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 filed April 28, 2026 is acknowledged.
Claims 41-46, 61-64, 66-74 and 76 were pending. Claims 41-42, 44-45, 61, 63-64, 66-72, 74, 76 and new claims 77-78 are being examined on the merits. Claims 46 and 62 remain withdrawn. Claims 43 and 73 are canceled.
Response to Arguments
Applicant’s arguments filed April 28, 2026 have been fully considered.
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 in view of the instant claim amendments. However, Applicant’s arguments that relate to the newly modified rejections are discussed below.
Before addressing Applicant’s specific arguments, the Examiner notes the following. Claim 41 is directed to a composition comprising an adapter which comprises several parts. The instant specification describes various embodiments of the composition and of methods for using the composition. For example, regarding the “index” limitation, the specification states “[a]s used herein, ‘DNA barcode’ or … ‘index’ … refers generally to a unique short (6-14 nucleotide) nucleic acid sequence within an adapter” (para. 49). The specification goes on to describe that in a method of using that adapter, the index/barcode “can act as a ‘key’ to distinguish or separate a plurality of amplified target sequences in a sample” (para. 49). It is noted, however, that claim 41 recites “an [singular] adapter sequence”. Thus, the broadest reasonable interpretation of claim 41, at least, comprises an embodiment limited to a single adapter. Claim 41 further does not require that the single adapter is actually attached to a target sequence, or that the single adapter is comprised within a plurality of different adapters, where each adapter in the plurality has a different index/barcode as compared to each of the other adapters. Claim 41 further does not require that the single, unligated adapter has any capability to distinguish “a plurality of [pooled?] amplified target sequences in a sample”. Rather, claim 41 merely requires a single, unligated adapter comprising the recited components.
Applicant argues that the cited art does not teach or suggest the limitation added to claim 41 reciting “wherein ligation of the adapter sequence …” (Remarks, p. 7).
This new limitation is addressed in the rejections below.
Applicant argues that the cited art does not teach or suggest the claimed adapter because, while Iafrate teaches an embodiment with an index sequence immediately adjacent to the portion of the forward oligonucleotide that is complementary to the reverse complementary oligonucleotide, it does so in an embodiment that is different from the embodiment that teaches that the entirety of the reverse complementary oligonucleotide sequence is in a duplex configuration. Thus, the rejection relies on impermissible hindsight to selectively extract and combine disparate teachings (Remarks, pp. 7-8).
The Examiner agrees in part and disagrees in part. As noted below and in the Non-Final Office Action mailed January 28, 2026, the Examiner agrees that Iafrate does not teach all of the various cited elements of claim 41 in a single embodiment. However, as noted in the rejection, the ordinary artisan would have been motivated to combine and optimize the known components of the Iafrate adapter. Further, for the Iafrate adapter to work for its intended purpose, there are a limited number of ways that the various components can be arranged. For example, consider the location of the index/barcode relative to other components. Iafrate teaches that the adaptor is used in enrichment (i.e., amplification) and sequencing steps, and that the barcode is used to deconvolute sequencing data from pooled samples (paras. 13, 112; claims 1 and 13). The ordinary artisan understands that for the barcode sequence to be comprised within the sequencing data, the barcode must be placed in the adapter downstream from both the amplification primer binding site and the sequencing primer binding site. Thus, at a minimum, such an adapter must be organized as 5’ – sequencing primer binding site – amplification primer binding site – barcode – 3’. The Iafrate adapters are relatively short, as depicted in Fig. 9. Consequently, there are only a very small number of locations that the barcode can be placed in the Iafrate adapter for the Iafrate adapter to work for its intended purpose. Thus, the Examiner is not randomly picking and choosing elements from the art and rearranging them using impermissible hindsight. Rather, NGS adapters are known in the art to have particular capabilities and particular components, and those components can only be re-arranged in particular ways and maintain their functionality. Thus, the various re-arrangements can be arrived at through routine optimization. The Examiner also notes MPEP 2144.04 (VI)(C) which provides legal precedent for the position that re-arranging known components is prima facie obvious in the absence of demonstrated criticality of a specific limitation.
Applicant argues that there would be no expectation of success in arriving at the instantly amended limitation reciting “ligation of the adapter sequence to an amplicon target nucleic acids …”. Applicant discusses the Earnshaw reference (already of record in the case) as to how mismatched structures inhibit dimer formation, and further asserts that Earnshaw teaches an “’essential’ sequence mismatch” that the Iafrate adapters do not comprise, and thus “Earnshaw cannot serve as a proxy for Iafrate to suggest that the adapter in Iafrate would have the same adapter-dimer reduction effect as disclosed in Earnshaw” and “[a]ccordingly, Earnshaw teaches away from the presently claimed adapters that do not include the essential sequence mismatch …”. (Remarks, p. 8).
