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’s preliminary amendment filed 12/23/2024, is acknowledged. Claims 1-18 are pending.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1, 3-5, 7, 8 and 12-17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wiesner et al. (WO 2013/192609) (hereinafter “Cornell ‘609 or Wiesner et al.).
Regarding claim 1, Cornell '609 discloses a method of making nanoparticles (Abstract, Mesoporous oxide nanoparticles, compositions comprising such nanoparticle, and methods of making and using such nanoparticles.) surface functionalized with polyethylene glycol (PEG) groups (Para. [0005], a composition comprising polyethylene-glycol (PEG) functionalized mesoporous oxide (e.g., silica) nanoparticles) or core-shell nanoparticles surface functionalized with PEG groups comprising a) forming a reaction mixture at room temperature comprising water and TMOS (Claim 13; Para. [0064], forming a reaction mixture in an aqueous solvent having a basic pH comprising: a surfactant and oxide precursor(s) (e.g., a silica source such as tetramethoxy orthosilicate (TMOS); Para. [0144], synthesis temperature from room temperature (RT) to 80 °C), wherein the pH of the reaction mixture is 6 to 9 (Para. [0067], The pH of the reaction mixture can range from neutral (pH 7) to slightly basic. The reaction mixture can be held at a temperature of 20 °C to 95 °C, including all integer °C values and ranges therebetween, for 0.1 to 24 hours, including all 0.1 hour values and ranges therebetween.); b) either i) holding the reaction mixture at a time (tl) and temperature (T1), whereby nanoparticles (Claim 13; Para. [0064], holding the reaction mixture at a temperature and for a time such that mesoporous oxide nanoparticles are formed) having an average size of 2 to 15 nm are formed (Para. [0045], mesoporous oxide nanoparticles have a range of sizes. The nanoparticles can have an average size of 3 nm to 15 nm, including all values to the 0.1 nm and ranges therebetween.; Claim 13, nanoparticles having an average size of 15 nm or less), or ii) cooling the reaction mixture to room temperature, if necessary, and adding a shell forming monomer to the reaction mixture from a) wherein the addition is carried out such that the shell forming monomer concentration is below the threshold for secondary nucleation, whereby core-shell nanoparticles having an average size of 2 to 50 nm are formed; c) adjusting, if necessary, the pH of the reaction mixture to a pH of 6 to 10 comprising the core nanoparticles or core-shell nanoparticles from b) i) or b) ii), respectively (Para. [0117], Furthermore, pH, concentration of TMOS and reaction temperature were varied to further control the condensation rate.; Para. [0131]); and d) adding at room temperature to the reaction mixture comprising the core nanoparticles or core-shell nanoparticles from b) i) or b) ii), respectively, a PEG-Silane (Claim 13; Para. [0064], adding a PEG-functionalized oxide precursor (e.g., a PEG-functionalized silane); Paras. [0067]-[0068]) and holding the resulting reaction mixture at a time (t2) and temperature (T2) (Claim 13; Para. [UU64], holding the reaction mixture at a temperature and for a time such that the PEG functional mesoporous oxide nanoparticles are formed); e) optionally heating the mixture from d) at a time (t3) and temperature (T3), whereby the nanoparticles surface functionalized with PEG groups or the core-shell nanoparticles surface functionalized with PEG groups are formed (Paras. [0064]-[0065], Optionally, the method comprises the step of holding the PEG-functionalized mesoporous oxide nanoparticles at an elevated temperature.... Without intending to be bound by any particular theory, it is considered this optional step facilitates condensation of PEG-functionalized oxide precursor with the surface of the mesoporous oxide nanoparticles.)
Regarding claim 3, Cornell '609 discloses the method of claim 1, wherein in the reaction mixture further comprises a dye precursor (Para. [0057], the molecular cargo is a fluorescent dye. For example, the molecular cargo can be present in the nanoparticle matrix (i.e., dispersed in the oxide (e.g., silica); Para. [0069], The reaction mixture can further comprise a molecular cargo. For example, the reaction mixture includes a fluorescent dye and the method provides fluorescent nanoparticles.) or covalently bonded to a surface of the nanoparticle.) and the nanopartides surface functionalized with PEG groups (Para. [0052], The nanoparticles can comprise a molecular cargo. ... For example, 80% or more of the nanopartides has accessible well-developed pores that can load one or more molecular cargo. By "well-developed pores" it is meant that pores have a desirable shape that is not blocked by PEG groups on the nanoparticle surface.; Paras. [0053];[0058];[0064]) or the core-shell nanopartides surface functionalized with PEG groups have one or more fluorescent dye molecules covalently encapsulated therein.
