DETAILED ACTION
Continued Examination Under 37 C.F.R. § 1.114
A request for continued examination under 37 C.F.R. § 1.114, including the fee set forth in 37 C.F.R. § 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 C.F.R. § 1.114, and the fee set forth in 37 C.F.R. § 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 C.F.R. § 1.114. Applicant’s submission filed on June 25, 2026 has been entered.
Status of Claims
Claims 1-29 and 31-34 are pending. Claims 14, 16 and 18 have been amended; claims 20-23 have been withdrawn; and claim 30 has been cancelled. Claims 1-19, 24-29 and 31-34 are currently under consideration. This Office Action is in response to the request for continued examination filed on July 21, 2026. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Office Action: Non-Final.
Withdrawn Claim Objections & Rejections
The objections to claims 16, 18 and 29 (items A., B. and C. at par. 6-7 of the 01/28/2026 Office action) are withdrawn in light of applicant’s 06/25/2026 amendments. Applicant’s 06/25/2026 remarks at p. 8, par. 2 to p. 9, par. 2, are acknowledged.
The rejection of claim 18 under 35 U.S.C. § 112 (b) or 35 U.S.C. § 112 (pre-AIA ), second paragraph, as being indefinite (at par. 8-10 of the 01/28/2026 Office action), is withdrawn, in light of applicant’s 06/25/2026 amendments. Applicant’s 06/25/2026 remarks at p. 9, par. 3-4, are acknowledged.
The rejection of claims 1-16, 18-19 and 24-34 under 35 U.S.C. § 103 over DENG (US 2017/0266119 A1), in view of KARNIK (US 2010/0022680 A1) (at par. 11-33 of the 01/28/2026 Office action), is withdrawn, in light of applicant’s 06/25/2026 amendments (in particular, the amendment to independent claim 24 reciting “wherein the first fluid and second fluid have a flow rate ratio configured to generate nanoparticles with a hydrodynamic diameter less than 500 nm and a polydispersity index less than 0.25”). Applicant’s 06/25/2026 arguments, at p. 9, par. 5-7 are acknowledged, but are moot in light of the new rejections presented herein.
The rejection of claims 1-16, 18-19 and 24-34 under 35 U.S.C. § 103 over DENG, in view of KARNIK, and further in view of DEL CAMPO (US 2011/0262406 A1) (at par. 34-38 of the 01/28/2026 Office action), is withdrawn, in light of applicant’s 06/25/2026 amendments
Claim Rejections – 35 U.S.C. § 112 - Indefiniteness
The following is a quotation of 35 U.S.C. § 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-19, 24-29 and 31-34 are rejected under 35 U.S.C. § 112 (b) or 35 U.S.C. § 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or, for pre-AIA , that applicant regards as the invention.
Claim 24 is drawn to
24. ([…]) A method of making a population of nanoparticles, the method comprising:
(i) providing a first fluid comprising a biodegradable polymer into a first channel of a microfluidic system;
(ii) providing a second fluid comprising a non-solvent of the biodegradable polymer into a second channel of the microfluidic system; and
(iii) contacting the first and second fluids downstream to form the population of nanoparticles,
wherein the first fluid and second fluid have a flow rate ratio between 1:1 and 10:1, inclusive, and
wherein the first fluid and second fluid have a flow rate ratio configured to generate nanoparticles with a hydrodynamic diameter less than 500 nm and a polydispersity index less than 0.25.
wherein the recitation, “wherein the first fluid and second fluid have a flow rate ratio between 1:1 and 10:1, inclusive,” renders the metes and bounds of the claim indefinite because it is unclear as to whether the intended “flow rate ratio” is “first fluid” to “second fluid,” or vice versa. In this regard, it is noted that the Board has held: “if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring the applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 U.S.C. §112, second paragraph, as indefinite.” Ex parte Miyazaki, 89 USPQ2d 1207, 1211 (BPAI 2008) (expanded panel). It is noted that par. [0125] of the instant published application, US 2022/0339294 A1, states “[i]n some forms, the flow rate ratio of the aqueous phase to organic phase is between 1: 10 and 10: 1, inclusive, between 1:5 and 5:1, inclusive, or between 1:1 and 5:1, inclusive,” which might appear to suggest that the intended ratio in claim 24 is “second fluid” to “first fluid.” However, it is noted that although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Subsequent claims 1-19, 25-29 and 31-34 depend on claim 24 and are thus, indefinite as well.
Further clarification is required.
Claim Rejections - 35 U.S.C. § 112(d)- Not Further Limiting
The following is a quotation of 35 U.S.C. § 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of 35 U.S.C. § 112 (pre-AIA ), fourth paragraph:
Subject to the [fifth paragraph of 35 U.S.C. 112 (pre-AIA )], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 8 is rejected under 35 U.S.C. § 112(d) or 35 U.S.C. § 112 (pre-AIA ), 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 8 is drawn to:
8. ([…]) The method of claim 1, wherein the nanoparticles have a polydispersity index less than 0.25.
while claim 1 recites “[…] to generate nanoparticles with a hydrodynamic diameter less than 500 nm and a polydispersity index less than 0.25.” Therefore, claim 8 is not further limiting with regard to a “polydispersity index less than 0.25.” Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections – 35 U.S.C. § 103
The following is a quotation of 35 U.S.C. § 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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 pre-AIA 35 U.S.C. § 103(a) 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 C.F.R. § 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 1-16, 18-19, 24-29 and 31-34 are rejected under 35 U.S.C. § 103 as being unpatentable over DENG (US 2017/0266119 A1, Publ. Sep. 21, 2017; US equivalent of WO 2015/172149 A on 05/22/2023 IDS; hereinafter, “Deng”; of record), in view of KARNIK (US 2010/0022680 A1, Publ. Jan. 28, 2010; on 05/22/2023 IDS; hereinafter, “Karnik”; of record) and SOLEIMANI (Soleimani, S., et al., Understanding biophysical behaviours of microfluidic-synthesized nanoparticles at nano-biointerface, Colloids Surf. B Biointerfaces 145 (2016) pp. 802-811; hereinafter, “Soleimani”).
