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 .
The preliminary amendment filed May 12, 2025 canceling claims 1-16 and newly adding claims 17-31 is acknowledged and has been entered.
Claims 17-31 are pending and will be examined.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on January 17, 2025 and August 27, 2025 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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. 61395850, 61398159, 61426208, 61462972, 61448547, 61516996 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. These priority documents of ‘850, ‘159, ‘208, ‘547 and ‘696 provide support for cell-free or free-floating DNA, universal and tagged amplification but do not provide support for replicate samples. While the 61462972 document provides support for cell free DNA, the document does not provide support for the inclusion of replicate samples, universal adaptors, tagging or amplifying tagged products, as claimed.
The earliest priority date with support for the claimed method is May 18, 2011 as provided by priority document US Patent 8825412.
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.
Claims 17-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,519,035 (‘035 Patent herein) in view of May et al. (US PgPub 20140227691; August 2014). Although the claims at issue are not identical, they are drawn to very similar subject matter. The instant claims require tagging adaptors on to cell free DNA with universal tails, followed by amplification, introducing a barcode and sequencing tag and then sequencing the products. The final step of the method includes high throughput sequencing.
The claims differ in that the ‘035 patent includes very similar steps in a different order, and includes a step of targeted amplification. Further, the steps of the ‘035 patent does not specifically include a step of amplifying the tagged products. However, the ‘035 patent includes universal and barcode sequences, amplification and high throughput sequencing in addition to the method steps that overlap. The ligation step is included in claim 2 of ‘035 patent as compared to instant claim 18. The step where a second adaptor primer is nested is recited in claim 6 of ‘035 patent as compared to instant claim 22. Further, the limitations regarding index primers and index tags is included in claims 7-8 of ‘035 patent as compared to instant claims 23-25.
Further, an additional distinction between the instant claims and the claims of the ‘035 patent is the inclusion of replicate samples in the instant claims. However, it is noted that replicate samples as claimed would have been obvious to one of ordinary skill in the art, sespecially as guided by the teaching of a May.
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 within the claims of the ‘035 patent to include replicate samples as described by May. May teaches replicates “increase the accuracy and/or precision of the relative copy number determination is to carry out a large number of parallel preamplification and/or amplification reactions (i.e., replicates)”. May further teaches “replicates in preamplification can increase the accuracy of the subsequent relative copy number determination, and the use or replicates during amplification/quantification can increase the precision of this determination” (paragraph 72 of May). Therefore, one of ordinary skill in the art at the time the invention was made would have adjusted the teachings within the claims of the ‘035 patent to include replicate samples as described by May with a reasonable expectation for success.
Therefore, while the claims are not the same, they are also not patentably distinct.
Claims 17-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-11 of copending Application No. 19028937 (reference application ‘937). 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 tagging adaptors on to cell free DNA with universal tails, followed by amplification, introducing a barcode and sequencing tag and then sequencing the products. The final step of the method includes high throughput sequencing.
The claims differ in that the ‘937 application includes very similar steps in a different order, and includes a step of targeted amplification. Further, the steps of the ‘937 application does not specifically include a step of amplifying the tagged products. However, the ‘937 application includes universal and barcode sequences, amplification and high throughput sequencing in addition to the method steps that overlap. The ligation step is included in claim 5 of ‘’937 application as compared to instant claim 18. The step where a second adaptor primer is nested is in claim 9 of ‘937 application as compared to instant claim 22.
Further, an additional distinction between the instant claims and the claims of the ‘937 application is the inclusion of replicate samples in the instant claims. However, it is noted that replicate samples as claimed would have been obvious to one of ordinary skill in the art, sespecially as guided by the teaching of a May.
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 within the claims of the ‘937 application to include replicate samples as described by May. May teaches replicates “increase the accuracy and/or precision of the relative copy number determination is to carry out a large number of parallel preamplification and/or amplification reactions (i.e., replicates)”. May further teaches “replicates in preamplification can increase the accuracy of the subsequent relative copy number determination, and the use or replicates during amplification/quantification can increase the precision of this determination” (paragraph 72 of May). Therefore, one of ordinary skill in the art at the time the invention was made would have adjusted the teachings within the claims of the ‘937 application to include replicate samples as described by May with a reasonable expectation for success.
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.