Regarding claim 4, Cornell '609 discloses the method of claim 3, wherein 1 to 7 dye molecules are present in each of the nanopartides surface functionalized with PEG groups (Para. [0046], The PEG-functionalized mesoporous oxide nanopartides have a porous morphology. ... The nanopartides can have 0 to 5 pores per nanopartide, including all portions of a pore and ranges therebetween.; Para. [0052], The nanopartides can comprise a molecular cargo. ... For example, 80% or more of the nanopartides has accessible well-developed pores that can load one or more molecular cargo. By "well-developed pores” it is meant that pores have a desirable shape that is not blocked by PEG groups on the nanoparticle surface.; Para. [0057], the molecular cargo is a fluorescent dye.) or core-shell nanopartides surface functionalized with PEG groups.
Regarding claim 5, Cornell ‘609 discloses the method of claim 4, wherein the core is an aluminosilicate core (Para. [0044], aluminosilicate nanopartides) and the number of dye molecules per particle is 1 to 7 (Paras. [0046];[0052];[0057]).
Regarding claim 7, Cornell '609 discloses the method of claim 1, wherein at least a portion of or all of the PEG-silane conjugate comprises a ligand (Para. [0005], polyethylene-glycol (PEG) functionalized mesoporous oxide (e.g., silica) nanoparticles ... and at least a portion of the non-pore surface is at least partially functionalized with polyethylene glycol groups; Para. [0059], the non-pore (exterior) surface is at least partially functionalized with targeting groups for specific diseases or targets related to a disease state. For example, the non-pore (exterior) surface is functionalized with cancer targeting agents (e.g., a cancer targeting ligand is conjugated to one terminus of a heterobifunctinal PEG group via a thiol maleimide reaction and the other terminus is conjugated to a silane via N-hydroxysuccinimide (NHS) esters amine reaction and the silane condensed on the surface of the nanoparticle (e.g., via a thiol) via a such that the nanoparticles have tumor targeting properties.).
Regarding claim 8, Cornell ‘609 discloses the method of claim 1, wherein PEG-silane conjugate comprising a ligand is added in addition to PEG-silane in d) (Para. [0059], Suitable, cancer targeting ligands include cRGDy and aMSH peptides; Para. [0169], Heterobifunctional PEGs with NHS ester and maleimido groups was first conjugated with amino silane through NHS ester amine reaction. cRGD peptide was then conjugated to the silane-PEG-mal via cysteine-maleimide linkage. The cRGD-PEG- silane was later attached onto the surface of Cy5 labeled mC dots together with the monofunctional PEG-silane to generate cRGD-labeled mC dots.; Para. [0068]), whereby nanoparticles surface functionalized with PEG groups and polyethylene groups comprising a ligand or core-shell nanoparticles surface functionalized with PEG groups and polyethylene groups compnising a ligand are formed (Para. [0064]).
Regarding claim 12, Cornell ‘609 teaches that at least 95% of the nanoparticles are within 3 nm of the average nanoparticle size of 15 m. See para. [0045]. Insofar as Cornell ‘609 is silent regarding
Regarding claims 13-17, Cornell ‘609 discloses the composition of claim 12, wherein the core is an aluminosilicate core (Para. [0044], aluminosilicate nanopartides) and the number of dye molecules per particle is 1 to 7 (Paras. [0046];[0052];[0057]).
Claim Rejections - 35 USC § 103
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.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claim 9-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wiesner et al. (WO 2013/192609).
Teachings of Wiesner et al. are discussed above.
