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 Claims
In the amendments filed November 12, 2025, claims 1, 8-9, 15, and 18 were amended, claims 4 and 17 were cancelled, and claims 19-20 were added. Claims 1-3, 5-16, and 18-20 are pending for examination and are considered on the merits below.
Response to Arguments
Applicant’s amendments, filed November 12, 2025, with respect to the specification objections have been fully considered and are persuasive. The objections to the specification have been withdrawn.
Applicant's arguments filed November 12, 2025, with respect to the objection to claim 1 have been fully considered but they are not persuasive. The shortened and lengthened form names “tetramethyl orthosilicate (TMOS)” are not recited at the first instance of TMOS in line 3 of amended claim 1.
Applicant’s arguments, see remarks and amendments, filed November 12, 2025, with respect to the rejection of claims 1-14 under 35 U.S.C. § 112(b) have been fully considered and are persuasive. The rejection of claims 1-14 under 35 U.S.C. § 112(b) has been withdrawn.
Applicant's arguments filed November 12, 2025, with respect to amended claim 1 have been fully considered but they are not persuasive. In response to applicant's argument that the references fail to show certain features of the invention in amended claim 1, it is noted that the feature upon which applicant relies (i.e., isolation of a selected portion of the inorganic nanoparticles, where the selected portion is a fraction of the nanoparticles) is not recited in rejected claim 1. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Amended claim 1 recites isolating a selected portion of a plurality of inorganic nanoparticles, which is a fraction of the reaction mixture from e). Wiesner teaches isolating a selected portion of a plurality of inorganic nanoparticles (wherein, “after synthesis (e.g., after e)… additional purification processes, including gel permeation chromatography and high-performance liquid chromatography, can be applied to the nanoparticles to further ensure the high purify of the synthesized particles (e.g., 1% or less unreacted reagents or aggregates),” and therefore unreacted reagents and aggregates are removed to 1% or less which thereby isolates the synthesized nanoparticles from the removed unreacted reagents and aggregates leaving the selected portion of the plurality of inorganic nanoparticles; ¶ [0044]), which is a fraction of the reaction mixture (wherein the selected, synthesized nanoparticles are a fraction of the reaction mixture; ¶¶ [0043]-[0044]) as discussed in the rejection of claim 1 below.
Applicant’s arguments with respect to amended claim 15 have been fully considered and are persuasive. The rejection of claim 15 under 35 U.S.C. § 102 has been withdrawn.
Applicant’s arguments with respect to claims 7-8 and 17-18 have been fully considered and are persuasive. The rejection of claims 7-8 and 17-18 under 35 U.S.C. § 103 has been withdrawn.
Claim Objections
Claim 1 is objected to because of the following informalities:
Regarding claim 1, the limitation “TMOS” is recited in line 3 which is the shortened form name for tetramethyl orthosilicate. Examiner suggests amending claim 1 to include both the shortened and lengthened form names “tetramethyl orthosilicate (TMOS)” at the first instance of TMOS to provide further clarity in the claims.
Appropriate correction is required.
Claim Rejections - 35 USC § 102
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 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.
Claims 1-3, 5-6, 9-11, and 13-14 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Wiesner et al. (U.S. Pat. Pub. No. 2018/0133346, listed on Information Disclosure Statement; hereinafter "Wiesner").
