DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s amendment filed on June 2, 2026 is acknowledged.
Claims 1-7, 9, 10, 12-19, 21, 22, 25, 29, 30, 33-40, and 46 have been canceled.
Claims 50-52 have been added.
Claims 8, 11, 20, 23, 24, 26-28, 31, 32, 41-45, and 47-52 are pending and currently under consideration.
3. In view of applicant’s amendment, following rejections are set forth.
4. 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.
5. 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.
6. Claims 8, 11, 20, 23, 24, 26-28, 31, 32, 41-45, and 47-52 are rejected under 35 U.S.C. 103 as being unpatentable over Grosskopf et al. (Bioeng Transl Med. 2020; 5:e10147:1-11, first published on October 12, 2019) in view of Atik et al. (J. Clin. Neurosci. 2018, Jul 21;56:163-168, reference on IDS), Momin et al. (Science Translational Medicine 2019, June 26, pages 1-13), and De Groot et al. (Int. J. Cancer 2002, 98:134-140).
Grosskopf et al. teach injectable supramolecular polymer-nanoparticle hydrogels for human mesenchymal stem cell delivery (e.g. see Title). Grosskopf et al. further teach:
Hydrogel system, hydroxypropylmethylcellulose (HPMC) was modified with hydrophobic lipid dodecyl chains (C12) (hydrophobically modified cellulose derivative), then coupled with plurality of PEG-PLA nanoparticles by mixing, resulting physical crosslinking non-covalently (e.g. see 2.1 and 2.2 in right col. in page 2). The ratio of polymer to nanoparticles is 1 wt% of polymer and 5 wt% nanoparticles (e.g. see 2.2. in right col. in page 2). The hydrogel encapsulated stem cells are delivered via injection using a syringe (e.g. see Figure 1). The hydrogel enhanced cell viability and expansion (e.g. see 1st paragraph in left col.). The hydrogel exhibits immunomodulatory effects that prove greater protection of the implanted cells. The injectable polymer-nanoparticle (PNP) hydrogel exhibits shear-thinning behavior which allowed self-healing after injection-caused broken interactions between the polymer chains and the NPs (e.g. see paragraph spanning pages 2-4).
Grosskopf et al. teaches administration of the hydrogel encapsulates with the stem cells into mice (e.g. see 2.6 in right col. in page 5). Grosskopf et al. teach that the hydrogel is new materials for cell delivery and can prolong cells retention in vivo for up to 2 weeks, presenting an excellent use for clinical application. Grosskopf et al. predicts that the prolonged local retention of soluble factors within the hydrogel in combination with therapeutic cells can be pursued to steer the fate of both the delivered cell and the surrounding tissues to increase efficacy of treatments (e.g. see Conclusion in left col. in page 8).
The reference teachings differ from the instant invention by not describing a method for immunotherapy delivery comprising delivery an immunotherapy system comprising the hydrogel comprising a first immunomodulatory cargo comprising a cell encapsulated in the hydrogel and a second immunomodulatory cargo comprising a cytokine encapsulated in the hydrogel.
Atik et al. teach hydrogel enhanced delivery of CAR T cells (e.g. see Title). Specifically, Atik et al. teach convection enhanced delivery (CED) of therapeutics to brain tumor Glioblastoma can both bypass the blood brain barrier (BBB) and increase delivery of agents to the tumor (e.g. see Introduction in page 2). Atik et al. teach CAR T cells from a donor were suspended in injectable hydrogel that is non-toxic to rodent brain and currently under development for human use, loaded into syringe pump, and injected to mice and showed that hydrogel efficiently delivered significantly higher amount of CAR T cells in first hour during day 1 as compared to control saline (e.g. see pages 3-5).
Atik et al. teach the hydrogel as carrier for delivery of CAR T cells is applicable for CAR T cell therapy and other cellular therapies which require migration out of the scaffold in order to mediate their therapeutic function (e.g. see paragraph spanning pages 7 and 8). Atik et al. teach that the hydrogel is compatible with human tissues including the brain with minimum adverse effects and can improve brain tumor therapy through the localized delivery of highly functional tumor-specific effectors, allow for rapid implementation of hydrogel as cell-carrier for CED in patients with glioblastoma (e.g. see last paragraph in page 8).
