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 .
Acknowledgement of Receipt
Applicant’s Response, filed 9/16/2025, in reply to the Office Action mailed 3/20/2025, is acknowledged and has been entered. It is noted that the Response indicates that in the previous Office Action, the claims of Group I set forth in in the Restriction Requirement were examined, rather than Group II, which was elected in the Response filed 3/4/2025. As discussed in the Interview Summary mailed 9/16/2025, the Examiner hereby withdraws the previous Office Action and issues a new Non-Final Office Action to address the elected claims.
It has been considered that because all of the claims of previous Group I have already been examined by the Examiner in the previous Office Action, the restriction requirement between Groups I and II, as set forth in the Office action mailed on 1/10/2025, is hereby withdrawn and the pending claims 1-23 will be examined together. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Status of Claims
Claims 1-23 are pending and are examined herein on the merits for patentability.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, the phrases "such as but not limited to" and “etc” render the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 2, the phrases “(e.g. serum albumin, plasma globulins)” and “(e.g. biodegradable polymers, liposomes or modified polypeptides)” render the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention.
Regarding claim 6, the phrase "such as” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention.
Regarding claim 7, the phrase "such as” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention.
Regarding claim 15, the phrases the phrases "such as but not limited to", multiple instances of “such as”, and “etc” render the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 20, the phrase "e.g.” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention.
Regarding claim 21, the phrase "such as” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention.
Claim 10 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claim contains the trademark/trade name Captisol. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a sulfobutylether-β-cyclodextrin and, accordingly, the identification/description is indefinite.
Claim 20 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claim recites the limitation "the fluorescent-saccharide complex" in line 3. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 102
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, 3, 4, 6, 8 and 11-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liu et al. (Nano Research, 14 April 2020, 13, p. 1100-1110).
Liu discloses ICG/β-cyclodextrins (β-CD) inclusion encapsulated PNIPAM nanogels via a one-pot free radical emulsion polymerization and in situ reduction method, see Scheme 1.
We speculate that the β-CD/ICG complex with its highly rigid structure and specific interactions will be contributed to reducing aggregation-dependent fluorescence degradation and avoiding the release or leakage of ICG inside the carrier. The hydrophilic functional groups of the β-CD exterior can also be used collectively as a hyperbranched crosslinking agent for building well-confined and stable polymer nanogels (page 1101).
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Accordingly thermosensitive PNIPAM/β-CD/ICG nanogels with a supramolecular crosslinking conjugated polymeric backbone and a β-CD/ICG-based inclusion complex using a free radical initiated emulsion polymerization and an in situ reduction strategy are taught (page 1103).
The switchable properties of PNIPAM-based nanogels with different ratios (1:1, 1:2 and 2:1) between the β-CD/ICG complex and the PNIPAM gel were further evaluated. The results of the normalized fluorescence vs. temperature show that all the three samples have the similar switching properties. However, the absolute value of the fluorescence intensity rises with the amount of the β-CD/ICG complex. It means that the sample with the ratio of 2:1 has the highest fluorescence intensity while the sample with the ratio of 1:2 has the lowest intensity (page 1105).
Regarding claim 4, a cyclodextrin is in beta-cyclodextrin form which forms an inclusion complex with ICG. The claim does not specific in what way and from what origin a cyclodextrin has been modified.
Regarding claim 6, recitation of conjugating moieties/crosslinkers are taught, as it is stated that hydrophilic functional groups of the β-CD exterior can also be used collectively as a hyperbranched crosslinking agent for building well-confined and stable polymer nanogels (page 1101).
Regarding claim 11, avoiding the release or leakage of ICG inside the carrier is taught (page 1101 and 1:1, 1:2 and 2:1 ratios are exemplified.
Regarding claims 12-14, dialyzed solution was lyophilized to obtain the β-CD/ICG complex-encapsulated PNIPAM freeze-dried monolithic materials (page 1102); PNIPAM/β-CD/ICG nanogels were injected into a silicone tube via a microsyringe (page 1102.
Claim(s) 1-4, 6, 8, 9 and 12-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated Choi et al. (US 2019/0224341).
