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 .
Applicants’ arguments, filed 07/21/2026, have been fully considered. Rejections and/or objections not reiterated from previous office action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Election/Restrictions
Applicant’s election without traverse of the species directed to a system employing irinotecan hydrochloride, claims 1-2, 4-7, 11-2, 14 and 17, in reply filed on 07/21/2026 is acknowledged.
Claims 8-10, 13, 15, 16 and 18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/21/2026.
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 11-12 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.
Claim 11 recites the limitation "the drug" in line 2. There is insufficient antecedent basis for this limitation in the claim. Antecedent basis is not established by the recitation of “drug delivery system” because such a disclosure is describing a delivery system, not a drug.
The term “configured” in claim 12 is a relative term which renders the claim indefinite. The term “configured” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear what is meant by this term such that the artisan would reasonably appreciate the metes and bound of what is encompassed by it. It is not clear how far from the base sustained release structure one can deviate and still meet the requirement of the claim. For the purposes of examination configured will be interpreted as “capable of”.
Claim Rejections - 35 USC § 103 – Necessitated by Amendment
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
1) Claims 1, 2, 4, 6, 7 are rejected under 35 U.S.C. 103 as being unpatentable over Sichuan University (CN 112316204 A, publication date 02/05/2021; cited in IDS; citing English Machine translation; previously cited).
Sichuan University discloses “a metal polyphenol collagen membrane material which is a hydrogel material and comprises collagen and a nano complex loaded on a collagen porous structure, wherein the nano complex is obtained by chelating metal ions and polyphenol” [p. 7, para. 1]. In one example, nano-complexes are first prepared with epigallocatechin gallate and magnesium ions (i.e., instant claim 4) [p. 9, para. 2, “Example 1”]. Then epigallocatechin gallate and magnesium ion complexes are incorporated into a collagen hydrogel at a weight ratio of 85 parts collagen hydrogel to 15 parts nano-complex (i.e., 1:5.6 complex to hydrogel; instant claim 7) [p. 10, para. 2, “Example 3”]. Sichuan University further discloses that “the metal ion is a water-soluble and antibacterial metal ion, specifically a mixture of one or more of magnesium ion, copper ion, and iron ion” [p. 7, para. 3].
Sichuan University does not anticipate the instant claims because it does not disclose one example or embodiment comprising the claimed metal ions.
It would have been obvious to one of ordinary skill in the art, at the time of filing, to have simply substituted the magnesium ion of the exemplary composition for the iron ion because Sichuan University discloses both ions a suitable for the polyphenol complex. The simple substitution of one known element (e.g., the iron ion of Sichuan University) in place of another (e.g., the magnesium ion of Example 1 disclosed by Sichuan University) in order to achieve predictable results (polyphenol metal ion complex) is prima facie obvious. See MPEP 2143, Exemplary Rationale B.
In regard to the in-situ formation, "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." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (See MPEP 2113.). In the present case, the prior art product appears to be the same or obvious as claimed, despite not teaching the claimed in situ formation of the supramolecular filler, insofar as the Sichuan University discloses a porous collagen hydrogel comprising epigallocatechin gallate and iron ion complex.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). In the present case, the instantly claimed weight ratio of supramolecular filler to hydrogel of instant claim 7 (1:5-10) overlaps with the range of the prior art (i.e., 1:5.6 complex to hydrogel) and so a prima facie case of obviousness exists.
Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have formulated a composition comprising a complex of epigallocatechin gallate and iron ions in a porous collagen hydrogel. Because the prior art contains substantially the same components as instantly claimed, it would have been expected to possess the same properties and be capable of satisfying the same applications, i.e. capable of interacting with a drug for sustained release, regulating pores, forming a multi-stage porous structure.
2) Claims 1, 2, 5, 7, 11, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Zhong et al. (US 2016/0022707 A1, publication date 01/28/2016; previously cited).