Momin et al. teach cytokines IL-2 and IL-12 can amplify and coordinate immune dell responses for tumor control and synergize with other immunotherapies (e.g. see Introduction in left col. in page 1). Momin et al. teach IL-2 is a compelling candidate for tumor localization because its antitumor efficacy requires sustaining a high intra-tumoral concentration and extended systemic IL-2 exposure potentiates the efficacy of adoptive T cell transfer (e.g. see left col. in page 3). Furthermore, Momin et al. teach that it has been an outstanding challenge to unleash cytokine’s anti-tumor therapeutic efficacy without exacerbating toxicity and cytokine fused to collagen-binding protein prolongs local retention and markedly reduces systemic exposure (e.g. see Abstract).
De Groot et al. teach IL-2 is a highly effective anticancer drug if it is applied locally (e.g. see Abstract). De Groot et al. teach hydrogel are 3D networks of hydrophilic polymers that can adsorb large amounts of water, yielding a good compatibility with the encapsulated protein (e.g. see left col. in page 134). De Groot et al. developed IL-2 encapsulated in injectable hydrogen from which most IL-2 was gradually released (e.g. see left col. in page 138). De Groot et al. teach that the therapeutic effect of the hydrogels was impressive as the therapeutic effects of 1 application of IL-2 containing hydrogels were as good as the therapeutic effects of IL-2 injection for 5 consecutive days (e.g. see the paragraph spanning left and right col. in page 138).
It would thus be obvious to one of ordinary skill in the art at the time the instant invention was filed to combine the teachings of the references to encapsulate the CAR T cells and cytokines such as IL-2 in the hydrogel disclosed by Grosskopf et al. An ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, because Grosskopf et al. teach that the prolonged local retention of soluble factors within the hydrogel in combination with the encapsulated therapeutic cells can be pursued to steer the fate of both the delivered cell and the surrounding tissues to increase efficacy of treatments. Given that Atik et al. teach hydrogel encapsulated CAR T cells can be delivered locally to brain tumor and in view of the well-known effect of Il-2 when prolonged locally delivery in synergizing with immunotherapy including adoptive T cell therapy as taught by Momin et al. and the effect of injectable hydrogel encapsulated IL-2 as disclosed by De Groot et al., an ordinary skill in the art would have been able to encapsulate both the CAR T cells for treating brain tumor with IL-2 in the new hydrogel system developed by Grosskopf et al. with a reasonable expectation of success in achieving the a hydrogel, a CAR T cells, and IL-2 for a method of treating brain tumor.
Applicant’s arguments have been fully considered but have not been found persuasive.
Applicant argues that the IL-2 and CAR T cell disclosed in Momin and Atik et al. were delivered via different delivery routes such as intravenously or intratumoral injection. Nothing in Momin discloses or suggests that the CAR-T cells and IL-12 would still be effective when delivered via the same delivery route, let alone via co-encapsulation in a hydrogel as recited in the instant claims. As such, applicant asserts that the independent claim 23 is not obvious over the prior art. Applicant further argues newly added claims 50-52 are depended upon claim 23 and thus also be allowable.
This is not found persuasive for following reasons:
Contrary to applicant’s arguments about the delivery route of the prior art, note that the instant claims do not specify any delivery route and thus read on any delivery route including intravenous delivery or intratumorally injection that disclosed in the prior art.
Further, 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).
It is noted that in considering the disclosure of a reference, it is proper to take into account not only specific teaching of the reference but also the inferences which one skilled in the art would be reasonably be expected to draw therefrom In re Preda, 401 F.2d 825, 159 USPQ 342, 344 (CCPA 1968). See MPEP 2144.01.
Furthermore, specific statements in the references themselves which would spell out the claimed invention are not necessary to show obviousness, since questions of obviousness involves not only what references expressly teach, but what they would collectively suggest to one of ordinary skill in the art. See CTS Corp. v. Electro Materials Corp. of America 202 USPQ 22 (DC SNY ); and In re Burckel 201 USPQ 67 (CCPA). In re Burckel is cited in MPEP 716.02.
Here, given that it was known in the art to deliver CAR T can be suspended in injectable hydrogel to be delivered locally as disclosed by Atik and it was also known that cytokines such as IL-2 can also be encapsulated into injectable hydrogel for local delivery to reduce toxicity and amplifying immune cells synergize with other immunotherapies, and ordinary skill in the art would have been motivated to encapsulate the CAR T and cytokines such as IL-2 (capable of potentiating the efficacy of adoptive T cell transfer) into the injectable hydrogel disclosed by Grosskopf for enhanced cell viability and expansion. The hydrogel system such as HPMC disclosed by Grosskopf would be expected to provide greater protection of the CAR T cells and prolonged local retention of soluble factor such as IL-2 and to increase efficacy of treatment.
As such, applicant’s arguments have not been found persuasive.
7. No claim is allowed.
8. 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.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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