DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application is being examined under the pre-AIA first to invent provisions.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejections set forth below will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejections, would be the same under either status.
Status of the Application
2. Applicant's response filed on October 15, 2025 has been entered.
Claims 51-69 and 71 are pending and under examination.
Response to Arguments
3. Applicant’s arguments filed on October 15, 2025 have been fully considered.
Rejection of claims 51 and 61 under pre-AIA 35 U.S.C. 102(b) as being anticipated by Jones
Arguments:
Large portions of the arguments on pages 6-9 of the Remarks are identical or essentially identical to those presented with the previous response of March 25, 2025 and also the preceding response of February 26, 2024.
Newly presented arguments appear at the following locations of the Remarks: (i) page 7, last two paragraphs; and (ii) page 9, first para. under the reproduction of Figure 3 of Jones.
In these new arguments, Applicant alleges that the Office has misinterpreted the teachings of Jones and cherry picks from the teachings in the reference to arrive at the claimed invention. And more specifically, Applicant argues that paras. 86-87 and Figure 3 of Jones relate to methods comprising the use of locus-specific capture probes that bind to amplicons and undergo extension, whereas para. 100 and Figure 4 of Jones describe a method that uses degenerate capture probes that bind adapter priming sites (Remarks, page 7). Therefore, Applicant argues, it is clear that the rejection results from cherry picking because these two embodiments of Jones are not combinable or interchangeable.
Applicant also argues that Figure 4 of Jones fails to describe a method that uses the required “single-stranded nucleic acid with a first adapter attached to its 5’ end” and “an oligonucleotide comprising a 5’ tail portion that is non-complementary to the sequence of interest as well as a second adapter sequence” as required by the claims (Remarks, page 7).
Lastly, Applicant argues on page 9 that Jones explicitly teaches that a separate enrichment step before amplification.
Response:
Applicant’s arguments have been fully considered, but they were not persuasive for the following reasons.
First, the arguments identified above as being identical or essentially identical to arguments presented previously have been reconsidered, but they remain unpersuasive for the reasons set forth previously (i.e., in the Final Rejection mailed on September 25, 2024 and the Non-Final Rejection mailed on July 15, 2025).
Second, Applicant’s new argument on page 7 concerning the teachings of Jones in (a) paras. 86-87 and Fig. 3 and also in (b) para. 100 and Fig. 4 was not persuasive because the rejection does not pick some elements from (a) and other elements from (b) and argue that together this indicates that Jones anticipates the claimed methods. Instead, the embodiment in (a) and the embodiment in (b) are each considered to meet all of the elements in the rejected claims. That is, either the method disclosed in Fig. 3 and discussed in para. 87 or the method described in para. 100 of Jones contains all of the required elements.
Further as to Applicant’s argument concerning the teachings of Jones in Figure 4, the examiner agrees that the description of this figure in para. 12 of Jones does not include all of the required steps because the ligation step occurs after the primer extension step. Para. 100, though, which is cited in the rejection discloses the required order of method steps.
Lastly, Applicant’s argument on page 9 regarding a separate enrichment step in Jones was not persuasive. First, the claims are written in open language and do not exclude an additional enrichment or purification step as taught in Jones. Second, the amplification step in the method disclosed in, e.g., Fig. 3 and para. 87 of Jones necessarily results in enrichment. The specification of the instant application teaches that performing the recited method steps—and in particular, the final amplification step—results in enrichment (see, e.g., paras. 9, 12, 15, and 36-39 of the originally filed specification, where the steps set forth in claim 51 and/or claim 61 are disclosed in combination with a conclusion that the amplification step is preformed “to enrich” (paras. 9 and 12) or results in enrichment (para. 39). Para. 39 in the originally filed specification is especially instructive as to this point since its last sentence states:
As illustrated in FIG. 1, a subtractive polymerase chain reaction (PCR) procedure is subsequently performed using a first primer directed against the forward adapter sequence and a second primer directed against the reverse adapter sequence such that only the oligonucleotide extension product with the forward adapter sequence at one end and the reverse adapter sequence at the other end can be amplified and thus enriched. (emphasis added).
Therefore, it is entirely reasonable to conclude, as was done in the rejection, that the final amplification step in the method of Jones necessarily results in enrichment. That is, when the claims are considered in light of the specification, it is clear that enrichment results from the final amplification step. Accordingly, a reference (e.g., Jones) that performs all of the steps recited in claims 51 and 61 need not explicitly mention enrichment for that element to be met.
