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 .
Claims 1-20 are pending and will be examined.
Priority
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 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. 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, Application No. 61462972, 61426208, 61398159, 61395850, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. While each of these priority documents include support for cell free nucleic acids and enrichment of nucleic acids, none of these priority documents include sufficient (or any) support for the inclusion of barcodes or barcode primers, no discussion of hybrid capture probes, or the inclusion of cancer or tumor or that polymorphic loci are associated with tumor or cancer. Therefore, as the priority documents of US Patent 8825412 and 61516996, for example, provide support, the claims are afforded an earliest priority of April 12, 2011.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1, 4-6, 9-11, 13-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-2 of U.S. Patent No. 11,519,035 ('035 patent). Although the claims at issue are not identical, they are not patentably distinct from each other because while the patents are not identical, they are drawn to very similar subject matter. The instant claims require steps of tagging, enrichment, amplification and sequencing. The claims of the '035 patent and the instant method include loci associated with cancer and a range of loci that includes up to 2000 loci. The differences between the instant claims and the claims of the '035 patent arise in the different specifics regarding the steps of tagging with barcodes, amplification and sequencing are recited in the '035 patent as compared to the instant claims. However, it is the shared features between the methods that renders the claims patent ineligible. For example, besides the similarities noted above, both methods are focused on isolation of cell free DNA, enriching using hybrid capture probes and analysis of loci associated with cancer.
Therefore, while the claims are not the same, they are also not patentably distinct.
Claim 1-2, 4-6, 11-12 and 14-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3 and 7-9 of copending Application No. 18678417 (reference application, ‘417 application herein). Although the claims at issue are not identical, they are not patentably distinct from each other because while the applications are not identical, they are drawn to very similar subject matter. The instant claims require steps of tagging, enrichment, amplification and sequencing. The claims of the '417 application and the instant method include loci associated with cancer and a range of loci that includes up to 2000 loci. The differences between the instant claims and the claims of the '417 application arise in the different specifics regarding the steps of tagging with barcodes, amplification and sequencing as recited in the '417 application as compared to the instant claims. However, it is the shared features between the methods that renders the claims patent ineligible. For example, besides the similarities noted above, both methods are focused on isolation of cell free DNA, enriching using hybrid capture probes and analysis of loci associated with cancer. Compare instant claims 4-6 and 14-16 to claims 2-3 and 8 of the ‘417 application where the same range of loci are encompassed by both sets of claims.
Therefore, while the claims are not the same, they are also not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1-2, 4-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-9, 11-14, 16-19 and 21 of copending Application No. 17196659 (reference application, ‘659 application herein). Although the claims at issue are not identical, they are not patentably distinct from each other because while the applications are not identical, they are drawn to very similar subject matter. The instant claims require steps of tagging, enrichment, amplification and sequencing. The claims of the ‘659 application and the instant method include loci associated with cancer and a range of loci that includes up to 2000 loci. The differences between the instant claims and the claims of the ‘659 application arise in the different specifics regarding the steps of tagging individual strands with barcodes, amplification and sequencing as recited in the ‘659 application as compared to the instant claims. However, it is the shared features between the methods that renders the claims patent ineligible. For example, besides the similarities noted above, both methods are focused on isolation of cell free DNA, enriching using hybrid capture probes and analysis of loci associated with cancer. Compare instant claims 4-6 and 14-16 to claims 2-3 and 8 of the ‘417 application where the same range of loci are encompassed by both sets of claims. Compare instant claims 6-10 and 17-20 to claims 6-9 and 16-19 encompass the same claim language regarding molecular barcodes and inclusion within the method.
Therefore, while the claims are not the same, they are also not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on January 17, 2025 and August 15, 2025 was filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-6 and 11-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pieprzyk et al. (US PgPub 20140186827; July 2014), Gnirke et al. (Nature Biotechnology, 2009, 27(2):182-189), Gormally et al. (Mutation Research, 2007, 635:105-117) and Quake et al. (US Patent 11,130,995 B2; September 2021).