Deng is directed to:
HYPERBRANCHED POLYGLYCEROL-COATED PARTICLES AND METHODS OF MAKING AND USING THEREOF
ABSTRACT
Core-shell particles and methods of making and using thereof are described herein. The core is formed of or contains one or more hydrophobic materials or more hydrophobic materials. The shell is formed of or contains hyperbranched polyglycerol (HPG). The HPG coating can be modified to adjust the properties of the particles. Unmodified HPG coatings impart stealth properties to the particles which resist non-specific protein absorption and increase circulation in the blood. The hydroxyl groups on the HPG coating can be chemically modified to form functional groups that react with functional groups and adhere the particles to tissue, cells, or extracellular materials, such as proteins.
Deng, title & abstract. In this regard, Deng teaches a preparation of nanoparticles using microfluidic devices:
[0163] Microfluidics
[0164] Nanoparticles can be prepared using microfluidic devices. A polymeric material is mixed with a drug or drug combinations in a water miscible organic solvent. The water miscible organic solvent can be one or more of the following: acetone, ethanol, methanol, isopropyl alcohol, acetonitrile and Dimethyl sulfoxide (DMSO). The resulting mixture solution is then added to an aqueous solution to yield nanoparticle solution. The targeted peptides or fluorophores or drugs may be associated with the surface of, encapsulated within, surrounded by, and/or distributed throughout the polymeric matrix of the particles.
Deng, par. [0163]-[0164].
Regarding independent claim 24 and the requirements:
24. ([…]) A method of making a population of nanoparticles, the method comprising:
(i) providing a first fluid comprising a biodegradable polymer into a first channel of a microfluidic system;
(ii) providing a second fluid comprising a non-solvent of the biodegradable polymer into a second channel of the microfluidic system; and
(iii) contacting the first and second fluids downstream to form the population of nanoparticles,
wherein the first fluid and second fluid have a flow rate ratio between 1:1 and 10:1, inclusive, and
wherein the first fluid and second fluid have a flow rate ratio configured to generate nanoparticles with a hydrodynamic diameter less than 500 nm and a polydispersity index less than 0.25.
Deng clearly teaches a preparation of nanoparticles using microfluidic devices (Deng, par. [0163]-[0164]), whereby it is noted:
“[a] polymeric material [that] is mixed with a drug or drug combinations in a water miscible organic solvent” resulting in a “mixture solution,” wherein “[t]he water miscible organic solvent can be one or more of the following: acetone, ethanol, methanol, isopropyl alcohol, acetonitrile and Dimethyl sulfoxide (DMSO)” (Deng, par. [0164]) relates to:
the active step of “providing a first fluid comprising a biodegradable polymer into a first channel of a microfluidic system” of independent claim 24,
as well as a “first fluid” that is an “organic solvent or solution” containing “therapeutic agents, diagnostic agents, prophylactic agents” of claims 26-27:
26. ([…]) The method of claim 24, wherein the first fluid comprises a therapeutic agents, diagnostic agents, and/or prophylactic agents.
27. ([…]) The method of claim 24, wherein the first fluid comprises an organic solvent or solution.
“an aqueous solution” (Deng, par. [0164]) relates to:
the active step of “(ii) providing a second fluid comprising a non-solvent of the biodegradable polymer into a second channel of the microfluidic system” of independent claim 24,
as well as a “non-solvent” and “aqueous solution” of claim 28:
28. ([…]) The method of claim 24, wherein the non-solvent of the biodegradable polymer is an aqueous solution.
wherein “[t]he resulting mixture solution is then added to an aqueous solution to yield [a] nanoparticle solution” (Deng, par. [0164]) relates to the active step of “(iii) contacting the first and second fluids downstream to form the population of nanoparticles” of independent claim 24, as well as the requirements of claim 25:
25. ([…]) The method of claim 24, wherein (i) and (ii) are performed simultaneously, or in any order.
wherein Deng teaches that “[t]he polydispersity is from about 0.05 to 0.30”:
[0168] The polydispersity is from about 0.05 to 0.30, preferably from about 0.05 to about 0.25, more preferably from about 0.05 to about 0.20, more preferably from about 0.05 to about 0.15, most preferably from about 0.05 to about 0.10.
(Deng, par. [0168]), which meets the requirement of independent claim 24 for “a polydispersity index less than 0.25,” as well as claim 8 for:
8. ([…]) The method of claim 1, wherein the nanoparticles have a polydispersity index less than 0.25.
(see MPEP § 2144.05 (I) regarding the obviousness of prior art overlapping claimed numerical ranges).
However, it is noted that:
(i) although Deng teaches “[t]he core of the particles is formed of or contains one or more hydrophobic or more hydrophobic materials, such as one or more polymeric materials”:
[0056] The core of the particles is formed of or contains one or more hydrophobic or more hydrophobic materials, such as one or more polymeric materials (e.g., homopolymer, copolymer, terpolymer, etc.). The material may be biodegradable or non-biodegradable. In some embodiments, the one or more materials are one or more biodegradable polymers.
