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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/19/2025 has been entered.
Applicants' arguments, filed 07/15/2025, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (Macromol Biosci, 2018, vol 19, issue 1, pp 1-12), in view of Park et al (US 20120100103 A1) and Chau et al (WO 2012171335 A1)1.
Chen et al teach injectable supramolecular hydrogel/microgel composites for localized and sustained therapeutic delivery comprising, combining beneficial properties of both systems (conclusions, abs, intro 5th ¶). The microgels entrap therapeutic agents, where the cross-linker controls degradation and entrapped therapeutic release (abs). The microgels used were hyaluronic acid based (intro 5th ¶, 2.2, 2.3). The microgels were fabricated with a DTT or PETMA crosslinker (fig 3), where the microgel was dispersed into the bulk gel (fig 4). In one embodiment, the therapeutic agent was interleukin-10 (IL-10), an anti-inflammatory cytokine (intro last ¶). The release rate of therapeutic agent in the hydrogel/microgel composites were extended, compared to microgels alone, and burst release was eliminated (3.2 6th ¶). The entrapment of the microgels within the bulk hydrogel improves localization of the therapy to the injection site and prevents the dispersion of microgels compared to when delivered alone (3.2 6th ¶). The hydrogel/microgels have been used to deliver cells, small molecules, etc. (3.1 1st ¶), and hydrogels were known to delivery various therapeutics, including drugs (intro 4th ¶). The microgels were generally uniform in size and had an average diameter of 59 +/- 7 microns (3.1 2nd ¶, fig 2D). The hydrogel/microgel composite system can be tuned for the delivery of a wide range of therapeutics with for numerous clinical indications and applications (intro 5th ¶, conclusions).
Chen et al do not teach the specific cross linking formula 2-1 for the hydrogel, wherein the hydrogel is a gelatine-polyethylene glycol-tyramine copolymer, nor wherein the hyaluronic acid microgel is crosslinked via chemical formula 1-1.
Park et al teach in situ forming injectable hydrogels for biomedical use (abs). In one embodiment the hydrogels are gelatin-PEG-tyramine (GPEG-TA) conjugates reacted with HRP/H2O2 to form a crosslinked hydrogel (fig 1 and 3). The injectable hydrogel is superior to conventional hydrogels in terms of in vivo stability and mechanical strength (abs). The injectable hydrogel can be used for sustained drug and cell delivery (¶¶ 2, 48), and can be used in the eye (¶ 40). Suitable drugs include protein drugs, anti-bacterial agents, anti-inflammatory agents, etc. (¶¶ 41-43). Release rate of the GPEG-TA hydrogel can be controlled by varying the concentrations of hydrogen peroxide or the polymer (¶ 102).
Park et al do not teach wherein the hyaluronic acid microgel is crosslinked via chemical formula 1-1.
Chau et al teach hydrogels for drug delivery formed from vinylsulfone-modified hyaluronic acid with dithiothreitol (DTT) (¶¶ 10, 88, 102, 108). The hydrogel provides controlled release for prolonged delivery of encapsulated therapeutic to a target site (¶¶ 62, 65). The hydrogel can be injected to the eye with minimum impact on the surrounding ocular tissues (¶ 60). In one embodiment, a steroid drug was used to treat ocular inflammation (¶ 116). Other drugs, such as Avastin (protein drug) can be used to treat various eye diseases (¶¶ 65, 109).
Regarding wherein the hydrogel is a gelatin-polyethylene glycol-tyramine copolymer, it would have been obvious to substitute the hydrogel of Chen et al with other known cross-linked hydrogels suitable for injectable formulations that can be used for sustained release of an active, such as the GPEG-TA hydrogel of Park et al.
Regarding the cross-linking functional group of the hydrogel, it would have been obvious to modify the combination of Chen et al and Park et al by selecting from known cross linking agents suitable for GPEG-TA hydrogels, such as the crosslinking functional groups in fig 3 of Park et al, where these crosslinked GPEG-TA hydrogels are used in injectable drug delivery compositions and have improved stability and mechanical strength over traditional hydrogels, as taught by Park et al.
