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 .
Status of Application
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/16/2025 has been entered.
Claims 1,3-4,6-7 and 10-27 are pending.
Claims 2, 5, 8 and 9 have been have been cancelled.
Claim 1 is amended. Claim 27 is new.
Claims 14-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Restriction/Election filed 9/1/2023), there being no allowable generic or linking claim.
Claims 1,3-4,6-7,10-13 and 27 are pending and under examination in this application.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1,3-4,6-7,10-13 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Lombardo et al., “Key for Crossing the BBB with nanoparticles: the rational design” (hereinafter the reference is referred as Lombardo in view of Mukherjee et al., “Lipid-polymer hybrid nanoparticles as a next-generation drug delivery platform: state of the art, emerging technologies, and perspectives” (hereinafter the reference is referred as Mukherjee).
Lombardo teaches that the blood-brain barrier (BBB) is a selective barrier formed by the endothelial cells of the cerebral micro vessels, which at the same time acts as a bottleneck for drug delivery by preventing the vast majority of drugs to reach the brain, and to overcome this obstacle, drugs can be loaded inside nanoparticles (NPs) that can carry the drug through the BBB (abstract) (Lombardo suggests encapsulation). Furthermore, Lombardo disclose specific criteria, factors, NP materials, size and surface properties (functionalization and charge) should be tailored to fit the specific route of BBB crossing when developing a carrier system for this purpose (abstract).
Regarding claims 1, 3, 4, 6, 7, Lombardo teaches strategies to enhance NP BBB permeation comprising nanomaterials that contain at least 50 % of particles in a size range of 1 to 100 nm, solid colloidal NPs in size between 1 and 1000 nm, produced from a variety of different materials including polymers, lipids or inorganic materials, wherein the polymeric NPs are prepared with PBCA and polymers from the poly(ethylene) family, for example, poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid)(PLGA), and a prior art disclose successful delivery of the antinociceptive peptide dalargin in vivo (page 868, left column, ¶ 2). Moreover, Lombardo teaches specific molecules for example nutrients or amino acids and transport proteins GLUT-1, large neutral amino acid transporters (LAT), nucleoside transporters and also organic cation and anion transporters have all been reported to play an important role for sustaining the high metabolic needs of the brain and their substrate can cross the BBB through carrier-mediated transport, wherein these carriers are size and stereo-selective (page 868, right column, 2nd ¶). Additionally, Lombardo discloses Receptor-mediated transcytosis (RMT) and adsorptive mediated transcytosis (AMT) is another path to cross the BBB (page 868 to 870), and strategies to enhance NP BBB permeation, wherein the design of NPs to be able to cross the BBB through transcytosis (as noted above), wherein the NPs surfaces have to be modified, either non-covalently with a coating or covalently by functionalization (page 869 to 870, entire left to right column, 2nd ¶). Additionally, Lombardo discloses the three steps involved in transcytosis (endocytosis, intracellular vesicular trafficking and exocytosis) wherein molecules bind to their receptors on the luminal side of the endothelial cells and endocytosis is initiated, wherein the receptor-ligand complex is invaginated, which leads to the formation of intracellular transport vesicles, and some of the receptors, for example, found on the luminal side of the BBB are transferrin receptor (TfR), insulin and insulin-like growth factor receptor, low-density lipoprotein receptor (LDLR), and the three major categories of endocytic vesicles have been identified and described in the brain endothelial cells: clathrin-coated pits, caveolae and macropinocyctosis vesicles, wherein clathrin-coated pits are involved in most of the internalization processes mediated by receptor TfR or insulin receptors, and after endocytosis, the vesicles converge in the early endosome network, which functions as an intracellular sorting station (page 868 right column, last ¶ to page 869 left column, 1st and 2nd ¶) and another investigated way to increase BB permeation is to use cell-penetrating peptides (CPPs), wherein these peptides are able to enhance membrane penetration and cell internalization of their conjugated cargo in a large variety of cells (page 873 right column, 1st ¶) (this reads on the limitation of interpenetrating network). Furthermore, Lombardo discloses superparamagnetic iron oxide nanoparticles (SPIONs) are based on magnetite (Fe3O4) or maghemite (γ-Fe2O3) molecules encapsulated in polysaccharides, synthetic polymers or monomer coatings and have a size range from 1 to 100 nm (page 877, left column, 2nd ¶). Therefore, the limitations and structural features are met.