Regarding instant claim 1, 2, 11 and 12, Zhong disclose “drug delivery compositions that allow for immediate and/or sustained release of a therapeutic agent contained within the system” [abstract], “comprising a therapeutic agent or a salt thereof, a polyelectrolyte and a polyvalent metal ion” [0012]. “In some embodiments, the metal ion comprises a divalent metal ion, such as but not limited to beryllium, magnesium, zinc, cadmium, mercury, lead, calcium, copper (II), barium, iron (II), nickel, and tin” [0129]. Additionally, Zhong discloses that “hydrogel scaffolds are used to encapsulate particles comprised of therapeutic agent/poly electrolyte/metal ion complexes” (see sentence spanning columns in [0137]). In one example of the drug delivery system, Zhong discloses “[a]n injectable hydrogel system comprising agarose, and particles comprised of DS/Mg2+/MH complexes” (see last sentence of [0192]). Zhong defines such particle complexes as “a complex coacervation composed of MH, divalent metal ions (Ca2+ and Mg2+) and dextran sulfate (DS), a biocompatible natural polysaccharide” [0164]. “MH” is minocycline hydrochloride (i.e., drug loaded into hydrogel)[0123]. Furthermore, according to Zhong “[t]he particle was formed inside agarose solution. Components for particle fabrication, for example, single component among DS, MH and divalent metal ions (Ca/Mg), or multiple components among DS, MH and divalent metal ions, were dissolved in agarose solution (agarose concentration ranged from 0.5% to 5%), and then mixed with other components. […] Equal volumes of DS solution (containing MgC12 and agarose) and MH solution were mixed; particles were formed immediately. This mixture was cooled to 4 ° C. for 20 min to allow gel formation” [0200].
Zhong does not anticipate the instant claims because it does not disclose the claimed metal ions (i.e., Al, Fe, Zn, Mn, Ni, Co, and V) in one example or embodiment with all the claimed components.
However, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have simply substituted the magnesium and calcium ions of the exemplary composition for the zinc and iron (II) ions disclosed by Zhong. One would have been motivated to, and had an expectation of success in making this substitution because Zhong discloses the ions as equivalents for the same purpose and they would have provided the same cumulative charge. The simple substitution of one known element (e.g., the zinc and iron (II) ions of Zhong) in place of another (e.g., the magnesium and calcium of Zhong’s exemplary composition) in order to achieve predictable results (metal ion complex) is prima facie obvious. See MPEP 2143, Exemplary Rationale B.
Furthermore, the particles of the prior art are complexed “in situ” insofar as the sustained release drug (MH; minocycline hydrochloride), a natural polysaccharide (DS; dextran sulfate) and divalent metal ions are dissolved in a solution of agarose to form complexes of DS, MH and metal ions before the solution is gelled. Since the prior art composition contains substantially the same components, i.e., agarose hydrogel comprising a complexed particle of a polysaccharide, divalent metal ion and a drug, in the same relative proportions as instantly claimed and made by the same instantly claimed “in situ” formation, it would be expected to inherently possess the same chemical and physical properties, such as being regulating pores and forming a multi-stage porous structure.
Therefore, it would have been obvious for one of ordinary skill in the art, at the time of filling, to have formulated a sustained release composition comprising a multistage porous agarose hydrogel and a complex of polysaccharide biomass (i.e., dextran sulfate) and iron (II) metal ions (instant claims 1-2). Where the complex further comprises a drug which is loaded into the hydrogel (instant claim 11). Wherein the complexed particles are formed in situ. Because the prior art contains substantially the same components as instantly claimed, it would have been expected to possess the same properties and be capable of satisfying the same applications, i.e. the supramolecular filler would have been capable of interacting with a drug for sustained release, regulating pores, forming a multi-stage porous structure, and capable of interacting with the drug via at least two of coordination bonding, pi-pi interaction, hydrogen bonding, electrostatic interaction and hydrophilic interaction (i.e., instant claim 12).
Regarding instant claim 5, Zhong discloses that in some embodiments “the polyelectrolyte comprises a polyanion. Examples of polyanions include, but are not limited to, dextran sulfate, heparin, chondroitin sulfate, hyaluronic acid, … carboxymethyl cellulose (CMC), or any combinations thereof” [0127].
It would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have simply substituted the dextran sulfate of the exemplary composition for the carboxymethyl cellulose. One would have been motivated to, and had an expectation of success in making this substitution because Zhong discloses the dextran sulfate and carboxymethyl cellulose are equivalents for the same purpose (i.e., polyelectrolyte polyanions). The simple substitution of one known element (e.g., the carboxymethyl cellulose of Zhong) in place of another (e.g., the dextran sulfate of Zhong’s exemplary composition) in order to achieve predictable results (polyanion for the complexed particle) is prima facie obvious. See MPEP 2143, Exemplary Rationale B.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have formulated a sustained release composition comprising a multistage porous agarose hydrogel and a complex of carboxymethyl cellulose, an iron (II) metal ion and a drug, wherein the drug is loaded into the hydrogel.
