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 .
Summary
Claims 1-7, 9-10, and 12-22 are pending in this office action. Claims 8 and 11 are cancelled. All pending claims are under examination in this application.
Priority
The current application was filed on January 8, 2024 is a 371 of PCT/US2022/073598 filed July 11, 2022, which in turn claims domestic priority to provisional patent application 63/203,128 filed on July 9, 2021.
Information Disclosure Statement
Receipt of the Information Disclosure Statements dated January 8, 2024 and August 23, 2024 (3) are acknowledged. A signed copy of the four documents are attached to this office action.
Claim Objections
Claim 10 is objected to because of the following informality:
Claim 10 needs to identify the full sequence of SEQ ID NO: 1 within the claim. The Applicant cannot refer to just the SEQ ID in order for the reader to refer to the specification.
Appropriate correction is required.
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 non-obviousness.
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 1-7, 9-10, 12-22 are rejected under 35 U.S.C. 103 as being unpatentable over Yi et al. (Advanced Functional Materials, 2019) in view of Li et al. (CN111617036A), Nair et al. (WO2019/217459A1), Shi et al. (Journal of Gynecologic Oncology, 2015), and Eixenberger et al. (US2019/0388559A1).
[The Examiner is going to introduce each reference and then combine them where appropriate to reject the instant claims.]
1. Yi et al.
Yi et al. is considered the closest prior art as it teaches surface engineered polymersomes for enhanced modulation of dendritic cells during cardiovascular immunotherapy (see title). In addition, Yi et al. disclose that the principle cause of cardiovascular disease (CVD) is atherosclerosis, a chronic inflammatory condition characterized by immunologically complex fatty lesions within the intima of arterial vessel walls. Dendritic cells (DCs) are key regulators of atherosclerotic inflammation, with mature DCs generating pro-inflammatory signals within vascular lesions and tolerogenic DCs eliciting atheroprotective cytokine profiles and regulatory T-cell (Treg) activation. Here, the surface chemistry and morphology of synthetic nanocarriers composed of poly(ethylene glycol)-b-poly(propylene sulfide) copolymers to enhance the targeted modulation of DCs by transporting the anti-inflammatory agent 1,25-dihydroxyvitamin D3-(aVD) and ApoB-100-derived antigenic peptide P210 are engineered. Polymersomes decorated with an optimized surface display and density for a lipid construct of the P-D2 peptide, which binds CD11c on the DC surface, significantly enhance the cytosolic delivery and resulting immunomodulatory capacity of aVD in vitro. Weekly low dose intravenous administration of DC-targeted, aVD-loaded polymersomes significantly inhibit atherosclerotic lesion development in high-fat-diet-fed ApoE−/− mice. The results validate the key role of DC immunomodulation during aVD-dependent inhibition of atherosclerosis and demonstrate the therapeutic enhancement and dosage lowering capability of cell-targeted nanotherapy in the treatment of CVD (see abstract).
2. Li et al.
Li et al. teach targeted controlled-release anti-arthritis medicinal preparation and preparation method thereof (see title). Furthermore, Li et al. disclose that the invention belongs to the technical field of polymer chemistry, biomedical materials and pharmacy, and discloses a targeted controlled-release anti-arthritis medicinal preparation and a preparation method thereof. The pharmaceutical preparation is a drug-loaded micelle, the drug-loaded micelle is composed of a segmented copolymer PEG-PPS and tripterine, and the tripterine is loaded in the micelle formed by the segmented copolymer PEG-PPS. The preparation method comprises the following preparation steps: (1) dissolving 20-80 parts by mass of PEG-PPS and 1-10 parts by mass of tripterine in 5-10 parts by volume of tetrahydrofuran; and (2) under ultrasonic dispersion, adding the solution obtained in the step (1) into 50-100 parts by volume of water, carrying out vacuum distillation to remove tetrahydrofuran, and carrying out repeated ultrafiltration and sterile microporous filtration membrane filtration to obtain the anti-arthritis nano-drug preparation. The medicinal preparation disclosed by the invention is sensitive to rheumatoid arthritis inflammation, controllable release of the medicine can be realized, and joint synovitis and bone erosion can be obviously inhibited (see abstract).
3. Nair et al.
Nair et al. teach extrahepatic delivery (see title). Additionally, Nair et al. disclose that the invention relates to a method of gene silencing, comprising administering to a cell or a subject in need thereof a therapeutically effective amount of the lipophilic moieties-conjugated double-stranded iRNAs at one or more internal positions on at least one strand, optionally via a linker or carrier (see abstract).
