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 .
Claim Rejections 35 USC 102(A)(1)
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-7 are rejected under 35 U.S.C. 102(A)(1) as being anticipated by Nguyen et al. (Highly Retina-Permeating and Long-Acting Resveratrol/Metformin Nanotherapeutics for Enhanced Treatment of Macular Degeneration. 4, ACS Nano. 2023, 17, 168−183, published on 12/16/2022).
Nguyen teaches a nanomedicine strategy to develop nanotherapeutics with high retinal permeability and sustained bioactive delivery (abstract). Specifically, Nguyen teaches rationally designed ocular therapeutics made of resveratrol-encapsulated polycaprolactone nanoparticles (R@PCL NPs), followed by the formation of amide linkages with carboxyl-terminated transacting activator of transcription cell penetrating peptide (T) and metformin (M), to form the nanoparticle: R@PCL-T/M NP (Abstract). Nguyen also teaches that such nanotherapeutics demonstrated persistent drug release profiles, good ocular biocompatibility, and potent bioactive activities in vitro, for targeting prevailing risk factors associated with retinal diseases (abstract). This reference further teaches that in vivo studies indicate that single-dose intravitreal administration of the R@PCL-T/M NPs can effectively improve retinal permeability (∼15-fold increase), prevent loss of endogenous antioxidants, and suppress the growth of abnormal vessels in the retina with macular degeneration for 56 days (Abstract). This reference concludes that the high treatment efficacy of R@PCL-T/M NPs can be ascribed to the enhanced retinal permeability of the nanotherapeutics in conjunction with the sustained pharmacological activity of the dual drugs (R and M) in the retinal pigment epithelial region (Abstract).
Nguyen also teaches that teaching that TAT peptides are conjugated (grafted) to the surface of a poly(ɛ-caprolactone)(PCL) nanoparticle, as part of the process of making the nanoparticles, which comprises aminolysis of resveratrol encapsulated PCL NPs (R@PCL NPs) in combination with the formation of amide linkages between R@PCL NPs and carboxyl-terminated TAT CPP and metformin. The process of making the nanoparticles is divided into four main steps (p. 170, Col. 1, and Figure S1) as follows:
(Step I) synthesis of amine-terminated PCL NPs loading with resveratrol (R@PCL NPs-NH2) using a double emulsion method, where 40 mg of resveratrol was first dissolved in 0.5 mL of the oily phase and 50 mL of acetone containing PCL polymer (100 mg) was added, followed by mixing with 50 mL of an aqueous solution containing Pluronic F68 (p. 178, Col. 2) After the emulsion, the dispersion was centrifuged at 65 400g for 10 min, followed by resuspending in deionized water. The R@PCL NPs were achieved after two cycles of washing/centrifuging cycles, which are followed by an aminolysis process with 1,6 hexanediamine to encapsulate the resveratrol in the PCL nanoparticle;
(Step II) combining TAT CPP with maleimide polyethylene glycol carboxylic acid (Maleimide PEG-COOH) linker to form the TAT-PEG-COOH conjugate through a reaction between the sulfhydryl groups of cysteine in TAT and the maleimide group;
(Step III) conjugation of metformin with NHS-PQ-COOH to form metformin-con jugated PQ-COOH (Met-PQ-COOH); and
(Step IV) functionalization of R@PCL NPs-NH2 with both TAT CPP and metformin in the carboxyl-terminated conjugates via an amide bond formation using carbodiimide coupling chemistry, i.e., formulating the R@PCL-T/M NP nanotherapeutics (p. 170, Col. 1).
