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 .
Receipt is acknowledged of Amendments and remarks filed on 07/09/26. The Specification and claims 15, 21-22, 28-29 and 32-34 have been amended, no claims have been canceled, and no new claims have been added. Accordingly, claims 15-34 remain pending and under examination on the merits.
Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
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.
The factual inquiries 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 15-34 are rejected under 35 U.S.C. 103 as being unpatentable over Raemdonck et al (US 20190328768) in view of Chen et al (Cationic nanoparticles induce nanoscale disruption in living cell plasma membranes) and Raemdonck et al (Biodegradable dextran nanogels for RNA interference: Focusing on endosomal escape and intracellular siRNA delivery), herein Raemdonck et al 2.
Raemdonck et al ‘768 teach a method and compositions for optimized intracellular delivery of active agents, in particular nucleic acids, using a specific class of adjuvants. The said method and compositions enhance cytosolic release of the agents and can be used for the treatment of various disorders. Disclosed is a combination comprising a small non-coding RNA or antisense oligonucleotide, a polymeric nanoparticle and at least one cationic amphiphilic compound (See abstract, [0009] and claim 1).
Regarding claims 15, 18 and 29, Raemdonck et al teach that the nanocarrier is a polymeric nanoparticle, in particular a dextran nanogel and is coupled to or comprises an active agent. The said method, composition, kit or combination are particularly useful for delivering an agent, such as a membrane-impermeable agent, into the cytosol of a cell by release of the agent from the lysosomal compartment. The agent can be a diagnostic or therapeutic agent, in particular a nucleic acid, more in particular a small interfering RNA (siRNA) (See [0011]-[0012]).
Further regarding claims 15, 18 and 29, Raemdonck et al teach that preferably, the cationic agent may be a polycationic agent such as chitosan, peptides, polyethylenimine, poly(amido ethylenimine), etc. A preferred polycationic agent is a polymer, preferably dextran, which is functionalized with a reactive (meth)acrylate moiety and subsequently co-polymerized with a cationic (meth)acrylate monomer such as 2-aminoethyl methacrylate, 2-(diethylamino)ethyl methacrylate, 2-(dimethylamino)ethyl methacrylate, 2-N-morpholinoethyl methacrylate, 2-(tert-butylamino)ethyl methacrylate, 2-(diisopropylamino)ethyl methacrylate, [2-(methacryloyloxy)-ethyl]trimethylammonium chloride (See [0044]).
Also, regarding claims 15, 18 and 29, Raemdonck et al teach a method for delivering small non-coding RNA or antisense oligonucleotide into the cytosol of a cell, the method comprising administering the said combination to the cell (See [0030] and claim 16).
Regarding claims 21-22 and 32-33, in part, Raemdonck et al teach synthesis of cationic dextran nanogels wherein dispersion of lyophilized NG (dex-HEMA with a degree of substitution (DS) of 5.2) was prepared in ice-cooled nuclease free water and sonicated briefly (See [0068]).
Regarding claim 25, Raemdonck et al teach synthesis of cationic dextran nanogels and loading siRNA, wherein the mixture is incubated for 4 hours (See [0027]).
Regarding claim 26, Raemdonck et al teach a method of delivering an agent into the cytosol of a cell by in vitro, ex vivo or in vivo application (See [0012], [0036] and [0051]).
Regarding claim 27, Raemdonck et al teach that the cells may be cell lines (See [0071]).
Regarding claims 28 and 34, Raemdonck et al teach that said compositions comprising the nanocarriers may be administered in a number of ways, e.g. by oral administration, by inhalation (e.g. intranasally or orally), by injection (into the blood stream or directly into a site requiring treatment), as topical use, or incorporated within a slow- or delayed-release device (See [0062]).
Raemdonck et al ‘768 lack an express disclosure on the sequential delivery. This is rendered obvious by the disclosure and Chen et al. Raemdonck et al ‘768 also lack specific disclosure on the specific polycationic material of claims 19-20 and 30-31 or the zeta potential of the dextran nanogel. These limitations would have been obvious to incorporate in view of the teachings of Raemdonck et al 2.
Chen et al teach that it has long been recognized that cationic nanoparticles induce cell membrane permeability. Recently, it has been found that cationic nanoparticles induce the formation and/or growth of nanoscale holes in supported lipid bilayers. In this paper, we show that noncytotoxic concentrations of cationic nanoparticles induce 30-2000 pA currents in 293A (human embryonic kidney) and KB (human epidermoid carcinoma) cells, consistent with a nanoscale defect such as a single hole or group of holes in the cell membrane ranging from 1 to 350 nm2 in total area. There is significant evidence that exposure of cells to many types of nanoparticles results in enhanced porosity of the cellular membrane with implications for drug and gene delivery (See abstract and Introduction).
The experimental results show the following: (a) exposure of cells to noncytotoxic levels of cationic nanoparticles results in the formation of defects that enhance conductance through the cellular membrane, (b) these defects can “recover” over time allowing a decrease in transmembrane conductance toward its original value, and (c) the size scale of these defects is comparable to that observed in model membrane studies by AFM and large enough to explain the observed diffusion of macromolecules through the cellular membrane (See Page 11179, 2nd col).
