DETAILED ACTION
Status of the Claims
Claims 1-25 are pending in the instant application. Claims 10-24 have been withdrawn based upon Restriction/Election. Claims 1-9 and 25 are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
The U.S. effective filing date has been determined to be 04/05/2021, the filing date of the U.S. Provisional Application No. 18/553,986.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-9 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Das et al. (“Covalent organic nanosheets for bioimaging,” 2018, RSC; Chemical Science, Vol. 9, pp. 8382-8387) in view of Zhang et al. (“Polymer- Covalent Organic Framework Composites for Glucose and pH Dual- Responsive Insulin Delivery in Mice,”2020, WILEY-VCH; Advanced Science News, Vol. 9, No. 2000221, pp. 1-10); PUIGMARTI-LUIS (WO 2019/243602; published December, 2019) and FARHA (WO 2019/173571; published March, 2019).
Applicants Claims
Applicant claims a covalent organic framework (COF) nanoparticle, comprising 10-25 COF nanosheets, wherein the COF nanosheets are stacked in a staggered configuration and each COF nanosheet is a co-condensate of 2,6-diformylpiridine (DFP) and 4,4’,4’’-(1,3,5-triazine-2,4,6-triyl)trianiline (TTA) and the COF nanoparticle has a longest linear dimension of 75-300 nm (claim 1). Applicant further claims the molar ratio during condensation of DFP and TTA is 5:1 (DFP:TTA)(claim 2), the COF has a longest linear dimension of about 120 nm, and the COF nanoparticle has 16-20 or 18 COF nanosheets (claims 4 & 5). Applicant further claims the COF nanoparticle incorporates a plurality of protein cargos (claim 6), wherein the protein is insulin (claim 7) in an amount of 30-75 wt.%, relative to the weight of the COF nanoparticle (claim 8). Applicant further claims a kit or composition comprising the COF nanoparticle, or the components to prepare the COF nanoparticle (claim 25), and a pharmaceutically acceptable carrier (claim 9).
Determination of the scope
and content of the prior art (MPEP 2141.01)
Das et al. teaches that: “Covalent organic nanosheets (CONs) obtained by exfoliation of their counterparts, such as covalent organic frameworks (COFs), have emerged as a new class of porous, thin two-dimensional (2D) nanostructures with distinctive dimension related properties that differ from their corresponding bulk materials. Exfoliation of COFs into CONs reduces the size of the material while also imparting novel physical and chemical properties, which for example, allows for the circumvention of a few serious COF drawbacks, namely their dispersibility and bioavailability within the cells. In this regard, CONs are a promising nanomaterial for applications in biomedicine including drug delivery and bioimaging.” (p. 8382, col. 1, 1st paragraph).
Das et al. teaches that: “We describe here the synthesis of a crystalline, porous, and luminescent triazine-based COF (denoted as TTA—DFP COF) from the condensation of 2,6-diformylpyridine (DFP) with 4,40,400-(1,3,5-triazine-2,4,6-triyl)trianiline (TTA) under 30 min of microwave irradiation (Fig. 1). As synthesized, the bulk material is constituted of nanosheets and is weakly Fluorescent with micrometer lateral dimensions. Exfoliation of the bulk material in pure water drastically reduces the lateral dimensions to the nanometer scale and enhances the photoluminescence properties by a factor of 6.” (p. 8382, col. 2, 1st full paragraph)(instant clam 1, “COF nanosheets are stacked in a staggered configuration and each COF nanosheet is a co-condensate of 2,6-diformylpyridine (DFP) and 4,4’,4”-(1,3,5-triazine-2,4,6-triyl)trianiline (TTA)”).