In regard to claim 7, it would have been obvious to one of ordinary skill in the art, at the time of filing, to have formulated a composition comprising the hydrogel and the complexed particle within the instantly claimed weight ratio through routine optimization. It has been held that it is not inventive to discover the optimum workable ranges by routine experimentation where, as is here, the general conditions of the claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). One of ordinary skill in the art would have been motivated to optimize the amount of the complexed particles present in composition, and therefore the ratio of complexed particle to hydrogel, to affect the dosage of the compositions. One would have had an expectation of success because the complexed particle comprises the therapeutic agent.
3) Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Zhong et al. (US 2016/0022707 A1, publication date 01/28/2016; previously cited), as applied to instant claims 1, 2, 5-7, 11, and 12, and further in view of Sichuan University (CN 112316204 A, publication date 02/05/2021; cited in IDS; citing English Machine translation; previously cited).
Zhong, which is discussed above, differs from instant claim 4 insofar as it does not disclose a polyphenol complex.
Zhong does discloses the composition may be employed with “tissues replacing a lost or damaged function of human body” (i.e., tissue engineering; see p. 3, [0029], line 12). Zhong also discloses the therapeutic agent may provide anti-biotic and anti-inflammatory action [0022]. Finally, Zhong desires a controlled release: “The drug delivery system of the present invention facilitates the sustained and controlled release of a therapeutic agent from a therapeutic agent/polyelectrolyte/metal ion complex” [0153].
Sichuan University discloses an “porous structure of collagen to load a large amount of metal polyphenol nano particles, and forms a novel hybridization responsive film through the actions of hydrogen bonds and the like. The polyphenol chelates metal ions, so that the collagen membrane material can release and combine the metal ions under the condition of acid-base response” [p. 6, last paragraph]. According to Sichuan University the “material can release polyphenol and metal ions under the PH response, and the polyphenol can absorb excessive active oxygen, eliminate inflammation, inhibit bacterial growth and promote wound healing” [p. 6, para. 1]. Specific polyphenols include epigallocatechin gallate [p. 7, para. 5].
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have simply substituted the therapeutic agent/polyelectrolyte/metal ion complex of Zhong for the polyphenol metal ion complexes of Sichuan University. One would have been motivated to make this substitution to gain the pH responsive release described in Sichuan University because Zhong desires a controlled release. One would have had an expectation of success because Sichuan University discloses the polyphenol metal ion complexes may be loaded into a hydrogel to delivery anti-bacterial and anti-inflammation to promote wound healing (i.e., delivery of an active agent for tissue engineering), as desired by Zhong. The skilled artisan would have been motivated to have substituted the polyphenol metal ion complexes of Sichuan University in place of the therapeutic agent / polyelectrolyte / metal ion complex of Zhong to provide anti-bacterial and anti-inflammatory action with a reasonable expectation of success. The simple substitution of one known element (e.g., the polyphenol metal ion complexes of Sichuan University) in place of another (e.g., the therapeutic agent / polyelectrolyte / metal ion complex of Zhong) in order to achieve predictable results (controlled release of anti-bacterial and anti-inflammation) is prima facie obvious. See MPEP 2143, Exemplary Rationale B.
Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have formulated a drug delivery system, as discussed above, to comprising a hydrogel loaded with epigallocatechin gallate (i.e., polyphenol) and metal ion complexes.
4) Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Zhong et al. (US 2016/0022707 A1, publication date 01/28/2016; previously cited), as applied to instant claims 1, 2, 5, 7, 11, and 12 above, and further in view of Yu et al. (US 2006/0019362 A1, publication date 01/26/2006; previously cited) and Rosa et al. (Biomaterials, 2003, vol. 24, p. 207–212; previously cited).
Zhong, which is discussed above, differs from instant claim 4 insofar as it does not disclose a gelatin or collagen complex with a metal ion.
Zhong does discloses the composition may be employed with a device selected from a group consisting of an orthopedic implant, a bone plate or “tissues replacing a lost or damaged function of human body” (i.e., tissue engineering; see p. 3, [0029], line 12). Additionally, Zhong discloses that “[a]ny polyelectrolyte is contemplated for use in the present invention, as would be understood by one skilled in the art” [0126], and provides the example of polyanionic alginate (see [0127], lines 4 and 6).
Yu discloses a biological scaffold comprising a complex of oppositely charged polymers [abstract]. According to Yu, suitable polymers include polyanionic alginate and negatively charged collagen [0044].