The Examiner disagrees. The instantly amended limitation in claim 41 does not merely require a decrease in adapter dimer formation, or an adapter with a capability of decreasing adapter dimer formation, per se. Rather, it requires a reduction of adapter-dimer formation during subsequent amplification reactions, and further that this reduction is caused by ligation of the adapter sequence to an amplicon target nucleic sequence. As noted below in the indefiniteness rejections, it is not clear what additional structural requirements (if any) are required to produce such a capability. Accordingly, Applicant’s arguments as to how the teachings of Earnshaw and Iafrate would apply to such an (unknown) structure cannot be assessed. It is also noted that Earnshaw is not cited in the instant rejections, and, as noted above, claim 41 does not require that the adapter is ligated to a target nucleic acid.
Applicant argues unexpected results. Specifically. Applicant argues that the average of all of the relevant comparisons shows an 8% decrease in adapter dimer formation, and the ordinary artisan “would have recognized even this level of improvement as unexpected and superior” (Remarks, p. 11).
The Examiner disagrees. First, considering Applicant’s data, exome pool 1 is directed to a standard full-length adapter and shows that such adapters produce 16.2% dimer formation. Then, shortening the adapter so that the reverse complementary strand is 34 nucleotides in length, as shown in exome pool 3, decreases the adapter dimer formation by 87% compared to the standard adapter. Adding an amino (exome pool 4) or phosphorothioate (exome pool 5) modification decreases adapter dimer formation by 89% and 94%, respectively, compared to the standard adapter. Thus, Applicant’s data clearly shows that the vast majority of the decrease in adapter dimer formation (87%) is generated by shortening the adapter, with additional modest decreases (an additional 2% and 7%, respectively) due to the amino or phosphorothioate modifications. Applicant’s data also shows significant variability between replicate experiments. For example, exome pools 6 and 8-10 appear to be replicates of exome pools 1 and 3-5. However, in exome pool 8 there is only a reduction of 77% of dimer formation, compared to 87% in exome pool 3, while exome pools 9 and 10 provide an additional decrease of 11% and 12%, respectively, as compared to 2% and 7%, respectively, in apparent duplicate pools 4 and 5.
The MPEP requires that the instantly claimed product is compared with the closest prior art product. MPEP 716.02(e). Here, the closest prior art structure is the Iafrate structure with a fully duplex portion, but unmodified. This appears to correspond to exome pool 3, while the claimed adapters apparently correspond to exome pools 4 and 5. Thus, the relevant comparison shows that the amino and phosphorothioate modifications in the instantly claimed structures are responsible for a 2% and 7%, respectively, decrease in adapter dimer formation.
Further, considering Applicant’s arguments about the average of exome pools 4, 5, 9 and 10 being a reduction of 8%, it is not clear how to assess this value given the significant variability between the replicates, as noted above. Further, even assuming that the 8% value represents an accurate measure of decrease in primer dimer formation, Applicant has not provided any evidence as to why such a decrease would be unexpected and significant, other than to simply assert that it is. See MPEP 716.02(b). Also, it is explicitly stated in the specification that “In the case of unmodified and 3’ phosphorothioate versions, adapters could potentially be blunted by residual polymerase activity, leading to production of increased dimer formation, while the 3‘ amino modified version is non-extendable” (p. 29, para. 1). Thus, at least as to the amino modification, the specification teaches that a 3’ amino modification prevents blunting which leads to the production of increased dimer formation1. Clearly then, it was not unexpected that creating an adapter with an amino modification would decrease dimer formation. In fact, quite the opposite. Further, Sun (cited below in the prior art rejections) explicitly teaches that a 3’ phosphorothioate modification results in a decrease in adapter dimer formation. Thus, according to both the instant specification and the teachings of, at least, Sun, both the amino modification and the phosphorothioate modification were expected to result in a decrease in adapter dimer formation. Clearly then, Applicant’s statement that the ordinary artisan would not “expect a decrease in adapter dimer formation … of any magnitude” is incorrect (Remarks, p. 11).
Finally, regarding dependent claim 78 (and also presumably independent claim 41) Applicant argues that van Eijk teaches the use of a 3’-amino modification to block polymerase extension, but does not teach or suggest use of that modification in the claimed configuration or for reducing adapter-dimer formation (Remarks, p. 12).
The Examiner disagrees. MPEP 2144 (IV) states that “[t]he reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant”.
These arguments are not persuasive. The rejections are modified in view of the instant claim amendments.
Claim Interpretation
Claim 41 recites "wherein ligation of the adapter sequence to an amplicon target nucleic acid reduces adapter-dimer formation ...". Since claim 41 is a product claim, the "wherein" clause is construed as requiring a capability of the adapter sequence, as opposed to a method step requiring ligation of the adapter sequence to an amplicon. That is, the limitation is being interpreted as "wherein, when ligated to an amplicon target nucleic acid, the adapter sequence has the capability of reducing adapter-dimer formation during subsequent amplification ...".
