FINAL ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Amendments and Status of the Claims
2. This action is in response to papers filed 20 April 2026 in which the specification and claims 1-2,5, 10, and 15 were amended, no claims were canceled, and new claim 21 was added. All of the amendments have been thoroughly reviewed and entered.
All previous objections and/or all previous rejections reiterated below are withdrawn in view of the amendments.
Applicant’s arguments have been thoroughly reviewed and are addressed following the rejections necessitated by the amendments.
Claims 1-15 and 21 are under prosecution.
3. This Office Action includes new rejections necessitated by the amendments.
Information Disclosure Statement
4. The Information Disclosure Statement filed 20 April 2026 is acknowledged and has been considered.
Claim Rejections - 35 USC § 103
5. 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.
6. 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.
7. Claims 1-2, 6-7, 12-15, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Kawashima et al. (U.S. Patent Application Publication No. US 2005/0100900 A1, published 12 May 2005) and Lui et al. (U.S. Patent Application Publication No. US 2012/0208194 A1, published 16 August 2012) and, as applied to claim 21, as evidenced by Cheeseman (U.S. Patent No. 5,302,509, issued 12 April 1994.
Regarding claim 1, Kawashima et al. teach methods comprising providing a surface having a first surface bound oligonucleotide bound thereto via the 5’ end (paragraph 0125) and having a first polynucleotide template (Figure 1A (b) and paragraphs 0109-0117) with a free 3’ end attached thereto (paragraphs 0037-0042). The surface comprises a second surface primer that the polynucleotide template hybridizes to at its 3’ end (Figure 1A(g)). The second surface primer is then extended using the second surface primer and a portion of the first polynucleotide template to generate the structure comprising a first read sequence as claimed in (b) of the instant claim (Figure 1A (g)-(h)), thereby “sequencing” the first polynucleotide template as discussed above.
In addition, it is noted that Kawashima et al. teach the sequence of a complementary strand to a nucleic acid to be sequenced, or a part thereof, may be obtained initially (paragraph 0236); thus, it would have been obvious to sequence a first read of a partial extension (i.e., the claimed first portion) of the second surface primer.
Kawashima et al. further teach continuing extension of the first portion using step by step sequencing, which extends by a single nucleotide, which is determined prior to addition of a further nucleotide (paragraph 0238), followed by cleaving the obtained structure at a portion of the first polynucleotide template using a restriction endonuclease to produce the claimed structure (Figure 12B(c)-(d) and paragraphs 0171-0173); it is noted that the “5’ portion” interpreted as any portion of the first polynucleotide template that is upstream from the free 3’ end.
Kawashima et al. also teach Figure 13A(a), which shows a bound extended first surface oligonucleotide having a sequence bound thereto, which is analogous to the hybridized second polynucleotide template, wherein the primer is extended to form a read region (i.e., the claimed second read region; Figure 13A(b)), thereby sequencing at least a portion of the second polynucleotide template as discussed above.
Kawashima et al. also teach the process is repeated to provide amplified immobilized molecules (Abstract) and repetition of the extension with least one extended molecule (paragraph 0024), and that the methods have the added advantage of being useful for many different purposes, including gene expression (Abstract). Thus, Kawashima et al. teach the known techniques discussed above.
In addition, Liu et al. methods comprising providing surface having immobilized extended DNA molecules hybridized to cleavable primers (Figure 2(b) which is analogous to Figure 12B(c) of Kawashima et al.), wherein the primer is cleaved and sequence by extension and stand displacement (Figure 2 and paragraph 0030). Liu et al. also teach that sequencing is performed using sequencing by synthesis (paragraphs 0004 and 0154) and that the methods have the added advantage of maximizing the efficiency of sequencing reactions (paragraph 0015). Thus, Liu et al. teach the known techniques discussed above.
It would therefore have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Kawashima et al. and Liu et al. The combination result in using sequencing by synthesis as taught by Liu et al. (paragraph 0004 and 0154), which is either the same as, or a functional equivalent of, the “step-by-step sequencing of Kawashima et al. (paragraph 0238) to sequence each of the products produced in the method, thereby arriving at the instantly claimed method with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in a method having the added advantage of being useful form many different purposes, including gene expression as explicitly taught by Kawashima et al. (Abstract) and maximizing the efficiency of sequencing reactions as explicitly taught by Liu et al. (paragraph 0015). In addition, it would have been obvious to the ordinary artisan that the known techniques of the cited prior art could have been combined with predictable results because the known techniques of the cited prior art predictably result in useful methods for sequencing nucleic acids.