Note, it appears the hydrogel of figs 1 and 3 of Park et al, is identical to the hydrogel of figs 14 and 15a of the instant specification, thereby reading on the chemical formula 2-1 and 2-2.
Regarding the hyaluronic acid microgel, it would have been obvious to modify the hydrogel/microgel composites by selecting from other known cross linked hydrogels suitable for injectable drug delivery, such as vinylsulfone-modified hyaluronic acid with dithiothreitol (DTT), as the microgel, where the gels were known to be used for controlled release for prolonged delivery of encapsulated therapeutic to a target site, and provides minimal impact on tissues, as taught by Chau et al. Further, it was known from Chen et al that hyaluronic acid hydrogels with DTT containing cross linkers were suitable for the microgel, and therefore a skilled artisan would have a reasonable expectation of success in using the cross linked vinylsulfone-modified hyaluronic acid with DTT of Chau et al.
Examiner notes that the hydrogel and microgel require a particular crosslinker, however, the claimed invention is the product formed after the crosslinker reacts with the polymer to form a crosslinked polymer. As such, claim limitations drawn to the chemical structure of a crosslinker prior to having been crosslinked can be considered to be product-by-process limitations. See MPEP 2113.
Regarding wherein the drug is a protein therapeutic agent, it would have been obvious to include a protein therapeutic agent as the active agent for sustained release, where Chen et al, Park et al, and Chau et al, all teach protein therapeutic agents as suitable active agents for sustained release.
Regarding the microgel size, it would have been obvious to formulate the microgels made obvious above by Chen et al, Park et al, and Chau et al, with known sizes suitable for hydrogel/microgel compositions, such as with an average diameter of 59 +/- 7 microns, as taught by Chen et al.
Response to Arguments
First, Applicants assert Park et al do not disclose whether GPT hydrogel is suitable for intraocular injection. Applicants assert Examples 3-6 of the present disclosure show that when injected into the eye, no bacterial infection was observed, and there was no change in the expression of MIP-3 alpha inflammatory factor, and the expression of IL-2 beta was rather reduced. Second, Applicants assert Park et al do not disclose whether GPT hydrogel can achieve sustained release of protein-based drugs. Applicants assert the present invention, when injected into the eye, shows improved drug uniformity in the retina compared to when only the drug-loaded microgel is administered. Applicants refer to Examples 1-4 and 3-5, where GPT hydrogel with drug-loaded hyaluronic acid microgel improved sustained release in all biological environments in the eye, compared to administering only the microgels, which Applicants assert are not taught by Chen et al, Park et al, nor Chau et al. Third, Applicants assert Park et al do not teach whether protein therapeutic agent loaded hyaluronic acid microgel/GPT hydrogel composite formulation can exhibit excelled sustained release without an inflammatory reaction when injected intraocularly. Applicants assert figs 20, 29, and 32 of the present disclosure shows the release profile was best when distributed in GPT hydrogels, compared to GH, or HA-VS+HA-SH. Fourth, Applicants assert it is not possible to conclude that the effects of the present invention can be easily predicted based only on the cited inventions that do not disclose GPT hydrogel or ocular administration without undue experimentation.
