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 .
The rejection under section 112(b) is maintained, below:
Claim Rejections - 35 USC § 112
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 1-20 remain 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 criteria for “cell membrane material” and “core particle” are undefined.
Notwithstanding Applicant’s remarks, the specification and claims do not specifically identify the structural or functional criteria of the cell membrane material or the core particle in a manner those of ordinary skill would not know what Applicant intends to cover by these terms. The specification may provide general examples f these materials u does not provide definitions. The examiner notes that it is also impermissible to import limitations and examples from the specification into the claims. Therefore, the rejection is maintained.
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.
Claims 1, 2, 4, 6-20 remain rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0243229 A1 to the Trustees of Princeton University (hereinafter 'Princeton Univ') or Fang et al., Adv. Mater. 2018, 30, 1706759, downloaded 13 May 2025 from https://doi.org/10.1002/adma.201706759 (hereinafter ‘Fang’) in view of US 2013/0337066 A1 to the Regents of the University of California (hereinafter 'Univ California').
Regarding claim 1, Princeton Univ teaches a method of using flash nanocomplexation to prepare a polymeric material-cloaked particle (Abstract - 'The invention described herein relates to sterically stabilized colloidal constructs comprising preformed colloidal particles encapsulated within a polymeric shell. The constructs, which are controllably sized, are nanoparticles comprising hydrophobic elements, electrostatically charged particles with hydrophobic surfaces, hydrophobic inorganic nanostructures, and amphiphilic copolymers with hydrophobic domains and hydrophilic domains. The constructs are made by a process that allows for the simultaneous encapsulation of a preformed colloidal agent as well as a dissolved hydrophobic active within the core of the polymeric nanoparticle.'; para [0028) - 'FIG. 1 is a schematic of a process for preparing multicomponent ('composite') nanoparticles by flash nanoprecipitation in a multi-inlet vortex mixer, and a product thereof.'), comprising:
loading a polymeric material and a core particle in a confined mixing cavity; and turbulent mixing of the polymeric material and the core particle in the mixing cavity to homogenously coat the core particle with the polymeric material and provide the polymeric material-cloaked particles, the turbulent mixing achieving a turbulent intershearing flow in the confined cavity and having a Reynold number larger than 1600 (para [0028) - 'FIG. 1 is a schematic of a process for preparing multicomponent ('composite') nanoparticles by flash nanoprecipitation in a multi-inlet vortex mixer, and a product thereof.'; para [0079) - 'Flash nano-precipitation, schematically summarized in FIG. 1, is a micromixing process comprising the steps of dissolving a hydrophobic organic compound in a compatible solvent, providing a polymer also dissolved in the solvent or in an aqueous solvent that is an anti-solvent to the organic compound, and rapidly micromixing the organic solution with the anti-solvent.'; para [0081) - 'The process of preparing multicomponent composite nano-particles using a multi-inlet or multi-stream vortex mixer is illustrated in FIG. 1 a confined impinging jet mixer as described in U.S. Patent Application Publication 2004/0091546 (incorporated herein in its entirety by reference for all purposes) can be employed.'; para [0086) - 'Intense mixing (i.e., the mixing system operates at a Reynolds number >1600) of the organic solvent stream with water or a predominantly aqueous stream in the multi-inlet vortex mixer'; para [0105) - 'The process depends on tuning three time scales: 1) time to attain homogeneous mixing').
Princeton Univ does not expressly teach a cell membrane-cloaked particle or loading a cell membrane material on a core nanoparticle. Univ California teaches preparing a cell-membrane cloaked nanoparticle (Abstract - 'Provided are nanoparticles and methods of using and making thereof. The inventive nanoparticle comprises a) an inner core comprising a non-cellular material; and b) an outer surface comprising a cellular membrane derived from a cell or a membrane derived from a virus.'; Claim 3 - 'The nanoparticle of claim 1, wherein the cellular membrane is derived from a blood cell, a tumor cell, a cancer cell, an immune cell, a stem cell, an endothelial cell, an exosome, a secretory vesicle or a synaptic vesicle.'). Since Univ California teaches cell-membrane cloaked nanoparticles have an extended half-life in blood circulation (Claim 7 - 'The nanoparticle of claim 1, wherein the nanoparticle has a half-life in blood circulation in vivo for at least about 2-5 times of the half-life of a PEG-coated, comparable nanoparticle'), it would have been obvious to one of ordinary skill in the art that the cell membrane material of Univ California could be used for the flash nanocomplexation method of Princeton Univ to prepare a cell membrane-cloaked particle with improved properties for therapeutic applications.