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 41-42, 44-45, 61, 63-64, 66-72, 74 and 76-78 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 41 recites the limitation "wherein ligation ...", which is being interpreted as noted
above in the Claim Interpretation section. However, even in view of the claim interpretation, the limitation is unclear. Specifically, it is not clear how an adapter that is ligated to an amplicon target nucleic acid can have the capability of reducing adapter formation in subsequent rounds of amplification. Adapter dimers form during library preparation when an adapter ligates to another adapter as opposed to a target nucleic acid. It is not clear how or why additional adapter dimers would form in subsequent amplification steps (are there residual unligated dimers left from the library preparation step that didn’t form dimers during that step, but then do form dimers during amplification?), or how ligation of the recited adapter sequence to an amplicon would prevent other adapters from forming dimers. It is also possible that Applicant intended to refer to amplification of adapter dimers in subsequent amplification steps, as opposed to formation of adapter dimers in those sequent steps. Nevertheless, it is not clear what structure an adapter would have to have where, when it is ligated to an amplicon target nucleic acid, it would be capable of either preventing adapter dimer formation during amplification, or preventing amplification of an existing adapter dimers. Thus, it is unclear what structure would be required for the adapter to have the recited capability. Since the ordinary artisan would not be able to determine the metes and bounds of the claim, it is indefinite.
Claims 42, 44-45, 61, 63-64, 66-72, 74 and 76-78 depend directly or indirectly from claim
41, and consequently incorporate the indefiniteness issues of claim 41.
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 41-42, 76 and 78 are rejected under 35 U.S.C. 103 as being unpatentable over Iafrate2 (US Patent App. Pub. No. 2013/0303461) in view of van Eijk3 (US Patent App. Pub. No. 2012/0202698).
Regarding independent claim 41 and dependent claim 78, 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).
Finally, as noted above, the meaning of the “wherein ligation …” clause cannot be ascertained. To the extent that the clause is reciting a property of the claimed adapter, and since the components of the adapter are taught in the art, the claimed adapter is presumed to have to the same properties as the prior art adapter. See MPEP 2112.01 (I).
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 claim 42, Iafrate teaches that the adapter has a T overhang sequence (Fig. 1: “adaptor ligation”).
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 Kim4 (WO 2017/222164, and English machine translation; priority date 20 June 2016) and Kaper5 (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 Illumina6 (Illumina Adapter Sequences, 2015).
Regarding dependent claims 72 and 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).
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.
Claims 41 and 77 are rejected under 35 U.S.C. 103 as being unpatentable over Iafrate7 (US Patent App. Pub. No. 2013/0303461) in view of Sun (WO 2018/031588 A1; effectively filed August 9, 2016).
Regarding independent claim 41 and dependent claim 77, 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’-phosphorothioate protected. However, Sun teaches this limitation (para. 44). Sun also teaches that the presence of a phosphorothioate bond on the 3’ terminal end of an adapter prevents adapter dimers which, in turn, “optimize[s] the signal-to-noise ratio” (para. 44).
Finally, as noted above, the meaning of the “wherein ligation …” clause cannot be ascertained. To the extent that the clause is reciting a property of the claimed adapter, and since the components of the adapter are taught in the art, the claimed adapter is presumed to have to the same properties as the prior art adapter. See MPEP 2112.01 (I).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious to incorporate the 3’ phosphorothioate residue of Sun into the double-stranded adapter taught by Iafrate. Iafrate teaches the need for high-throughput methods of genome and transcriptome sequencing, while Sun teaches that 3’ phosphorothioate-modified nucleotides are useful for reducing/eliminating adapter dimers. The ordinary artisan would thus understand that such a modification of the adapter would reduce undesirable formation and amplification of primer dimers, and would have been motivated to incorporate such a 3’ modification nucleotide into the Iafrate adapter with the expectation that doing so would result in a more efficient and accurate amplification reaction with an optimized signal-to-noise ratio, as taught in Sun. The ordinary artisan would have had an expectation of success as modifying nucleotides with phosphorothioate 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.
Conclusion
Claims 41-42, 44-45, 61, 63-64, 66-72, 74 and 76-78 are being examined, and are rejected. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Primary Examiner, Art Unit 1681
1 MPEP 707 states that an examiner may rely upon applicant admissions as to any matter affecting patentability.
2 Iafrate was cited in the PTO-892 Notice of References Cited mailed January 9, 2023.
3 Van Eijk was cited in the PTO-892 Notice of References Cited mailed December 7, 2023.
4 Kim was cited in the PTO-892 Notice of References Cited mailed February 16, 2022.
5 Kaper was cited in the PTO-892 Notice of References Cited mailed February 16, 2022.
6 Illumina was cited in the PTO-892 Notice of References Cited mailed January 9, 2023.
7 Iafrate was cited in the PTO-892 Notice of References Cited mailed January 9, 2023.
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