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 .
Election/Restrictions
Applicant’s election without traverse of invention group I, claims 1-8, in the reply filed on 08/03/2026 is acknowledged.
Claims 9-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 08/03/2026.
Applicants further elect the species of DDAB as (a) hydrophobic structural material; doxorubicin as (b) hydrophobic cargo molecule; mRNA as hydrophilic cargo molecule; and AuNPs as optional hydrophilic structural material. Claims 1-2, 4-8 read on the elected species and are under examination, claim 3 does not read on the elected species and is withdrawn from consideration.
Claims 1-20 are pending, claims 1-2 and 4-8 are under examination.
Priority
Acknowledge is made for priority claiming from US provisional application 63/494627, filed on 04/06/2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/04/2024 is being considered by the examiner.
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.
Claims 1-2 and 4-8 are rejected under 35 U.S.C. 103 as being unpatentable over Mukherjee et al. (US20190255088) in view of Irvine et al. (US9616020), Gong et al. (US20220177494), Lim et al. (US20150174549), Lichtenberger (CN101557828A. Machine translation) and Liang et al. (CN109077997A, Machine translation).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Mukherjee et al. teaches an organo-inorganic nanocomposite (OINC) and a method of use thereof, the OINC containing a lipid membrane component made of a cationic lipid, a fusogenic co-lipid, and a pore forming surfactant; and a cargo-inorganic conjugate component made of a negatively-charged cargo molecule bound electrostatically or covalently to a negatively-charged biocompatible inorganic nanoparticle wherein the cargo-inorganic component is substantially encapsulated within the lipid membrane component forming the OINC (abstract). A composition and method for the delivery of a cargo molecule (e.g., a therapeutic molecule, or agent useful in diagnosis or imaging), including but not limited to siRNA, miRNA, peptides, proteins, and small molecules such as fluorescently labelled dyes. In certain embodiments, the composition is a biocompatible organic nanocomposite (ONC) or an organo-inorganic nanocomposite (OINC). The ONC can comprise a lipid component (e.g., at least one or more lipid bilayers forming an outer lipid shell) which includes a cationic lipid, a non-cationic fusogenic co-lipid, and a pore-forming agent such as a surfactant, and an encapsulated core comprising a cargo molecule. The term non-cationic refers to either neutrally-charged or anionically-charged lipids. The encapsulated core containing the cargo molecule may be aqueous. The OINC can comprise a lipid component (e.g., at least one or more lipid bilayers forming an outer lipid shell) which includes a cationic lipid, a non-cationic fusogenic co-lipid, and a pore-forming molecule such as a surfactant, and a cargo-inorganic component including an inorganic nanoparticle, such as gold nanoparticle, which is conjugated (bound) to the organic cargo molecule directly via a covalent bond (such as a thiol or amine), or indirectly via electrostatic forces. The encapsulated core containing the cargo-inorganic component may be aqueous. The ONC or OINC may be used, for example, for treating a disease, such as cancer or any other disease or condition which responds to a therapy, or benefits from diagnostic or imaging techniques ([0050]). Before further describing various embodiments of the compositions and methods of the present disclosure in more detail by way of exemplary description, examples, and results, it is to be understood that the embodiments of the present disclosure are not limited in application to the details of methods and compositions as set forth in the following description. The embodiments of the compositions and methods of the present disclosure are capable of being practiced or carried out in various ways not explicitly described herein. As such, the language used herein is intended to be given the broadest possible scope and meaning; and the embodiments are meant to be exemplary, not exhaustive. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting unless otherwise indicated as so. Moreover, in the following detailed description, numerous specific details are set forth in order to provide a more thorough understanding of the disclosure. However, it will be apparent to a person having ordinary skill in the art that the embodiments of the present disclosure may be practiced without these specific details. In other instances, features which are well known to persons of ordinary skill in the art have not been described in detail to avoid unnecessary complication of the description. All of the compositions and methods of production and application and use thereof disclosed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of the present disclosure have been described in terms of particular embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit, and scope of the inventive concepts as described herein. All such similar substitutes and modifications apparent to those having ordinary skill in the art are deemed to be within the spirit and scope of the inventive concepts as disclosed herein ([0051]). Examples of lipids that can be used in the formation of the lipid components of the various nanocomposites of the present disclosure include, but are not limited to, those described in U.S. Pat. No. 9,616,020, and U.S. Patent Publication Nos. 20180021453, 20170232115, and 20170105936. Examples of pore-forming agents that can be used in accordance with the present disclosure include, but are not limited to, pore-forming surfactants. Examples of pore-forming surfactants include but are not limited to Tween 20, Triton X-100, Brij 56, pluronic F127, polyethylene glycols, and polypropylene glycols ([0069]). In at least one embodiment disclosed herein, the inorganic nanoparticles of the OINC are gold nanoparticles (AuNP or GNP), such as described in U.S. Pat. Nos. 9,382,346, 9,605,304, and 9,719,089, including AuNPs having of different sizes (e.g., diameters in a range of 5 nm to 50 nm, such as 5 nm, 20 nm and 50 nm), shape (e.g., 25 nm gold nanorod) and other types of similarly sized inorganic nanoparticle (e.g., 20 nm magnetic nanoparticles), For example, where 20 nm AuNP incorporation shows the substantial potential to silence the target gene (e.g. MICU1). In a non-limiting embodiment, the AuNP is citrate-capped and net-negatively-charged particle. In a non-limiting embodiment, the OINCs have an average diameter in a range of 100 nm to 200 nm ([0070]). Examples of anti-cancer agents, drugs, nucleic acid agents, targeting peptides, anti-infective agents, anti-fungal agents, inhibitors, imaging agents, reporter agents, and various other agents that can be used as the cargo molecule in the presently disclosed nanocomposite compositions include, but are not limited to, those described in U.S. Pat. No. 9,616,020 and U.S. Patent Publication Nos. 20180021453, 20170232115, and 20170105936 ([0071]). In a non-limiting embodiment, the liposomal formulations can be made as described in this example. Liposomes (LPs) can be prepared by using a common lipid film hydration method. Briefly, the cationic lipids and fusogenic lipids are separately dissolved in tert-butanol at a concentration of 5 mg/ml. For the preparation of AuNP-siRNA loaded LPs, firstly an AuNP-siRNA conjugate material containing 10 μg AuNPs and 1 ug siRNA (a ratio of 10:1 w/w) is formed by incubating the AuNP and siRNA 15 min at room temperature in 1 ml RNase/DNase-free water. Then, 12.5 μg of each lipid (1:1 w/w) is combined in a glass tube in the presence of excess tert-butanol. During vortexing of the lipids, the conjugate material is added drop by drop onto the lipid mixture, followed by the addition of Tween-20 (1.4 μg) at a ratio of 1:18 w/w of total lipids. The mixture is dried overnight under vacuum conditions in lyophillizer. RNase/DNase-free water (1.0 ml) is added onto the dried film and vortexed for 2 min. This material is then passed through an extruder using polycarbonate membrane (pore size: 0.1 μm) to form the nanoparticles (this step is considered as purifying step). Non-AuNP-containing siRNA-LPs, and empty-LPs are prepared in the same way, except with only the addition of siRNA for the siRNA-LPs, and water for the empty-LPs in lieu of the AuNP-siRNA conjugate. In non-limiting examples, the AuNP:siRNA ratio in the formulations can be in a range of 1:5 to 1:20 (w/w) ([0073]).