See also Fang:
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Regarding claim 2, Princeton Univ further teaches the core particle comprises a nanoparticle (para [0020) - 'Preferably, the organic compound and the inorganic nanoparticle are encapsulated in a hydrophobic core region of the composite nanoparticle').
Regarding claim 4, Univ California further teaches the core particle comprises a material selected from the group consisting of silica (para (0250) - 'The membrane coating approach in this study can also be extended to other nanostructures as the versatility of lipid coating has made its way to silica nanoparticles'; para (0107) - 'In other embodiments, the releasable cargo is a dendrimer particle or an inorganic particle comprising a silica particle, a porous silica particle').
Regarding claim 6, Princeton Univ further teaches the core particle is modified to have a desired surface charge (para (0015) - 'The organic compound may be electrostatically charged prior to step d, as may the inorganic nanoparticle.'). It would have been obvious to one of ordinary skill in the art that the modification could be made to add a positive or negative charge as desired, based on the intended cargo or shell.
Regarding claim 7, Princeton Univ further teaches the core particle is modified to have a desired surface charge (para (0015) - 'The organic compound may be electrostatically charged prior to step d, as may the inorganic nanoparticle.'). It would have been obvious to one of ordinary skill in the art that the core particle could be modified with an amine group to have a positive surface charge since amine groups were well known in the art to add a positive charge.
Regarding claim 8, Univ California further teaches the cell membrane material comprises cell membrane fragments of cells selected from the group consisting of cancer cells, non-immune cells, and immune cells (Claim 3 - 'The nanoparticle of claim 1, wherein the cellular membrane is derived from a blood cell, a tumor cell, a cancer cell, an immune cell').
Regarding claim 9, Univ California further teaches the cell membrane material comprises cell membrane fragments from a cell line selected from the group consisting of CaCo-2, HepG2, MCF-7, RAW 264.7, HEK, Hela, HITC, 816-F10, RBC, MSC (para (0112) - 'the pharmaceutical composition of the present invention is a neoplasm-specific immunogenic composition comprising nanoparticles coated with a cellular membrane derived from cancer cells, such as benign neoplasm cell, a potentially malignant neoplasm cell, a tumor or cancer cell of a subject or ce!l line'; para (0244) - 'The inventors then determined the serum stability and the in vivo circulation half-life of the RSC membrane-coated nanoparticles'; para (0260) - 'DiD labeled RBC membrane-coated PlGA nanoparticles').
Regarding claim 10, Princeton Univ in view of Univ California makes obvious the method of claim 1, wherein Univ California further teaches the core particle has a size ranging from about 50 nm to about 2um (para (0012) - 'The present invention further provides that in certain embodiments the inventive nanoparticle has a diameter from about 10 nm to about 10 um. In certain embodiments, the inner core supports the outer surface.').
Regarding claim 11, Univ California further teaches the core particle has a surface charge ranging from about -50 mV to about +50 mV (para (0242) - 'Over a span of two weeks the particle size increased from 85 to 130 nm, the zeta potential decreased from -10.2 to -12.7 mV').
Regarding claim 12, Princeton Univ further teaches the confined mixing cavity comprises a multi-inlet vortex mixer (para [0028) - 'FIG. 1 is a schematic of a process for preparing multicomponent ('composite') nanoparticles by flash nanoprecipitation in a multi-inlet vortex mixer, and a product thereof.').
Regarding claim 13, Princeton Univ further teaches a flow rate in each inlet of the multi-inlet vortex mixer ranges from about 5 mL/min to about 40 mL/min (para (0111) - 'The organic solution was fed (12 ml/min, stream 1), along with water (40 ml/min, streams 2-4), into a four-stream multi-inlet vortex mixer (FIG. 1)').
