DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 September 26 2025 has been entered.
Receipt of Arguments/Remarks filed on September 26 2025 is acknowledged. Claims 21-24 were/stand cancelled. Claim 1 was amended. Claims 1-20 and 25-37 are pending. Claims 4, 11, 20 and 33-37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 25 2024. Claims 1-3, 5-10, 12-19 and 25-32 are directed to the elected invention.
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 .
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
The drawings are objected to because they are in color but no petition to accept color drawings filed under 37 CFR 1.84(a)(2) or (b)(2) has been accepted. See MPEP 608.02, part VIII. The examiner notes this became apparent due to the response filed September 26 2025 which specifically directs the examiner attention to Fig. 11A and 11B. However, unless in color it is not possible to discern the distinction between the various drawings.
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 of this title, 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 5-7, 12-15, 18 and 25-32 are rejected under 35 U.S.C. 103 as being unpatentable over De Cola et al. (USPGPUB No. 20170119688, cited on PTO Form 1449) in view of Reategui et al. (US Patent No. 9427408, cited in the Office Action mailed on 11/14/24), Zeiadeh et al. (Molecules, 2018, cited in the Office Action mailed on 11/14/24) and Anraku et al. (Nature Communications, 2017, cited in the Office Action mailed on 11/14/24).
Applicant Claims
The instant application claims a nanoparticle comprising a silica network comprising crosslinked polysiloxanes wherein the polysiloxanes comprise siloxy subunits having the structure I or II; the crosslinks between polysiloxanes comprise disulfide linkages; the nanoparticle comprises an exterior surface comprising surface modifying groups attached to and surrounding the silica network (PEG as elected) and the nanoparticle has an average diameter of 15 to 200 nm wherein the surface modifying groups further comprise a dual targeting ligand comprising glucose and Rabies Virus Glycoprotein (RVG) peptide.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
De Cola et al. is directed to disintegrable core/shell silica particles for encapsulating and releasing bioactive macromolecules. Claimed is a nanoencapsulated bioactive macromolecule (i.e. nanoparticle) having a core/shell structure wherein the shell is made of a hybrid organosilica material comprising a three-dimensional framework of Si-O bonds wherein at least a subset of Si atoms in the framework is connected to at least another Si atom in the framework through a linker having the following structure: *-R1-L-R2-* wherein * denotes a point of attachment to a Si atom, L represents a cleavable covalent bond and a bioactive macromolecule (claim 28). Bioactive macromolecules include RNA (claim 31). Recombinant biomolecules include mRNA (paragraph 0072). The diameter is between 25 nanometers and 500 nanometers (claim 32). Preferable particle sizes are between 25 and 200 nm and most preferably between 40 and 80 nm (paragraph 0113). Table 2 shows exemplary synthetic conditions the first example is the use of TEOS (tetraethylorthosilicate) and
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(page 13). Advantageously, the surface of the core/shell silica nanocapsules are functionalized with a surface agent. The surface agent can be a PEG group linked to a trialkoxysilane (paragraph 0159 and claim 35). Surface agents can be those that specifically target certain organs/tissues (paragraph 0160). Several surface agents may be used. These include polyethylene glycol, polypeptides and oligosaccharides (paragraph 0164). Marking of the core/shell can be achieved by condensation of a marker-containing trialkoxysilane. The marker may be a contrast agent, a tracer, a radioactive marker, any commercial dye (paragraph 0159). The nanoparticles may have an electric charge, the magnitude of which advantageously have negative values which denotes that the outer surface of the particle is made of silica and the encapsulated bioactive macromolecules do not protrude on the surface of the nanocapsule. The nanoparticles have a negative charge ranging from -9 mV and -30 mV (paragraph 0115).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While De Cola et al. suggest the use of TEOS, De Cola et al. does not teach the use of triethoxyvinylsilane. However, this deficiency is cured by Reategui et al.
Reategui et al. is directed to silica-matrix forming compositions, materials formed thereof and methods of using the same. Table A (columns 15 and 16) show material commonly used to form silica compositions. These include network formers such as TEOS (tetraethylorthosilicate) as well as vinyltriethoxysilane.
De Cola et al. does not expressly teach the use of glucose and RVG peptide as targeting ligands. However, this deficiency is cured by Zeiadeh et al. and Anraku et al.
