DETAILED ACTION
Status of the Claims
Claims 11-23 and 25-30 are pending in the instant application. Claims 15, 17-20 and 27-30 have been withdrawn based upon Restriction/Election as discussed below. Claims 11-14, 16, 21-23, 25 and 26 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All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.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 instant Application is a U.S. entry (371) of PCT/CN2021/114083 filed 08/23/2021, and claims Foreign Priority to CN202010914907.4 filed 09/30/2020.
The U.S. effective filing date has been determined to be 08/23/2021, the filing date of PCT/CN2021/114083. Applicant's claim for a foreign priority date of, 09/30/2020, the filing date of document CN202010914907.4, is acknowledged, however no English translation of said foreign priority document has been provided. Accordingly, foreign priority to this document is cannot be afforded at this time.
Response to Arguments:
Applicant's arguments filed 03/04/2026 regarding the foreign priority document is acknowledged. A copy of the certified priority document CN202010914907.4 has been retrieved from the International Bureau (PCT Rule 17.2(a)). However, said copy is not in English language therefore the examiner cannot confirm written description support therein (112(a)). Therefore, priority to this document is cannot be afforded at this time. Applicant can perfect priority, though this is not a requirement. However, the examiner notes that 37 CFR 1.55(g)(4) states that: “If an English language translation of a non-English language foreign application is required, it must be filed together with a statement that the translation of the certified copy is accurate.”
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 11-14, 16, 21-23, 25 and 26 remain rejected under 35 U.S.C. 103 as being unpatentable over Hei et al. (“Phenylboronic acid functionalized silica nanoparticles with enlarged mesopores for efficient insulin loading and controlled release,” 2019, ELSEVIER, Journal of Drug Delivery Science and Technology, Vol. 51, pp. 320-326)XXX in view of VAN ANTWERP (US 6,319,540; published November, 2001); WEISS (US 2018/0057559; published March, 2018); Nicolay et al. (“Elaboration and characterization of a multifunctional silane/ZnO hybrid nanocomposite coating,” 2015, ELSEVIER; Applied Surface Science, Vol. 327, pp. 379-388).
Applicants Claims
Applicant claims a mesoporous silica nanomaterial for controlled release, wherein the mesoporous silica nanomaterial for controlled release comprises mesoporous silica nanoparticles functionalized with a polyhydroxy compound and a nanoparticle pore blocking agent functionalized by a phenylboronic acid compound; wherein the polyhydroxy compound has a structure as shown by R1-R2, wherein R1 is amino or carboxyl, and R2 is linear or branched C2-12 alkenyl or C2-12 alkynyl, and the alkyl, the alkenyl and the alkynyl are substituted by at least 2 hydroxyl groups, and at least to adjacent C atoms are respectively substituted by one hydroxyl group; wherein the phenylboronic acid compound is:
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373
214
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(instant claim 11).
Determination of the scope
and content of the prior art (MPEP 2141.01)
Hei et al. teaches insulin delivery using phenylboronic acid functionalized silica nanoparticles (see whole document), and particularly “Mesoporous silica particles have been extensively used to construct various drug delivery systems. An optimized design of pore size, surface functionalization and pore structure, is still needed for further application, especially for use as biomacromolecules carriers. Herein, one intelligent glucose-responsive insulin delivery system Insulin@ZnO-P@G-MSP was constructed based on mesoporous silica nanoparticles with large ordered mesopores (> 5 nm) and small particle sizes (∼150 nm), combined with phenylboronic acids as glucose-responsive units and zinc oxide nanoparticles as the capping agents. The release characteristics of this system showed a positive correlation with the species and concentration of the saccharides and could be switched on and off by adjusting the glucose concentration. The stable release rate in the serum and good biocompatibility with liver cells illustrated the feasibility of this system in further biological applications. This work demonstrates an innovative approach to the development of a biomolecules delivery system by introducing mesoporous silica particles with large ordered mesopores and nanometer-scale particle sizes.” [emphasis added](abstract) (instant claims 16, 25-26). Hei et al. teaches: “Synthesis of zinc oxide nanoparticles modified with phenylboronic acid (ZnO-P)” (p. 322, §2.2.3). Hei et al. teaches the ZnO-P as pore blocking agents (p. 321, Scheme 1)(instant claim 12, “(2) the size of the nanoparticle pore blocking agent matches the mesopore size of the mesoporous silica nanoparticles”).
