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 .
Terminal Disclaimer
The terminal disclaimer filed on August 13, 2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of Co-pending Application No: 17/127,159 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Election/Restrictions
Applicant’s election without traverse of Group II (claims 38-39) in the reply filed on December 23, 2024 is acknowledged.
Claim Status/Action Summary
This action is in response to the papers filed March 2, 2026.
Non-elected claims 20-37 were canceled by applicant and new claims 40-57 were added in dependent form on the elected group in the amendment filed with the response to requirement for restriction filed on December 23, 2024.
New claims 58-59 were added in the amendment to the claims filed on April 16, 2025.
Claim 59 was canceled by applicant and new claims 60 and 61 were added in the amendment to the claims filed on August 5, 2025. Rejections of claim 59 have been rendered moot due to applicant’s cancellation of this claim.
Claims 58-61 were canceled in the response dated March 2, 2026.
Claims 38-57 are under examination.
Any objections and rejections not reiterated below are hereby withdrawn.
The rejections under 35 U.S.C. 112(a) and (b) regarding claims 58 and 60-61 are moot in view of the cancellation of these claims.
The rejections of claims 58 and 60-61 under 35 U.S.C. 103 over Han in view of WalkerPeach and Zook et al. as applied to claims 38-39, 40, 48, 50 above and further in view of either of Ambion “ERCC RNA Spike-In Control Mixes”, 2012 or Quail et al. are moot in view of the cancellation of these claims.
Priority/Effective Filing Date
This application is a continuation of U.S. Patent Application No. 17/127,159, filed December 18, 2020, which is a continuation of U.S. Patent Application No. 15/535,768, filed on June 14, 2017, which is a 371 PCT/AU2015/050797, filed on December 15, 2015, which claims the benefit of priority to Australian application No. 2015903892, filed on September 24, 2015 and Australian application No. 2014905092, filed on December 16, 2014.
AU2015903892 and AU2014905092 do not provide support for the claimed “reversing” step required by claim 38 or for “contiguous nucleotides having a same relative order as in a 5’ to 3’ portion of a target polynucleotide… and are connected in the 3’ to 5’ direction” required by claim 39. Therefore, the priority date of claims 38-57 filed on 04/16/2025 is determined to be December 15, 2015, the filing date of PCT/AU2015/050797.
The newly added claim term “a polynucleotide fragmentation reagent of a next-generation sequencing (NGS) polynucleotide sample preparation kit”, recited by claim 58 and required by claims 60 and 61, is not present in the specification as originally filed, or in the priority documents. Therefore, the priority date of claims 58 and 60-61 as amended is determined to be August 5, 2025.
List of References in Specification
The listing of references in the specification on pages 116-119 of the specification filed April 16, 2025 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.
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.
Claims 38-41, 48, and 50-51 remain/are rejected under 35 U.S.C. 103 as being unpatentable over WO 9914376 A2 (Genaco Biomedical Products Inc and Han, 1999), (herein referred to as Han) in view of US 6,395,470 B2 (WalkerPeach, 2002), and Zook et al. “Integrating human sequence data sets provides a resource of benchmark SNP and indel genotype calls.” Nat Biotechnol 32, 246-251 (2014),
Regarding claims 38-41 and 50-51, Han teaches a method of synthesizing internal control templates for qPCR comprising: obtaining human genome sequences (i.e. a sequence comprising a human gene locus), (Han, page 12, line 35-page 13, line 10) scrambling the chosen sequence, (Han, page 11, line 5-20) and synthesizing 55-2,000 nucleotide long (i.e. at least 100; at least 1000) internal control DNA polynucleotides corresponding to target human genomic DNA sequences (Han, page 35, line 8-11) (i.e. the controls are distinguishable from the target sequence). Han teaches constructing control templates with a mutation that has the same nucleotide content (in terms of bases A,G, C, and T present) and hybridization characteristics as the wild type but differs in that the mutation is a radically different linear DNA sequence than the wild type (page 11, lines 15-20).
