodiment of circularizing and amplifying prior to attaching to a surface (Remarks, p. 13).
The Examiner disagrees and refers Applicant to MPEP 716.02(e) which states that the claimed subject matter must be “compare[d] … with the closest prior art to be effective to rebut a prima facie obviousness”. As noted, the Drmanac embodiment referred to by Applicant is not the embodiment cited in the Non-Final Office Action, and is not the closest prior art.
Finally, regarding the claims rejected over the secondary references O’Malley or Ammar, Applicant argues that the ordinary artisan would not have combined these references with Drmanac as they do not teach or suggest a sequencing method comprising a step of circularizing a target nucleic acid sequence (Remarks, pp. 14-15).
The Examiner disagrees and refers Applicant to MPEP 2145 (III) which states “[t]he test for obviousness is not whether the feature of a secondary reference may be bodily incorporated into the structure of the primary reference … Rather, the test is what the combined teachings of those references would have suggested to those of ordinary skill in the art …. It is not necessary that the inventions of the references by physically combinable to render obvious the invention under review”. O’Malley and Ammar were cited for teaching limitations unrelated to a sequencing method or circularizing a target nucleic acid sequence, and thus it is not relevant whether their respective methods could be “bodily incorporated” into the Drmanac sequencing or circularizing steps.
These arguments are not persuasive. The rejections are maintained. Additionally, a rejection for new claim 99 has been added.
Information Disclosure Statement
The Information Disclosure Statement submitted April 13, 2026 has been considered.
Claim Interpretation
Claims 1, 22, 24 and 28 each recite, in part, a “polymer-nucleotide conjugate”. The term “polymer-nucleotide conjugate” does not have a fixed meaning in the art, however, the instant specification describes it as “a polymer core and a detectable label coupled thereto” (para. 5), and as “a polymer core and a plurality of nucleotide moieties attached thereto” (para. 8). An embodiment of polymer-nucleotide conjugate is shown in Fig. 28 (para. 50). Thus, the broadest reasonable interpretation of the term “polymer-nucleotide complex”, when read in light of the specification, is a construct comprising a polymer core with nucleotides moieties and a detectable label attached thereto.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 9, 11, 15-19, 29, 31-32 and 36-38 are rejected under 35 U.S.C. 103 as being unpatentable over Drmanac2 (US Patent App. Pub. No. 2017/0175184 A1).
Regarding independent claim 1, Drmanac teaches …
A method of nucleic acid sequencing, said method comprising: (a) bringing a nucleic acid sequence into contact with a surface under conditions sufficient to couple said nucleic acid sequence to said surface (Fig. 1A; paras. 39, 136; Method 1: paras. 126-129: “the adapter can be prepared with an internal biotin … to allow for … direct amplification on the surface);
(b) enzymatically circularizing said nucleic acid sequence to produce a circular nucleic acid sequence (Fig. 1A; paras. 47, 136);
(c) contacting said circular nucleic acid sequence or a derivative thereof with a primer sequence complementary thereto, thereby producing a primed nucleic acid sequence (Figs. 1A, 1E; paras. 39, 136);
and (d) performing a nucleotide binding reaction with said primed nucleic acid sequence to identify a nucleotide of said primed nucleic acid sequence, which nucleotide binding reaction is performed in absence of incorporation of a nucleotide into said primed nucleic acid sequence (paras. 89, 136: sequencing by hybridization (“SBH”)).
Although Drmanac teaches all of the limitations of claim 1, it does not do so in a single embodiment. Specifically, the step (a) limitation “under conditions sufficient to couple said nucleic acid sequence to said surface” is taught in a separate embodiment from the remainder of the claim 1 steps. However, it would have been obvious to modify the cited Drmanac embodiment to incorporate a step where the nucleic acid sequence is coupled to the surface, or is capable of being coupled to the surface.
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to modify the cited Drmanac method with the step of coupling (or of making capable of being coupled) the nucleic acid sequence to the surface. The ordinary artisan would have been motivated to do so to achieve the expected advantage of allowing easy removal of unwanted reaction components (through washing) while retaining the target nucleic acid sequence on the surface. The ordinary artisan would have had an expectation of success as Drmanac specifically teaches that such nucleic acid sequences can be directly attached to the surface.
Regarding dependent claim 2, Drmanac additionally teaches that the enzymatically circularizing the nucleic acid sequence comprises performing splint ligation (Fig. 2A; paras. 48, 158-159).
Regarding dependent claim 9, Drmanac additionally teaches that the plurality of colonies is present at a surface density of greater than 300K/mm2 (para. 29: more than 10,000, 100,000 or 1 million spots/mm2).
Regarding dependent claim 11, Drmanac additionally teaches that the primed nucleic acid sequence comprises one or more adaptors comprising an index site having a sequence complementary to at least a portion of a capture nucleic acid molecule coupled to the surface (paras. 34, 46: DNA circles comprising an adapter sequence with an index site are formed – the DNA circles then have a primer hybridized to them and the primer is extended in RCA, thus generating a population of concatemers comprising the complement of the adapter oligonucleotide and the DNA fragment – the complement of the adapter is also considered an adapter sequence).
