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 .
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office Action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on June 17, 2026 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Status of Claims
Claims 16-23 are currently pending. Claims 16-20 have been amended by Applicants’ amendment filed 05-28-2026. No claims have been added or canceled by Applicants’ amendment filed 05-28-2026.
Therefore, claims 16-23 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed November 3, 2022 is a CON of US Patent Application 16721533 (now abandoned), which is a CON of 35 U.S.C. 371 national stage filing of International Application No. PCT/EP2018/067246, filed June 27, 2018; which claims the benefit of US Provisional Patent Application 62525595, filed June 27, 2017.
Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, the as-filed Specification, filed November 3, 2022, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. The specific method steps recited in independent claim 16 does not have support for; “attaching a pair of modular oligonucleotide adapters to a target nucleic acid, by attaching a first modular oligonucleotide adapter one end of a target nucleic acid, and attaching a second modular oligonucleotide adapter to the other end of the target nucleic acid.” Therefore, the priority date for the presently claimed invention is November 3, 2022, the filing date of US Patent Application 18/052,337.
Applicants are invited to specifically indicate the location of the cited phrase pertinent to claim 16 of the instant application.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed May 28, 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or
objection not specifically addressed below are herein withdrawn.
Specification Objections
The objection to the disclosure is withdrawn due to Applicant’s amendment of the as-filed Specification, filed November 3, 2022, to include the status of US Patent Application No. 16721533
(now abandoned), in the reply filed 05-28-2026.
Maintained Objections/Rejections
Claim Interpretation: the term “modular” as recited in claim 16 is interpreted to refer to customizable synthetic DNA or RNA sequences.
The term “variable length punctuation mark” in claim 16 is interpreted to refer to a single nucleotide or a nucleotide sequence of any length that is located at the end of each oligonucleotide adapter.
The term “adapter-target-adapter construct” in claim 16 is interpreted to refer to constructs that are (or are not) annealed and/or hybridized one to the other via the complementary sequences.
The term “common sequence” in claim 16 is interpreted to refer to any sequence including any sequence that is commonly found in nature, is commonly used in the method, is common in a sample or a sample type, is common within a species or common across different species, a sequence having a particular G/C content, etc.
The term “tail sequence” in claim 16 is interpreted to refer to any single-stranded sequence at the end of an adapter oligonucleotide.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 16-23 are maintained under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 16 is indefinite for the recitation of the term “attaching a pair of modular oligonucleotide adapters…at the other end of the target nucleic acid” in lines 3-6 because the as-filed Specification and original claims do not recite a step of attaching modular oligonucleotide adapters and, thus, the metes and bounds of the claim cannot be determined.
Claim 16 is indefinite for the recitation of the term “the modular oligonucleotide adapters” such as recited in claim 16, line 7. There is insufficient antecedent basis for the term “the modular oligonucleotide adapters” in the claim because claim 16, lines 3-5 recite the terms “a pair of modular oligonucleotide adapters”; “a first modular oligonucleotide adapter”; and “a second modular oligonucleotide adapter.”
Claim 16 is indefinite for the recitation of the term “each strand” such as recited in claim 16, line 24. There is insufficient antecedent basis for the term “each strand” in the claim because claim 16 does not recite any specific strands of an adapter-target-adapter construct. Moreover, it is unclear what ‘strands’ the extension products are complementary to and, thus, the metes and bounds of the claim cannot be determined.
Claims 17-20 are indefinite for the recitation of the term “the pairs of modular oligonucleotide adapters” such as recited in claim 17, line 2. There is insufficient antecedent basis for the term “the pairs of modular oligonucleotide adapters” in the claim because claim 16, line 3 recites the terms “a pair of modular oligonucleotide adapters.” The Examiner suggests that Applicant amend the claim to recite, for example, “each pair of modular oligonucleotide adapters.”
Claim 21 is indefinite for the recitation of the term “one-to-one mapping” such as recited in claim 21, line 2 because it is unclear what is meant by the term. It is unclear whether the term refers to identifier sequences that are complementary, whether the sequences are identical, whether the sequences are the same length, or whether the term refers to some other structure and, thus, the metes and bounds of the claim cannot be determined.
Claims 22 and 23 are indefinite insofar as they ultimately depend from instant claim 16.