Zeiadeh et al. is directed to strategies for enhancing the permeation of CNS-active drugs through the blood-brain barrier. The blood brain barrier (BBB) is a structural and functional barrier which protects and maintains a highly controlled environment for central nervous system (CNS) neurons. The BBB lines brain and spinal cord capillaries with endothelial cells, astrocytes, pericytes, microglia, and muscle cells. The cells are connected by tight junctions and express a variety of receptors, transporters, and pores which allow for penetration of specific substances from the blood into the CNS (page 1 introduction). Substances have been found to cross the BBB through many pathways. The most common include carrier mediated transport such as glucose transporter, choline transporter, among others (pages 1-2, BBB transport routes). One strategy to get substances across the BBB is the use of nanoparticles. Since nanoparticles possess surface functionalization, for example, they are being investigated. It is taught that Kim et al. used chitosan NPS targeted for BBB penetration through RVG conjugation. Pluronic-based nanocarriers in combination with RVG peptide and chitosan proved efficient in increasing BBB penetration (pate 6, section 2.3). Rabies virus glycoprotein (RVG) is likely to cross the BBB though nicotinic acetylcholine receptors but does not bind to nucleic acids and is incapable of delivery siRNA. But RVG-9R provides a safe means for delivery of siRNA across the BBB (page 6, section 2.2). Glucose is taught as being used to facilitate BBB through GLUT1 transporters. Glycosylated derivatives of drugs have the ability to increase CNS uptake by GLUT1. Glycosylated derivatives of dopamine enhance dopamine BBB penetration (page 8, section 2.4).
Anraku et al. teaches that glycemic control boosts glycosylated nanocarrier crossing the BBB into the brain. Among the various candidate ligands previously studied for promoting BBB traversal, glucose, the main energy source in the brain, is notable because glucose transporter-1 (GLUT1) is expressed at a remarkably high level compared to many other receptors and transporters (page 2, right column). GLUT1 recognizes glucose molecules principally through weak interactions such as hydrogen bonding and the hydrophobic effect. Binding of a single glucose to GLUT1 may not be strong enough to retain nanocarriers in the harsh flow of the bloodstream. Suggested is introducing many glucose molecules onto the surface of the nanocarrier. Taught is the use of a polymeric nanocarrier with a size of about 30 nm and PEG (pages 2-3 and figure 1).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of De Cola et al., Reategui et al., Zeiadeh et al. and Anraku et al. and substitute the TEOS of De Cola et al. with vinyltriethoxysilane. One skilled in the art would have been motivated to substitute the TEOS with vinyltriethoxysilane with a reasonable expectation of success as both are known network formers for forming silica networks. Note: MPEP 2143 (I)(B) KSR International Co. v. Teleflex Inc., 550 US 398, 82 USPQ 2d 1385 (2007).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of De Cola et al., Reategui et al., Zeiadeh et al. and Anraku et al. and utilize PEG (polyethylene glycol) as a surface agent. One skilled in the art would have been motivated to utilize PEG with a reasonable expectation of success as De Cola et al. teaches that the silica capsules can be surface functionalized with PEG via the use of a trialkoxysilane. Since vinyltriethoxysilane is a trialkoxysilane there is a reasonable expectation of success. Therefore, all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Note: MPEP 2143 (I) (A) KSR International Co. v. Teleflex Inc., 550 US 398, 82 USPQ 2d 1385 (2007).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of De Cola et al., Reategui et al., Zeiadeh et al. and Anraku et al. and utilize a marker with a trialkoxysilane in order to mark the shell of the nanocapsule. It would have been obvious to utilize a commercial dye or contrast agent in order to form a nanocapsule which can be visualized as suggested by De Cola et al. Therefore, all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Note: MPEP 2143 (I) (A) KSR International Co. v. Teleflex Inc., 550 US 398, 82 USPQ 2d 1385 (2007).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of De Cola et al., Reategui et al., Zeiadeh et al. and Anraku et al. and utilize a mRNA with the silica nanocapsules of De Cola et al. De Cola et al. teaches that the nanocapsules can be utilized to encapsulate bioactive macromolecules such as RNA. De Cola et al. teaches that mRNA is a recombinant biomolecule. Therefore, it would have been obvious to one of ordinary skill in the art with a reasonable expectation of success to select any of the specifically taught bioactive macromolecules for encapsulation.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of De Cola et al., Reategui et al., Zeiadeh et al. and Anraku et al. and utilize glucose and RVG peptide as additional surface modifications on the shell of De Cola et al. in order to enhance permeation through the blood brain barrier as suggested by Zeiadeh et al. and Anraku et al. Since De Cola et al. suggests the use of surface modification for targeting specific tissues and organs and suggests the use of PEG, it would have been obvious to one of ordinary skill in the art with a reasonable expectation of success to attach glucose and/or RVG peptide via the PEG group in order to allow for specific targeting (i.e. to the brain). Since the glucose and RVG peptide target are different (i.e. GLUT1 vs acetylcholine receptor) one of ordinary skill in the art would have been motivated to utilize both in order to ensure permeation through the BBB. De Cola et al. suggests that more than one surface agent can be utilized.