Regarding claim 1, Wiesner discloses a method for synthesizing an inorganic nanoparticle (e.g., fluorescent core-shell silica nanoparticles; [0012]) comprising one or more dyes and surface functionalized with polyethylene glycol (PEG) groups (see [0043], [0062]), comprising:
a) forming a reaction mixture at room temperature comprising water, TMOS, a base (see step a. in [0043]), and a dye precursor (wherein the reaction mixture further comprises a dye precursor; [0048]);
b) either i) holding the reaction mixture at a time (t1) and temperature (T1), whereby inorganic nanoparticles having an average size of 2 to 15 nm are formed, or ii) cooling the reaction mixture to room temperature, if necessary, and adding a shell forming monomer to the reaction mixture from a), whereby inorganic nanoparticles have a core size of 2 to 15 nm and/or an average size of 2 to 50 nm are formed (see step b. in [0043]);
c) adjusting, if necessary, the pH of the reaction mixture comprising the inorganic nanoparticles from b) i) or b) ii) to a pH of 6 to 10 (see step c. in [0043]);
d) adding at room temperature to the reaction mixture comprising the inorganic nanoparticles from b) i) or b) ii) a PEG-silane conjugate and holding the reaction mixture comprising the inorganic nanoparticles from b) i) or b) ii) and the PEG-silane conjugate at a time (t2) and temperature (T2) (see step d. in [0043]);
e) heating the mixture from d) at a time (t3) and temperature (T3), whereby the inorganic nanoparticles surface functionalized with PEG groups are formed (see step e. in [0043]); and
f) purifying the reaction mixture from e) by liquid chromatography (purification processes include gel permeation chromatography and high-performance liquid chromatography; [0044]), wherein the purifying comprises isolating a selected portion of a plurality of inorganic nanoparticles (wherein, “after synthesis (e.g., after e)… additional purification processes, including gel permeation chromatography and high-performance liquid chromatography, can be applied to the nanoparticles to further ensure the high purify of the synthesized particles (e.g., 1% or less unreacted reagents or aggregates),” and therefore unreacted reagents and aggregates are removed to 1% or less which thereby isolates the synthesized nanoparticles from the removed unreacted reagents and aggregates leaving the selected portion of the plurality of inorganic nanoparticles; ¶ [0044]), which is a fraction of the reaction mixture from e) (wherein the selected, synthesized nanoparticles are a fraction of the reaction mixture; ¶¶ [0043]-[0044]), from the reaction mixture from e) (see ¶¶ [0043]-[0044]), and
the method yields the inorganic nanoparticle comprising one or more dyes and surface functionalized with polyethylene glycol (PEG) groups (see [0043], [0062]).
Regarding claim 2, Wiesner discloses the method of claim 1 as discussed above. Wiesner further discloses wherein the base is chosen from ammonium hydroxide, ammonia in ethanol, triethyl amine, sodium hydroxide, potassium hydroxide, and combinations thereof (wherein the base is ammonium hydroxide or ammonia in ethanol; [0042]-[0043], [0082]).
Regarding claim 3, Wiesner discloses the method of claim 1 as discussed above. Wiesner further discloses wherein the base has a concentration and the concentration is 0.001 mM to 60 mM (0.02M ammonium hydroxide which is a base having a concentration of 20 mM; [0088]).
Regarding claim 5, Wiesner discloses the method of claim 1 as discussed above. Wiesner further discloses analyzing the selected portion of the plurality of inorganic nanoparticles via gel permeation chromatography (GPC) (see [0044]).
Regarding claim 6, Wiesner discloses the method of claim 1 as discussed above. Wiesner further discloses analyzing the selected portion of the plurality of inorganic nanoparticles via high performance liquid chromatography (HPLC) (see [0044]).
Regarding claim 9, Wiesner discloses the method of claim 1 as discussed above. Wiesner further discloses wherein the reaction mixture further comprises an alumina or aluminosilicate core forming monomer (see [0046]) and the pH of the reaction mixture is adjusted to a pH of 1 to 2 prior to addition of the alumina or aluminosilicate core forming monomer (see [0047]) and, optionally, PEG is added to the reaction mixture prior to adjusting the pH to a pH of 7 to 9, and the core is an aluminosilicate core (see [0047]; Examiner’s Note – the term “optionally” is interpreted to mean that the step following that term is not required and therefore a teaching in the art for that step is not required).