Claim Rejections - 35 USC § 102
The rejection of claims 16-23 is maintained under 35 U.S.C. 102(a1)/(a2) as being anticipated by Diehn et al. (hereinafter “Diehn”) (International Application WO2016040901, published March 17, 2016; of record).
Regarding claim 16, Diehn teaches polynucleotide adapter and method of use thereof for identifying and analyzing nucleic acids, including cell-free nucleic acids from a patient sample; as well as, methods of using the adaptors to detect, diagnose, or determine prognosis of cancers (Abstract). Diehn teaches that the invention is a pool of unique adaptors for analyzing nucleic acids in a sample, each adaptor comprising: a double stranded portion at a proximal end and two single stranded portions at a distal end (interpreted as a first and second tail sequence), wherein the double stranded portion comprises a double-stranded barcode of at least two base pairs specific to the adaptor (interpreting the double-stranded portion of the adaptor as a variable length punctuation mark comprising complementary sequences), and wherein the single-stranded portion comprises: a pre-defined single-stranded barcode of at least two nucleotides specific to the sample (interpreted as first and second common sequence); and a random single-stranded barcode of at least two nucleotides specific to the adaptor (interpreted as the first and second unique identifier sequence), wherein the pool of adaptors can have the double-stranded portion further comprising one or more G/C base pairs between the double-stranded barcode of at least two base pairs and the proximal end of the adaptor, such that the pool of adaptors can also a number of G/C base pairs that varies among the adaptors in the pool (interpreting the barcodes/UID comprising G/C base pairs as a first and second variable length punctuation mark that are complementary), wherein the double-stranded barcode can comprise 2-20 base pairs; the pre-defined single-stranded barcode can comprise 4-20 nucleotides; and the random single-stranded barcode can comprise 4-20 nucleotides (interpreted as an adapter-target-adapter construct, claim 16) (paragraph [0005]). Diehn teaches that a method of analyzing a plurality of double-stranded nucleic acids, the method comprising: attaching a pool of adaptors according to claims 1-6 to both ends of the plurality of double-stranded nucleic acids; amplifying both strands of the adaptor-nucleic acids to produce first amplicons and second amplicons, wherein the first amplicons are derived from a first strand of the double-stranded nucleic acids and contain a first strand of the double-stranded barcodes, and the second amplicons are derived from a second strand of the double-stranded nucleic acids and contain a second strand of the double-stranded barcodes; determining the sequence of the first and second amplicons; and identifying mutations in the first and second amplicons, where the amplicons of (c) comprise different random barcodes derived from the random single-stranded barcode of the adaptor (interpreted as attaching one of the oligonucleotide adaptors to each end of the target nucleic acid; and where the unique identifier sequences of the oligonucleotide pairs are different, claims 16 and 17) (paragraph [0007], lines 1-10 and 20-22). Diehn teaches in Figure 1(c) that the Y-shaped adaptor comprised a random barcode and a fixed barcode on its non-hybridizable portion, and a primer sequence on its hybridizable portion (interpreted as a first and second priming sequence comprising a sample identifier sequence, claim 16) (paragraph [0018]; and Figure 1(c)). Diehn teaches that Figures 1b and 2b show the ligation of Y-shaped sequencing adaptors to each end of a target cfDNA (corresponding to attaching a pair of oligonucleotide adaptors to one end and the other end of a target nucleic acid, claim 16) (paragraph [0019]; and Figure 2b). Figure 1b and 2b is shown below:
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Diehn teaches that Figure 2C illustrates a plurality of Y-shaped sequencing adaptors that can attach to each end of the target nucleic acid (corresponding to modular oligonucleotide adaptors, claim 16) (Figure 2c). Figure 2c is shown below:
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Diehn teaches that Figure 1c shows the components of the Y-shaped sequencing adaptors (e.g., modular adaptors) (corresponding to modular oligonucleotide adaptors, claim 16) (Figure 1c), as shown below:
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Diehn teaches that primers for amplification can be covalently attached to slides in the flow cells and then the flow cells can be exposed to reagents for nucleic acids extension and sequencing (interpreted as forming extension products complementary to each strand, claim 16) (paragraph [00147], lines 8-10). Diehn teaches that cfDNA is commonly obtained from blood or plasma (interpreting cfDNA to comprising common sequences, claim 16) (paragraph [0055]). Diehn teaches that each Y-shaped adaptor can further comprise a primer sequence, which can be a PCR primer sequence or a sequencing primer sequence, wherein the primer sequence can be on the non-hybridizable portion of the Y-shaped adaptor or on the hybridizable portion of the Y-shaped adaptor (interpreted as primer sequences, claim 16) (paragraph [0076]). Diehn teaches the preparation of pre-capture sequencing libraries, wherein cfDNA was input for a cfDNA sample that was 12-plexed in an Illumina HiSeq 2000 High Output lane, while germline or tumor DNA was used as input for a 24-plexed Illumina HiSeq 2000 High Output lane, wherein sequencing library preparation was performed using the KAPA LTP Library Prep Kit (interpreted as preparing a library of nucleic acid molecules, claim 16) (paragraph [0232], lines 1-9). Diehn teaches that DNA was diluted, end repaired, bead cleanup performed, A-tailing performed, ligation was performed using excess adaptors relative to the input DNA samples, such that after ligation, DNA was isolated, PCR was performed with KAPA HiFi and Illumina Universal Primers with an annealing step (interpreted as a first tail and a second tail; annealing first and second primers; and extending the first and second primers to form extension products, claim 16) (paragraph [0232], lines 9-20). Diehn teaches that the barcodes on the two strands are complementary to each other, such as if UID are located in the stem region of the adaptor (interpreting the barcode as unique identifier sequences that are complementary and/or variable length punctuation marks that are complementary, claim 16) (paragraph [0199], lines 4-5). Diehn teaches that pairing the sequences into a double-stranded nucleic acid if the sequences have complementary barcodes (interpreting the barcode as unique identifier sequences that are complementary and/or variable length punctuation marks that are complementary, claim 16) (paragraph [0015]).
Regarding claim 17, Diehn teaches a method of analyzing a plurality of double-stranded nucleic acids, the method comprising: attaching a pool of adaptors according to claims 1-6 to both ends of the plurality of double-stranded nucleic acids; amplifying both strands of the adaptor-nucleic acids to produce first amplicons and second amplicons, wherein the first amplicons are derived from a first strand of the double-stranded nucleic acids and contain a first strand of the double-stranded barcodes, and the second amplicons are derived from a second strand of the double-stranded nucleic acids and contain a second strand of the double-stranded barcodes; determining the sequence of the first and second amplicons; and identifying mutations in the first and second amplicons, where the amplicons of (c) comprise different random barcodes derived from the random single-stranded barcode of the adaptor (interpreted as attaching one of the oligonucleotide adaptors to each end of the target nucleic acid; and where the unique identifier sequences of the oligonucleotide pairs are different, claim 17) (paragraph [0007], lines 1-10 and 20-22).
Regarding claims 18 and 19, Diehn teaches A-tailing, which can comprise performing an A-tailing reaction on the plurality of nucleic acids to produce a plurality of A-tailed nucleic acids, wherein the A-tailing reaction can be conducted prior to attaching the adaptors to the plurality of nucleic acids, prior to amplification of the adaptor-modified nucleic acids, conducted after amplification of the adaptor-modified nucleic acids, conducted prior to or after fragmenting, and/or prior to or after end repair of the plurality of nucleic acids (interpreted as the first tail sequences are the same; and the second tail sequences are the same, claims 18 and 19) (paragraphs [00157]-[00160]).
Regarding claim 20, Diehn teaches in Figure 2b, that Y-shaped adaptors were attached to cfDNA (interpreted as a forked adaptor, claim 20) (paragraph [0019]; and Figure 2b). Figure 2b is shown below:
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Regarding claim 21, Diehn teaches that if the short barcodes are complementary to each other and the genomic coordinates of the insert map to the opposite strands, the reads represent reciprocal strands of a duplex molecule (interpreted as sample identifier sequences have a one-to-one mapping, claim 21) (paragraph [00199], lines 11-13). Diehn teaches that the invention is a method of analyzing nucleic acids that comprises a step of error suppressing using barcodes including a step of mapping the sequence to the reference genome and identifying all single nucleotide variants (SNVs) (i.e., bases different from the reference sequence) (interpreted as sample identifier sequences have a one-to-one mapping, claim 21) (paragraph [00200], lines 1-4).
