DETAILED ACTION
Status of the Claims
Claims 1 and 4-12 are pending in the instant application. Claims 9-12 have been withdrawn based upon Restriction/Election. Claims 1, 4-8 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All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.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 08/03/2022, the filing date of the instant application. Applicant's claim for a priority date of, 10/20/2021, the filing date of document ROK 10-2021-0140276, is acknowledged, however no English translation of this document has been filed for verification of written description support therein. The examiner notes that a certified copy of ROK 10-2021-0140276 has been electronically retrieved and made of record in the instant Application.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 has been amended to recite “wherein the mucoadhesive material comprises a chitosan polymer having catechol groups introduced thereto by coupling with hydrocaffeic acid” (lines 8-10) where claim 4 recites “wherein a degree of substitution in the mucoadhesive material” which fails to further limit the parent claim “the mucoadhesive material” is broader than “a chitosan polymer” which is indicated as “having catechol groups introduced thereto by coupling with hydrocaffeic acid”.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 and 4-7 are rejected under 35 U.S.C. 103 as being unpatentable over Ryu et al.1 (“Chitosan oral patches inspired by mussel adhesion,” 2020; ELSEVIER; Journal of Controlled Release, Vol. 317, pp. 57-66) in view of Arias et al. (Iron Oxide Nanoparticles for Biomedical Applications: A Perspective on Synthesis, Drugs, Antimicrobial Activity, and Toxicity,” 2018; Antibiotics, Vol. 7, No. 2, article 46, pp. 1-32); Zvarec et al. (“Catechol-Functionalized Chitosan/Iron Oxide Nanoparticle Composite Inspired by Mussel Thread Coating and Squid Beak Interfacial Chemistry,” 2013; ACS; Langmuir, Vol. 29, pp. 10899-10906); Shete et al. (“Magnetic chitosan nanocomposite for hyperthermia therapy application: Preparation, characterization and in vitro experiments,” 2014; ELSEVIER; Applied Surface Science, Vol. 288, pp. 149-157); and PAULETTI (US 2004/0151774 A1; published August, 2004).
Applicants Claims
Applicant claims a therapeutic patch for the gastrointestinal tract, comprising: a mucoadhesive material; and magnetic nanoparticles and a drug to be delivered to a living body, which are supported on the mucoadhesive material, wherein the magnetic nanoparticles are included in an amount of 5 mg/mL to 30 mg/mL based on the total amount of DI water added to for the therapeutic patch, a chitosan polymer having catechol groups introduced thereto by coupling with hydrocaffenic acid (HCA, elected species), wherein the mucoadhesive material is obtained by freeze-drying a mixture of the chitosan polymer and a catechol precursor at a temperature of -70°C to -90°C, wherein the chitosan polymer and the catechol precursor are mixed at a ratio of 1:1-1.2. (instant claim 1). Applicant further claims the mucoadhesive material comprises a mucoadhesive polymer is chitosan (instant claim 3, elected species), among others. Applicant further claims the magnetic nanoparticles are iron oxide magnetic nanoparticles (instant claim 5).
Elected Species: The examiner required an election of species of (a) a species of therapeutic patch with specificity to: (i) a mucoadhesive material, (ii) a species of magnetic nanoparticles, and (iii) a species of catechol precursor. Applicants have elected the following species in the reply filed 08/30/2023: (a)(i) is chitosan, (a)(iii) is Fe2O3 or Fe3O4 and (a)(iii) is hydrocaffeic acid (HCA).
With regard to the process steps of claims “wherein the mucoadhesive material is obtained by freeze-drying a mixture of the mucoadhesive polymer and a catechol precursor at a temperature of -70°C to -90°C”, “Even though product-by process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” See MPEP § 2113.
Determination of the scope
and content of the prior art (MPEP 2141.01)
Ryu et al. teaches “Oral mucosal drug delivery systems have been developed to expedite the regeneration of oral mucosa, there are still many challenges related to residence time for drugs because the ceaseless changes of saliva, mouth movement, and involuntary swallowing prevent robust adhesion of drugs and/or drug-loaded biomaterials. Thus, it is highly desirable to develop the delivery platforms exhibiting robust, stable adhesion within oral cavities. Herein, we have developed an adhesive polysaccharide oral patch called ‘Chitoral’ that utilizes chemical principles shown in wet-resistant mussel adhesion.” (see whole document, abstract).
