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 .
Applicants' arguments, filed October 7, 2025, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Comments and Notes
It is respectfully suggested that “the fluorescent dyes” in line 5 of claim 5 be amended to read “the fluorescent dyes having alkoxysilyl group” for exact antecedent basis.
Information Disclosure Statement
Applicants request consideration of 4 references which were listed on the first page of the Remarks filed October 7, 2025, indicating that copies were filed and that these references should be considered.
These specific references have been considered as these 4 references are not lined through on the Information Disclosure Statement filed August 31, 2022. As noted on the initialed copy of the Information Disclosure Statement filed June 19, 2024, the identified references are duplicates of the references considered on the Information Disclosure Statement filed August 31, 2025. Therefore given the duplicative nature of the citations on the Information Disclosure Statements, there references were lined through on one Information Disclosure Statement and indicated as considered on the other Information Disclosure Statement.
Specification
The disclosure was objected to in the Office Action mailed July 9, 2025 because certain portions of the specification as filed were blurry and the information shown could not be readily discerned. An amendment to the specification was filed on October 7, 2025 but the replacement chemical structures in the file wrapper remain blurry and are not well-defined. Therefore the specification remains objected to as not being of sufficient quality to clearly show the disclosed subject matter.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 – New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 11 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Claim 11 requires the use of any carbodiimide in combination with any fluorescent dye and 3-aminopropyltriethoxy silane (APS but also abbreviated as APTS or APTES in the art) to prepare the fluorescent dye having alkoxysilyl groups. No citations were given for possible support by Applicants but the only mention of any carbodiimide is at ¶ [0053] in the PGPub of the instant application. In this reaction scheme in this paragraph, a specific carboxylic acid containing fluorescent dye in THF (tetrahydrofuran) was reacted with EDC (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide) and N-hydroxysuccinimide (NHS) to obtain a fluorescent dye derivative that was again dissolved in THF then reacted with APS to prepare a fluorescent dye with alkoxysilyl groups.
In contrast to this very specific reaction using just one possible diimide disclosed in the disclosure as originally filed, claim 11 is much broader and encompasses the labeling of any fluorescent dye of any structure with alkoxysilyl using any carbodiimide containing reagent in a condensation reaction along with APS.
The single example in the specification is insufficient to demonstrate possession at the time of filing of the entire scope of the claimed subject matter encompassed by claim 11 and therefore new claim 11 contains new matter.
Claim Rejections - 35 USC § 112 – Scope of Enablement
Claim 11 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the introduction of alkoxysilyl groups to carboxylic acid containing fluorescent dyes, does not reasonably provide enablement for the introduction of alkoxysilyl groups to fluorescent dyes that do not contain carboxylic acid groups. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The disclosure and claims of the application have been compared per the factors indicated in the decision In re Wands, 8 USPQ2nd 1400 (Fed. Cir. 1988) as to undue experimentation
The factors include:
1. The nature of the invention;
2. The breadth of the claims;
3. The predictability or unpredictability of the art;
4. The amount of direction or guidance presented;
5. The presence or absence of working examples
6. The quantity of experimentation necessary;
7. The state of the prior art; and
8. The relative skill of those skilled in the art.
Each relevant factor is addressed below on the basis of comparison of the disclosure, the claims and the state of the art in the assessment of undue experimentation.
The nature of the invention; the breadth of the claims:
Claim 11 recites a broad reaction scheme for the preparation of a fluorescent dye containing alkoxysilyl groups by condensation reactions involving APS and “a condensation reagent including carbodiimide”. The fluorescent dye and carbodiimide reagent are not limited by the claims beyond the resulting fluorescent dye product containing alkoxysilyl groups after a reaction with the specific compound APS.
The predictability or unpredictability of the art; the amount of direction or guidance presented; the presence or absence of working examples; the quantity of experimentation necessary; the state of the prior art; the relative skill of those skilled in the art:
The relative level of skill of those skilled in the art is relatively high, such as a scientist with at least a bachelor’s degree or graduate student tasked with preparing silica nanoparticles and other nanoscale materials.