Hei et al. teaches that: “A rational structural design of phenylboronic acid could achieve better glucose selectivity and would optimize its physicochemical and biological properties, avoiding the introduction of glucose oxidase at the same time. Thus, phenylboronic acid-based systems have promising applications in glucose-responsive insulin delivery.” (p. 321, col. 1, 3rd paragraph).
Hei et al. teaches that: “Most biomolecules usually have diameters larger than 3 nm, such as insulin, which exists as a hexamer with an approximately diameter around 5.3 nm to keep its bioactivity under pH 7.4.” and that classic MCM-41 type mesoporous silica with channel sizes of 2-3 nm cannot be used – “Therefore, mesoporous silica materials with small particle sizes of around 200 nm and ordered channel sizes of above 5 nm are very necessary for the delivery of biomolecules, such as insulin.” (p. 320, col. 2, 2nd paragraph though p. 321, col. 1, 1st paragraph). Hei et al. teaches that: “The glucose responsive insulin release system is also known as the ‘artificial islet’, which is used to mimic the release of insulin from the real islet cells according to the blood glucose concentration. As for the construction of such systems, the most widely used principle is that glucose oxidase oxidizes glucose and converts it to gluconic acid under physiological conditions, causing volume changes in pH-sensitive materials and leading to corresponding insulin release.” (p. 321, col. 1, 2nd paragraph).
Hei et al. teaches that: “Herein, we prepared 150 nm mesoporous silica particles with large ordered mesopores (5.6 nm), then constructed a glucose-responsive novel insulin release platform Insulin@ZnO-P@G-MSP by integrating phenylboronic acid as the glucose responsive unit, and zinc oxide nanoparticles as the capping agent. The in vitro release profiles showed that the amount of released insulin was dependent on the concentration of the monosaccharide species. In addition, the release process could be adjusted by changing the monosaccharide concentration in the solution. Furthermore, this system presented glucose concentration-dependent release characteristics in the fetal bovine serum and good biocompatibility with liver cells.” (p. 321, paragraph bridging cols. 1-2).
Hei et al. teaches the preparation of mesoporous silica particles (MSP) modified by glucosamine by combining the MSP composition with N-(3-trimethoxysilylpropyl) glucosamine (p. 321, col. 2, §2.2.2)(instant claim 11, “mesoporous silica nanoparticles functionalized by a polyhydroxy compound”; instant claim 12, “the polyhydroxy compound is a monosaccharide and its derivatives retaining at least two adjacent hydroxyl groups, a polysaccharide and its derivatives retaining at least two adjacent hydroxyl groups”; instant claims 13 & 21).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of Hei et al. is that Hei et al. does not expressly teach (1) the species of phenylboronic acid of instant claim 11, or (2) the structure VII in claim 14. Additionally, Hei et al. uses the polyhydroxy compound glucosamine and not gluconic acid (instant claims 22-23), and Hei et al. utilizes thiol chemistry to functionalize the zinc oxide nanoparticles modified with phenylboronic acid whereas instant claim 14 requires 3-aminopropyltriethoxysilane (APTES) bonded to zinc oxide and to the phenylboronic acid through an amide bond.