[0057] In general, synthetic polymers are preferred, although natural polymers may be used and have equivalent or even better properties, especially some of the natural biopolymers which degrade by hydrolysis, such as some of the polyhydroxyalkanoates. Representative synthetic polymers are: poly(hydroxy acids) such as poly(lactic acid), poly(glycolic acid), and poly(lactic acid-co-glycolic acid), poly(lactide), poly(glycolide), poly(lactide-co-glycolide), polyanhydrides, polyorthoesters, polyamides, polycarbonates, polyalkylenes such as polyethylene and polypropylene, polyalkylene glycols such as poly(ethylene glycol), polyalkylene oxides such as poly(ethylene oxide), polyalkylene terepthalates such as poly(ethylene terephthalate), polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides such as poly(vinyl chloride), polyvinylpyrrolidone, polysiloxanes, poly(vinyl alcohols), poly(vinyl acetate), polystyrene, polyurethanes and co-polymers thereof, derivativized celluloses such as alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxy-propyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxylethyl cellulose, cellulose triacetate, and cellulose sulfate sodium salt (jointly referred to herein as “synthetic celluloses”), polymers of acrylic acid, methacrylic acid or copolymers or derivatives thereof including esters, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate) (jointly referred to herein as “polyacrylic acids”), poly(butyric acid), poly(valeric acid), and poly(lactide-co-caprolactone), copolymers and blends thereof. As used herein, “derivatives” include polymers having substitutions, additions of chemical groups and other modifications routinely made by those skilled in the art.
[0058] Examples of preferred natural polymers include proteins such as albumin, collagen, gelatin and prolamines, for example, zein, and polysaccharides such as alginate, cellulose derivatives and polyhydroxyalkanoates, for example, polyhydroxybutyrate. The in vivo stability of the microparticles can be adjusted during the production by using polymers such as poly(lactide-co-glycolide) copolymerized with polyethylene glycol (PEG). If PEG is exposed on the external surface, it may increase the time these materials circulate due to the hydrophilicity of PEG.
(Deng, par. [0056]-[0058]), inter alia, “poly(lactide-co-glycolide) copolymerized with polyethylene glycol (PEG)” (Deng, par. [0058]),which encompasses “poly(lactic acid-co-glycolic acid)” of claim 12, a “hydrophobic polymer portion” of claims 10-12, a “polyester” of claims 10-11, “polyethylene glycol (PEG)” of claim 13, a “hydrophilic polymer portion” of claim 13, “amphiphilic polymer” of claim 9, and “biodegradable polymers” of claims 1, 9 and 24:
9. ([…]) The method of claim 1, wherein the biodegradable polymers comprise a hydrophobic polymer; a hydrophilic polymer; an amphiphilic polymer comprising a hydrophobic polymer portion and a hydrophilic polymer portion; co-polymers; or blends thereof.
10. ([…]) The method of claim 9, wherein the hydrophobic polymer or hydrophobic polymer portion comprises a polyester, poly(anhydride), poly(orthoester), hydrophobic polypeptide, polyamide, poly(ester-amide), poly(beta-amino ester)s, poly(amine-co-ester)s; poly(amine-co-ester-co-ortho ester)s, poly(alkyl acrylate); poly(alkyl alkacrylate); poly(alkyl acrylamide); poly(alkyl alkacrylamide), alkyl cellulose, cellulose ester, polyurethane, polyurea, poly(urea ester), poly(amide-enamine), hydrophobic polyethers, or copolymers thereof.
11. ([…]) The method of claim 9, wherein the hydrophobic polymer or hydrophobic polymer portion comprises a polyester.
12. ([…]) The method of claim 9, wherein the hydrophobic polymer or hydrophobic polymer portion comprises poly(lactic acid-co-glycolic acid), poly(lactic acid), poly(glycolic acid) or poly(amine-co-ester).
13. ([…]) The method s of claim 9, wherein the hydrophilic polymer or hydrophilic polymer portion comprises polyalkylene glycol; polysaccharides; hydrophilic polypeptides; poly(oxyethylated polyol); poly(olefinic alcohol); poly(vinylpyrrolidone); poly(N-hydroxyalkyl methacrylamide); poly(N-hydroxyalkyl methacrylate); hydrophilic poly(hydroxy acids); and copolymers thereof.
(as well as par. [0055] of the instant published application, US 2022/0339294 A1), Deng DOES NOT EXPRESSLY TEACH a specific exemplary embodiment for the preparation of nanoparticles using microfluidic devices (Deng, par. [0163]-[0164]) with “poly(lactide-co-glycolide) copolymerized with polyethylene glycol (PEG)” (Deng, par. [0058]), which is well within the purview of the ordinarily skilled artisan in light of Deng’s broader disclosure; AND
(ii) DENG DOES NOT EXPRESSLY TEACH the flow rate requirements of claim 24 for “wherein the first fluid and second fluid have a flow rate ratio between 1:10 and 10:1, inclusive,” as well as the requirements of claims 31-34 for:
31. ([…]) The method of claim 24, wherein the first fluid and the second fluid independently have flow rates between 1 mL/min and 20 mL/min, inclusive.
32. ([…]) The method of claim 24, wherein the first fluid and the second fluid independently have formulation volumes between 1 mL and 10 mL, inclusive.
33. ([…]) The method of claim 24, wherein the first fluid has a concentration between 1 mg/mL and 250 mg/mL.
