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 .
Applicant Response
Applicant's response, filed 07/25/2025, has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Election/Restrictions
Claims 14-19 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 09/01/2022.
Claim Status
Claims 3-5 and 7-8 are canceled.
Claims 1-2, 6 and 9-19 are pending.
Claims 14-19 are withdrawn.
Claims 1-2, 6 and 9-13 are under examination herein.
Claims 1-2, 6 and 9-13 are rejected.
Priority
The instant application claims priority to US Provisional Application 62/568998 , filed 10/06/2017. As such, the effective filing date assigned to each of claims 1-2, 6 and 9-13 is 10/06/2017.
Drawings
The drawings were accepted in the office action mailed 07/08/2024.
Claim Rejections - 35 USC § 112
The rejection of claims 1-2, 6, 9 and 11-13 under 35 U.S.C. 112(b) is withdrawn in view of claim amendments filed 07/25/2025.
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 10 remains 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. This rejection is newly recited and necessitated by claim amendments.
Claim 10 recites the limitation "the imaging device" in line 2. There is insufficient antecedent basis for this limitation in the claim, as claim 1, on which claim 10 depends, does not recite an imaging device.
Response to applicant’s arguments
Applicant’s arguments have been fully considered, but they do not address the issue discussed above.
Claim Rejections - 35 USC § 101
The rejection of claims 1-2, 6 and 9-13 under 35 U.S.C. 101 is withdrawn in view of claim amendments and Applicant’s argument filed 07/25/2025. Applicant states the claim 1 amendment to provides additional features to the one-pot synthesis method, specifying that it comprises "generating a barcoded microparticle in a one-pot synthesis, wherein the one-pot synthesis comprises linking the light- emissive components to the 3' end of oligonucleotides that are 21-nucleotides in length, annealing the linked light-emissive component-oligonucleotides to a complimentary 5' biotinylated strand to generate linker oligonucleotides, and cross-linking the linker oligonucleotides to streptavidin-coupled microparticles to generate a barcoded microparticle" and that these additional elements provided by amended claim do not represent well-understood, routine, conventional activity, as the disclosed invention does not merely comprise using commercially available kits, but rather the Applicants designed their own one-pot microparticle labelling method to achieve accurate control over dye proportions, which is a requisite not met by commonly used labelling techniques and therefore, the claims recite an inventive concept that provides significantly more than the judicial exception itself (Applicant’s Arguments, p 8, para 2-p 9, para 4). This argument was found to be persuasive.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 2, 6 and 9–13 remain rejected under 35 U.S.C. 103 as being unpatentable over Corry et al. (Biophysical Journal 2005; previously cited; hereafter referred to as Corry); Li et al. (Nature Biotechnology 2005; hereafter referred to as Li) as evidenced by Li et al. (Nature Materials 2004; newly cited); and Bunt et al. (Biophysical Reviews 2017; previously cited; hereafter referred to as Bunt) is withdrawn in view of claim amendments filed 07/25/2025.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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, 2, 6 and 9–13 are rejected under 35 U.S.C. 103 as being unpatentable over Corry et al. (Biophysical Journal 2005; previously cited; hereafter referred to as Corry) in view of Li et al. (Nature Biotechnology 2005; hereafter referred to as Li) as evidenced by Li et al. (Nature Materials 2004; newly cited), Bunt et al. (Biophysical Reviews 2017; previously cited; hereafter referred to as Bunt), and Wu et al. (US9476089B2; newly cited; hereafter referred to as Wu). This rejection is newly cited and necessitated by claim amendments.
With respect to claim 1, Corry teaches
a) a plurality of different fluorophores attached to a plurality of host molecules (p. 3824, col. 2)
b) obtaining a fluorescence emission spectrum from a sample containing the host molecules with attached fluorophores (p. 3824, col. 2; p. 3828 § "Comparison with experimental results")
c) a model of stochastically-distributed fluorophores and the imaging system (pp. 3823–3826 § "Monte Carlo calculation scheme"); the model was implemented as computer software (p. 3835 § "Appendix B"); the imaging system comprises a plurality of detectors, and the model takes bleedthrough into account (p. 3828 § "Comparison with experimental results")
d) calculating a concentration of the fluorophores in the sample (p. 3829, Fig. 6A)
Corry teaches particles with attached fluorophores, but does not teach "coupling oligonucleotides linked to the [fluorophores] to a microparticle to generate [] barcoded microparticle in a one-pot synthesis, wherein the barcoded microparticle is identifiable by the proportion of each light-emissive component on the microparticle, wherein the [fluorophores] are different from one another".
Li teaches oligonucleotides coupled to microbeads, in which (p. 885, bot. of col. 2 – p. 886, top of col. 1; p. 887, Fig. 2). The coupling allows the microbeads to be barcoded with a fluorescently-labeled oligonucleotide such that the identity of the barcode can be identified based on the proportion of each fluorophore attached to the bead (p. 886, Fig. 1). Li teaches the details of methods used to synthesize DNA nanobarcodes labeled with either Alexa Fluor 488 or BODIPY 640/650 can be found in Li et al. (p 888, col 1, para 4). Li et al. teaches one-pot synthesis can be used (p 38, para 1-2). Li teaches that this is an advantageous system for multiplexed DNA detection assays (p. 888, mid. of col. 1).