4. Shi et al.
Shi et al. teach identification of high-affinity VEGFR3-binding peptides through a phage-displayed random peptide library (see title). Furthermore, Shi et al. disclose the following abstract:
Objective: Vascular endothelial growth factor (VEGF) interaction with its receptor, VEGFR-3/Flt-4, regulates lymphangiogenesis. VEGFR-3/Flt-4 expression in cancer cells has been correlated with clinical stage, lymph node metastasis, and lymphatic invasion. The objective of this study is to identify a VEGFR-3/Flt-4-interacting peptide that could be used to inhibit VEGFR-3 for ovarian cancer therapy.
Methods: The extracellular fragment of recombinant human VEGFR-3/Flt-4 (rhVEGFR-3/Flt-4) fused with coat protein pIII was screened against a phage-displayed random peptide library. Using affinity enrichment and enzyme-linked immunosorbent assay (ELISA) screening, positive clones of phages were amplified. Three phage clones were selected after four rounds of bio-panning, and the specific binding of the peptides to rhVEGFR-3 was detected by ELISA and compared with that of VEGF-D. Immunohistochemistry and immunofluorescence analyses of ovarian cancer tissue sections was undertaken to demonstrate the specificity of the peptides.
Results: After four rounds of bio-panning, ELISA confirmed the specificity of the enriched bound phage clones for rhVEGFR-3. Sequencing and translation identified three different peptides. Non-competitive ELISA revealed that peptides I, II, and III had binding affinities for VEGFR-3 with Kaff (affinity constant) of 16.4±8.6 μg/mL (n=3), 9.2±2.1 μg/mL (n=3), and 174.8±31.1 μg/mL (n=3), respectively. In ovarian carcinoma tissue sections, peptide III (WHWLPNLRHYAS), which had the greatest binding affinity, also co-localized with VEGFR-3 in endothelial cells lining lymphatic vessels; its labeling of ovarian tumors in vivo was also confirmed.
Conclusion: These finding showed that peptide III showed high specificity and activity and, therefore, may represent a potential therapeutic approach to target VEGF-VEGFR-3 signaling for the treatment or diagnosis of ovarian cancer.
5. Eixenberger et al.
Eixenberger et al. teach encapsulation of metal oxide nanomaterials for controlled release and targeted delivery (see title). Also, Eixenberger et al. disclose that the present invention is directed to micro and nanosized capsule compositions and methods of using and making the capsule compositions. The capsule compositions comprise an outer layer of lipids and/or polymers and inner contents comprising semiconductor nanoparticles. The nanoparticles are either metal oxides or quantum dots and will produce reactive oxygen species when irradiated with either electromagnetic radiation or ultrasound. The reactive oxygen species will degrade the outer layer of the capsule and cause the release of the contents, including the reactive oxygen species, into the local environment. The contents may optionally include cancer treating agent, water treating agents, antimicrobials, imaging and/or contracting agents. The outer layer may be further coated to protect it from environmental factors and/or be conjugated with a targeting molecule to increase delivery to a target (see abstract).
Combination of Yi et al., Li et al., Nair et al., and Shi et al.
Regarding instant claim 1, Yi et al., Li et al., Nair et al., and Shi et al. teach a system for targeted delivery of a therapeutic agent to a Schlemm's canal (SC) endothelial cell. The necessary citations of Yi et al., Li et al., Nair et al., and Shi et al. that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Yi et al., Li et al., Nair et al., and Shi et al. Citations
A system for targeted delivery of a therapeutic agent to a Schlemm's canal (SC) endothelial cell, the system comprising:
Nair et al. disclose the preparation of a therapeutic agent for delivery within a subject (see title, abstract, and paragraph [0006] all within Nair et al.). Furthermore, Nair et al. disclose the intracanalicular injection may be into the venous collector channels draining Schlemm's canal or into Schlemm's canal (SC) (flattened tube made of endothelial cells; see PTO-892 NPL 2X and 3U) (see paragraph [0728] within Nair et al.).
a. a nanocarrier comprising a poly(ethylene glycol)-block-poly(propylene sulfide) (PEG-b-PPS) copolymer; b. the therapeutic agent loaded in the nanocarrier; and c. a targeting moiety that targets SC endothelial cells incorporated into the surface of the nanocarrier;
Yi et al. disclose the surface chemistry
and morphology of synthetic nanocarriers composed of poly(ethylene glycol)-b-poly(
propylene sulfide) copolymers to enhance the targeted modulation of dendritic cells (DC)
by transporting the (therapeutic agent)… (see abstract within Yi et al.).
Yi et al. incorporate a polypeptide within the nanocarrier in order to target DC (different from SC) (see Figure 1 and page 2 of 16, right column, paragraph 1; both within Yi et al.).