34. ([…]) The method of claim 24, wherein the second fluid has a concentration between 0.1% w/v and 5% w/v, inclusive.
(iii) Deng DOES NOT EXPRESSLY TEACH the requirements of independent claim 24 for “wherein the first fluid and second fluid have a flow rate ratio configured to generate nanoparticles with a hydrodynamic diameter less than 500 nm.
Based on the state of the art, an artisan of ordinary skill would have found each of these features obvious.
Regarding (i), it is noted that a reference is analyzed using its broadest teachings. MPEP § 2123 [R-5] states: “[W]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007)(quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976). “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious”, the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR v. Teleflex, 127 S.Ct. 1727, 1741 (2007). The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.” Id. at 1742. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to prepare nanoparticles using microfluidic devices (Deng, par. [0163]-[0164]) with “poly(lactide-co-glycolide) copolymerized with polyethylene glycol (PEG)” (Deng, par. [0058]) per Deng’s broader disclosure.
Therefore, Deng renders (i) obvious.
Regarding (ii) and (iii), Karnik, for instance, is directed to:
MICROFLUIDIC SYNTHESIS OF ORGANIC NANO PARTICLES
ABSTRACT
The present invention provides microfluidic systems and methods for the production of particles ( e.g., nanoparticles) for drug delivery. The present invention provides microfluidic devices useful for production of particles by nanoprecipitation. The present invention provides highly homogenous compositions of particles produced by inventive microfluidic devices.
Karnik, title & abstract. In this regard, Karnik teaches that the characteristics of the particles can be modified by adjusting concentration of therapeutic agent, non-solvent to solvent ratio of the fluid in the mixing apparatus, and flow rate:
[0231] In some embodiments, the characteristics of the particles may be modified by adjusting the concentration of a therapeutic agent in the polymeric stream or in the nonsolvent stream.
[0232] In some embodiments, the characteristics of the particles may be modified by adjusting the concentration of a targeting moiety in the polymeric stream or in the non-solvent stream. In general, these concentrations fall within solubility limits. In some embodiments, the concentration of a targeting moiety in the polymeric stream or in the non-solvent stream ranges from 0.1 mg/ml to 100 mg/ml. In some embodiments, the concentration of a targeting moiety in the polymeric stream or in the non-solvent stream is approximately 0.1 mg/ml, approximately 1.0 mg/ml, approximately 10 mg/ml, or approximately 100 mg/ml.
[0233] In some embodiments, the characteristics of the particles may be modified by adjusting the non-solvent to solvent ratio of the fluid in the mixing apparatus. In some embodiments, the non-solvent to solvent ratio of the fluid in the mixing apparatus can be controlled by adjusting the flow rates of the polymeric stream(s) and the non-solvent stream(s). In some embodiments, the solvent to non-solvent ratio ranges from 10:1 to 1:30. In some embodiments, the solvent to non-solvent ratio is approximately 10:1, approximately 5:1, approximately 1:1, approximately 1:5, approximately 1:10, approximately 1:15, approximately 1:20, approximately 1:25, or approximately 1:30. In some embodiments, the solvent to non-solvent ratio can be greater than 10: 1 or smaller than 1:30. In specific embodiments, the solvent to non-solvent ratio is approximately 1 :20. In general, for hydrodynamic focusing, a larger ratio of solvent flow rate to nonsolvent flow rate may yield particles that are more monodispersed than particles produced by a smaller ratio of solvent flow rate to non-solvent flow rate (see, e.g., Example 3).
[0234] In some embodiments, the characteristics of the particles may be modified by adjusting the flow rate of at least one fluid stream (e.g. polymeric stream, non-solvent stream, and/or inlet stream). In certain embodiments, the flow rate of a fluid stream may be zero. In some embodiments, the flow rate may range from 0.001 μI/min to 1.0 ml/min. In some embodiments, the flow rate is approximately 0.01 μI/min, approximately 0.1 μI/min, approximately 0.5 μI/min, approximately 1.0 μI/min, approximately 5 μI/min, approximately 10 μI/min, approximately 50 μI/min, approximately 100 μI/min, or approximately 1.0 ml/min. In specific embodiments, the flow rate is approximately 10 μI/min for aqueous solutions (e.g. a non-solvent such as water). In specific embodiments, the flow rate is approximately 0.5 μI/min for polymeric solutions. In some embodiments, adjusting the flow rate of one or more of the streams containing a component of the particle and/or the polymeric stream results in modifying the composition of the fluid in the mixing apparatus.
(Karnik, par. [0231]-[0234]), with polymer concentrations for PLGA-PEG at 50 mg/ml (Karnik, par. [0242]), which relates to the microfluidic device parameters of claim 31-34 and (ii). Further in this regard, Soleimani, for instance, is directed to:
Understanding biophysical behaviours of microfluidic-synthesized nanoparticles at nano-biointerface
ABSTRACT
Encapsulating drugs in nanoparticles (NPs) provide some advantages over free drugs; for example the probability of distribution in off-target tissues decreases and drugs remain safe from environment degrading factors. Upon entering the bioenvironment, NPs establish a number of interactions with their surroundings based on their physicochemical properties. Here we demonstrate how the size-surface charge interplay of chitosan NPs affects the protein corona formation and endocytosis pathway in the HeLa cells at non-toxic concentrations. Generally, large NPs (102 and 161 nm) with low surface charge (+6.7 and +3.6 mV) exhibited weaker tendency for endocytosis compared with smaller ones (63 and 83 nm with 10 and 9.3 mV surface charge, respectively). This is mainly because the interactions of larger NPs with the plasma membrane were too weak to release enough free energy required for cellular internalization. Furthermore, we tested the upright and inverted cell culture configurations to better understand the impact of the sedimentation and diffusion velocities of NPs on the resulting cellular uptake pattern in both serum free and serum containing culture medias. Considering the different particokinetics, the amount of internalized NPs in upright and inverted positions differed in all cases by a factor of approximately three (for 161 nm particles), or less for smaller ones. Ultimately, our results offer a paradigm for analyzing the biobehavior of NPs under the precise control of their physicochemical characteristics.
