DETAILED ACTION
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/18/2025 has been entered.
Response to Amendment
Applicant’s response of 12/18/2025 has been received and entered into the application file. Claims 16-19 and 21-35 are pending in this 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 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Bohley et al. (Intracellular availability of poorly soluble drugs from lipid nanocapsules, European Journal of Pharmaceutics and Biopharmaceutics, 03/07/2019), Formica et al. (Triamcinolone acetonide-loaded lipid nanocapsules for ophthalmic applications, International Journal of Pharmaceutics, 2019), Luo et al. (Targeted Intraceptor Nanoparticle Therapy Reduces Angiogenesis and Fibrosis in Primate and Murine Macular Degeneration, ACSNano, 2013), York et al. (WO 2013/023003 A1), and Duncan et al. (Human RPE Cells Express Scavenger Receptors BI and BII, Bioch. And Biophys. Research Communications, 2002).
Bohley discloses that lipid nanocapsules (LNCs) are widely used as delivery systems. Bohley teaches that neovascular ocular diseases are associated with pronounced choroidal or intraretinal neovascularization. Bohley developed antiangiogenic drug-loaded LNCs that allow for choroidal endothelium-specific anti-VEGF therapy (page 23). The αVβ3 integrins were chosen as a promising target for selective nanoparticle delivery, as they are significantly over-expressed during neovascularization. Additionally, integrins stand out due to their high rates of receptor-mediated endocytosis, which could facilitate the intracellular delivery of targeted nanoparticles. Therefore, the highly potent and integrin-specific ligand cyclo(Arg-Gly-Asp-D-Phe-Cys) (RGD) was attached to the LNC surface to target proliferating endothelial cells. Two drugs were chosen: Cyclosporin A (CsA) and itraconazole (It). They are well known and widely used as an immunosuppressant and an antifungal drug, respectively. They both interfere with the VEGF signaling pathway (page 24). CsA is able to suppress the intracellular VEGF signaling pathway and alleviates endothelial cell sprouting and proliferation in vitro. Additionally, CsA counteracts the TGFB-related increase of VEGF production in retinal pigment epithelial cells (page 24, left col). LNCs were prepared by – subjecting Kolliphor HS15, Lipioid S75-3, Medium Chain Triglycerides (MCTs) to three cycles of heating and cooling. Then CsA were dissolved in MCT and particles were prepared as described above (Section 2.3). RGD-peptides were then grafted on LNCs (Section 2.5). The LNCs with a diameter of approximately 50 nm (Section 3.2). Bohley discloses that the proliferation rate of microvascular endothelial cells was decreased with CsA RGD-LNC (Fig. 4).
The method of preparation of lipid nanocapsules taught by Bohley are almost if not identical to the production method described in this application (Example 1).
Formica discloses triamcinolone acetonide-loaded lipid nanocapsules (TA-LNCs) for ophthalmic applications. TA-LNCs showed a high anti-inflammatory activity below the toxicity level, with a reduction of 30% of interleukin (IL)-6 secretion observed in an in vitro model. The TA-LNCs revealed a therapeutic efficacy in the endotoxin-induced uveitis (Abstract). Formica teaches that LNCs are composed of an oily liquid triglyceride core surrounded by a surfactant rigid membrane which can convey both hydrophobic and hydrophilic active ingredients (page 2, left col). Formica discloses similar production method as discussed by Bohley above – Kolliphor HS15 and Lipoid S75-3 and co-surfactants (oleic acid or Captex 500p) were mixed and three cycles of heating and cooling were performed. Then TA was added. For TA-LNCs, drug incorporation in formulations with a lipid core composed of a 20% co-surfactant (oleic acid or Captex 500p) was investigated (Section 2.3).
