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 .
This Office Action is in reply to Applicants’ correspondence of 04/13/2026.
Applicants’ remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. New grounds of rejection are presented in this Office Action which were not necessitated by Applicants’ amendments to the claims. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.
This Action is made NON-FINAL.
Please Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
In the reply filed on 07/31/2025, Applicants elected, without traverse, the invention of Group I (claims 65-82, drawn to methods of capturing target nucleic acid molecules), and the particular gene that is FGFR3 (species election requirement).
Claims 83-86 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, as set forth on page 2 of the Office Action of 11/13/2025.
Priority to CN202010815673.8 (08/13/2020)
Applicants’ reply of 04/13/2026 includes a certified translation of the foreign priority document CN202010815673.8 (08/13/2020).
Withdrawn Objection to the Specification
The objection to the specification, as set forth on pages 3-4 of the Office Action of 11/13/2025, is withdrawn in light of the amendments to the specification provided with the reply of 04/13/2026.
Withdrawn Claim Rejections - 35 USC § 112 - Indefiniteness
The rejections of claims under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as set forth on pages 4-5 of the Office Action of 11/13/2025, are withdrawn in light of the amendments to the claims.
Withdrawn Claim Rejections - 35 USC § 102
The rejection of claims made under 35 U.S.C. 102(a)(1) as being anticipated by CN111951890 published 11/17/2020 (as cited on the IDS of 03/01/2024), is withdrawn in light of the certified translation of the foreign priority document CN202010815673.8 (08/13/2020) provided with the reply of 04/13/2026.
Claim Rejections - 35 USC § 103
Newly Applied the Amended Limitations of Claim 65
Claim(s) 65, 67, 68, 71, 72, 75, 76, 79, and 82 are is/are rejected under 35 U.S.C. 103 as being unpatentable over Metsky et al (US PG Pub 2018/0340215 A1) in view of Oliveira et al (2020).
Relevant to instantly rejected claim 65, Metsky et al teaches methods of hybrid selection of target nucleic acid molecules using capture probes (referred to in the reference as “capture baits”) comprising hybridizing a target nucleic acid from a sample with a capture probe (e.g.: paras: 0097; 0187; p.27 - right col). Metsky does not exemplify the use of a capture probe that is complementary to a SNP, where the position in the capture probe corresponding the SNP site is selected from an A, C, G or T nucleotide that has a lowest difference in pairing kinetics between SNP site reference allele and the SNP site alternative allele. But Metsky et al does teach aspects of a single capture probe directed to multiple targets such SNP alleles. Metsky et al teaches (e.g.: para 0083) that bait sequences (i.e.: capture probes) may be designed using a universal base such as inosine or 5-nitroindole at the position(s) of a common SNP to optimize the bait sequences to catch both alleles (i.e., SNP and non-SNP). Further relevant to the rejected claims, Metsky et al teaches aspects of melting temperatures of probes (e.g.: para 0098).
Relevant to claim 67 and 68, Metsky et al teaches detecting nucleic acids obtained from cells such as in a lysate (e.g.: para 0096-0097; 150).
Relevant to claims 71 and 72, Metsky et al teaches that probe lengths in the range of 70 bp to 200 bp are suitable for hybrid selection, and specifically suggests lengths of 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 and 200 nucleotides in length (e.g.: para 0074; para 0086; para 0240).
Relevant to claim 75 and 76, Metsky et al teaches that capture probes may be bound to a solid support, or may be in solution (e.g.: para 0035).
Relevant to claim 79, Metsky et al teaches sequencing target nucleic acids (e.g.: para 0141; para 0248).
Relevant to claim 82, Metsky et al teaches methods comprising a plurality of different capture probes.
As noted above, Metsky et al suggest the use of single capture probe directed to multiple targets such SNP alleles. Metsky et al does not teach a capture probe where the position in the capture probe corresponding the SNP site is selected from an A, C, G or T nucleotide that has a lowest difference in pairing kinetics, determined at least in part by measuring a melting temperature for the first hybridizing and the second hybridizing between SNP site reference allele and the SNP site alternative allele. However, the stability of any mismatched nucleotide in the base pairing of a double stranded polynucleotides, determined by a measurement if melting temperatures, was known in the art and is taught by Oliveira et al.