Regarding claim 9, Cornell ‘609 discloses the method of claim 1, wherein before or after the PEG-silane conjugate is added in d) a PEG-silane conjugate comprising a ligand is added at room temperature to the reaction mixture comprising the core nanoparticles or core-shell nanoparticles from b) i) or b) ii), respectively (Paras. [0059];[0169];[0064];[0068]), holding the resulting reaction mixture at a time (t4) and temperature (T4) (Paras. [0064];[0070], Determination of the reaction conditions (e.g., reaction time and temperature) required to make nanoparticles of a desired size are within the purview of one having skill in the art.), subsequently heating the resulting reaction mixture at a time (t5) and temperature (T5), whereby nanoparticles surface functionalized with PEG groups comprising a ligand or core-shell nanoparticles surface functionalized with PEG groups comprising a ligand are formed (Paras. [0064]-[0065], Optionally, the method comprises the step of holding the PEG-functionalized mesoporous oxide nanoparticles at an elevated temperature.... Without intending to be bound by any particular theory, it is considered this optional step facilitates condensation of PEG-functionalized oxide precursor with the surface of the mesopornus oxide nanoparticles.; Para. [0048], The non-pore surface of the PEG-functionalized mesoporous oxide nanoparticles is at least partially functionalized with PEG groups. The PEG groups are covalently bonded to the surface of the nanoparticle.; Paras. [0059];[0169]-[0170]), optionally, subsequently adding at room temperature to the resulting reaction mixture comprising nanoparticles surface functionalized with PEG groups comprising a ligand or core-shell nanoparticles surface functionalized with PEG groups comprising a ligand a PEG-silane conjugate, holding the resulting reaction mixture at a time (t6) and temperature (T6) whereby at least a portion of the PEG-silane conjugate molecules are adsorbed on at least a portion of the surface of the nanoparticles surface functionalized with PEG groups comprising a ligand or at least a portion of the core-shell nanoparticles surface functionalized with PEG groups comprising a ligand a PEG-silane conjugate, and heating the resulting mixture from at a time (t7) and temperature (T7) whereby nanoparticles surface functionalized with PEG groups and PEG groups comprising a ligand or core-shell nanoparticles surface functionalized with PEG groups and polyethylene groups comprising a ligand are formed (Para. [0060], The nanoparticles can have combinations of functionalization and molecular cargo.; Para. [0169]). Cornell ‘609 fails to explicitly disclose the specific method steps of claim 9 in one single embodiment.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to modify Cornell '609 to create nanoparticles surface functionalized with PEG groups and polyethylene groups comprising a ligand, since selection of any order of process steps which did not result in a new or unexpected result would involve only routine skill in the art. The motivation for doing so would be to create a nanoparticle having combinations of functionalization and molecular cargo for the delivery of medical treatments and imaging applications to an individual (Cornell '609, Abstract; Paras. [0058]-[0061]).
Regarding claim 10, Cornell '609 discloses the method of claim 1, wherein at least a portion of or all of the PEG-silane has a reactive group on a terminus of the PEG moiety opposite the terminus conjugated to the silane moiety of the PEG-silane conjugate and after formation of the nanoparticles surface functionalized with PEG groups having a reactive group, and, optionally, PEG groups, coreshell nanoparticles surface functionalized with PEG groups having a reactive group (Para. [0048], The non-pore surface of the PEG-functionalized mesoporous oxide nanoparticles is at least partially functionalized with PEG groups. The PEG groups are covalently bonded to the surface of the nanoparticle.; Para. [0059], The non-pore (exterior) surface can be functionalized with functional groups for specific applications. In an embodiment, the non-pore (exterior) surface is at least partially functionalized with targeting groups for specific diseases or targets related to a disease state. For example, the non-pore (exterior) surface is functionalized with cancer targeting agents (e.g., a cancer targeting ligand is conjugated to one terminus of a heterobifunctinal PEG group via a thiol maleimide reaction and the other terminus is conjugated to a silane via N-hydroxysuccinimide (NHS) esters amine reaction and the silane condensed on the surface of the nanoparticle (e.g., via a thiol) via a such that the nanoparticles have tumor targeting properties. Suitable, cancer targeting ligands include cRGDy and aMSH peptides.), and, optionally, PEG groups, are reacted with a second ligand functionalized with a second reactive group thereby forming nanoparticles surface functionalized with polyethylene groups functionalized with a second ligand and, optionally, PEG groups, core-shell nanoparticles surface functionalized with polyethylene groups functionalized with a second ligand and PEG groups and, optionally, PEG groups (Para. [0060], The nanoparticles can have combinations of functionalization and molecular cargo.; Para. [0169]). Cornell ‘609 fails to explicitly disclose the specific method steps of claim 10 in one single embodiment.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to modify Cornell ‘609 to create nanoparticles surface functionalized with PEG groups and polyethylene groups comprising one or more ligands, since selection of any order of process steps which did not result in a new or unexpected result would involve only routine skill in the art. The motivation for doing so would be to create a nanoparticle having combinations of functionalization and molecular cargo for the delivery of medical treatments and imaging applications to an individual (Cornell ‘609, Abstract; Paras. [0058]-[0061]).