Luo discloses that leading retinal causes of blindness (e.g., age-related macular degeneration, angioid streaks, choroidal rupture, and high myopia) share the development of choroidal neovascularization (CNV). Currently, the primary treatment for CNV consists of monthly injections of antibody-based inhibitors of VEGF into the vitreous (pg 3264). CNV also involves subretinal fibrosis, which can adversely affect vision even if angiogenesis resolves. Unfortunately, current treatments for AMD do not address fibrosis. Therefore, combinations of antiangiogenic and antifibrotic factors with long-term effects have been suggested to more effectively improve vision. Integrins are the main mediators of the interaction between fibroblasts and extracellular matrix (ECM) during scar formation. The tripeptide adhesion motif Arg-Gly-Asp (RGD) is contained in the ECM and binds Rvβ3 and R5β1 integrins, which are selectively expressed in areas of neovascularization and scarring (pg 3265). Luo developed an intracellular antiangiogenic therapy relying on a three-component system:14 (1) Plasmids expressing Flt23k intraceptors, which consists of the VEGF-binding domains 2-3 of Flt (the highest affinity VEGF receptor); (2) PLGA biodegradable nanoparticles as a delivery system; (3) the tripeptide adhesion motif Arg-Gly-Asp (RGD) to coat nanoparticles and facilitate selective homing to CNV after systemic intravenous injection (pg 3265). In conclusion, RGD-targeted nanoparticles delivering Flt23k intraceptor plasmids offer a new pathway to ocular drug delivery via systemic administration, successfully suppressing neovascularization and fibrosis in models of macular degeneration while avoiding significant drawbacks associated with intraocular injection of anti-VEGF agents (pg 3272).
Both Bohley and Formica teach a method of preparing lipid nanocapsules by using a phase inversion temperature (PIT) process as mentioned above. Both references describe that LNCs are useful for delivering active ingredients into the eye. Luo teaches that a RGD-targeted nanoparticles can be administered via systemic administration instead of local administration.
Above references do not disclose scavenger receptors.
York discloses nanoparticle compositions and treatment of cardiovascular disease using nanoparticles to target Class A and B scavenger receptors (Abstract). The nanoparticle comprises a hydrophobic core and a bioactive amphiphilic shell ([0005]). The present invention provides a method to detect a scavenger receptor or a CD36 receptor expressed by a cell comprising contacting a cell with a pharmaceutical composition comprising one or more nanoparticles ([0016]). In a further embodiment, the pharmaceutical composition may further comprise at least one diagnostic or targeting agent or both ([0012]). Targeting agents refer to ligands ([0064]).
York does not mention retinal disease.
Duncan discloses that the retinal pigment epithelial (RPE) cells that underlie the retina ingest and metabolize thousands of lipid-rich photoreceptor outer segments (POS) every day. The scavenger receptor (SR) CD36 and integrin avb5 have been shown to participate in POS binding and internalization by RPE cells (Abstract). A scavenger receptor, CD36, has been detected in RPE cells (pg 1017, right col).
One of ordinary skill in the art would immediately envisage that a nanoparticle comprising a targeting ligand for a scavenger receptor would bind to cells expressing those receptors such as CD36 in RPE cells.
Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined teachings of Bohley and Formica to create a nanoparticle comprising a core, an amphiphilic shell and a targeting ligand coupled to said amphiphilic shell for treating a retinal disease in addition to exploring various administration routes, whether it be systemic or local injection. York discloses that a nanoparticle is used to target specific receptors such as scavenger receptors. Duncan teaches that RPE cells express scavenger receptors. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claim 17, Formica discloses that the ocular use of TA is based on its anti-inflammatory and immunomodulatory properties, which inhibit the inflammatory and angiogenic processes. TA affects the vascular endothelial cells (Discussion Section, 1st paragraph). Bohley discloses that free CsA inhibited cell proliferation more effectively in the presence of VEGF. Additionally, CsA RGD-LNCs and It + CsA RGD-LNCs induced significant decreases in proliferation rate compared to the untreated control (page 27, left col). One of ordinary skill in the art would envisage that nanoparticles comprising TA or CsA would suppress or reduce retinal neovascularization or inflammation or immune-response in the eye.
Claims 18-19, and 21-35 are rejected under 35 U.S.C. 103 as being over Bohley et al. (Intracellular availability of poorly soluble drugs from lipid nanocapsules, European Journal of Pharmaceutics and Biopharmaceutics, 03/07/2019), Formica et al. (Triamcinolone acetonide-loaded lipid nanocapsules for ophthalmic applications, International Journal of Pharmaceutics, 2019), Luo et al. (Targeted Intraceptor Nanoparticle Therapy Reduces Angiogenesis and Fibrosis in Primate and Murine Macular Degeneration, ACSNano, 2013), York et al. (WO 2013/023003 A1), and Duncan et al. (Human RPE Cells Express Scavenger Receptors BI and BII, Bioch. And Biophys. Research Communications, 2002) as applied to claims 16-17 above, and further in view of Rodriguez et al. (EP 2656837 A1, 2012) as evidenced by Burnett (PEGylated Oils, CIR Expert Panel Meeting, 2012).