Since Applicant’s arguments were not persuasive, the rejection has been maintained.
Rejections of claims 52-60, 62-69, and 71 under pre-AIA 35 U.S.C. 103(a) citing Jones as the primary reference
Arguments:
Large portions of the arguments on pages 10-16 of the Remarks are identical to those presented with the previous response of March 25, 2025 and also the preceding response of February 26, 2024.
Newly presented arguments appear at the following locations of the Remarks: (i) page 13, first full para – page 14, first full para; and (ii) page 15, last para. – page 16, first para.
In newly presented argument (i), Applicant first argues that the claimed methods are not obvious in view of the guidance set forth in MPEP 2144.04(II)(B), which states that “[O]misson of an element and retention of its function is an indication of nonobviousness.” In re Edge, 359 F.2d 896, 149 USPQ 556 (CCPA 1966). In this case, Applicant argues, “Applicant does not implement a separate enrichment step like Jones…[but] the recited claims still provide an enriched set of target amplicons” (page 13, last full para.). Therefore, Applicant argues, the claims are clearly not obvious in view of the guidance in MPEP 2144.04(II)(B).
In newly presented argument (i), Applicant also argues that the Office has failed to provide sufficient evidence to support the conclusion that the method of Jones necessarily results in enrichment (page 13, last full para. – page 14, first full para.).
In newly presented argument (ii), Applicant argues that the newly cited Rothberg reference does not teach annealing amplification products to oligonucleotides on a flow cell surface as required by claim 71 (Remarks at page 15, last para. – page 16, first para.).
Response:
The previously presented arguments have been reconsidered, but they remain unpersuasive for the reasons set forth previously (i.e., in the Final Rejection mailed on September 25, 2024 and the Non-Final Rejection mailed on July 15, 2025).
Newly presented argument (i) was unpersuasive for the following reasons.
First, it is noted that the word “enriching” only appears in the preamble of independent claims 51 and 61. As discussed in MPEP 2111.02 II, preamble statements that limit structure are limiting, but those that only recite an intended purpose or use may not. In this case, it is not clear that the preamble requires anything in addition to the positively recited method steps, particularly since the specification of the instant application teaches that performing the recited method steps—and in particular the final amplification step—results in enrichment (see, e.g., paras. 9, 12, 15, and 36-39 of the originally filed specification, where the steps set forth in claim 51 and/or claim 61 are disclosed in combination with a conclusion that the amplification step is preformed “to enrich” (paras. 9 and 12) or results in enrichment (para. 39). Para. 39 in the originally filed specification is especially instructive as to this point since its last sentence states:
As illustrated in FIG. 1, a subtractive polymerase chain reaction (PCR) procedure is subsequently performed using a first primer directed against the forward adapter sequence and a second primer directed against the reverse adapter sequence such that only the oligonucleotide extension product with the forward adapter sequence at one end and the reverse adapter sequence at the other end can be amplified and thus enriched. (emphasis added).
Therefore, it is entirely reasonable to conclude, as was done in the rejection, that the final amplification step in the method of Jones necessarily results in enrichment. That is, when the claims are considered in light of the specification, it is clear that enrichment results from the final amplification step. Accordingly, a reference (e.g., Jones) that performs such steps need not mention enrichment for that element to be met, and additional documentary evidence is not necessary.
Second, Applicant’s argument regarding the guidance in MPEP 2144.04(II)(B) was not persuasive because the claims are written in open, “comprising” language and do not prohibit the inclusion of additional steps (e.g., any additional steps conducted by Jones for further enrichment or purification). Therefore, the facts of the instant case are not the same as the situation discussed in MPEP 2144.04(II)(B).
Newly presented argument (ii) was unpersuasive because claim 71 does not require annealing amplification products to oligonucleotides attached to a flow cell surface. Only claim 69 requires a flow cell surface, and claim 71 depends from claim 68 rather than claim 69. Accordingly, the combined teachings of the cited references do suggest all of the required limitations.
Since Applicant’s arguments were not persuasive, the rejections under pre-AIA 35 U.S.C. 103(a) have been maintained.
