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 .
Effective Filing Date
The present application, filed on June 8, 2022, is a 371 of PCT/CN2020/092900, filed on May 28, 2020, and claims the benefit of foreign priority to CHINA 201911330414.X, filed on December 20, 2019.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Status/Action Summary
Claims 1 and 4-11 are pending in the present application. Claims 2 and 3 were canceled in the response and claim 11 was added.
Claims 1 and 4-11 are under examination.
Any objections and rejections not reiterated below are hereby withdrawn.
The objections to the specification have been withdrawn in view of the substitute specification submitted with the October 16, 2025 response.
The 112(b) rejections of record have been withdrawn in view of the cancellation of claims 2-3 and the amendments to claim 1.
Nucleotide and/or Amino Acid Sequence Disclosures
After further consideration in view of the Nucleotide Sequence Disclosures previously objected to in the previous office action, and the amended claims, it is apparent that the sequence disclosure in the drawings (Figure 2) is the only disclosure in the present application of the sequence of “a Y-type universal adapter” as recited by claim 11. This sequence (Figure 2) is not identified by a Sequence Identifier, and the sequence is not present in the Sequence Listing as presently filed.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claim 11 is rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor at the time the application was filed, had possession of the claimed invention.
Claim 11 recites “constructing a genomic library” using “a Y-type universal adapter” and “PCR amplification is performed with a forward universal primer and a reverse universal primer… wherein the forward universal primer is SEQ ID NO: 93… and the reverse universal primer is SEQ ID NO: 94”
The claims do not require the use of a Y-type universal adapter having any particular sequence (i.e. any Y-type adapter may be used). However, the claim requires that the Y-type adapter ligated library molecules are amplified using SEQ ID NO: 93 and SEQ ID NO: 94.
The specification teaches one particular Y-type universal adapter (Fig 2, see below) corresponding to the 3’ ends of the universal primers SEQ ID NO: 93 and SEQ ID NO: 94.
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The claims therefore encompass a genus of structurally undefined Y-type adapters.
For claims drawn to a genus, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. Further, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that:
To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“ [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
An adequate written description of a DNA, such as the cDNA of the recombinant plasmids and microorganisms of the '525 patent, "requires a precise definition, such as by structure, formula, chemical name, or physical properties," not a mere wish or plan for obtaining the claimed chemical invention. Fiers v. Revel, 984 F.2d 1164, 1171, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). Accordingly, "an adequate written description of a DNA requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it; what is required is a description of the DNA itself." Id. at 1170, 25 USPQ2d at 1606.
In the case of the instant claims, the functionality of “PCR amplification”…using SEQ ID NO: 93 and 94 is a critical feature of the claimed methods.
The specification provides only one exemplary Y-type universal adapter (Figure 2). However, this adapter sequence is one of many present in the prior art. For example, the NEBNext Adaptor for Illumina (complementary stem sequences underlined) (taught by NEB manual E7600):
5’- ACACTCTTTCCCTACACGACGCTCTTCCGATC-s-T-3’
3’- CTGACCTCAAGTCTGCACACGAGAAGGCTAG-5’/5Phos/-5’
The specification does not teach any “universal primers” that have the requisite complementary sequences to any Y-type adapter other than that described in Figure 2.
Thus considering the breadth of the compounds required by the claimed methods, their specific required functionalities, and the teachings of the instant specification, it is the conclusion that the specification does not provide an adequate written description of the broadly claimed subject matter.
Claim Rejections - 35 USC § 112(b)
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.
Claims 11 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
This is a new grounds of rejection necessitated by the new claim 11.
