DETAILED ACTION
Status of claim rejections
The rejections of record under 35 USC 112(b) are withdrawn in view of Applicant’s amendments in the remarks filed 06/05/2026.
The rejections under 35 USC 103 are modified in view of Applicant’s amendments/arguments in the response filed 06/05/2026.
This Action is FINAL, as necessitated by Applicant’s amendments.
New Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims have been amended to recite “A method for preparing immobilized enzyme nanogels, comprising: dissolving oxidized sodium alginate and an enzyme separately in deionized water, mixing uniformly, and without using calcium ion or metal ion cross-linking agents, reacting an aldehyde group of the oxidized sodium alginate with an amino group of the enzyme via a Schiff base reaction to obtain immobilized enzyme nanogels” (emphasis added).
Neither the instant specification nor the originally filed claims appear to provide support for the recitation of “without using calcium ion or metal ion cross-linking agents”. The instant specification is silent to lack of calcium or metal ion crosslinking agents (i.e., the exclusion thereof), and Applicant has not pointed to anywhere in the specification to support the amendment (see Applicant’s remarks, pg. 6-7). The specification only recognizes that Schiff base reactions using oxidized sodium alginate do not require additional conditions such as heating or catalysts (see paragraph 0012).
Any negative limitation or exclusionary proviso must have basis in the original disclosure. If alternative elements are positively recited in the specification, they may be explicitly excluded in the claims. See In re Johnson, 558 F.2d 1008, 1019, 194 USPQ 187, 196 (CCPA 1977). See also MPEP 2173.05(i).
Thus, such a recitation constitutes NEW MATTER. In response to this rejection, Applicant is required to point to support for the recitation of “without using calcium ion or metal ion cross-linking agents” or to cancel the new matter.
Modified Claim Rejections - 35 USC § 103
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.
First rejection
Claims 1-2, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Wei et al. (Ion-assisted fabrication of neutral protein crosslinked sodium alginate nanogels. Carbohydr Polym. 2018 Apr 15;186:45-53; prior art of record), in view of Qin et al. (Nanogel fabricated from oxidized sodium alginate and hydrophilic-modified chitosan exhibits great potential as pH-responsive drug delivery system. J IRAN CHEM SOC 20, 921–930 (published Dec. 2022)) and Goodman et al. (Increased nanoparticle penetration in collagenase-treated multicellular spheroids. Int J Nanomedicine. 2007;2(2):265-74; prior art of record).
Wei teaches creation of protein crosslinked nanogels (see title, abstract). Wei teaches creation of hemoglobin crosslinked nanogels (HbNGs) and rhodamine B (RhB) crosslinked nanogels by mixing Hb (4 mg/mL) and oxidized sodium alginate (OSA) (4 mg/mL) in 10 mL deionized water and stirred for 10 mins (dissolving oxidized sodium alginate and a protein in deionized water, mixing uniformly as in claim 1) (see pg. 47, col 1; “Preparation of Ca2+ crosslinked sodium alginate nanogels (OSANGs) and hemoglobin crosslinked nanogels” section). Wei also teaches RhB nanogel creation by mixing with OSA and stirred for 6 h in dark (see pg. 47, col 1, “Fabrication of fluorescence-labelled HbNG” section). Wei further teaches fabrication of protein crosslinked nanogels was performed in water at ambient temperature without the use of any organic solvent and crosslinker, which circumvents the limitation of fragility, low reactive groups density, particularly low electric density of neutral proteins (see pg. 52, col 1). Wei also teaches hemoglobin and myoglobin were used as representative neutral proteins to fabricate stable protein crosslinked OSA nanogels under the assistance of divalent cation followed by in situ Schiff base formation between OSA and proteins. The mild fabrication condition guaranteed the structural integrity and bioactivity of proteins in the obtained protein crosslinked nanogels (see abstract).
Wei does not explicitly teach creation of nanogels without calcium ion.
However, Qin teaches nanogels fabricated from OSA and hydrophilic-modified chitosan (see title, abstract). Qin explicitly teaches the successful creation of pH-sensitive nanogels using chitosan (a polysaccharide without metal ions) in distilled water before being loaded with a berberine drug as a potential drug carrier and exhibited pH-sensitive release in vitro and low toxicity on normal human cells (see abstract; see first Fig. and scheme 1, pg. 923; conclusion section).