With regard to claim 1, Pieprzyk teaches a method for enriching and sequencing cell-free DNA, comprising:
tagging cell-free DNA isolated from a biological sample with molecular barcodes to obtain a library of DNA, wherein the cell-free DNA from a single biological sample are tagged with a plurality of molecular barcodes (paragraph 71, which points to Figure 11A-B and Example 13, paragraph 501, where universal tags are included; see also Example 13 and Example 14, where universal or common sequences are used in amplification; see also paragraph 173, where sequencing libraries are also generated in different embodiments; see Example 10, where cell free nucleic acids are used for determination of fetal aneuploidy and which recites the reasons why barcodes are important to the implementation of the method of Pieprzyk as applies to the determination of fetal aneuploidy; specifically at Example 10, Pieprzyk teaches that the inclusion of unique barcodes allows for multiplexing);
amplifying the library of DNA and enriching for a plurality of target loci to obtain an enriched library of amplicons (paragraph 70, which refers to Fig 10A-M and Example 12, where the method enriches for products for use within the method, as claimed; see also paragraph 644, within Example 12; see also paragraph 183, for example, where a plurality up to 1000 target loci can be analyzed);
and performing high-throughput sequencing to sequence the amplicons to obtain sequence reads of at least 50 target loci (see for example, sequencing as described in Example 10, paragraph 632).
With regard to claim 2, Pieprzyk teaches a method of claim 1, wherein the biological sample is a blood, plasma, serum, or urine sample (paragraph 57, 172-173, 225, 713, where whole blood or maternal whole blood is used for extraction; see also pp 185, 191, 299, where the method is applicable to cancer patients).
With regard to claim 4, Pieprzyk teaches a method of claim 1, wherein the plurality of target loci comprises between 100 and 2,000 single nucleotide polymorphism or variant loci (paragraph 183, for example, where a plurality up to 1000 target loci can be analyzed).
With regard to claim 5, Pieprzyk teaches a method of claim 1, wherein the plurality of target loci comprises between 200 and 1,000 single nucleotide polymorphism or variant loci (paragraph 183, for example, where a plurality up to 1000 target loci can be analyzed).
With regard to claim 6, Pieprzyk teaches a method of claim 1, wherein the plurality of target loci comprises between 300 and 2,000 single nucleotide polymorphism or variant loci (paragraph 183, for example, where a plurality up to 1000 target loci can be analyzed).
With regard to claim 11, Pieprzyk teaches a method for enriching and sequencing cell-free DNA, comprising: tagging cell-free DNA isolated from a biological sample with molecular barcodes to obtain a library of DNA (paragraph 71, which points to Figure 11A-B and Example 13, paragraph 501, where universal tags are included; see also Example 13 and Example 14, where universal or common sequences are used in amplification; see also paragraph 173, where sequencing libraries are also generated in different embodiments; see Example 10, where cell free nucleic acids are used for determination of fetal aneuploidy and which recites the reasons why barcodes are important to the implementation of the method of Pieprzyk as applies to the determination of fetal aneuploidy; specifically at Example 10, Pieprzyk teaches that the inclusion of unique barcodes allows for multiplexing),
wherein the cell-free DNA from a single biological sample are tagged with a plurality of molecular barcodes;
enriching the library of DNA for a plurality of target loci to obtain an enriched library of amplicons, wherein at least one amplicon comprises two or more target loci (paragraph 70, which refers to Fig 10A-M and Example 12, where the method enriches for products for use within the method, as claimed; see also paragraph 644, within Example 12; see also paragraph 183, for example, where a plurality up to 1000 target loci can be analyzed);
and performing high-throughput sequencing to sequence the amplicons to obtain sequence reads of at least 50 target loci and determine whether the target loci comprise a cancer- associated mutation based on the sequence reads (see for example, sequencing as described in Example 10, paragraph 632).