Rosa discloses polyanionic collagen “showed low inflammatory reaction associated with bone formation, partially or completely integrated to the cranial bone” [abstract]. Rosa further discloses that collagen has been widely used because it has a low immune response, low toxicity and promotes cellular growth and attachment [p. 207, col. 2, para. 1, lines 4-8].
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have simply substituted the negatively charged collagen (i.e., polyanionic collagen) of Yu in place of the polyanionic alginate of Zhong to form a complex comprising collagen and a metal ion. One would have been motivated to substitute these elements because Rosa discloses polyanionic collagen has the desirable properties of low immune response and low toxicity. One would have had an expectation of success because Yu discloses polyanionic alginate and negatively charged collagen are suitable to form complexes in compositions for tissue engineering. Additionally, Zhong desires any polyelectrolyte as would be understood by one skilled in the art. The skilled artisan would have been motivated to have substituted the polyanionic collagen of Yu in place of the polyanionic alginate of Zhong to form a complex with a reasonable expectation of success. The simple substitution of one known element (e.g., the polyanionic collagen of Yu) in place of another (e.g., the polyanionic alginate of Zhong) in order to achieve predictable results (form a complex) is prima facie obvious. See MPEP 2143, Exemplary Rationale B.
5) Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Zhong et al. (US 2016/0022707 A1, publication date 01/28/2016), as applied to instant claims 1, 2, 5, 7, 11, and 12 above, and further in view of Weiyi Zhang et al. (Angewandte Chemie International Edition, 2018, vol. 57, p. 6754-6773), Sawhney (WO 00/09088, publication date 02/24/2000) and Hersel et al. (EP 1625856 A1, publication date 02/15/2006).
Zhong, which is taught above, differs from the instant claims insofar as it does not disclose the claimed particle size, particle pore size and hydrogel pore size.
However, Zhong does discloses that “the complex size may play a role in controlling initial burst. The surface area to volume ratio of the complexes decreases with the increase of complexes size, which may reduce the rate of DOX release from the complex” [0283] and suggests the drug release system should be optimized to provide an effective dose [0284]. Zhong further teaches that the complex particle size can be controlled by adjusting the concentration of drug and polyelectrolyte [0301]. Finally, Zhong desires an immediate and/or sustained release, i.e., controlled release rate [abstract].
Weiyi Zhang relates to porous polyelectrolyte particles as drug carriers for nanomedicine [p. 6762, col. 1, 2nd full para.]. Weiyi Zhang discloses porous polyelectrolyte particles appropriate for drug delivery were prepared having pore sized of 5-50nm and that “[t]his work opened up a generic pathway to nanoporous polyelectrolyte particles with tailored compositions, such … drug-loading particles“ [p. 6762, col. 1, 3rd full para.].
Sawhney disclose compositions and methods “to control the release of relatively low molecular weight therapeutic species through hydrogels by first dispersing or dissolving such therapeutic species within relatively hydrophobic rate modifying agents to form a mixture” [abstract]. Sawhney discloses “the pore size of hydrogels depends upon the concentration of the starting macromer or monomer used to make the gel (generally 4 to 30% w/w concentrations of the precursors are used to prepare gels). The pore size may be varied further by the degree of crosslinking and the molecular weight between crosslinks of the gel. For example, if the molecular weight of the bioactive agent is known, one skilled in the art could prepare a gel to obtain the approximate diffusion rate desired by controlling crosslinking of the gel, hence controlling its pore size” [p. 37, lines 18-34].
Hersel discloses “[i]t has now been surprisingly discovered, that mesoporous hydrogels can be used as polymer carriers for drug depots if provided as a carrier in a prodrug system” [0037]. “[t]he MHP may be administered to a patient to form a depot inside the patient which provides for a sustained release of the biologically active moiety over a desired period of time” [0038]. According to Hersel, mesopore means between 1-100 nm [0003].
Regarding the complexed particle size, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have formulated complexed particle to have a size within the instantly claimed range through routine optimization. It has been held that it is not inventive to discover the optimum workable ranges by routine experimentation where, as is here, the general conditions of the claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). One of ordinary skill in the art would have been motivated to optimize the particle size as a means of effecting the surface area and therefore the release rate, as desired by Zhong. A skilled artisan would have had an expectation of success because Zhong discloses how to change the particles size and that doing do affects the release rate.