Han does not teach synthesizing an internal control template that is reversed relative to a target sequence in a human gene locus is obtained from NA12878 or hg38 or hg19. However, WalkerPeach teaches a method of synthesizing an internal control polynucleotide comprising a portion of a gene sequence wherein the 5’ to 3’ connectivity of the nucleic acid sequence is reversed (i.e. in the 3’ to 5’ direction) (WalkerPeach, figure 1 and column 4, lines 35-50). For example, WalkerPeach teaches an internal control cassette (i.e. a polynucleotide)) comprising a portion of a gene sequence wherein the 5’ to 3’ connectivity of the nucleic acid sequence is reversed (i.e. 3’ to 5’ direction) (WalkerPeach, figure 1 and column 4, lines 35-50). For example, WalkerPeach teaches an internal control cassette comprising a 148 base pair segment of the HSV gB gene, with the central 39 base pairs in the reverse orientation (WalkerPeach, column 6, line 55-65 and SEQ ID NO: 2). Furthermore, WalkerPeach teaches several advantages of synthesizing internal controls with inverted polynucleotide sequences. Namely, WalkerPeach teaches that control sequences produced by her method of inverting the target sequence share many of the same biochemical characteristics of the target sequences (e.g. reaction kinetics, melting temperature, and base composition). (WalkerPeach, Column 5, line 18-27) In addition, WalkerPeach teaches: Another important feature of the present invention is the length and composition of the control sequence. The length and composition of the sequence amplified may affect the signal obtained from the assay. During polymerization, the action of the synthesizing enzyme traveling down the template strand is known as processivity. The processivity of the enzyme may decrease as the length of the target sequence increases. So, the longer the target sequences, the more likely that it is that the PCR enzyme will fall off the template before completing the synthesis of the replicated strand. Premature termination of polymerization results in a product that differs in length from the target sequence and that difference could be misread as a negative result. The positive control of the present invention eliminates this problem. Since the amplified region of the positive control plasmid is the same length as the target sequence, the rate of premature termination should be the same for both sequences. As a result, if there are apparent qualities of the target sequence which cause the PCR enzyme to fall off, those same characteristics should be present in the inverted control sequence and the PCR enzyme should fall off that sequence as well.” (WalkerPeach, Column 6, line 24-45) Finally, WalkerPeach teaches an example of an internal control for a branched oligonucleotide signal amplification assay wherein the entire internal sequence is reversed (Walkerpeach, column 13, lines 30-66).
Additionally, Zook teaches NA12878 as a “genome in a bottle”, “a whole-genome reference material… for sequencing and assessing variant-call accuracy and understanding biases.”
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to modify the method of Han for synthesizing internal control polynucleotides comprising at least 100 nucleotides from human sequences by reversing, rather than scrambling, the selected target sequence as taught by WalkerPeach. The ordinary artisan would have been motivated to modify the scrambling sequence method taught by Han with the reversing method taught by WalkerPeach because both Han and WalkerPeach teach that the target and control polynucleotides must be as similar in length and base composition as possible to reduce signal amplification bias in nucleic acid detection assays. Furthermore, the ordinary artisan would have been motivated to invert the entire internal sequence (i.e. the entire amplicon in which a subset of nucleotides are inverted in some embodiments) because of the teaching of WalkerPeach that inverting the entire internal sequence is useful as an internal control for branched oligonucleotide signal amplification assays. Therefore, the ordinary artisan would have been reasonably confident that inverted internal control polynucleotides synthesized by the method of Han in view of WalkerPeach would have functioned as successful internal controls in nucleic acid detection assays.
It would likewise have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to modify the method of synthesizing inverted internal control polynucleotides comprising human gene loci taught by Han in view of WalkerPeach by selecting an extremely well characterized benchmark genome as a source material for derived control polynucleotides as taught by Zook. The ordinary artisan would have been motivated to use the NA12878 as taught by Zook as a source material for the method of synthesizing sequence-reversed internal control polynucleotides taught by Han in view of WalkerPeach because Zook teaches that “high-confidence genotype calls from a well-characterized whole genome are useful for assessing biases and rates of accurate and inaccurate genotype calls in any combination of sequencing and bioinformatics methods. High-confidence genotype calls for publicly available genomes will be particularly useful for performance assessment of rapidly evolving sequencing and bioinformatics methods.” (Zook, page 251, column 1, paragraph 3). Therefore, the ordinary artisan would have been reasonably confident that sequence reversed polynucleotides derived from NA12878 gene loci would have been successful as internal controls for quantitation of the corresponding 5’ to 3’ sequences in an experimental sample.