Regarding the claimed diameter in claim 1 and 28, De Cola et al. teaches an overlapping range. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05.
Regarding the claimed structure, vinyltriethoxysilane (aka triethoxyvinylsilane of claim 7) is interpreted as reading on structure I (based on the election), this compound contains ethyl at Ra reading on claim 2 and vinyl group reading on claim 3 and 5-6.
Regarding claims 12-14,
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reads on structure V wherein Rd is ethyl or a bond to another polysilane chain, L1 and L2 are propylene.
Regarding claims 15 and 18, De Cola et al. teaches PEG via the use of a trialkoxysilane (i.e. PEG attached to a trialkoxysilane). This results in structure VI where Ra is ethyl and Re being the linker group.
Regarding claims 26-27, De Cola et al. teaches an overlapping range. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05. Furthermore, De Cola et al. suggests the negative charge comes from the silica but a more positive charge could come from the bioactive macromolecule.
Claims 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over De Cola et al. in view of Reategui et al., Zeiadeh et al. and Anraku et al. as applied to claims 1-3, 5-7, 12-15, 18 and 25-32 above and in further view of Wang et al. (Journal of Controlled Release, 2020, cited on PTO Form 1449).
Applicant Claims
The instant application claims the polysiloxane further comprise silyloxy subunits having structure IVC. As elected the weakly basic group is imidazolyl and the C1-6 linker is -C(O)NH-propyl-.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of De Cola et al. and Reategui et al. are set forth above. De Cola et al. teaches precursor compounds used to make the nanoencapsulated bioactive molecule include Si(XA)4 wherein at least two occurrence of XA is a hydrolysable group and nonhydrolyzable groups include optionally substituted C1-20 heteroalkyl (claim 37). Hydrolysable groups represent C1-C6 alkoxy (for example ethoxy) (claim 37 and paragraph 0043). The nanocapsule shell is disintegratable as a stimulus is applied. Stimulus include a change in pH (claim 34).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While De Cola et al. teaches silyloxy subunits comprising a heteroalkyl, De Cola et al. does not teach an imidazole with a -C(O)NH-propyl- linker to the Si. However, this deficiency is cured by Wang et al.
Wang et al. is directed to a pH responsive silica-metal organic framework hybrid nanoparticle for the delivery of hydrophilic drugs, nucleic acids and CRISPR-Cas9 genome-editing machineries. Zeolitic imidazolate framework (ZIF) is a subclass of metal-organic frameworks formed by the coordination between Zn2+ ions and 2-methylimidazole with good biocompatibility. ZIF-based nano systems have been used for drug, gene and protein delivery (page 194-195, bridging paragraph). Taught is the fabrication of a pH-responsive silica-metal-organic framework hybrid consisting of both silica and ZIF allowing for the delivery of a variety of hydrophilic payloads including nucleic acids. The proton sponge effect of the imidazole in the ZIF moiety contributes to the pH-controlled release and endosomal escape capabilities while the surface is customizable via functional groups (page 195, left column, first complete paragraph). Section 2.2 teaches the synthesis of N-(3-(triethoxysilyl)propyl)-1H-imidazole-4-carboxamide (TESPIC):
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. It was shown that when formed without TESPIC the nanoparticles exhibited significantly lower DNA transfection efficiencies, indicating that TESPIC was essential for bridging the silica component (page 199, right column). The ZIF component is pH-responsive and degrades in acidic environments, leading to a rapid release of the payload. The ZIF component can also facilitate the endosomal escape of the payload because the imidazole group can be protonated in the acidic endocytic compartments leading to endosomal membrane disruption by the proton sponge effect (page 200, left column).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of De Cola et al., Reategui et al., Zeiadeh et al., Anraku et al. and Wang et al. and incorporate N-(3-(triethoxysilyl)propyl)-1H-imidazole-4-carboxamide (TESPIC) into the silica network of De Cola et al. One skilled in the art would have been motivated to incorporate TESPIC in order to facilitate the endosomal escape of the payload as taught by Wang et al. There is a reasonable expectation of success as De Cola et al. teaches silica groups which can be incorporated can include heteroalkyl groups (i.e. imidazole) and suggests that the nanocapsules disintegrate in response to pH and Wang et al. teaches that the TESPIC group is pH-responsive.