Regarding dependent claim 15, Drmanac additionally teaches that the surface comprises a hydrophilic polymer layer coupled thereto (para. 53: polyacrylamide-coated glass).
Regarding dependent claim 16, Drmanac additionally teaches that the primed nucleic acid sequence comprises a concatemer of two or more repeats of an identical sequence (Fig. 1A; paras. 10, 31, 87).
Regarding dependent claim 17, Drmanac additionally suggests amplifying the circular nucleic acid sequences using RCA prior to step (c). Specifically, Drmanac teaches modifying amplification steps depending on the target nucleic acid (e.g., paras. 29, 34, 45, 126, 129).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Drmanac method, discussed above, to arrive at the amplification steps of claim 17. The ordinary artisan would have been motivated to do so customize the assay as needed through routine optimization, and would have had an expectation of success as the design and modification of nucleic acid amplification assays is well-known in the art.
Regarding dependent claims 18-19, Drmanac teaches performing a primer extension reaction on the primed nucleic acid sequence, and repeating the steps for each successive nucleotide to identify a sequence of said primed nucleic acid sequence (Fig. 1A; paras. 15, 33, 89, 136). Drmanac also teaches various times associated with the steps (e.g., para. 108).
Regarding dependent claim 29, Drmanac additionally teaches or suggests that enzymatically circularizing comprises (i) hybridizing a 5’ end of a single-stranded nucleic acid molecule to a 3' end of said nucleic acid sequence and hybridizing a 3' end of said single-stranded nucleic acid molecule to a 5' end of said nucleic acid sequence, or (ii) hybridizing a 3' end of a single-stranded nucleic acid molecule to a 5' end of said nucleic acid sequence and hybridizing a 5' end of said single-stranded nucleic acid molecule to a 3' end of said nucleic acid sequence (Fig. 2A; paras. 48, 128-129, 158-159). Specifically, Drmanac teaches, in part, circularizing the (target) nucleic acid sequence by hybridizing it to the (splint) single-stranded nucleic acid molecule. It does not explicitly teach which end of the splint hybridizes to the target first, but the ordinary artisan understands that there are only a limited number options (perhaps, the 2 recited options) that can occur in this step.
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Drmanac method, discussed above, to arrive at the claim limitations of claim 29. The ordinary artisan would have been motivated to do so customize the assay as needed through routine optimization, and would have had an expectation of success as there are only two options to select from.
Regarding dependent claim 31, Drmanac additionally teaches or suggests that the nucleic acid sequence comprises one or more UMIs at a 5’ end or a 3’ end (Fig. 8; paras. 34, 46, 128-129). Specifically, Drmanac teaches attaching UMIs to the nucleic acid sequence via an adapter, and teaches that adapters can be attached at either the 5’ end or the 3’ end of the nucleic acid sequence.
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Drmanac method, discussed above, to arrive at the claim limitations of claim 31. The ordinary artisan would have been motivated to do so customize the assay as needed through routine optimization, and would have had an expectation of success as there are only two options of positions to attach the UMI to the nucleic acid sequence.
Regarding dependent claim 32, Drmanac additionally teaches adding one or more adaptors to a 5’ end or a 3’ end of said nucleic acid sequence comprising an index site having a nucleic acid sequence coupled to the surface (Method 1: paras. 126-129: “the adapter can be prepared with an internal biotin … to allow for … direct amplification on the surface), and suggests that the nucleic sequence has at least a portion corresponding to at least a portion of a capture nucleic acid molecule. Specifically, Drmanac teaches attaching a nucleic acid to the surface through the use of a corresponding portion of a capture nucleic acid molecule in another embodiment (para. 46).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Drmanac method, discussed above, to attach the nucleic acid sequence to the surface through hybridization with at least a portion of a capture nucleic acid molecule. The ordinary artisan would have been motivated to do so customize the assay as needed through routine optimization, and would have had an expectation of success as Drmanac teaches that nucleic acid sequences can be coupled to surfaces in such a manner.
Regarding dependent claim 36, Drmanac additionally teaches that the enzymatically circularizing the nucleic acid sequence comprises ligating a 5’ end and a 3’ end of the nucleic acid sequence together under conditions sufficient to produce the circular nucleic acid sequence (Fig. 1A; paras. 47, 136).
Regarding dependent claim 37, Drmanac additionally teaches performing steps (a) through (d) for a plurality of nucleic acid sequences (Fig. 1A; paras. 89, 136).
Regarding dependent claim 38, Drmanac additionally teaches incorporating a nucleotide into the primed nucleic acid sequence (Fig. 1A; para. 33: rolling circle replication).