Ryu et al. teaches that “the chemistry explaining the wet-resistant adhesion of mussels has been regarded as poly(catecholamine), in which catechol is the side-chain of DOPA, and amine is the terminal moiety of lysine. A mussel-inspired approach attempting to mimic poly (catecholamine) (i.e., synthetic poly(catecholamine)) exhibited material- independent wet-resistant surface adhesion.” (p. 58, col. 1, lines 5-10). And further that: “One well-known example is chitosan-catechol [28,29]. The abundant D-glucosamine in the backbone presents amine moieties to which a carboxyl-terminated catechol, 3,4-dihydroxyhydrocinnamic acid (HCA), was conjugated with a degree of modifications between 5 and 20%.” (p. 58, col. 1, 2nd paragraph, lines 9-13)(instant claims 1-4, chitosan conjugated with hydrocaffeic acid -- degree of substitution is 5% to 20%) The resulting chitosan-catechol conjugate, abbreviated as Chi-C […].”
Ryu et al. teaches that: “Chitoral is a freeze-dried form from Chi-C solution to create porous, sponge-like adhesive materials in which therapeutic drugs can be loaded in the polymer networks. As the name indicates, Chitoral exhibits superior mucoadhesion in the oral cavity.” (p. 58, col. 1, last paragraph)(instant claim 1, “wherein the mucoadhesive material is obtained by freeze-drying a mixture of the mucoadhesive polymer and the catechol precursor”).
Regarding the limitation “wherein the chitosan polymer and the catechol precursor are mixed at a ratio of 1:1-1.1.2, Ryu et al. teaches that: “Catechol was conjugated to a chitosan backbone by EDC chemistry. Briefly, chitosan (1 g, 5.4 mmol for the monomer) was hydrated in 5 N HCl solution (5 mL), and then DDW (44.5 mL) was added. After the chitosan was homogeneously dissolved in water, the pH was adjusted to 5.5. HCA (1.18 g, 6.5 mmol) and EDC (1.25 g, 6.5 mmol) were each dissolved in ethanol (5 mL, 20 mL) and were slowly added to the pre-dissolved chitosan solution.” [emphasis added](p. 58, col. 2, §2.2). Which is consistent with Applicants own disclosure in Example – “A chitosan solution was prepared by mixing 1 g of chitosan, 5 ml of HCI (hydrochloric acid), and 44.5 ml of DDW (deionized distilled water). The chitosan solution was mixed to homogeneity, after which the pH thereof was adjusted to 5.5. 1.18 g of hydrocaffeic acid (HCA), serving as a catechol precursor, and EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride) (1.24 g, 8.0 mmol) were mixed respectively with 5 ml and 20 ml of ethanol, after which the resulting mixture was mixed with the chitosan solution.” [emphasis added](instant Specification, p. 12, last paragraph; [0038], as published). Ryu et al. and the instant Specification both use 1 g chitosan polymer with 1.18 g hydrocaffeic acid (HCA), therefore the limitation “wherein the chitosan polymer and the catechol precursor are mixed at a ratio of 1:1-1.2” is taught by Ryu et al. (1 g chitosan polymer : 1.18 g hydrocaffeic acid (HCA)).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of Ryu et al. is that Ryu et al. does not expressly teach the inclusion of magnetic nanoparticles such as iron oxide magnetic nanoparticles coated with chitosan (instant claims 1, 5-7); or the freeze-drying is conducted at a temperature of -70°C to -90°C.
Ryu et al. clearly suggests that: “The resulting chitosan-catechol conjugate, abbreviated as Chi-C, has exhibited effective hemostasis [29,30], served as a drug delivery reservoir [31–33], a bio-printing material [34] and allowed nanoparticle surface functionalization [35-37].” And Ryu et al. cites references that include iron oxide nanoparticles: [35], [36] and [37] (p. 66, col. 2), clearly suggesting that magnetic nanoparticles could be advantageously included in their patch.
Arias et al. teaches that: “Medical applications and biotechnological advances, including magnetic resonance imaging, cell separation and detection, tissue repair, magnetic hyperthermia and drug delivery, have strongly benefited from employing iron oxide nanoparticles (IONPs) due to their remarkable properties, such as superparamagnetism, size and possibility of receiving a biocompatible coating. Ongoing research efforts focus on reducing drug concentration, toxicity, and other side effects, while increasing efficacy of IONPs-based treatments. This review highlights the methods of synthesis and presents the most recent reports in the literature regarding advances in drug delivery using IONPs-based systems, as well as their antimicrobial activity against different microorganisms. Furthermore, the toxicity of IONPs alone and constituting nanosystems is also addressed.” [emphasis added](see whole document, particularly the abstract).