Choi discloses a nanocarrier, comprising one or more cyclodextrin moieties conjugated to a polymer. In some embodiments, the polymer defines a micelle, a liposome, a nanosphere, a dendrimer, or a hollow shell. In some embodiments, the polymer comprises ϵ-polylysine, L-polylysine, polylactic acid, and poly(lactic-co-glycolic acid), polyaspartic acid, polyglutamic acid, or polyglutamic acid-poly(ethylene glycol) copolymer. In some embodiments, the cyclodextrin moiety is derived from a-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, methyl-β-cyclodextrin, a β-cyclodextrin thioether, or a cyanoethylated β-cyclodextrin. In some embodiments, at least one cyclodextrin moiety is conjugated to an amino group of the polymer. In some of these embodiments, the amino group is a terminal amino group (paragraph 0006-7).
In some embodiments, the nanocarrier comprises one or more therapeutic agents that form a complex with the one or more cyclodextrin moieties. In some embodiments, the one or more therapeutic agents comprise an anticancer agent. In some embodiments, the one or more therapeutic agents are conjugated with a fluorescent dye. In some embodiments, the stoichiometric ratio of the cyclodextrin moiety to the therapeutic agent is 1:1. In some embodiments, the complex is stable at a pH of about 7.4 (paragraph 0009-0014).
Nanocarrier 7 and the dye-conjugated imatinib are shown in FIG. 9A. Prior to carrying out in vivo tumor targeting, the imatinib-CDPL ± inclusion complex was tested for pH-induced drug release by measuring the changes in absorbance spectra of Cy3 (FIGS. 9B, 900 corresponds to Cy3-imatinib, 902 corresponds to ZW800-CDPL, 904 corresponds to inclusion complex; and 9C, triangles correspond to pH 5.0, diamonds correspond to pH 7.4) (paragraph 0108). The product is lyophilized (see paragraph 0093) and are injected which necessitates a device (paragraph 0049).
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Accordingly, a fluorescent dye, a saccharide with a high non-covalent affinity for
a), and c) a suitable macromolecular carrier that can harbor a) + b) are taught.
Regarding claim 2, polylysine is a degradable polymer capable of being tolerated in the blood of a living being.
Regarding claim 4, various substituted cyclodextrins are taught.
Regarding claim 6, recitation of conjugating moieties are taught as the cyclodextrin is linked to the polymer. Regarding claims 8-9, ICG and fluorescein are taught (paragraph 0064).
Claim(s) 1-4, 6, 8 and 11-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fischer et al. (WO 2007/025768).
Fischer discloses optically fluorescent nanoparticles comprising a nanoparticle matrix comprising a co-aggregate of at least one charged polyelectrolyte and at least one oppositely charged active agent, wherein the active agent is a hydrophilic optically fluorescent agent, and the invention further refers to a nanoparticle comprising said nanoparticle matrix. Optionally, the nanoparticle is surface modified. The invention also refers to a method for preparing said nanoparticle, and to a method of surface modification. Furthermore, the invention refers to uses of said nanoparticle in vitro and in vivo, and to methods for in vitro and in vivo diagnosis (abstract).
In Example 4 Nanoparticles based on beta-cyclodextrin phosphate, PEI and ICG are taught. An aqueous solution of 0.1 % beta-cyclodextrin phosphate is mixed with an aqueous solution of 0.02 % indocyanine green (ICG) and is further stirred for about I h. This mixture is injected into an aqueous solution of 0.1 % PEI (25 or 750 kDa). The aggregation progress is monitored by UV-Vis spectra starting form 900 nm down to 600 nm. The nanoparticle suspension is concentrated by ultrafiltration and lyophilized after addition of a cryoprotector (page 23).
The property of cyclodextrin as a solubilising agent is based on the formation of an inclusion complex wherein a hydrophobic active agent is entrapped into the hydrophobic core. In some cases, the inclusion is accompanied by enhanced chemical and physical stability of the active agent (page 6). The application route may be a systemic one, e.g. i.v. infusion, i.v., s.c. or i.m. injection, or can be local (i.e. which requires a device).
Accordingly, a fluorescent dye, a saccharide with a high non-covalent affinity for
a), and c) a suitable macromolecular carrier that can harbor a) + b) are taught.