VAN ANTWERP teaches detection of biological molecules using chemical amplification and optical sensors (title, see whole document), and particularly teaches “Methods are provided for the determination of the concentration of biological levels of polyhydroxylated compounds, particularly glucose.” (abstract). VAN ANTWERP teaches “FIG. 13 provides another synthesis scheme for the compounds of formula I. In this scheme, 10-(hydroxymethyl)-9-anthraldehyde […] is reductively aminated using methylamine in a two-step process involving imine formation followed by sodium borohydride reduction of the imine. Alkylation of the secondary amine with a suitable arylboronic acid derivative then provides the desired compound of formula I. In this family of D1 compounds, the moiety ( e.g., anthracene) has an attached hydroxymethyl group which facilitates covalent attachment of the compound to a biocompatible matrix.” (col. 10, 2nd paragraph). Where Figure 13 discloses the following phenylboronic acid species:
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539
299
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(p. 13)(instant claim 11 – phenylboronic acid compound).
VAN ANTWERP teaches that “In order to use the amplification components for analyte sensing in vivo, the components for the reactions must be immobilized in a polymer matrix that can be implanted subdermally.” (col. 10, lines 25-30), and that “The biocompatible matrix can include either a liquid substrate ( e.g., a coated dialysis tube) or a solid substrate (e.g., polyurethanes/polyureas, silicon-containing polymers, hydrogels, solgels and the like).” (col. 10, lines 38-42).
WEISS teaches insulin analogous with a glucose-regulated conformational switch (title, see whole document). WEISS teaches that: “It is, therefore, an aspect of the present invention to provide insulin analogues that provide glucose-responsive binding to the insulin receptor and hence glucose-regulated bioactivity. The analogues of the present [invention] contain two essential elements. The first element is a phenylboronic acid derivative […]. The second element is a N-linked or O-linked monosaccharide, disaccharide, or oligosaccharide at one or near the C-terminus of the B-chain polypeptide […].” ([0011]). WEISS teaches that: “It is an additional aspect of the present invention that the N-linked or O-linked saccharide moiety may be replaced by any organic moiety of similar molecular mass that contains a diol function (or an a-hydroxycarboxylate group as an alternative PEA-binding function) conferring reversible binding to PEA or a PEA derivative attached at or near the N-terminus of the A chain. In some embodiments, the dial may be 3-26 carbons long. […] Examples of such non-saccharide diol-containing elements are provided by organic acids (such as gluconic acid, […]), […] and amino compounds (such as (±)-3-amino-l,2-propanediol, (±)-3-amino-l,2-propanediol, and glucosamine).” ([0018]).
WEISS further teaches NHS/DCC chemistry to link the phenylboronic acid (NHS-ester of PBA) to insulin fragment ([0103-[0105]).
Nicolay et al. teaches “ZnO/sol–gel nanocomposite coating, which can provide a number of properties such as UV-absorption, mechanical and barrier effects, etc. depending on targeted applications.” (abstract, see whole document). Nicolay et al. further teaches ZnO nanoparticle functionalization by combining zinc nanoparticles (Zano 20) with propyltrimethoxysilane (APTES) resulting in APTES-ZnO functionalized nanoparticles:
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364
649
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(p. 380, §2.2, Figure 2).
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 substitute the phenylboronic acid species of Hei et al. with that of VAN ANTWERP in Figure 13, and to substitute the polyhydroxy compound glucosamine with gluconic acid, as suggested by WEISS, both the phenylboronic acid species and the polyhydroxy compound were equivalents, as per VAN ANTWERP and WEISS, respectively, and further to utilize NHS/carbodiimide chemistry to link the phenylboronic acid to the zinc oxide nanoparticles, as suggested by WEISS and Nicolay et al. in order to link the phenylboronic acid to the zinc oxide nanoparticle capping agent (instant claim 14, structure VII).
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 phenylboronic acid compounds were well-known use in glucose-responsive controlled delivery systems, and the chemistry of producing the compounds and linking the compounds to the mesoporous silica or zinc oxide was know as per the disclosure of the cited prior art and the ordinary level of knowledge therein. 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 03/04/2026 have been fully considered but they are not persuasive.