Arias et al. teaches that: “IONPs have also been coated with CS. This material is a natural, long-chain polymer, generated by the combination of 2-amino-2-deoxy-β-D-glucan with glycosidic linkages, which can be obtained by chitin deacetylation. Its positive charge drives the CS carriers to the cell membrane (negatively charged) and its mucoadhesive properties extend the CS retention in the target sites, making it interesting for application in drug delivery systems. Furthermore, CS is biocompatible, biodegradable and presents low toxicity.
Many CS-nanosystems have been developed over the last few years, relying on the aforementioned advantages and water solubility. Coating of IONPs with this polymer does not change the thermal and magnetic properties of the nanoparticles, serving as support for drug binding. Also, a one-pot synthesis in the presence of CS of low molecular weight showed that it was capable of protecting IONPs from aggregation due to the electrostatic repulsion between the positively charged nanoparticles.” [emphasis added](pp. 5-6, §3.1.4).
Arias et al further teaches IONP mediated drug delivery, including anticancer drugs (pp. 8-12, §4).
Zvarec et al. teaches catechol-Functionalized chitosan/iron oxide nanoparticle composite inspired by mussel thread coating (see whole document), and particularly that: “Biological materials offer a wide range of multifunctional and structural properties that are currently not achieved in synthetic materials. Herein we report on the synthesis and preparation of bioinspired organic/inorganic composites that mimic the key physicochemical features associated with the mechanical strengthening of both squid beaks and mussel thread coatings using chitosan as an initial template. While chitosan is a well-known biocompatible material, it suffers from key drawbacks that have limited its usage in a wider range of structural biomedical applications. First, its load-bearing capability in hydrated conditions remains poor, and second it completely dissolves at pH < 6, preventing its use in mild acidic microenvironments. In order to overcome these intrinsic limitations, a chitosan-based organic/inorganic biocomposite is prepared that mimics the interfacial chemistry of squid beaks and mussel thread coating. Chitosan was functionalized with catechol moieties in a highly controlled fashion and combined with superparamagnetic iron oxide (γ-Fe2O3) nanoparticles to give composites that represent a significant improvement in functionality of chitosan-based biomaterials. The inorganic/organic (γ-Fe2O3/catechol) interfaces are stabilized and strengthened by coordination bonding, resulting in hybrid composites with improved stability at high temperatures, physiological pH conditions, and acid/base conditions. The inclusion of superparamagnetic particles also makes the composites stimuli responsive.” (abstract).
Zvarec et al. teaches that: “In the first stage of our composite strategy, we functionalized chitosan fibers (CS) with catecholic moieties (CAT) in a controlled manner, with the dual goals of (i) reducing the number of hydrophilic amine motifs along the backbone, and (ii) providing the polymer with side-chain functionality that triggers subsequent cross-linking (Scheme 1).
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Catecholic functional groups were chosen because of their versatile characteristics, including covalent cross-linking8 and coordination bonding. This is followed by induced coordination of functionalized chitosan with superparamagnetic iron oxide (γ-Fe2O3) nanoparticles, allowing catecholic side groups to form a robust coordinated-bonded network with the surface of iron oxide nanoparticles, similar to the catechol-Fe3+ coordination cross-linked network observed in mussel thread coatings. The addition of superparamagnetic γ-Fe2O3 nanoparticles (MNP) enables magnetic functionality, making these hybrid composites multifunctional, robust, and stimuli-active materials that could be employed in various biomedical devices.” (p. 10900, col. 1, 2nd paragraph).
Regarding instant claim 7, Ryu et al. teaches that: “Catechol was conjugated to a chitosan backbone by EDC chemistry.” (p. 58, §2.2); and Zvarec et al. teaches that: “Respective Catechol […] and N-ethyl-N’-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) […] in ethanol (100 mL) was added and the solution stirred for 7 days.” both being carbodiimide chemical bonding.