Regarding claim 11, Cornell ‘609 discloses the method of claim 8, wherein at least a portion of or all of the PEG-silane has a reactive group on a terminus of the PEG moiety opposite the terminus conjugated to the silane moiety of the PEG-silane conjugate and after formation of the nanoparticles surface functionalized with PEG groups and, optionally having a reactive group (Para. [0048], The non-pore surface of the PEG-functionalized mesoporous oxide nanoparticles is at least partially functionalized with PEG groups. The PEG groups are covalently bonded to the surface of the nanoparticle.; Para. [0059], The non-pore (exterior) surface can be functionalized with functional groups for specific applications. In an embodiment, the non-pore (exterior) surface is at least partially functionalized with targeting groups for specific diseases or targets related to a disease state. For example, the non-pore (exterior) surface is functionalized with cancer targeting agents (e.g., a cancer targeting ligand is conjugated to one terminus of a heterobifunctinal PEG group via a thiol maleimide reaction and the other terminus is conjugated to a silane via N-hydroxysuccinimide (NHS) esters amine reaction and the silane condensed on the surface of the nanoparticle (e.g., via a thiol) via a such that the nanoparticles have tumor targeting properties. Suitable, cancer targeting ligands include cRGDy and aMSH peptides.), and, optionally, PEG groups, core-shell nanoparticles surface functionalized with PEG groups having a reactive group, and, optionally, PEG groups, are reacted with a second ligand functionalized with a second reactive group thereby forming nanoparticles surface functionalized with polyethylene groups functionalized with a second ligand (Para. [0060], The nanoparticles can have combinations of functionalization and molecular cargo.) and, optionally, PEG groups, coreshell nanoparticles surface functionalized with polyethylene groups functionalized with a second ligand and PEG groups and, optionally, PEG groups, wherein at least a portion of the PEG-silane has a reactive group on a terminus of the PEG moiety opposite the terminus conjugated to the silane moiety of the PEG-silane conjugate and after formation of the nanoparticles surface functionalized with PEG groups having a reactive group (Paras. [0048];[0059];[0060]), core-shell nanoparticles surface functionalized with PEG groups having a reactive group, nanoparticles surface functionalized with PEG groups having a reactive group and PEG groups comprising a ligand, or core-shell nanoparticles surface functionalized with PEG groups having a reactive group and PEG comprising a ligand the reactive group are reacted with a second ligand functionalized with a reactive group thereby forming nanoparticles surface functionalized with PEG groups and polyethylene groups functionalized with a second ligand, core-shell nanoparticles surface functionalized with PEG groups and polyethylene groups functionalized with a second ligand, nanoparticles surface functionalized with PEG groups comprising a ligand, or core-shell nanoparticles surface functionalized with PEG groups and polyethylene groups comprising a ligand that is functionalized with the second ligand (Paras. [0048];[0059];[0060];[0169]). Cornell '609 fails to explicitly disclose the specific method steps of claim 11 in one single embodiment.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to modify Cornell ‘609 to create nanoparticles surface functionalized with PEG groups and polyethylene groups comprising one or more ligands, since selection of any order of process steps which did not result in a new or unexpected result would involve only routine skill in the art. The motivation for doing so would be to create a nanoparticle having combinations of functionalization and molecular cargo for the delivery of medical treatments and imaging applications to an individual (Cornell '609, Abstract; Paras. [0058]-[0061 ]).
Claim 2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wiesner et al. (WO 2103/192609) in view of Poduval et al. Eindhoven University of Technology Library, Thesis, pp. 3, 17, 25, 30-33, 39, 40 (2011).
Teachings of Wiesner et al. are discussed above.
