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 .
Status of the Claims
Claims 1-6, 9-17, 19-20, 33, 56, 101, and 115 are pending. Claims 1-6, 9-17, 19-20, and 33 are the subject of this NON-FINAL Office Action. Claims 56, 101, and 115 have been withdrawn. This is the first action on the merits.
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-6, 9-17, 19-20, and 33, in the reply filed on 12/30/2025 is acknowledged. The traversal is on the ground(s) that Nir does not teach or suggest a readout molecule comprising the claimed 3' barcode-hybridizing region. Applicant states that the common technical feature is the set of claim 1. Applicant cites par. 00170 of the originally filed application and states that the claimed readout molecules hybridize to an oligonucleotide tag, which oligonucleotide tag binds to the target molecule to be detected. Applicant further states that the Examiner appears to be comparing the “imager strands” or “secondary oligos” of Nir to the readout molecules and the “Oligopaint oligo” of Nir to the oligonucleotide tags of the present disclosure.
This is not found persuasive as the restriction requirement is based upon the technical feature of a readout molecule comprising a 3’ barcode-hybridizing region comprising a unique sequence, a 5’ non-barcode-hybridizing region, and a sulfur modification in place of the bridged oxygen and is not based on the set of claim 1. As described in the restriction requirement and described below, this is a known technical feature.
Claims 56, 101, and 115 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
The requirement is still deemed proper and is therefore made FINAL.
Claim Interpretation
Par. 00170 of the specification states “the term “readout molecule” refers to a molecule comprising at least 1) a detectable label and 2) a barcode-hybridizing region, which refers to an oligonucleotide sequence that is complementary to at least a portion of at least one oligonucleotide tag and/or hybridizes specifically with at least a portion of at least one oligonucleotide tag. As used herein, the term ‘oligonucleotide tag’ is an oligonucleotide that comprises a recognition domain and/or at least one street. The recognition domain binds specifically to a target molecule to be detected, and the street comprises a barcode region that comprises at least one barcode bit (or unit).”
The barcode-hybridizing region will be interpreted as a region that hybridized with an oligonucleotide tag or a portion of an oligonucleotide tag, wherein the oligonucleotide tag comprises a region that binds specifically to a target molecule to be detected.
The readout molecule is therefore interpreted as hybridizing to an oligonucleotide which can hybridize to a target molecule.
Claim 1 recites the limitation “a 5’ non-barcode-hybridizing region of nucleotides or analogs thereof.” This limitation will be interpreted as a region which can hybridize to another molecule, but is not hybridized to a barcode of another molecule.
Claim Objections
Claim 3 is objected to because of the following informalities:
Claim 1 recites “an optically detectable label” while claim 3 recites “the optically-detectable label.” Claim 3 should be corrected to remove the hyphen in “optically-detectable” to match the format used in claim 1.
Appropriate correction is required.
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.
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 1-6, 9-17, 19-20, 33, and 101 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.
Claim 1 recites the limitation "the region" in lines 3 and 6. There is insufficient antecedent basis for this limitation in the claim. It is unclear from the claim whether “the region” in line 3 and “the region” in line 6 refer to the same region or different regions. It is unclear whether “the region” refers to the 3’ barcode-hybridizing region, the 5’ non-barcode-hybridizing region, or whether it is meant to refer to a different region.
Claim 1 recites the limitation "the 3' region sequence" in line 4. There is insufficient antecedent basis for this limitation in the claim. It is unclear whether “the 3’ region sequence” refers to the 3’ barcode-hybridizing region, whether it refers to any 3’ region sequence, or whether it refers to another 3’ region sequence.
Claim 1 recites the limitation "the 5' region sequence" in line 7. There is insufficient antecedent basis for this limitation in the claim. It is unclear whether “the 5’ region sequence” refers to the 5’ non-barcode-hybridizing region, whether it refers to any 5’ region sequence, or whether it refers to another 5’ region sequence.
Claim 1 recites the limitation "the bridged oxygens of the phosphate backbone" in line 8. There is insufficient antecedent basis for these limitations in the claim. It is unclear whether this limitation refers to a specific bridged oxygen, or whether the limitation refers to any bridged oxygen. It is not clear whether the sulfur modification must be in a particular place or whether it can be in any location between the 5’ and 3’ regions.
Claim 1 recites the limitation "the 5' and 3' regions" in line 9. There is insufficient antecedent basis for this limitation in the claim. It is unclear whether “the 5’ and 3’ regions” refers to the 5’ non-barcode-hybridizing region and the 3’ barcode-hybridizing region, respectively, whether it refers to the 5’ region sequence and the 3’ region sequence, respectively, or whether it refers to another 5’ and 3’ region of the molecules.
Claim 2 recites the limitation "the label" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 1 does not recite “a label.” It is unclear whether “the label” in claim 2 refers to the optically detectable label in claim 1, or whether it refers to another label.
Claim 4 recites the limitation "the label" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 1 does not recite “a label.” It is unclear whether “the label” in claim 2 refers to the optically detectable label in claim 1, or whether it refers to another label.