Regarding claim 14, Univ California teaches determining the mixture ratio (para (0262) - 'To fuse the RBC membrane-derived vesicles with the PLGA nanoparticles, 1 mg of PLGA nanoparticles was mixed with RBC membrane-derived vesicles prepared from 1 ml of whole blood and then extruded 7 times through a 100 nm polycarbonate porous membrane using an Avanti mini extruder. The mixture ratio was estimated based on the membrane volume of RBC’s and the total membrane volume required to fully coat 1 mg of PLGA nanoparticles. Parameters used for the estimation include mean surface area of mouse RBC’s (75 um2) (34), membrane thickness of RBC (7 nm), density of 50:50 PLGA nanoparticles (1.34 g/cm3) (35), red blood cell concentration in mouse blood (7 billion per ml) (36), and the mean particle size as measured by DLS before and after the RSC membrane coating (FIG. 8).'), it would have been obvious to one of ordinary skill in the art that a mass ratio of the cell membrane coating material to core particle could be determined and adjusted according to Univ California, to achieve a desired range such as from about 0.1 to about 100 based on routine experimentation to achieve optimized results.
Regarding claim 15, Univ California further teaches the cell membrane material comprises a tumor-associated antigen and the core particle is loaded with an adjuvant (para (0051) - 'FIG. 16. Schematic illustrating the working mechanism of the proposed personalized cancer treatment vaccine: (i) cancer cells are collected from individual patient's tumor and the natural cancer cell membranes are used to wrap adjuvant-loaded nanoparticles'; para (0383) - 'Current strategies concentrate only on individual tumor associated antigens (TAAs) that are expressed by the general cancer type in question.').
Regarding claim 16, Univ California further teaches the core particle comprises a mesoporous silica nanoparticle loaded with the adjuvant (para (0051) - 'FIG. 16. Schematic illustrating the working mechanism of the proposed personalized cancer treatment vaccine: (i) cancer cells are collected from individual patient's tumor and the natural cancer cell membranes are used to wrap adjuvant-loaded nanoparticles'; para (0250) - 'The membrane coating approach in this study can also be extended to other nanostructures as the versatility of lipid coating has made its way to silica nanoparticles'; para (0107) - 'In other embodiments, the releasable cargo is a dendrimer particle or an inorganic particle comprising a silica particle, a porous silica particle').
Regarding claim 17, Univ California further teaches a biomimetic vaccine comprising the cell membrane cloaked particle prepared according to the method of claim 16 (para [0251) - 'Alternatively, this biomimetic delivery platform could be an elegant method for personalized medicine whereby the drug delivery nanocarrier is tailored to individual patients with little risk of immunogenicity by using their own RBC membranes as the particle coatings.'; para (0051) - 'FIG. 16. Schematic illustrating the working mechanism of the proposed personalized cancer treatment vaccine').
Regarding claim 18, Princeton Univ teaches a method of using flash nanocomplexation to prepare a polymeric material-cloaked particle (Abstract - 'The invention described herein relates to sterically stabilized colloidal constructs comprising preformed colloidal particles encapsulated within a polymeric shell. The constructs, which are controllably sized, are nanoparticles comprising hydrophobic elements, electrostatically charged particles with hydrophobic surfaces, hydrophobic inorganic nanostructures, and amphiphilic copolymers with hydrophobic domains and hydrophilic domains. The constructs are made by a process that allows for the simultaneous encapsulation of a preformed colloidal agent as well as a dissolved hydrophobic active within the core of the polymeric nanoparticle.'; para (0028) - 'FIG. 1 is a schematic of a process for preparing multicomponent ('composite') nanoparticles by flash nanoprecipitation in a multi-inlet vortex mixer, and a product thereof.'), comprising:
loading a polymeric material and a core particle into a multi-inlet vortex mixer; and turbulent mixing of the cell membrane material and the core particle in the multi-inlet vortex mixer to provide the polymeric material-cloaked particle (para (0028) - 'FIG. 1 is a schematic of a process for preparing multicomponent ('composite') nanoparticles by flash nanoprecipitation in a multi-inlet vortex mixer, and a product thereof.'; para (0079) - 'Flash nano-precipitation, schematically summarized in FIG. 1, is a micromixing process comprising the steps of dissolving a hydrophobic organic compound in a compatible solvent, providing a polymer also dissolved in the solvent or in an aqueous solvent that is an anti-solvent to the organic compound, and rapidly micromixing the organic solution with the anti-solvent.'; para (0081) - 'The process of preparing multicomponent composite nano-particles using a multi-inlet or multi-stream vortex mixer is illustrated in FIG. 1.
