DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
The Amendment and Response, and the Request for Continued Examination, each filed November 11, 2025 are acknowledged.
Claims 41-46, 61-64 and 66-75 were pending. Claims 41-45, 61, 63-64, 66-74 and new claim 76 are being examined on the merits. Claims 46 and 62 remain withdrawn. Claim 75 is canceled.
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 November 11, 2025 has been entered.
Response to Arguments
Applicant’s arguments filed November 11, 2025 have been fully considered.
The following rejections are WITHDRAWN in view of Applicant’s arguments and amendments to the claims:
Rejection of claims 41-45, 61, 63-64 and 66-75 under 35 USC § 112(b), indefiniteness
Rejection of claim 75 under 35 USC § 112(d)
The following rejections are MODIFIED in view of Applicant’s claim amendments:
Prior art rejections
Response to arguments regarding prior art rejections
The prior art rejections have been modified to account for the instant claim amendments. However, to the extent that Applicant’s arguments relate to the newly modified rejections below, the Examiner notes the following.
First, Applicant reproduces instant independent claim 41 in the Remarks (pp. 7-8). Merely for the sake of clarity of record, the Examiner notes that claim 41 in the claim listing and claim 41 in the Remarks are not the same.
Second, Applicant argues that Iafrate does not teach the limitation requiring “the reverse complementary oligonucleotide adapter sequence is complementary to the forward oligonucleotide adapter sequence over the entire length of the reverse complementary oligonucleotide adapter sequence” (Remarks, p. 8).
The Examiner disagrees. This issue has been addressed repeatedly in prior Office Actions and is addressed below. Briefly, Iafrate teaches various embodiments of adapters, and expressly teaches the recited limitation at, e.g., para. 67 (“the entirety of the blocking strand [i.e., the reverse complimentary oligonucleotide adapter sequence] is a duplex portion”).
Third, Applicant argues that Iafrate further cannot teach that the limitation requiring that “the index sequence … is immediately adjacent to the portion of the forward oligonucleotide is complementary to the reverse oligonucleotide because claim 41 also requires that the reverse oligonucleotide be complementary to the forward over its entire length” (Remarks, p. 8).
The Examiner disagrees. As noted above, Iafrate does teach an embodiment where the reverse oligonucleotide is complementary to the forward oligonucleotide over its entire length.
Fourth, Applicant argues that Iafrate does not teach a reverse oligonucleotide that is 32, 33 or 34 nucleotides in length (Remarks, p. 9).
The Examiner disagrees. Iafrate expressly teaches these limitations, at least, at para. 70.
Fifth, Applicant argues that Van Eijk teaches that the bottom stand of the adapter is blocked at the 3’ end to block extension of a polymerase, but fails to teach that the block would “offer the benefit of reduced adapter dimer formation” (Remarks, p. 10).
The Examiner disagrees. This issue has also been addressed repeatedly in prior Office Actions. Briefly, instant claim 41 does not require that the adapter have any capability as to reducing adapter dimer formation. Also, Applicant is referred to MPEP 2144(IV) and 2112.01(I).
Finally, Applicant argues that the claimed invention possesses “superior, unexpected results” as compared to full-length adapters (Remarks, p. 10).
The Examiner disagrees. This issue has also been addressed repeatedly in prior Office Actions. Applicants have not demonstrated unexpected results, at least, because they have not compared the claimed product with the closest prior art product. See MPEP 716.02(e). That is, a full-length adapter is not the closest prior art structure.
Regarding the rejections of the dependent claims, Applicant argues that, as to claims 44, 45 and 61, the sequences taught in the art are not identical to the claimed sequences because, e.g., the sequence cited for SEQ ID NO: 4 is the reverse complement of SEQ ID NO: 4, and that the secondary references do not teach combining sequences to make adapters (Remarks, p. 11-13).
The Examiner disagrees. As to the latter point, the secondary references were not cited for teaching combining sequences to make adapters. As to the former point, the Examiner notes that Iafrate plus Van EIjk teach making the recited adapters which are suitable for next-generation sequencing, while the additional cited references teach various nucleic acid sequences that can be used for the purpose of making adapters for next generation sequencing. The Examiner does not agree that the ordinary artisan would not be motivated to optimize prior art sequences to make next generation sequencing adapters from these combined teachings, as asserted by Applicant.
These arguments are not persuasive. The rejections are modified in view of the instant claim amendments.
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.
Claims 41-43 and 76 are rejected under 35 U.S.C. 103 as being unpatentable over Iafrate1 (US Patent App. Pub. No. 2013/0303461) in view of van Eijk2 (US Patent App. Pub. No. 2012/0202698).