With regard to claim 12, Pieprzyk teaches a method of claim 11, wherein the biological sample is a blood, plasma, serum, or urine sample (paragraph 57, 172-173, 225, 713, where whole blood or maternal whole blood is used for extraction; see also pp 185, 191, 299, where the method is applicable to cancer patients).
With regard to claim 14, Pieprzyk teaches a method of claim 11, wherein the plurality of target loci comprises between 100 and 2,000 single nucleotide polymorphism or variant loci (paragraph 183, for example, where a plurality up to 1000 target loci can be analyzed).
With regard to claim 15, Pieprzyk teaches a method of claim 11, wherein the plurality of target loci comprises between 200 and 1,000 single nucleotide polymorphism or variant loci (paragraph 183, for example, where a plurality up to 1000 target loci can be analyzed).
With regard to claim 16, Pieprzyk teaches a method of claim 11, wherein the plurality of target loci comprises between 300 and 2,000 single nucleotide polymorphism or variant loci (paragraph 183, for example, where a plurality up to 1000 target loci can be analyzed).
Regarding claims 1 and 11, while Pieprzyk teaches enrichment of short nucleic acids,
Pieprzyk does not teach the use of hybrid capture probes. Further, while Pieprzyk teaches
sequencing, Pieprzyk is not specific regarding massively parallel sequencing.
With regard to claim 1 and 11, Gnurke teaches enriching for a plurality of target loci using a plurality of target-specific hybrid capture probes to obtain an enriched library of amplicons (Abstract, Figure 1, where hybrid capture probe enrichment is described).
Regarding claims 1 and 11, while Gnirke teaches massively parallel sequencing, neither Pieprzyk or Gnirke are specific in detecting cancer specific mutations using the method, as claimed.
With regard to claims 1 and 11, Gormally teaches methods that determine whether the target loci comprise a cancer- associated mutation based on the sequence reads (Fig 1, p 107-108, where the role of cell free DNA in mutation detection is generally described; Table 3, p 112, col. 1, top of page).
Regarding claims 1 and 11, while Pieprzyk teaches steps of amplification, enrichment and sequencing, Pieprzyk is not specific about capturing more than one loci within an amplicon.
With regard to claims 1, 3, 11 and 13, Quake teaches wherein at least one amplicon comprises two or more target loci (col. 18, where linked and unlinked SNPs and loci are described in detail).
With regard to claim 3, Quake teaches a method of claim 1, wherein at least one amplicon comprises two or more nearby single nucleotide polymorphism or variant loci (col. 18, where linked and unlinked SNPs and loci are described in detail).
With regard to claim 13, Quake teaches a method of claim 11, wherein at least one amplicon comprises two or more nearby single nucleotide polymorphism or variant loci (col. 18, where linked and unlinked SNPs and loci are described in detail).
Further, it would have been prim a facie obvious to one of ordinary skill in the art at the time the invention was made to have adjusted the teachings of Pieprzyk to include the hybrid capture probes, enrichment and massively parallel sequencing techniques as taught by Gnirke to arrive at the claimed invention with a reasonable expectation for success, Pieprzyk teaches a method of sequencing of cell-free nucleic acids using steps of analysis of cell free mideic acids for amplification and sequencing. While Pieprzyk does not specifically teach the inclusion of hybrid capture probes, Gnirke teaches specific library-based enrichment of nucleic acids with the inclusion of hybrid capture probes. Gnirke teaches "We developed a capture method that uses biotinylated RNA 'baits' to fish targets out of a 'pond' of DNA fragments. The RNA is transcribed from PCR-amplified oligodeoxynucleotides originally synthesized on a micro array, generating sufficient bait for multiple captures at concentrations high enough to drive the
hybridization. We tested this method with 170-mer baits that target 415,000 coding exons (2.5
Mb) and four regions (1.7 Mb total) using Illumina sequencing as read-out". As noted in that
statement, Gnirke also focuses on massively parallel sequencing and also notes 'With further
optimization, routine implementation of hybrid selection would enable deep, targeted next-generation sequencing of thousands of exons as well as of megabase-sized candidate regions implicated by genetic screens. Targeting based on hybrid selection may be potentially useful for a variety of other applications as well, where traditional singleplex PCR is either too costly or too specific in that specific primers may fail to produce a PCR product that represents all genetic variation in the sample. Examples are enrichment of precious ancient DNA that is heavily
contaminated with unwanted DNA, deep sequencing of viral populations in clinical samples, or
metagenomic analyses of environmental or medical specimens" (p. l 86, col. 2 "Discussion"
heading). Therefore, one of ordinary skill in the art at the time the invention was made would
have adjusted the teachings of Pleprzyk to include the hybrid capture probes, enrichment and
massively parallel sequencing as taught by Gnirke to arrive at the claimed invention with a reasonable expectation for success.