Claims 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over De Cola et al. in view of Reategui et al., Zeiadeh et al. and Anraku et al. as applied to claims 1-3, 5-7, 12-15, 18 and 25-32 above and in further view of Chen et al. (ACS Appl. Mater. Interfaces, 2018, cited in Office Action mailed on 11/14/24).
Applicant Claims
The instant application claims the polysiloxane further comprise silyloxy subunits having structure IVC. As elected the weakly basic group is imidazolyl and the C1-6 linker is -C(O)NH-propyl-.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of De Cola et al. and Reategui et al. are set forth above. De Cola et al. teaches precursor compounds used to make the nanoencapsulated bioactive molecule include Si(XA)4 wherein at least two occurrence of XA is a hydrolysable group and nonhydrolyzable groups include optionally substituted C1-20 heteroalkyl (claim 37). Hydrolysable groups represent C1-C6 alkoxy (for example ethoxy) (claim 37 and paragraph 0043). The nanocapsule shell is disintegratable as a stimulus is applied. Simulus include a change in pH (claim 34). De Cola et al. teaches that the use of (3-aminoproyl)triethoxysilane (APTES) (paragraph 0158).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While De Cola et al. teaches silyloxy subunits comprising a heteroalkyl, De Cola et al. does not teach an imidazole with a -C(O)NH-propyl- linker to the Si. However, this deficiency is cured by Chen et al.
Chen et al. is directed to a universal GSH-responsive nanoplatform for the delivery of DNA, mRNA and Cas9/sgRNA ribonucleoprotein. Cationic polymers can interact with negatively charged genetic materials via electrostatic interactions to form polyplexes. To improve their transfection efficiency, several factors need to be taken into consideration: (1) efficient cellular uptake; (2) rapid endosomal escape to prevent degradation; (3) efficient payload decomplexation from polyplexes in the cytosol; and (4) nucleus transport for certain payloads, such as DNA and RNP. To fulfill these strict criteria, one of the most promising and possibly indispensable strategies is to use certain biological triggers, including pH changes and the presence of certain molecules or enzymes inside cells. The most widespread theory used to achieve sufficient endosomal escape is the proton sponge effect. Imidazole groups, (pKa ∼ 6.0) possessing a large proton buffering capacity in the acidic endocytic compartments, have been frequently incorporated into polymeric vectors to enable endosomal escape, thus enhancing delivery efficiency. As shown in scheme 1, a free amine is coupled with 4-imidazolecarboxylic acid (see also section 2.4).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of De Cola et al., Reategui et al., Zeiadeh et al., Anraku et al. and Chen et al. and couple 4-imidazlecarboxyilic acid to the (3-aminoproyl)triethoxysilane (APTES) of De Cola et al. in order to form a silica precursor which can be incorporated to add the imidazole functionality to the silica network. One skilled in the art would have been motivated to add imidazole functionality in order to enhance delivery efficiency as taught by Chen et al.
Claims 16-17 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over De Cola et al. in view of Reategui et al., Zeiadeh et al. and Anraku et al. as applied to claims 1-3, 5-7, 12-15, 18 and 25-32 above and in further view of Prasse et al. (USPGUB No. 20150011705, cited in Office Action mailed on 11/14/24).