Claim 5 recites the limitation "four distinguishable labels.” It is unclear whether these four distinguishable labels refer to the optically detectable label of claim 1 (e.g. four distinguishable optically detectable labels) or whether the set requires both the optically detectable label and four distinguishable labels.
Claim 6 recites the limitation “at least two distinguishable labels.” It is unclear whether the at least two distinguishable labels refer to the optically detectable label of claim 1 (e.g. at least two distinguishable optically detectable labels), or whether the set requires both the optically detectable label and at least two distinguishable labels.
Claim 9 recites the limitation “wherein the readout molecules of each set which comprise a first 3’ region only comprise a first distinguishable label.” It is unclear what is meant by this limitation. It is not clear which readout molecules the claim is referring to. Claim 1 recites a set of at least two readout molecules comprising a 3’ barcode-hybridizing region and a 5’ non-barcode-hybridizing region. It is unclear whether “a first 3’ region” refers to the 3’ barcode-hybridizing region or whether it refers to a different region that distinguishes a particular number of the readout molecules from the remaining readout molecules in the set. It is unclear whether “only a first distinguishable label” refers to the optically detectable label or whether it refers to an additional label. It is further unclear whether the first distinguishable label is within the 3’ region of the readout molecule, or whether the first distinguishable label can be at any location on the readout molecule.
Claim 10 recites the limitation “wherein the readout molecules of each set which comprise any selected 3’ region only comprise a corresponding given distinguishable label.” It is unclear what is meant by this limitation. It is unclear whether the 3’ region is the 3’ barcode-hybridization region or whether it is a different 3’ region. It is further unclear whether the “corresponding given distinguishable label” is the optically detectable label or whether it refers to another label.
Claim 20 recites the limitation "the region" in line 3. There is insufficient antecedent basis for this limitation in the claim. It is unclear from the claim whether “the region” in line 3 It is unclear whether “the region” refers to the 3’ barcode-hybridizing region, or whether it is meant to refer to a different region.
Claim 20 recites the limitation "the 3' region sequence" in line 4. There is insufficient antecedent basis for this limitation in the claim. It is unclear whether “the 3’ region sequence” refers to the 3’ barcode-hybridizing region, whether it refers to any 3’ region sequence, or whether it refers to another 3’ region sequence.
Claim 20 recites the limitation "the bridged oxygens of the phosphate backbone" in line 7. There is insufficient antecedent basis for these limitations in the claim. It is unclear whether this limitation refers to a specific bridged oxygen, or whether the limitation refers to any bridged oxygen. It is not clear whether the sulfur modification must be in a particular place or whether it can be in any location between the 5’ and 3’ regions.
Claim 20 recites the limitation "the 5' and 3' regions" in line 8. There is insufficient antecedent basis for this limitation in the claim. It is unclear whether “the 5’ and 3’ regions” refers to the 5’ non-barcode-hybridizing region and the 3’ barcode-hybridizing region, respectively, whether it refers to the 5’ region sequence and the 3’ region sequence, respectively, or whether it refers to another 5’ and 3’ region of the molecules.
Claim 33 recites the limitation "the region" in lines 5. There is insufficient antecedent basis for this limitation in the claim. It is unclear from the claim whether “the region” in line 2 and “the region” in line 5 refer to the same region or different regions. It is unclear whether “the region” refers to the 3’ barcode-hybridizing region, the 5’ non-barcode-hybridizing region, or whether it is meant to refer to a different region.
Claim 33 recites the limitation "the 3' region sequence" in line 3. There is insufficient antecedent basis for this limitation in the claim. It is unclear whether “the 3’ region sequence” refers to the 3’ barcode-hybridizing region, whether it refers to any 3’ region sequence, or whether it refers to another 3’ region sequence.
Claim 33 recites the limitation "the 5' region sequence" in line 6. There is insufficient antecedent basis for this limitation in the claim. It is unclear whether “the 5’ region sequence” refers to the 5’ non-barcode-hybridizing region, whether it refers to any 5’ region sequence, or whether it refers to another 5’ region sequence.
Claim 33 recites the limitation "the bridged oxygens of the phosphate backbone" in line 7. There is insufficient antecedent basis for these limitations in the claim. It is unclear whether this limitation refers to a specific bridged oxygen, or whether the limitation refers to any bridged oxygen. It is not clear whether the sulfur modification must be in a particular place or whether it can be in any location between the 5’ and 3’ regions.
Claim 33 recites the limitation "the 5' and 3' regions" in line 8. There is insufficient antecedent basis for this limitation in the claim. It is unclear whether “the 5’ and 3’ regions” refers to the 5’ non-barcode-hybridizing region and the 3’ barcode-hybridizing region, respectively, whether it refers to the 5’ region sequence and the 3’ region sequence, respectively, or whether it refers to another 5’ and 3’ region of the molecules.
Claim 101 recites the limitation “the sample” in lines 3 and 8. There is insufficient antecedent basis for this limitation in the claim. A biological sample was previously recited. It is unclear whether the sample is the same as the biological sample, or whether they are different.
Claims 3, 11-17, and 19 are rejected by virtue of their dependency upon claim 1.