Claim 11 is indefinite because it is unclear how the preamble is intended to breathe life and meaning into the claim. The preamble of claim 11 is directed to “The…method… according to claim 1, wherein the method is for detecting 46 SNPs”. However, the claim only requires steps of: designing forward-strand probes and reverse-strand probes for 46 SNPs…constructing a genomic library…amplifying the genomic library: the forward-strand probe and the reverse universal primer form an amplification primer combination 1, the reverse-strand probe and the forward universal primer form an amplification primer combination 2, the constructed genomic library is amplified using the two combinations, separately; amplification products of the primer combination 1 and… 2 are mixed in equal mole amounts; the mixture is amplified with PCR primers… and the product… is subjected to high-throughput pair-ended sequencing… performing genome sequence alignment… [and] analyzing sequencing data”. Therefore, it is not clear if applicant intends to cover a method comprising designing any forward-strand probes and reverse-strand probes for any 46 SNPs, and whether the method is intended to cover methods using the designed probes to amplify said 46 SNPs in parallel, or in some combination(s). The claim does not recite any “detecting 46 SNPs” steps or recite any steps for amplifying more than one SNP using: i) a forward-strand probe and reverse universal primer, ii) a reverse-strand probe and forward universal primer; separately. It is unclear if applicant intends to cover any method comprising designing primers, constructing a sequencing library, amplifying said library with a first and second primer combination separately, combining the products of said amplifying, amplifying the mixture with universal primers, sequencing the products, aligning the sequences to a genome, and analyzing the sequencing data, of if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If the claim requires something more, it is unclear what additional active process step the method requires and it appears that the claim is incomplete. The claim fails to provide any active steps that clearly accomplish the goal set forth by the preamble of the claim.
Claim 11 is indefinite because the claim recites “designing forward-strand probes and reverse-strand probes for 46 SNPs” and provides a table consisting of 46 pairs of polynucleotide sequences, each consisting of a “primer_F” and “primer_R” and assigned to a SNP with an “rs” identifier, but the claim does not recite any active step that requires the use of any particular primer or primer pair, much less 92 pairs of “forward-strand probe and reverse universal primer” and “reverse-strand probe and forward universal primer”. It is unclear whether the “designing” step is intended to require primers consisting of the specific nucleotide sequences of SEQ ID NOs: 1-92 for the specific SNPs listed, or whether these SNPs and primers are merely exemplary of the claimed method. Furthermore, it is unclear whether the “amplifying the genomic library step” is intended to require any particular forward-strand probe and reverse strand probe, or whether the method is intended to be generic to any SNP or set of SNPs of interest to the user.
Claim 11 is indefinite because it recites a generic “Y-type universal adapter” and a “forward universal primer” and “reverse universal primer” having specific nucleotide sequences. It is unclear whether the claim requires a Y-type universal adapter, such as that disclosed by Figure 2 of the present drawings, or is intended to claim that the recited forward and reverse universal primers are capable of amplifying any genomic library prepared using any adapter within the genus of “a Y-type universal adapter”.
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.
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 1 and 4-10 are/remain rejected under 35 U.S.C. 103 as being unpatentable over Zimmermann et al., US 2013/0123120 A1 (Published May 16, 2013) in view of Chen et al., “gencore: An Efficient Tool to Generate Consensus Reads for Error Suppressing and Duplicate Removing of NGS data”, bioRxiv 501502; doi: https://doi.org/10.1101/501502 (Published September 6, 2019).
This rejection has been updated as necessitated by the claim amendments.
Regarding claim 1, Zimmermann et al. teach high throughput, highly multiplex methods for detecting allele frequencies of targeted genetic variants (Zimmermann et al., paragraph 0008). Zimmermann et al. teach that said methods comprise designing gene-specific probes, constructing a genomic library, amplifying the genomic library by so-called “hemi-nested” PCR reactions wherein a product is amplified from each strand of a library molecule comprising a genetic variant of interest using a gene-specific primer wherein the 5’ end of the gene specific primer has a universal adapter sequence, and a primer specific to the universal adapter sequence on the target library molecule (Zimmermann et al., figure 9).
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Zimmermann et al. further teach sequencing the hemi-nested PCR products, performing genome alignment, and analyzing the sequencing data (i.e. counting a sequencing depth of each allele) to calculate the allele frequency (i.e. mutation/allele proportion) at a given target locus (i.e. “X” in figure 9) (Zimmermann et al., paragraph 0605-0612).