Regarding claim 22, Diehn teaches that the pool of adaptors can have the double-stranded portion further comprising one or more G/C base pairs between the double-stranded barcode of at least two base pairs and the proximal end of the adaptor, such that the pool of adaptors can also a number of G/C base pairs that varies among the adaptors in the pool (interpreted as a first and second variable length punctuation mark), wherein the double-stranded barcode can comprise 2-20 base pairs; the pre-defined single-stranded barcode can comprise 4-20 nucleotides; and the random single-stranded barcode can comprise 4-20 nucleotides (interpreting the random barcodes as encompassing that the unique identifier sequences have a length of at least 5 nucleotides, claim 22) (paragraph [0005]).
Regarding claim 23, Diehn teaches that to make the index adaptors, standard 8-base barcode Illumina adaptors were used, replacing the 8-base indexes with 4 random bases followed by a 4-base multiplexing barcode, such that 24 different adaptor sequences were designed such that all pairs of multiplexing barcodes had edit distances of at least 2 (interpreted as encompassing a first unique identifier sequence as having a pairwise edit distance of at least 3, claim 23) (paragraph [00235]). Diehn teaches that tandem adaptors were designed with index adaptors as a starting point, wherein 12 index adaptors with pairwise edit distances of at least 3 were used (interpreted as a first unique identifier sequence as having a pairwise edit distance of at least 3, claim 23) (paragraph [00236], lines 1-2).
Diehn meets all the limitations of the claims and, therefore, anticipates the claimed invention.
Response to Arguments
Applicant’s arguments filed May 28, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) Diehn does not teach modular oligonucleotide adapters (Applicant Remarks, pg. 11, last partial paragraph through pg. 12, first partial paragraph).
Regarding (a), although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26USPQ2d 1057 (Fed. Cir. 1993). Additionally, MPEP 2112.01(I) states that:
where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). “When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Applicant’s assertion that Diehn does not teach modular oligonucleotide adapters, is not found persuasive. Please see the Office Action mailed March 31, 2026 indicating where Diehn teaches the attachment of the adaptors comprising the specific adaptor components as recited in instant claim 16. Additionally, it is noted that the as-filed Specification and original claims filed November 3, 2022 do not teach:
“attaching a pair of modular oligonucleotide adapters to a target nucleic acid, by attaching a first modular oligonucleotide adapter one end of a target nucleic acid, and attaching a second modular oligonucleotide adapter to the other end of the target nucleic acid” as recited in instant claim 16 (underline added).
Instead, the as-filed Specification and original claims teach:
“attaching one of a plurality of oligonucleotide adapters to each end of a target nucleic acid to provide an adapter-target-adapter construct” (paragraph [025]).
Moreover, the as-filed Specification and original claims do not define the term “modular oligonucleotide adapters,” and/or indicate how “modular oligonucleotide adapters” are different from any other pair of oligonucleotide adaptors. Furthermore, the Examiner contends that Diehn clearly teaches the attachment of a pair of oligonucleotide adaptors to each of two (undefined) ends of a target nucleic acid as recited in instant claim 16, wherein the oligonucleotide adapters comprise the same components as required in instant claim 16, such that the oligonucleotide adapters are interpreted to be ‘modular’ oligonucleotide adapters. For example -
Diehn teaches:
Figure 1b shows the ligation of Y-shaped sequencing adaptors to each end of a target cfDNA (corresponding to attaching a pair of oligonucleotide adaptors to one end and the other end of a target nucleic acid, claim 16) (paragraph [0019]; and Figure 2b). Figure 2b is shown below:
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Figure 2C illustrates a plurality of Y-shaped sequencing adaptors that can attach to each end of the target nucleic acid (corresponding to modular oligo adaptors). Figure 2c is shown below:
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Figure 1c shows the components of the Y-shaped sequencing adaptors (corresponding to modular oligonucleotide adaptors), as shown below:
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Diehn teaches attaching oligonucleotide Y-adaptors that comprise the same components as the adapters recited in instant claim 16, such that Diehn teaches all of the limitations as recited in claim 16. Thus, the rejection is maintained.
Claim Rejections - 35 USC § 103
The rejection of claims 16-23 is maintained under 35 U.S.C. 103 as being unpatentable over Diehn et al. (hereinafter “Diehn”) (International Application WO2016040901, published March 17, 2016; of record) in view of Newman et. al. (hereinafter “Newman”) (Nature Biotechnology, 2016, 34(5), 547-560; and Supplementary Information, 2016, 34(5), 1-22; of record).