Applicant Claims
The instant application claims the surface-modifying groups comprise PEG attached to a siloxy subunit having structure VII wherein Rf has the structure E1.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of De Cola et al. and Reategui et al. are set forth above. De Cola et al. teaches the use of PEG as a surface modifying group. De Cola et al. teaches that the surface agent can provide advantages such as enabling the silica shell to specifically target specific organs/tissues (paragraph 0160-0164).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While De Cola et al. suggests the use of a PEG surface modifying group linked to a trialkoxysilane, De Cola et al. does not expressly teach instantly claimed structure E1. However, this deficiency is cured by Prasse et al.
Prasse et al. is directed to cross-linkable compositions based on organosilicon compounds. Taught are the use of organosilicons which contain a polyoxyethylene glycol (PEG) terminated on one end and an alkoxysilyl group on the other end. A specific compound taught is:
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wherein A is a divalent optionally substituted hydrocarbon radical which optionally can contain an amide bond (claim 9). A specific radical A is:
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out of a possible 20 choices (claim 10 and paragraph 0092). The compounds can be used with other compounds such as crosslinkers such as vinyltriethoxysilane, tetraethoxysilane, etc. (paragraph 0057). Examples of additives which can be used include pigments, dyes, fungicides, cell generating agent (paragraph 0069). The compounds have a very strong hydrophilizing effect (paragraph 0082).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of De Cola et al., Reategui et al., Prasse et al., Zeiadeh et al. and Anraku et al. and utilize
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as a linker between the trialkoxysilane and PEG. One skilled in the art would have been motivated to utilize this linker as Prasse et al. teaches it is a way to add hydrophilicity. Since they are formed by methods customary in chemistry (see paragraph 0022 of Prasse et al.), there is a reasonable expectation of success. Since De Cola et al. specifically teaches surface functionalization of the silica with PEG, it would have been obvious to one of ordinary skill in the art to look to Prasse et al. for ways to functionalize the silica network with PEG.
Response to Arguments
Applicants’ arguments filed September 26 2025 have been fully considered but they are not persuasive.
Applicants argue (page 10) that (1) claim 1 has been amended to recite that the surface-modifying groups further comprise a dual targeting ligand comprising glucose and Rabies Virus Glycoprotein (RVG) peptide.
Regarding Applicants’ first argument, the recitation “dual targeting ligand” does not evoke any additional structural limitations on the glucose and RVG peptide. If the prior art teaches surface modification with glucose and a RVG peptide, then it necessarily suggests a dual targeting ligand.
Applicants argue (pages 11-12) that (2) Anraku’s disclosure is an invention to experiment that does not fall under routine optimization law. It is argued that Anraku is speculative and the reference itself teaches Anraku’s nanocarrier system to only have potential in non-disease states, highlights unpredictability in diseased states and provides not guidance as to how and what portions the structure would reasonably be expected to successfully be optimized. Applicants argue that under current case law, a particular parameter must first be recognized as a result-effective variable before the determination of the optimum or workable range might be characterized as routine experimentation. Anraku’s disclosure is bereft of evidence hosing that such alteration of the variable is reasonably expected to provide a particular result.
Regarding Applicants second argument, first, MPEP 2144.05 II. B. makes it clear that after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. Secondly, the rejection itself never argues that the motivation to combine is routine optimization. Specifically the rejection states that it would be obvious to utilize both glucose and RVG peptide to target different receptors to allow for specific targeting to the brain. The optimization argument came up in the arguments discussion of the teachings of Anraku. Specifically, Applicants argued that there would not be a reasonable expectation of success because GLUT1 might have altered expression level in diseased conditions. The examiner couldn’t agree. Firstly, a reasonable expectation of success does not require absolute predictability. NOTE: MPEP 2143.02. Anraku suggests that the glucose structure can be optimized to reflect the changes of the receptor in each disease state so that the BBB can still be crossed. This reference itself suggests the motivation for a person of ordinary skill in the art to experiment to reach another workable product which allows for targeting of the GLUT1. Furthermore, this is not the only reference within the art to suggest that glucose can be used to help transport nanoparticles across the human brain. Gromnicova et al. (PLoS One, 2013) which teaches that the transfer rate of glucose-coated gold nanoparticles across primary human brain endothelium was at least 3 times faster than across non-brain endothelia (abstract). Tamba et al. (Arabian Journal of Chemistry, 2018) teaches that glucose modified silica nanoparticles (SNPs) were designed and tested for their ability to penetrate the blood-brain barrier in mice brain (abstract). The glucose modified silica nanoparticles passed the BBB (conclusions). Therefore, the preponderance of evidence supports that one skilled in the art would expect that providing for surface modifications, which are clearly taught by De Cola, of glucose would be expected to target the brain with a reasonable expectation of success.