Regarding claim 2, the method of claim 1 is discussed above. Kawashima et al. teach a fourth polynucleotide template complementary to and hybridized to the first polynucleotide template and covalently bound to the 3’ end of a second surface primer and hybridized to a portion of the first surface oligonucleotide; namely, because the claimed fourth polynucleotide template is attached at the 3’ end of the second primer, the fourth polynucleotide template is merely a portion of the 3’ end of the second surface primer. Kawashima et al. teach the second surface primer is extend all the way to the end of the first surface primer through the first surface oligonucleotide (e.g., Figure 10A(a). Liu et al also teach an analogous extended structure (Figure 2). Liu et al. teach sequencing of the same sequence in parallel on the surface of an array (paragraph 0161). Thus, it would have been obvious to have and additional (i.e., fourth template complementary to the first template and bound to a different second surface oligonucleotide as described above. Liu et al. also teach both primers are modified for cleavage (paragraph 0149); thus, it would have been obvious to cleave both the first surface oligonucleotide (which is a primer) and the second surface primer, thereby generating the claimed structure.
Regarding claim 6, the method of claim 1 is discussed above. Kawashima et al. teach both immobilized primers retain hybridized portions of the cleaved and extended molecules (e.g., Figure 12B(d)). Thus, cleavage of both primers as taught by Liu et al. results in the instantly claimed structure.
Regarding claim 7, the method of claim 2 is discussed above. Liu et al. teach strand displacement to extend the second surface primer, which creates the fourth polynucleotide (Figure 2 and paragraphs 0030 and 0091).
It is noted that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930); Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959)). See MPEP §2144.04 IV C. Thus, the claimed order of steps is an obvious variant of the steps of the cited prior art.
MPEP 716.01(c) makes clear that “[t]he arguments of counsel cannot take the place of evidence in the record” (In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965)). Thus, counsel’s mere arguments cannot take the place of evidence in the record.
It is noted that the Response above should not be construed as an invitation to file an after final declaration. See MPEP 715.09.
Regarding claim 12, the method of claim 2 is discussed above. Kawashima et al. teach washing after denaturation (paragraph 0165). Liu et al. also teach washing (paragraphs 0209-0210) and denaturation (Abstract).
It is reiterated that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results. Thus, the claimed order of steps is an obvious variant of the steps of the cited prior art.
Applicant is again cautioned to avoid merely relying upon counsel’s arguments in place of evidence in the record, and that the Response above should not be construed as an invitation to file an after final declaration.
Regarding claim 13, the method of claim 1 is discussed above. Liu et al. teach cleavage comprises removing an excisable base (i.e., uridine), and generating a free 3’ hydroxyl at the end (paragraph 0030). It is noted that while the claim 13 recites removing a “second” excisable base, only claim 3 recites a first excisable base, and claim 13 does not depend upon claim 3. Thus, claim 13 only requires removal of one excisable base.
It is reiterated that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results. Thus, the claimed order of steps is an obvious variant of the steps of the cited prior art.
Applicant is again cautioned to avoid merely relying upon counsel’s arguments in place of evidence in the record, and that the Response above should not be construed as an invitation to file an after final declaration.
Regarding claims 14 and 15, the method of claim 1 is discussed above. Kawashima et al. teach washing after cleavage (i.e., claim 14; paragraph 0165) treating the surface with and exonuclease (i.e., claim 15; paragraph 0166). Liu et al. also teach washing (paragraphs 0209-0210).
It is reiterated that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results. Thus, the claimed order of steps is an obvious variant of the steps of the cited prior art.
Applicant is again cautioned to avoid merely relying upon counsel’s arguments in place of evidence in the record, and that the Response above should not be construed as an invitation to file an after final declaration.
Regarding claim 21, the method of claim 1 is discussed above. Kawashima et al. teach part of the sequence of a complementary strand to a nucleic acid to be sequenced may be obtained initially (paragraph 0236); thus it would have been obvious to only sequence a first read of a partial extension (i.e., the claimed first portion) of the second surface primer using sequencing by synthesis (i.e., Liu et al.)/step-by-step synthesis (i.e., Kawashima et al.) as discussed above. Sequencing by synthesis utilizes blocked nucleotides (paragraph 0157 of Liu et al) in particular as discussed by Cheeseman (Abstract), which is discussed in paragraph 0005 of Liu et al. Thus, because the remainder (i.e., he second portion) of the second polynucleotide is not sequences in tis embodiment, it would have been obvious to use ordinary (i.e., unblocked) nucleotides for the extension, in particular since Kawashima et al. do not explicitly discuss the use of blocked nucleotides.
8. Claims 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Kawashima et al. (U.S. Patent Application Publication No. US 2005/0100900 A1, published 12 May 2005) and Lui et al. (U.S. Patent Application Publication No. US 2012/0208194 A1, published 16 August 2012) as applied to claim 2 above, and further in view of Wu et al. (U.S. Patent Application Publication No. US 2019/0352327 A1, published 21 November 2019).
Regarding claims 3-5, the method of claim 2 is discussed above in Section 7.