Das et al. teaches that: “The morphology of the TTA—DFP COF was investigated by high resolution transmission electron microscopy (HRTEM) and atomic force microscopy (AFM). HRTEM images showed transparent nanosheets, an indication of the thickness of TTA—DFP COFs (Fig. 3a). AFM analysis of TTA DFP COFs revealed a 2D sheet-like morphology (Fig. 3b). The topological height profile for the 2D sheets was found to be 1.5 nm. PXRD analysis indicates an interlayer stacking distance of 0.35 nm, which is consistent with the well-defined lattice fringes obtained from HRTEM analysis (0.38 nm, Fig. 3a). Based on these microscopy data, we determined that TTA—DFP COFs are comprised of about four stacked layers.” (p. 8383, col. 2, 3rd paragraph)(instant claim 1, “comprising 10-25 COF nanosheets, wherein the nanosheets are stacked in a staggered configuration).
Das et al. teaches that “The nanosheets were biocompatible and non-toxic and showed ability to stain HeLa cell nuclei without additional assistance of an external targeting agent.” (abstract, last three lines). And that: “In this regard, CONs [(Covalent Organic Nanosheets)] are a promising nanomaterial for applications in biomedicine including drug delivery and bioimaging.” (p. 8382, col. 1, 1st paragraph, last three lines).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of Das et al. is that Das et al. does not expressly teach that their COF nanoparticles have a longest linear dimension of 75-300 nm.
Zhang et al. teaches polymer-covalent organic frameworks composites for glucose and pH dual-responsive insulin delivery in mice (title, see whole document). Zhang et al. teaches problems associated with diabetes treatment, and that: “To circumvent these problems and improve patient satisfaction and compliance, the development of an effective and intelligent insulin delivery system capable of sensing changes in glucose concentration and correspondingly releasing the appropriate amount of insulin is extremely important for the treatment of diabetes.” (p. 1, §Introduction, 1st paragraph).
Zhang et al. teaches that: “Covalent organic frameworks (COFs) are an emerging class of crystalline porous materials constructed by stitching organic building blocks with strong covalent bonds. Owing to their periodical structures, pre-designable skeletons, large surface areas, and biocompatible nature, COFs have shown enormous potential as drug delivery cargos. As the first porotype COF, the boroxine-linked COF has garnered significant attention since 2005. The boron atom in the boronate ester linkage is an electron-deficient group that can coordinate with the amine and imidazole groups in the protein or insulin by nitrogen–boron complexation. Apart from the beneficial effect on insulin binding, the boronate ester moiety, which is chemically vulnerable toward acids, provides an opportunity for pH-responsible drug release and circumvent the barriers in insulin delivery in vivo.” (p. 2, col. 1, 1st paragraph). And that: “COFs provided a confined microenvironment for insulin and GOx, and sustained biological activity. Importantly, boroxine-linked COFs have excellent chemical stability under mild conditions, but undergo rapid decomposition in acidic solutions and release the entrapped insulin and glucose oxidase (GOx) efficiently. Specifically, under hyperglycemic conditions, internalized glucose is converted to gluconic acid catalyzed by GOx, followed by the acid degradation of COFs to release insulin (Figure 1c). Through the dual response of hyperglycemia and pH, the polymer–COFs composites can effectively cope with hyperglycemia and shift to a resting state of normal BGLs. To the best of our knowledge, this is the first intravenous nano-platform that utilizes the COFs to achieve glucose and pH dual-responsive insulin delivery. The rationally designed COFs (COF-1 and COF-5) carriers will shed new light on the development of an efficient platform for the delivery of native insulin with high generality.” (paragraph bridging pp. 2-3)(instant claims 6-7, insulin protein delivery).
Zhang et al. teaches that: “Dynamic Light Scattering (DLS) tests showed that the hydrodynamic radius of the pristine COF-1 and COF-5 were 143 nm and 211 nm (DMSO as solvent) (Figure S3, Supporting Information).” (p. 3, col. 2, lines 6- 9)(instant claim 1, “the COF nanoparticle has a longest dimension of 75-300 nm.”). It would have been prima facie obvious to utilize the TTA-DFP COF of Das et al. for drug delivery, as suggested by Das et al., having a size for the same as suggested by Zhang et al. in a range of 75-300 nm or about 120 nm (Figure S3), the drug being insulin as suggested by Zhang et al.
