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 .
Claim Status/Action Summary
Claims 1-14 are pending in this application.
Claims 1-14 are under examination.
This action is in response to the papers filed on September 15, 2025.
Any objections and rejections not reiterated below are hereby withdrawn.
It is noted that a substitute specification was not filed with the required corrections to the deficiencies identified in the nucleotide sequence disclosures. In particular: The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
The objection to the language of the abstract is withdrawn in view of the amended abstract language in the amendment.
The objections to the claims are withdrawn in view of the amendments to the claims.
The rejection of record under 112(b) of claim 1 regarding the orientation of the 3’ and 5’ ends of the recited first and second probe oligonucleotides and the bridge oligonucleotide is withdrawn in view of the amendment to the claim.
The rejection of record under 112(b) regarding reference to specific figure signs has been withdrawn in view of the amendments to the claims.
The rejection of record under 112(b) of claims 9 and 10 are withdrawn in view of the amendments to the claims.
The rejection of record under 112(b) of claim 1 regarding the apparently conflicting scope of recited ranges does not appear to have been addressed in the response. See the 112(b) rejection below.
The rejections of record under U.S.C. 103 have been withdrawn in view of the amendments to the claims.
In particular, the newly inserted feature “and wherein the barcode oligonucleotides contain one or two mismatches to bridge gap region” distinguishes the claimed invention from the combination of references of record. The prior art generally teaches methods comprising ligation of two (or more) short oligonucleotide probes requires the absence of mismatches between the probes and the sequence to which the probes are hybridized. Furthermore, the cited prior art employs sequencing by ligation to read a target sequence and/or a barcode sequence encoded by a rolling circle amplification product of a circularized padlock probe. The present claims instead require ligation of short oligonucleotides comprising one or two mismatches to a splint oligonucleotide (i.e. NOT the target sequence). This claimed feature generates a barcode sequence that is hybridized to the splint oligonucleotide and differs from the sequence of the complement to the splint oligonucleotide because it comprises specific mismatches conferred by the gap filling oligonucleotides.
Priority/Effective Filing Date
The present application, filed on May 24, 2022 claims foreign priority to EU 21181309.2, filed on June 24, 2021. It is noted, however, that applicant has not filed a certified copy of the EU 21181309.2 application as required by 37 CFR 1.55. Therefore, the effective filing date of the present application is determined to be May 24, 2022.
Nucleotide and/or Amino Acid Sequence Disclosures
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 - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, 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
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 1-14 are/remain 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 rejection is maintained from the nonfinal action of record.
The limitations “…a bridge oligonucleotide comprising 5-100 nucleotides wherein a gap region… is created” and “filling the gap region in part with 1 to 16 barcode oligonucleotides comprising 4-20 nucleotides…” render the metes and bounds of the claim unclear. Filling the gap region in part with 1 to 16 oligonucleotides comprising 4-20 nucleotides (each) encompasses embodiments in which 4-320 nucleotides (1x4 to 16x20 nucleotides) are hybridized to the gap region. As currently recited by the claim, the range of encompassed lengths of the gap formed in the 5-100 nucleotide bridge oligonucleotide is broader than the recited range of encompassed lengths of the bridge oligonucleotide. Furthermore, the requirement that the 5-100 nucleotide long bridge oligonucleotide must be hybridized to the two detection probes further restricts the possible length of a gap therein to 3-98 nucleotides because at least one nucleotide of the bridge oligonucleotide must be hybridized to each of the two detection probes. Therefore, it is unclear whether one or either of the recited length ranges are intended to be limiting, or if these ranges are merely exemplary of different preferred embodiments of the claim(s).
Claims 1-14 are 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 amendments to the claims.
Claims 1 and 2 recite “wherein the barcode oligonucleotides contain one or two mismatches to bridge gap region”. It is unclear whether this limitation requires that a) each of the 1 to 16 barcode oligonucleotides, each comprising 4-20 nucleotides, contain one or two mismatches to [the] bridge gap region; b) the 1 to 16 barcode oligonucleotides, each comprising 4-20 nucleotides together contain one or two mismatches to [the] bridge gap region; or c) something else.
If the claim is intended to require that each of the 1 to 16 barcode oligonucleotides contains one or two mismatches to the bridge gap region, it is unclear how a barcode oligonucleotide comprising as few as 4 nucleotides and having 2 mismatches to [the] bridge gap region is intended to hybridize to said bridge gap region.
Claims 1-14 are 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 amendments to the claims.
Regarding claim 1, the phrase “partially hybridizing a second detection probe…wherein one of its 3’ end or 5’ end is hybridized to the complementary part of the same or cDNA strand…”, recited in step c. renders the claim indefinite because it is unclear to what “the same or cDNA strand” refers. It is unclear whether applicant intended to reference “the complementary part of the [same] at least one RNA or cDNA strand”, similar to the language recited in step a., or whether the amended claim language is intended to refer to something else.
Newly added claim 14 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 amendments to the claims.
Claim 14 recites “Method according to any of the claim 1…” it is unclear whether this claim is intended to be dependent only upon claim 1 (i.e. “The method according to claim 1…”) or something else.
Claim 14 recites “…characterized in that the and wherein the…” it is unclear whether this language is simply redundant (i.e. “The method according to claim 1, wherein…” vs. “The method according to claim 1 characterized in that…”) or if applicant intends to use some special definition distinguishing a method that is “characterized in that [further limitation]” compared to a method wherein [further limitation].
Claim 14 recites “the barcode oligonucleotides have a ratio of mismatches with the bridge gap region of 10:1 bp.” It is unclear whether this limitation is intended to somehow require: i) “10 mismatches per 1 base pair between the barcode oligonucleotides… and the bridge gap region” (remarks dated September 15, 2025) (i.e. 10 barcode variations at each 1 nucleotide of bridge gap region); ii) that the barcode oligos have 1 mismatch with the bridge gap region per every 10 nucleotides (i.e. the ratio appears to be inverted); or iii) something else. In the event that the limitation requires that the barcode oligonucleotides have (ii), one mismatch with the bridge gap region per every 10 nucleotides, the scope of claim 14 appears to be broader than claim 1, from which it depends, because a barcode oligonucleotide comprising 4-9 nucleotides (i.e. fewer than 10 nucleotides) would therefore comprise zero mismatches with the bridge gap region and claim 1 requires that the barcode oligonucleotides have one or two mismatches with the bridge gap region.
Applicant is reminded that no new matter may be added.
Allowable Subject Matter
When sequence compliance issue is resolved, the subject matters of claims 1 and 2 could potentially be allowable if rewritten or amended properly to overcome the rejections under 35 U.S.C. 112(b), set forth in this Office action.
When sequence compliance issue is resolved, the subject matters of claims 3-13 could potentially be allowable if rewritten properly to overcome the rejections under 35 U.S.C. 112(b) set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
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