Soleimani, title & abstract. In this regard, Soleimani discloses that “hydrodynamic diameter” ranges from about 65 to 95 nm for nanoparticles synthesized at “flow ratios” of about 0.02 to 0.20, and “[t]he Polydispersity index (PDI) of microfluidic-assisted synthesized nanoparticles are 0.108, 0.122, and 0.113”:
3.1. Nanoparticle fabrication
Due to the fact that NPs’ size has remarkable impact on the nanobio interactions, it is crucial to choose a fabrication method that is successful in terms of monodispersity, stability, compactness and ordered composition over bulk and surface [30]. To set up a system that can effectively control these properties, we need to have a precise control over inter and intra-molecular interactions as well as their strengths [31].
One of the easiest ways to control the electrostatic interactions is changing the pH spectrum, which affects the ionic strength of solutions and their impacts on NPs’ assembly. We have previously designed a microfluidic system that arrests the NPs’ growth when the electrostatic repulsion and hydrophobic attraction forces are balanced as a function of pH [20]. In addition, convective forces and flow ratio play critical roles in giving the NPs’ an ordered pattern both in bulk and the surface [20], [32].
Using the unique molecular mechanisms underlying this microfluidic system, the NPs were made from the assembly of cationic chitosan chains modified with the hydrophobic groups of N-palmytoil with the degree of substitution of 18.2 ± 0.3 mol% (measured by the Ninhydrin assay). Four series of cationic NPs were fabricated: microfluidic fabricated nanoparticles (μF NPs) of 63, 83, and 102 nm as well as the bulk synthesized spheres of 161 nm.
The hydrodynamic diameter of synthesized nanoparticles at various flow ratios has been shown in Fig. 1a. As can be seen, the time of mixing affect the size of the nanoparticles and size of the nanoparticles increases with increasing flow ratio. It should be noticed that over the whole flow ratio range the microfluidic generated nanoparticles were found to be smaller with narrower size distribution compared to the bulk synthesized nanoparticles. In fact, turbulence and convective mixing in the bulk method cause residence time distributions and consequently broader particle size distribution. The Polydispersity index (PDI) of microfluidic-assisted synthesized nanoparticles are 0.108, 0.122, and 0.113 for μF–63 nm, μF–83 nm, μF–102 nm respectively, in comparison with 0.560 for bulk synthesized NPs (μF–161 nm).
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Greyscale
(Soleimani, p. 804, par. 7-10, cont. on p. 805, Fig. 1, wherein “flow ratio” appears to be previously discussed as “R,” which is “R is the ratio of the polymeric stream and basic water flow rates (R = 0.03–0.2),” Soleimani, p. 803, par. 6), and relates to (iii) above.
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to prepare nanoparticles using microfluidic devices (Deng, par. [0163]-[0164]) with “poly(lactide-co-glycolide) copolymerized with polyethylene glycol (PEG)” (Deng, par. [0058]) per Deng’s broader disclosure (as discussed above), and to have further incorporated microfluidic parameters per Karnik (Karnik, par. [0021] & [0231]-[0234]) and Soleimani for hydrodynamic diameter (Soleimani, p. 804, par. 7-10, cont. on p. 805, Fig. 1). One would have been motivated to do so with a reasonable expectation of success since Deng, Karnik and Soleimani are concerned with similar problems in the art, namely the preparation of nanoparticles (Deng, abstract; Karnik, abstract; Soleimani, abstract) with microfluidic devices (Deng, par. [0163]-[0164]; Karnik, abstract; Soleimani, abstract). Further, it is well within the skill of the ordinary artisan to select suitable parameters known in the art for obtaining nanoparticles by use of a microfluidic device. Doing so amounts to no more than combining prior art elements according to known methods to yield predictable results, namely the incorporation of a surfactant (in either the solvent or non-solvent, Karnik, par. [0021]) in order to obtain the advantage of a component for “[p]romot[ing] the production of particles with increased stability, improved uniformity, or increased viscosity” (Karnik, par. [0202]). With regard to the microfluidic device parameters of claims 24 and 31-34, it is noted that MPEP § 2144.05 (I), states, “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).” In this respect, it is further noted, “[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); and also MPEP § 2144.05(II)(A). In the instant case, surfactant in the first or second fluid, flow rate ratio, flow rate, formulation volume, “hydrodynamic diameter” and concentration are clearly result-effective variables, which are disclosed by:
Karnik for adjusting/modifying the characteristics of the particles by concentration of therapeutic agent, non-solvent to solvent ratio of the fluid in the mixing apparatus, and flow rate (Karnik, par. [0231]-[0234]); and
Soleimani, wherein hydrodynamic diameter” ranges from about 65 to 95 nm for nanoparticles synthesized at “flow ratios” of about 0.02 to 0.20, and “[t]he Polydispersity index (PDI) of microfluidic-assisted synthesized nanoparticles are 0.108, 0.122, and 0.113” (Soleimani, p. 804, par. 7-10, cont. on p. 805, Fig. 1; wherein “flow ratio” appears to be previously discussed as “R,” which is “R is the ratio of the polymeric stream and basic water flow rates (R = 0.03–0.2), Soleimani, p. 803, par. 6), and appears to the inverse of the “flow rate ratio” of claim 24 because:
Soleimani’s “polymeric stream” is likened to the “first fluid comprising a biodegradable polymer” of claim 24, and “organic phase” of the instant published application; and
Soleimani’s “water flow” is likened to the “second fluid comprising a non-solvent of the biodegradable polymer” of claim 25 and “aqueous phase” of the instant published application
(see also par. [0125] of the instant published application, US 2022/0339294 A1, stating “[i]n some forms, the flow rate ratio of the aqueous phase to organic phase is between 1: 10 and 10: 1, inclusive, between 1:5 and 5:1, inclusive, or between 1:1 and 5:1, inclusive”), wherein Soleimani’s “flow ratios” for “aqueous phase”/”organic phase” of about 0.02 to 0.20 would be a ratio of “organic phase”/”aqueous phase” of 0.2:10 to 2:10.
