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 .
Election/Restrictions
Applicant’s election without traverse of 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) in the reply filed on 07/31/2025 is acknowledged.
Claims 83-86 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. It is noted that Applicants’ reply indicates that claim 86 is part of elected Group I; claim 86 was inadvertently left out of the listing of claims relevant to Group IV as present in the Requirement of 06/04/2025 but where claim 86 is drawn to a “computer-readable storage medium comprising instructions operable, when executed by one or more computer processors”, the subject matter of this claim is part of Group IV which is identified as “computer systems and software on a storage medium”.
Election was made without traverse in the reply filed on 07/31/2025.
Priority to CN202010815673.8 (08/13/2020)
Applicant cannot rely upon the certified copy of the foreign priority application to overcome a rejection based on the prior art because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Information Disclosure Statement
The listing of references (e.g.: see pages 5-6 of the specification as filed) in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
It is noted that in the IDS of 03/01/2024 there is an indication (i.e.: check marked box in column T6) that an English Translation of the document is provided. However, no English translations appear to have been provided.
Specification
The disclosure is objected to because of the presentation of nucleic acid sequences. The presentation of sequences that are SEQ ID NOs: 7-12 provides two target sequences (i.e.: SEQ ID NOs: 7 and 8) ad four capture probes (i.e.: SEQ ID NOs: 9-12). The sequences, as described in the Sequence Listing, are presented in a 5’ to 3’ orientation (i.e.: the first nucleotide of the sequence is the 5’-end, and the last nucleotide is the 3’-end. But the sequences as presented fail to provide a capture probes that are in fact the ‘reverse complement’ of the identified target sequences; the capture probes provide complementary bases, but to not provide the appropriate reverse orientation of the complementary bases. So the capture probes (SEQ ID NOs: 9-12) will not hybridize to the target sequences (SEQ ID NOs: 7-8) with the melting temperatures as provided in Table 16. Here it is noted that while the specification asserts that the target sequences (i.e.: SEQ ID NOs: 7 and 8) are alleles of SNP site rs7321990 (specification at page 79), the target sequences appear to be in the wrong orientation based on the rs7321990 entry from dbSNP.
Appropriate correction is required. Applicant is reminded to provide an update sequence listing reflective of any change to polynucleotide sequences set forth in the text of the specification.
Claim Rejections - 35 USC § 112 - Indefiniteness
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 78 and 81 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.
Claims 78 and 81 are each unclear over recitation of the phrase “the chromosomal abnormality comprises maternal trisomy type I, maternal trisomy type II, paternal trisomy type I, paternal trisomy type II, maternal deletion, or paternal deletion” because the phrases “maternal trisomy type I, maternal trisomy type II, paternal trisomy type I, paternal trisomy type II” do not appear to be phrases that are used in the art. It is unclear what sort of abnormalities are intended to be required or encompassed by the limitations.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 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 –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
The instant rejection makes use of the patent document CN11951890 published 11/17/2020 (as cited on the IDS of 03/01/2024). As noted above, the rejection is appropriate where Applicant cannot rely upon the certified copy of the foreign priority application to overcome a rejection based on the prior art because a translation of said application has not been made of record. Furthermore, the rejection is appropriate where the document does not disclose the inventor (i.e.: translation of part (72) on second page of the document submitted by Applicants on 03/01/2024 provides “The inventor does not announce the inventor), and as such it is not clear that an exception under 35 USC 102(b)(1) applies.
Claim(s) 65-83 is/are rejected 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). Machine translation of the text of the document is provided by https://patentscope.wipo.int.
Relevant to claim 65, the reference teaches methods that include hybridizing a target nucleic acid with a capture probe, where the target nucleic acid comprises a SNP position, and the capture probe has a nucleotide at the position corresponding to the SNP position that has smallest difference in melting temperature (i.e.: ΔTm) between the nucleotide in the capture probe and the nucleotides in the alleles of the SNP (e.g.: p.15 of the translation).
Relevant to claims 66-69, the reference teaches capture of isolated nucleic acids that are cell-free and originate from the cells of the organism, as well as the amplification of nucleic acids (e.g.: p.1 and p.19-20 of the translation).
Relevant to claim 70-72, the reference teaches determining melting temperatures of capture probes to wild type and mutant SNP sequences, and teaches probes of the required length (e.g.: p.15 of the translation).
Relevant to claim 73, the reference exemplifies capture probes with GC content of 40%-60% (e.g.: p.24 of the translation).
Relevant to claim 74, the reference exemplifies the capture of a region of the FGFR3 gene that includes a polymorphism.
Relevant to claims 75 and 76, the reference teaches the use of probes which are free floating, and then captured using a magnetic rack (e.g.: p.21 of the translation).
Relevant to claim 77-81, the reference teaches detection of trisomy by sequencing capture nucleic acids (e.g.: p.24-25 of the translation).
Relevant to claim 82, the reference teaches capture probes directed to a plurality of different genes (e.g.: p.16 of the translation).
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.
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).
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 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 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.
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 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.
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