Regarding claim 2, PEI is degradable polymer capable of being tolerated in the blood of a living being.
Regarding claim 4, various substituted cyclodextrins are taught.
Regarding claim 11, the components are taught in the ratios set forth in the example which encompass 1:B:C.
Claim(s) 1-7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kitagishi et al. (Chem. Asian J., 2015, 10, 1768 – 1775) as evidenced by Huszank (J Biol Inorg Chem, 2007, 12, p. 681–690).
Kitagishi discloses that HemoCD is an inclusion complex of per-O-methylated b-cyclodextrin dimer and an iron(II) porphyrin, which forms a stable O2 complex in water. Therefore, hemoCD has the potential for use as a synthetic O2 carrier in mammalian blood. In this study, a hemoCD derivative having a maleimide group (Mal-hemoCD) was conjugated to a Cys residue of serum albumin via a Michael addition reaction in order to increase the circulation time of the O2 carrier that the supramolecular complex,
HemoCD, which is made of FeIITPPS and Py3CD (Scheme 1), is the first completely artificial complex that shows reversible O2- binding properties in aqueous solution.
The present study reports the use of serum albumin as a scaffold for hemoCD in the bloodstream.
The long circulation time of serum albumin is related not only to its relatively large molecular size (3.5 nm in the hydrodynamic radius for human serum albumin).
We chose a maleimide functional group attached to a phenyl group of FeIITPPS in hemoCD because it reacts with a thio group at the surface of serum albumin via the Michael addition reaction (Scheme 1) (page 1768).
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Normally, only one reference should be used in making a rejection under 35 U.S.C. 102. However, a 35 U.S.C. 102 rejection over multiple references has been held to be proper when the extra references are cited to: (A) Prove the primary reference contains an "enabled disclosure;" (B) Explain the meaning of a term used in the primary reference; or (C) Show that a characteristic not disclosed in the reference is inherent. For example, "to serve as an anticipation when the reference is silent about the asserted inherent characteristic, such gap in the reference may be filled with recourse to extrinsic evidence. Such evidence must make clear that the missing descriptive matter is necessarily present in the thing described in the reference, and that it would be so recognized by persons of ordinary skill." Continental Can Co. USA v. Monsanto Co., 948 F.2d 1264, 1268, 20 USPQ2d 1746, 1749 (Fed. Cir. 1991). See MPEP 2131.01.
Huszank is included to show that FeTPPS is fluorescent (pages 684+).
Accordingly, a fluorescent dye, a saccharide with a high non-covalent affinity for
a), and c) a suitable macromolecular carrier that can harbor a) + b) are taught.
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.
Claim(s) 1-4, 6, 8 and 10-14 are rejected under 35 U.S.C. 103 as being unpatentable Liu et al. (Nano Research, 14 April 2020, 13, p. 1100-1110) in view of DeDora et al. (J. Biomed. Mat. Res. B: Appl. Mat., 2015, 104, p. 1457-64).
Liu teaches ICG/β-cyclodextrins (β-CD) inclusion encapsulated PNIPAM nanogels, as set forth above.
With regard to claim 10, Liu does not specifically recite Captisol as the cyclodextrin.
DeDora teaches that as the only FDA-approved near-infrared fluorophore, indocyanine green (ICG) is commonly used to image vasculature in vivo. ICG degrades rapidly in solution, which limits its usefulness in certain applications, including time-sensitive surgical procedures. We propose formulations that address this shortcoming via complexation with β-cyclodextrin derivatives (β-CyD), which are known to create stabilizing inclusion complexes with hydrophobic molecules. Here, we complexed ICG with highly soluble methyl β-CyD and FDA-approved sulfobutyl ether β-CyD (Captisol(®) ) in aqueous solution. We measured the fluorescence of the complexes over 24 h. We found that both CyD+ICG complexes exhibit sustained fluorescence increases of >2.0× versus ICG in water and >20.0× in PBS. Using transmission electron microscopy, we found evidence of reduced aggregation in complexes versus ICG alone. We thus conclude that this reduction in aggregation helps mitigate fluorescence autoquenching of CyD+ICG complexes compared in ICG alone. We also found that while ICG complexed with methyl β-CyD severely reduced the viability of MRC-5 fibroblasts, ICG complexed with sulfobutyl ether β-CyD had no effect on viability. These results represent an important first step toward enhancing the utility of aqueous ICG by reducing aggregation-dependent fluorescence degradation.