... a confined impinging jet mixer as described in U.S. Patent Application Publication 2004/0091546 (incorporated herein in its entirety by reference for all purposes) can be employed.'; para (0086) - 'Intense mixing (i.e., the mixing system operates at a Reynolds number >1600) of the organic solvent stream with water or a predominantly aqueous stream in the multi-inlet vortex mixer'; para (0105) - 'The process depends on tuning three time scales: 1) time to attain homogeneous mixing'), wherein the turbulent mixing achieves a flow rate in each inlet of the multi-inlet vortex mixer ranging from about 5 ml/min to about 40 mL/min (para (0111) - 'The organic solution was fed (12 ml/min, stream 1), along with water (40 ml/min, streams 2-4), into a four-stream multi-inlet vortex mixer (FIG. 1)'). Princeton Univ does not expressly teach a cell membrane-cloaked particle.
Univ California teaches preparing a cell-membrane cloaked nanoparticle (Abstract - 'Provided are nanoparticles and methods of using and making thereof. The inventive nanoparticle comprises a) an inner core comprising a non-cellular material; and b) an outer surface comprising a cellular membrane derived from a cell or a membrane derived from a virus.'; Claim 3 - 'The nanoparticle of claim 1, wherein the cellular membrane is derived from a blood cell, a tumor cell, a cancer cell, an immune cell, a stem cell, an endothelial cell, an exosome, a secretory vesicle or a synaptic vesicle.'). Since Univ California teaches cell-membrane cloaked nanoparticles have an extended half-life in blood circulation (Claim 7 - 'The nanoparticle of claim 1, wherein the nanoparticle has a half-life in blood circulation in vivo for at least about 2-5 times of the half-life of a PEG-coated, comparable nanoparticle'), it would have been obvious to one of ordinary skill in the art that the cell membrane material of Univ California could be used for the flash nanocomplexation method of Princeton Univ to prepare a cell membrane-cloaked particle with improved properties for therapeutic applications.
Regarding claim 19, Univ California teaches determining the mixture ratio (para (0262) - 'To fuse the RBC membrane-derived vesicles with the PLGA nanoparticles, 1 mg of PLGA nanoparticles was mixed with RBC membrane-derived vesicles prepared from 1 ml of whole blood and then extruded 7 limes through a 100 nm polycarbonate porous membrane using an Avanti mini extruder. The mixture ratio was estimated based on the membrane volume of RBCs and the total membrane volume required to fully coat 1 mg of PLGA nanoparticles. Parameters used for the estimation include mean surface area of mouse RBCs (75 um2) (34), membrane thickness of RBC (7 nm), density of 50:50 PLGA nanoparticles (1.34 g/cm3) (35), red blood cell concentration in mouse blood (7 billion per ml) (36), and the mean particle size as measured by DLS before and after the RBC membrane coaling (FIG. 8).'), it would have been obvious to one of ordinary skill in the art that a mass ratio of the cell membrane coating material to core particle could be determined and adjusted according to Univ California, to achieve a desired range such as from about 0.1 to about 100 based on routine experimentation to achieve optimized results.
Regarding claim 20, Univ California further teaches the core particle has a surface charge ranging from about -50 mV to about +50 mV (para (0242) - 'Over a span of two weeks the particle size increased from 85 to 130 nm, the zeta potential decreased from -10.2 to -12.7 mV').