However, Shi et al. identifies the polypeptide to target the SC. Shi et al. identifies that non-competitive ELISA revealed that peptide III had binding affinities for VEGFR-3 of 174.8±31.1 μg/mL (see Discussion, page 9 of 19 within Shi et al.). Peptide III (WHWLPNLRHYAS) binds to the VEGFR-3/Flt-4 receptor (see abstract and Discussion, page 9 of 19 within Shi et al.). Thus, a skilled artisan (POSITA; person having ordinary skill in the art) would substitute the targeting polypeptide within Shi et al. for the targeting polypeptide within Yi et al. under routine experimental conditions. This modification would ensure targeting of the VEGFR-3/FLT-4 receptor and the SC cells which express this lymphatic lineage receptor (see PTO-892 NPL 3U).
Additionally, Li et al. disclose a drug-loaded micelle is composed of block copolymer PEG-PPS and (therapeutic agent), and (the therapeutic agent) is loaded in micelles formed by block copolymer PEG-PPS (see claim 1 within Li et al.).
wherein the targeting moiety comprises: i. a peptide that specifically binds to SC endothelial cells; ii. a polyethylene glycol (PEG) spacer; and iii. a hydrophobic anchor.
Yi et al. disclose the general motif:
Targeting peptide – PEG spacer – hydrophobic tail (anchor)
(see Figure 1B within Yi et al.). Following the simple substitution protocol as discussed directly above targeting of the SC cells would be accomplished.
Therefore, a skilled artisan (POSITA) would consult the disclosures of Yi et al., Li et al, Nair et al., and Shi et al. to teach all the elements of instant claim 1.
The remainder of the instant claims which are either directly or indirectly dependent on claim 1 are taught in full by the combination of Yi et al., Li et al., Nair et al., and Shi et al.
Regarding instant claim 2, Yi et al., Li et al., Nair et al., and Shi et al. teach wherein the nanocarrier is a micelle. Li et al. disclose the nanocarrier is a micelle (see claim 1; also see paragraph [0035] indicating the micelle is a nanomedicine formulation within Li et al.).
Regarding instant claims 3 and 4, Yi et al., Li et al., Nair et al., and Shi et al. teach wherein the nanocarrier has a diameter within the range of 5 nm to 60 nm or 100 nm to 300 nm. Li et al. disclose the particle size of the obtained nanomedicine formulation is between 60 and 220 nm, with an average particle size of 110 nm (see paragraph [0035] within Li et al.).
Regarding instant claims 9 and 10, Yi et al., Li et al., Nair et al., and Shi et al. teach wherein the peptide binds to a FLT4/VEGFR3 receptor and has a sequence of SEQ ID NO:1. Please see the discussion and citations within Shi et al. of Table I for the relevant rejection text. [SEQ ID NO:1 = WHWLPNLRHYAS].
Regarding instant claims 12 and 13, Yi et al., Li et al., Nair et al., and Shi et al. teach wherein the molar ratio of the targeting moiety to the PEG-b-PPS copolymer is from 1% to 5%. Yi et al. disclose he molar ratio of the targeting moiety to the PEG-b-PPS copolymer is from 1% to 5% (see Table 1 within Yi et al.).
Regarding instant claim 14, Yi et al., Li et al., Nair et al., and Shi et al. teach wherein the PEG spacer has from 6 to 48 units. Yi et al. disclose wherein the PEG spacer has from 0 to 16 units (overlapping region; see page 3 of 16, left column, paragraph 2 within Yi et al.).
Regarding instant claim 16, Yi et al., Li et al., Nair et al., and Shi et al. teach wherein the hydrophobic anchor is palmitoleic acid. Yi et al. disclose wherein the hydrophobic anchor is palmitoleic acid (see page Figure 1 within Yi et al.).
Regarding instant claim 17, Yi et al., Li et al., Nair et al., and Shi et al. teach the pharmaceutical composition containing and one or more pharmaceutically acceptable carriers. Yi et al. disclose a pharmaceutical composition containing and one or more pharmaceutically acceptable carriers (see injection data within Section 1.5 on page 6 of 16 within Yi et al.). Although not specifically disclosed by Yi et al. a skilled artisan (POSITA) using the Yi et al. disclosure (injection data) would select from one or more pharmaceutically acceptable carriers.
Combination of Yi et al., Li et al., Nair et al., Shi et al., and Eixenberger et al.
Regarding instant claims 6 and 7, Yi et al., Li et al., Nair et al., Shi et al., and Eixenberger et al. teach wherein the therapeutic agent is a cell softening agent such as latrunculin A. Eixenberger et al. disclose the cell softening agent (see PTO-892 NPL 2U), latrunculin A (see paragraph [0084] within Eixenberger et al.).