Regarding claim 10, Wiesner discloses the method of claim 1 as discussed above. Wiesner further discloses wherein the dye precursor is a positively charged dye precursor (Cy5, Cy5.5, Cy7, ATTO647N; [0048]), a negatively charged dye precursor (negatively charged fluorophores; [0119]), or a net neutral dye precursor (TMR; [0048]).
Regarding claim 11, Wiesner discloses the method of claim 10 as discussed above. Wiesner further discloses wherein the positively charged dye precursor is formed from a positively charged dye chosen from Cy5.5, Cy5, Cy3, ATTO647N, methylene blue, ATTO663, ATTO620, ATTO665, ATTO465, ATTO495, ATTO520, ATTORho6G, ATTORho3B, ATTORho11, ATTORho12, ATTOThio12, ATTO580Q, ATTORho101, ATTORho13, ATTO610, ATTO612Q, ATTO647N, ATTORho14, ATTOOxa12, ATTO725, ATT0740, ATTOMB2, and combinations thereof (Cy5.5, Cy5, ATTO647N; [0048]).
Regarding claim 13, Wiesner discloses the method of claim 10 as discussed above. Wiesner further discloses wherein the net neutral dyes precursor is formed from a net neutral dye chosen from tetramethylrhodamine (TMR), ATTO390, ATTO425, ATTO565, ATTO590, ATTO647, ATTO650, ATTO655, ATTO680, ATTO700, and combinations thereof (TMR; [0048]).
Regarding claim 14, Wiesner discloses the method of claim 1 as discussed above. Wiesner further discloses wherein the one or more dyes are fully encapsulated in the inorganic nanoparticle (see [0132]).
Claim Rejections - 35 USC § 103
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.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Wiesner in view of Karathanasis et al. (U.S. Pat. Pub. No. 2019/0111133, previously cited; hereinafter “Karathanasis”).
Regarding claim 12, Wiesner discloses the method of claim 10 as discussed above. As noted above, Wiesner discloses a negatively charged dye precursor (negatively charged fluorophores; [0119]). However, Wiesner does not explicitly disclose wherein the negatively charged dye precursor is formed from a negatively charged dye chosen from sulfo-Cy5.5, sulfo-Cy5, sulfo-Cy3, Alexa Fluor 532, Alexa Fluor 430, ATTO430LS, ATTO488, ATTO490LS, ATTO532, ATTO594, and combinations thereof.
Karathanasis, in the analogous art of silica nanoparticles, teaches detectable labels, such as fluorescent dyes (e.g., fluorescein isothiocyanate, cyanines such as Cy5, Cy5.5 and analogs thereof (e.g., sulfo-Cyanine 5 NHS ester and Cy5.5 maleimide)) (see [0075]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Wiesner to choose a negatively charged dye, such as sulfo-Cy5.5, sulfo-Cy5, as taught by Karathanasis for the benefit of generating a desired water solubility (Wiesner, [0119])
Allowable Subject Matter
Claim 15-16 and 18-20 are allowed.
Regarding claims 15-16 and 18, Wiesner teaches a composition comprising a plurality of inorganic nanoparticles, wherein individual inorganic nanoparticles of the plurality of inorganic nanoparticles comprise 1-7 dye group(s) (a composition wherein the core nanoparticles surface functionalized with PEG groups or core-shell nanoparticles surface functionalized with PEG groups have one or more dye molecules encapsulated therein and the number of dye molecules per core is 1 to 7; [0048], [0077]), wherein: none of the dye groups are disposed or partially disposed on a surface of the inorganic nanoparticles (fully encapsulated; [0048], [0077], [0132]), wherein the dye group is positively charged (Cy5, Cy5.5, Cy7, ATTO647N; [0048]) or has a net neutral charge (TMR; [0048]). However, none of the prior art of record nor any other references found (alone or in combination) teaches or fairly suggests wherein the plurality of inorganic nanoparticles do not exhibit size-dependent surface inhomogeneity as recited in claim 15.