Claim 3 remains rejected under 35 U.S.C. 103 as being unpatentable over Princeton Univ or Fang in view of Univ California in further view of US 2006/0257485 A1 to Kumacheva (hereinafter 'Kumacheva').
Regarding claim 3, Princeton Univ and Univ California do not expressly teach wherein the core particle comprises a microparticle.
However, Kumacheva teaches wherein the core particle comprises a microparticle (Claim 1 - 'A process of synthesizing a composite colloidal polymer-inorganic material, comprising the steps of:
a) synthesizing a dispersion of polymer microparticles in a liquid; b) treating said dispersion of polymer microparticles to modify an outer surface of the polymer microparticles to provide an effective concentration of ligands on the outer surface of the polymer microparticles, the ligands being selected to form a complex with atoms of a metal, ions of the metal, or molecular moieties containing the metal at the surface of the polymer microparticle').
It would have been obvious to one of ordinary skill in the art that the method of Kumacheva could be combined with that of Princeton Univ in view of Univ California to provide nanoparticles wherein the core particle comprises a microparticle, for better control of particle size according to Kumacheva (Abstract - 'We demonstrated that by changing the composition of the polymer beads good control could be achieved over the size of the nanoparticles.').
Claim 5 remains rejected under 35 U.S.C. 103 as being unpatentable over Princeton Univ or Fang in view of Univ California in further view of He et al., Nanoscale, 2018,10, 3307-3319 (hereinafter 'He').
Regarding claim 5, Princeton Univ in view of Univ California does not expressly teach wherein the core particle has a positive surface charge.
He teaches nanocomplexalion wherein the core particle has a positive surface charge (p3309, col 1, para 2 - 'L-Penetralin is a polycationic peptide that possesses strong affinity and readily complex with negatively charged insulin to form CPP/insulin NPs which was termed as NP-A. The positively charged NP-A and negatively charged HA were further assembled to form NPs with NP-A core surrounded by HA coating which was termed as NP-B, as shown in Scheme 1.').
Since He teaches flash nanocomplexation to form therapeutic nanoparticles (Abstract - 'Here we devised a sequential flash nanocomplexation (FNC) technique for the scalable production of a core-shell structured nanoparticle system'), ii would have been obvious to one of ordinary skill in the art that the flash nanocomplexation method of He could be combined with that of Princeton Univ in view of Univ California to provide a core particle that has a positive surface charge and can be cloaked by a negatively charged shell to enhance mucosa! transport for oral delivery of insulin or other therapeutics according to He.
Applicant argues that California expresses the comparable benefits of the cell membrane-cloaked particle with a PEG-coated particle - not the method of preparing the cell membrane-cloaked particle…that benefit described in California has nothing to do with the instant subject matter, focused on the method of preparing cell membrane-cloaked nanoparticles.
However, those of ordinary skill could have applied the nano-complexation of the primary references in the manner required and in a predictable fashion for the purposes of obtaining the recited cell membrane-cloaked particles. As outlined above, the primary references teach the required method of using flash nano-complexation to prepare a polymeric material-cloaked particle. California is added for the proposition that cell membrane-cloaked particles are applicable to this process of cloaking particles. Specifically, the primary references teach that the particular known technique of using nano-complexation to prepare cloaked-particles was recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying the known technique to other particles, such as the cell membrane-cloaked particles taught by California, would have yielded predictable results. Accordingly, using a nano-complexation for the purposes of preparing nano-cloaked particles, such as cell membrane-cloaked particles, would have been prima facie obvious.
Applicant has not proffered any objective evidence demonstrating why those of ordinary skill would not expect that cell membrane-cloaked particles could be prepared by nano-complexation.
Any alleged showing of unexpected results is not commensurate across the entire scope of recited cell membrane materials and core particles. Therefore, the rejection is maintained.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARL J PUTTLITZ whose telephone number is (571)272-0645. The examiner can normally be reached on Monday to Friday from 9 a.m. to 5 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's acting supervisor, Janet Epps-Smith, can be reached at telephone number (571)272-0757. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KARL J PUTTLITZ/ Primary Examiner, Art Unit 1646