Claims 22, 24 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Drmanac (US Patent App. Pub. No. 2017/0175184 A1 as applied to claim 1 above, and further in view of O’Malley3 (US Patent App. Pub. No. 2004/0023248 A1).
Regarding dependent claim 22, Drmanac additionally teaches that the nucleotide binding reaction in (d) comprises: (i) bringing the primed nucleic acid sequence into contact with one or more polymer-nucleotide conjugates under conditions sufficient to form a stable multivalent binding complex between a nucleotide moiety of said one or more polymer-nucleotide conjugates and a nucleotide of said primed nucleic acid sequence. Specifically, Drmanac teaches the use of linear and branched polymers to which target polynucleotides are attached (e.g., para. 40), but does not teach using the conjugate as described in claim 22 (ii).
However, O’Malley teaches (ii) detecting the stable multivalent binding complex to determine the identity of said nucleotide of said primed nucleic acid sequence or derivative thereof. Specifically, O’Malley teaches contacting the target nucleic acid sequence with a polymer-conjugate with a detectable label (e.g., Fig. 1; paras. 5, 7, 10).
Regarding dependent claims 24 and 28, O’Malley teaches (paras. 5, 10, 16) that the polymer-nucleotide conjugates two or more types of conjugates, as recited in claim 24, and that the plurality of types each comprise a distinct detectable label, as recited in claim 28.
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Drmanac method, discussed above, to use the polymer-nucleotide conjugate to determine the identity of the primed nucleic acid sequence, as taught by O’Malley. Drmanac teaches the need for improved detection schemes for high density arrays. O’Malley teaches that the polymer-nucleotide conjugates are particularly useful to detect target nucleic acids on microarrays and are highly sensitive compared to other detection methods used with microarrays. Thus, the ordinary artisan would have been motivated to further modify the modified Drmanac method to achieve the expected advantage of a microarray with an improved detection sensitivity. The ordinary artisan would have had an expectation of success as the substitution of detection schemes is well-known in the art, and because O’Malley teaches that the detection system is highly useful for microarrays.
Claims 3 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Drmanac (US Patent App. Pub. No. 2017/0175184 A1) as applied to claim 1 above, and further in view of Ammar4 (A comparative analysis of DNA barcode microarray feature size, BMC Genomics, 10:471, 1-7, 2009).
Regarding dependent claim 7, Ammar teaches that the surface density of about 4,000
oligonucleotides per µm2 (p. 2, left col., para. 2).
Regarding dependent claim 3, as noted above, Drmanac teaches the colony density (para. 29), while Ammar teaches the density of the nucleic acids in each colony (p. 2, left col., para. 2), but neither explicitly teaches the concentration of the fluid comprising the nucleic acid sequence when it is placed into contact with the surface. However, it would be obvious to arrive at this concentration.
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Drmanac method, discussed above, to arrive at the recited surface density and solution concentration limitations. The ordinary artisan would have been motivated to do so customize the assay as needed through routine optimization, and would have had an expectation of success as Drmanac and Amman teach principles of array design and modification.
Claim 99 is rejected under 35 U.S.C. 103 as being unpatentable over Drmanac (US Patent App. Pub. No. 2017/0175184 A1) as applied to claim 1 above, and further in view of Abrams WO 2016/061416 A1).
Regarding dependent claim 99, Drmanac teaches attaching adaptors to the nucleic acid
Sequence (paras. 34, 46), while Abrams teaches using a transposase to transpose a hairpin adapter to the nucleic acid sequence. Abrams also teaches that the hairpin adapter comprises a PacBio sequencing primer bind site (para. 159).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Drmanac method, discussed above, to incorporate a hairpin adapter into the nucleic acid sequence. The ordinary artisan would be motivated to do so with the expectation of achieving the advantage of optimizing the nucleic acid construct for high throughput sequencing platforms, which are understood in the art to provide highly efficient sequencing. The ordinary artisan would have also used a transposase to do so as transposases are known in the art as being suitable for such a purpose. MPEP 2144.07. The ordinary artisan would have had an expectation of success as the design and modification of nucleic acid constructs is well-known in the art.
Conclusion
Claims 1-3, 7, 9, 11, 15-19, 22, 24, 28-29, 31-32, 36-38 and 99 are being examined and are rejected. No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROLYN GREENE whose telephone number is (571)272-3240. The examiner can normally be reached M-Th 7:30-5:30 EST.
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/CAROLYN L GREENE/Primary Examiner, Art Unit 1681
1 The specification does describe various embodiments of nucleotide binding reactions (e.g., paras. 237-240), but does not define “nucleotide binding reactions”, nor indicate that such reactions are limited to those described in the embodiments.
2 Drmanac was cited in the PTO-892 Notice of References Cited mailed January 13, 2026.
3 O’Malley was cited in the PTO-892 Notice of References Cited mailed January 13, 2026.
4 Ammar was cited in the PTO-892 Notice of References Cited mailed January 13, 2026.
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