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 .
Receipt is acknowledged of Applicant’s Request for Continued Examination and Amendment filed on 06/25/2025.
Claims 1-2 have been amended.
Claims 1-2, 7, 10-16 are pending in the instant application.
Claims 7, 10-16 have been previously withdrawn from consideration.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn. The following rejections or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/25/2025 has been entered.
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.
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.
Claim(s) 1-2 is/are rejected under 35 U.S.C. 103 as being unpatentable over MESSAGER et al (Photochemical crosslinking of hyaluronic acid confined in nanoemulsions: towards nanogels with a controlled structure. J. Mater. Chem. B, 2013, 1, 3369–3379) in view of HUANG et al (Co-delivery of doxorubicin and 131I by thermosensitive. Journal of Controlled Release 220 (2015) 456–464) and XU et al (Hyaluronic Acid-Based Hydrogels: from a Natural Polysaccharide to Complex Networks. Soft Matter. 2012; 8(12): 3280–3294).
MESSAGER teaches a hydrogel composition for drug delivery comprised of: hyaluronic acid (“HA”; see abstract) with polymerizable methacrylate groups (“MA”; see abstract), which reads on X, wherein upon UV irradiation of the emulsion containing HA-MA, crosslinked HA-MA particles with a well-defined size were obtained (see abstract), which reads on photo-crosslinkable. Hyaluronic acid has Y is OH, R2 is hydrogen, and m2 is 1. Additional disclosures include:
Hyaluronic acid molecular weight of 100,000 g/mol (see pg. 3370, under Materials), which is 100 kDa and is similar in size to Applicant’s commercially bought 90 kDa hyaluronic acid used in Applicant’s examples (see Applicant’s specification at [0094]; wherein 1 Da = 1 g/mol; degree of polymerization (repeating units) is the ratio of polymer molecular weight to molecular weight of the repeating unit, which is 802 g/mol for a unit of hyaluronic acid; in this case 90kDa hyaluronic acid is about 112 repeating units (n= 112) and 100kD is about 124 repeating units (n =124)) and would be within Applicant’s range of n = 20 – 4,000 repeating units of hyaluronic acid;
Methacrylated hyaluronic acid (HA-MA) derivatives, which reads on X, were synthesized by reaction of methacrylic anhydride with the hydroxyl groups of HA (see pg. 3372, under Results and discussion), which is the same method used by Applicant (see Applicant’s specification at [0096]; degree of methacrylation (DM) for the whole HA-MA is 0.15, 0.25, and 0.4 (see Table 1), which is within Applicant’s range of 100-217% per disaccharide monomer, since Applicant’s n=20 to 4,000 and 100-217% per monomer, to calculate the DM for Applicant’s whole HA-MA polymer would be 100-217% divided by n, which gives 0.025 for the lower end (100%/4000) and 10.85 for the high end (217%/20). Additionally, MESSAGER teaches “controlled cross-linking densities were obtained by the degree of methacrylation” (see abstract) and “controlled crosslinking densities and thus various swelling degrees were obtained. Their potential use for drug delivery applications was evaluated through biocompatibility, degradability and encapsulation/release studies” (see pg. 3370, 2nd col). Thus, the percentage/degree of methacrylation in a methacrylated composition is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve the desired results, such as crosslinking density (see abstract). Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of ingredient amount would have been obvious at the time of Applicant's invention.
Microgels and nanogels have received considerable attention in recent years and offer great potential in the biomedical field as drug delivery systems (see Introduction); microgels and nanogels can entrap a molecule and release it at a rate depending on its diffusion through the network (see Introduction); in order to scale down macrogels to nanogels, linear polymers with cross-linkable functions have to be cross-linked in small, defined and discrete volumes (see pg. 3372, 2nd col).
Note, it does not appear that Applicant’s claims require a radioactive isotope, such as 131I, but rather the hydrogel is capable of labeling radioactive isotopes.
MESSAGER does not teach Y with chemical Formula 2, which is an amino linker with R1 as an imidazole, which include commonly known linkers, such as aminopropyl-imidazole (CAS No.: 5036-48-6); or the microgel has an average particle size of 10-200 um.
HUANG teaches the hydrogel (see title) prior art had known of using linkers, such as N-(3-amnopropyl-imidozole (“API”; see pg. 457, under 2.1. Materials; and Scheme 2 below with labels), conjugated to hyaluronic acid (“HA”; see pg. 457, under 2.2) in order to attach/label with 131I (see pg. 451, under 2.2) for treating tumors (see abstract).
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XU teaches the prior art had known of microgels and nanogels (see pg. 8), wherein methacrylated HA (hyaluronic acid) has been extensively investigated for use in drug delivery (see pg. 7). Additional discloses include: average diameters, such as 29 um (see pg. 8), used for delivery of 5-fluorouracil drug (see pg. 8).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate Y with chemical Formula 2, which is an amino linker with R1 as an imidazole, which is commonly linker known as aminopropyl-imidazole (CAS No.: 5036-48-6). The person of ordinary skill in the art would have been motivated to make those modifications, because it would allow attach/label the hydrogel with 131I radioactive agents for treating tumors or attach any other active agents/drugs for treating ailments, and reasonably would have expected success because the references dealt in the same field of endeavor, such as hyaluronic acid gels.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate an average particle size of 29 um. The person of ordinary skill in the art would have been motivated to make those modifications, because it would allow drug delivery, and reasonably would have expected success because the references dealt in the same field of endeavor, such as gel composition for drug delivery.