Regarding the molar ratio of the DFP:TTA being 5:1 during condensation, this is being regarded as a product-by-process limitation, however, it would have been prima facie obvious to optimize the molar ratio to produce the best COF material for drug delivery as taught by Das et al., and particularly insulin as taught by Zhang et al.
Regarding instant claims 4-5, Das et al. clearly teaches a layered structure including several alternating layers of DFP and TTA, and it would have been prima facie obvious to optimize the molar ratio to produce the best COF material for drug delivery as taught by Das et al., and particularly insulin as taught by Zhang et al.
PUIGMARTI-LUIS teaches nanocarriers including porous crystalline materials (PCMs), more particularly to metal organic frameworks (MOFs) and covalent organic frameworks (COFs)(title, abstract, see whole document). PUIGMARTI-LUIS teaches micellar dispersions, particularly colloidal dispersions having a size in the range of 15-200 nm (p. 7, 1st paragraph)(instant claims 1 and 3, longest dimension). PUIGMARTI-LUIS teaches that: “In one embodiment, the dispersions described herein are used as a vehicle/ nano-carrier, particularly for drug delivery.” (p. 18, lines 1-3). And “In principle any active ingredient may be used, preferred are Biomolecules (such as proteins and sugars) and small molecules (APIs, such as ibuprofen).” (p. 18, lines 17-19)(instant claim 6, “cargo proteins”). PUIGMARTI-LUIS teaches their dispersions include additives such as surfactants, pH modifiers (claims 1-2).
FARHA teaches insulin-loaded metal organic frameworks (title, see whole document) including “embodiments of the insulin-loaded MOFs having an insulin loading of at least 30 wt.% and further includes embodiments of the insulin-loaded MOFs having an insulin loading of at least 40 wt.%.” (p. 7, [0035])(instant claim 8). FARHA teaches that: “Then they can be formulated into a liquid or solid oral dosage form, such as a tablet containing the insulin-loaded MOFs with or without suitable diluents that is designed to disintegrate in a physiological environment.” (p. 8, [0037])(instant claims 9 & 25).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
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 produce a COF composed of TTA and DFP for drug delivery, as suggested by das et al., and the drug being protein drug, as suggested by PUIGMARTI-LUIS, and particularly insulin as suggested by, Zhang et al. and FARHA, for the treatment of diabetes in a patient in need thereof.
From the 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 because it would have required no more than an ordinary level of skill to produce the DFP:TTA COF nanoparticles according to Das et al. for drug delivery and incorporating insulin, as suggested by Zhang et al. and FARHA. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Response to Arguments:
Applicant's arguments filed 02/22/2026 have been fully considered but they are not persuasive.
Applicant argues that: “The Examiner has cited Das because the material disclosed therein is formed from 2,6-diformylpyridine (DFP) and 4,4',4"-(l,3,5-triazine-2,4,6-triyl)trianiline (TTA). However, as conceded by the Examiner, the material disclosed in Das has different dimensions. See Office Action at pp. 6-7. The Examiner cites the remaining references to teach a combination of a COF encapsulating insulin. However, none of the cited references, when combined, would result in a COF network as described in the instant claims.” And that: “As described in the instant application, the method used to form the material of claim 1 is due to an increased rate of monomer consumption, which induces ‘supersaturation in crystalline nanosheets and inhibition of crystallite growth into bigger structures.’ Instant Specification at ¶ [0101]. The method of Das, which is also described in the instant application, forms "small crystalline nanosheets with limited stacking ... without observing nanoparticle formation." Id. at ¶[0101] and Fig. 7. Even if all the cited references were combined using the method taught in Das to synthesize the compositions described therein, the method could not and would not result in a nanoparticle having the same architecture as recited instant claim 1.” (p. 5, last two paragraphs through p. 6, 1st paragraph). And that: “This is further supported by the Rule § 1.132 declaration submitted herewith. This declaration from Prof Ali Trabolsi, who is an author on Das, describes that the methods described therein could not form the instant nanoparticles. Further, it describes that the formation of the nanoparticles is surprising and unexpected.” (p. 6, 3rd paragraph).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to Applicant’s suggestion that the compositions of Das et al. “the method could not and would not result in a nanoparticle having the same architecture as recited instant claim 1”, the examiner acknowledges Applicants distinction in the method of making, however, the claims are directed at compositions of matter, and adjusting the concentration of reactants would have been prima facie obvious to one of ordinary skill in the art, particularly the concentration of acetic acid to achieve the best possible COF nanoparticle for drug delivery, as suggested by das et al., and the drug being protein drug, as suggested by PUIGMARTI-LUIS, and particularly insulin as suggested by, Zhang et al. and FARHA, for the treatment of diabetes in a patient in need thereof.
