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 .
Election/Restrictions
Applicant’s election without traverse of Group II in the reply filed on 01/29/2026 is acknowledged.
Claims 1-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/29/2026.
Status of Claims
Applicant’s amendment filed 03/24/2023 is acknowledged. Claim 13 has been amended. Claims 1-17 are pending in the instant application and claims 13-17 are the subject of this non-final office action.
Information Disclosure Statement
The listing of references 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 or listed as considered on an IDS, they have not been considered.
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.
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.
Claim 14 and 16-17 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.
Regarding claims 14 and 16-17, claim 14 recites “wherein the adapters further comprise a mosaic and a Seq-1 primer”. Claim 16 recites “wherein the adapter further comprises a mosaic and/or a Seq-1 primer”. Claims 13 and 14 recite wherein the adapter(s) comprise(s) “an amplification primer sequence”.
First, it is unclear what is encompassed by “a mosaic” or “a mosaic primer” and ”Seq-1 primer”. If the terms are intended to reference specific SEQ ID NO (or set of SEQ ID NO), these must be included in the claim.
Second, it is unclear whether the adapters are intended to have additional elements beyond the four recited in claims 13 and 15 when the claim recites “further comprising”; if these are intended to further limit already recited elements; or if the “the adapters” or “the adapter” further comprises such a separate primer molecule (i.e., “the adapters” of claim 14 is intended to be “the set of adapters”. For example, claim 17 recites SEQ ID NO: 4, which comprises SEQ ID NO: 2, which is taught as an exemplary amplification primer (Brief Description of the Sequences) and complementary to a sequencing primer “Seq-1” (pg. 14, para 2). This, in part, an antecedent basis rejection.
For the purposes of applying art, the Seq-1 primer was interpreted to be a species of an amplification primer sequence and a mosaic was interpreted to be an annealing sequence.
Claim 17 is indefinite for depending from claim 16 and not rectifying the deficiency.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 13-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) without significantly more. The claim(s) recite(s) natural products. This judicial exception is not integrated into a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The following three inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter?
Yes, the claims are directed to a composition of matter.
Step 2A, prong 1. Does the claim recite a law of nature, a natural phenomenon, or an abstract idea (recognized judicial exceptions)?
The claims recite a natural product. The structures required by claims 13 and 15 are “an amplification primer sequence”, “a DNA-specific or RNA-specific barcode”, “a unique molecular identifier sequence”, and “an annealing sequence”. Claim 13 requires that one oligonucleotide of a set have one “DNA-specific” barcode and another have an “RNA-specific” barcode.
Claim 14 recites that the adapters further comprise “a mosaic and a Seq-1 primer”. Claim 16 recites that the adapter further comprise “a mosaic and/or a Seq-1 primer”. As discussed, in the 112(b), these have been interpreted to be species of the annealing sequence and the amplification primer sequence, respectively.
Szuplewska (Szuplewska M, et al. Mobility and generation of mosaic non-autonomous transposons by Tn3-derived inverted-repeat miniature elements (TIMEs). PLoS One. 2014 Aug 14;9(8):e105010) teaches mosaic elements in TIMEs, the acquisition of additional genes in resolutive TIMEs, and the mobilization of genomic DNA in composite TIMEs (Fig. 5).
Libudalab (Libudalab. Libudalab/transposon-tracking: A guide for annotation and tracking transposable elements between genome assemblies [Internet]. 2023 [cited 2026 Mar 24]. Available from: https://github.com/libudalab/transposon-tracking) teaches that transposable elements may acquire SNPs and can be used to track copies of said transposable elements (Tracking the Movement of Transposable Elements).
An amplification primer sequence may be a random hexamer primer sequence within the acquired sequence of the genes/mobilized genomic DNA of the resolutive or composite TIMEs. A “DNA-specific” barcode may be a SNP allele and the “RNA-specific” barcode may be the other allele. An UMI may be a de novo acquired SNP. The annealing sequence may be the mosaic element inverted repeat, for example, wherein the function of annealing is met by annealing to the complementary strand. The mosaic and Seq-1 primer are not defined by the specification by may comprise a further sequence overlapping the mosaic element inverted repeat (e.g., in the opposing direction) or overlapping the flanking gene.
None of the structures require non-natural sequences or features that would have markedly different characteristics from such natural sequences. The courts have found that, even should the product be directed to single-stranded oligonucleotides, such would not be a markedly different characteristic. See. MPEP 2106.04(c)(II). As such, they encompass such products of nature.
Step 2A, prong 2. Is the judicial exception(s) integrated into a practical application?
No. The claims are limited to the set of oligonucleotide adapters and under the best possible interpretation a sequence thereof or a primer sequence may overlap a portion thereof. There is no requirement that they have additional components or sequences other than what may be found in nature.
Step 2B. Does the claim amount to significantly more?
No. As above, the claims encompass only structures that may encompass what be found in nature. As such, the claims as a whole do not encompass “significantly more” than the natural product. Nor are the claimed structures markedly different than the natural product.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 13-16 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Giannoukos (US 2020/0232022 A1; published 07/23/2020; priority to 01/06/2017).