Claims 17-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-11 of copending Application No. 18620822 (reference application ‘822). 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 tagging adaptors on to cell free DNA with universal tails, followed by amplification, introducing a barcode and sequencing tag and then sequencing the products. The final step of the method includes high throughput sequencing.
The claims differ in that the ‘822 application includes very similar steps in a different order, and includes a step of targeted multiplex amplification. The ‘822 application includes universal and barcode sequences, amplification and high throughput sequencing in addition to the method steps that overlap. The ligation step is included in claim 1 of ‘822 application as compared to instant claim 18. The step where a second adaptor primer is nested is recited in claim 7 of ‘822 application as compared to instant claim 22.
Further, an additional distinction between the instant claims and the claims of the ‘822 application is the inclusion of replicate samples in the instant claims. However, it is noted that replicate samples as claimed would have been obvious to one of ordinary skill in the art, sespecially as guided by the teaching of a May.
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 within the claims of the ‘822 application to include replicate samples as described by May. May teaches replicates “increase the accuracy and/or precision of the relative copy number determination is to carry out a large number of parallel preamplification and/or amplification reactions (i.e., replicates)”. May further teaches “replicates in preamplification can increase the accuracy of the subsequent relative copy number determination, and the use or replicates during amplification/quantification can increase the precision of this determination” (paragraph 72 of May). Therefore, one of ordinary skill in the art at the time the invention was made would have adjusted the teachings within the claims of the ‘822 application to include replicate samples as described by May with a reasonable expectation for success.
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.
Claims 17-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-10 of copending Application No. 18812696 (reference application ‘696). 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 tagging adaptors on to cell free DNA with universal tails, followed by amplification, introducing a barcode and sequencing tag and then sequencing the products. The final step of the method includes high throughput sequencing.
The claims differ in that the ‘696 application includes very similar steps in a different order, and includes a step of specifically targeted amplification. The ‘696 application includes universal and barcode sequences, amplification and high throughput sequencing in addition to the method steps that overlap. The specific strandedness of the adaptors is recited in claim 3 of the ‘696 application as compared to instant claim 19. The inclusion of the barcode within the claimed method is described in claims 1 and 4 of the ‘696 application as compared to instant claims 17, 25 and 26 of the instant claims.
Further, an additional distinction between the instant claims and the claims of the ‘696 application is the inclusion of replicate samples in the instant claims. However, it is noted that replicate samples as claimed would have been obvious to one of ordinary skill in the art, sespecially as guided by the teaching of a May.
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 within the claims of the ‘696 application to include replicate samples as described by May. May teaches replicates “increase the accuracy and/or precision of the relative copy number determination is to carry out a large number of parallel preamplification and/or amplification reactions (i.e., replicates)”. May further teaches “replicates in preamplification can increase the accuracy of the subsequent relative copy number determination, and the use or replicates during amplification/quantification can increase the precision of this determination” (paragraph 72 of May). Therefore, one of ordinary skill in the art at the time the invention was made would have adjusted the teachings within the claims of the ‘696 patent to include replicate samples as described by May with a reasonable expectation for success.
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 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) 17-22 and 26-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over May et al. (US PgPub 20140227691; August 2014) in view of McCloskey et al. (US Patent 20070020640; January 2007).
With regard to claim 17, May teaches a method for amplifying and sequencing DNA, comprising:
obtaining a plurality of replicate samples each comprising a portion of original cell-free DNA isolated from a blood sample collected from a human subject (paragraph 72, where a “large number of parallel preamplification and/or amplification reactions (i.e., replicates)” and further “The use of replicates in preamplification can increase the accuracy of the subsequent relative copy number determination, and the use of replicates during amplification/quantification can increase the precision of this determination” and that up to 10,000 or more replicates can be included);
tagging the cell-free DNA in the plurality of replicate samples with one or more universal tail adaptors to generate tagged products (paragraph 78, where universal or common tags can be included within the method; see also paragraph 80, where May teaches when "common nucleotide tags are employed, common tag-specific primers can be used to produce amplicons for detection");
amplifying the tagged products in the plurality of replicate samples in parallel one or more times to generate final amplification products, wherein one of the amplification steps comprises targeted amplification of a plurality of single nucleotide polymorphism (SNP) loci in a single reaction volume (paragraph 120, where rounds of pre-amplification include tags “such that the two rounds of amplification produce tagged target amplicons” and further see paragraph 166-167 where multiple cycles “to produce tagged target nucleotide sequence(s)” and also paragraph 80, where May teaches when "common nucleotide tags are employed, common tag-specific primers can be used to produce amplicons for detection");
and sequencing the plurality of SNP loci on the cell free DNA by conducting massively parallel sequencing on the final amplification products, wherein the plurality of SNP loci comprises 25-2,000 loci associated with cancer (paragraph 199 where up to 1000 loci are amplified via multiplex; paragraph 71, 198, 110 where the method of amplification includes pre-amplification steps before multiplex amplification; see paragraph 76, where cell free nucleic acid is amplified using steps of pre-amplification and multiplex amplification), wherein the method further comprises determining the likelihood of the presence or absence of a single gene disease in the fetus using sequence reads of the plurality of SNP loci generated from the massively parallel sequencing (abstract; paragraph 202, where the method can be employed in genotyping and diagnosis of disease).