Therefore, it would have been customary for an artisan of ordinary skill to select appropriate surfactant in the first or second fluid, flow rte ratio, flow rate, concentration of first/second fluid, “hydrodynamic diameter,” and formulation volumes of the first/second fluid in optimizing Deng’s nanoparticles per the disclosures of Karnik and Soleimani for microfluidic device conditions.
Therefore, the prior art renders (ii) and (iii) obvious.
Thus, the prior art renders claims 8-13, 24-28 and 31-34 obvious.
Regarding claims 1 and 5-7 and the requirements
1. ([…]) The method of claim 24, wherein the population of nanoparticles have a diameter between about 50 nm and about 350 nm, wherein at least 85% of the nanoparticles have a diameter between about 120 nm and about 145 nm;
wherein the nanoparticles comprise biocompatible biodegradable polymers; and wherein a subset or all of the nanoparticles comprise therapeutic agents, diagnostic agents, and/or prophylactic agents.
[…]
5. ([…]) The method of claim 1, wherein the population of nanoparticles have a diameter between about 70 nm and about 300 nm.
6. ([…]) The method of claim 1, wherein at least 90% of the nanoparticles have a diameter between about 120 nm and about 145 nm.
7. ([…]) The method of claim 1, wherein at least 90% of the nanoparticles have a diameter between about 100 nm and about 135 nm.
it is noted that MPEP § 2144.05 (I), states, “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).” In this regard, Deng teaches nanoparticles obtained from “[a] polymeric material [that] is mixed with a drug or drug combinations in a water miscible organic solvent” resulting in a “mixture solution,” wherein “[t]he water miscible organic solvent can be one or more of the following: acetone, ethanol, methanol, isopropyl alcohol, acetonitrile and Dimethyl sulfoxide (DMSO)” (Deng, par. [0164]), wherein suitable polymers include “poly(lactide-co-glycolide) copolymerized with polyethylene glycol (PEG)” (Deng, par. [0058]), and wherein the “particles can have a diameter of between about 1 nm and about 1000 microns,” which is “typically is based on a population, wherein 60, 70, 80, 85, 90, or 95% of the population has the desired size range”:
[0167] The particles may have any diameter. The particles can have a diameter of between about 1 nm and about 1000 microns, about 1 nm and about 100 microns, about 1 nm and about 10 microns, about 1 nm and about 1000 nm, about 1 nm and about 500 nm, about 1 nm and about 250 nm, or about 1 nm and about 100 nm. In preferred embodiments, the particle is a nanoparticle having a diameter from about 25 nm to about 250 nm. In more preferred embodiments, the particles are nanoparticles having a diameter from about 180 nm to about 250 nm, preferably from about 180 nm to about 230 nm. Particles size typically is based on a population, wherein 60, 70, 80, 85, 90, or 95% of the population has the desired size range.
Deng, par. [0167].
Thus, the prior art renders claims 1, 5-7 and 9-13 obvious.
Regarding claims 2-4, it is noted that the requirements:
2. ([…]) The method of claim 1, wherein the nanoparticles are selectively taken up by lung cells and/or bone marrow cells of a mammal, as measured by flow cytometry.
3. ([…]) The method of claim 2, wherein the lung cells include or are type I alveolar epithelial cells and/or alveolar macrophage cells.
4. ([…]) The method of claim 2, wherein the bone marrow cells include or are hematopoietic stem and progenitor cells.
are functional limitations of the product obtained from the instant method of making. In this regard, it is noted that the structure, material or act in the claim that is connected to (i.e., performs) the recited function is the combination of recited elements of claim 1, which achieve the resulting uptake effects. Therefore, the broadest reasonable interpretation (see MPEP § 2111 with respect to broadest reasonable interpretation) of the functional language is: an intended uptake effect of a composition that meets the structural requirements of claim 1. Because this functional language merely recites the intended result of the recited structural limitations, it imposes no patentable distinction on the claim (i.e., the functional language is not further limiting beyond the noted structural limitations). Therefore, one of ordinary skill in the art would understand that a composition meeting the structural requirements of claim 1 will achieve the intended result of the functional limitations and fall within the boundaries of the claims.
Thus, the prior art renders claims 2-4 obvious.
Regarding claim 14 and the requirements:
14. ([…]) The method of claim 1, wherein the nanoparticles comprise therapeutic agents, diagnostic agents, prophylactic agents in a loading between about 0.2 mg/mL and about 5 mg/mL, between about 0.2 mg/mL and about 2 mg/mL, between about 0.2 mg/mL and about 1 mg/mL, as measured by absorbance.