Regarding claim 13-16, Giannoukos teaches a set of oligonucleotide adapters with the format 5’-i5-pooling barcode-UMI barcode-mosaic end (entire document, including Fig. 2A; Table 2; instant claims 13-16), wherein the i5 is an amplification primer sequence (Fig. 2B); the mosaic end (Table 5) may be considered to be an annealing sequence as it is hybridizes to the other end of the Tn5-A bottom sequence (Table 5; Fig. 2A); and the pooling barcode may instead be referred to as a DNA- or RNA-specific barcode as such is a matter of nomenclature and does not further define the structures in view of the specification (see Giannoukos para [0056]; instant pg. 13, para 1). Giannoukos teaches that the set comprises two different pooling barcodes (Table 2:, e.g., OLI6380 and OLI6381; see [0056])).
The “Seq-1” primer has not been defined by the specification; as such it is interpreted to be the i5 amplification primer binding sequence of Fig. 2A and Table2 (instant claims 14 and 16).
Giannoukos teaches each and every limitations of claims 13-16 and therefore Giannoukos anticipates claims 13-16.
Claim(s) 13-16 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Steemers (WO 2020/112604 A2; published 06/04/2020; priority to 11/30/2018).
Regarding claim 13-16, Steemers teaches a set of adapter sequences comprising 5’-A14-barcode-UMI-(T)n-3’ (Fig. 4; instant claims 13 and 15-16), wherein A14 may be considered to be and/or utilized as an amplification primer sequence, which may be interpreted to be a “Seq-1 primer” (see, e.g., Fig. 12 and [0053]). Steemers teaches that the set of adapters may have different barcodes for identifying different analytes (para [0055]; instant claim 13).
Under the interpretation that the claims recite a separate primer molecule:
Steemers teaches a composition further comprising a mosaic and “Seq-1” (broadly interpreted) primer sequence ME’-(A)n (Fig. 4; instant claim 14 and 16).
Under the interpretation that the adapters are required to have an additional element for a mosaic and Seq-1 primer (claim 14) or a mosaic and/or Seq-1 primer (claim 16):
Steemers also teaches that adapter sequences may comprise a primer sequence, an anchor sequence [i.e., annealing sequence], a universal sequence [i.e., additional primer sequence, e.g., a mosaic and a Seq-1 primer], an index sequence (e.g., UMI), and a barcode sequence (para [0050]; claim 14 and 16).
Steemers teaches each and every limitations of claims 13-16 and therefore Steemers anticipates claims 13-16.
Claim Rejections - 35 USC § 103
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 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.
Claim(s) 15-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Steemers (WO 2020/112604 A2; published 06/04/2020; priority to 11/30/2018) and in view of Giannoukos (US 2020/0232022 A1; published 07/23/2020; priority to 01/06/2017) and Shokralla (Shokralla S, et al. Massively parallel multiplex DNA sequencing for specimen identification using an Illumina MiSeq platform. Sci Rep. 2015 Apr 17;5:9687).
Regarding claims 15-17, Steemers teaches B15ME:
5' GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAG-3' (SEQ ID NO: 2) and the sequences of components B15 (SEQ ID NO: 5) and ME (SEQ ID NO: 6). Steamers teaches binding ME’ (a “mosaic”) to such a construct in Fig. 6B (instant claim 16).
Steemers teaches a barcode can have a length of 5 (para [0056]) and that it may be of a length sufficient to be unique within a plurality of barcodes in a population and/or within a plurality of polynucleotides and target nucleotides being analyzed (para [0056]). Steemers teaches tag sizes (para [0043]).
Steamers teaches that the transposon includes an adapter (para [0050]), wherein the adapters may include primer sequence, barcode sequence, index sequence, and anchor sequence [i.e., the transposon-specific ME sequence; see para (0049) and Fig. 6B; instant claim 15].
Steemers fails to explicitly teach the order of the barcode and index sequence within the transposon adapter sequence of the claimed SEQ ID NO.
Giannoukos rectifies this by teaching transposon adapters with internal known barcode sequences followed by UMIs (Table 2; Fig. 2A) flanked by a 5’ primer-binding sequence and a 3’ transposon anchor sequence (Fig. 2A). Giannoukos teaches that such barcoding/indexing can help remove biases associated with variable-length PCR amplification (para [0084]).
Steemers and Giannoukos fail to teach the particular barcode of SEQ ID NO: 4.
Shokralla rectifies this by teaching a dual indexed system with 5-mer multiple identifiers including the identifier TCATG (Methods, para 2).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have inserted a barcode and UMI between the B15 and ME sequences of the adapter of Steemers in view of Giannoukos, motivated by the desire to reduce PCR amplification bias and/or as a rearrangement of parts of the suggested parts of Steemers. Further, it would have been obvious to have obvious to have chosen dual 5-mer indexes including TCATG of Shokralla as it is taught in the art for the same purpose and/or as part of a routine optimization for the length and of the sequence, wherein Steemers teaches choosing a length sufficient for uniqueness and various tag sizes to optimize within. There would have been a strong expectation for success as all are directed to improvement of multiplex sequencing, especially with transposon adapters (Steemers and Giannoukos).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Emma R Hoppe whose telephone number is (703)756-5550. The examiner can normally be reached Mon - Fri 11:00 am - 7:00 pm.
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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636