Regarding the pore size of the complexed particle, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have combined the pore size disclosed by Weiyi Zhang with the complexed particles disclosed by Zhong. A skilled artisan would have understood that pore size affects release rate because pore size affects surface area, which affects release rate according to Zhong. Thus, skilled artisan would have been motivated to select the pore size of Weiyi Zhang for the polyelectrolyte particle drug carriers of Zhong because Weiyi Zhang discloses the pore size is suitable for polyelectrolyte particle drug carriers. One would have had an expectation of success because Weiyi discloses the pore size is suitable for particles similar to Zhong. Additionally, in combining these elements one would have expected nothing more than predictable results because, when combined by known methods, each prior art element would have performed the same function as it had separately. See MPEP 2143, Exemplary Rationale A.
Furthermore, in making this combination the instantly claimed pore size range (i.e., 2-8 nm) would have overlapped with the range of the prior art (i.e., 5-50 nm of Weiyi Zhang) and so a prima facie case of obviousness exist. "[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 MPEP 2144.05 IIA quoting In re Aller, 220 F.2d 454, 456 (105 USPQ 233)).
Regarding the pores formed between the supramolecular fillers (i.e., hydrogel pore size), it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have formulated hydrogel of Zhong to comprise pores within the instantly claimed range through routine optimization. It has been held that it is not inventive to discover the optimum workable ranges by routine experimentation where, as is here, the general conditions of the claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). One of ordinary skill in the art would have been motivated to optimize the hydrogel pore size because Sawhney discloses that hydrogel pore size affects the drug release rate, an affect desired by Zhong. Additionally, a skilled artisan would have been motivated to use mesoscale pores as a starting point because Hersel discloses mesoporous hydrogels provide a suitable drug release rate. Finally, a skilled artisan would have had an expectation of success because Sawhney discloses methods for adjusting hydrogel pore size.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have formulated the sustained release system taught by Zhong, and discussed above, wherein particle and pore size of the supramolecular particle (i.e., complexed particle) along with the pore size of the pores between the supramolecular filler particles (i.e., hydrogel pore size) within the instantly claimed ranges.
6) Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Zhong et al. (US 2016/0022707 A1, publication date 01/28/2016 ; previously cited) and Sichuan University (CN 112316204 A, publication date 02/05/2021; cited in IDS; citing English Machine translation; previously cited) as applied to instant claims 1, 2, 4-7, and 11-12 above, and further in view of Jia et al. (CN 106748250 A, publication date 05/31/2017; citing machine English translation), Tang et al. (CN 106860871 A, publication date 06/17/2017; citing machine English translation), Sinko et al. (US 20090104254 A1, publication date 04/23/2009), Sawhney (WO 00/09088, publication date 02/24/2000) and Hersel et al. (EP 1625856 A1, publication date 02/15/2006).
Zhong and Sichuan differ from the instant claims insofar as they do not disclose carboxymethyl chitosan, catechin gallate, irinotecan hydrochloride and pore sizes. As discussed in rejection statement three (3) above, Zhong and Sichuan University teach a drug delivery system comprising a hydrogel loaded with epigallocatechin gallate (i.e., polyphenol) and iron (II) ion complexes.
Zhong discloses the hydrogel matrix may be chitosans [0138] and desires an immediate and/or sustained release, i.e., controlled release rate [abstract]. Additionally, Zhong discloses iron is a suitable cation for the therapeutic agent/polyectrolyte/metal ion complexes [0128-0129] and that “[a]ny polyelectrolyte is contemplated for use in the present invention, as would be understood by one skilled in the art” [0126]. Finally, Zhong desires a chemotherapeutic [0122].
Jia discloses a slow release composition wherein the active agent is coated “so that the polyphenolic compound and the metal ion form a three-dimensional network structure on the outer surface of the particle” [abstract]. According to Jia, the polyphenol compound may be catechin gallate [p. 9, claim 3], and the metal ion may be iron [p. 9, claim 2].
Tang discloses “a carboxymethyl chitosan pH-sensitive chemical hydrogel drug carrier” [abstract] to carry, for example, doxorubicin [p. 9, para. 1].
Sinko relates to formulations of hydrogels and one or more liposomes containing a therapeutic agent [abstract], such as pharmaceutically acceptable salts of irinotecan [0067]. According to Sinko, irinotecan hydrochloride has received FDA approval as first line therapy for the treatment of colorectal cancer (i.e., chemotherapeutic) [0072].