Particularly Das et al. describes “Synthesis of TTA-DFP COF under Microwave condition: A microwave reaction vessel (25 mL), was charged with 1,3,5-tris(4-aminophenyl)benzene (21 mg, 0.06 mmol, 2 equiv) and 2,6- pyridinedicarboxaldehyde (12 mg, 0.09 mmol, 3 equiv). Anhydrous 1,4-dioxane (3.0 mL) was added, and the resulting mixture was sonicated for 1 min. An aqueous solution of acetic acid (0.5 mL, 3.0 M) was added, resulting in immediate formation of a yellow precipitate.” (S2 – Synthetic Procedure).
The instant Specification describes: “[0101] TTA-DFP-nCOF was synthesized by co-condensation of DFP (21 mg, 0.15 mmol, 5 equivalents) and TTA (12 mg, 0.03 mmol, 1 equivalent), in anhydrous 1,4-dioxane (3 mL) in the presence of acetic acid (0.5 mL, 13 M, [acetic acid]final = 4.0 M) at room temperature for 10 min (Figure 1a). The solution was cleaned using dialysis in H2O to obtain a stable nanoparticle suspension. At room temperature for 10 minutes, imine-linked covalent organic nanoparticles with 123.7 nm average diameter (Figures 1b and 5) emerge from clear solution without forming amorphous polyimine precipitates. A high concentration of acetic acid ([acetic acid]final = 4.0 M) induces a rapid imine condensation reaction at room temperature and thus the formation of discrete nCOF crystalline nanosheets (Figures 5-6). The increased rate of monomer consumption induces both supersaturation in crystalline nanosheets and inhibition of crystallite growth into bigger structures. Subsequently, nanosheets agglomerate by stacking to each other to form polycrystalline nanoparticles of spherical shape with rough surfaces and small protrusions (Figure 6); this latter phenomenon is due to the small presence of H2O co-solvent which favors hydrogen bonding between nanosheets. When the synthesis is performed with pure acetic acid in the absence of H2O ([acetic acid]final = 5.0 M), small crystalline nanosheets with limited stacking were obtained without observing nanoparticle formation (Figure 7).
The examiner cites Li et al. (“Laminated self-standing covalent organic framework membrane with uniformly distributed subnanopores for ionic and molecular sieving,” 2020, Nature Communications, Vol. 11, Article 599, pp. 1-9) directed at self-standing covalent organic framework membranes, and disclosing that: “In our case, we think the acetic acid is critical for the membrane formation as there is no obvious interface formation between the two main miscible organic solvents without acetic acid. So, firstly, concentrations (3–12 M) and amounts of acetic acid (20–60 mL) were employed to explore their effects on the experimental results. Not surprisingly, we found that the concentrations of acetic acid are important for the formation of COF membranes. For low acetic acid concentrations of 3 and 6M, only membranes were obtained in the 250 mL beakers. When the concentration of acetic acid increased to 9M, a mixture of COF membrane and nanoparticles could be obtained. And as the concentration increased further to 12 M, only COF nanoparticles are generated.” [emphasis added](p. 5, col. 1, last line through col. 2, line 12). Therefore, it would have been prima facie obvious to adjust the concentration of the acetic acid in Das et al. to produce COF nanoparticles.