Claim Rejections - 35 USC § 102
4. The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
5. Claims 51 and 61 are rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by Jones et al. (US 2005/0142577 A1).
Regarding claims 51 and 61, Jones teaches a method for enriching a target nucleic acid that comprises the following steps (see, for example, Figure 3 and paragraphs 86-87 and 100):
(a) fragmenting nucleic acids in the sample to generate fragments comprising the sequence of interest;
(b) ligating a partial duplex adapter to each end of the nucleic acid fragments, thereby providing a plurality of fragments having a common first adapter sequence ligated at a 5’ end;
(c) annealing an oligonucleotide in solution to a nucleic acid sequence of interest in the adapter-containing fragments, wherein said oligonucleotide comprises a 3’ target-specific portion that binds to the nucleic acid sequence of interest and a 5’ tail portion comprising a common second adapter sequence that is not complementary to the nucleic acid sequence of interest;
(d) extending the annealed oligonucleotide using a polymerase, thereby obtaining extension products comprising a sequence complementary to the ligated first adapter at one end and the second adapter at the other end;
(e) amplifying the extension products using a primer that comprises a sequence in the first adapter and a primer that comprises a sequence in the second adapter sequence to enrich for the nucleic acid sequence of interest.
Further regarding claims 51 and 61, the methods of Jones are practiced using a sample that contains a plurality of different nucleic acids (see, e.g., Fig. 3 and para. 87).
Further regarding claim 61, in the method disclosed in the aforementioned portions of Jones, the single-stranded nucleic acid to which the oligonucleotide is annealed contains an adapter sequence at each end (see, e.g., Fig. 3).
Thus, Jones anticipates the methods of claims 51 and 61.
Claim Rejections - 35 USC § 103
6. The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
7. This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
8. Claims 52 and 62 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Jones et al. (US 2005/0142577 A1) in view of Tucker et al. (The American Journal of Human Genetics 2009; 85: 142-154).
As discussed above, the teachings of Jones anticipate the methods of claims 51 and 61.
Regarding claims 52 and 62, which depend from claims 51 and 61, respectively, Jones teaches sequencing amplification products (see, e.g., paras. 79-80 and 100), but the reference Jones does not teach massively parallel sequencing.
Tucker, though, describes methods of obtaining sequence information about a region of interest in a nucleic acid, and specifically describes a number of massively parallel sequencing methods (abstract, pages 142-146, and Figures 2-5). The reference states that “Massively parallel sequencing will allow simultaneous screening for mutations in hundreds of loci in genetically heterogeneous disorders, whole-genome screening for novel mutations, and sequence-based detection of novel pathogens that cause human disease. In addition, massively parallel sequencing will permit clinical application of our expanding knowledge of pharmacogenetics, cancer genetics, epigenetics, and complex traits” (page 142, column 2). The reference further teaches that massively parallel sequencing “has reduced the cost and increased the throughput of genomic sequencing by more than three orders of magnitude...and may also replace arrays and Sanger sequencing in clinical applications where they are currently being used” (abstract).
It would have been prima facie obvious for one of ordinary skill in the art at the time of the invention to analyze the amplification products generated by the method of Jones using one of the massively parallel sequencing methods described in Tucker. The ordinary artisan would have been motivated to do so since Tucker taught that such methods offered very high-throughput sequencing (abstract and page 142) and as well as the ability to accurately detect minor alleles (page 144, column 2). Additional motivation is provided in the abstract of Tucker, which teaches that massively parallel sequencing methods may replace array-based methods (i.e., one of the sequencing methods disclosed in Jones). The ordinary artisan would have had a reasonable expectation of success in view of the guidance provided by Tucker concerning the use of massively parallel sequencing methods and also since Jones taught that the amplification products could be analyzed using any desired method. Therefore, it would have been obvious to use any of the massively parallel sequencing methods disclosed in Tucker. The ordinary artisan would have had a reasonable expectation of success since many of the methods disclosed in Tucker have been commercialized and the reference provides guidance as to how the different sequencing methods are conducted. Thus, the methods of claims 52 and 62 are prima facie obvious over Jones in view of Tucker.
9. Claims 53-59 and 63-69 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Jones et al. (US 2005/0142577 A1) in view of Tucker et al. (The American Journal of Human Genetics 2009; 85: 142-154) and further in view of Toloue et al. (US 2012/0028814 A1).
As discussed above, the teachings of Jones in view of Tucker render obvious the methods of claims 52 and 62.
Regarding claims 53 and 63, which depend from claims 51 and 61, respectively, neither Jones nor Tucker teaches the use of barcode-containing adapters.