Therefore, it would have been prima facie obvious to one of ordinary skill to modify the method of making sodium alginate nanogels as taught by Wei by using chitosan (i.e., without calcium or metal ion crosslinking agent) as taught by Qin to arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill would have been motivated to make the modification because Qin explicitly teaches that sodium alginate nanogels can be successfully created without eth use of calcium or metal crosslinking agents as a drug carrier.
Neither reference explicitly teaches mixing the OSA with an enzyme.
However, Goodman teaches nanoparticulate delivery vehicles such as polymer-small molecule conjugates, liposomes, and viruses offer distinct advantages for anti-cancer treatment approaches, including selective accumulation in tumor areas due to the enhanced permeability and retention (EPR) effect, cocktail packaging of molecular imaging and therapeutic agents, and delivery of macromolecules such as nucleic acids and proteins (see pg. 265, paragraph 1). Goodman teaches collagenase was immobilized onto the surface of nanoparticles for site-specific degradation of ECM (an enzyme as in claim 1; a collagenase as in claim 2) which results in significantly increased nanoparticle penetration and delivery efficiency into multicellular spheroid tissue (see pg. 269, col 2 and 263). Goodman further teaches a nanoparticle delivery system, with proper targeting to tumor tissue and solid tumors, could result in local delivery of active collagenase leading to increased penetration of delivered therapeutics (see pg. 272-273 col 1, paragraph 1-4).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to modify the method of creating nanogels as taught by Wei by including a collagenase enzyme as taught by Goodman to arrive at the claimed invention. One of ordinary skill would have been motivated to make the modification because Goodman explicitly teaches the treatment of spheroids with collagenase immobilized on nanoparticle surfaces results in significantly increased nanoparticle penetration and delivery efficiency and that with proper targeting to tumor tissue and solid tumors, could result in local delivery of active collagenase leading to increased penetration of delivered therapeutics.
Further regarding claim 2, Wei teaches creation of hemoglobin crosslinked nanogels (HbNGs) and rhodamine B (RhB) crosslinked nanogels by mixing Hb (4 mg/mL) and oxidized sodium alginate (OSA) (4 mg/mL) in 10 mL deionized water (see above). The ratio of protein to OSA used by Wei is a 1:1 ratio, which falls within Applicant’s claimed range of 0.01 to 50:1; and 4 mg/mL of OSA in the deionized water also falls within Applicant’s claimed range of 1-50 mg/mL. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (see MPEP 2144.05).
Regarding claim 9, Goodman teaches the use of collagenase as the enzyme (see above).
Accordingly, the claimed invention was prima facie obvious at the time of filing, especially in the absence of evidence to the contrary.
Second rejection
Claims 3-8 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Wei, Qin, and Goodman, and further in view of Siegwart et al (Cellular uptake of functional nanogels prepared by inverse miniemulsion ATRP with encapsulated proteins, carbohydrates, and gold nanoparticles. Biomacromolecules. 2009 Aug 10;10(8):2300-9) and Gao et al ("BIOLOGICAL CHARACTERIZATION OF A SYNTHETIC CXCR4 ANTAGONIST WITH DUAL ANTIMETASTASIS AND ANTIANGIOGENESIS ACTIVITIES"; International Journal of Current Research Vol. 9, Issue, 06, pp.52597-52600, June, 2017).
As discussed above, Wei, Qin, and Goodman (in combination) teach creation of protein crosslinked nanogels by mixing oxidized sodium alginate, a collagenase matrix-degrading enzyme and deionized water (see above).
Neither reference explicitly teaches stirring the reaction mixture in an ice bath.
However, Siegwart (in a similar field of creating protein nanogels) teaches creation of functional nanogels using mini-emulsion with encapsulated proteins, carbohydrates, and gold nanoparticles (see title, abstract). Siegwart teaches the creation of, e.g., nanogels loaded with BSA protein by combining BSA, OEOMA, HO-EBiB, CuBr2/TPMA, PEO DMA, and water into an aqueous solution before sonication/mixing in an ice bath at 0 degrees C for 2 mins to form stable mini-emulsions (see pg. 5, paragraph 4; see also pg. 12).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to modify the method of Wei, Qin and Goodman by stirring using an ice bath as taught by Siegwart to arrive at the claimed invention. One of ordinary skill would have been motivated to make the modification because Siegwart explicitly teaches that ice baths can advantageously be used to create protein nanogels to form stable mini-emulsions.
None of the references explicitly teach adding a CXCR4 antagonist peptide to the nanogels.