The examiner further cites Wu et al. (“Covalent organic frameworks embedded membrane via acetic-acid catalyzed interfacial polymerization for dyes separation: Enhanced permeability and selectivity,” 2020, ELSEVIER; Chemosphere, Vol. 261, Article 127580, pp. 1-10) teaching that: “The imine and triazine-linked COFs are the most widely used fillers for fabricating hybrid membranes due to their high structural stability at high temperature and in solvents (Kandambeth et al., 2012). […] Acetic acid acted as a highly active catalyst for imine-linked COF formation with increased crystallinity and specific surface area at room temperature (Peng et al., 2016). Since the reaction producing COFs could happen in a short time only under the catalyzation of acetic acid, COFs were fabricated in the membrane pores where acetic acid existed and separated successfully, which prevented agglomeration effectively.” [emphasis added](p. 2, col. 2, 2nd paragraph). And that: “Acetic acid is the key catalyst in the fabrication of COFs under ambient conditions.” (p. 7, col. 2, §3.3.2, lines 1-2).
The examiner further cites Zhang et al. (“Construction of Flexible Amine-linked Covalent Organic Frameworks by Catalysis and Reduction of Formic Acid via the Eschweiler–Clarke Reaction,” 2021, Wiley-VCH; Angewandte Chemie Int. Ed., vol. 60, pp. 12396-12405) teaching that “acetic acid, the most common catalyst for COF synthesis.” (abstract, lines 9-10), and that: “It is worth noting that more than 80%of the imine-linked COFs are synthesized in the presence of acetic acid as a catalyst in literature-reported methods.” (p. 12397, col. 1, §Introduction, 3rd paragraph, lines 1-3). The examiner notes that imine bonds in COF’s (imine-linked COF) is a -C=N- bond, as in the COF produced by TTA and DFP (TTA-DFP COF) of the instant Application/claims.
The examiner has fully considered Applicant’s Declaration (Rule 1.132 declaration filed 06/22/2026) and understands Applicant’s position that the Das et al. reference process results in COF nanoparticles having less than 10 nanosheets, and the distinction being that the concentration of the acetic acid used was increased to produce the claimed TTA-DFP COF having 10-15 nanosheets. In response the prior art clearly suggest that acetic acid is the most commonly utilized catalyst for the formation of imine-linked COF’s of which the TTA-DFP COF of Das et al. is an example. Additionally, Li et al. clearly suggests that the concentration of the acetic acid utilized is an important parameter that results in structural changes, and particularly teaching that: “concentrations (3–12 M) and amounts of acetic acid (20–60 mL) were employed to explore their effects on the experimental results. Not surprisingly, we found that the concentrations of acetic acid are important for the formation of COF membranes. For low acetic acid concentrations of 3 and 6M, only membranes were obtained in the 250 mL beakers. When the concentration of acetic acid increased to 9M, a mixture of COF membrane and nanoparticles could be obtained. And as the concentration increased further to 12 M, only COF nanoparticles are generated.” [emphasis added](p. 5, col. 1, last line through col. 2, line 12). Therefore, it would have been prima facie obvious, based on the ordinary skill/knowledge in the art to which the invention pertains, to adjust the concentration of the acetic acid in Das et al. to produce COF nanoparticles suitable for drug delivery, and particularly for insulin delivery (a protein drug), and Applicant’s arguments are not convincing, in view of the cited combination of references and the ordinary skill/knowledge in the art to which the invention pertains.
Conclusion
Claims 1-9 and 25 are pending and have been examined on the merits. Claims 1-9 and 25 are rejected under 35 U.S.C. 103. No claims allowed at this time.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
Prosecution Insights