Regarding independent claim 41, Iafrate teaches …
A composition comprising an adapter sequence comprising a forward oligonucleotide adapter sequence having a 5’ single-stranded overhang and a reverse complementary oligonucleotide adapter sequence over less than 70, 60, 55, 50, 45 or 40 percent of the length at its 3' end. Specifically, Iafrate teaches an a partially double-stranded adapter comprising a 5’ single-stranded overhang and a reverse complementary sequence corresponding to part of the forward sequence (Fig. 1: “adaptor ligation”; para. 7). In addition, Iafrate teaches various lengths for the duplex portion of the adapter (para. 70), and Fig. 9 shows an embodiment with the reverse complementary sequence being 13% of the length of the forward adapter sequence (i.e., the forward adapter sequence/top strand is 46 nucleotides in length, and the reverse complementary portion of the adapter is 6 nucleotides in length). Iafrate also teaches that the reverse complementary oligonucleotide adapter sequence is complementary to the forward oligonucleotide adapter sequence over the entire length of the reverse complementary adapter sequence (paras. 7, 67), and that the reverse complementary sequence oligonucleotide sequence of 32, 33 or 34 nucleotides in length (para. 70).
Iafrate also teaches that the forward oligonucleotide adapter sequence comprises an index sequence immediately adjacent to the portion of the forward oligonucleotide adapter sequence that is complementary to the reverse complementary oligonucleotide adapter sequence (Fig. 9).
Iafrate does not teach that the reverse complementary oligonucleotide adapter sequence is 3’-amino modified. However, van Eijk teaches this limitation (para. 90).
Regarding dependent claim 76, Iafrate additionally teaches that the forward oligonucleotide adapter sequence is 70 nucleotides long (Fig. 9, SEQ ID NO: 47).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious to incorporate the 3’ amino-modified nucleotide of van Eijk into the double-stranded adapter taught by Iafrate. Iafrate teaches the need for high-throughput methods of genome and transcriptome sequencing, while van Eijk teaches that 3’ amino-modified nucleotides are useful in high-throughput sequencing adapters for blocking polymerase extension of the adapter itself. The ordinary artisan would thus understand that blocking extension of the adapter would reduce undesirable amplification reactions, and would have been motivated to incorporate such a 3’ modified nucleotide into the Iafrate adapter with the expectation that doing so would result in a more efficient and accurate amplification reaction. The ordinary artisan would have had an expectation of success as modifying nucleotides with amino groups is well-known in the art.
It would have been additionally obvious to optimize the location and length of the various portions of the adapter, including, e.g., the index/barcode. For example, the ordinary artisan would have been motivated to optimize the length of adapter sequences and the location of the index/barcode to allow for downstream processing with the expectation that doing so would result in an adapter that could be used in a next generation sequencing method with improved efficiency. For example, the index/barcode would have to be 5’ of the target sequence, 5’ of the duplex portion of the adapter and 3’ of a sequencing primer binding site so that it would be incorporated into an amplicon in such a configuration as to permit deconvolution of data post-sequencing. The ordinary artisan would have had an expectation of success as the design and modification of nucleic acid molecules is well-known in the art, and because Iafrate provides guidance on how such adapters are to be structured.
Regarding dependent claims 42-43, Iafrate teaches that the adapter has a T overhang sequence (Fig. 1: “adaptor ligation”), as recited in claim 42, and that the 5’ and 3’ adapter sequences are capable of ligating to amplicon target sequences (Figs. 1, 9; para. 70), as recited in claim 43.
Claims 44-45, 61 and 63-64 are rejected under 35 U.S.C. 103 as being unpatentable over Iafrate (US Patent App. Pub. No. 2013/0303461) in view of van Eijk (US Patent App. Pub. No. 2012/0202698), as applied to claims 41 and 42 above, and further in view of Kim3 (WO 2017/222164, and English machine translation; priority date 20 June 2016) and Kaper4 (WO 2015/168161).
Regarding dependent claims 44-45 and 61, the combination of Iafrate, Kim and Kaper teach that the reverse complementary oligonucleotide adapter sequence is SEQ ID NO: 4, as recited in claims 44-45 and 61, and wherein the forward oligonucleotide adapter sequence comprises SEQ ID NO: 1, as recited in claim 45. Specifically, Iafrate teaches the basic structure of the adapter, while Kim teaches a sequence that comprises the entire sequence of SEQ ID NO: 1 (p. 12, top sequence). Kaper teaches both a sequence comprising part of SEQ ID NO: 4 (Kaper SEQ ID NO: 3), and a sequence that comprises the entire reverse complement of SEQ ID NO: 4 (Kaper SEQ ID NO: 2), and teaches that such sequences can be used as next-generation sequencing adapters (p. 17, ll. 1-25). In addition, Iafrate teaches creating double-stranded adapters using oligonucleotides that are partially complementary to one another (e.g., Figs. 1, 9).