1t would have been prima facie obvious to one of ordinary skill in the art at the tie the invention was made to have adjusted the teachings of Pieprzyk and Gnirke to apply the method to detection of cancer as described by Gormally to arrive at the claimed invention with a reasonable expectation for success. First Pieprzyk specifically teaches the method could be useful in cancer, "These enrichment/selective tagging methods can be combined with methods described above to further facilitate the detection and or quantification of target sequences in samples having mixed length nucleic acids (e.g. fetal DNA in maternal plasma or tumor DNA in plasma from cancer patients.". Pieprzyk also notes "These methods can also be employed in determinations DNA or RNA copy number. Determinations of aberrant DNA copy number in genomic DNA is useful, for example, in the diagnosis and/or prognosis of genetic defects and diseases, such as cancer" (paragraph 299). These methods can be carried out, for example, to determine a fetal genotype or determine the presence of a mutation or fetal aneuploidy" (paragraph 60). Pieprzyk also teaches "These methods can be carried out, for example, to determine a fetal genotype or determine the presence of a mutation or fetal aneuploidy" (paragraph 176). Next, Gormally teaches ''the technical issues involved in obtaining, using and analyzing CFDNA in cancer or healthy subjects. We also summarize the literature available on the mechanisms of CDNA release as well as on cross-sectional or prospective studies aimed at assessing the clinical and biological significance of CFDNA. These studies show that, in some circumstances, CFDNA alterations are detectable ahead of cancer diagnosis, raising the possibility of exploiting them as biomarkers for monitoring cancer occurrence" (Abstract).
Therefore, one of ordinary skill in the art at the ti1ne the invention was made would have adjusted the teachings of Pieprzyk and Gnirke to apply the method to detection of cancer as described by Gormally to arrive at the claimed invention with a reasonable expectation for success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have adjusted the teachings of Pieprzyk, Gnirke and Gormally to include at least two loci within an amplicon as guided by Quake to arrive at the claimed invention with a reasonable expectation for success. Pieprzyk teaches a method of sequencing of cell-free nucleic acids using steps of analysis of cell free nucleic acids for amplification and sequencing. Quake teaches “SNPs that are encompassed by the method of the invention include linked and unlinked
SNPs. Each target nucleic acid comprises at least one polymorphic site e.g. a single SNP, that differs from that present on another target nucleic acid to generate a panel of polymorphic sites e.g. SNPs, that contain a sufficient number of polymorphic sites of which at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40 or more are informative” (col. 18). Therefore, one of ordinary skill in the art at the time the invention was made would have adjusted the teachings of Pieprzyk, Gnirke and Gormally to include at least two loci within an amplicon as guided by Quake to arrive at the claimed invention with a reasonable expectation for success.
Claim(s) 7-10 and 17-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pieprzyk et al. (US PgPub 20140186827; July 2014), Gnirke et al. (Nature Biotechnology, 2009, 27(2):182-189), Gormally et al. (Mutation Research, 2007, 635:105-117) and Quake et al. (US Patent 11,130,995 B2; September 2021) as applied above over claims 1-6 and 11-16 and further in view of McCloskey et al. (US PgPub 20070020640; January 2007).