Regarding claim 48, Han teaches synthesizing several different internal control DNA sequences (Han, page 7, line 13-17) and demonstrates an example comprising 4 different gene loci, each associated with a different genetic disorder (Han, figure 2 and page 18, lines 9-13).
The response traverses the rejection of claims 38-41, 48, 50-51, and 58. The response argues that the combination of Han in view of WalkerPeach and Zook would not produce the invention as claimed and asserts that the lengths of the artificial portions of polynucleotides of the cited references are all less than 100 contiguous nucleotides. This argument has been reviewed but is not persuasive because Han teaches internal control templates between 55 and 2,000 nucleotides long and WalkerPeach teaches an example wherein the entirety of an internal control template (corresponding to a 148 bp target sequence) is reversed to provide an internal control for a branched oligonucleotide signal amplification assay (Walkerpeach, column 13, lines 30-66).
Response to arguments
The response asserts that Walkerpeach teaches a shorter fragment of the HSV gB gene is inverted within the longer target sequence to produce the control reagent. Without conceding the correctness of the asserted interpretation of the length of the WalkerPeach control construct, the claimed invention would still have been obvious in view of the cited references.
To reiterate, Han teaches control templates between 55 and 2,000 nucleotides long and both Han and WalkerPeach teach that it is critical in nucleic acid assays (including those based on nucleic acid amplification) (i.e. such as NGS sequencing) that control sequences share as many biochemical properties as possible with the target sequences they are designed to correspond to. Furthermore, WalkerPeach specifically teaches that correspondence between the length of the target and control polynucleotides is critical: “Another important feature of the present invention is the length and composition of the control sequence. The length and composition of the sequence amplified may effect the signal obtained from the assay. During polymerization, the action of the synthesizing enzyme traveling down the template strand is known as processivity. The processivity of the enzyme may decrease as the length of the target sequence increases. So, the longer the target sequences, the more likely that it is that the PCR enzyme will fall off the template before completing the synthesis of the replicated strand. Premature termination of polymerization results in a product that differs in length from the target sequence and that difference could be misread as a negative result. The positive control of the present invention eliminates this problem. Since the amplified region of the positive control plasmid is the same length as the target sequence, the rate of premature termination should be the same for both sequences. As a result, if there are apparent qualities of the target sequence which cause the PCR enzyme to fall off, those same characteristics should be present in the inverted control sequence and the PCR enzyme should fall off that sequence as well.” (WalkerPeach, Column 6, line 24-45).
Therefore, as discussed above, the ordinary artisan would have recognized that the sequence inversion step taught by WalkerPeach would have predictably provided an ideal method for synthesizing control polynucleotides for PCR-based nucleic acid assays, such as those taught by Han, requiring longer control polynucleotides, regardless of the length of the particular control sequence that was useful in the particular application taught by WalkerPeach.
To summarize another way, WalkerPeach teaches, from first principles, that control sequences are ideally the same length and the same sequence composition as the sequences for which they are meant to control. Therefore, it would have been obvious to the ordinary artisan that control sequences, prepared by the sequence-inversion techniques taught by WalkerPeach, may advantageously and predictably be applied to a target sequence of any length to generate an “artificial” derived control polynucleotide having the advantageous and predictable properties of maximum biochemical similarity to the target polynucleotide from which they were derived.
