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 .
Information Disclosure Statement
The information disclosure statements filed 06/20/2024, 03/05/2025, and 10/23/2025 fail to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. From these information disclosure statements, approximately 34, 2, and 36 references have not been provided, respectively.
Additionally, the information disclosure statements filed 06/20/2024 and 10/23/2025 fail to comply with the provisions of 37 CFR 1.97, 1.98, and MPEP § 609. Specifically, multiple references have been cited incorrectly or cite a version of the reference which was not provided (i.e., pre-print vs print).
Objections to the Specification
The use of multiple trade names or marks used in commerce, such as “Sepharose” on page 12 of the specification, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Objections to the Claims
Claims 16 and 85 are objected to because of the following informalities:
Claim 16, L2: “barcode the first’ should be “barcode of the first”
The clarity of claim 85 would be enhanced if each recitation of a molecular label was modified to denote if it is referring to the first or second molecular label (L3, 5, and 9).
Appropriate correction is required.
Claim Interpretation
Based upon the Examiner’s understanding of claim 5 and its relevant dependent claims, in light of the accompanying rejections under 112(b) and for the purposes of compact prosecution:
All recitations of “a/the second plurality of barcoded nucleic acid molecules” is being interpreted as “a/the first plurality…”
All recitations of “a/the second plurality of extended barcoded nucleic acid molecules” is being interpreted as “a/the second plurality of barcoded nucleic acid molecules”
Recitations of “a/the second plurality of single-labeled nucleic acid molecules” in claim 13 is being interpreted as the “a/the first plurality…”
Recitations of “a/the third plurality of single-labeled nucleic acid molecules” in claim 14 is being interpreted as “a/the second plurality…”
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.
Claims 5, 6, 8, 9, 13-24, 26, 27, and 29 are rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, 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.
Claim 5, L9 recites “a second plurality of barcoded nucleic acid molecules” and L20-21 recites “a second plurality of extended barcoded nucleic acid molecules”; however, in both instances, a first plurality was never mentioned. Therefore, it is unclear if the plurality mentioned in L9 was intended to be the first plurality or if there are two unnamed pluralities. This is further obfuscated by dependent claims 13, 17, and 18 which contain references to:
“the first and/or second pluralities of barcoded nucleic acid molecules” (claim 17, L3 and L13);
“the second plurality of barcoded nucleic acid molecules” (claim 18, L3);
“the first plurality of barcoded nucleic acid molecules” (claim 18, L6);
“a third plurality of extended barcoded nucleic acid molecules” (claim 18, L9);
“a second plurality of single-labeled nucleic acid molecules” (claim 13, L4); and
“a third plurality of single-labeled nucleic acid molecules” (claim 14, L4).
Additional recitations of these indefinite pluralities exist in the following claims: claim 8, L6; claim 13, L2 and L8; claim 14, L2 and L8; and claim 19, L2.
Claims 6, 13, 14, 16, 17, 22, 23, 24, and 27 recite the following limitations for which there is insufficient antecedent basis:
“the copy number” (claim 6, L1)
“wherein determining the copy number” (claim 13, L6; claim 14, L6)
“the invariable sequence” (claim 16, L5; claim 23, L2)
“the region” (claim 17, L5, L7, L9, and L11)
“the cell label” (claim 22, L2)
“the blocker nucleotide” (claim 24, L3 and L5)
“the target-binding region, or portion thereof” (claim 27, L3)
Finally, claim 19, L5 makes reference to “a blocking sequence.” It is unclear from this language if this is referencing the blocking sequence of claim 5 or this is the introduction of a different blocking sequence.
Claims rejected under 35 USC § 112(b) for which no explicit rationale is provided are rejected by virtue of their dependency upon an explicitly rejected claim.
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.
Claim 85 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon (including a product of nature) without significantly more.
The claim is directed towards a kit comprising two pluralities of oligonucleotides and/or a template switch oligonucleotide.