Regarding claims 19-20, Wiesner discloses a method for synthesizing an inorganic nanoparticle (e.g., fluorescent core-shell silica nanoparticles; [0012]) comprising one or more dyes and surface functionalized with polyethylene glycol (PEG) groups (see [0043], [0062]), comprising: a) forming a reaction mixture at room temperature comprising water, TMOS, a base (see step a. in [0043]), and a dye precursor (wherein the reaction mixture further comprises a dye precursor; [0048]); b) either i) holding the reaction mixture at a time (t1) and temperature (T1), whereby inorganic nanoparticles having an average size of 2 to 15 nm are formed, or ii) cooling the reaction mixture to room temperature, if necessary, and adding a shell forming monomer to the reaction mixture from a), whereby inorganic nanoparticles have a core size of 2 to 15 nm and/or an average size of 2 to 50 nm are formed (see step b. in [0043]); c) adjusting, if necessary, the pH of the reaction mixture comprising the inorganic nanoparticles from b) i) or b) ii) to a pH of 6 to 10 (see step c. in [0043]); d) adding at room temperature to the reaction mixture comprising the inorganic nanoparticles from b) i) or b) ii) a PEG-silane conjugate and holding the reaction mixture comprising the inorganic nanoparticles from b) i) or b) ii) and the PEG-silane conjugate at a time (t2) and temperature (T2) (see step d. in [0043]); e) heating the mixture from d) at a time (t3) and temperature (T3), whereby the inorganic nanoparticles surface functionalized with PEG groups are formed (see step e. in [0043]); and f) purifying the reaction mixture from e) by liquid chromatography (purification processes include gel permeation chromatography and high-performance liquid chromatography; [0044]), the method yields the inorganic nanoparticle comprising one or more dyes and surface functionalized with polyethylene glycol (PEG) groups (see [0043], [0062])..
However, none of the prior art of record nor any other references found (alone or in combination) teaches or fairly suggests wherein the purifying comprises: depositing a plurality of inorganic nanoparticles in a chromatography column comprising an input in fluid communication with a stationary phase in fluid communication with an output in fluid communication with a detector; passing a mobile phase through the chromatography column, such that at least a portion of the plurality of inorganic nanoparticles elutes from the column in an eluent; and collecting the eluent comprising a selected portion of the plurality of inorganic nanoparticles, which is a fraction of the reaction mixture from e) as recited in claim 19.
Claims 7-8 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. None of the prior art of record nor any other references found (alone or in combination) teaches or fairly suggests (i) wherein the purifying comprises: depositing a plurality of inorganic nanoparticles in a chromatography column comprising an input in fluid communication with a stationary phase in fluid communication with an output in fluid communication with a detector; passing a mobile phase through the chromatography column, such that the plurality of inorganic nanoparticles elutes from the column; and collecting an eluent comprising the selected portion of the plurality of inorganic nanoparticles, as recited in claim 7, or (ii) depositing the selected portion of the plurality of inorganic nanoparticles in an HPLC column comprising an input in fluid communication with a stationary phase in fluid communication with an output in fluid communication with a detector; passing a mobile phase through the HPLC column, such that the selected portion of the plurality of inorganic nanoparticles elutes from the column and enters the detector, such that the detector generates a signal, wherein the signal indicates a location of the one or more dye on and/or in individual inorganic nanoparticles of the selected portion of the plurality of the inorganic nanoparticles; analyzing the signal to determine the location of the one or more dye on and/or in the individual inorganic nanoparticles of the selected portion of the plurality of inorganic nanoparticles; and optionally, collecting one or more fraction(s) of the mobile phase as recited in claim 8.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Steven R. Castaneda whose telephone number is (571)272-0998. The examiner can normally be reached Monday through Friday 10am - 6pm ET.
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/STEVEN RAY CASTANEDA/Examiner, Art Unit 1797
/JENNIFER WECKER/Primary Examiner, Art Unit 1797