This reference teaches that TAT CPP competes with metformin during the EDC coupling reaction, therefore, a rationale on their feeding ratios is requisite to achieve an optimized formulation, thus establishing the T/M ratio as a result effective variable (p. 170, Col. 1). This reference further teaches that 1g of amine-terminated R@ PCL NPs was dispersed in 5 mL of a MES buffer containing 0.26 g of EDC, which was then mixed with TAT CPP(1.5 g) and metformin (selected from each amount of 0.15, 0.75, and 1.5 g) in 5 mL of MES buffer, i.e., forming the three R@ PCL-T/M1, R@PCL-T/M2, and R@PCL-T/M3 formulations, respectively (Spanning p. 177, Col. 2- 178, Col. 1). This equates to R/T/M ratios of 1g: 1.5g: .15-.75g, which is directly within the ratios of claim 4 and 1g: 1.5g : .75g is the exact ratio described in claim 5.
Nguyen provides the following schematic of the structural attributes of the resveratrol-containing pol(e-caprolactone) nanoparticles with TAT CPP’s, and metformin grafted on the surface of the nanoparticle for retinal delivery:
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Nguyen teaches that Figure 1. Is a schematic representation of the pharmacological treatment of the neovascular AMD eye using PCL NPs as nanocarriers, a cell penetrating peptide as a retinal penetration enhancer, and resveratrol and metformin as model drugs for synchronic attenuation of oxidative stress, inflammation, and angiogenesis in the diseased retina. Abbreviations: ILM, Inner Limiting Membrane; NFL, Nerve Fiber Layer; GCL, Ganglion Cell Layer; IPL, Inner Plexiform Layer; INL, Inner Nuclear Layer; OPL, Outer Plexiform Layer; ONL, Outer Nuclear Layer; ELM, External Limiting Membrane; PL, Photosensitive Layer; RPE, Retinal Pigment Epithelium; PR, Photoreceptors; BM: Bruch’s Membrane.
Nguyen also teaches that a rat model of experimental AMD was used to assess treatment efficacy in vivo with the R@PCL-T/M NPs, compared to control, Resveratrol alone, Metformin alone, R@PCL (resveratrol nanoparticle), R@PCL-T (resveratrol nanoparticle with TAT peptides on the surface), R@PCL-M (resveratrol nanoparticle with metformin on the surface), and R@PCL-T/M (resveratrol nanoparticle with TAT peptides and metformin on the surface) (Fig. 7). Nguyen found that the highest permeability and the sustained release of metformin was the R@PCL-T/M formulation, which could lower the vascular front density to that of the AMD group (∼37%), suggesting the efficient prevention of choroidal neovascularization progression in neovascular AMD and showing that the that the R@PCL T/M NPs could provide the best treatment efficacy because of their capability of effectively delivering and releasing both metformin and resveratrol in the retinal pigment epithelium regions.
The limitations of claim 1 are met because Nguyen teaches an ophthalmic resveratrol encapsulating PCL nanoparticle carrier with both metformin and TAT grafted to the surface. Claim 2 is met because Nguyen teach nanoparticles sized between 108.1 ± 17.9 and 115.5 ± 19.4 nm (Figure S2), which is directly within the range of 80nm-150nm (p. 170, Col. 2). Claim 3 is met because Nguyen teaches a MW ratio of 1.34, TAT/Metformin (p. 171, Col. 1). Claims 4 and 5 are met because Nguyen teaches each of mixing the resveratrol with PCL in a double emulsion, centrifuging out the precipitate, followed by reacting the precipitate with 1,6 hexanediamine, subjecting both TAT and metformin to conjugation to obtain TAT-PEG-COOH and Met-PQ-COOH, and then attaching (grafting) metformin and TAT to the surface of the R-PCL nanoparticle. Nguyen also teaches the same ratios of claims 4 and 5 (1g: 1.5g: .75g), meeting the limitations of each.
Claim 6 is met because Nguyen teaches a method of treating macular degeneration with the same Resveratrol/PCL/metformin/TAT nanoparticle as claimed. Claim 7 is met because the nanoparticle carrier is in an ophthalmic pharmaceutical formulation for treating AMD.
Conclusion
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/JEANETTE M LIEB/Primary Examiner, Art Unit 1654
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