However, Gao teaches metastasis and angiogenesis are two major obstacles that hinder successful treatment of human cancers and that CXCR4 is an important regulator of cancer metastasis and angiogenesis which is predominantly expressed in many metastatic cancers (see abstract). Gao teaches that DV1, a mimetic of the essential molecular moieties of a naturally existing CXCR4 ligand is capable of strongly inhibiting in vitro tubule formation activity of HUVECs, trans-well migration of CXCR4+ cancer cells, in vivo cancer metastasis and growth, and is a potential CXCR4 antagonist and a therapeutic drug that targets angiogenesis and cancer metastasis (see abstract; see also pg. 52598-52599).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to modify the method of Wei, Qin, Goodman, and Siegwart by including the CXCR4 antagonist as taught by Gao to arrive at the claimed invention. One of ordinary skill would have been motivated to make the modification because CXCR4 antagonists such as DV1 is advantageously capable of strongly inhibiting in vitro tubule formation activity of HUVECs, trans-well migration of CXCR4+ cancer cells, in vivo cancer metastasis and growth, and is a potential CXCR4 antagonist and a therapeutic drug that targets angiogenesis and cancer metastasis.
Furthermore, it would have been prima facie obvious to one of ordinary skill in the art to add the CXCR4 antagonist peptide dropwise to the mixture as taught by Siegwart because Siegwart further teaches the use of dropwise addition to synthesize nanogels (see pg. 5, paragraph 4).
Regarding claim 4, Goodman teaches collagenase as an ECM-degrading enzyme (see above) and Gao teaches the CXCR4 antagonist is DV1 (see above).
Regarding claim 5, Goodman teaches using 5 mg/mL of collagenase (as claimed) and Wei teaches use of OSA at 4 mg/mL (see above). While none of the references explicitly teach a 1-10:1 ratio of matrix-degrading enzyme to OSA (see claim 5), the concentration of enzyme to deionized water is 1.11 mg/mL (as in claim 12) or a ratio of enzyme to OSA is 5:1 by weight, generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05(II)). Further, Siegwart teaches using an ice bath at 0 degrees C (see above) for 2 mins. While none of the references teach stirring for 0.1h-5hours, one of ordinary skill would have been motivated to optimize the stirring time using standard laboratory techniques available at the time of filing with a reasonable expectation of successfully forming stable mini-emulsions when making nanogels (see MPEP 2144.05).
Regarding claim 6 and 13, none of the references explicitly teach the concentration of CXCR4 antagonist peptide is 0.5-5mg/mL (see claim 6), 1 mg/mL (see claim 13) or the ratio of antagonist peptide to matrix degrading enzyme is 1:0.1-10 by weight or 1:2 by weight (see claim 13). However, generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05(II)). Further, Siegwart teaches using an ice bath at 0 degrees C (see above) for 2 mins. While none of the references teach a reaction time of 0.1-5 hours, one of ordinary skill would have been motivated to optimize the stirring time using standard laboratory techniques available at the time of filing with a reasonable expectation of successfully forming stable mini-emulsions when making nanogels (see MPEP 2144.05).
Regarding claim 7, the combination of references teaches nanogels containing matrix degrading enzyme and a CXCR4 antagonist peptide (see above). Gao teaches the collagenase enzyme is capable of significantly increased nanoparticle penetration and delivery efficiency and that with proper targeting to tumor tissue and solid tumors, could result in local delivery of active collagenase leading to increased penetration of delivered therapeutics and CXCR4 antagonist DV1 is capable of strongly inhibiting in vitro tubule formation activity of HUVECs, trans-well migration of CXCR4+ cancer cells, in vivo cancer metastasis and growth (i.e., for use as an anti-tumor drug).
Regarding claim 8, the combination of references teaches an anti-tumor drug composition comprising a CXCR4 antagonist peptide-modified immobilized matrix degrading enzyme nanogels capable of strongly inhibiting in vitro tubule formation activity of HUVECs, trans-well migration of CXCR4+ cancer cells, and in vivo cancer metastasis and growth.
Accordingly, the claimed invention was prima facie obvious at the time of filing, especially in the absence of evidence to the contrary.
Third rejection
Claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Wei, Qin, Goodman, Siegwart, and Gao as applied to claims 3-8 and 12-13 above, and further in view of Zhang et al (WO 2022165260 A1).