Irvine et al. teaches delivery systems comprised of stabilized multilamellar vesicles, as well as compositions, methods of synthesis, and methods of use thereof. The stabilized multilamellar vesicles may comprise prophylactic, therapeutic and/or diagnostic agents (abstract). Typically, the lipids are phospholipids. Phospholipids include without limitation phosphatidylcholine, phosphati dylethanolamine, phosphatidylglycerol, phosphatidylinosi tol, phosphatidylserine, and the like. It is to be understood that other lipid membrane components, such as cholesterol, sphingomyelin, cardiolipin, etc. may be used (column 13, line 34-40). Additional nonphosphorous containing lipids include Stearylamine, dodecylamine, hexadecylamine, acetyl palmi tate, glycerolricinoleate, hexadecyl Stereate, isopropyl myristate, amphoteric acrylic polymers, triethanolamine lauryl sulfate, alkyl-aryl sulfate polyethyloxylated fatty acid amides, dioctadecyldimethyl ammonium bromide and the like, diacylphosphatidylcholine, diacylphosphatidyletha nolamine, ceramide, Sphingomyelin, cephalin, and cerebro sides. Lipids such as lysophosphatidylcholine and lysophos phatidylethanolamine may be used in some instances. Noncationic lipids also include polyethylene glycol-based polymers such as PEG 2000, PEG 5000 and polyethylene glycol conjugated to phospholipids or to ceramides (referred to as PEG-Cer) ([column 14, line 14-27). The agent may be without limitation a protein, a poly peptide, a peptide, a nucleic acid, a small molecule (e.g., chemical, whether organic or inorganic) drug, a virus-like particle, a steroid, a proteoglycan, a lipid, a carbohydrate, and analogs, derivatives, mixtures, fusions, combinations or conjugates thereof. The agent may be a prodrug that is metabolized and thus converted in vivo to its active (and/or stable) form (column19, line 41-49). Examples of anti-cancer agents include without limitation such as Doxorubicin (column 23, line 15-35). Nucleic acids that can be delivered to a subject according to the invention include naturally or non-naturally occurring DNA (including cDNA, genomic DNA, nuclear DNA, mito chondrial DNA), RNA (including mRNA, rRNA, tRNA), oligonucleotides, a triple-helix forming molecule, immuno stimulatory nucleic acids such as those described in U.S. Pat. No. 6,194,388 (the teachings of which relating to immuno stimulatory CpG nucleic acids are incorporated herein by reference), small interfering RNA (siRNA) or microRNAs (miRNA) used to modulate gene expression, antisense oli gonucleotides used to modulate gene expression, aptamers, ribozymes, a gene or gene fragment, a regulatory sequence, including analogs, derivatives, and combinations thereof ([column 29, line 16-30).
Gong et al. teaches nanoparticle comprising doxorubicin or the salt thereof, ribonucleoprotein (RNP), plasmid DNA (pDNA), single-stranded donor oligonucleotide (ssODN), complementary (cDNA), messenger RNA (mRNA), small interfering RNA (siRNA), microRNA (miRNA), short hairpin RNA (shRNA), single guide RNA (sgRNA), transfer RNA (tRNA), ribozymes, and combinations of two or more thereof (claims 1, 13-14, 21-24).
Lim et al. teaches A method for preparing nanoparticles comprising: flowing a first stream of a first solution into a conduit, wherein the first solution contains precursors of the nanoparticles; flowing a second stream of a second solution into the conduit; and mixing the first stream and the second stream to form a mixed stream having a Reynolds number of between 300 and 1,000,000 in which the nanoparticles are formed, wherein the formation of the nanoparticles is continuous, wherein the nanoparticles are formed by nanoprecipitation or emulsion formation, wherein the first stream is introduced within the second stream; wherein the nanoparticles are substantially uniformly distributed in the mixed stream after formation, wherein the mixed stream includes a vortex regime, a turbulence regime, or a turbulent jet regime. In certain embodiments, the conduit can be a tube (claims 1-11; [0006]). The tee union tube fittings made of clear polycarbonate (McMaster-Carr) or PTFE (Plasmatech Co.) were used for fabrication. A hole was drilled using a 0.025 inch diameter drill bit (#72, Drill bit city) and a 23 G blunt needle (337 μm I.D. and 641.4 μm O.D., Strategic applications Inc.) was inserted through the drilled hole and fixed by optical adhesive (NOA81, Norland products) and cured under UV light. Silastic tubing (VWR scientific products) or PTFE tubing (Plasmatech Co.) with inner diameters D=3.175 mm were connected to the tee union tube fitting using a connector and adaptor (IDEX Health & Science) ([0053]). Working examples include Preparation of Lipid Vesicles ([0066]). Lim et al. also recites several millifluidic systems in the art ([0043-0044]). Since Lim et al. teaches tubing with inner diameters D=3.175 mm, and it is obvious to have millifluidic tubing for the intended application of nanoparticle preparation.