The teachings of Diehn as applied to claims 16-23 are described supra.
Diehn does not specifically exemplify the term oligonucleotide pairs (claim 17-20, in part).
Regarding claim 17-20 (all in part), Newman teaches that high-throughput sequencing of circulating tumor DNA (ctDNA) promises to facilitate personalized cancer therapy; wherein low quantities of cell-free DNA (cfDNA) in the blood and sequencing artifacts currently limit analytical sensitivity, such that to overcome these limitations, an approach for integrated digital error suppression (iDES) was introduced, which combines in silico elimination of highly stereotypical background artifacts with a molecular barcoding strategy for the efficient recovery of cfDNA molecules, wherein these two methods each improve the sensitivity of cancer personalized profiling by deep sequencing (CAPP-Seq) by about threefold, and synergize when combined to yield ~15-fold improvements, such that iDES-enhanced CAPP-Seq facilitates noninvasive variant detection across hundreds of kilobases; and when applied to non-small cell lung cancer (NSCLC) patients, the method enabled biopsy-free profiling of EGFR kinase domain mutations with 92% sensitivity and >99.99% specificity at the variant level, and with 90% sensitivity and 96% specificity at the patient level, which allowed monitoring of NSCLC ctDNA down to 4 in 105 cfDNA molecules, such that iDES is anticipated aid the noninvasive genotyping and detection of ctDNA in research and clinical settings (Abstract). Newman teach in Supplementary Figure 1(a), a diagram illustrating the design and usage of custom sequencing adaptors that implement two types of molecular barcodes (pg. 1, Supplementary Information, Figure 1a). Supplementary Figure 1(a) is shown below:
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Figure 2a and Supp. Figure 1a begin with an index adapter design in which a random molecular barcode (index barcode) is incorporated in the single-stranded portions of the adapter immediately adjacent to the sample multiplexing barcode (pg. 556, col 1, sixth full paragraph, lines 1-4; and Supplementary Figure 1a). Newman teaches that pairs of single-stranded oligonucleotides harboring individual insert barcodes of predefined sequence were chemically synthesized, wherein these pairs were then annealed individually, before pooling, to generate a diverse mixture with defined composition and desired diversity; and additional advantages of this approach are described in Supplementary Note, such that tandem adapters with 12 different sample multiplexing barcodes (with pairwise edit distances ≥3) were designed (interpreted as oligonucleotide pairs, claim 17-20) (pg. 556, col 2, first full paragraph). Newman teaches that by matching complementary insert UIDs, this allows for reconstruction of parental double-stranded DNA duplexes as shown in Figure 2a (interpreted complementary UIDs as unique identifier sequences that are complementary and/or variable length punctuation marks that are complementary, claim 16) (pg. 548, 1, last full paragraph; and Figure 2a). Newman teaches that a constant 2-bp sequence (GT) was incorporated at the ligating end of each tandem adapter, immediately adjacent to the insert barcodes, wherein the T was required for ligation, and the G was chosen to maintain the GC ‘clamp’ base pair located at the end of standard Illumina adapters, such that the GT dinu-cleotide additionally served as a punctuation mark, allowing for the assess-ment of proper adapter ligation in sequencing data; and for each of the 12 sample multiplexing barcodes, 16 pairs of oligonucleotides were obtained—one for each two-base insert barcode (interpreted as a variable length punctuation marks, claim 16) (pg. 556, col 2, second full paragraph).
It is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of improving analytical sensitivity as exemplified by Newman, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of identifying and analyzing nucleic acids from a patient’s sample including a patient’s cfDNA sample using indexed and barcoded polynucleotide adaptors to detect, diagnose and/or determine a prognosis of cancer as disclosed by Diehn to include the integrated digital error suppression method and tandem adaptors with 12 different multiplexing barcodes as taught by Newman with a reasonable expectation of success in creating a non-invasive method having improved sensitivity and specificity in personalized cancer profiling through improvements in the analysis of low nucleic acid yields, reducing analytical artifacts and/or reducing sequencing errors; and/or in improving the non-invasive detection of cancer-derived cfDNA in a patient sample including the ability to monitor a patient in clinical settings.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly rejected under 35 USC §103(a) as obvious over the art.