Chen et al teach that “poly(ethyleneimine) (PEI), poly-L-lysine (PLL), generations 5 and 7 poly(amidoamine) (PAMAM) dendrimers (G5-NH2 and G7-NH2, respectively), poly(vinylalcohol) (PVA), and poly (ethyleneglycol) (PEG) were selected for this study because they represent an important group of biomedical polymers being developed for drug and gene delivery applications (See Page 11180, 1st col. 1st full para).
Raemdonck et al 2 teach the successful therapeutic application of small interfering RNA (siRNA) largely relies on the development of safe and effective delivery systems that are able to guide the siRNA therapeutics to the cytoplasm of the target cell. Thus, the potential of biodegradable cationic dextran nanogels as siRNA carriers is evaluated. The nanogels are able to entrap siRNA with a high loading capacity, based on electrostatic interaction. Furthermore, it is shown that an efficient gene silencing requires the degradation of the nanogels. As the degradation kinetics of the nanogels can easily be tailored, these particles show potential for intracellular controlled release of short interfering RNA (See abstract).
Raemdonck et al 2 also state that the intracellular siRNA release mechanism is shown by performing control experiments with nondegradable dex-MA-co-TMAEMA nanogels. The accumulation of nanogel degradation products in the endosomal lumen is able to disrupt the vesicular membrane, possibly through an osmotic effect, thereby releasing active siRNA into the cytosol (See page 1412, 1st col. last para).
Regarding claims 22 and 33, Raemdonck et al 2, teach that adding TMAEMA to the aqueous dex-HEMA solution before emulsification enables copolymerization of this methacrylate monomer with dex-HEMA in the emulsion droplets, leading to nanogels with a cationic surface charge, as revealed from zeta-potential measurements (Table 1). Increasing the amount of TMAEMA increased the surface charge of the nanogels, indicating that more TMAEMA groups became incorporated in the nanogel network.
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(See Page 1407).
It would have been prima facie obvious to a person of ordinary skilled in the art at the time the invention was made to have combined the teachings of Chen et al and Raemdonck et al 2 with Raemdonck et al ‘768 to arrive at the instant invention. It would have been obvious to do so because Raemdonck et al ‘768 is directed to cellular delivery of cell-impermeable compounds such as siRNA via a carrier including a polycationic material such as dextran nanogel. Raemdonck et al ‘768 discloses that the polymeric nanoparticle, in particular a dextran nanogel and is coupled to or comprises an active agent. Thus, while in some embodiments Raemdonck et al discloses making a complex of the two, it is also disclosed that they can be in combination or in each other’s presence without complexation. Additionally, Chen et al teach that cationic nanoparticles /polymers such as polycationic polymers are effective cell membrane disruptors and good for drug and gene delivery applications. The combined references teach that the cell delivery can be either by carrier material or by membrane disruption. Thus, one of ordinary skill in the art given both references would have easily deduced that the effective combination of polycationic polymers and a gen or drug compound can be in a composition and effective in drug delivery to the cells for various treatments. This also encompasses sequential delivery.
Raemdonck et al ‘768 is also silent regarding the zeta potential of the dextran nanogel. However, Raemdonck et al 2 teaches that measuring and maintaining the zeta potential of the said polycationic nanogel is important in determining the surface charge of the particle specially at cell membrane. Raemdonck et al 2 teaches a range of zeta potentials for the said polymers. Also, Raemdonck et al 2 teaches specific crosslinked polycationic polymers as claimed. One ordinary skill in the art is more than motivated to incorporate the said limitations into the method and compositions of Raemdonck et al ‘768 with a reasonable expectation of success.
In other words, the claims would have been obvious because the technique for improving a particular formulation was part of the ordinary capabilities of a person of ordinary skill in the art, in view of the teaching of the technique for improvement in other situations. That is measuring the zeta potential and mainlining the zeta potential of the said nanogels provides for an optimum result in cellular delivery.
From the combined teaching of the cited references, 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, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Stewart et al (In vitro and ex vivo strategies for intracellular delivery).
Stewart et al teach that intracellular delivery of materials has become a critical component of genome-editing approaches, ex vivo cell-based therapies, and a diversity of fundamental research applications. The study focuses on membrane-disruption-based delivery methods and the transformative role of nanotechnology, microfluidics and laboratory-on-chip technology in advancing the field (See abstract).
Regarding claims 16-17, Stewart et al, teaches that intracellular delivery can be achieved by a range of carrier-based or membrane-disruption-based techniques. Unlike carriers, membrane-disruption-based approaches are less dependent on cargo properties, being able to deliver almost any submicrometre material dispersed in solution. The ability to rapidly switch membrane-perturbing effects on and off enables temporal control and rapid, almost instantaneous delivery. A further strength of membrane-disruption techniques in vitro and ex vivo is the broad range of cell types and materials that can be addressed. Membrane-disruption-based approaches may furthermore be combined with carriers to synergize the strengths of both, such as by delivering a nuclear-targeted DNA lipoplex to the cytoplasm. Membrane-disruption-based delivery has also enabled several protein-delivery applications, featuring antibodies, etc, (See page 185, 1st col and paragraph bridging pages 186-187).
Response to Arguments
Applicant’s arguments with respect to claim(s) 15-34 have been considered but are moot because the new ground of rejection does not rely on the primary reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Claims 15-34 are rejected.
Applicants’ amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for replying 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mina Haghighatian whose telephone number is (571)272-0615. The examiner can normally be reached M-F, 7-5 EST.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616
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