With regard to claim 7, McCloskey teaches a method of claim 1, wherein the cell-free DNA are tagged with up to 1024 molecular barcodes (paragraph 21, where "random barcode" refers to an arbitrary sequence that can uniquely identify a target nucleic acid in an experiment, and whose sequence is unknown at the start of the experiment; later in the same paragraph, McCloskey notes “a second sequence of 7 random nucleotides N selected from A, G, C, and T will provide a maximum of 47 or 16,384 unique barcodes. In some embodiments, the length of the second sequence is between 3 and 30 nucleotides, such as between 5 and 25 nucleotides or between 7 and 13 nucleotides”; see Example 1, p 6, paragraph 53, where barcodes are useful in identifying unique sequences; see also Example 2, p 7, paragraph 63, where barcodes are again useful in identification of unique sequences; see also Table 1, for example).
With regard to claim 8, McCloskey teaches a method of claim 1, wherein the cell-free DNA are tagged with 1024-65536 molecular barcodes (paragraph 21, where "random barcode" refers to an arbitrary sequence that can uniquely identify a target nucleic acid in an experiment, and whose sequence is unknown at the start of the experiment; later in the same paragraph, McCloskey notes “a second sequence of 7 random nucleotides N selected from A, G, C, and T will provide a maximum of 47 or 16,384 unique barcodes. In some embodiments, the length of the second sequence is between 3 and 30 nucleotides, such as between 5 and 25 nucleotides or between 7 and 13 nucleotides”; see Example 1, p 6, paragraph 53, where barcodes are useful in identifying unique sequences; see also Example 2, p 7, paragraph 63, where barcodes are again useful in identification of unique sequences; see also Table 1, for example).
With regard to claim 9, McCloskey teaches a method of claim 1, wherein the cell-free DNA are tagged with the molecular barcodes through adaptor ligation (paragraph 21, where "random barcode" refers to an arbitrary sequence that can uniquely identify a target nucleic acid in an experiment, and whose sequence is unknown at the start of the experiment; later in the same paragraph, McCloskey notes “a second sequence of 7 random nucleotides N selected from A, G, C, and T will provide a maximum of 47 or 16,384 unique barcodes. In some embodiments, the length of the second sequence is between 3 and 30 nucleotides, such as between 5 and 25 nucleotides or between 7 and 13 nucleotides”; see Example 1, p 6, paragraph 53, where barcodes are useful in identifying unique sequences; see also Example 2, p 7, paragraph 63, where barcodes are again useful in identification of unique sequences; see also Table 1, for example).
With regard to claim 10, McCloskey teaches a method of claim 1, wherein sequence reads originating from the same original molecule are identified using the molecular barcodes (paragraph 21, where "random barcode" refers to an arbitrary sequence that can uniquely identify a target nucleic acid in an experiment, and whose sequence is unknown at the start of the experiment; later in the same paragraph, McCloskey notes “a second sequence of 7 random nucleotides N selected from A, G, C, and T will provide a maximum of 47 or 16,384 unique barcodes. In some embodiments, the length of the second sequence is between 3 and 30 nucleotides, such as between 5 and 25 nucleotides or between 7 and 13 nucleotides”; see Example 1, p 6, paragraph 53, where barcodes are useful in identifying unique sequences; see also Example 2, p 7, paragraph 63, where barcodes are again useful in identification of unique sequences; see also Table 1, for example).
With regard to claim 17, McCloskey teaches a method of claim 11, wherein the cell-free DNA are tagged with up to 1024 molecular barcodes (paragraph 21, where "random barcode" refers to an arbitrary sequence that can uniquely identify a target nucleic acid in an experiment, and whose sequence is unknown at the start of the experiment; later in the same paragraph, McCloskey notes “a second sequence of 7 random nucleotides N selected from A, G, C, and T will provide a maximum of 47 or 16,384 unique barcodes. In some embodiments, the length of the second sequence is between 3 and 30 nucleotides, such as between 5 and 25 nucleotides or between 7 and 13 nucleotides”; see Example 1, p 6, paragraph 53, where barcodes are useful in identifying unique sequences; see also Example 2, p 7, paragraph 63, where barcodes are again useful in identification of unique sequences; see also Table 1, for example).
