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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 10, 2026 has been entered.
Applicants' arguments, filed February 10, 2026, 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.
Specification
The disclosure was objected to because of the following informalities: 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 February 10, 2026 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 was 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 new matter rejection is MAINTAINED for the reasons of record set forth herein.
Claim 11 has been amended to a more specific method than before but the is still broader than supported by the disclosure as filed. For example, there is no disclosure of derivation of carboxylic acid groups from 1,6,7,12-tetrachloroperylene tetracarboxylic dianhydride as the reaction only occurs in the example that uses one specific compound. The APS ((3-aminopropyl)triethoxysilane) was also only added at a molar ratio of 1 while the claims encompass any molar ratio of the two reactants.
Additionally, the recited active step of causing a reaction between a carboxylic acid group, derived from 1,6,7,12-tetrachloroperylene tetracarboxylic dianhydride, and the two recited reagents is not disclosed in the disclosure as originally filed.
Therefore claim 11 as amended still contains new matter.
If Applicant is in disagreement with the Examiner regarding support for the amended claim, Applicant is respectfully requested to point to page and line number wherein support may be found for the instant invention.
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 – 16 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 5, from which all other claims under examination depend, was previously rejected as being indefinite and has been amended. However, those amendments to the claims do not sufficiently clarify the scope of the claims to result in the claims being definite.
The amendments have resulted in clarity in that the molar ratio is based on the first amount of fluorescent dyes having alkoxysilyl group and the second amount of tetraalkoxysilane but this phrasing indicates that at least one other amount of tetraalkoxysilane is present at some unknown stage that is not included and the molar ratio is calculated and the implied second amount of fluorescent dyes having alkoxysilyl group would similarly be excluded from the calculation of the molar ratio.
As amended, claim 5 recites a first amount of the fluorescent dyes having alkoxysilyl group but there is never a second amount of fluorescent dyes having alkoxysilyl group mentioned anywhere else in claim 5 or any other claim.
Claim 5 also now recites a second amount of tetraalkoxysilane but there is never a first amount of tetraalkoxysilane recited anywhere else in claim 5 or any other claim.
The first and second amounts cannot be considered to be the required two amounts since each refers to a completely different ingredient.
The dependent claims fall therewith.
Please clarify.
Claim 11 is 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 use of the word “causing” in reference to a required chemical reaction is not understood. This implies that some unspecified action(s) must be taken to bring about or cause the reaction but what such action(s) would be are not set forth. Please clarify.
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 and 12 – 16 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 set forth herein.
van Blaaderen et al. discloses the synthesis of monodisperse, fluorescent silica nanoparticles (whole document, e.g., title). The fluorophores can be distributed on the surface, in a thin shell in the particle interior, throughout the volume of the inner core or the entirety of the nanoparticle (p 2921, col 1, ¶ 1 and figure 1). The disclosed synthesis procedure uses a dye chemically bound to a silane coupling agent that is used in the synthesis of colloidal silica by hydrolysis and condensation of TES (TEOS; tetraethoxysilane, a species within the genus of tetraalkoxysilane) in mixtures of water, ammonia and ethanol (p 2921, col 1, ¶ 2). The coupling agent was APS (p 2921, col 1, ¶ 2). The reaction product of the APS and dye was added to a thoroughly mixed solution ammonia in distilled ethanol (p 2924, col 2, ¶ 1), which due to the ammonia being a 25% solution (p 2924, col 1, ¶ 2) also contained water. Immediately after homogenization, distilled TES was added to a concentration of 0.17 M with a funnel placed in the reaction mixture for the synthesis of the core particles (p 2924, col 2, ¶ 1), reading on continuous addition. Given these steps, the particles formed will contain dye throughout the entirety of the particle. As detailed in the remainder of col 2 on p 2924, different steps were then used to prepare the different distributions of silica regions not containing dye and regions that do contain dye.