Sawhney disclose a compositions and methods “to control the release of relatively low molecular weight therapeutic species through hydrogels by first dispersing or dissolving such therapeutic species within relatively hydrophobic rate modifying agents to form a mixture” [abstract]. Sawhney discloses “the pore size of hydrogels depends upon the concentration of the starting macromer or monomer used to make the gel (generally 4 to 30% w/w concentrations of the precursors are used to prepare gels). The pore size may be varied further by the degree of crosslinking and the molecular weight between crosslinks of the gel. For example, if the molecular weight of the bioactive agent is known, one skilled in the art could prepare a gel to obtain the approximate diffusion rate desired by controlling crosslinking of the gel, hence controlling its pore size” [p. 37, lines 18-34].
Hersel discloses “[i]t has now been surprisingly discovered, that mesoporous hydrogels can be used as polymer carriers for drug depots if provided as a carrier in a prodrug system” [0037]. “[t]he MHP may be administered to a patient to form a depot inside the patient which provides for a sustained release of the biologically active moiety over a desired period of time” [0038]. According to Hersel, mesopore means between 1-100 nm [0003].
It would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have selected the catechin gallate and iron ion of Jia as the polyphenol and metal ion desired by Zhong. One would have been motivated to make this combination because Jia discloses that the catechin gallate and iron complexes can provide a sustained release for active agents, as desired by Zhong. One would have had an expectation of success because Zhong discloses iron ions and desires polyelectrolytes as would be understood by a skilled artisan, e.g., understood to provide sustained release. Additionally, in combining these elements one would have expected nothing more than predictable results because, when combined by known methods, each prior art element would have performed the same function as it had separately. See MPEP 2143, Exemplary Rationale A.
Generally, it is prima facie obvious to select a known material based on its suitability for its intended use. See MPEP 2144.07.
In the present case, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have selected the carboxymethyl chitosan of Tang for the chitosans desired for the hydrogel of Zhong because Tang discloses carboxymethyl chitosan hydrogel is a suitable hydrogel carrier for drug delivery systems.
Similarly, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have selected the irinotecan hydrochloride of Sinko for the chemotherapeutic desired by Zhong because Sinko discloses irinotecan hydrochloride is a suitable chemotherapeutic to load into a drug carrier which is dispersed in a hydrogel.
Regarding the pores formed between the supramolecular fillers (i.e., hydrogel pore size), it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have formulated hydrogel of Zhong to comprise pores within the instantly claimed range through routine optimization. It has been held that it is not inventive to discover the optimum workable ranges by routine experimentation where, as is here, the general conditions of the claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). One of ordinary skill in the art would have been motivated to optimize the hydrogel pore size because Sawhney discloses that hydrogel pore size affects the drug release rate, an affect desired by Zhang. Additionally, a skilled artisan would have been motivated to use mesoscale pores as a starting point because Hersel discloses mesoporous hydrogels provide a suitable drug release rate. Finally, a skilled artisan would have had an expectation of success because Sawhney discloses methods for adjusting hydrogel pore size.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have formulated the sustained release system taught by Zhong, and discussed above, wherein the complexed particles comprise catechin gallate and iron cations and the hydrogel is carboxymethyl chitosan and comprises irinotecan hydrochloride. Wherein the pores formed in the hydrogel are within the instantly claimed range.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 4-7, 11-12, and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,878,082 B2 in view of Garcia-Brand et al. (Fermentation, 03/08/2022, vol. 8, no. 117) and Sichuan University (CN 112316204 A, publication date 02/05/2021; cited in IDS; citing English Machine translation).
The claims of ‘082 disclose a probiotics solution comprising biomass-based encapsulating material for the probiotic that comprises macromolecules and metal ions formed in situ [claim 1]. The metal ions are selected from the group consisting of cations of Al, Fe, Zn, Mn, Ni, Co and V while the biological macromolecules are selected from the group consisting of polyphenol, dopamine, dopamine derivatives, polysaccharide biomass, and combinations thereof [claim 1].
The claims of ‘082 does not disclose a hydrogel, specific polyphenols, specific polysaccharides or a protein biomass.
Garcia-Brand discloses that “the inertness of hydrogels in environments with high water activity makes them suitable to entrap molecules and microorganisms, and ensure their integrity and viability in physiological environments” [p. 8, para. 1, lines 4-6] and that “[a]lginate, gelatin, and chitosan are the three main polymers of choice for hydrogel synthesis” [p. 8, para. 1, last 3 lines]. Garcia-Brand also discloses that, with respect to probiotics, “[m]icroparticles, microcapsules, and microspheres usually made of food-grade polymers, such as alginate, chitosan, carboxymethyl cellulose, cellulose acetate phthalate, xanthan gum, starch, carrageenan, gelatin, and pectin [59,110], have demonstrated to be protective barriers of high performance against the GIT’s environmental conditions” [p. 9, para. 1, lines 1-4].