Wu teaches methods of making oligonucleotide probes from nucleic acids that can be about 10 nucleotides to about 100 nucleotides, between about 10 nucleotides to about 70 nucleotides, between about 15 nucleotides to about 50 nucleotides, between about 20 nucleotides to about 60 nucleotides and all ranges and values in between whether overlapping or not in one-pot synthesis, and discloses fluorophore-conjugated nucleotides or probes labeled indirectly with nucleotide-conjugated haptens, such as biotin and digoxigenin and subsequently bound by a avidin/streptavidin derivative (col 1; lines 39-47; col 7, lines 34-50; col 15, line 1-col 16, line 49; col 22, line 41-58).
Corry teaches a method of modeling fluorescence transfer among stochastically-distributed particles, but does not teach "multicolor fluorescence resonance energy transfer".
Bunt teaches modeling multi-color FRET (p. 123 § "FRET with multiple acceptors: going beyond one-on-one"), and how to adapt a two-color FRET model into a multicolor FRET model (p. 125 § "Detection and quantitative analysis of multiplexing FRET"). Bunt teaches that the multicolor FRET efficiency
E
is calculated as
E
=
k
T
'
k
T
'
+
1
(p. 127, col. 2, eqn. 9), where
k
T
'
=
Δ
τ
D
τ
D
A
(p. 126, col. 1, eqn. 8).
Δ
τ
D
is "the difference between the donor lifetime without (
τ
D
) and with FRET to an acceptor (
τ
D
A
)" (p. 126, bot. of col. 1). Save for differences in variable names, this is equivalent to the claimed equation.
With respect to claim 2, Bunt teaches three-color FRET (p. 120, bot. of col. 1 — mid. of col. 2), but also teaches that the model can be extended to an arbitrary number of fluorophores (pp. 123–125 § "FRET with multiple acceptors: going beyond one-on-one").
With respect to claim 6, Corry teaches that both the total fluorophore concentration, and the percentage of donors within that concentration, can be varied (p. 3828, Fig. 5; p. 3829, Fig. 6). In other words, the concentration of the donor and the concentration of the acceptor can be varied independently.
With respect to claim 9, the AlexaFluor488 and AlexaFluor568 fluorophores (p. 3828 § "Comparison with experimental results") spectrally overlap.
With respect to claim 10, Corry teaches obtaining a fluorescence emission spectrum from a sample containing a mixture of two fluorophores using an imaging device (p. 3828 § "Comparison with experimental results").
With respect to claims 11–13, Li teaches fluorophores coupled to microbeads via oligonucleotides (p. 885, bot. of col. 2 – p. 886, top of col. 1; p. 887, Fig. 2). Additionally, Corry teaches modeling fluorophores stochastically attached to pentameric proteins (p. 3831 § "Energy transfer in pentameric structures"); the specification states that proteins are a type of substrate to which fluorophores can be attached (¶ 0030), and interpreting a protein as a "microparticle" is not inconsistent with the plain meaning of the term "particle" or the specification.
An invention would have been obvious to one of ordinary skill in the art if some motivation or teaching in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention.
Prior to the effective filing date of the invention, said practitioner would have been motivated to use the fluorescently-labeled beads taught by Li in the modeling method of Corry, because Li teaches that this is an advantageous system for multiplexed DNA detection assays.
Prior to the effective filing date of the invention, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have generated a barcoded microparticle in a one-pot synthesis by linking fluorescent probes to the 3’ end of oligonucleotides that are 21-nucleotides in length and annealing it to a complimentary 5’ biotinylated strand and cross-linking them to streptavidin-coupled microparticles through routine experimentation of the length of primary nucleic acids within the prior art conditions of making oligonucleotide probes as disclosed by Wu. See MPEP 2144.05 II. A.
Equivalently, said practitioner would have been motivated to use the modeling method of Corry to analyze a mixture of beads as taught by Li, because Corry teaches that the method is effective for characterizing mixtures of fluorophores. Given that the method of Corry can be applied to any kind of mixture with randomly-distributed fluorophores, said practitioner would have readily predicted that the modification would successfully result in a method of characterizing a mixture of fluorescently-labeled microbeads, the fluorescent labels being coupled to the beads with oligonucleotides.
Prior to the effective filing date of the invention, said practitioner also would have followed the teachings of Bunt, and modified the modeling method of Corry to include multicolor FRET. Given that this modification merely requires adding another set of fluorophores to the model of Corry, and that Bunt teaches how to adapt two-color models to multi-color models, said practitioner would have readily predicted that the modification would successfully result in a method of modeling multicolor fluorescence transfer among stochastically-distributed particles.
The invention is therefore prima facie obvious.
Response to applicant’s arguments
Applicant states that the newly amended claim 1 is non-obvious over the asserted combination of Corry, Li 2005, Li 2004, and Bunt because these references, alone or in combination, do not teach or disclose, inter alia, "generating a barcoded microparticle in a one-pot synthesis, wherein the one-pot synthesis comprises linking the light-emissive components to the 3' end of oligonucleotides that are 21-nucleotides in length, annealing the linked light-emissive component-oligonucleotides to a complimentary 5' biotinylated strand to generate linker oligonucleotides, and cross-linking the linker oligonucleotides to streptavidin-coupled microparticles to generate a barcoded microparticle" as recited in claim 1 and constitutes an improvement that is more than the predictable use of prior art elements according to their established functions, and therefore the rejection should be withdrawn (Applicant’s Arguments, p 9, para 5- p 10, para 4).
Applicant’s remarks have been fully considered, and the prior art to Wu et al. (US9476089B2) has been newly cited to teach the amended limitations.
Conclusion
No claims 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.
Inquiries
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Larry D Riggs II can be reached on (571) 270-3062. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/N.D./ Examiner, Art Unit 1686
/Karlheinz R. Skowronek/ Supervisory Patent Examiner, Art Unit 1687