Zimmermann et al. further teach alternative nesting workflows comprising “one-sided mini-PCR” wherein target loci are amplified using a pair of primers comprising one or a set of forward primers and a tag-specific (i.e. universal) reverse primer or one or a set of reverse primers and a tag-specific (i.e. universal) forward primer (Zimmermann et al., paragraph 0251).
Zimmermann et al. does not teach grouping/aligning sequences with the same start and end coordinates and filtering bases occurring with less than 10% frequency among sequences with the same start and end coordinates at a target site (i.e. filtering sequencing/PCR errors).
However, Chen et al. teach a publicly available sequence analysis tool “gencore” that groups reads with the same start and end coordinates by “position clustering”, subsequently filtering clusters with fewer supporting reads than a user-defined threshold, scoring each position in the cluster based on the frequency of a given base at that position, and generating a consensus sequence for the cluster of reads with the same start and end coordinates (Chen et al., Figure 1 and pages 7-8). Chen et al. further teaches gencore is particularly useful for reducing sequencing errors when detecting low-frequency mutations in cancer sequencing data such as in liquid biopsies because the detection of such low-frequency variants can be seriously affected by PCR and sequencing errors (Chen et al., page 9, line 197- page 10, line 204). Finally, Chen et al. teach that gencore filters out PCR/sequencing errors that occur at random positions in a minority of reads with the same start and end coordinates (Chen et al., Figure 4).
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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 have combined: (A) The molecular techniques taught by Zimmermann et al. comprising preparing a genomic sequencing library and amplifying targeted loci comprising a particular variant of interest by so-called “hemi-nested” PCR resulting in two clusters of PCR products with the same start and end positions comprising: a universal adapter sequence, genomic DNA, a position of interest “X”, genomic DNA, the target-specific primer binding site, and a universal adapter sequence with (B) the sequence analysis method taught by Chen et al. comprising aligning/clustering sequencing reads with the same start and end coordinates, filtering “random” PCR/sequencing errors based on their inconsistency among a cluster of presumed PCR duplicates, and scoring the proportion of each nucleotide at each position along the consensus generated from said cluster (i.e. reporting a sequencing depth/mutation proportion of each observed variant/allele).
The ordinary artisan would have been motivated to combine the analytical techniques taught by Chen et al. with the multiplexed, “hemi-nested” PCR amplification molecular techniques taught by Zimmermann et al. because of the teaching of Chen et al. that said analysis is particularly important for determining the frequency of low-frequency variants in applications such as liquid biopsy of cancer from samples such as blood, urine, or malignant effusion wherein the minor allele fraction of important variants can be much lower than 1%. Chen et al. further teaches that at such low-frequencies, the detection of these true mutations/variants can be seriously affected by sequencing/PCR errors, thus necessitating their filtration from deep-sequencing data. The ordinary artisan would have been reasonably confident that the analytical methods taught by Chen et al. would have improved the sensitivity of the molecular methods taught by Zimmermann et al. because they are both specifically intended to detect and quantify the frequency of sequence variants in complex populations of nucleic acid molecules (such as the fraction of fetal DNA in maternal blood or the fraction of cancer DNA in blood).
Regarding claim 4, Zimmermann et al. teach the target-specific sequences bind to a region of DNA upstream from the polymorphic site “X”, separated from the polymorphic site by a small number of bases (1-60 bp) (i.e. 2-100bp) (Zimmermann et al., paragraph 0059).
Regarding claims 5 and 6, Zimmermann et al. teach the specific probe (i.e. the primer) can have a length between 18 to 30 nucleotides (i.e. 18 to 36 bp or 20-27 bp) (Zimmermann et al., paragraph 0030).
Regarding claim 7, Zimmermann et al. teach the forward and reverse universal primers can contain sequences corresponding to a Y-type universal adapter (Zimmermann et al., paragraphs 0239-0240).