Applicant argues that: “The applicant respectfully disagrees with the rejection at least for the following reasons. Van Antwerp teaches methods for the determination of the concentration of biological levels of polyhydroxylated compounds, particularly glucose. The methods utilize an amplification system that is an analyte transducer immobilized in a polymeric matrix. See abstract of Van Antwerp. The polyhydroxylated analyte, such as glucose, will bind to the amplification component following permeation into a biocompatible matrix (see lines 54-57, column 3 of Van Antwerp) and determination of the concentration of biological levels of the polyhydroxylated compounds, particularly glucose, could be performed.” And that: However, what is provided in the instant claim 11 is a mesoporous silica nanomaterial for controlled release, wherein the mesoporous silica nanomaterial for controlled release comprises: (1) mesoporous silica nanoparticles functionalized by a polyhydroxy compound, and (2) a nanoparticle pore blocking agent functionalized by a phenylboronic acid compound, […] In the mesoporous silica nanomaterial for controlled release of the subject application, the phenylboronic acid compound reacts with the polyhydroxy compound, such that the nanoparticle pore blocking agent functions to block pores of the mesoporous silica nanomaterial to prevent the active ingredients, such as insulin, contained therein from releasing in the presence of glucose.” (p. 12, last paragraph through p. 13, 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). The primary reference clearly teaches the Hei et al. clearly teaches “mesoporous silica nanomaterial for controlled release comprises: (1) mesoporous silica nanoparticles functionalized by a polyhydroxy compound, and (2) a nanoparticle pore blocking agent functionalized by a phenylboronic acid compound”
Applicant points to Examples of the instant Specification, arguing the function of the claimed compositions “In other words, in the subject application, glucose competes with the polyhydroxy compound on the mesoporous silica nanoparticles to bind to the phenylboronic acid compound, thus removing the nanoparticle pore blocking agent from the mesoporous silica nanoparticles, resulting in release of the active ingredients.” And that: “Although Van Antwerp discloses the phenylboronic acid compound of the instant claim 11 , it is completely silent on the fact that this phenylboronic acid compound exhibits stronger competitiveness in binding to glucose compared to other phenylboronic acid compounds.” And that: “Therefore, from the viewpoint of competitive binding to glucose, the skilled artisan would not have been motivated to replace the phenylboronic acid compound of Hei et al. with that of Van Antwerp.” (p. 13, last paragraph through p. 14, 5th paragraph).
In response the examiner argues that a prima face case of obviousness based upon a substitution rationale requires (1) a finding of fact that the prior art contained a product which differed from the claimed product by the substitution of some components with other components; (2) a finding of fact that the substituted components and their functions were known in the art; (3) a finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable; and (4) whatever additional findings based upon the Graham factual inquiries may be necessary, in view of the case under consideration, to explain a conclusion of obviousness (MPEP § 2143-B). In the instant case the Hei et al. differs from the claimed product by the substitution of the species of phenylboronic acid of instant claim 11, or the structure VII in claim 14, and uses the polyhydroxy compound glucosamine and not gluconic acid (1). One of ordinary skill in the art could have substituted the phenylboronic species of claim 11 with the phenylboronic species of VAN ANTWERP, and the glucosamine with gluconic acid, as suggested by WEISS (2), and to utilize NHS/carbodiimide chemistry to link the phenylboronic acid to the zinc oxide nanoparticles, as suggested by WEISS; Hei et al. teaches the preparation of mesoporous silica particles (MSP) modified by glucosamine by combining the MSP composition with N-(3-trimethoxysilylpropyl) glucosamine and Nicolay et al. further teaches ZnO nanoparticle functionalization by combining zinc nanoparticles (Zano 20) with propyltrimethoxysilane (APTES), therefore one of ordinary skill could have linked a polyhydroxy compound to a mesoporous silica nanoparticle, and particularly using APTES and gluconic acid (3). Additionally, Hei et al. clearly teaches their phenylboronic acid functionalized silica nanoparticles for controlled release of insulin (title). Therefore, the claims are properly rejected as being prima facie obvious over the cited combination of references based on substitution rationale (MPEP §2143(I)(B)).