Lichtenberger teaches In some embodiments, through heating and mixing components to facilitate preparation to prepare the composition. Alternatively the method of the phospholipids and 5ASA heating to a second temperature sufficient to temperature of 5ASA melted in the phospholipid, generally good mixed intimately mixing and form an association complex of 5ASA and phospholipid at a molecular level. The method can be performed in a high temperature solvent or bio-compatible oil lower in the absence of air to promote 5ASA/ phosphatide association complex is formed so as not to be oxidation degradation. preparing one alternative method the preparation of aqueous formulation is prepared containing 5ASA, and then the aqueous solution is added to the PC coated with dried lipid film container, then strongly mixing, vortex, ultrasonic or other means of stirring to produce a 5ASA/PC lipid suspension. the other method is the 5ASA and lecithin is dissolved in solvents that can dissolve the two substances. heating or not heating while mixing the solution, then evaporating the solvent. then the obtained substance and resin encapsulated for delayed release in the distal intestinal tract. (page 6, first paragraph).
Liang et al. teaches weighing 2.3 mg disodium dissolved in 2 ml of water, mixing them evenly to obtain pemetrexed disodium solution for use, then weighing 5 mg SPC3 was dissolved in 3 ml of chloroform, 1 ml disodium solution prepared adding SPC3 chloroform solution, water bath ultrasonic vortex 10 min, organic solvent 5 min, then transfer to speed evaporation 1h 150mbar, 30rpm under 25 degrees centigrade to evaporating the mixed solution; adding 1 ml water fully washing; mixing uniformly. using dialysis method to remove free pemetrexed disodium pemetrexed disodium lipid compound solution. removing the free drug encapsulation rate is 90% (page 7, example 5).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02)
The difference between the instant application and Mukherjee et al. is that Mukherjee et al. do not expressly teach mix two streams and ultrasonic bath. This deficiency in Mukherjee et al. is cured by the teachings of Irvine et al., Gong et al., Lim et al., Lichtenberger and Liang et al.
Finding of prima facie obviousness
Rational 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 modify the invention of Mukherjee et al., as suggested by Irvine et al., Gong et al., Lim et al., Lichtenberger and Liang et al., and produce the instant invention.
Mukherjee et al. teaches an organo-inorganic nanocomposite (OINC) and a method of use thereof, the OINC containing a lipid membrane component made of a cationic lipid, a fusogenic co-lipid, and a pore forming surfactant; and a cargo-inorganic conjugate component made of a negatively-charged cargo molecule bound electrostatically or covalently to a negatively-charged biocompatible inorganic nanoparticle wherein the cargo-inorganic component is substantially encapsulated within the lipid membrane component forming the OINC. In a working example, the cationic lipids and fusogenic lipids are separately dissolved in tert-butanol at a concentration of 5 mg/ml. For the preparation of AuNP-siRNA loaded LPs, firstly an AuNP-siRNA conjugate material containing 10 μg AuNPs and 1 ug siRNA (a ratio of 10:1 w/w) is formed by incubating the AuNP and siRNA 15 min at room temperature in 1 ml RNase/DNase-free water. Then, 12.5 μg of each lipid (1:1 w/w) is combined in a glass tube in the presence of excess tert-butanol. During vortexing of the lipids, the conjugate material is added drop by drop onto the lipid mixture, followed by the addition of Tween-20 (1.4 μg) at a ratio of 1:18 w/w of total lipids. Thus, Mukherjee et al. teaches the mixing of a first liquid comprising lipid in tert-butanol and a second liquid comping AuNP-siRNA conjugate in RNase/DNase-free water followed by addition of surfactant Tween 20 to form a lipid bilayer and encapsulated AuNP-siRNA conjugate in RNase/DNase-free water. And then purifying the encapsulated therapeutics.
One of ordinary skill in the art would have been motivated to add Tween 20 in the first liquid comprising lipid in tert-butanol before mixing first and second liquid because selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results, and Selection of any order of mixing ingredients is prima facie obvious. MPEP 2144.04 IV. C. Furthermore, it is with skill of one artisan in the art to replace Polysorbate 80 for Polysorbate 20 (Tween 20) because Polysorbate 80 is a known surfactant alternative to Polysorbate 20 (examiner’s position).
Regarding cholesterol and dimethyldioctadecylammonium bromide, since Mukherjee et al. teaches lipids described in U.S. Pat. No. 9,616,020, as evidenced by Irvine et al. (US9616020) teaching cholesterol and dioctadecyldimethyl ammonium bromide (dimethyldioctadecylammonium bromide), it is obvious to have cholesterol and dimethyldioctadecylammonium bromide in the first liquid comprising lipid.