Garcia-Brand does not disclose a polyphenol.
Sichuan University discloses a nanocomplex comprising a metal ion and a polyphenol [p. 6, last paragraph]. The metal ion may be iron and the polyphenol may be dopamine or epigallocatechin gallate [p. 7, para. 3-4].
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have combined the hydrogels (e.g., chitosan hydrogel) of Garcia-Brand as the carrier for the solution of the ‘082 claims. One would have been motivated to, and had an expectation of success in combing these elements because Garcia-Brand discloses hydrogels ensure integrity of molecules and microorganisms in physiological environments. Additionally, in combining these elements one would have expected nothing more than predictable results because, when combined, each prior art element would have performed the same function as it had separately. See MPEP 2143, Exemplary Rationale A.
Furthermore, since the prior art composition contains substantially the same components, i.e., agarose hydrogel comprising a complexed particle of a polysaccharide, divalent metal ion and a drug, in the same relative proportions as instantly claimed and made by the same instantly claimed “in situ” formation, it would be expected to inherently possess the same chemical and physical properties, such as being regulating pores and forming a multi-stage porous structure.
Response to Arguments filed 03/11/2026
1) On page 11 of their Remarks, Applicant argues “Sichuan University does not teach or suggest forming a supramolecular filler in situ in a hydrogel matrix for the purpose of regulating pores of the hydrogel matrix to create a multi-stage porous structure, as now required by amended Claim 1.”
This argument is not persuasive. As discussed above, "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." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (See MPEP 2113.). In the present case, the prior art product appears to be the same or obvious as claimed, despite not teaching the claimed in situ formation of the supramolecular filler, insofar as the Sichuan University discloses a porous collagen hydrogel comprising epigallocatechin gallate and iron ion complex. See, for example, Sichuan University at paragraph 1 of page 7: “a metal polyphenol collagen membrane material which is a hydrogel material and comprises collagen and a nano complex loaded on a collagen porous structure, wherein the nano complex is obtained by chelating metal ions and polyphenol” [p. 7, para. 1].
To expound on the reasoning set forth above and in rejection 1) discussed above starting at page 5 of this Office Action, the methods of Sichuan University appear to be substantially the same as the methods of the exemplary embodiments disclosed in the instant specification. The instant specification discloses muti-stage porous hydrogels are formed by first obtaining precipitated tannic acid/iron complexes which are then mixed with sodium alginate and lidocaine hydrochloride. The resulting composition is then crosslinked (see paragraphs [0035] to [0036]). On the other hand, Sichuan University discloses combining collagen (hydrogel material) with epigallocatechin gallate nanoparticles (epigallocatechin gallate/magnesium complexes [p. 8, Example 1]) “and placing the mixture in an oven at the temperature of 35-37 ℃ for incubation for 24 hours until gelling” (see Example 3 of Sichuan University on page 10). The prior art discloses compositions made by substantially the same methods as examples of the instantly claimed multi-stage porous hydrogel.
2) On pages 11-12 of their Remarks, Applicant argues “Zhong does not teach or suggest the claimed mechanism of in situ formation of a supramolecular filler within the hydrogel matrix that regulates hydrogel pores to form a multi-stage porous structure, nor does Zhong teach or suggest that such a supramolecular filler is configured to interact with a drug for sustained release as now claimed.”
The Examiner respectfully disagrees. As discussed above Zhong discloses particles formed inside an agarose solution at paragraph [0200] which reads on the in situ formation as instantly claimed.
3) On page 12 of their Remarks, Applicant argues that the in situ formation is critical to the multi-stage porous structure, i.e., pores sized between 2 and 20nm. Applicant also asserts that conventional methods of blending nano-complexes with hydrogels inevitably leads to irreversible aggregation.
This argument is not persuasive. “Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.” See MPEP 716.01(C)II.
In the present case, applicant has alleged in situ formation is critical to the function of the invention, but has not provided supporting evidence. Similarly, applicant has alleged inoperability of the prior art, but has provided no supporting evidence. Accordingly, the Examiner is not able to determine if the claimed in situ formation is truly critical to the function of the invention.
Furthermore, in situ formation does not appear to be critical to the invention according to the examples disclosed in the instant specification. Embodiment 1 of the present invention disclose first obtaining precipitated supramolecular filler, and then adding the formed supramolecular filler into a solution of sodium alginate (see paragraph [0037]).