Regarding the limitation that “the magnetic nanoparticles are included in an amount of 5 mg/ml to 30 mg/ml based on the total amount of DI water added to form the therapeutic patch.” (instant claim 1, lines 6-7), Shete et al. teaches magnetic chitosan nanocomposite for hyperthermia therapy application, including preparation, characterization and in vitro experiments (see whole document), and particularly that: “In the present investigation, Fe3O4 NPs were prepared by alkaline precipitation method and were surface modified with chitosan. Conventional co-precipitation method uses mixture of FeCl2 and FeCl3 for MNPs synthesis. This method is more simplified and made cost-effective in this work.” (p. 150, col. 1, lines 3-7). Shete et al. teaches that: “A reasonable assumption is that 5–10 mg of magnetic material concentrated in each cm3 of tumor tissue is appropriate for magnetic hyperthermia in human patients. Fig. 13(a) and (b) represents the induction heating ability of both MNPs at different AC-magnetic fields (200–400 A i.e. 167–335 Oe) for 10 min with the variation of particle concentration from 2 to 10 mg mL-1 in water.” [emphasis added](p. 156, col. 1, lines 7-12). Shete et al. teaches that: “Particles are dispersed in water with a concentration ranging from 2, 5 and 10 mg mL-1 and ultrasonicated for 20 min to achieve a good dispersion of the NPs in carrier fluid.” (p. 151, col. 1, lines 8-10). Shete et al. teaches that: “Fig. 12(a)–(c) represents the temperature kinetic curves obtained after application of an alternating magnetic field on both mL-1 and samples dispersed in water with concentration of 2 mg (d) Specific Absorption Rate (SAR) vs applied magnetic field for both samples.” (p. 154, col. 2, 2nd paragraph, lines 1-5; Figures 12(a)-(c)). Shete et al. teaches that: “Both the NPs showed that heating ability depend on the applied field and their concentration. From Fig. 13 it can be observed that, a hyperthermia temperature (42–46 °C) can be achieved by both the samples at magnetic field of 167–335 Oe and at a frequency of 265 kHz. It was also observed experimentally that the CS coated Fe3O4 achieves higher temperature than the bare Fe3O4 and it was attributed to the efficient Brownian and Neel’s spin relaxations.” [emphasis added](p. 156, col. 1, lines 13-19). MPEP 2144.05 makes clear that: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.”
PAULETTI teaches therapeutic compositions for drug delivery to and through an epithelia (title, see whole document), and particularly a polymer foam or film having a controllable rate of gelling, swelling and degradation and is preformed into a device or is applied as a coating to a surface of a more complex drug delivery system (abstract).
PAULETTI teaches that “Lyophilized foams are open cell, high-surface-area, biodegradable or non-degradable constructs that can be manufactured from a variety of polymers, preferably from hydrophilic polymers.” ([0067]). And that: “Lyophilization conditions and apparatuses and equipment are known in the art and any type of lyophilization process or equipment is intended to be within the scope of this invention.” ([0071]). And further that: “Typically, the polymer or polymer mixture and drug solution, as described above, is first frozen for at least 15 minutes, and typically at least 30 minutes, in a form having the shape and size desired for the finished lyophilized foam. For water solutions, the freezing temperature is from 0° C. to -80° C. and preferably less than -10° C. After freezing, the frozen samples are ejected or removed from the forms, optionally by brief warming on the outside of the forms. The frozen samples are placed in trays pre-cooled to a temperature below the freezing point of the solvent. While under vacuum, the samples are then converted to foams by lyophilization (freeze-drying) at 0° C. to -80° C. and preferably below -20° C. for about 48 hours to about 144 hours.” ([0072]).
It would have been prima facie obvious to freeze-dry (lyophilize) a mucoadhesive chitosan patch as suggested by Ryu et al., teaching that: “Finally, the solution was frozen in a−20 °C refrigerator and was lyophilized.” And it would have been prima facie obvious to utilize a lower freeze-drying (lyophilizing) temperature of -80° C, as suggested by PAULETTI.
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 mucoadhesive patch for delivery to the oral mucosa including HCA-chitosan conjugate, as taught by Ryu et al., and to further incorporate iron oxide nanoparticles (IONPs), as suggested by Arias et al., the IONPs being coated with catechol functionalized chitosan, as taught by Zvarec et al. in order to improve the properties of the mucoadhesive patch for delivery to the oral mucosa taught by Ryu et al. by inclusion of IONPs for drug delivery and/or hyperthermia applications, the product being freeze-dried as suggested by Ryu et al. and PAULETTI.
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 chitosan is a known mucoadhesive polymer with many groups for substitution (conjugation) of functional groups such as catechol (HCA), and the specific combination with iron oxide nanoparticles is also taught by the prior art, the combination being well within the ordinary level of skill in the art to which the invention pertains. 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(a).