Response to Arguments
Applicant’s arguments filed May 28, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) a prima facie case of obviousness has not been established at least because the combination of the references do not teach the claimed methods, as amended because Diehn does not teach the claimed generation of modular adapters and uses thereof (pg. 15, first full paragraph).
Regarding (a), please see the discussion supra regarding the teachings of the as-filed Specification and original claims; as well as, the teachings of Diehn. Additionally, please see the Office Action mailed March 31, 2026 demonstrating where Diehn teaches the attachment of the adaptors comprising the specific adaptor components as recited in claim 16. It is noted that none of the references has to teach each and every claim limitation. If they did, this would have been anticipation and not an obviousness-type rejection. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant’s assertion that a prima facie case of obviousness has not been established at least because Diehn does not teach the claimed generation of modular adapters and uses thereof, is not found persuasive. As an initial matter, instant claim 16 does not recite the generation of modular adapters, only their individual components and their attachment to a target nucleic acid. As noted supra, Diehn teaches the attachment of a pair oligonucleotide Y-adaptors to the ends of target nucleic acids, wherein the oligonucleotide adaptors taught by Diehn and Newman comprise the same components as the adapters recited in instant claim 16. For example, as noted supra –
Diehn teaches:
Figure 1b shows the ligation of Y-shaped sequencing adaptors to each end of a target cfDNA (corresponding to attaching a pair of oligonucleotide adaptors to one end and the other end of a target nucleic acid, claim 16) (paragraph [0019]; and Figure 2b). Figure 2b is shown below:
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Figure 2C illustrates a plurality of Y-shaped sequencing adaptors that can attach to each end of the target nucleic acid (corresponding to modular oligo adaptors). Figure 2c is shown below:
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Newman teaches:
CAPP-Seq barcode adapters comprising the same components as recited in claim 16.
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wherein the diagram illustrates the design and usage of custom sequencing adaptors that implement two types of molecular barcodes (Supplementary Figure S1), including an index adapter design in which a random molecular barcode (index barcode) is incorporated in the single-stranded portions of the adapter immediately adjacent to the sample multiplexing barcode (pg. 556, col 1, sixth full paragraph, lines 1-4; and Supplementary Figure 1a).
Thus, the combined references of Diehn and Newman teach the attachment of ‘modular’ oligonucleotide adaptors to target nucleic acids. The claims remain rejected.
New Objections/Rejections
Claim Rejections - 35 USC § 112(a) – New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 16-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112, para. 1, as lacking adequate written description”. According to MPEP § 2163.I.B, “While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure” and “The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117”.
The claim contains subject matter that was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art (hereafter the Artisan), that the inventor(s), at the time the application was filed, had possession of the claimed invention. 37 CFR §1.118 (a) states that "No amendment shall introduce new matter into the disclosure of an application after the filing date of the application". Claim 16 recites (in part): “attaching a pair of modular oligonucleotide adapters, by attaching a first modular oligonucleotide adapter to one end of a target nucleic acid, and attaching a second modular oligonucleotide adapter to the other end of the target nucleic acid” in lines 5-6. However, support was not found for these limitations in the as-filed Specification and/or the original claims.
Upon review of the instant as-filed Specification and original claims, support was not found for attaching a pair of modular oligonucleotide adapters, including attaching a first modular oligonucleotide adapter to one end of a target nucleic acid, and attaching a second modular oligonucleotide adapter to the other end of a target nucleic acid as recited in instant claim 16. Applicant pointed to paragraphs [008]; [035]; [036]; [053]-[055]; [068]; and Figures 1 and 2A. The instant as-filed Specification, filed November 3, 2022 teaches, for example: “a kit for preparing a library of nucleic acids having adapter sequences for sequencing, the kit comprising: a plurality of oligonucleotide pairs” (paragraph [015], lines 5-6); “attaching one of a plurality of oligonucleotide adapters to each end of a target nucleic acid to provide an adapter-target-adapter construct” (paragraphs [025]); “Figure 1 is a schematic diagram depicting an embodiment of the components of a modular adapter according to the present disclosure” (paragraph [035]); and “a pool of forked adapter is prepared with each adapter having a UID selected from a set of two or more different UID sequences” (paragraph [053], lines 20-22). No such corresponding teaching of attaching a pair of modular oligonucleotide adapters including attaching a first modular oligonucleotide adapter to one end, and attaching a second modular oligonucleotide adapter to the other end of a target nucleic acid as recited in instant claim 16 is taught by the instant as-filed Specification and/or the original claims.