The coupling of amines and carboxylic acids to form amide bonds using carbodiimide containing reagents such as EDC is well known in the art. A schematic of the reaction is shown in Figure 1 of Vashist (Diagnostics, 2012). As APS contains an amine group and no carboxylic acid group, the other reagent (the fluorescent dye) must contain a carboxylic acid group that will react in the presence of the carbodiimide to form the amide bond. However, nothing in the claims or the specification limits the fluorescent dye to only those that contain carboxylic acid groups. The carbodiimide coupling reaction is specific for amine and carboxylic acid groups to yield an amide bond. A single example of alkoxysilyl group introduction to a perylene dye is shown in the specification as filed with the alkoxysilyl groups being added via amide bond formation using carboxylic acid groups present in the dye (see reaction scheme at ¶ [0053] of the PGPub of the instant application). No other discussion as to how carbodiimides can be used with APS to introduce alkoxysilyl groups into non-carboxylic acid group containing fluorescent dyes is present in the disclosure as filed.
Given the well-known coupling chemistry carried out with carbodiimide containing reagents and the requirement that APS be used as a source of alkoxysilyl groups, undue experimentation would be required in order to enable the full scope of claim 11 to prepare any fluorescent dye with alkoxysilyl groups.
Claim Rejections - 35 USC § 112 – Indefiniteness
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 – 7 and 11 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.
The claims under examination were rejected in the July 9, 2025 Office Action as being indefinite because the molar ratio was unclear.
In response, Applicants amended claim 5 and state in the Remarks that it is clear that the claimed molar ratio refers to the total amounts of fluorescent dye [bearing alkoxysilyl groups] and alkoxysilane groups.
However, the claim as amended does not recite the molar ratio in any step relating to the combined materials or addition step but rather only when defining the alkoxysilane preparation as no semicolon is used between “preparing alkoxysilane” and the molar ratio language which is used elsewhere in the claim to set apart different steps. That solution only contains one of the required ingredient and beyond naming the material forming the other part of the ratio, no further explanation is given in the claim.
As currently presented, the molar ratio appears to define the molar concentration of the alkoxysilane in relation to the concentration of the fluorescent dye having alkoxysilyl groups present in a completely different solution. Nothing in the claim language requires the use of the totality of the liquid containing fluorescent dye having alkoxysilyl group, ammonia and water prepared or the totality of the prepared alkoxysilane. If all of each solution were added, then the molar ratio added would be the same as the total added, but the claims encompass methods in which only portions of each of the prepared materials are used, which then alters the molar ratio of the components that were added together. Therefore the required molar ratio(s) and what time point or calculations are used remains unclear. The dependent claims still fall therewith.
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(s) 5 - 7 were rejected under 35 U.S.C. 103 as being unpatentable over van Blaaderen et al. (Langmuir, 1992). This rejection is MAINTAINED for the reasons of record sets forth in the Office Action mailed July 9, 2025 and those set forth herein.
Applicants argue that the molar ratios of ingredients in example 1A of van Blaaderen are significantly different than the claimed range. Unexpected results are also shown in the examples of the application as filed using differing manufacturing conditions including the TEOS addition method, TEOS addition time and molar ratio of fluorescent dye to TEOS. Examples 1 – 7 show superior results as to the amount of dye and the CV (coefficient of variation) compared to Comparative Examples 1 – 5. The claimed manufacturing method not only pursues intensity of luminance but also product quality, not just optimization of the amount of fluorescent dye that is present.