Toloue, though, discloses a method that comprises ligating adapters to a target nucleic acid, amplifying the ligation products, and sequencing the amplification products (see, e.g., paras. 12, 14, 16, 17, and 28-30).
Regarding claims 53 and 63, the method of Toloue may be used with DNA or RNA targets and includes ligating a barcode-containing adapter to each end of the nucleic acid target (see, e.g., paras. 12, 14, 28, and 30). The resulting products may then be sequenced using a massively parallel sequencing method (see, e.g., the abstract and para. 3).
Further regarding claims 54, 55, 64, and 65, Toloue teaches that the disclosed method is designed to prepare a plurality of different nucleic acid targets for sequencing analysis (see, e.g., the abstract and paras. 3 and 27-30). Thus, in the method of Toloue, a plurality of different target nucleic acids are ligated to a common first adaptor that contains the aforementioned barcode, which is common to all of the first adaptor molecules. Toloue also teaches that the first adaptor contains a common universal priming site (see, e.g., paras. 14 and 17). And, since amplified barcode-containing nucleic acids are to be sequenced and analyzed, the common universal priming site in the adaptor of Toloue is necessarily 5’ of the barcode.
Further regarding claims 56 and 66, Toloue teaches that the first and second adapter may contain different barcode sequences (see, e.g., paras. 14 and 41).
Further regarding claims 57-59 and 67-69, which depend directly or indirectly from claim 56 or claim 66, Tucker describes a massively parallel sequencing method developed by Illumina in Figure 2. The method comprises bridge amplification and the use of four labeled reversible terminators (Fig. 2). The Illumina sequencing method also comprises attaching an adapter to each end of a nucleic acid fragment of interest and using the adapters to hybridize the nucleic acid of interest to flow cell sequences (Fig. 2). Each of the two adapters is also complementary to a sequencing primer (Fig. 2), and thus contains a universal priming site as required by claims 54 and 64.
It would have been prima facie obvious for the ordinary artisan practicing the target nucleic acid enrichment and sequencing method suggested by Jones in view of Tucker to further include a barcode sequence in the first and/or the second (or third) adapter sequence of Jones (i.e., in the 5’ adapter sequence of Jones and/or in the A1-containing oligonucleotides shown in Fig. 3).1 The ordinary artisan would have been motivated to do so since Toloue taught that barcodes could be added to one or both adapters to be ligated to a nucleic acid of interest to facilitate massively parallel sequencing by allowing simultaneous analysis of multiple samples, thus “increase[ing] scale and throughput while reducing costs” in addition to “enabl[ing] the user to detect rare sample events” (see, e.g., the abstract and paras. 6, 30, and 41). The ordinary artisan would have had a reasonable expectation of success in view of the guidance provided throughout Toloue and particularly since Toloue teaches that barcoded nucleic acids produced by the disclosed method may be sequenced using any of a number of massively parallel sequencing platforms, including the Illumina platform discussed in Tucker (see, e.g., para. 40). Thus, the methods of claims 53 and 63 are prima facie obvious.
Further regarding claims 54, 55, 64, and 65, as discussed above, the teachings of Jones in view of Tucker and further in view of Toloue suggest including a barcode sequence in the first adapter of Jones. As well, as also discussed above, the method of Jones includes amplification with a common universal primer (Fig. 3, where amplification with A1 and A2 primers is taught). The references also suggest the use of first adaptors with a common universal priming site located 5’ of the barcode. As discussed above, the first adaptors of each of Jones and Toloue contain a common universal priming site, and Toloue teaches that the barcode-containing nucleic acids are to be amplified using the common universal priming site and then sequenced. Therefore, the ordinary artisan would have recognized that the barcode suggested by Toloue would have to be located 3’ of the common universal priming site for the barcode to still be present in the sequencing step. Lastly, Jones teaches amplification of different target nucleic acids using a plurality of single-stranded oligonucleotides containing a 5’ common adaptor region and a 3’ target-specific region (see, e.g., Fig. 3 and paras. 11, 76, and 83). Thus, the methods of claims 54, 55, 64, and 65 are prima facie obvious.
Further regarding claims 56 and 66, which depend from claim 55 and 65, respectively, as noted above, Toloue suggests using a different barcode sequence in the first and second oligonucleotides to be ligated to the target nucleic acid (see, e.g., paras. 14 and 41). Thus, claims 56 and 66 are prima facie obvious.