Therefore, as stated above, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to modify the method comprising rearranged sequences (i.e. scrambled sequences) within a long (55-2000 base pair) internal control template, taught by Han, by reversing, rather than scrambling the entirety of the control template to provide a suitable internal control template for branched nucleic acid amplification reactions or PCR amplification reactions as taught by WalkerPeach. Furthermore, Han and WalkerPeach teach that the target and control polynucleotides must be as similar in length and base composition as possible to reduce signal amplification bias in nucleic acid detection assays. A simple reversal of the sequences is a particular scrambling of the sequences that would have been expected to have the same benefits.
Thus, the rejection is maintained.
Claims 42-47, 49, and 52-57 remain/are rejected under 35 U.S.C. 103 as being unpatentable over WO 9914376 A2 (Han, 1999) in view of US 6395470 B2 (WalkerPeach, 2002) and Zook et al. “Integrating human sequence data sets provides a resource of benchmark SNP and indel genotype calls.” Nat Biotechnol 32, 246-251 (2014) as applied to claims 38-39, 40, 48, 50 above and further in view of US 2015/0133314 A1 (Shahbazian, 2015, publication of US application 14/461,306 filed on 04/15/2014).
Regarding claims 42-45 and 52-55, the method of synthesizing nucleic acids taught by Han in view of WalkerPeach and Zook does not teach that the first nucleotide sequence selected from a gene locus in a human genome or human reference genome comprises a single nucleotide polymorphism, insertion or deletion, inversion or translocation, or a cancer-associated genetic variation relative to human genome NA12878, hg38, or hg19 .
However, Shahbazian teaches a method comprising “designing a control sequence comprising a representative sequence of a particular gene of interest and/or variants thereof (e.g. those targeted by commercially-available NGS tests such as the AMPLISEQ Cancer Hotspot Panel v2… comprising identifying a sequence from a genome reference source (e.g. Genome Reference Consortium Human Reference 37 (GRCh37)).” (i.e. hg19) (Shahbazian, 0045-0047)
Shahbazian teaches that the “variants may include at least one of a single nucleotide polymorphism… insertion(s)… deletion(s)…. Inversion(s)” (Shahbazian, 0028)
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to modify the method of synthesizing one or more internal control polynucleotides having a same relative order as in a human gene locus, wherein the sequence is reversed relative to the source genome taught by Han in view of WalkerPeach and Zook by designing a control sequence comprising a single nucleotide polymorphism, insertion, deletion, inversion, or cancer-associated genetic variation relative to the human reference genome hg19 as taught by Shahbazian. The ordinary artisan would have been motivated to modify the method taught by Han in view of WalkerPeach and Zook with the control sequences comprising genetic variation relative to hg19 taught by Shahbazian because of the teaching of Shahbazian that “There is a recognized need in the market for flexible, reliable control materials for NGS testing… representing reference sequences and/or variants thereof (e.g. mutations) (Shahbazian, 0025-0026) The ordinary artisan would have been reasonably confident that control sequences produced by the method taught by Han in view of WalkerPeach and Zook, when modified to comprise genetic variants as taught by Shahbazian, would have successfully provided for the recognized need in the market for NGS control materials taught by Shahbazian.
Regarding claims 46 and 56, Shahbazian teaches that the gene and gene locus comprises: BRAF and COSM476, KRAS and COSM521, IDH1 and COSM28746, EGFR and COSM6224, FGFR3 and COSM715, PIK3CA and COSM775, CTNNB1 and COSM5664, NRAS and COSM584, and FOXL2 and COSM33661. (Shahbazian, table 1A)
Regarding claims 47 and 57, Shahbazian teaches that the gene and gene locus comprises: EGFR and COSM6223, and KIT and COSM1326. (Shahbazian, table 1A)
Regarding claim 49, Shahbazian teaches synthesizing multiple control polynucleotides comprising nucleotide sequences corresponding to exons in human reference genome hg19 (Shahbazian, table 1A)
Response to arguments:
The response argues that “it is unnecessary at this time to argue the further distinguishing features of all of the dependent claims” and requests to “reserve the right to specifically address in the future the further patentability of the dependent claims not specifically addressed herein.” Thus, for the reasons above and those already of record, the rejection is maintained.
Conclusion
No claim is allowed.
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.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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