Regarding doxorubicin and mRNA, since Mukherjee et al. teaches cargo molecule described in U.S. Pat. No. 9,616,020, as evidenced by Irvine et al. (US9616020) teaching doxorubicin and mRNA, in view of Gong et al. teaches nanoparticle comprising both doxorubicin and mRNA, it is obvious to have both doxorubicin and mRNA in the nanocomposite. Since mRNA is hydrophilic, it is obvious to have mRNA in the second liquid just like siRNA. Since doxorubicin is hydrophobic, it is more like than not in the first liquid comprising lipid, Furthermore, since there is only finite choice (only two choice), it is obvious to have doxorubicin in first liquid comprising lipid.
Since Mukherjee et al. teaches encapsulated core containing the cargo molecule may be aqueous, and buffer such as PBS is a known aqueous media for core in the liposome or lipid bilayer encapsulation (examiner’s position), it is obvious to have buffer as aqueous media in the core and in the second liquid.
Since these above modifications are apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit, and scope of the inventive concepts as described by Mukherjee et al., it is obvious to have first liquid comprising polysorbate 80, cholesterol, dimethyldioctadecylammonium bromide and doxorubicin in tert-butanol, and a second liquid comprising AuNP-mRNA conjugate in buffer, and mixing the first and second liquid under vortex to produce nanocomposite.
Mukherjee et al. is silent about providing a first and second stream and combining them through a millifluidic tubing to from encapsulated therapeutics, and one of ordinary skill in the art would have been motivated to provide first liquid as hydrophobic liquid stream comprising polysorbate 80, cholesterol, dimethyldioctadecylammonium bromide and doxorubicin in tert-butanol, and providing a second aqueous stream comprising AuNP-mRNA conjugate in aqueous buffer, and combine both stream to form a mixed stream through a millifluidic tubing because this is use of known technique to improve similar methods in the same way. MPEP 2143. Under guidance from Lim et al. teaching a method for preparing nanoparticles comprising: flowing a first stream of a first solution into a conduit (millifluidic tubing), wherein the first solution contains precursors of the nanoparticles; flowing a second stream of a second solution into the conduit (millifluidic tubing); and mixing the first stream and the second stream to form a mixed stream in which the nanoparticles are formed, it is obvious for one of ordinary skill in the art to provide first liquid as hydrophobic liquid stream comprising polysorbate 80, cholesterol, dimethyldioctadecylammonium bromide and doxorubicin in tert-butanol, and provide a second aqueous stream comprising AuNP-mRNA conjugate in aqueous buffer, and combine both stream to form a mixed stream through a millifluidic tubing to form encapsulated therapeutics and produce instant claimed invention with reasonable expectation of success.
Mukherjee et al. teaches vortexing and Lim et al. teaches vortex regime, but silent about ultrasonic bath, One of ordinary skill in the art would have been motivated to replace ultrasonic bath for vortex because ultrasonic bath is alternative to vortex for mixing. Under guidance from Lichtenberger teaches ultrasonic is alternative to vortex for mixing and stirring in the encapsulation process; Liang et al. teaching water bath ultrasonic in the encapsulation process; it is obvious for one of ordinary skill in the art to ultrasonic bath for vortex and produce instant claimed invention with reasonable expectation of success.
Regarding claims 1-2, 4-5, 7-8, prior art teaches a method of encapsulation therapeutics comprising providing a first liquid as hydrophobic liquid stream comprising polysorbate 80 (surfactant), cholesterol, dimethyldioctadecylammonium bromide (hydrophobic structure) and doxorubicin (hydrophobic cargo molecules) in tert-butanol, and provide a second aqueous stream comprising AuNP (hydrophilic structure materials)-mRNA (hydrophilic cargo molecules) conjugate in aqueous buffer, and combine both streams to form a mixed stream through a millifluidic tubing under ultrasonic bath (obvious at room temperature since not indicated, at 0ºC-37ºC). to form encapsulated therapeutics, followed by purifying the encapsulated therapeutics.
Regarding claim 6, prior art is silent about percentage of polysorbate, cholesterol and DDAB, and one artisan in the art would have been motivated to optimize and obtain those percentage through routing experimentation. MPEP 2144.05. Especially in the absence of showing criticality of claimed range.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
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/JIANFENG SONG/Primary Examiner, Art Unit 1613
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