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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/28/2026 has been entered.
Response to Amendment
No claims were amended, and two new claims were added. Regarding the Office action mailed 07/30/2025, the rejections set forth therein under 35 USC 103 are maintained and reiterated below. Applicant’s arguments will be addressed following the rejections.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 10, 13, 15-18 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (US 2016/0312303, previously cited) in view of Shen (Genome Medicine 5:50, 2013, IDS reference).
Regarding claim 10, Wang disclosed a method for capturing a region of interest from double-stranded genomic DNA (gDNA; see Fig. 1). The method involved hybridizing an upstream probe (custom probe 1) and a downstream probe (custom probe 2) to one strand of the double-stranded gDNA, extending the 3’ end of the upstream probe until it reached the downstream probe, whereupon the 3’ end of the extended upstream probe was ligated to the 5’ end of the downstream probe. The upstream probe and downstream probe had 5’ and 3’ “tails”, respectively, which included binding sites for primers that were subsequently used to amplify the ligated product (see Fig. 1 and paragraph [0167]).
Regarding claim 13, Wang disclosed isolating the ligated probe product from the reaction mixture (paragraph [0167]; “a purification step to remove any unbound probes”).
Regarding claim 15, Wang disclosed that the region of interest “can be of any suitable length (e.g., 20, 25, 30, 35, 40, 50, 100, 200, 300, or more nucleotides in length)” (paragraphs [0069], [0073], [0077]). It would have been obvious to target regions of 1,000 or more bp since Wang taught the range of 300 or more, which encompasses the range of 1,000 or more. MPEP 2144.05.
Regarding claim 16, the ligated product is amplified with a primer pair, each primer comprising a 5’ first or second sequencing primer binding site (P5 or P7), followed by a first or second identifier sequence (index 1 or index 2), followed by the first or second primer sequence corresponding to the tails of the upstream or downstream probe, respectively; see Fig. 1.
Regarding claim 17, Wang disclosed sequencing the amplified ligated product; paragraph [0167]: “The PCR product is then purified and quantified using real-time PCR. Up to 24 uniquely indexed individual libraries are mixed equally, denatured and diluted to make a pooled library at a concentration of 20 pM. This pooled library is further heat-denatured before being added to the MiSeq reagent cartridge which then is loaded onto the MiSeq for sequencing.”
Regarding claim 18, MiSeq is a paired end sequencing platform, as evidenced by Applicant’s specification: “Non-limiting examples of the paired-end sequencing technology are provided by Illumina MiSeq™, Illumina MiSeqDx™ and Illumina MiSeqFGx™.”
Wang did not disclose double-stranded probes, where the double-stranded probes were denatured and annealed to each strand of the double-stranded genomic DNA.
Shen, also in the field of target capture of genomic DNA, disclosed the use of a double-stranded probe that was denatured, wherein each strand of the denatured probe annealed to a different strand of the genomic DNA. The 3’ end of each probe was extended until it met the 5’ end of the probe, upon which the 3’ end of the extended probe was ligated to the 5’ end of the probe, thereby forming a circle. See Figure 1. Note that, like Wang, Shen amplified the ligated probes using primers that incorporated a P5 or P7 sequencing primer sequence and first and second identifier (index sequences); figure 1, panel C. It is noted that the difference between the claimed “upstream” and “downstream” double-stranded probes and Shen’s “upstream” and “downstream” probes is that, in Shen, the probes are connected by an intervening sequence:
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Shen noted that by using two probes per target (i.e., a probe for each strand of the double-stranded target) “increases sensitivity for variant detection” (abstract).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to modify the method of Wang by using a second pair of probes complementary to the probes of Wang’s disclosure (which would in essence be double-stranded probes analogous to the end portions of Shen’s probes), thereby arriving at the claimed invention. One would have been motivated to do so because Shen taught that capturing both strands of the genomic region of interest increased sensitivity of variant detection, and one of ordinary skill in the art would have understood that Shen’s method of a single (circularizable) probe versus Wang’s method of using two linear probes to capture a genomic region of interest were functionally equivalent in capturing the same region for analysis, and therefore represented obvious variants of one another.
Claims 11, 12 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (US 2016/0312303, previously cited) in view of Shen (Genome Medicine 5:50, 2013, IDS reference) as applied to claims 10, 13, 15-18 and 22 above, and further in view of Collins (US 2018/0023138, previously cited).
Neither Wang nor Shen disclose modifications at the respective 5’ and 3’ ends of the upstream or downstream probes, such as phosphorothioate, to render those ends protected from exonuclease, or treating with exonuclease after ligation to remove unligated probes.
Collins disclosed this technique (see figure 75 and paragraph [0292]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to modify the method suggested by the combined disclosures of Wang and Shen by using phosphorothioate modification of the probes and exonuclease to remove unligated probes as disclosed by Collins. This represents nothing more than an art-recognized way to remove unligated probes, and the combining of prior art elements according to known techniques to yield predictable results.
Claim(s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang (US 2016/0312303, previously cited) in view of Shen (Genome Medicine 5:50, 2013, IDS reference) and Collins (US 2018/0023138, previously cited) as applied to claim 12 above, and further in view of Kim (US 2010/0291558).
The teachings of Wang, Shen and Collins have been discussed. These references did not teach formacetal as an exonuclease-resistant substitute for a phosphodiester bond (rather, Collins taught phosphorothioate; ).
Kim disclosed (paragraph [0036]): “In one embodiment, at least one phosphodiester bond of the first region may be substituted with a bond which cannot be cleaved by an exonuclease. The bond includes a modified phosphate backbone that is not cleaved by an exonuclease. For example, the bond may be phosphorothioate, boranophosphate, methylphosphonate, phosphorodithioate, phosphoramidothioate, phosphoramidite, phosphordiamidate, alkyl phosphotriester, formacetal, or an analog thereof, but is not limited thereto. Due to the bond of the first region, the first region is not removed by the exonuclease, while the second region is selectively removed by the exonuclease.”
Thus, Kim taught both phosphorothioate and formacetal as alternative substitutes for phosphodiester bonds to confer exonuclease resistance.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to modify the method suggested by the combined teachings of Wang, Shen, and Collins by using formacetal as an alternative to phosphorothioate.
Response to Arguments
Applicant’s arguments on page 6, last paragraph through the first paragraph on page 9 of the reply filed 01/28/2026 are identical to the arguments presented in the reply filed 12/01/2025 and are not found persuasive for the reasons discussed in the advisory action mailed 12/09/2025. As to the remaining arguments, Applicant argues (beginning at final paragraph, page 9 of the reply) that Wang’s and Shen’s probes are not “analogous structures” and that, “Wang already teaches that its Custom Probes were successful in achieving satisfactory variant detection and did not provide any reason or suggestion that a change or improvement of its method would be desirable or needed.” These arguments are not persuasive. While it is debatable whether Wang’s and Shen’s probes were analogous in structure, one of skill in the art would have appreciated them to be analogous in function, that is, to capture an intervening target sequence by extension and ligation of the probes. Secondly, one of ordinary skill in the art would have appreciated that what Shen teaches with regard to improved sensitivity by capturing both strands of a double stranded target (by using a second probe) would have been applicable to Wang’s probe-based target capture as well. Therefore, the rejection is maintained.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMUEL C WOOLWINE whose telephone number is (571)272-1144. The examiner can normally be reached 9am-5:30pm.
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/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
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