In addition, regarding dependent claims 63-64, when the Kim and Kaper sequences are aligned, the reverse complementary adapter sequence is 51.5% (i.e., the forward sequence is 66 nucleotides in length, while the reverse complementary portion is 34 nucleotides in length).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious to combine the sequences of Kim and Kaper into a double-stranded adapter, as taught by modified Iafrate, discussed above. The ordinary artisan would have been motivated to use the sequences of Kim and Kaper to construct an adapter, as, at least, Kaper teaches that the cited sequences can be used as next-generation sequencing adapters, and because Iafrate teaches combining such sequences into double-stranded molecules. Therefore, the ordinary artisan would have been motivated to combine the Iafrate, Kim and Kaper structures and sequences in order to customize an adapter as needed for a particular next-generation sequencing assay. The ordinary artisan would have had an expectation of success as creating next-generation sequencing adapters is well-known in the art.
Claims 72-74 are rejected under 35 U.S.C. 103 as being unpatentable over Iafrate (2013/0303461) in view of van Eijk (US Patent App. Pub. No. 2012/0202698), as applied to claim 41 above, and further in view of Illumina5 (Illumina Adapter Sequences, 2015).
Regarding dependent claims 72-74, Iafrate teaches buffers, enzymes and dNTPs (e.g., paras. 9, 72, 76, 79, 103, 132-148; Example 1), while Illumina teaches assembling the various components into kits (e.g., pp. 11-12), as recited in claims 72 and 74. In addition, Iafrate teaches a second distinct adapter (para. 13: describes contacting each sample of multiple samples with a tail-adapter with a unique barcode portion – thus, each uniquely barcoded tail-adaptor is a “distinct adapter” according to the instant claim), as recited in claim 73.
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious to assemble the various adapters and reagents of Iafrate into a kit, as taught by Illumina, as doing so would increase the efficiency and convenience of using the adapters. The ordinary artisan would have had an expectation of success as assembling components into kits is well-known in the art.
Claims 66-71 are rejected under 35 U.S.C. 103 as being unpatentable over Iafrate (US Patent App. Pub. No. 2013/0303461) in view of van Eijk (US Patent App. Pub. No. 2012/0202698), as applied to claim 41 above, and further in view of Kim (WO 2017/222164, and English machine translation; priority date 20 June 2016), Kaper (WO 2015/168161), and Illumina (Illumina Adapter Sequences, 2015).
Regarding dependent claims 66-71, Illumina teaches each of the i7 index sequences of instant SEQ ID NOs: 15-38 (p. 11-12, Nextera XT Index Kit v2 Index 1 (i7) Adapters, N701-N707, N710-N712 and N714-N729, respectively) and each of the i5 index sequences of instant SEQ ID NOs: 39-54 (p. 12-13, Nextera XT Index Kit v2 Index 2 (i5) Adapters, S502-S503, S505-S508, S510-S511, S513, S515-S518 and S520-S522, respectively). In addition, as noted above in conjunction with the rejection of claims 44-45 and 61, Kim plus Kaper teach a partially-double-stranded adapter, with Kim teaching a forward adapter sequence comprising the index sequence “TCGCCTTA”, while Kaper suggests the partially reverse complementary sequence of the forward adapter sequence. When the Kim and Kaper sequences are aligned, the index sequence is positioned near the 3’ end of the 5’ single-stranded overhang.
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious to incorporate the various index sequences, taught by Illumina, into the modified Iafrate adapters, discussed above. Iafrate teaches the need for barcoding/indexing samples prior to being pooled into a single reaction volume. The Illumina indexes are designed for such a purpose. The selection of a known material based on its suitability for its intended use is obvious. MPEP 2144.07. In addition, the ordinary artisan would have optimized the location of the barcode/index in the adaptor through routine experimentation so that the barcode/index does not otherwise interfere with the function of the adaptor. The ordinary artisan would have had an expectation of success as barcoding adapters is well-known in the art.
Conclusion
Claims 41-45, 61, 63-64, 66-74 and 76 are being examined, and are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROLYN GREENE whose telephone number is (571)272-3240. The examiner can normally be reached M-Th 7:30-5:30 EST.
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/CAROLYN L GREENE/Examiner, Art Unit 1681
1 Iafrate was cited in the PTO-892 Notice of References Cited mailed January 9, 2023.
2 Van Eijk was cited in the PTO-892 Notice of References Cited mailed December 7, 2023.
3 Kim was cited in the PTO-892 Notice of References Cited mailed February 16, 2022.
4 Kaper was cited in the PTO-892 Notice of References Cited mailed February 16, 2022.
5 Illumina was cited in the PTO-892 Notice of References Cited mailed January 9, 2023.