A claim-by-claim analysis and for independent claim 16, and a method step by method step analysis regarding where support can be found for the composition found in each of the plurality of microcapillaries in the originally filed specification is respectfully suggested. See MPEP § 2163 particularly § 2163.06.
Claims 16-23 will remain rejected until Applicant cancels all new matter.
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 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.
Claims 16-23 are rejected under 35 U.S.C. 102(a1)/102(a2) as being anticipated by Bignall et al. (hereinafter “Bignall”) (US Patent No. 9512478, issued December 6, 2016) as evidenced by Rosalind (Rosalind Platform, 2014, 1).
Regarding claim 16, Bignall teaches methods for indexing samples during the sequencing of polynucleotide templates, resulting in the attachment of tags specific to the source of each nucleic acid sample such that after a sequencing run, both the source and sequence of each polynucleotide can be determined (Abstract). Bignall teaches a method, comprising: (a) providing at least two samples of randomly fragmented double-stranded nucleic acid targets, wherein each of said randomly fragmented double-stranded nucleic acid targets is isolated from a different source; (b) ligating a universal adaptor to the ends of each target fragment of each sample to generate adaptor-target-adaptors of each sample (interpreted as adaptor-target-adaptor), each of said adaptor-target-adaptors comprising a target fragment flanked by universal adaptor sequences and said universal adaptor comprises a region of double-stranded nucleic acid and at least one region of single-stranded nucleic acid (interpreted as a tail); (c) amplifying adaptor-target-adaptors of each sample with two or more sample specific amplification primers to generate amplified nucleic acids (interpreted as annealing primers, extending, unique identifiers; and variable punctuation marks), wherein one of said amplification primers comprises a sample specific tag sequence, and wherein amplified nucleic acids of each sample comprise said sample specific tag sequence and said sample specific tag sequence differentiates amplified nucleic acids originating from different samples (corresponding to attaching adaptors each comprising a tail, unique identifier sequences, and/or a variable punctuation mark; priming the adapter-target-adaptor sequence; annealing primers; and extending the primers to prepare a library, claim 16) (col 3, lines 66-67; col 4, lines 1-18). Bignall teaches that the target polynucleotide sequences are prepared with single overhanging nucleotides by, for example, activity of certain types of DNA polymerase such as Taq polymerase or Kienow exo minus polymerase, which has a non-template-dependent terminal transferase activity that adds a single deoxynucleotide, for example, deoxyadenosine (A) to the 3' ends of, for example, PCR products (interpreted as producing an overhang; and adding a punctuation mark, claim 16) (col 9, lines 24-31). Bignall teaches an 'A’ could be added to the 3' terminus of each end repaired duplex strand of the target polynucleotide duplex by reaction with Taq or Kienow exo minus polymerase, whilst the adaptor polynucleotide construct could be a T-construct with a compatible ‘T’ overhang present on the 3’ terminus of each duplex region of the adaptor construct (interpreted as adding a punctuation mark, claim 16) (col 9, lines 33-39). Bignall teaches that depending on the embodiment of the invention, the adaptors can be universal for all samples, or one or both strands of the duplexes can carry the tag sequence to code or track the identity of the samples (interpreted as adaptors comprising common sequences and/or a unique identifier sequence, claim 16). Bignall teaches that the tags can be on the adaptors (interpreted as uniquely tagged, claim 16) (col 10, lines 3-5; and Figure 3). Bignall teaches that Figure 2 shows the use of tagged adaptors for each sample and one pair of universal amplification primers; while Figure 3 shows two (2) adaptor oligos per tag, and two (2) amplification primers per tag (interpreted as adaptors comprising a common sequence; and different unique tags, claims 16 and 17) (Figures 2 & 3). Figure 2 (in part) and Figure 3 (in part) are shown below:
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Figure 3