The examiner further argues Applicant’s allegation of a stronger competitive binding to glucose as compared to other phenylboronic acid compounds - “phenylboronic acid compound exhibits stronger competitiveness in binding to glucose compared to other phenylboronic acid compounds” – does not in itself render the claims non-obvious. MPEP §2145(II) - Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention.
Applicant further argues that: “All the above results demonstrate that the use of the phenylboronic acid compound P3 as defined in claim 1 produce unexpected effects. This is unobvious to the skilled artisan over Hei et al. in view of Van Antwerp.” (p. 14, through p. 15, last paragraph).
Although the record may establish evidence of secondary considerations which are indicia of nonobviousness, the record may also establish such a strong case of obviousness that the objective evidence of nonobviousness is not sufficient to outweigh the evidence of obviousness. Newell Cos. v. Kenney Mfg. Co., 864 F.2d 757, 769, 9 USPQ2d 1417, 1427 (Fed. Cir. 1988), cert. denied, 493 U.S. 814 (1989); Richardson-Vicks, Inc., v. The Upjohn Co., 122 F.3d 1476, 1484, 44 USPQ2d 1181, 1187 (Fed. Cir. 1997). Applicant is reminded that the submission of objective evidence of patentability does not mandate a conclusion of patentability in and of itself. In re Chupp, 816 F.2d 643, 2 USPQ2d 1437 (Fed. Cir. 1987).
Applicant particularly argues that: “Specifically, as shown in Fig. 14, the blood sugar concentration of the animals receiving M3-2 is maintained at a level of higher than 100mg/dL with a 10mg/dl of fluctuation. Therefore, there is no risk of hypoglycemia. However, the blood sugar concentration of animals receiving insulin decrease from 115mg/dl to 57mg/dl, resulting in a risk of hypoglycemia.” (p. 15, 3rd paragraph). The instant Specification discloses that: “Figure 14 shows the changes in blood sugar concentration of the normal rats over time after the normal rats in Example 39 are injected with 2.0 mg M3-2 (4.1 IU) and insulin ( 4.1 IU) respectively.”(p. 9, lines 8-10)
In response the examiner argues that a comparison with an intelligent system for insulin delivery as compared to standard insulin injections does not constitute a comparison with the closest prior art or closer as Hei et al. teaches such an intelligent system for insulin delivery (MPEP §716.02(e)).
Applicant particularly argues that: “In addition to the above experiments, experiment in Example 37 was repeated with 4.1 IU of M2-2 prepared in Example 20 of the subject application. Result of M2-2 is shown below: […] As compared to Fig. 12 of the subject application, it can be found that M2-2 could not effectively control the blood sugar, which was maintained at a high level during the experiments.” (p. 15, paragraphs 4-5).
Again it is not clear that M3-2 as compared with M2-2 constitutes a comparison with the closest prior art (Hei et al.) or closer (MPEP §716.02(e)). However, in any case claim 11 is not limited to Applicant’s M3-2 sample, and it is not clear how such results should be extended to the scope of claim 11. MPEP §716.02(d) makes clear that: “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.” And the burden is on Applicant to explain their results (MPEP §716.02(b)) such that it is clear how the results correspond to the claims and the closest prior art or closer. For example, instant claim 11 does not even require a functionally active molecule, as in claim 16, and is only required to be an insulin in claim 26. Therefore, Applicants arguments of unexpected results are not considered commensurate with base claim 11.
Applicant is reminded that “In order to retain the right to rejoinder, applicant is advised that the claims to the nonelected invention(s) should be amended during prosecution to require the limitations of the elected invention. Failure to do so may result in a loss of the right to rejoinder.” (MPEP §821.04).
Conclusion
Claims 11-14, 16, 21-23, 25 and 26 are pending and have been examined on the merits. Claims 12 and 14 are rejected under 35 U.S.C. 112(b); claim 14 is rejected under 35 U.S.C. 112(d); and claims 11-14, 16, 21-23, 25 and 26 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
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