The size and amount of dye per particle is shown in Table III on p 2926 but are not set forth as % of volume of fluorescent dye and the emission quantum yield is not disclosed.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to add the dye to the water, ammonia and alcohol solution to prepare a liquid to which the alkoxysilane such as TEOS is added and optimize the amount of fluorescent dye present in the resulting nanoparticles. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because such an artisan would routinely optimize the amount of fluorophore present in the particles. Given the desire for the resulting particle to be as bright and stable as possible, one of ordinary skill in the art would routinely optimize the amount of dye incorporated into the silica nanoparticles. The amount of a specific ingredient such as the fluorescent dye in a composition is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve the desired results. Due to possible quenching that will be affected by covalent attachment of the dye to the silica matrix when conjugates as in van Blaaderen et al. are prepared, there may not be a linear relationship between the absolute amount of dye (reflected in one interpretation of the percent of the fluorescent dye to total volume of silica nanoparticle limitations) and the observed fluorescence from the particles (at least partially reflected in the emission quantum yield). One of ordinary skill in the art would optimize the amount of fluorescent dye present in the silica nanoparticles and the distribution of the fluorescent dye therein to produce the brightest possible particles. Such brighter particles can result in observable signals at lower concentrations of particles or smaller particles that still produce an observable signal. There is no evidence of record as to the criticality of the claimed volume % of fluorescent dye or the emission quantum yield. While the prior art does not explicitly determine the claimed parameters, there is no evidence that the materials prepared do not contain such amounts and that such amounts cannot be arrived at through routine optimization to maximize the observed fluorescence from the prepared particles.
It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). “As a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.” MPEP 2113
Applicants traverse this rejection on the grounds that van Blaaderen et al. fails to teach or suggest the claimed molar ratio. The claimed manufacturing process can provide unexpected results sufficient to establish non-obviousness. The table from the specification is reproduced in the Remarks and it is stated that examples 1 – 7 show superiority in the contained amount of dye, emission quantum yield, the CV (coefficient of variation) value and luminance compared to the comparative examples. One of ordinary skill would have expected that higher luminance could be obtained by causing the silica particles to contain more fluorescent dyes but that was not found to be the case as quenching occurs in the particles and emission quantum yield decreases. The continuous addition prevents the dyes from being polycondensed to approximate each other [sic] with advance presence of the tetraalkoxysilane would likely result in the fluorescent dyes being localized such that concentration quenching occurs. The present inventors have found that the molar ratio is preferably large but too large of a ratio means that particles cannot be formed. Claim 5 has been amended to limit the alkoxysilane to tetraalkoxysilane, amongst other amendments to the claims. Although the amount of dye in volume % in the resultant nanoparticles increase, this is not a linear increase due to the influence of the emission quantum yield. None of the cited art teaches or suggests the possible mechanism of the decreased emission quantum yield, let alone the claimed manufacturing method to provide the unexpected results.
These arguments are unpersuasive. Arguments without factual support are mere allegations and are not found persuasive. General statements were made but it remains unclear what the expected results would have been to determine if the differences observed were in fact unexpected. The fact that different methods resulted in different products does not necessarily establish that those differences were in fact unexpected. The explanation provided seems to suggest that the differences could in fact be expected as part of routine optimization as to the amount of fluorescent dye being added, which necessarily alters the molar ratio to the other components. While the alkoxysilane has been somewhat narrowed, all but claim 11 remain open to any fluorescent dyes and the same dye was used in all the examples. Even claim 11 encompass fluorescent dyes derived from 1,6,7,12-tetrachloroperylene tetracarboxylic dianhydride. Therefore the evidence of record in support of the allegations of unexpected results is insufficient to outweigh the prima facie case of obviousness.
Claim(s) 5, 7 and 12 – 16 were rejected under 35 U.S.C. 103 as being unpatentable over van Blaaderen et al. as applied to claims 5, 7 and 12 – 16 above, further in view of Ribeiroei et al. (Dyes and Pigments, 2014). This rejection is MAINTAINED for the reasons of record set forth herein.
van Blaaderen et al. is discussed above.
The use of the elected species of perylene fluorescent dye is not disclosed.
Ribeiro et al. discloses that silica nanoparticles (SiNPs) in particular have been used in applications including imaging with increasing interest in SiNPs due to the possibilities of tuning particle diameter, particle porosity, surface functionalization and loading large amounts of fluorophores, drugs or other molecules and how and if that cargo is released (p 227, col 1, ¶ 1). Perylenediimide based dyes (PDIs) have many applications due to their typically high photochemical stability and extinction coefficients and large fluorescent quantum yields (p 227, col 1, ¶ 2). The incorporation of PDIs into SiNPs results in higher brightness, better photostability due to lower oxygen and diffusivity inside the nanoparticle and widen the range of solvents/materials in which they can be used due to the ability to modify the surface of the nanoparticle (p 227, col 2, ¶ 1). Two different dyes including one emitting in the near-infrared region (NIR) were incorporated into SiNPs which given the increased brightness and photostability, biocompatibility and efficient cell internalization make promising candidates for in vivo laser-scanning imaging applications (p 227, col 2, ¶ 2). As shown in scheme 1, the PDI derivatives used comprised ethoxysilane groups that leads to covalent attachment of the fluorophores to the silica network during synthesis as shown in scheme 2.
