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 . Applicant’s preliminary amendment filed 6/15/2023 is acknowledged. Claims 1, 3, 5-6, 9, 11, 13-19 and 21 have been amended. Claims 2, 4, 7-8, 10, 12, 25 and 27-41 have been canceled. Claims 1, 3, 5-6, 9, 11, 13-24 and 26 are pending.
Priority
This application is a 371 of PCT/US2021/064248 filed 12/18/2021 which claims benefit of 63/127,566 filed 12/18/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/15/2023 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings were received on 6/15/2023. These drawings are found acceptable by the Examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located in Example 1 at pages 17-19. These sequences do not appear to be recited in the raw sequence listing or CFRE.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Specification
The disclosure is objected to because of the following informalities:
(a) The specification is objected to because it contains sequences of <10 nucleotides in at pages 17-19 in Example 1 that are not represented by a proper sequence identifier (SEQ ID NO:). See MPEP 2417.
Claim Objections
Claim 3 is objected to because of the following informalities:
(a) The limitation “complimentary” in line 3 of the claim 3 should be replaced with --complementary---. Appropriate correction is required.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 3, 5 is/are rejected under 35 U.S.C. 102(a)(1) and/or alternatively 35 U.S.C. 102(a)(2) as being anticipated by Guettouche et al {Guettouche, used interchangeably herein} (W0 2018077847, May 2018, effective filing date October 2016, citation made of record on IDS filed 6/15/2023).
Regarding claims 1, 3 and 5, Guettouche et al teach a construct and making a library of target nucleic acid molecules from a sample comprising a plurality of target molecule, comprising for each target molecule, ligation of an adaptor to each end of the target molecule forming a circular molecule, wherein the adaptor comprises two barcodes, two primer binding sites facing away from each other and at least one modified nucleotide effecting a strand synthesis termination by a nucleic acid polymerase situated between the two primer binding sites (page 4), wherein the modified effecting a strand synthesis termination by a nucleic acid polymerase may be selected from abasic nucleotides, nucleotides with protein side groups, synthetic nucleotide or ethylene glycol spacer (page 4, lines 3-15). Guettouche further teaches preparation of a sequencing library barcoded with unique molecular identifiers (UID tags. A-tailed DNA fragments are circularized by ligation to a single double stranded adaptors with T-overhang followed by denaturation. The adaptor comprises an extension bocking stop site (e.g., a non-replicable abasic site or ethylene glycol spacer which cannot be copied) and priming sites (see pages 13,16, claim 1 and Figure 1). Guettouche teaches that the structures are circularized by binding a 5’ end and thereof to a 3’ end there and having the structure 5'P[T] -BC-R-STOP-F— BC-3'
3'BC'-R'-STOP-F-BC'-[T]5'P
Where 5'P is a 5'-phosphate, [T] is the added T that base pairs with A at the 3'-end of the target molecule, BC is a barcode, STOP is the terminator nucleotide, and R and F are reverse and forward primer binding sites respectively (see example 1 at page 22). In view of the foregoing, Guettouche meets the limitations of the claims as broadly recited.
Claim Rejections - 35 USC § 103
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.
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.
Claim(s) 6, 9, 11, 13-24 and 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guettouche et al {Guettouche, used interchangeably herein} (W0 2018077847, May 2018, effective filing date October 2016, citation made of record on IDS filed 6/15/2023) in view of Weng et al (20180057871, March 2018).
