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
Claim(s) 1-4, 7-8, and 12-14 are pending and under examination.
The following Office Action is in response to Applicant's communication dated 08/31/2026.
Applicant’s amendments to independent claims 1 overcame the previous rejection based on Hardenbol et al. (U.S. Patent No. 10,221,436) and Absalan et al. (WO 2019/055819 A1).
Accordingly, rejection(s) and/or objection(s) not reiterated from previous office actions are hereby withdrawn. The following rejection(s) and/or objection(s) are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
New Claim Rejections - 35 USC § 112(b)
Necessitated by amendments
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim(s) 7 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.
Claim 7 recites “oligonucleotide sequences coupled to the nicks”, which is indefinite because the amended claim 1 no longer recites coupling step. It is unclear whether claim 7 refers to oligonucleotide ligated in step (d) or requires a separate coupling operation at nick generation of step (b).
For purposes of examination only, and to facilitate a complete analysis of the claim, the Examiner interprets the “oligonucleotide sequences coupled to the nicks” as referring to oligonucleotide ligated to blunt end fragments in claim 1 step (d). This interpretation is adopted solely for examination and does not resolve the lack of clarity in the claim language.
New Claim Rejections - 35 USC § 103
Necessitated by amendments
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.
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.
Claim(s) 1-4, 7-8, and 12-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Drmanac et al. (US20140005056A1, EFD: Sep. 16, 2013) in view of Matz et al. (US20100120097A1, EFD: Jun. 1, 2009).
Regarding claims 1 and 2, Drmanac discloses method for obtaining a nucleic acid library of a sample comprising polynucleotides, comprising the steps of:
(a) multiplying the polynucleotides by a polymerase by providing A, T, G, C and U nucleotides wherein the molar ratio of T and U is between 200: 1 and 5: 1; (e.g. amplify nucleic acids with dNTP and 4% dUTP with respect to dTTP (i.e. 25 T: 1 U molar ratio, which is within the claimed range) [¶¶0079, 0081-0082]. A skilled artisan would have understood the conventional dNTP substrates for nucleic acid amplification would comprise dATP, dCTP, dGTP, and dTTP. Together with expressly disclosed dUTP and dTTP, these disclosures provide the claimed A, T, G, C and U nucleotides.)
(b) fragmenting the multiplied polynucleotides by excising the U nucleotides, thereby creating nicks to generate fragmented nucleic acids, and separating the fragmented nucleic acids; (e.g. U excision fragmentation is shown in Fig. 1 and described in ¶0081. After fragmenting, target nucleic acids are further modified to prepare them for later applications, such as in the preparation of nucleic acid constructs [¶0082])
(c) treating the fragmented nucleic acids with an enzyme or an enzyme mix exhibiting a 5' to 3' polymerase activity and a 3'to 5' exonuclease activity to create blunt-ended nucleic acid fragments; (e.g. after fragmenting, target nucleic acids frequently have a combination of blunt and overhang ends as well as combinations of phosphate and hydroxyl chemistries at the termini. Such fragments can be treated with several enzymes to create blunt ends. In one embodiment, a polymerase and dNTPs is used to fill in any 5′ single strands of an overhang to create a blunt end. Polymerase with 3′ exonuclease activity is used to remove 3′ overhangs. [¶¶0086-0087])
(d) ligating double-stranded oligonucleotides to the blunt-ended nucleic acid fragments, wherein the double-stranded oligonucleotides comprise a primer binding sequence (e.g. blunt end ligate target nucleic acid to adaptor [¶0142]; where in adaptor may comprise sites for primer binding [¶0108]).
However, Drmanac does not disclose the arrangement, where first primer binding sequences are provided at both ends before amplification, second primer binding sequences introduced to blunt end nucleic acid fragments, and fragments containing first primer binding sequence are amplified using original fist primer and newly added second primer.
Matz discloses this arrangement. Matz discloses provide nucleic acid with cap primer sequences at both ends, amplify nucleic acid using cap primer, fragments, end polishes, and ligate to adapters having double strand ligation ends and primer binding sequence; wherein primer binding sequence is different from cap primer sequences [Fig.1, ¶¶0033-0039]. The product of ligation is then amplified using The A+-cap primer (hybridize to 3’ cap primer sequence) with primer B (hybridize to adapter). [¶¶0040-0041].
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to implement Matz’s terminal primer sites arrangement in Drmanac’s method because Matz teaches this primer binding sites arrangement enable preserving access to original nucleic acid termini, allow representation of transcript ends and separate amplification of terminal fragment populations [¶¶0040, 0056-0057]. Accordingly, killed artisan would have been motivated to use this arrangement to recover amplified terminal fragments from Drmanac’s fragmented library.
Regarding claim 3, Drmanac further discloses at least one of the steps (a), (b), (c), or (d) is performed without purification of the obtained product. (e.g. Drmanac teaches DNA fragmentation, blunt end generation, and adapter ligation through five enzymatic steps without any intervening purification steps [¶0483])
Regarding claim 4, Drmanac and Matz further discloses blunt end ligation is performed using a ligase. [Drmanac’s Fig.2 and ¶0165; Matz’s ¶¶ 0034, 0053, 0117]
Regarding claim 7, Drmanac further discloses oligonucleotide sequences coupled to the nicks are primer sequences. (e.g. generating fragments through uracil excision and nick translation [¶0081] blunt end ligate target nucleic acid to adaptor [¶0165]; where in adaptor may comprise sites for primer binding [¶0108])
Regarding claim 8, Drmanac further discloses the polynucleotides are derived from synthetic or genomic DNA or RNA or a plurality of DNA or RNA molecules comprising 50 to 2000 nucleotides. (e.g. target nucleic acids can be human genomic DNA [¶0059] or mRNAs or cDNAs [¶0057]. Fragment sizes of the target nucleic acid can vary, such as 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1200, 1400, 1600, 1800, and 2000 nucleotides in length. [¶0065])
Regarding claim 12, Drmanac further discloses the multiplying the polynucleotides in step (a) is conducted by polymerase chain reaction. (e.g. In CoRE method, a number of amplification methods can be used in the step to replace nucleotides with modified nucleotides or nucleotide analogs. Such amplification methods are described in further detail below and can include without limitation polymerase chain reaction (PCR) [¶0082].)
Regarding claim 13, Drmanac further discloses the nicks are generated by providing one or more enzymes selected from the group consisting of DNA glycosylases, endonucleases, engineered recombinant proteins and thermolabile engineered recombinant proteins. (e.g. The U moieties are then excised usually through use of one or more enzymes, including without limitation Uracil-DNA Glycosylase (UDG), Endonuclease IV (EndolV), Endonuclease VIII (EndoVllI) [¶0081])
Regarding claim 14, Drmanac further discloses the nucleic acid library is sequenced. (e.g. nucleic acids of the invention, including fragments in LFR aliquot libraries and DNBs, can be used in any sequencing methods known in the art, including without limitation sequencing by ligation, sequencing by hybridization, sequencing by synthesis (including sequencing by primer extension), chained sequencing by ligation of cleavable probes, and the like. [¶0316]).
Conclusion
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 Khai Quynh Tien Pham whose telephone number is (571)272-6998. The examiner can normally be reached M-T, 9-4 ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Heather Calamita can be reached at (571) 272-2876. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KHAI QUYNH TIEN PHAM/Examiner, Art Unit 1684
/JEREMY C FLINDERS/Primary Examiner, Art Unit 1684
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