Note, the prior art would have been capable of being injected into a body and stay at an injection site, because the prior art’s composition has the same ingredients as claimed by Applicant.
Response to Arguments
Applicant argues that Messager describes the preparation of photocrosslinkable hyaluronic acid modified with methacrylate groups (HA-MA) to form nanogels for drug delivery. The HA-MA in Messager has a low degree of methacrylation ( e.g., on the order of 15-40% DM, see Table I), and the resulting particles are nano-scale ( on the order of a few hundred nanometers in diameter, ~350 nm, see page 3372). As such, Messager does not teach or suggest: (a) highly methacrylated HA (DM >100%); (b) any imidazole or other iodine-binding group attached to HA; and (c) incorporation of any radioisotope into the HA nanogels. Messager' s nanogels were loaded with insulin as a model drug, focusing on pH-responsive release, and were intended for general drug delivery - there is no discussion of radiotherapy or radioactive labeling in Messager. Thus, Messager is silent on the concepts of extremely high DM HAMA, radioactive iodine labeling, or microscale particle size as now claimed.
The Examiner finds these arguments unpersuasive, because as discussed in the rejection, MESSENGER teaches methacrylated hyaluronic acid (HA-MA) derivatives, which reads on X, were synthesized by reaction of methacrylic anhydride with the hydroxyl groups of HA (see pg. 3372, under Results and discussion), which is the same method used by Applicant (see Applicant’s specification at [0096]; degree of methacrylation (DM) for the whole HA-MA is 0.15, 0.25, and 0.4 (see Table 1), which is within Applicant’s range of 100-217% per disaccharide monomer, since Applicant’s n=20 to 4,000 and 100-217% per monomer, to calculate the DM for Applicant’s whole HA-MA polymer would be 100-217% divided by n, which gives 0.025 for the lower end (100%/4000) and 10.85 for the high end (217%/20). Additionally, the percentage/degree of methacrylation in a methacrylated composition is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve the desired results, such as crosslinking density (see abstract). Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of ingredient amount would have been obvious at the time of Applicant's invention. Additionally, the secondary references teach radiotherapy and microgels.
Applicant argues that Huang's HA was not methacrylated or crosslinked - it was used as a linear polymer in solution. Huang does not teach or suggest forming a photocrosslinked microgel from the labeled HA. Instead, Huang relies on the separate PECT polymer matrix for gelation and localization. There is no teaching in Huang of high DM HAMA, nor any suggestion that the HA itself should be crosslinked or have a high density of methacrylate groups. In fact, Huang's HA is likely unmodified apart from the API linker (DM = 0%). Huang's focus is on a macro-scale injectable depot (the entire mixture undergoes sol-to-gel transition) rather than discrete microgel particles. Accordingly, Huang fails to disclose: (a) any methacrylation of HA, let alone high DM; (b) photocrosslinkable microgel particles of HA; and ( c) any motivation to crosslink the 131I-HA into a microgel format. Huang simply provides one method to label HA with 131I for use in a different type of drug delivery system.
The Examiner finds this argument unpersuasive, because in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this instance the primary reference teaches methacrylated hyaluronic acid.to form macrogels and nanogels.
Applicant argues that Xu provides only general knowledge. Xu does not specifically teach hyaluronic acid with DM in the 100-217% range - to the contrary, the typical methacrylation degrees in the field are much lower. Xu does not mention imidazole functionalization or radioactive iodine at all, since the review's focus is on scaffolds and drug delivery generally (there is no teaching of radiotherapy applications in Xu).
The Examiner finds this argument unpersuasive, because in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this instance the primary reference teaches methacrylated hyaluronic acid.to form macrogels and nanogels; and HUANG teaches radiotherapy application.
Applicant argues no reasonable expectation of success.
The Examiner finds this argument unpersuasive, because as discussed in the rejection above, it would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate Y with chemical Formula 2, which is an amino linker with R1 as an imidazole, which is commonly linker known as aminopropyl-imidazole (CAS No.: 5036-48-6). The person of ordinary skill in the art would have been motivated to make those modifications, because it would allow attach/label the hydrogel with 131I radioactive agents for treating tumors or attach any other active agents/drugs for treating ailments, and reasonably would have expected success because the references dealt in the same field of endeavor, such as hyaluronic acid gels. It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate an average particle size of 29 um. The person of ordinary skill in the art would have been motivated to make those modifications, because it would allow drug delivery, and reasonably would have expected success because the references dealt in the same field of endeavor, such as gel composition for drug delivery.
Additionally, MESSANGER teaches degree of methacrylation controls the crosslinking density.
Telephonic Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAKE MINH VU whose telephone number is (571)272-8148. The examiner can normally be reached Mon-Fri 9:00am-5:30pm.
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/JAKE M VU/Primary Examiner, Art Unit 1618