Claim 8 remains rejected under 35 U.S.C. 103 as being unpatentable over Ryu et al. in view of Arias et al.; Zvarec et al. and Shete et al., as applied to claims 1, and 3-7 above, and further in view of Quaglia et al. (“Wireless Robotic Capsule for Releasing Bioadhesive Patches in the Gastrointestinal Tract,” 2014; ASME; Journal of Medical Devices, Vol. 8, Article 014503, pp. 1-6).
Applicants Claims
Applicant claims a therapeutic patch for the gastrointestinal tract, comprising a mucoadhesive material; and magnetic nanoparticles and a drug to be delivered to a living body, which are supported on the mucoadhesive material, wherein the magnetic nanoparticles are included in an amount of 5 mg/mL to 30 mg/mL (instant claim 1). Applicant further claims the mucoadhesive material comprises a mucoadhesive polymer (chitosan) having a catechol structure introduced thereto (hydrocaffenic acid - HCA)(instant claims 2-3, elected species). Applicant further claims the magnetic nanoparticles are iron oxide magnetic nanoparticles (instant claim 5).
Determination of the scope
and content of the prior art (MPEP 2141.01)
Ryu et al. teaches oral mucosal drug delivery including HCA conjugated chitosan, as discussed above and incorporated herein by reference.
Arias et al. teaches iron oxide nanoparticles (IONPs) for drug delivery and hyperthermia, and suggest the combination with chitosan, as discussed above and incorporated herein by reference.
Zvarec et al. teaches catechol-Functionalized chitosan/iron oxide nanoparticle composite inspired by mussel thread coating, as discussed above and incorporated herein by reference.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of Ryu et al., Arias et al. and Zvarec et al. is that these references do not expressly teach the patch is delivered by “capsule endoscopy”.
Quaglia et al. teaches “A novel, miniature wireless robotic capsule for releasing bioadhesive patches in the gastrointestinal (GI) tract was designed, fabricated, and preliminarily tested. In particular, the assembled prototype was successfully navigated in a GI phantom, up to a target site where the release mechanism was verified. Then, deployment of a bioadhesive patch onto ex vivo porcine tissue was accomplished, and patch adhesion strength was verified. The main application of the present system is the deployment of anchoring patches for miniature robotic modules to be operated in the targeted anatomical domain. Such an innovative application stems from the wise blend of robotics and bioadhesion. Obtained results, which are consistent with previous investigations by the group, confirm the viability of the adopted bioadhesives for the envisaged anchoring tasks.” (see whole document, particularly the abstract).
Quaglia et al. teaches that: “Current medical research is increasingly moving toward minimally invasive approaches for both diagnosis and therapy, and robotic capsule endoscopy is one of the medical technologies that best represents this trend. Starting from imaging and telemetry capsules, nowadays robotic capsule endoscopes possess active locomotion capabilities for reliable control and they can also perform some simple interventional tasks.” (p. 1, §Introduction, 1st paragraph).
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 mucoadhesive patch for delivery to the oral mucosa including HCA-chitosan conjugate, as taught by Ryu et al., and to further incorporate iron oxide nanoparticles (IONPs), as suggested by Arias et al., the IONPs being coated with catechol functionalized chitosan, as taught by Zvarec et al. in order to improve the properties of the mucoadhesive patch for delivery to the oral mucosa taught by Ryu et al. by inclusion of IONPs for drug delivery and/or hyperthermia applications; and to delivery the mucoadhesive patch to a mucoadhesive surface in the GI Tract by “robotic capsule endoscopy,” as suggested by Quaglia et al., as a minimally invasive means mucoadhesive patch delivery.
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 chitosan is a known mucoadhesive polymer with many groups for substitution (conjugation) of functional groups such as catechol (HCA), and the specific combination with iron oxide nanoparticles is also taught by the prior art, the combination being well within the ordinary level of skill in the art to which the invention pertains. 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(a).