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 a perylene dye such as those used in Ribeiro et al. in the process of making SiNPs used in van Blaaderen 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 different fluorophores have different properties such as excitation and emission wavelengths and depending on the application (e.g., material being studied and if multiple fluorescent molecules are required for a particular application), SiNPs comprising different fluorophores can be readily prepared by the conjugation of siloxy groups to the fluorophores such as the PDI derivatives used in Ribeiro et al.
It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). “As a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.” MPEP 2113 It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to add the dye to the water, ammonia and alcohol solution to prepare a liquid to which the alkoxysilane such as TEOS is added and optimize the amount of fluorescent dye present in the resulting nanoparticles. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because such an artisan would routinely optimize the amount of fluorophore present in the particles. Given the desire for the resulting particle to be as bright and stable as possible, one of ordinary skill in the art would routinely optimize the amount of dye incorporated into the silica nanoparticles. The amount of a specific ingredient such as the fluorescent dye in a composition is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve the desired results. Due to possible quenching that will be affected by covalent attachment of the dye to the silica matrix when conjugates as in van Blaaderen et al. and Ribeiro et al. are prepared, there may not be a linear relationship between the absolute amount of dye (reflected in one interpretation of the percent of the fluorescent dye to total volume of silica nanoparticle limitations) and the observed fluorescence from the particles (at least partially reflected in the emission quantum yield). One of ordinary skill in the art would optimize the amount of fluorescent dye present in the silica nanoparticles and the distribution of the fluorescent dye therein to produce the brightest possible particles. Such brighter particles can result in observable signals at lower concentrations of particles or smaller particles that still produce an observable signal. There is no evidence of record as to the criticality of the claimed volume % of fluorescent dye or the emission quantum yield. While the prior art does not explicitly determine the claimed parameters, there is no evidence that the materials prepared do not contain such amounts and that such amounts cannot be arrived at through routine optimization to maximize the observed fluorescence from the prepared particles.
Regarding Ribeiro et al., Applicants traverse this rejection on the grounds that this reference teaches addition of the various reagents at the same time, contrary to the claimed continuous addition method.
These arguments are unpersuasive. Ribeiro et al. is relied upon to teach the particular type of fluorescent dye and not the other claimed method steps. "The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference .... Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 413,425 (CCPA 1981) MPEP 2145(III). Therefore it is not required that method of preparation used in Ribeiro et al. be used.
Claim(s) 11 is rejected under 35 U.S.C. 103 as being unpatentable over van Blaaderen et al. and Ribeiro et al. as applied to claims 5, 7 and 12 – 16 above, and further in view of Park et al. (WO 2008/117918) and Vashist (Diagnostics, 2012). This rejection is MAINTAINED for the reasons of record set forth herein.
van Blaaderen et al. and Ribeiro et al., that discloses dyes derived from 1, 6, 7, 12-tetrachloriperylene tetracarboxylic anhydride, are discussed above.
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 in 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). Typical organic solvents can be used although dimethylformamide (DMF) and triethyl amine (TEA) are exemplified. The solution containing the fluorescent dye is preferably 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. and to use suitable typical organic solvents to dissolve the various products during the synthesis procedure. 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. Solvent selection is also within the skill of those of ordinary skill in the art based on the solvents that are available in the laboratory and the solubility of the particular compounds being reacted in the different solvents such THF and DMF. There is no evidence of record as to the criticality of the solvent used in the various stages of the synthesis procedure.
Applicants argue that Park and Vashist are cited for allegedly teaching a process for obtaining fluorescent dyes with alkoxysilane groups but do not cure the aforementioned deficiencies of van Blaaderen in view of Ribeiro.
As discussed in greater detail above, van Blaaderen and Ribeiro are not deficient as alleged by Applicants so Park et al. and Vashist are not required to cure the alleged deficiencies.
Conclusion
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618
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