Deng teaches an exemplary “Evaluation of NPs in Blood Circulation and Biodistribution” (Deng, par. [0244]-[0254], Ex. 6) involving “tail vein injection of 150 μL DiD [i.e., 4-chlorobenzenesulfonate Salt, Deng. Par. [0239]] loaded NPs (3 mg/ml in PBS solution)” (Deng, par. [0245], Ex. 6) and “150 μL DiD loaded NPs (3 mg/ml in PBS solution) were administrated intravenously through tail vein” (Deng, par. [0247], Ex. 6). See MPEP § 2144.05 (I) regarding the obviousness of prior art overlapping claimed numerical ranges.
Thus, the prior art renders claim 14 obvious.
Regarding claims 15-16 and 18 and the requirements:
15. ([…]) The method of claim 1, wherein therapeutic agents, diagnostic agents, prophylactic agents comprise a nucleic acid, protein, peptide, lipid, polysaccharide, small molecules, or combination thereof.
16. ([…]) The method of claim 1, wherein therapeutic agents, diagnostic agents, prophylactic agents comprise nucleic acid, optionally selected from the group consisting of a peptide nucleic acid (PNA), deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and combinations thereof.
[…]
18. ([…]) The method of claim 16, wherein the PNA, DNA, and/or RNA are oligonucleotides.
Deng teaches suitable “Therapeutic Agent, Diagnostic Agents, Prophylactic Agents, and/or Nutraceuticals,” inter alia, “oligonucleotide drugs”:
[0084] 2. Therapeutic Agent, Diagnostic Agents, Prophylactic Agents, and/or Nutraceuticals
[0085] Agents to be delivered include therapeutic, nutritional, diagnostic, and prophylactic compounds. Proteins, peptides, carbohydrates, polysaccharides, nucleic acid molecules, and organic molecules, as well as diagnostic agents, can be delivered. The preferred materials to be incorporated are drugs and imaging agents. Therapeutic agents include antibiotics, antivirals, anti-parasites (helminths, protozoans), anti-cancer (referred to herein as “chemotherapeutics”, including cytotoxic drugs such as doxorubicin, cyclosporine, mitomycin C, cisplatin and carboplatin, BCNU, 5FU, methotrexate, adriamycin, camptothecin, epothilones A-F, and taxol), antibodies and bioactive fragments thereof (including humanized, single chain, and chimeric antibodies), antigen and vaccine formulations, peptide drugs, anti-inflammatories, nutraceuticals such as vitamins, and oligonucleotide drugs (including DNA, RNAs, antisense, aptamers, ribozymes, external guide sequences for ibonuclease P, and triplex forming agents).
(Deng, par. [0084]-[0085]), which are encompassed by “nucleic acid” of claim 15, “deoxyribonucleic acid (DNA)” of claim 16 and “oligonucleotides” of claim 18.
Thus, the prior art renders claims 15-16 and 18 obvious.
Regarding claim 19 and the requirements:
19. ([…]) The method of claim 1, wherein some or all of the nanoparticles do not contain a targeting agent on their surface.
Deng teaches: “[t]he targeted peptides or fluorophores or drugs may be associated with the surface of, encapsulated within, surrounded by, and/or distributed throughout the polymeric matrix of the particles”
(Deng, par. [0164]), which overlaps “all of the nanoparticles do not contain a targeting agent on their surface” of claim 19.
Thus, the prior art renders claim 19 obvious.
Regarding claim 29 and the requirements:
29. ([…]) The method of claim 24, wherein the second fluid comprises a surfactant, optionally poly(vinyl alcohol).
Deng DOES NOT EXPRESSLY TEACH the incorporation of a surfactant, which is would be well within the purview of the ordinarily skilled artisan. Karnik, for instance, teaches the incorporation of a surfactant mixed with a solvent or non-solvent:
[0021] In some embodiments, fluid streams may optionally comprise one or more surfactants. A surfactant may be mixed with a solvent, non-solvent, and/or other component of a particle. In some embodiments, fluid streams may optionally comprise buffering agents and/or salts.
(Karnik, par. [0021]), for “[p]romot[ing] the production of particles with increased stability, improved uniformity, or increased viscosity” (Karnik, par. [0202]). Also, Karnik teaches “polyvinyl alcohols” among “[a]ny polymer that is more soluble in the polymer stream than in the solution in which the polymer stream is mixed may be used in the microfluidic systems of the present invention” (Karnik, par. [0017]). In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to prepare nanoparticles using microfluidic devices (Deng, par. [0163]-[0164]) with “poly(lactide-co-glycolide) copolymerized with polyethylene glycol (PEG)” (Deng, par. [0058]) per Deng’s broader disclosure (as discussed above), and to further incorporate a surfactant per Karnik (Karnik, par. [0021]). In this respect, it is well within the skill of the ordinary artisan to select suitable components known in the art for obtaining nanoparticles by use of a microfluidic device. Doing so amounts to no more than combining prior art elements according to known methods to yield predictable results, namely the incorporation of a surfactant (in either the solvent or non-solvent, Karnik, par. [0021]) in order to obtain the advantage of a component for “[p]romot[ing] the production of particles with increased stability, improved uniformity, or increased viscosity” (Karnik, par. [0202]).
Thus, the prior art renders claim 29 obvious.