Regarding claim 8, Zimmermann et al. teach the input DNA is fragmented with a typical average length less than 500 bp (i.e. the DNA has a length of 200-1000 bp) (Zimmermann et al., paragraph 0204).
Regarding claim 9, Zimmermann et al. teach during the construction of the genomic library, 7 cycles (i.e. 6-12) of PCR was used after adapter ligation (Zimmermann et al., paragraph 0597).
Regarding claim 10, Zimmermann et al. teaches that the amount of PCR required at the specific target amplification step may be optimized to achieve an optimal depth of reads for particular applications. Zimmermann et al. teaches that low depth is associated with higher statistical noise, while with increasing depth, the marginal usefulness of each additional read is relatively small (Zimmermann et al., paragraph 0239). Furthermore, Zimmermann et al. teaches one could increase depth of reads by increasing the number of PCR cycles at the specific target amplification step to comprise more than 25, more than 30, or even more than 40 cycles. Assuming only a single input target molecule, 25 cycles of PCR would be expected to generate 1x2^25, or ~33.5 million molecules from each input molecule (i.e. more than 50,000x). Finally, Zimmermann et al. teaches that accuracy of measures of allele fraction is generally increased with increasing number of reads (Zimmermann et al., paragraph 0515). The ordinary artisan would therefore have recognized that the depth of sequencing for a particular locus is easily optimizable and increasing the depth of sequencing could be arbitrarily increased to any value given an arbitrary number of cycles of PCR and sequencing reads.
Response to arguments
The response asserts that Zimmerman teaches only sequential amplifications, rather than parallel amplifications with a target-specific (forward or reverse) tagged primer and a corresponding (reverse or forward) universal primer.
However, as described in the updated 103 rejection above, Zimmermann et al. teach alternative nesting workflows comprising “one-sided mini-PCR” wherein target loci are amplified using a pair of primers comprising one or a set of forward primers and a tag-specific (i.e. universal) reverse primer or one or a set of reverse primers and a tag-specific (i.e. universal) forward primer (Zimmermann et al., paragraph 0251). Therefore, this argument is not persuasive.
The response further asserts that Chen et al. do not teach the specific filtering conditions “a certain base type whose count is below 10%*N at a target site is regarded as a sequencing error and filtered” because Chen et al. base their filter criterion on the number of “supporting reads”.
This argument is not persuasive. The teachings of Chen et al. filter out variants with fewer than 5 or fewer than 8 reads (for ctDNA and tissue samples, respectively) among the total number of reads containing the putative variant (Chen et al., line 254-267). Chen et al. do not teach setting the number of supporting reads for a particular sample or a particular locus as a function of the number of total reads mapped on that particular sample or locus (i.e. 10% of reads, as presently recited). However, as evidenced by the different “supporting reads” thresholds applied by Chen et al. to different sample types (filter for fewer than 5 or fewer than 8 supporting reads for ctDNA and tissue samples, respectively), the ordinary artisan would have recognized this parameter as being dependent on the particularities of the sample/locus for removing sequencing errors that occur as a minority of variants not common to a group of reads (Chen et al., Figure 4). Therefore, it would have been obvious to the ordinary artisan to optimize this particular parameter based upon the sample in question.
Finally, the response asserts that Table 2 provides unexpected results because the claimed method detected variant sequences in simulated samples with set mutation frequencies as low as 0.1%. Zimmermann et al. does not perform such a limit of detection assay. However, it has been demonstrated in the art (for example, Quek et al., “Mutational analysis of disease relapse in patients allografted for acute myeloid leukemia” Blood advances vol 1, number 3, page 193-204 December 27, 2016) that SNPs with low variant allele frequencies are detectable down to 0.002% variant allele frequency (Quek et al., page 195, column 1, paragraph 3-4). Therefore, the assertion that detection of SNPs at variant allele frequencies as low as 0.1% constitutes an unexpected result is not persuasive.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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