Regarding claims 10, 11, 12, Lombardo teaches active agent of small molecule compound, peptide, protein, oligonucleotide, RNA and DNA (entire page 873) and inorganic NPs of non-covalently attached surface ligands, small molecules to proteins and nucleic acids and specific ligands such as transferrin, THR peptide (a transferrin receptor ligand), insulin and CLPFFD peptide, a peptide derived from β-amyloids, and the use of targeting ligands, angiiopep-2, TAT or EGF, allows their accumulation to the be increased in these specific areas (page 876, right column, 2nd and 3rd ¶).
Regarding claim 13, Lombardo teaches apolipoprotein E (ApoE) was adsorbed on the surface of nanoparticles coated with polysorbate 20, 40, 60 or 80 after their incubation in human plasma (page 870 left column, 3rd ¶). Therefore, the limitation of targeting agent bound to the surface of the particles is taught.
Lombardo fails to specifically disclose BBB-crossing agent is tightly anchored on the particle surface and can sustain multiple washing cycles.
Mukherjee teaches that polymeric NPs can be manufactured (via
nanoprecipitation or the double emulsion method) by self-assembly of biodegradable amphiphilic block copolymers with varying hydrophobicities and are appropriate for systemic administration, wherein the core–shell structure of polymeric NPs facilitates encapsulation of hydrophobic drugs and sustained drug release and extends circulation time. Moreover, Mukherjee disclose that their surfaces can also be decorated with ligands for targeted drug delivery. For instance, Genexol-PM is a polymer-based NP formulation of paclitaxel (PCX) and poly (d,l-lactide)-b-polyethylene glycol-methoxy (PLGA-mPEG), which has been approved for metastatic breast cancer therapy in Korea and the European Union, and in order to utilize the unique attributes of liposomes and polymeric NPs that led to their initial clinical success, but overcome limitations like structural disintegration, limited circulation time, and content leakage, a new progeny of delivery system has been developed: lipid–polymer hybrid nanoparticles (LPHNPs). The hybrid system can be a sturdy drug delivery rostrum with high encapsulation efficiency, well-defined release kinetics, well-tolerated serum stability, and well-triggered tissue, cellular, and molecular targeting properties (page 1938, left column last ¶ to right column 1st ¶).
Regarding claim 27, as noted above, Mukherjee teaches particles comprising a biodegradable polymer and a BBB-crossing agent formulated through the double emulsion method. The instant claimed feature of a BBB-crossing agent is tightly anchored on the particle surface and can sustain multiple washing cycles is considered a known and expected result variable because Mukherjee teaches this same method of double emulsion to produce the particles comprising a biodegradable polymer and a BBB-crossing agent. Therefore the limitation of this feature is taught.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to formulate particles comprising a biodegradable polymer and a BBB-crossing agent that is tight attached on the surface thereof as taught by Lombardo in view of Mukherjee. One would have been motivated to increase the permeability of the BBB-crossing agent for drug delivery and would look to the teachings of Mukherjee to improve the formulation process, for example the double emulsion method. One would have been motivated to do so because the combined teaching of Mukherjee discloses nanotechnology with compelling medicinal platform to greatly impact the delivery of small molecule therapeutics, genes, RNAs, peptides for delivery into the brain. One of ordinary skill in the art would have been motivated to do this because all the references are drawn to nanoparticles, drug delivery platform for crossing the Blood-Brain-Barrier.
One of ordinary skill in the art would have found it obvious to apply the different formulation methods of producing BBB-crossing agent for drug delivery to improve permeation and use as taught by Lombardo in view of Mukherjee.
From the combine 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.
It is obvious to combine prior art elements according to the known methods to yield predictable results.
Response to Arguments/Amendments
In view of newly added features in the claims, new obviousness rejections under Lombardo in view of Mukherjee is noted above.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDRE MACH whose telephone number is (571)272-2755. The examiner can normally be reached 0800 - 1700 M-F.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A Wax can be reached at 571-272-0323. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615