Rodriguez teaches a lipid nanoparticle system, where the nanoparticles comprise a nucleic acid, a lipid component, a cationic surfactant, a non-ionic surfactant, a polysaccharide and optionally a peptide for the treatment and prevention of eye diseases (Abstract). Rodriguez discloses that the nanoparticle formulation comprises at least one solid lipid at room temperature which is part of the nanoparticle core ([0023]); this includes triglycerides or saturated fatty acids with a chain of at least 10 carbon atoms ([0023-0025]). Non-ionic (both hydrophobic and hydrophilic) surfactant can be used within the nanoparticle formulation ([0036]). The positively charged peptide can be RGD peptides (cell surface recognition peptides containing the arg-gly-asp sequence and variants thereof) ([0049]). The nanoparticle comprises nucleic acids such as ribonucleotides or deoxyribonucleotide ([0057]). The term “eye diseases” includes any disease, disorder or condition affecting the eye ([0060]). This includes retinal degenerative diseases ([0062]), corneal dystrophies ([0063]). Rodriguez discloses that glaucoma can be targeted with this nanoparticle system by introducing regulatory activity on gene expression (page 8 & [0073]).
Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined teachings of above to arrive at a nanoparticle comprising a core, shell, a targeting ligand for potentially treating a retinal disease as well as glaucoma. Depending on which drug is encapsulated and released from nanoparticles, the activities of such drug would also be different. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claim 19, Rodriguez teaches that “prevention or treatment” means improving, relieving, or eliminating one or more symptoms associated with eye diseases ([0074]). In the exemplary case of glaucoma, it would be overexpressing MMP1 (page 8). Additionally, CsA is able to suppress the intracellular VEGF signaling pathway and alleviate endothelial cell sprouting and proliferation (page 24). Therefore, a nanoparticle system comprising CsA would inherently have those activities if CsA was properly released from the nanoparticle within the eye.
Regarding claim 21, a drug having one or several activities listed is discussed above.
Regarding claim 22, nucleic acids as well as cyclosporin A are discussed above.
Regarding claim 23, phospholipid is discussed above.
Regarding claim 24, Bohley discusses CsA can be loaded in LNCs containing MCT as the oily core (page 27, 5th paragraph).
Regarding claim 25, a similar preparation method of producing the nanoparticle of claim 16 is already discussed above.
Regarding claim 26, triglycerides are discussed above.
Regarding claim 27, Bohley discloses that drug-loaded LNCs with particle sizes around 50 nm were grafted with an integrin (Abstract).
Regarding claim 28, Bohley teaches that a significantly higher internalization of TGD-LNCs confirmed the interaction between the RGD peptide and integrins on the cell surface of endothelial cells (Section 3.3). One of ordinary skill in the art would immediately envisage that a targeting ligand would increase the nanoparticle concentration by higher internalization of RGD-LNCs.
Regarding claim 29, the instant specification defines “enrichment” to mean “accumulation”. As stated above in claim 28, nanoparticle comprising a targeting ligand would yield higher internalization of said nanoparticle, resulting in accumulation in the eyes.
Regarding claim 30, local or systemic administration is discussed above.
Regarding claim 31, glaucoma is discussed above.
Regarding claim 32, integrin is discussed above.
Regarding claim 33, glyceryl polyethylene glycol ricinoleate is also known as PEG castor oil. Rodriguez discloses castor oil ([0029]) and ricinoleate can easily be derived from castor oil. Furthermore, Burnett evidences that PEGylated castor oils are often used in cosmetics (page 1).
Regarding claim 34, lipophilic drugs are discussed above.
Regarding claim 35, triglycerides are discussed above.
Response to Arguments
Applicant’s arguments filed 12/18/2025 have been fully considered and new references are incorporated to maintain the rejection.
Conclusion
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/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615