Regarding claims 6, 9, 11, 13-24, and 26, Guettouche et al teach a product and method of making a library of target nucleic acid molecules from a sample comprising a plurality of target molecule, comprising for each target molecule, ligation of an adaptor to each end of the target molecule forming a circular molecule, wherein the adaptor comprises two barcodes, two primer binding sites facing away from each other and at least one modified nucleotide effecting a strand synthesis termination by a nucleic acid polymerase situated between the two primer binding sites (page 4), wherein the modified effecting a strand synthesis termination by a nucleic acid polymerase may be selected from abasic nucleotides, nucleotides with protein side groups, synthetic nucleotide or ethylene glycol spacer (page 4, lines 3-15). Guettouche further teaches preparation of a sequencing library barcoded with unique molecular identifiers (UID tags. A-tailed DNA fragments are circularized by ligation to a single double stranded adaptors with T-overhang followed by denaturation. The adaptor comprises an extension bocking stop site (e.g., a non-replicable abasic site or ethylene glycol spacer which cannot be copied) and priming sites (see pages 13,16, claims and Figure 1). Guettouche teaches wherein the adaptor has two primer binding sites facing in the opposite direction so as to enable copying of each strand and subsequent PCR amplification and further teaches wherein the method comprises an amplification step (page 4 and 17).
Guettouche teaches that the structures are circularized by binding a 5’ end and thereof to a 3’ end there and having the structure 5'P[T] -BC-R-STOP-F— BC-3'
3'BC'-R'-STOP-F-BC'-[T]5'P
Where 5'P is a 5'-phosphate, [T] is the added T that base pairs with A at the 3'-end of the target molecule, BC is a barcode, STOP is the terminator nucleotide, and R and F are reverse and forward primer binding sites respectively (see example 1 at page 22).
Guettouche teaches that the sample may include cell-free material from bodily fluid, such as cell-free DNA (cfDNA) or circulating tumor DNA (ctDNA) (page 6 and 11) and may further comprises of naturally occurring bases, (adenosine, guanosine, cytosine, uracil and thymidine) as well as non-natural bases that may have a particular function, e.g., increasing the stability of the nucleic acid duplex, inhibiting nuclease digestion or blocking primer extension or strand polymerization (pages 6-7). The reference further teaches wherein the plurality of barcodes included with the plurality of adaptors comprise of UID that may be a random sequence or 1-20 nucleotides long or between 40-20 bases long (page 14). Guettouche also teaches the use of splint oligonucleotides used along with the adapter sequence (page 13). Guettouche teaches wherein the cfNA originates from diseased cells (pages 11 and 12).
While Guettoouche teaches that uracil may be a naturally occurring based that is part of the target nucleic acid, the reference does not teach the conversion or cytosine to uracil or expressly discuss wherein polyethylene glycol rather than ethylene glycol is associated with the linker.
Weng et al teach a composition and method for making and using circularized template structures, wherein the target nucleic acid may comprise of one or more modified nucleotide, such as methylated nucleotides (e.g., conversion of cytosine to uracil) and nucleotide analogs ([0073], [0133] and [0152]), and wherein the method of circularizing polynucleotides, comprises the use of adapter that can be added to either the 5’ end and/or 3’ end of a polynucleotide. The template DNA can have a free hydroxyl group at the 3’ end and the adapter can have a blocked 3’ end that in the presence of a ligase, joins he 3’ end of the DNA template to the 4’ end of the adapter in the presence of polyethylene glycols (PEGs) to drive the intermolecular ligation of the DNA fragments and the adapter(s) to forma circle [0120] – [0121]. Weng teaches using a double stranded adapter and the formation of circularized double stranded circles that are capable of primer binding and amplification of circularized strands ([0120], see also Figures 6-8). Weng et al teach wherein the target nucleic acid may encompass cell-free nucleic acid, including cell-free RNA, cell-free DNA or circulating tumor RNA isolated from bodily fluids of both healthy and diseased individuals ([00195]).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the claimed invention to have been motivated to utilize polyethylene glycol or ethylene glycol in the making of a circularized template as taught by both Guettouche and Weng. The ordinary artisan would have been motivated to do so for the advantage of promoting intermolecular ligation as suggested by Weng by promoting synthesis termination by a nucleic acid polymerase as suggested by Guettouche. The ordinary artisan would have been motivated to target circulated template wherein the cytosines have been converted to uracils for the obvious benefit of disease detection and epigenetic analyses.
Conclusion
No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CYNTHIA B WILDER whose telephone number is (571)272-0791. The examiner can normally be reached Flexible.
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/CYNTHIA B WILDER/Primary Examiner, Art Unit 1681