While Liu et al. teach cleavage comprises cleavage, in the form of removing an excisable base (i.e., uridine) and generating a free 3’ hydroxyl at the end (paragraph 0030), neither Kawashima et al. nor Lui et al. teach use of a dihydroxylation reagent.
However, Wu et al. teach methods wherein bridged (i.e., clustered) immobilized polynucleotides are cleaved (abstract and Figure 1) using the dihydroxylation reagent osmium tetroxide (i.e., claims 3 and 5, paragraphs 0246-0247), Wu et al. also teach the use of allyl-T as a cleavage site (i.e., claim 4; paragraph 0019), and that the methods have the added advantage of being an effective alternative method of cleavage (paragraph 0007). Thus, Wu et al. teach the known techniques discussed above.
It is reiterated that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results. Thus, the claimed order of steps is an obvious variant of the steps of the cited prior art.
Applicant is again cautioned to avoid merely relying upon counsel’s arguments in place of evidence in the record, and that the Response above should not be construed as an invitation to file an after final declaration.
It would therefore have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Wu et al. with Kawashima et al. and Liu et al. to arrive at the instantly claimed method with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in a method having the added advantage of utilizing an effective alternative method of cleavage as explicitly taught by Wu et al. (paragraph 0007). In addition, it would have been obvious to the ordinary artisan that the known techniques of Wu et al. could have been combined with the cited prior art with predictable results because the known techniques of Wu et al. predictably result in useful methods for cleaving nucleic acids.
8. Claims 8-11 are rejected under 35 U.S.C. 103 as being unpatentable over Kawashima et al. (U.S. Patent Application Publication No. US 2005/0100900 A1, published 12 May 2005) and Lui et al. (U.S. Patent Application Publication No. US 2012/0208194 A1, published 16 August 2012) as applied to claim 2 above, and further in view of Ma et al. (U.S. Patent Application Publication No. US 2003/0134349 A1, published 17 July 2003).
Regarding claims 8-11, the method of claim 2 is discussed above in Section 12.
Kawashima et al. teach the molecules are DNA and RNA molecules (paragraph 0031), and Liu et al. teach RNA (i.e., ribonucleotides; paragraph 0023).
While Liu et al. also teach polynucleotides with flaps (e.g., Figure 2), neither Kawashima et al. nor Liu et al. teach a flap nuclease.
However, Ma et al. teach methods wherein cleavage of flaps (i.e., removal of nucleotides; claim 8) is performed with an enzyme having flap nuclease activity (i.e., claim 9) in the form of an operably linked construct (i.e., chimera) of the nuclease and a DNA polymerase (i.e., claim 10; paragraph 0132). Ma et al. teach the polymerase is derived from Taq DNA polymerase or the flap activity is derived from FEN-1 (i.e., claim 11; paragraph 0101), and that the methods have the added advantage of allowing direct detection and quantitation of nucleic acids (Abstract). Thus, Ma et al. teach the known techniques discussed above.
It is reiterated that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results. Thus, the claimed order of steps is an obvious variant of the steps of the cited prior art.
Applicant is again cautioned to avoid merely relying upon counsel’s arguments in place of evidence in the record, and that the Response above should not be construed as an invitation to file an after final declaration.
It would therefore have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Ma et al. with Kawashima et al. and Liu et al. to arrive at the instantly claimed method with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in a method having the added advantage of allowing direct detection and quantitation of the nucleic acids as explicitly taught by Ma et al. (Abstract). In addition, it would have been obvious to the ordinary artisan that the known techniques of Ma et al. could have been combined with the cited prior art with predictable results because the known techniques of Ma et al. predictably result in useful methods for cleaving nucleic acids.
Response to Arguments
9. Applicant's arguments filed 20 April 2026 (hereafter the “Remarks”) have been fully considered but they are not persuasive for the reasons discussed below.
A. Pages 18-21 of the Remarks refer to the amendments and the objections and indefiniteness rejections, which are withdrawn in view of the amendments.
B. Applicant argues on pages 21-22 of the Remarks that the cited prior art does not teach generating the second portion of the second polynucleotide as clamed.
However, Figure 1A g-h of Kawashima et al. clearly shows extension of the second polynucleotide template from its 5’ end s that it is hybridized to the first polynucleotide template in proximity to the 3’end of the second polynucleotide template.
C. Applicant’s remaining arguments rely on alleged deficiencies previously addressed, which are unpersuasive for the reasons discussed above. Therefore, the claims remained rejected based on the prior art citations presented in the rejections.
Conclusion
10. No claim is allowed.
11. 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).
12. 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.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Robert T. Crow whose telephone number is (571)272-1113. The examiner can normally be reached M-F 8:00-4:30.
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Robert T. Crow
Primary Examiner
Art Unit 1683
/Robert T. Crow/Primary Examiner, Art Unit 1683
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