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) 1-6, 9-12, 17, 19-20, and 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dunaway et al. (US 2018/0142286 A1) in view of Church et al. (US 2014/0349294 A1, cited on the IDS filed 08/28/2023; previously cited).
Regarding claims 1 and 20, Dunaway teaches a reporter probe comprising a region with hybridizes to the barcode domain of a molecule bound to a target molecule and an optically detectable label (Fig. 3; par 161). Dunaway teaches the barcodes are unique (par. 0276-0277; 0378-0379).
Dunaway does not teach that a sulfur modification in place of the bridged oxygen of the phosphate backbone, and does not teach that the non-barcode-hybridizing region comprises a sequence identical to the 5’ region sequence of all other readout molecules in a set of readout molecules.
Dunaway teaches the inclusion of a cleavable linker in the nucleic acid molecules (par. 0025, 0028, 0031).
Church teaches that a template non-hybridizing nucleic acid structure can be cleavable attached to a terminal hybridized nucleotide of an oligonucleotide probe (par. 0013), which promotes cleavage at the desired cleavage site and leaves a precise oligonucleotide probe of known length, thereby reducing bias (par. 0013).
Church teaches the template non-hybridizing nucleic acid structure can be the same sequence (Fig. 6; par. 0045).
Church further teaches the cleavable moiety can include phosphorothioate, including a bridged-phosphorothioate linkage (par. 0097).
It would have been obvious to one of ordinary skill in the art to include the template non-hybridizing nucleic acid structure as taught by Church in the probe taught by Dunaway, as Church teaches the template non-hybridizing nucleic acid structure promotes cleavage at the desired cleavage site and leaves a precise oligonucleotide probe of known length, thereby reducing bias (par. 0013), with no evidence of unexpected results.
It would have been obvious to one of ordinary skill in the art to use a sulfur modification as taught by Church in the molecule taught by Dunaway, as both Dunaway and Church teach a cleavable moiety and it would be a simple substitution of one type of cleavable moiety for another, with no evidence of unexpected results.
It further would have been obvious to use an identical sequence in each of the non-barcode-hybridizing regions for each of the readout molecules in the set, as Church teaches the same sequence, and it would simplify the construction of the readout molecules, with no evidence of unexpected results.
It further would have been obvious to include the barcode-hybridizing region at the 3’ end and the non-barcode-hybridizing region at the 5’ end as it would be obvious to try including the regions on these ends as there are only two options (e.g. located at the 3’ end or the 5’ end for the barcode-hybridizing region), with no evidence of unexpected results.
Regarding claim 33, Dunaway teaches the inclusion of metallic silver or gold particles (par. 0202).
Regarding claim 2, Dunaway teaches a fluorescent label (par. 0171-0172).
Regarding claim 3, Dunaway teaches the optical label can comprise quantum dots, biotin, or metals (par. 0199-0204).
Regarding claim 4, Dunaway teaches the optical label at the end of the molecule (Fig. 3).
Regarding claims 5 and 6, Dunaway teaches at least four distinguishable labels (Fig. 3, Fig. 17; par. 0171-0172, 0191, 0277).
Regarding claims 9 and 10, Dunaway teaches a given label corresponds to a given barcode (Fig. 3; par. 0265-0267, 0315).
Regarding claims 11-12, Dunaway teaches the length of the barcode domain is not limited as long as there is sufficient space for at least three attachment positions (par. 0146).
It would have been obvious to one of ordinary skill in the art to select a length of 5 nucleotides as it would be routine optimization with no evidence of unexpected results.
Regarding claims 17 and 19, Dunaway teaches the probes can comprise a polypeptide or DNA (par. 0011, 0140).
Claim(s) 13-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dunaway and Church as applied to claim 1 above, and further in view of Beechem (US 2016/0194701 A1).
Dunaway teaches at least two nucleotides in the target binding domain that do not identify a corresponding nucleotide in the target nucleic acid molecule can be universal bases (par. 0015).
Dunaway does not teach the 5’ region comprises only universal nucleotide bases, or that the 5’ region comprises only deoxyinosine nucleotides.
Regarding claims 13-16, Beechem teaches a sequencing probe with six nucleotides corresponding to six positions in the barcode domain, and four nucleotides added to increase the length of the target binding domain thereby affecting the likelihood that a probe will hybridize and remain hybridized to a target nucleic acid (par. 0081). Beechem further teaches that the nucleotides may be universal bases such as deoxyinosine which can base pair with any of the four canonical bases (par. 0081).
It would have been obvious to one of ordinary skill in the art to use universal bases such as deoxyinosine as taught by Beecham to increase the likelihood that the probe will remain hybridized to the target nucleic acid. It would further be obvious to one of ordinary skill in the art to use three nucleotides as it would be routine optimization with no evidence of unexpected results.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Randi L Beil whose telephone number is (571)272-1147. The examiner can normally be reached M-F 8:00 am - 5:00 pm.
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/R.L.B./Examiner, Art Unit 1684
/AARON A PRIEST/Primary Examiner, Art Unit 1681
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