Relevant to the requirements of the instantly rejected claims, Oliveira et al teaches the base pairing kinetics of every possibly single nucleotide mismatch, including the mismatches in difference sequence contexts, in double stranded nucleic acid sequences (e.g.: p.8276 - Base pair context groups; p.8277 – Melting temperature measurements; Table 1; Table S1) and provides measures of the melting temperature of different mismatches (relevant to the limitations of claim 65).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have created a single capture probe for the capture of a target nucleic acid with either allele of a SNP, as taught by Metsy et al, using a single capture probe with an A, C, G or T nucleotide at the position corresponding to the SNP site as included in the teachings of Oliveira et al. The skilled artisan would have been motivated to create a single capture oligonucleotide directed to both alleles based on the expressed teachings of Metsky et al that such embodiments of capture hybridization may use a single capture oligonucleotide capable of catching both alleles. The skilled artisan would have been motivated to use a single capture probe with an A, C, G or T nucleotide at the position corresponding to the SNP site (modifying the methods of Metsky et al which teach a universal base such as inosine or 5-nitroindole) to create a single capture oligo without the need for specialty reagents requiring more than the four nucleotides used in the rest of the capture probe(s), thus providing for more efficient and economical chemical synthesis of capture probes. The skilled artisan in possession of the teachings of Oliveira et al would recognize that a single capture oligo with lowest difference in pairing kinetics, as measured by melting temperature, between each of the SNP alleles (i.e.: reference allele and alternative allele) would allow for the most selective capture of both alleles in a sample at a particular hybridization condition. The skilled artisan would have a reasonable expectation of success based on the expressed teachings of Oliveira et al that single mismatches and melting temperatures have important consequences for applications such as SNP detection.
Response to Remarks
Applicants’ remarks of 04/13/2026 have been fully considered but are not persuasive to withdraw the rejection as provided above. Applicants have argued (p.10-11 of the Remarks) that the amended claims require the limitations of previous claim 70, where previous claim 70 was not rejection under 35 USC 103 as obvious in view of Metsky et al and Oliveira et al. The argument is no persuasive because upon further review of the references, both Metsky et al and Oliveria et al provide teachings related to the methods temperatures of probes, and as such the relevant limitation (i.e.: the pairing kinetics is determined at least in part by measuring a melting temperature for the first hybridizing and the second hybridizing) in the claimed methods is rendered obvious by the teachings of the cited prior art.
Claim(s) 66, 69, 77, 78, 80, and 81 is/are rejected under 35 U.S.C. 103 as being unpatentable over Metsky et al (US PG Pub 2018/0340215 A1) in view of Oliveira et al (2020), as applied to claims 65, 67, 68, 71, 72, 75, 76, 79,and 82 above, and further in view of Rabinowitz et al (US PG Pub 20110288780 A1).
Metsky et al in view of Oliveira et al renders obvious methods including contacting a target nucleic acid with a capture probe that is complementary to a SNP, where the position in the capture probe corresponding the SNP site is selected from an A, C, G or T nucleotide that has a lowest difference in pairing kinetics between SNP site reference allele and the SNP site alternative allele.
Metsky et al in view of Oliveira et al does not teach methods where the target nucleic acid is cell-free (claim 66), or amplifying nucleic acid from a sample (claim 69) or methods related to the target nucleic acids from a pregnant subject to detect chromosomal aneuploidy (claims 77, 78, 80 and 81). However, such methods related to target capture were known in the prior art and are taught by Rabinowitz et al.
Rabinowitz et al teaches methods related to determining fetal ploidy in non-invasive samples including the detection of alleles of SNPs and target enrichment using capture hybridization (e.g.: para 0011; para 0055; p.20).
Relevant claim 66, Rabinowitz et al teaches methods applied to cell-free samples (e.g.: para 0289).
Relevant to claim 69, Rabinowitz et al teaches methods including amplification of target nucleic acids (e.g.: para 0213-0276).
Relevant to claims 77, 78, 80 and 81, Rabinowitz et al teaches that the methods of analysis, including sequencing cell-free genomic material obtained from a pregnant subject, may be used in the non-invasive prenatal diagnosis of aneuploidy (e.g.: para 0050; para 0148-0150).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have used capture probes suggested by Metsky et al in view of Oliveira et al in the non-invasive prenatal diagnosis methods suggested by Rabinowitz et al. The skilled artisan would have been motivated to used capture probes based on the expressed teachings of Rabinowitz et al that target enrichment using capture probe hybridization can be a part of non-invasive prenatal testing (para 0115, para 0193-0200), and that hybridization may maximize uniform capture of different alleles in a sample (para 0199-0200). The use of capture probes rendered obvious by Metsky et al in view of Oliveira et al in the methods of Rabinowitz et al would be the simple substitution of one element (maximizing allele capture using probes that flank a SNP locus) for another (capture probes where the position corresponding the SNP site is selected from an A, C, G or T nucleotide that has a lowest difference in pairing kinetics between SNP site reference allele and the SNP site alternative allele) with the predictable result of capturing both alleles of a target SNP locus. The skilled artisan would have a reasonable expectation of success because. The skilled artisan would have a reasonable expectation of success where Oliveira et al teaches calculation of melting temperatures of different probe:target combinations.