Applicants argue (page 12) that (3) the prevent inventors have shown that with surface PEGylation and glucose/RVG conjugation, SNPS can bypass the BBB and induce payload delivery in different brain cells with up to 20% editing efficiency, instant example 11. Figs. 11A and 11B of the application clearly evidence that RNP-SNP1 with dual targeting ligand exhibited the highest tdTomato expression in the brain whereas RNP-SNP1 with only glucose modification showed moderate tDTomato signal while RNP-SNP1 without targeting ligand and with glycemic control showed tdTomato expression in the liver but barely in the brain.
Regarding Applicants’ third argument, firstly, the fundamental requirement is that “any superior property must be unexpected to be considered as evidence of non-obviousness.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir. 2007). While the data in Figure 11A and B shows that the combination of RNA-SNP1-Glu + RVG produced highest expression, this is not evidence of an unexpected effect. Firstly, the results with just RVG are not shown. Since both Glu and RVG would be expected to increase transport into the BBB, as set forth in the prior art cited above, it would be expected that combining the two would produce an expression level higher than just glu alone. Furthermore, Kang et al. (Advanced Materials, 2016, cited herein) shows silicon nanoparticles for targeted siRNA delivery to the injured brain. Shown is attachment of targeting and cell penetrating peptides. Two peptides, one of which is a rabies virus-derived peptide (RVG) was conjugated to the silica nanoparticles The dual targeting showed better cellular affinity and gene knockdown (page 7965 right and left columns). As shown in Figure 3, dual targeting is better than just RVG but RVG has an effect. Figure 4 also shows greater fluorescence with the dual targeting. This is further evidence that the expectation in the art that use of both glucose and RVG, which both are taught as targeting the brain, would be expected to perform better than either one individually.
Secondly, as set forth in the MPEP, a difference in kind is required to show an unexpected result. Specifically, that the combination produced a new and unexpected result which is different in kind and not merely in degree from results of the prior art. See In re Huang, 100 F.3d 135, 139 (Fed. Cir. 1996); In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005). See MPEP 716.01(b); 716.02. Therefore, while the results show that the claimed combination has the highest expression level, this does not rise to level that the combination produced an unexpected effect.
Applicants argue (page 13) that (4) Wang and Chen fails to cure the deficiencies.
Regarding Applicants’ fourth argument, these arguments are not persuasive for the reasons set forth above.
Applicants argue (page 14) that (5) Prasse fails to suggest or guide a POSITA to modify the responsively disintegrable silica particles of De Cola with thixotropic gel materials. It is argued that the cited prior art fails to provide the requisite reasonable expectation in arriving at Applicants’ presently claimed nanoparticles.
Regarding Applicants’ fifth argument, the argument does not indicate specifically why the combination of references fail to provide the requisite reasonable expectation of success. Prasse et al. specifically teaches linkers which are known to link between PEG and trialkoxysilane. De Cola et al. also teaches linking PEG to a trialkoxysilane. Therefore, it is unclear to the examiner why there wouldn’t be a reasonable expectation of success in using the linkers taught in Prasse et al. to link a PEG to a trialkoxysilane when De Cola et al. expressly teaches linking PEG to a trialkoxysilane.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5-10, 12-19 and 25-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of copending Application No. 17926113 (USPGPUB No. 20230183723) in view of De Cola et al., of Prasse et al., Zeiadeh et al. and Anraku et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant application claims a nanoparticle comprising a silica network comprising crosslinked polysiloxanes wherein the polysiloxanes comprise siloxy subunits having the structure I or II; the crosslinks between polysiloxanes comprise disulfide linkages; the nanoparticle comprises an exterior surface comprising surface modifying groups attached to and surrounding the silica network (PEG as elected) and the nanoparticle has an average diameter of 15 to 200 nm wherein the surface modifying groups further comprises a dual targeting ligand comprising glucose and Rabies Virus Glycoprotein (RVG) peptide.