With regard to claim 18, May teaches a method of claim 17, wherein tagging the cell free DNA comprises ligating the one or more universal tail adaptors to the cell free DNA (paragraph 78, where universal or common tags can be included within the method; see also paragraph 80, where May teaches when "common nucleotide tags are employed, common tag-specific primers can be used to produce amplicons for detection"; paragraph 127, where ligation can be used to add adapters to a nucleic acid fragment).
With regard to claim 19, May teaches a method of claim 18, wherein the one or more universal tail adaptors each comprise a first strand and a second strand, wherein a first end of each of the universal tail adaptors comprises a double-stranded section comprising the 5' portion of the first strand and the 3' portion of the second strand, wherein the first end is ligated to the cell free DNA (paragraph 78, where universal or common tags can be included within the method; see also paragraph 80, where May teaches when "common nucleotide tags are employed, common tag-specific primers can be used to produce amplicons for detection"; paragraph 127, where ligation can be used to add adapters to a nucleic acid fragment).
With regard to claim 20, May teaches a method of claim 19, wherein amplifying the tagged products comprises a first amplifying step and a second amplifying step, wherein the first amplifying step comprises using a first target-specific primer that specifically anneals to a target sequence and a first adaptor primer having a nucleotide sequence identical to a first portion of the first strand to generate a first amplification product (paragraph 120, where rounds of pre-amplification include tags “such that the two rounds of amplification produce tagged target amplicons” and further see paragraph 166-167 where multiple cycles “to produce tagged target nucleotide sequence(s)” and also paragraph 80, where May teaches when "common nucleotide tags are employed, common tag-specific primers can be used to produce amplicons for detection").
With regard to claim 21, May teaches a method of claim 20, wherein the second amplifying step comprises using a second target-specific primer that specifically anneals to the first amplification product and a second adaptor primer having a nucleotide sequence identical to a second portion of the first strand to generate the final amplification product (paragraph 119-123, where nested pre-amplification is described).
With regard to claim 22, May teaches a method of claim 21, wherein the second adaptor primer is nested relative to the first adaptor primer (paragraph 120, where rounds of pre-amplification include tags “such that the two rounds of amplification produce tagged target amplicons” and also include nesting of primers within multiple rounds of amplification and further see paragraph 166-167 where multiple cycles “to produce tagged target nucleotide sequence(s)” and also paragraph 80, where May teaches when "common nucleotide tags are employed, common tag-specific primers can be used to produce amplicons for detection").
With regard to claim 27, McCloskey teaches a method of claim 17, wherein the one or more universal tail adaptors comprise a tag (paragraph 78, where universal or common tags can be included within the method; see also paragraph 80, where May teaches when "common nucleotide tags are employed, common tag-specific primers can be used to produce amplicons for detection").
With regard to claim 28, May teaches a method of claim 17, wherein the one or more universal tail adaptors comprise a first universal tail adaptor and a second universal tail adaptor (paragraph 78, where universal or common tags can be included within the method; see also paragraph 80, where May teaches when "common nucleotide tags are employed, common tag-specific primers can be used to produce amplicons for detection").
With regard to claim 29, May teaches a method of claim 28, wherein tagging the cell free DNA comprises amplifying the cell free DNA with a first primer comprising the first universal tail adaptor and a second primer comprising the second universal tail adaptor (paragraph 78, where universal or common tags can be included within the method; see also paragraph 80, where May teaches when "common nucleotide tags are employed, common tag-specific primers can be used to produce amplicons for detection").