Regarding claim 2, Cornell ‘609 discloses the method of claim 1, wherein the reaction mixture further comprises an alumina or aluminasilicate core forming monomer, the pH of the solution is adjusted to a pH of 7 to 9 and, optionally, PEG with molecular weight between 0.1k and 1k and concentration between 10mM and 75mM is added to the reaction mixture right before adjusting a pH of 7 to 9, the core is an aluminosilicate core (Para. [U044], The PEG-functionalized mesoporous oxide nanoparticles can be non-metal oxide nanoparticles, metal oxide nanoparticles, or mixed non-metal and metal oxide nanoparticles.... Examples of mixed non-metal and metal oxide nanoparticles include aluminosilicate nanoparticles and calcium phosphate/silica composites.; Paras. [0048];[0064];[0067];[0096]; [0117]). Cornell '609 fails to explicitly disclose and the pH of the reaction mixture is adjusted to a pH of 1 to 2 prior to addition of the alumina or aluminasilicate core forming monomer. However, Poduval is in the field of silica-alumina nanoparticles (Poduval, Pg. 3, Summary; Pg. 39-40, Distribution of Al in a mixed silica-alumina phase and alumina domains, nanometer-sized crystalline particles) and teaches the pH of the reaction mixture is adjusted to a pH of 1 to 2 prior to addition of the alumina or aluminasilicate core forming monomer (Pg. 17, Second Paragraph, the deposition of aluminium on silica as a function of pH and the initial aluminium concentration; Pg. 25, First Paragraph, deposition process, the Al 3+ species in an aqueous solution as a function of pH; Pg. 25, Fig. 2.1, deposition of Al on silica at a pH as low as 1; Pg. 32, Last Paragraph, grafting of aluminium species on silica takes place via hydrolytic adsorption involving condensation reactions between silanol groups and hydrolyzed Al complexes from the solution at relatively low pH ... The majority of Al species deposit at relatively low pH where grafting via heterolytic and homolytic adsorption is dominant over precipitation.; Pg. 17, Last Paragraph, aluminosilicate core). It would have been obvious to one of ordinary skill in the art at the time the invention was made to modify Cornell ‘609 to adjust the pH of the solution to create an aluminosilicate core, as taught by Poduval. The motivation for doing so would be to avoid unwanted interactions while depositing alumina on silicate to create an aluminosilicate core nanoparticle (Poduval, Pg. 30-31, Last Paragraph - First Paragraph; Cornell ‘609, Para. [0044]).
Claim 6 lacks an inventive step under PCT Article 33(3) as being obvious over Wiesner et al. (WO 2013/192609) in view of WO 2014/130643 to Cornell University (hereinafter Cornell ’643).
Regarding claim 6, Cornell '609 discloses the method of claim 1. Cornell ‘609 fails to explicitly disclose wherein in b) ii) the shell-forming monomer is added in separate aliquots and, if necessary, periodically adjusting the pH to maintain a pH of 7 to 8 during the addition of the shell-forming monomer. However, Cornell ‘643 is in the field of PEG functionalized nanoparticles (Cornell ‘643, Para. [0007], multicolor fluorescent silica nanoparticles (also referred to herein as multilayer, fluorescently responsive material (FRM)-containing nanoparticles, mcC dots, and tricolor C dots, and multicolor C dots) with optional surface PEG coatings (for functionalization with different moieties such as proteins, nucleic acids, small molecules)) and teaches wherein in b) ii) the shell-forming monomer is added in separate aliquots (Cornell '643, Para. [0009], dyes are added to a dye doped particle core in a layer-by-layer fashion and each spectrally distinct dye is spatially separated by a pure silica shell; Para. [0054], In the FRM-containing silica layer forming reaction the concentration of silica precursor is kept below the nucleation threshold concentration. In one embodiment, the reaction is added in serial aliquots to keep the concentration of silica precursor below the nucleation threshold concentration.). It would have been obvious to one of ordinary skill in the art at the time the invention was made to modify Cornell '609 to form a core shell nanoparticle, as taught by Cornell '643. The motivation for doing so would be to reduce energy transfer between dyes (Cornell ‘643, Paras. [0009]-[0010]; Cornell ‘609, Paras. [0155]-[0156]).
Conclusion
No claims are allowed.
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/ROBERT S CABRAL/ Primary Examiner, Art Unit 1614
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