It would have been obvious to one of ordinary skill in the art at the time of the invention to substitute Captisol as a functionally equivalent cyclodextrin to β-cyclodextrin for forming an inclusion complex with ICG the ICG/cyclodextrin inclusion encapsulated PNIPAM nanogels taught by Liu when the teaching of Liu is taken in view of DeDora.
The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. ___, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. One such rationale includes the simple substitution of one known element for another to obtain predictable results. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. See MPEP 2143. In the instant case, the substituted cyclodextrins and their functions were known in the art at the time of the instant invention. One of ordinary skill in the art could have substituted one known cyclodextrin for another, and the results of the substitution would have been predictable, that is formation of an inclusion complex with ICG for incorporation into nanogels.
Claim(s) 1-4, 6, 8, 11-18 and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (Nano Research, 14 April 2020, 13, p. 1100-1110).
Liu teaches ICG/β-cyclodextrins (β-CD) inclusion encapsulated PNIPAM nanogels via a one-pot free radical emulsion polymerization and in situ reduction method, see Scheme 1, as set forth above.
With regard to claims 15+, the synthetic methods taught by Liu are set forth on pages 1101-2. The β-CD/ICG complex was firstly prepared through a host guest self-assembly process. Briefly, the 4.5 mg of ICG and 17.0 mg of β-CD were completely dissolved in 3 mL methanol and 10 mL deionized (DI) water accordingly. After that, the ICG solution was dropwise added into the β-CD aqueous solution to obtain the β-CD/ICG complex, followed by over 6 h of stirring.
The β-CD/ICG complex-encapsulated temperature-sensitive PNIPAM nanogels were synthesized by a free radical emulsion polymerization and in situ reduction method. Briefly, 1.50 g NIPAM (monomer), 0.15 g acrylamide (lower critical solution temperature modifier), 22.0 mg BIS (cross-linking agent) and 0.15 g sodium dodecyl sulfonate (SDS) were completely dissolved with 40 mL deionized water in a 250 mL Schlenk tube. Then, 15 mL β-CD/ICG complex (0.03 mg ICG per mL methanol aqueous solution) and 50.0 mg AIBN (initiator) were added into the tube in sequence, and the mixture was further stirred for 30 min, followed by purging with nitrogen at room temperature for 1.5 h. Afterwards, the vacuuming/filling procedure was repeated for three times to secure nitrogen-protected environment inside the reaction tube. To protect ICG from being degraded by free radicals and/or oxygen, the 3 mL degassed aqueous solution containing 0.15 g sodium ascorbate (reducing agent) was injected into the reaction mixture after reaction 1.5 h. The reaction was further carried on at 338 K for 13 h. The resultant sample was further dialyzed against deionized water
using a 10 kDa molecular weight cut-off membrane for 4 days to remove extra surfactants, unreacted monomers and other substances. Finally, about 95.0 mL of dialyzed solution was further lyophilized to obtain the β-CD/ICG complex-encapsulated PNIPAM freeze-dried monolithic materials (Scheme 1). The as-prepared sample was denoted as PNIPAM/β-CD/ICG nanogels in the following research.
Accordingly, Liu teaches separate dissolution of saccharide and fluorescent dye in solution, and then adding the dye followed by stirring; further with regard to step g, directed to adding a solution to a macromolecular carrier to the combined solution of saccharide and dye, it is submitted that one of ordinary skill in the art would have found it obvious to modify the order of addition of components a matter of routine optimization of reaction conditions. See MPEP 2144.04 directed to changes in sequences of adding ingredients in process steps, Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In reBurhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In reGibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.). With regard to b,c and e,f, it is noted that agitation and incubating are not specifically recited upon dissolution of the dye and saccharide prior to combining, however the resulting solution is stirred and would necessarily be incubated prior to addition to macromolecular carrier as a means of time passed prior to addition.