Further regarding claims 57-59 and 67-69, as noted above, Tucker discloses a massively parallel sequencing method in Figure 2 that includes the features of hybridizing amplified products to an oligonucleotide immobilized on a surface of a flow cell. Thus, the ordinary artisan practicing the method suggested by the references would have been motivated to conduct the sequencing step in the recited way. It is also noted that when using the Illumina sequencing method discussed in Tucker, the ordinary artisan would have recognized that the 3’end of the amplification products should be complementary to a surface-immobilized sequence (i.e., as recited in claims 57, 58, 67, and 68) and, accordingly, would have been motivated to design the adapters such that they are complementary to sequences on a support to be used in the Illumina sequencing method. Thus, the methods of claims 57-59 and 67-69 are prima facie obvious.
10. Claim 60 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Jones et al. (US 2005/0142577 A1) in view of Tucker et al. (The American Journal of Human Genetics 2009; 85: 142-154) and further in view of Toloue et al. (US 2012/0028814 A1) and further in view of Gormley et al. (US 7,741,463 B2).
As discussed above, the teachings of Jones in view of Tucker and further in view of Toloue render obvious the methods of claims 53-59 and 63-69.
Regarding claim 60, Jones does not teach that the sequence of interest in the target nucleic acid comprises cDNA. Neither Tucker nor Toloue remedies this deficiency in Jones.
Gormley, though, describes a method for preparing a library for sequencing that comprises fragmenting nucleic acids contained in a sample, purifying the fragments, end-repair of the purified fragments, ligation of a partial duplex adapter, and PCR (see the working example at columns 23-26 and especially column 23, lines 25-67, column 25, line 41 – column 26, line 20, and column 26, lines 25-62; see also Figs. 2a-2b). Gormley further teaches using sequencing the nucleic acids in the library using a massively parallel method comprising the steps disclosed in Figure 2 of Tucker (i.e., bridge amplification and the use of reversible terminators) (column 20, line 18 – column 22, line 20). Further regarding claims 60 and 70, Gormley teaches that libraries for sequencing may be prepared from cDNA fragments (col. 6, ll. 5-27).
It would have been prima facie obvious for one of ordinary skill in the art at the time of the invention to practice the method suggested by Jones in view of Tucker and further in view of Toloue using cDNA fragments of interest prepared from RNA by reverse transcription. Gormley provides motivation to do so as well as a reasonable expectation of success since the teachings cited above indicate that cDNA libraries are a desirable template for massively parallel sequencing. Thus, the method of claim is prima facie obvious.
11. Claim 71 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Jones et al. (US 2005/0142577 A1) in view of Tucker et al. (The American Journal of Human Genetics 2009; 85: 142-154) and further in view of Rothberg et al. (Nature 2011; 475: 348-352 + Supplementary Information).
As discussed above, the teachings of Jones in view of Tucker render obvious the methods of claims 53-59 and 63-69.
These references do not teach that the surface to which the amplified products are attached via hybridization to a surface-immobilized oligonucleotide comprises a semiconductor chip of a DNA sequencing machine.
Rothberg, however, describes massively parallel sequencing using a semiconductor device (Fig. 1 and pp. 348-350) and discloses that this sequencing method is highly robust, scalable, and advantageously does not require the use of optics or labeled nucleotides (abstract and p. 348). Further, as can be seen in Figure 1 and on pages 349-350 of Rothberg, nucleic acids to be sequenced are hybridized to bead-immobilized oligonucleotides located in a well of a semiconductor chip.
It would have been prima facie obvious for one of ordinary skill in the art at the time of the invention to select semiconductor sequencing as described by Rothberg as the massively parallel sequencing method when practicing the method of Jones in view of Tucker. Rothberg provides motivation to do so by stating that the disclosed semiconductor sequencing method is robust, highly scalable and requires neither optical detection nor modified nucleotides (abstract and p. 348). The ordinary artisan would have had a reasonable expectation of success in view of Rothberg’s guidance concerning practice of the method (pp. 349-350 and the Supplemental Methods). Thus, the method of claim 71 is prima facie obvious.
Conclusion
12. No claims are currently allowable.
THIS ACTION IS MADE FINAL. 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 Angela Bertagna whose telephone number is (571)272-8291. The examiner can normally be reached on 8-5, M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached on 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see https://ppair-my.uspto.gov/pair/PrivatePair. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1637
1 As can be seen in, e.g., Fig. 3, the different A1-containing oligonucleotides anneal to different sequences of interest in different single-stranded nucleic acids.