Copending ‘113 claims a nanoparticle comprising: a silica network comprising crosslinked polysiloxanes, wherein the crosslinks comprise disulfide linkages, and the nanoparticle has a surface bearing charged functional groups and a surface potential of either less than -30 mV or greater than +30 mV, and wherein the nanoparticle has an average diameter of 20 nm to 60 nm (claim 1). The plurality of siloxy subunits are derived from triethoxyvinyl silane (corresponding to instant structure I) (claim 3). The polysiloxanes further comprise a plurality of siloxy subunits bearing imidazolyl groups (claim 5) with a specific compound being TESPIC (claim 6) which reads on instant claims 8-10. The polysiloxanes comprise a plurality of crosslinking submits (claim 7) which are the same as instant claims 12-14. A water-soluble biomolecule with which mRNA is claimed (claim 21).
Copending ‘113 does not claim a PEG surface modification or an imaging agent. However, this deficiency is cured by De Cola et al.
De Cola et al. is directed to disintegrable core/shell silica particles for encapsulating and releasing bioactive macromolecules. Claimed is a nanoencapsulated bioactive macromolecule (i.e. nanoparticle) having a core/shell structure wherein the shell is made of a hybrid organosilica material comprising a three-dimensional framework of Si-O bonds wherein at least a subset of Si atoms in the framework is connected to at least another Si atom in the framework through a linker having the following structure: *-R1-L-R2-* wherein * denotes a point of attachment to a Si atom, L represents a cleavable covalent bond and a bioactive macromolecule (claim 28). Bioactive macromolecules include RNA (claim 31). Recombinant biomolecules include mRNA (paragraph 0072). The diameter is between 25 nanometers and 500 nanometers (claim 32). Preferable particle sizes are between 25 and 200 nm and most preferably between 40 and 80 nm (paragraph 0113). Table 2 shows exemplary synthetic conditions the first example is the use of TEOS (tetraethylorthosilicate) and
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(page 13). Advantageously, the surface of the core/shell silica nanocapsules are functionalized with a surface agent. The surface agent can be a PEG groups linked to a trialkoxysilane (paragraph 0159 and claim 35). Marking of the core/shell can be achieved by condensation of a marker-containing trialkoxysilane. The marker may be a contrast agent, a tracer, a radioactive marker, any commercial dye (paragraph 0159). The nanoparticles may have an electric charge, the magnitude of which advantageously have negative values which denotes that the outer surface of the particle is made of silica and the encapsulated bioactive macromolecules do not protrude on the surface of the nanocapsule. The nanoparticles have a negative charge ranging from -9 mV and -30 mV (paragraph 0115).
Copending ‘113 does not claim a targeting ligand or the linker of E1. However, these deficiencies are cured by Prasse et al., Zeiadeh et al. and Anraku et al.
Prasse et al. is directed to cross-linkable compositions based on organosilicon compounds. Taught are the use of organosilicons which contain a polyoxyethylene glycol (PEG) terminated on one end and an alkoxysilyl group on the other end. A specific compound taught is:
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wherein A is a divalent optionally substituted hydrocarbon radical which optionally can contain an amide bond (claim 9). A specific radical A is:
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out of a possible 20 choices (claim 10 and paragraph 0092). The compounds can be used with other compounds such as crosslinkers such as vinyltriethoxysilane, tetraethoxysilane, etc. (paragraph 0057). Examples of additives which can be used include pigments, dyes, fungicides, cell generating agent (paragraph 0069). The compounds have a very strong hydrophilizing effect (paragraph 0082).