Regarding claim 2, PNIPAM is a polymer capable of being tolerated in the blood of a living being, see page 1107, directed to metabolism and in vivo biodistribution of the PNIPAM/β-CD/ICG nanogels.
With regard to claims directed to relative concentration and ratios, it would have been further obvious to modify the amounts of components as a matter of routine optimization in preparation of PNIPAM/β-CD/ICG nanogels, further differences in concentration or temperature will generally not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; or In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Claim(s) 1-7, 15-18 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Kitagishi et al. (Chem. Asian J., 2015, 10, 1768 – 1775) in view of Huszank (J Biol Inorg Chem, 2007, 12, p. 681–690).
The rejection over Kitagishi as evidenced by Huszank is applied as above.
With regard to claims 15+, the synthetic methods taught by Kitagishi are set forth on pages 1774-5.
Mal-FeIIITPPS and Py3CD were prepared. The mole of BSA was quantified by using the molar absorption coefficient e-ported previously. To an Ar-saturated aqueous solution of Mal-met-hemoCD ([Mal-FeIIITPPS] = 1.2 mm, [Py3CD] = 1.4 mm, 0.3 mL), BSA (3.6 x 107 mol) was added and the mixture was gently stirred at room temperature for 5 h. The progress of the bioconjugation reaction was confirmed by disappearance of the reactive SH group monitored by an assay using Ellman’s reagent (5,5’-dithiobis(2-ni-trobenzoic acid), DTNB). The solution was then subjected to re-peated ultrafiltration (Amicon Ultra-4 Centrifugal Filter Device, 30 kMW cut-off) with PBS to remove unreacted Mal-met-hemoCD. The resulting solution containing albumin-conjugated met-hemoCD (Alb-met-hemoCD) was used for further studies. The concentration of Alb-met-hemoCD was determined by using the molar absorption coefficients of met-hemoCD. The albumin-conjugated free-base derivative (Alb-Fb-hemoCD) was also prepared by using the same method.
Accordingly, Kitagishi teaches separate addition of saccharide and fluorescent dye in solution and then addition of macromolecular, followed by stirring; with regard to steps a-g, directed to adding a solution to a macromolecular carrier to the combined solution of saccharide and dye, it is submitted that one of ordinary skill in the art would have found it obvious to modify the order of addition of components a matter of routine optimization of reaction conditions. See MPEP 2144.04 directed to changes in sequences of adding ingredients in process steps, Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In reBurhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In reGibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.). With regard to a-g, it is noted that agitation and incubating are not specifically recited upon dissolution of the dye and saccharide prior to combining, however the resulting solution is stirred and would necessarily be incubated prior to addition to macromolecular carrier as a means of time passed prior to addition.
Regarding steps j-k, it is noted that Alb-met-hemoCD was dosed into the femoral vein via injection, accordingly the solution was placed in a container capable of injection and was at least stored under suitable conditions to be usable in the experiments.
With regard to claims directed to relative concentration and ratios, it would have been further obvious to modify the amounts of components as a matter of routine optimization in preparation of albumin-conjugated met-hemoCD, further differences in concentration or temperature will generally not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; or In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Claim(s) 1-9, 12-20 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Choi et al. (US 2019/0224341) in view of Lee et al. (Colloids and Surfaces B: Biointerfaces, 2016, 147, p. 281-290).
Choi teaches a nanocarrier, comprising one or more cyclodextrin moieties conjugated to a polymer. In some embodiments, the polymer defines a micelle, a liposome, a nanosphere, a dendrimer, or a hollow shell. In some embodiments, the polymer comprises ϵ-polylysine, L-polylysine, polylactic acid, and poly(lactic-co-glycolic acid), polyaspartic acid, polyglutamic acid, or polyglutamic acid-poly(ethylene glycol) copolymer. In some embodiments, the cyclodextrin moiety is derived from a-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, methyl-β-cyclodextrin, a β-cyclodextrin thioether, or a cyanoethylated β-cyclodextrin. In some embodiments, at least one cyclodextrin moiety is conjugated to an amino group of the polymer. In some of these embodiments, the amino group is a terminal amino group (paragraph 0006-7).