Claim 17 is rejected under 35 U.S.C. § 103 as being unpatentable over DENG (US 2017/0266119 A1, Publ. Sep. 21, 2017; US equivalent of WO 2015/172149 A on 05/22/2023 IDS; hereinafter, “Deng”; of record), in view of KARNIK (US 2010/0022680 A1, Publ. Jan. 28, 2010; on 05/22/2023 IDS; hereinafter, “Karnik”; of record) and SOLEIMANI (Soleimani, S., et al., Understanding biophysical behaviours of microfluidic-synthesized nanoparticles at nano-biointerface, Colloids Surf. B Biointerfaces 145 (2016) pp. 802-811; hereinafter, “Soleimani”), as applied to claims 1-16, 18-19, 24-29 and 31-34, above, and in view of DEL CAMPO (US 2011/0262406 A1, Publ. Oct. 27, 2011; on 05/22/2023 IDS; hereinafter, “del Campo”; of record).
The teachings of Deng and Karnik, as set forth above, are hereby incorporated. However, the references DO NOT TEACH a “combination of PNA and donor DNA” per the requirements of claim 17 for:
17. ([…]) The method of claim 1, wherein the therapeutic, diagnostic, and/or prophylactic agent comprises a combination PNA and donor DNA.
Which is well within the purview of the ordinarily skilled artisan.
Del Campo, for instance, is directed to:
COMPOSITIONS AND METHODS FOR TARGETED INACTIVATION OF HIV CELL SURFACE RECEPTORS
ABSTRACT
Compositions for targeted mutagenesis of cell surface receptors for HIV and methods of their use are provided herein. The compositions include triplex-forming molecules that displace the polypyrimidine strand of target duplex and form a triple-stranded structure and hybrid duplex in a sequence specific manner with the polypurine strand of the target duplex. The triplex-forming molecules include a mixed-sequence “tail” which increases the stringency of binding to the target duplex, improves the frequency of modification at the target site, and reduces the requirement for a polypurine: polypyrimidine stretch. Methods for using the triplex-forming molecules in combination with one or more donor oligonucleotides for targeted modification of sites within or adjacent to genes that encodes cell surface receptors for human immunodeficiency virus (HIV) are also disclosed. Methods for ex vivo and in vivo prophylaxis and therapy of HIV infection using the disclosed compositions are also provided.
Del Campo, title & abstract. In this regard, Del Campo teaches triplex forming molecules including peptide nucleic acids may be administered in combination with, or tethered to, a donor oligonucleotide via a mixed sequence linker or used in conjunction with a non-tethered donor oligonucleotide that is substantially homologous to the target sequence
[0089] E. Donor Oligonucleotides
[0090] The triplex forming molecules including peptide nucleic acids may be administered in combination with, or tethered to, a donor oligonucleotide via a mixed sequence linker or used in conjunction with a non-tethered donor oligonucleotide that is substantially homologous to the target sequence. Triplex-forming molecules can induce recombination of a donor oligonucleotide sequence up to several hundred base pairs away. It is preferred that the donor oligonucleotide sequence is between 1 to 800 bases from the target binding site of the triplex-forming molecules. More preferably the donor oligonucleotide sequence is between 25 to 75 bases from the target binding site of the triplex-forming molecules. Most preferably that the donor oligonucleotide sequence is about 50 nucleotides from the target binding site of the triplex-forming molecules.
(Del Campo, par. [0089]-[0090]), wherein a PNA/DNA/PNA triple helix and PNA/DNA for producing displacement of the pyrimidine-rich strand, creating an altered helical structure that has been shown to strongly provoke the nucleotide excision repair pathway and to activate the site for recombination with a donor DNA molecule:
[0168] […]. In this complex, the PNA/DNA/PNA triple helix and the PNA/DNA duplex both produce displacement of the pyrimidine-rich strand, creating an altered helical structure that has been shown to strongly provoke the nucleotide excision repair pathway and to activate the site for recombination with a donor DNA molecule (Rogers, et al., Proc Natl. Acad. Sci., USA, 99(26):16695-700 (2002)). A second tail-clamp PNA with a shorter Hoogsteen binding domain (tcPNA-684; FIG. lC) was also tested. In vitro gel shift analysis shows a concentration dependent band shift when duplex DNA is incubated with increasing amounts (0, 0.2 μM, 0.4 μM, 0.8 μM and 1.2 μM) of PNA, confirming the formation of a triplex (Table 1 ). All three PNAs were found to bind to their specific CCR5 target sites in a plasmid substrate at physiological pH, however, tcPNA-679 showed superior target site binding.
(Del Campo, par. [0168]).
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to prepare nanoparticles using microfluidic devices (Deng, par. [0163]-[0164]) with “poly(lactide-co-glycolide) copolymerized with polyethylene glycol (PEG)” (Deng, par. [0058]) per Deng’s broader disclosure (as discussed above), and to incorporate PNA/DNA/PNA triple helix with donor DNA per Del Campo (Del Campo, par. [0089]-[0090] & [0168]). . One would have been motivated to do so with a reasonable expectation of success in order to obtain the advantage of a triplex forming molecules including peptide nucleic acids may be administered in combination with, or tethered to, a donor oligonucleotide (Del Campo, par. [0089]-[0090]) to “provoke the nucleotide excision repair pathway and to activate the site for recombination” (Del Campo, par. [0168]).
Thus, the prior art renders claim 17 obvious.
Conclusion
Claims 1-19, 24-29 and 31-34 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOMINIC LAZARO whose telephone number is (571)272-2845. The examiner can normally be reached on Monday through Friday, 8:30am to 5:00pm EST; alternating Fridays out.
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/DOMINIC LAZARO/Primary Examiner, Art Unit 1611
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