With regard to claim 30, May teaches a method of claim 28, wherein amplifying the tagged products comprises a single amplifying step (paragraph 120, where rounds of pre-amplification include tags “such that the two rounds of amplification produce tagged target amplicons” and further see paragraph 166-167 where multiple cycles “to produce tagged target nucleotide sequence(s)” and also paragraph 80, where May teaches when "common nucleotide tags are employed, common tag-specific primers can be used to produce amplicons for detection").
With regard to claim 31, May teaches a method of claim 30, wherein amplifying the tagged products comprises using a third primer and a fourth primer, wherein the third primer comprises a first sequencing tag and wherein the fourth primer comprises a second sequencing tag (paragraph 120, where rounds of pre-amplification include tags “such that the two rounds of amplification produce tagged target amplicons” and further see paragraph 166-167 where multiple cycles “to produce tagged target nucleotide sequence(s)” and also paragraph 80, where May teaches when "common nucleotide tags are employed, common tag-specific primers can be used to produce amplicons for detection").
Regarding claim 17, 26-27, while May teaches the steps of the method as recited above, May does not teach wherein one of the amplifications introduces a barcode and one or more sequencing tags or where May does not teach a sequencing tag specifically using those terms.
With regard to claim 17, McCloskey teaches wherein one of the amplifying steps introduces a barcode and one or more sequencing tags (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 Twill 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; see also paragraph 5-6 and 106, for example, where sequencing tags are added).
With regard to claim 26, McCloskey teaches a method of claim 17, wherein the one or more universal tail adaptors comprise a second barcode (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 Twill 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; see also paragraph 5-6 and 106, for example, where sequencing tags are added).
With regard to claim 27, McCloskey teaches a method of claim 17, wherein the adaptors comprise a second sequencing tag (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 Twill 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; see also paragraph 5-6 and 106, for example, where sequencing tags are added).
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 May to include multiple individual barcodes of McCloskey to arrive at the claimed invention with a reasonable expectation for success. Both May and McCloskey teach methods that include steps of primers, amplification and sequencing. May and McCloskey use the barcodes within the method in different ways. 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 May to include random and different, individual barcodes of McCloskey to arrive at the claimed invention with a reasonable expectation for success.
Claim(s) 23-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over May et al. (US PgPub 20140227691; August 2014) in view of McCloskey et al. (US Patent 20070020640; January 2007) as applied over claims 17-22 and 26-31 above and further in view of Cronn et al. (Nucleic Acids Research 2008, 36(19):e122).
With regard to claim 25, McCloskey teaches a method of claim 24, wherein the index primer comprises the barcode and a first sequencing tag (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 Twill 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; see also paragraph 5-6 and 106, for example, where sequencing tags are added).
Regarding claim 25 and 23-24, while May and McCloskey teach the methods of claim 22, neither May or McCloskey are specific regarding an index tag or index primer.
With regard to claim 23, Cronn teaches a method of claim 22, wherein the second target-specific primer comprises an index tag (Abstract, p. 2 and p. 6).
With regard to claim 24, Cronn teaches a method of claim 23, wherein the second amplifying step further comprises using an index primer comprising a sequence complementary to the index tag (Abstract, p. 2 and p. 6).
With regard to claim 25, Cronn teaches a method of claim 24, wherein the index primer comprises a first sequencing tag (Abstract, p. 2 and p. 6).
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 May and McCloskey to include the index tag as taught by Cronn to arrive at the claimed invention with a reasonable expectation for success. Cronn teaches “To gain maximal access to the historical record contained within chloroplast genomes, we have adapted multiplex sequencing-by-synthesis (MSBS) to simultaneously sequence multiple genomes using the Illumina Genome Analyzer. We PCR-amplified ~120 kb plas-tomes from eight species (seven Pinus, one Picea)in 35 reactions. Pooled products were ligated to mod-ified adapters that included 3 bp indexing tags and samples were multiplexed at four genomes per lane. Tagged microreads were assembled by de novo and reference-guided assembly methods, using pre-viously published Pinus plastomes as surrogate references” (Abstract). Therefore, one of ordinary skill in the art at the time the invention was made would have adjusted the teachings of May and McCloskey to include the index tag as taught by Cronn to arrive at the claimed invention with a reasonable expectation for success.
Conclusion
No claims are allowed. All claims stand rejected.
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/STEPHANIE K MUMMERT/Primary Examiner, Art Unit 1681
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