In some embodiments, the nanocarrier comprises one or more therapeutic agents that form a complex with the one or more cyclodextrin moieties. In some embodiments, the one or more therapeutic agents comprise an anticancer agent. In some embodiments, the one or more therapeutic agents are conjugated with a fluorescent dye. In some embodiments, the stoichiometric ratio of the cyclodextrin moiety to the therapeutic agent is 1:1. In some embodiments, the complex is stable at a pH of about 7.4 (paragraph 0009-0014).
In some embodiments, the one or more therapeutic agents are conjugated with a fluorescent dye. In certain instances, conjugating a fluorescent dye to the therapeutic agent enables tracking (e.g., imaging) of the therapeutic agent in vivo. In some embodiments, the fluorescent dye includes a xanthene derivative (e.g., fluorescein, ICG, etc. (paragraph 0064).
Nanocarrier 7 and the dye-conjugated imatinib are shown in FIG. 9A. Prior to carrying out in vivo tumor targeting, the imatinib-CDPL ± inclusion complex was tested for pH-induced drug release by measuring the changes in absorbance spectra of Cy3 (FIGS. 9B, 900 corresponds to Cy3-imatinib, 902 corresponds to ZW800-CDPL, 904 corresponds to inclusion complex; and 9C, triangles correspond to pH 5.0, diamonds correspond to pH 7.4) (paragraph 0108). The product is lyophilized (see paragraph 0093) and are injected which necessitates a device (paragraph 0049).
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Accordingly, a fluorescent dye, a saccharide with a high non-covalent affinity for
a), and c) a suitable macromolecular carrier that can harbor a) + b) are taught.
Regarding claim 2, polylysine is a degradable polymer capable of being tolerated in the blood of a living being.
Regarding claim 4, various substituted cyclodextrins are taught.
Regarding claim 6, recitation of conjugating moieties are taught as the cyclodextrin is linked to the polymer. Regarding claims 8-9, ICG and fluorescein are taught (paragraph 0064).
With regard to claims 5 and 7, Choi does not teach HSA as a carrier.
Lee teaches that albumin has been viewed as one of the most attractive biomacromolecules for making nanoparticulate systems due to its biocompatibility and chemical functionality. Thus far, albumin nanoparticles (NPs) are prepared by several limited methods, such as, desolvation, emulsification or high-pressure homogenization. In this article, we introduce a new albumin NPs prototype fabricated via a ‘host’ (β-cyclodextrin)-‘guest’ (adamantane) supramolecular association. These NPs (GC-CD/HSA-ADA NPs) consisted of β-cyclodextrin-modified glycol chitosan (GC-CD) and adamantane-conjugated human serum albumin (HSA-ADA) (GC-CD/HSA-ADA NPs) that were facilely prepared by a consequent dropwise mixing and sonication method. Doxorubicin-loaded GC-CD/HSA-ADA NPs exhibited an appropriate particle size (∼260 nm), good physicochemical stability (∼48 h), significant HCT116 cell cytotoxicity (IC50: 0.32 μg/ml) and cell internalization. Furthermore, GC-CD/HSA-ADA NPs showed excellent tumor targetability probably due to gp60-mediated transcytosis mechanism because it was markedly accumulated in the tumor site of a HCT116 cell-xenograft mouse. Based on these results, these albumin NPs will be promising for a new NP platform that can be applied for cancer therapy or imaging (page 281).
It would have been obvious to one of ordinary skill in the art to provide HSA a carrier for the cyclodextrin and therapeutic/fluorescent complexes taught by Choi when the teaching of Choi is taken in view of Lee. One would have been motivated to do so, with a reasonable expectation of success, because Choi teaches a variety of polymeric nanoparticulate carriers are suitable as the nanoparticulate carrier, and Lee teaches that albumin has been viewed as one of the most attractive biomacromolecules for making nanoparticulate systems due to its biocompatibility and chemical functionality, and that albumin NPs will be promising for a new NP platform that can be applied for cancer therapy or imaging, as well as for use in cyclodextrin host/guest chemistry.
With regard to claims 15+, the synthetic methods taught by Choi are taught in the Examples and those by Lee are set forth on pages 283-4.