With regard to claim 18, McCloskey teaches a method of claim 11, wherein the cell-free DNA are tagged with 1024-65536 molecular barcodes (paragraph 21, where "random barcode" refers to an arbitrary sequence that can uniquely identify a target nucleic acid in an experiment, and whose sequence is unknown at the start of the experiment; later in the same paragraph, McCloskey notes “a second sequence of 7 random nucleotides N selected from A, G, C, and T will provide a maximum of 47 or 16,384 unique barcodes. In some embodiments, the length of the second sequence is between 3 and 30 nucleotides, such as between 5 and 25 nucleotides or between 7 and 13 nucleotides”; see Example 1, p 6, paragraph 53, where barcodes are useful in identifying unique sequences; see also Example 2, p 7, paragraph 63, where barcodes are again useful in identification of unique sequences; see also Table 1, for example).
With regard to claim 19, McCloskey teaches a method of claim 11, wherein the cell-free DNA are tagged with the molecular barcodes through adaptor ligation (paragraph 21, where "random barcode" refers to an arbitrary sequence that can uniquely identify a target nucleic acid in an experiment, and whose sequence is unknown at the start of the experiment; later in the same paragraph, McCloskey notes “a second sequence of 7 random nucleotides N selected from A, G, C, and T will provide a maximum of 47 or 16,384 unique barcodes. In some embodiments, the length of the second sequence is between 3 and 30 nucleotides, such as between 5 and 25 nucleotides or between 7 and 13 nucleotides”; see Example 1, p 6, paragraph 53, where barcodes are useful in identifying unique sequences; see also Example 2, p 7, paragraph 63, where barcodes are again useful in identification of unique sequences; see also Table 1, for example).
With regard to claim 20, McCloskey teaches a method of claim 11, wherein sequence reads originating from the same original molecule are identified using the molecular barcodes (paragraph 21, where "random barcode" refers to an arbitrary sequence that can uniquely identify a target nucleic acid in an experiment, and whose sequence is unknown at the start of the experiment; later in the same paragraph, McCloskey notes “a second sequence of 7 random nucleotides N selected from A, G, C, and T will provide a maximum of 47 or 16,384 unique barcodes. In some embodiments, the length of the second sequence is between 3 and 30 nucleotides, such as between 5 and 25 nucleotides or between 7 and 13 nucleotides”; see Example 1, p 6, paragraph 53, where barcodes are useful in identifying unique sequences; see also Example 2, p 7, paragraph 63, where barcodes are again useful in identification of unique sequences; see also Table 1, for example).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have adjusted the method of enrichment and sequencing as taught by Pieprzyk to include the individual barcodes of McCloskey to arrive at the claimed invention with a reasonable expectation for success. Pieprzyk teaches a method of sequencing of cell-free nucleic acids using steps of analysis of cell free nucleic acids for amplification and sequencing. McCloskey teaches “the present invention provides methods for authenticating a nucleic acid molecule and its sequence with a molecular barcode and batch-stamp. In another aspect, the present invention provides methods for authenticating a nucleic acid amplification product” (Abstract). As an example, McCloskey also teaches “There were 22 sequences with a barcode that was identical to a sequence already obtained (i.e., redundant sequences). The remaining 110 sequences had distinct barcode regions that were 5 nucleotides long, indicating that those sequences originated from separate cells, or separate genomic target molecules” (paragraph 53). Therefore, one of ordinary skill in the art at the time the invention was made would have adjusted the method of enrichment and sequencing as taught by Pieprzyk to include the individual barcodes of McCloskey to arrive at the claimed invention with a reasonable expectation for success.
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Ryan et al. (US Patent 10774380; September 2020)
Conclusion
No claims are allowed. All claims stand rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE KANE MUMMERT whose telephone number is (571)272-8503. The examiner can normally be reached M-F 9:00-5:30.
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/STEPHANIE K MUMMERT/Primary Examiner, Art Unit 1681