Regarding instant claim 18, Yi et al., Li et al., Nair et al., Shi et al., and Eixenberger et al. teach a method of reducing the intraocular pressure (IOP) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the system of instant claim 1. Eixenberger et al. disclose the therapeutic agent, latrunculin A (please see the discussion and citations within instant claims 6 and 7). Incorporation of this therapeutic agent into the nanocarrier of instant claim 1 would afford a pharmaceutical composition for reducing IOP within a patient (see PTO-892 NPL 2V).
Regarding instant claims 19 and 22, Yi et al., Li et al., Nair et al., Shi et al., and Eixenberger et al. teach wherein the therapeutic agent is latrunculin A and the concentration of latrunculin A in the pharmaceutical composition is 0.05 mM-20 mM. Commercial sources of latrunculin A are supplied as a solution having a common molarity between 1 and 10 mM (see PTO-892 NPL 2W). This would ensure these claim limitations would be met by a skilled artisan (POSITA).
Regarding instant claim 20, Yi et al., Li et al., Nair et al., Shi et al., and Eixenberger et al. teach wherein the IOP is reduced by at least 35% after 24 hours from the administration. Reduction of IOP would be observed by a skilled artisan (POSITA). The pharmaceutical composition of instant claim 1 incorporating latrunculin A would target the SC cells and afford an IOP reduction. Routine administration and data collection by a skilled artisan (POSITA) would ensure at least a 35% reduction of IOP after 24 hours from the administration.
Regarding instant claim 21, Yi et al., Li et al., Nair et al., Shi et al., and Eixenberger et al. teach a method of treating glaucoma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the system of instant claim 1. Nair et al. disclose the treatment of glaucoma (see paragraphs [0552-0555] within Nair et al.). Furthermore, latrunculin A can be used both as an IOP reducing agent and in the treatment of glaucoma (see PTO-892 NPL 2U and 2V). Preparation of the pharmaceutical composition of instant claim 1 incorporating latrunculin A would, therefore be used to treat glaucoma (used to soften trabecular meshwork cells, reducing intraocular pressure; see PTO-892 NPL 2U) as well as IOP.
Analogous Art
The Yi et al., Li et al., Nair et al., Shi et al., and Eixenberger et al. references are directed to the same field of endeavor as the instant claims, that is, a system for targeted delivery of a therapeutic agent to a Schlemm's canal (SC) endothelial cell, the system comprising:a. a nanocarrier comprising a poly(ethylene glycol)-block-poly(propylene sulfide) (PEG-b- PPS) copolymer; b. the therapeutic agent loaded in the nanocarrier; and c. a targeting moiety that targets SC endothelial cells incorporated into the surface of the nanocarrier; wherein the targeting moiety comprises: i. a peptide that specifically binds to SC endothelial cells; ii. a polyethylene glycol (PEG) spacer; and iii. a hydrophobic anchor.
Obviousness
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 modify the nanocarrier disclosed by Yi et al., using the teachings of Li et al., Nair et al., Shi et al., and Eixenberger et al.to incorporate the necessary claim limitations.
Motivation to combine the Yi et al., Li et al., Nair et al., Shi et al., and Eixenberger et al. references would rely on the common theme of a nanocarrier for the treatment of IOP and glaucoma within these disclosures. Both Yi et al. and Li et al. support the synthesis of the nanocarrier of the present application. Nair et al., Shi et al., and Eixenberger et al. support the biology to ensure the targeting of SC cells and the use of latrunculin A. These five citations are thus analogous art and would be consulted by a skilled artisan (POSITA).
Starting with Yi et al., the skilled person only had to try the necessary claim limitations disclosed by Li et al., Nair et al., Shi et al., and Eixenberger et al. The combination of Yi et al., Li et al., Nair et al., Shi et al., and Eixenberger et al. would allow one to arrive at the present application without employing inventive skill. This combination of the nanocarrier taught by Yi et al. along with the use of the necessary claim limitations taught by Li et al., Nair et al., Shi et al., and Eixenberger et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application.
It would have only required routine experimentation to modify the nanocarrier disclosed by Yi et al. with the use of the necessary claim limitations taught by Li et al., Nair et al., Shi et al., and Eixenberger et al. This combined modification would have led to an enhanced nanocarrier designed for the treatment of IOP and glaucoma that would be beneficial for patients.
Allowable Subject Matter
Claims 5 and 15 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim 5 lists a specific copolymer (PEG45-b-PPS23) within the claim limitation. There is no evidence of this block polymer within the prior art. Motivation is lacking to add this copolymer to the closest prior art of Yi et al., Li et al., Nair et al., Shi et al., and Eixenberger et al.
Claim 15 identifies a specific PEG spacer (48 units) within the claim limitation. There is no evidence of this PEG spacer within the prior art. Motivation is lacking to add this specific spacer to the closest prior art of Yi et al., Li et al., Nair et al., Shi et al., and Eixenberger et al.
Conclusion
No claims are allowed.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615