Under the broadest reasonable interpretation, the oligonucleotide components are which are merely nucleic acid molecules defined by their intended use. The recited universal sequences, molecular labels, cell label, bait sequence, and blocking sequence complement may each comprise naturally occurring nucleotide sequences. Furthermore, the claim does not require any structural modifications that distinguishes these nucleic acids from naturally occurring nucleic acid molecules.
The claimed kit further comprises a DNA polymerase lacking exonuclease activity in at least one direction and/or a reverse transcriptase. These enzymes are naturally occurring and the claim does not present any structural modifications to the enzymes which would otherwise distinguish them.
Therefore, the claimed kit can be interpreted as being comprised only of products of nature, which are judicial exceptions. These judicial exceptions are not integrated into a practical application because merely placing a product(s) of nature in a kit does nothing more than attempt to generally link it to a technological environment without altering its structure or function. Therefore, this is considered to be insignificant extra-solution activity. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exceptions as there are no additional limitations. Therefore, claim 85 does not contain eligible subject matter.
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)(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 85 is rejected under 35 U.S.C. 102(a)(2) as being anticipated by Applied Biosystems (Applied Biosystems. High Capacity cDNA Reverse Transcription Kit User Guide. 2018 July 16).
Applied Biosystems sells the High Capacity cDNA Reverse Transcription Kit. The user manual lists a reverse transcriptase as one of the components (p6). Therefore, this kit anticipates the kit of the instant application. As the claim recites several components with “and/or” before the last component, the “and/or” is construed to mean the kit can comprise any one or more of the listed components.
Indication of Allowable Subject Matter
Claims 5, 6, 8, 9, 13-24, 26, 27, and 29 would be allowable if rewritten or amended to overcome any objections or rejection(s) under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, 2nd paragraph, set forth in this Office action.
The following is a statement of reasons for the indication of allowable subject matter:
Tang (Tang DT. Nucleic acids research. 2013 Feb 1;41(3):e44) discusses the use of template-switching reaction to introduce DNA barcodes or indexes into different samples, cell, or molecules. However, methods which do this introduce unsystematic biases due to the formation of artifacts that result from strain invasion (Tang, abstract). Tang found that the extent of strand inversion is highly dependent on the sequence of the template switch oligonucleotide (TSO), particularly the last six nucleotides. Tang inserted a 6 nucleotide long spacer at the end of the TSO which has a reduced potential for strand inversion thereby reducing its overall occurrence (Tang, p10-11). Therefore, Tang appears to be addressing a similar concern as the instant application; however, they do so in a wholly different manner with no mention of blocking sequences.
Lazaruk (US 20210371909 A1, IDS reference) describes a method for labeling a nucleic acid in which a first plurality of oligonucleotide barcodes is hybridized to a targeted nucleic acid and extended via reverse transcription and the use of a TSO. This product is then hybridized with a second plurality of oligonucleotide barcodes and further extension occurs. While the oligonucleotide barcodes are identical to those of the instant application and the overall process is similar, Lazaruk does not teach that the TSO is comprised of the complement of a blocking sequence [Lazaruk, 005].
Finally, Prosen (WO 2021155284 A1, IDS reference) describes a method for labeling a nucleic acid in which a plurality of oligonucleotide barcodes is hybridized to a targeted nucleic acid and extended via reverse transcription and the use of a TSO. Blocker oligonucleotides are then used to prevent unwanted extension in subsequent steps by hybridizing to the oligonucleotide barcodes. Therefore, Prosen discloses the use of blocking oligonucleotides (a.k.a. blocking sequences) in the context of TSO reactions. However, Prosen differs from the instant application in that these blocking oligonucleotides, or a complement thereof, are not a component of the TSO and are not introduced into the actual sequence of the TSO product [Prosen, 004].
As such, any of the listed references could be considered the closest prior art, but the claims of the instant application are not obvious over them either independently or in combination.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kara N Kovach whose telephone number is (571)272-8134. The examiner can normally be reached Monday - Friday, 9am - 3pm.
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/K.N.K./Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
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