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 election without traverse of Group II (drawn to a method of treating a disease) in the Response filed on January 6, 2026 is acknowledged.
Claims 1-7, 12, 13, 15-19, 21, 22, 25, 29, 30, 33-40, and 46 have been canceled.
Claims 8-11, 14, 20, 23, 24, 26-28, 31, 32, 41-45, and 47-49 are pending and currently under consideration.
3. 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.
4. Claim 44 is 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 44 recites the limitation "wherein the cytokine comprises IL2…". There is insufficient antecedent basis for this limitation in the claim. Claim 44 is depended upon claim 23 which does not recite cytokine.
5. 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.
6. Claims 8-11, 14, 20, 23, 24, 26-28, 31, 32, 41-45, and 47-49 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed.Cir.1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of the skilled in the art to practice the claimed invention.
The independent claim 23 is drawn to a method of treating a disease comprising delivering an immunotherapy system to a patient comprising a hydrogel comprising a polymer non-covalently cross-linked with a plurality of nanoparticles, a first immunomodulatory cargo comprising cells encapsulated in the hydrogel, and a second immunomodulatory cargo encapsulated in the hydrogel, and releasing the cells from the hydrogel into the patient.
Dependent claims, e.g. claim 28, further limit the disease to be a solid tumor. Dependent claims, e.g. claim 31, further limit the cell to be a cell expressing CAR that recognizes a tumor antigen. Dependent claims, e.g. claim 44, further limit the second cargo to be a cytokine including IL-2. Dependent claims, e.g. claim 8, further limit the cell to comprise T cells or natural killer cell.
The specification discloses adoptive cell therapy (ACT) is a promising strategy to treat cancer and the ACT using CAR-T are immune cells engineered to target an antigen that over expressed on cancer cells.
The specification further discloses the challenge of CAR-T therapies for solid tumors such as intravenous administered CAR-T cells become trapped in the lungs and exhibit poor infiltration of solid tumors and it is difficult to activate CAR-T in vivo (e.g. see [0004]-[0009] of the specification as-filed). The specification further discloses hydrogel hydroxypropylmethylcellulose (HPMC) was modified with hydrophobic lipid dodecyl chains (C-12) and mixed with PEG-PLA nanoparticles suspended with cells. The supramolecular polymer nanoparticle hydrogel with encapsulated cells can be injected via a syringe (e.g. see [0126]). The specification further discloses working examples of B7H3 CAR 41BBZ CAR-T cells in hydrogel in treating xenograft model of human dedulloblastoma in mice (e.g. see [0127]).
However, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The breath of the claims encompasses a method of treating any unspecified disease by delivering an immunotherapy system comprising a hydrogel comprising a polymer non-covalently cross-linked with nanoparticles, a first immunomodulatory cargo comprising cells encapsulated in the hydrogel and a second immunomodulatory cargo encapsulates in the hydrogel. The specification discloses B7H3 CAR-T cells encapsulated in hydrogel comprising HPMC modified with hydrophobic lipid dodecyl chains (C-12) and mixed with PEG-PLA nanoparticles and treating mice xenografted with human medulloblastoma.
There is insufficient evidence that the disclosure of the specific CAR-T cells encapsulated in the hydrogel in mice model is sufficient to enable the full breath of the claims encompass a method of treating any or all diseases as recited.
Therapeutic T cell bioprocessing can be unpredictable. For example, Chin et al. (Applied Materials & Interfaces. 2020, 12:47355-47367) teach that the ability to sense mechanical cues in the environment, mechanosensitivity, underlies the fundamental functioning of numerous cellular processes including cell spreading, proliferation, and differentiation (e.g. see lines 1-5 in left col. in page 47355). Chin et al. further teach that T cells use their TCR to sense physical cues, such as matrix stiffness, geometry, and topography, however, direct comparison between experimental studies and identification of key parameters is difficult due to variations in experimental design, including the choice of biomaterials, stiffness range, antibodies, conjugation methods, and T cell types (e.g. see 1st full paragraph in right col. in page 47356). Chin et al. conclude that further phenotypic analyses is needed to elucidate how different cure combinations can affect differentiation in human T cells that would significantly impact adoptive immunotherapy (e.g. see right col. in page 47365).
There is insufficient direction or guidance in the instant specification to enable one skilled in the art in selecting all possible “hydrogel comprising a polymer non-covalently cross-linked with a plurality of nanoparticles, a first immunomodulatory cargo comprising cells encapsulated in the hydrogel and a second immunomodulatory cargo encapsulated in the hydrogel” for the method of treating any or all unspecified disease.
The amount of direction presented and the lack of working examples provided in the application as filed is very narrow despite the wide breadth of the claims at issue, the unpredictability of Therapeutic T cell bioprocessing and the high quantity of experimentation necessary to practice the breadth of claims.
The instant specification does not set forth sufficient procedures that will necessarily lead to discovery or identification for a hydrogel comprising a polymer non-covalently cross-linked with a plurality of nanoparticles, a first immunomodulatory cargo comprising cells, and a second immunomodulatory cargo.
The specification does not identify a sufficient number of species, other than hydroxypropylmethylcellulose (HPMC) was modified with hydrophobic lipid dodecyl chains (C-12) and mixed with PEG-PLA nanoparticles, human B7H3 CAR-T cells, and IL-15, to support the claimed “genus” by providing sufficient disclosure to teach those of ordinary skill in the art how to make and use the genus as broadly as it is claimed in the subject matter concerning biological materials and reactions in the unpredictable area of T cell bioprocessing for the method of treating any or all disease.
In view of the lack of predictability of the art to which the invention pertains and the lack of established protocols for effective method of treating any or all disease by administering hydrogel encapsulated cells; undue experimentation would be required to practice the claimed methods with a reasonable expectation of success, absent a specific and detailed description in applicant's specification.
7. 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.
8. 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.
9. Claims 8-11, 14, 20, 23, 24, 26-28, 31, 32, 41-45, and 47-49 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) and Momin et al. (Science Translational Medicine 2019, June 26, pages 1-13).
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), then coupled with plurality of 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.
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 of treating disease by administering a hydrogel, a first immunomodulatory cargo comprising cells and a second immunomodulatory cargo, both cargos are 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).
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., 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.
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.
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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