Claim(s) 73 is/are rejected under 35 U.S.C. 103 as being unpatentable over Metsky et al (US PG Pub 2018/0340215 A1) in view of Oliveira et al (2020), as applied to claims 65, 67, 68, 71, 72, 75, 76, 79, and 82 above, and further in view of Hansen et al (2019).
Metsky et al in view of Oliveira et al renders obvious methods including contacting a target nucleic acid with a capture probe that is complementary to a SNP, where the position in the capture probe corresponding the SNP site is selected from an A, C, G or T nucleotide that has a lowest difference in pairing kinetics between SNP site reference allele and the SNP site alternative allele.
Metsky et al in view of Oliveira et al does not specify capture probes with a GC content of 40% to 60%. However, the GC content of a capture probe as a parameter that can be modified to adjust the characteristics of a capture probe was known in the prior art and is taught by Hansen et al.
Hansen et al teaches GOPHER, software to generate probes for hybridization capture. Relevant to rejected claim 73, Hansen teaches that the software includes the ability to adjust minimum (default 35%) and maximum (default 65%) GC content of a capture probe (e.g.: Table 1, Fig 2B; page 5, left col).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have created probes with a GC content of 40-60% for use in the methods rendered obvious by Metsky et al in view of Oliveira et al. Where Hensen et al teaches that GC content of a capture probe may be adjusted (p.11 - Mean G/C content of probes), that GC content is a results effective variable (e.g.: p.7), and teaches a range (35%-65%) that largely overlaps the claimed range (40%-60%) the skilled artisan would have been motivated to select a GC content with suitable specificity for any desired target nucleic acid sequence(s). In this regard the selection of the claimed range as part of the determination of the optimum or workable ranges would be obvious to the skilled artisan as a matter of routine experimentation (MPEP 2144.05 (II)).
Claim(s) 74 is/are rejected under 35 U.S.C. 103 as being unpatentable over Metsky et al (US PG Pub 2018/0340215 A1) in view of Oliveira et al (2020) and Rabinowitz et al (US PG Pub 20110288780 A1), as applied to claims 66, 69, 77, 78, 80, and 81 above, and further in view of Ren et al (2018).
Metsky et al in view of Oliveira et al and Rabinowitz et al renders obvious methods including contacting a target nucleic acid with a capture probe that is complementary to a SNP, where the position in the capture probe corresponding the SNP site is selected from an A, C, G or T nucleotide that has a lowest difference in pairing kinetics between SNP site reference allele and the SNP site alternative allele for the detection of fetal alleles in a sample from a pregnant subject for non-invasive prenatal diagnosis.
Metsky et al in view of Oliveira et al and Rabinowitz et al does not teach capture probes directed to the FGFR3 gene (as recited in the claims, and consonant with the election). However, the detection of SNP allele content in the FGFR3 gene in maternal blood samples for prenatal diagnosis of pathology was known in the art and is taught by Ren et al.
Ren et al teaches the detection of FGFR3 mutations (e.g.: p.824 - Identification of mutations) in maternal blood samples from women carrying ACH or TD fetuses (e.g.: p.822 - Maternal blood collection and processing) to determine the presence of alleles in the fetus (e.g.: p.825 - Clinical validation).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to include the target capture methods rendered obvious by Metsky et al in view of Oliveira et al and Rabinowitz et al, and to have captured target nucleic acids with the FGFR3 SNP loci, in the methods of Ren et al. The skilled artisan would have been motivated to include target capture methods based on the expressed teachings of Rabinowitz et al that enrichment for target sequences by capture probe hybridization is a useful part of non-invasive prenatal testing. The skilled artisan would have a reasonable expectation of success because Ren et al teaches target capture as part of the workflow of the diagnostic test (e.g.: p.822 – Prenatal diagnosis).
Conclusion
No claim is allowed.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
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