These arguments are unpersuasive. When considering evidence proffered in support of alleged unexpected results, key points considered include what the expected results are, if the comparison presented is with the closest prior art or possible something closer and if the evidence offered is reasonably commensurate in scope with the claims (see MPEP 716.02 et seq. for a complete discussion of unexpected results). The claims are very broad with only a molar ratio specified and no limitations on the identity of the dye and silyl groups attached or alkoxysilane. The continuous addition time is very broad as long as the definition at ¶ [0042] of the PGPub of the instant application is met and the remaining 0 – about 20% of composition remaining after the single addition of at least 80% can be added over any time frame. No discussion as to what the expected results would be has been set forth (see MPEP 716.02(b)) so if the obtained results are different from the expected results cannot be determined. Comparing examples 1 – 4 and comparative example 1 that differ only in the molar ratio of fluorescent dye to TEOS, the amount of dye in volume % in the resultant nanoparticles increases as the molar ratio increases. Comparing examples 1 and 5 – 7 that differ only in the addition time with a constant ratio of fluorescent dye to TEOS, there appears to be little effect on the amount of dye in the final nanoparticles although particle size increases with increasing addition time, which could be an expected result. The evidence and explanation of record to not establish the criticality of the claimed molar ratio such that one of ordinary skill in the art would not arrive at the claimed range through routine optimization of the amount dye. van Blaaderen et al. even states that no investigation into the optimum dye concentration has been conducted (p 2925, col 2, last sentence). The evidence of record in support of unexpected results does not outweigh the prima facie case of obviousness and therefore this rejection is maintained.
Claim(s) 5 - 7 were rejected under 35 U.S.C. 103 as being unpatentable over van Blaaderen et al. (Langmuir, 1992) in view of Ribiero et al. (Dyes and Pigments, 2014). This rejection is MAINTAINED for the reasons of record sets forth in the Office Action mailed July 9, 2025 and those set forth herein.
Ribiero et al. is mentioned in the Remarks but no specific arguments regarding this reference were set forth for the Examiner to address herein.
Claim(s) 11 is rejected under 35 U.S.C. 103 as being unpatentable over van Blaaderen et al. (Langmuir, 1992) in view of Park et al. (WO 2008/117918) and Vashist (Diagnostics, 2012).
Please see the Office Action mailed July 9, 2025 for a complete discussion of the teachings of van Blaaderen et al.
The use of a fluorophore bearing a carboxylic acid and APS coupled using EDC is not disclosed as the isothiocyanate group of FITC is used for APS conjugation van Blaaderen et al.
Park et al. discloses fluorescently dye labeled glucose analogs and synthesis methods for such analogs (whole document, e.g., abstract). Various fluorescent dyes are disclosed as suitable including FITC, Cy5 and Cy3 with Cy3 being preferred because of its extensive use in bioassay system and stability with respect to high intensity light sources (p 6, ln 5 – 9). The solution containing the fluorescent dye is preferably dimethylformamide (DMF) with Cy3-COOH and the reaction reagent EDC (p 6, ln 9 – 11). As can be seen in reaction equation 1 beginning on p 10, ln 20, step d) results in amide bond formation between the COOH group of the Cy3 and amine of the glucose analog.
Vashist discloses that EDC is a carboxyl and amine-reactive zero-length crosslinker and can be used alone or in combination with sulfoNHS or NHS to enhance coupling efficiency (p 2). As shown Figure 1, after reaction of the antibody bearing carboxylic acid groups with EDC, the reactive intermediate can be further reacted with APTES functionalized platforms bearing amine groups.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use dye other than the FITC specifically exemplified by van Blaaderen et al. with carboxylic acid dyes such as Cy3 disclosed by Park et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Park et al. discloses a list of fluorescent dyes that includes both Cy3 and FITC and indicates that Cy3 is stable under high intensity light sources and is extensively used in bioassays. The choice of fluorescent dye from those that are known in the art for use in the fluorescent silica spheres of van Blaaderen et al. is within the skill of those in the art. Given the different functional groups available in Cy3 compared to FITC, EDC can be selected given the well-known nature of the EDC carboxyl and amine crosslinker reaction to prepare a fluorescent dye conjugate that will be covalently incorporated into the fluorescent silica spheres of van Blaaderen et al. Given the presence of the COOH group in Cy3, the EDC conjugation reaction of Vashist will result in a fluorescent dye-APS conjugate containing an amide bond.
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 Nissa M Westerberg whose telephone number is (571)270-3532. The examiner can normally be reached M - F 8 am - 4 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Hartley can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618
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