First, this argument is not persuasive. Applicants appear to be arguing results based off of the intended use of the hydrogel. As discussed in the previous Office Action and discussed above, where the combination made obvious above comprises a hyaluronic acid based microgel cross-linked by chemical formula 1-1 that is loaded with a protein and is distributed in a hydrogel comprising a gelatin-polyethylene glycol-tyramine cross-linked by a cross-linking functional group represented by instant chemical formulas 2-1 and 2-2, and are injectable, it appears that the hydrogel would be capable of being intraocularly injected, where the structure appears to be the same, there satisfying the intended use limitation. Further, Park et al teach GPEG-TA hydrogels are suitable for injection into the eye and Chau et al teach vinylsulfone-modified hyaluronic acid with dithiothreitol (DTT) can be injected into the eye, therefore it would be expected that the combination would also be capable of being injected into the eye. Applicants assert the present invention has no observed bacterial infection, however, where Chen et al, Park et al, and Chau et al are all directed to injectable hydrogel formulations for pharmaceutical use in biomedical applications, it would be expected that the formulations would not cause bacterial infection, and there are no teachings or suggestions in any of the cited references that suggest a bacterial infection would occur. Even if not, the skilled artisan would reasonably be expected to formulate a sterile hydrogel injection as to not cause a bacterial infection. Lastly, Applicants assert no change in MIP-3 alpha inflammatory factor and expression of IL-2 beta was reduced with the instantly claimed formulation, however, Applicant have not compared the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. See MPEP 716.02(e). Here, Applicants are comparing what appears to be the MIP-3 alpha and IL-2 beta inflammatory factor expression of ranibizumab injected group (A), 10-fold concentrated ranibizumab injected group (B), and the instant formulation (C) (see also ¶ 182 of the instant specification), which is not compared to the closest prior art which teaches an injectable hydrogel/microgel formulation. Even so, while it appears formulation (C) has the lowest MIP-3 alpha and IL-2 beta at 1 day, at 30 days formulation (B) and (A) has the lowest MIP-3 alpha and IL-2 beta values, respectively, which appears to be in contrast to Applicants assertion of lower expression of these inflammatory factors.
Second, this argument is not persuasive. Examiner respectfully disagrees that Park et al does not disclose whether GPT hydrogel can achieve sustained release of protein-based drugs, where Park et al teaches the injectable hydrogel is used for sustained release of a drug, and suitable drugs include protein drugs. Therefore, it would be expected that the GPT hydrogel of Park et al would be suitable for sustained release of protein-based drugs, contrary to Applicants assertion. Regarding improved drug uniformity, Applicant must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. See MPEP 716.02(e). Here, Applicants are comparing the instantly claimed formulation to hydrogels alone, which is not the closest prior art where the combination of Chen et al, Park et al, and Chau teach a hydrogel/microgel composite. Still, Chen et al teach the entrapment of the microgels within the bulk hydrogel improves localization of the therapy to the injection site and prevents the dispersion of microgels compared to when delivered alone. It would be expected that the prevention of the hydrogel dispersion would lead to increased drug uniformity at the desired site of injection. Applicants assert improved sustained release compared to administering only microgels, however, this would be expected based on the teachings of Chen et al, where it is taught that the release rate of therapeutic agent in the hydrogel/microgel composites were extended, compared to microgels alone, and burst release was eliminated.
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Third, this argument is not persuasive. As discussed above, Chen et al, Park et al, and Chau et al all teach sustained release of protein therapeutics, and therefore, it would be expected that the combination would be suitable for sustained release of protein based therapeutic agents, as instantly claimed. Applicants assert figs 20, 29, and 32 of the present disclosure shows a better release profile in HA microgel/GPT hydrogels compared to HA microgel/GH hydrogel or HA-VS+HA-SH, however, it is respectfully not seen that one is improved over the other, as the cumulative release rates appear to be substantially similar and not statistically significant, all displaying a burst release followed by sustained release over a 30 day period. Figs 20, 29 and 32 are reproduced side-by-side below for convenience.
Fourth, this argument is not persuasive. Applicants arguments are based off the intended use of the claimed hydrogel formulations and it appears that the formulation made obvious above would be capable of being used as an injectable intraocular hydrogel, as instant claimed, for the same reasons discussed above and of record. While the Examiner agrees that the release rates, etc., of hydrogels can vary depending on their structure, the size of the active, etc., Chen et al, Park et al, and Chau et al, all teach injectable sustained release formulations suitable for protein therapeutic agents, and Chen et al teach the hydrogel/microgel composite system can be tuned for the delivery of a wide range of therapeutics with for numerous clinical indications and applications. Thus, it appears that it would be well within the relative skills of the skilled artisan to formulate the hydrogel as instantly claimed without undue experimentation, as asserted by Applicants.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSHUA A ATKINSON whose telephone number is (571)270-0877. The examiner can normally be reached M-F: 9:00 AM - 5:00 PM + Flex.
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/JOSHUA A ATKINSON/Examiner, Art Unit 1612
/ISAAC SHOMER/Primary Examiner, Art Unit 1612
1 Chau et al (WO 2012/171335 A1) was cited in the IDS submitted to the file record on 22 April 2022 as foreign document #1.