Response to Applicant Declaration filed under CFR §1.132:
The examiner agrees that Applicants results showing increased adhesive force in newtons (N) may be considered unexpected. However, given that the prior art suggest it is standard procedure to lyophilize (freeze dry mucoadhesive compositions) and the temperature range suggested for the same overlaps with Applicants own temperature “wherein the mucoadhesive material is obtained by freeze-drying a mixture of the chitosan polymer and the catechol precursor at a temperature of -70°C to -90°C.” (instant claim 1, lines 11-13), it would have been prima facie obvious to perform the step of freeze drying at -80°C - PAULETTI teaching that “Lyophilized foams are open cell, high-surface-area, biodegradable or non-degradable constructs that can be manufactured from a variety of polymers, preferably from hydrophilic polymers.” ([0067]). And that: “Lyophilization conditions and apparatuses and equipment are known in the art and any type of lyophilization process or equipment is intended to be within the scope of this invention.” ([0071]). And further that: “Typically, the polymer or polymer mixture and drug solution, as described above, is first frozen for at least 15 minutes, and typically at least 30 minutes, in a form having the shape and size desired for the finished lyophilized foam. For water solutions, the freezing temperature is from 0° C. to -80° C. and preferably less than -10° C. After freezing, the frozen samples are ejected or removed from the forms, optionally by brief warming on the outside of the forms. The frozen samples are placed in trays pre-cooled to a temperature below the freezing point of the solvent. While under vacuum, the samples are then converted to foams by lyophilization (freeze-drying) at 0° C. to -80° C. and preferably below -20° C. for about 48 hours to about 144 hours.” ([0072]).
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).
Response to Arguments:
Applicant's arguments filed 11/14/2025 have been fully considered but they are not persuasive.
Applicant argues that: “As an initial matter, Applicant respectfully directs the Examiner's attention to Lee et al. Drug-Loaded Mucoadhesive Patch with Active Delivery and Controlled Releasing Ability. Adv. lntell. Syst. 2022, 4, 2100203, submitted herein. As discussed during the interview of 10/14/2025, Figs. 2(c) and 2(d) of Lee et al. authored by the present inventors (reproduced below), show the SEM images when freeze-drying is carried out at -80 °C. At this temperature, the pore size is smaller than in the case of freezing at -4 °C.” (p. 5, last paragraph). And that: “In addition, as seen in the Rule 1.132 Declaration submitted herein, which was
also discussed during the interview of 10/14/2025, when freeze-drying is performed at -80 °C, the adhesion strength is significantly higher than in the cases of freezing at -4 °C and -20 °C as well.” (p. 6, 5th paragraph). And “This is not merely a routine parameter but is an unexpectedly critical condition that structurally and functionally distinguishes the final therapeutic patch from any patch taught or suggested in the prior art references. No prior art reference discloses or suggests these surprising improvements in mucoadhesive strength attributable to the low-temperature freeze step, nor the synergy with the final patch's concentration of iron oxide nanoparticles for controlled hyperthermia. Such results are unexpected and differ in kind from merely "routine optimization," especially in light of the fact that Claim 1 is now amended read, inter alia, "[ ... ] wherein the mucoadhesive material comprises a chitosan polymer having catechol groups introduced thereto by coupling with hydrocaffeic acid, wherein the mucoadhesive material is obtained by freeze-drying a mixture of the chitosan polymer and a catechol precursor at a temperature of -70°C to - 90°C, wherein the chitosan polymer and the catechol precursor are mixed at a ratio of 1:1-1.2."” (paragraph bridging pp. 6-7).
In response the examiner argues that the Ryu et al. reference clearly teaches producing the chitosan-HCA - Ryu et al. teaches that: “Chitoral is a freeze-dried form from Chi-C solution to create porous, sponge-like adhesive materials in which therapeutic drugs can be loaded in the polymer networks. As the name indicates, Chitoral exhibits superior mucoadhesion in the oral cavity.” [emphasis added](p. 58, col. 1, last paragraph). Applicants point to Figs. 2(c) and 2(d) of Lee et al.2 showing the image:
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However, Ryu et al. show a similarly small pore size in their micrograph:
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(supplemental info, Figure S2, attached). And more importantly Ryu et al. teaches that: “Chitoral is a freeze-dried form from Chi-C solution to create porous, sponge-like adhesive materials in which therapeutic drugs can be loaded in the polymer networks. As the name indicates, Chitoral exhibits superior mucoadhesion in the oral cavity.” [emphasis added](p. 58, col. 1, last paragraph). MPEP §716.02(b) makes clear that the burden is on Applicant to establish results are unexpected and significant: “The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance."” Additionally, MPEP 2144(IV) makes clear that: “The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant.”
Conclusion
Claims 1, and 4-8 are pending and have been examined on the merits. Claim 4 is rejected under 35 U.S.C. 112(d); and claims 1, and 4-8 are rejected under 35 U.S.C. 103. No claims allowed at this time.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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
/DAVID J BLANCHARD/Supervisory Patent Examiner, Art Unit 1619
1 Of record as cited on Applicants IDS filed 08/03/2022, Non-Patent literature citation No. 5.
2 Of record as cited by the Examiner on 10/20/2025.