As discussed above, Wei, Qin, and Goodman (in combination) teach creation of protein crosslinked nanogels by mixing oxidized sodium alginate, a collagenase matrix-degrading enzyme and deionized water (see above). Gao teaches the CXCR4 antagonist is DV1 (see above).
None of the references explicitly teach the matrix degrading enzyme is collagenase I-V (claim 10) or that the matrix degrading enzyme is collagenase IV.
However, Zhang teaches methods and compositions for treatment of cancers using modified immunomodulatory agents (see title, abstract). Zhang teaches collagenases are tumor dissociating enzymes that can be used for treating tumors/cancers including collagenase IV(see paragraph 001211-20).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to modify the method of Wei, Qin, Goodman, and Siegwart by including the collagenase IV of Zhang to arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill would have been motivated to make the modification because Zhang explicitly teaches collagenase IV can be successfully used as a tumor dissociating enzyme for the therapeutic treatment of tumors/cancers.
Accordingly, the claimed invention was prima facie obvious at the time of filing, especially in the absence of evidence to the contrary.
Response to arguments
Applicant's arguments filed 07/29/2026 have been fully considered but they are not persuasive.
On pg. 6-7 of the remarks, Applicant argues the rejections under 103. Specifically, Applicant argues that while Wei teaches crosslinking generic proteins like hemoglobin with oxidized sodium alginate, modifying this process by substituting Goodman’s collagenase fails to appreciate delicate stability requirements of functional enzymes compared to standard proteins. Applicant argues the Goodman utilizes enzymes immobilized on nanoparticles but does not teach or suggest using specific mild Schiff base nanogel crosslinking method. Applicant also argues that claim 3 requires creating the immobilized enzyme nanogels via an ice bath and then adding CXCR4 antagonist dropwise while stirring and none of the references teach this specific sequential surface modification process and the combination of references ignores the unique technical problem solved by the invention producing an unexpected synergistic result. Applicant argues using enzymes like collagenase carries a severe, known clinical risk causing acceleration of tumor metastasis and that by adding a CXCR4 peptide, the invention ensures that the collagenase degrades the ECM and the CXCR4 peptide simultaneously blocks the metastasis pathways that would be triggered by the ECM degradation. Applicant urges that the dual delivery system achieves an unexpected 1+1>2 synergistic effect and the references do not identify the problem of ECM degradation accelerating metastasis and provide no motivation for a PHOSITA to formulate Goodman’s collagenase with Gao’s CXCR4 antagonist.
In response, the examiner disagrees. First, while Wei teaches use of neutral proteins like hemoglobin to make nanogels, Goodman provides a PHOSITA a teaching, suggestion, and motivation to immobilized collagenase onto the surface of nanoparticles (i.e., like nanogels as taught by Wei) for site-specific degradation of ECM (an enzyme as in claim 1; a collagenase as in claim 2) which results in significantly increased nanoparticle penetration and delivery efficiency (see pg. 269, col 2 and 263). Second, Wei explicitly teaches that the OSA nanogels are made using mild Schiff base crosslinking (see Wei above), such that Goodman does not have to provide this teaching. Third, the sequence of the steps and the use of dropwise edition was taught by the combination of references as well as the Siegwart reference, which discloses the use of dropwise addition to synthesize nanogels as required by the claims (see pg. 5, paragraph 4). Finally, Gao explicitly teaches metastasis and angiogenesis are two major obstacles that hinder successful treatment of human cancers and that CXCR4 is an important regulator of cancer metastasis and angiogenesis which is predominantly expressed in many metastatic cancers (see abstract). Gao teaches that DV1, a mimetic of the essential molecular moieties of a naturally existing CXCR4 ligand is capable of strongly inhibiting in vitro tubule formation activity of HUVECs, trans-well migration of CXCR4+ cancer cells, in vivo cancer metastasis and growth, and is a potential CXCR4 antagonist and a therapeutic drug that targets angiogenesis and cancer metastasis (see abstract; see also pg. 52598-52599). Thus, Gao provides a PHOSITA a teaching, suggestion, and motivation to include CXCR4 as an inhibitor of in vivo cancer metastasis and growth to address known cancer metastasis risks. The selection of a known material based on its suitability for its intended use supports a prima facie obviousness determination (see Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945); MPEP 2144.07). As such, the rejections of record are maintained and modified as set forth above.
Conclusion
NO CLAIMS ALLOWED.
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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/G.C.R./Examiner, Art Unit 1651
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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