Choi teaches combination of fluorescent and saccharide, see Examples. Choi teaches Dox-loaded GC-CD/HSA-ADA NPs were prepared using a modification of self-assembled of albumin NPs. A 0.5 ml aliquot of HSA-ADA (2 mg/ml) was dropped into a 1.5 ml solution of GC-CD dissolved in DW (final molar ratio of CD: ADA= 0.5, 1.0, 2.0 or 4.0:1), and the resulting solution was dispersed with a sonicator (in an ice bath at an amplitude of 40% for 2 min. Dox incorporation into the GC-CD/HSA-ADA NPs was investigated separately at a 2:1 molar ratio of CD: ADA. A mixed solution (0.5 ml) of HSA-ADA (1 mg) and Dox (0.4 mg) in DW was added dropwise to 1.5 ml GC-CD (5.4 mg) in DW using a 1 ml syringe over 25 min and then dispersed using a sonicator in an ice bath at an amplitude of 40% for 2 min.
Accordingly, Choi teaches separate addition of fluorescent and saccharide and Lee teaches separate addition of saccharide in solution and then addition of macromolecular, followed by stirring; with regard to steps a-g, directed to adding a solution to a macromolecular carrier to the combined solution of saccharide and dye, it is submitted that one of ordinary skill in the art would have found it obvious to modify the order of addition of components a matter of routine optimization of reaction conditions. See MPEP 2144.04 directed to changes in sequences of adding ingredients in process steps, Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In reBurhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In reGibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.). With regard to a-g, it is noted that agitation and incubating are not specifically recited upon dissolution of the dye and saccharide prior to combining, however the resulting solution is stirred and would necessarily be incubated prior to addition to macromolecular carrier as a means of time passed prior to addition.
Regarding steps j-k, it is noted that vials are taught see Figures 4 and 5, accordingly the solution was placed in a container capable of injection and was at least stored under suitable conditions to be usable in the experiments.
With regard to claims directed to relative concentration and ratios, it would have been further obvious to modify the amounts of components as a matter of routine optimization in preparation of albumin-conjugated met-hemoCD, further differences in concentration or temperature will generally not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; or In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Claim(s) 1-4, 6, 8, 9 and 11-14 are rejected under 35 U.S.C. 103 as being unpatentable Liu et al. (Nano Research, 14 April 2020, 13, p. 1100-1110) in view of Izadmanesh (Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy, 2016, 165, p. 54-60).
Liu teaches ICG/β-cyclodextrins (β-CD) inclusion encapsulated PNIPAM nanogels, as set forth above.
With regard to claim 9, Liu does not specifically teach fluorescein as the dye.
Izadmanesh teaches gradient flow injection technique has been applied for the thermodynamic study of β-CD inclusion complexes with crystal violet, methyl orange, phenol red, fluorescein, and PAR. Mole ratio data were obtained by calibrating the dispersion pattern. Singular value decomposition (SVD) was applied to determine the stoichiometric ratios and noise reduction of experimental absorbance data. Nonlinear least squares curve fitting was applied to spectral-mole ratio data to calculate stability constants and estimate concentration-spectral profiles of the contributing species. The calculated stability constants were in good agreement with the batch titration results, which demonstrated the reliability of the method. In comparison with usual titration methods, gradient flow injection technique is time saving and reliable, and experimental noise is greatly reduced. Molecular modeling was employed to find the probable binding conformations of dye molecules within the β-CD cavity and evaluate the involved interactions between host and guest molecules (page ). Fluorescein and β-CD are shown at 1:1 ratio (Table 2).
It would have been obvious to one of ordinary skill in the art at the time of the invention to substitute fluorescein as a functionally equivalent dye to ICG for forming an inclusion complex with cyclodextrin in the dye/cyclodextrin inclusion encapsulated PNIPAM nanogels taught by Liu when the teaching of Liu is taken in view of Izadmanesh. The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. ___, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. One such rationale includes the simple substitution of one known element for another to obtain predictable results. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. See MPEP 2143. In the instant case, the substituted dyes and their functions were known in the art at the time of the instant invention. One of ordinary skill in the art could have substituted one known dye for another, and the results of the substitution would have been predictable, that is formation of an inclusion complex with cyclodextrin for incorporation into nanogels.
Conclusion
No claims are allowed at this time.
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