Zeiadeh et al. is directed to strategies for enhancing the permeation of CNS-active drugs through the blood-brain barrier. The blood brain barrier (BBB) is a structural and functional barrier which protects and maintains a highly controlled environment for central nervous system (CNS) neurons. The BBB lines brain and spinal cord capillaries with endothelial cells, astrocytes, pericytes, microglia, and muscle cells. The cells are connected by tight junctions and express a variety of receptors, transporters, and pores which allow for penetration of specific substances from the blood into the CNS (page 1 introduction). Substances have been found to cross the BBB through many pathways. The most common include carrier mediated transport such as glucose transporter, choline transporter, among others (pages 1-2, BBB transport routes). One strategy to get substances across the BBB is the use of nanoparticles. Since nanoparticles possess surface functionalization, for example, they are being investigated. It is taught that Kim et al. used chitosan NPS targeted for BBB penetration through RVG conjugation. Pluronic-based nanocarriers in combination with RVG peptide and chitosan proved efficient in increasing BBB penetration (pate 6, section 2.3). Rabies virus glycoprotein (RVG) is likely to cross the BBB though nicotinic acetylcholine receptors but does not bind to nucleic acids and is incapable of delivery siRNA. But RVG-9R provides a safe means for delivery of siRNA across the BBB (page 6, section 2.2). Glucose is taught as being used to facilitate BBB through GLUT1 transporters. Glycosylated derivatives of drugs have the ability to increase CNS uptake by GLUT1. Glycosylated derivatives of dopamine enhance dopamine BBB penetration (page 8, section 2.4).
Anraku et al. teaches that glycemic control boosts glycosylated nanocarrier crossing the BBB into the brain. Among the various candidate ligands previously studied for promoting BBB traversal, glucose, the main energy source in the brain, is notable because glucose transporter-1 (GLUT1) is expressed at a remarkably high level compared to many other receptors and transporters (page 2, right column). GLUT1 recognizes glucose molecules principally through weak interactions such as hydrogen bonding and the hydrophobic effect. Binding of a single glucose to GLUT1 may not be strong enough to retain nanocarriers in the harsh flow of the bloodstream. Suggested is introducing many glucose molecules onto the surface of the nanocarrier. Taught is the use of a polymeric nanocarrier with a size of about 30 nm and PEG (pages 2-3 and figure 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘113, De Cola et al., Prasse et al., Zeiadeh et al. and Anraku et al. and utilize PEG (polyethylene glycol) as a surface agent. One skilled in the art would have been motivated to utilize PEG with a reasonable expectation of success as De Cola et al. teaches that the silica capsules can be surface functionalized with PEG via the use of a trialkoxysilane. Since vinyltriethoxysilane is a trialkoxysilane there is a reasonable expectation of success. Therefore, all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Note: MPEP 2143 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘113, De Cola et al., Prasse et al., Zeiadeh et al. and Anraku et al. and utilize a marker with a trialkoxysilane in order to mark the shell of the nanocapsule. It would have been obvious to utilize a commercial dye or contrast agent in order to form a nanocapsule which can be visualized as suggested by De Cola et al. Therefore, all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention Note: MPEP 2143 (I) (A) KSR International Co. v. Teleflex Inc., 550 US 398, 82 USPQ 2d 1385 (2007).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘113, De Cola et al., Prasse et al., Zeiadeh et al. and Anraku et al. and utilize
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as a linker between the triallkoxysilane and PEG. One skilled in the art would have been motivated to utilize this linker as Prasse et al. teaches it is a way to add hydrophilicity. Since they are formed by methods customary in chemistry (see paragraph 0022 of Prasse et al.), there is a reasonable expectation of success. Since the use of PEG as a surface modifier is obvious for the reasons set forth above, it would have been obvious to one of ordinary skill in the art to look to Prasse et al. for ways to functionalize the silica network with PEG.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘113, De Cola et al., Prasse et al., Zeiadeh et al. and Anraku et al. and utilize glucose and/or RVG peptide as the R group in the silica compound of Prasse et al. One skilled in the art would have been motivated to add this additional surface modifications on the surface of the nanoparticle of copending ‘113 in order to enhance permeation through the blood brain barrier as suggested by Zeiadeh et al. and Anraku et al. Since De Cola et al. suggests the use of surface modification for targeting specific tissues and organs and suggests the use of PEG, it would have been obvious to one of ordinary skill in the art with a reasonable expectation of success to attach glucose and/or RVG peptide via the PEG group in order to allow for specific targeting (i.e. to the brain). Since the glucose and RVG peptide target are different (i.e. GLUT1 vs acetylcholine receptor) one of ordinary skill in the art would have been motivated to ut