4) On page 12 of their Remarks, Applicant argues that the prior art differs from present invention because “the presently claimed "in situ" process allows the biological-based polymers and metal ions to orchestrate a controlled self-assembly simultaneously with the cross-linking of the hydrogel matrix. This synchronized formation enables the filler molecules to serve as "molecular templates," effectively partitioning the hydrogel's large pores into a sophisticated architecture of micropores (2-8 nm) and mesopores (10-20 nm).”
This argument is not persuasive. It is noted that the features upon which applicant relies (i.e., simultaneous complex formation and hydrogel crosslinking) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
5) On page 12 of their Remarks, Applicant asserts a skilled artisan would not have expected the superior release profiles achieved by the present invention.
This argument is not persuasive. The instant specification does not indicate the release profiles of the presently claimed composition to have unexpected results, nor does it identify what results may have been expected. Furthermore, overcoming a rejection based on unexpected results requires the combination of three different elements: (i) the results must fairly compare with the prior art, (ii) the results must truly be unexpected and (iii) the claims must be commensurate in scope. MPEP §716.02. The burden rests with Applicant to establish results are unexpected and significant. MPEP §716.02(b). Applicant's showing of allegedly unexpected results does not satisfy any of these requirements.
(i) Applicant has not compared the instantly claimed composition to the closest prior art. The closes prior art is Example 3 of Sichuan University, disclosed on page 10 therein. Example 3 comprises a collagen hydrogel having epigallocatechin gallate/magnesium ion nanoparticles dispersed therein.
(ii) Where the unexpected properties of a claimed invention are not shown to have a significance equal to or greater than the expected properties, the evidence of unexpected properties may not be sufficient to rebut the evidence of obviousness. In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) (MPEP 716.02(c)). In the present case, a skilled artisan would have expected changes in pore sizes to affect the drug release profile. For example, see Sawhney at page 37, lines 18-34: “one skilled in the art could prepare a gel to obtain the approximate diffusion rate desired by controlling crosslinking of the gel, hence controlling its pore size.”
(iii) The "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support" (see MPEP 716.02(d) quoting In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)). In the present case, the claims are not commensurate in scope because the independent claim does not recite pore diameters which is important to the function of the invention. Additionally, the independent claim does not actually require a drug. While the preamble of the claim recites “sustained release drug delivery system”, this is merely intended use and does not require a drug in the composition. Finally, the narrow showing of tannic acid and iron with sodium alginate and lidocaine hydrochloride, tannic acid and aluminum with gelatin and terazosin hydrochloride and catechin gallate and iron with carboxymethyl chitosan and irinotecan hydrochloride does not reasonably represent the broadly claimed compositions.
7) On page 13 of their Remarks, Applicant argues that “[n]one of the cited references teaches or suggests configuring a supramolecular filler within a hydrogel matrix such that the drug is retained by at least two of the recited interactions in combination.”
This argument is not persuasive. “[T]he PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on ‘inherency’ under 35 U.S.C. 102, on ‘prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same.” In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977) (footnote and citation omitted). The burden of proof is similar to that required with respect to product-by-process claims. In re Fitzgerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (citing Best, 562 F.2d at 1255). MPEP 2112 (V). As discussed above, the prior art composition would have been capable of at least two of the claimed interaction and so the burden of proof is now on applicant to demonstrate the prior art is not capable of at least two of the interactions.
8) On page 13 of their Remarks, Applicant argues that none of the cited references disclosed the limitations set forth in instant claims 14 and 17.
These arguments are moot in view of the new rejections set forth above.
9) On page 15 of their Remarks, Applicant argues that the double patenting rejection should be withdrawn because the conflicting claims do not disclose multistage porous hydrogel configured to interact with a drug.
This argument is not persuasive. The Examiner respectfully notes that while the preamble of the instant claim recites “sustained release drug delivery system”, this is merely intended use and does not require a drug in the composition. Furthermore, as discussed above, the conflicting claims in view of Garcia-Brand, and Sichuan University teach substantially the same composition as instantly claimed wherein the complexes are formed in situ and so a skilled artisan would have expected the same properties, i.e., forming multistage porous hydrogel. The conflicting claims continue to read on instant claims 1-2, 4-7, 11-12, and 14.
Conclusion
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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/C.T.W./Examiner, Art Unit 1612
/WALTER E WEBB/Primary Examiner, Art Unit 1612
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