Bignall teaches in Example 1, that two libraries were made, wherein the DNA was first prepared for ligation to forked adaptors by: fragmentation of the DNA by nebulization, end repair of the DNA ends to render them blunt-ended and phosphorylated, then the addition of a single 'A' nucleotide onto the 3' ends of the DNA fragments, wherein the ligation reaction was performed with the prepared fragmented DNA and adaptors pre-formed by annealing 'Oligo A’ and 'Oligo B' (corresponding to attaching a pair of modular oligo adapters to each end of a target nucleic acid, claim 16) (col 21, lines 20-30). Bignall teaches that the product of the ligation reaction was subjected to cycles of PCR to selectively amplify ligated product that contained genomic DNA with adaptor at both ends of the fragments, such that during the PCR a unique tag was added to each library using a unique PCR primer, so that the library was indexed with the unique sequence tag ‘ATC’ and the PhiX library was indexed with the unique sequencing tag ‘CGA’ (See; Figure 1) (corresponding to annealing a primer including a first tail; unique identifier sequence; and variable length punctuation marks, claim 16) (col 21, lines 33-39; and Figure 1). Bignall teaches that the steps include: (1) nebulization; (2) end-repair; (3) A-tailing reaction; (4) annealing adaptors during PCR; (5) ligation; (6) gel purification; (7) exonuclease treatment; and (8) PCR of gel purified DNA (corresponding to attaching adaptors each comprising a tail, unique identifier sequences, and/or a variable punctuation mark; priming the adapter-target-adaptor sequence; annealing primers; and extending the primers to prepare a library, claim 16) (col 21, line 42 through col 24, line 67). Bignall teaches in Figure 8, tags comprising end sequences including ATCATCG, CGATGT, TTAGGC, ACAGTG, GGCTAC, etc. (interpreted as punctuation marks, claim 16) (Figure 8).
Regarding claim 17, Bignall teaches that the tags consist of eight four base 'words' , where each word uses only three bases (A, T and C) in various combinations resulting in a total of 16,777,216 different tags that all have the same base pair composition and melting points, wherein such tags are used to label target molecules in a sample so that after an amplification reaction each original molecule in the sample has unique tag (corresponding to each first tag is different, claim 17) (col 3, lines 13-19). Bignall teaches that the nucleic acid sequence tag can be up to 20 nucleotides in length, more preferably 1-10 nucleotides, and most preferably 4-6 nucleotides in length, such that a four nucleotide tag gives a possibility of multiplexing 256 samples on the same array, a six base tag enables 4096 samples to be processed on the same array (interpreting the unique identifier sequences are different, claim 17) (col 9, lines 58-63).
Regarding claims 18 and 19, Bignall teaches that step (3) comprises A-tailing the adaptor sequences (interpreted as the first and second tail sequence of each of the pairs of oligo adaptors is the same, claims 18 and 19) (col 22, lines 20-21).
Regarding claim 20, Bignall teaches that he DNA was prepared for ligation to forked adaptors (corresponding to forked adaptors, claim 20) (col 21, lines 24-25).
Regarding claim 21, Bignall teaches that the insert DNA from each of the libraries aligned to the correct reference (interpreted as one-to-one mapping, claim 21) (col 30, lines 18-19). Bignall teaches that Figure 4 shows that all the clusters sequenced aligned against a known sample (PhiX, BAC or E. coli contamination), and that for the samples that aligned correctly (interpreted as one-to-one mapping, claim 21) (col 41, lines 65-67; and Figure 4). Bignall teaches that each sample from the 12 was represented by a reasonable number of clusters, and for each tag read, the large majority (>90%) of the reads aligned against the source genome identified by the tag (interpreted as one-to-one mapping, claim 21) (col 46, lines 51-54).
Regarding claims 22 and 23, Bignall teaches that the nucleic acid sequence tag can be up to 20 nucleotides in length, more preferably 1-10 nucleotides, and most preferably 4-6 nucleotides in length, such that a four nucleotide tag gives a possibility of multiplexing 256 samples on the same array, a six base tag enables 4096 samples to be processed on the same array (interpreting the unique identifier sequences to comprise at least 5 nucleotides; and an edit distance of at least 3, claims 22 and 23) (col 9, lines 58-63). Bignall teaches in Figure 8, tags comprising end sequences including ATCATCG, CGATGT, TTAGGC, ACAGTG, GGCTAC, etc. (interpreted as an edit distance of at least 3, claim 23) (Figure 8), wherein the edit distance between ATCATCG and TGACCA from Figure 8 is 4 as evidenced by Rosalind.
Bignall meets all the limitations of the claims and, therefore, anticipates the claimed invention.
Conclusion
Claims 16-23 are rejected.
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/AMY M BUNKER/Primary Examiner, Art Unit 1684
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