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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 1/5/2026 has been entered.
Claim Status
Applicant’s reply filed on 12/02/2025 is acknowledged. Claims 1, 2, 5, 6, 8, 16, 22, and 23 have been amended. Claim 27 is cancelled. Claim 28 is newly added.
Claims 1-26 and 28 are pending and under examination.
Rejections Withdrawn
All rejections from the Office Action dated 09/03/2025 are withdrawn.
New Grounds of Rejection
Claim Rejections - 35 USC § 112(a)
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.
WRITTEN DESCRIPTION
Claims 1-26 and 28 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.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
The teachings of the specification and the claimed invention
The invention is directed to a method of preparing an immunological composition for treatment of cancer in an individual, the method comprising the generation of a differentiated neoplastic-like cells that have been exposed to one or more mutagenic agents.
The specification provides hydrogen peroxide as a single exemplary mutagenic agent for use in the method. The specification provides two examples wherein murine embryonic fibroblast-derived iPSC cells were differentiated to a neural lineage and exposed to hydrogen peroxide. (Specification, Pg. 23, Example 1). The applicant provides evidence in a preclinical model that administration of the resulting cells inhibited growth of B16 melanoma (Fig. 1) and glioma (Fig. 2) compared with non-mutated cells.
The state of the relevant art
It is known in the art that there are a wide variety of agents that cause genetic mutations, including physical, chemical and biological mutagens. Basu (Int J Mol Sci. 2018 Mar 23;19(4):970) reviews the history of the discovery of known chemical carcinogens including polycyclic aromatic hydrocarbons, nitroaromatics, asbestos, chromium, nickel, arsenic compounds, vinyl chloride, aflatoxins, diesel exhaust, tobacco smoke and physical agents like UV light and gamma radiation (Pg. 2, Paragraph 1, Lines 9-13). Each agent has a distinct method of causing genetic mutations with UV light for example, acting as a direct agent that damages DNA and also damages DNA indirectly via generation of reactive oxygen species (Pg. 2, Full paragraph 2, Lines 1-3).
Moore (Nat Rev Cancer. 2010 Dec;10(12):878-89) teach viruses can also be mutagenic and are classified in two broad categories – direct carcinogens which express viral oncogenes that directly contribute to cancer cell transformation and indirect carcinogens that presumably cause cancer through chronic infection and inflammation which lead to carcinogenic mutations in host cells (Pg. 4, Full paragraph 2, Lines 1-5). Table 1 of Moore list known cancer-causing viruses, including Epstein-Barr virus, Hepatitis B virus and Human papillomaviruses (Pg. 28) and provides the specific cancer types caused by each known virus. Table 1 importantly highlights that the cancer types are virus-specific.
To this end, Basu teaches that each mutagenic agent has a unique mutation profile and mutation-inducing capacity, teaching that “Carcinogens and mutagens usually generate multiple DNA adducts, and it was shown that certain adducts are biologically more relevant than others. Many diseases in humans are the result of specific genetic mutations.” (Pg. 5, Full paragraph 3, Lines 1-3). As an example, Basu teaches in the rat, 53 adducts per 108 nucleotides for the aflatoxin B1 to 2082 adducts per 108 nucleotides for dimethylnitrosamine relate to the normalized 50% level of liver tumor incidences, suggesting that the aflatoxin–DNA adducts are 40 times more potent than the adducts formed by dimethylnitrosamine for inducing hepatocellular carcinoma (Pg. 6, Full paragraph 1, Lines 2-7).
The art thus teaches great diversity of mutagenic agents, target tissues, and tumorigenic potential. In light of this diversity, the instant specification does not provide a means of determining which mutagens are suited for use in the method to result in the production of a composition suited for the treatment of cancer.
Claim analysis
Regarding claim 1, the composition of differentiated neoplastic-like cells exposed to one or more mutagens generated by the instant methods are claimed to have the function of treating cancer in an individual. In view of the number and diversity of mutagens in existence and only one representative mutagen provided in the specification, the specification does not give guidance as to how to identify which agents are encompassed by the claimed methods.
Regarding claim 28, the claim discloses a single mutagen as exemplified in the specification, but does not cure the deficiency of the limitation wherein cells are exposed to one or more mutagens and does not provide guidance as to what other mutagens can be used in tandem with hydrogen peroxide.
The claimed mutagens are defined by their function only and the disclosure fails to provide a representative number of species required for the composition to perform its claimed function. Therefore, the skilled artisan would not reasonably conclude that the inventors, at the time the application was filed, had full possession of method as broadly claimed.
Therefore claim 1 and all dependent claims are rejected under 35 U.S.C. 112(a) for being dependent on claim 1 and not providing limitations that overcome the written description rejection.
SCOPE OF ENABLEMENT
Claims 1-26 and 28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for: (1) preparing an immunological composition for treatment of melanoma and glioma comprising the generation of pluripotent-like cells differentiated to the neural lineage and exposed to the mutagen hydrogen peroxide, or (2) a composition comprising inactivated fetal cells obtained by differentiation of a population of pluripotent cells towards the pathway pertaining to the specific cancer of the patient and treated with N-ethyl-N-nitrosourea (ENU) as taught by Griscelli (WO2019/101956A1), does not reasonably provide enablement for a method for preparing an immunological composition for treatment of any cancer comprising the generation of pluripotent-like cells differentiated to any lineage and exposed to any one or more mutagen. 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 the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and the nature of the invention
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed method is that immunological compositions for cancer treatment can be prepared by exposing pluripotent-like cells to any mutagenic agents and any differentiation factors.
The specification discloses murine embryonic fibroblast-derived iPSC cells differentiated to a neural lineage and exposed to the mutagen hydrogen peroxide. (Specification, Pg. 23, Example 1). The applicant provides evidence in a preclinical model that administration of the resulting cells inhibited growth of B16 melanoma (Fig. 1) and glioma (Fig. 2) compared with non-mutated cells.
The specification does not distill to practice or even suggest the use of any other mutagenic agent. The specification does not distill to practice differentiation of pluripotent cells to a lineage other than neural for use in the instant claimed method.
The state of the relevant art
The art provides limited enabling support for in vitro modeling cancer by generation of iPSC-derived tumorigenic cells generated in the presence of mutagens.
Telliam (Blood 2016; 128 (22): 933) teaches a cancer modelling method called “blast crisis in a dish” comprising exposure of iPSC to the mutagenic agent N-ethyl-N-nitrosourea (ENU) resulting in chromosomal abnormalities of the iPSC (Pg. 2, Lines 6-7).
Griscelli (WO2019/101956A1) teaches generation of “mutagenized” tissue-specific fetal cells by lineage-specific differentiation of induced pluripotent stem cells. Griscelli teaches the use of a wide range of mutagens in the method, but distills to practice only the use of ENU (Pg. 72, Lines 19-20) to recapitulate the “blast crisis in a dish” model (Pg. 68, Figure 5, Lines 20-25), teaching that ENU treatment produces cells with an increased number of novel mutations compared to the population of cells derived without exposure to ENU (Pg. 45, Lines 7-15).
Griscelli importantly teaches that within their method it is necessary to validate the genes (markers, proteins or antigens) that are expressed by cells when they have entered in their differentiation pathway (Pg. 11, Lines 4-11) and provides exemplary markers to validate differentiation into neural, hematopoietic, renal, liver pancreatic, intestinal, lung and thyroid lineage (disclosed on Pg. 11 and 12). In all, Griscelli’s disclosure highlights the inventive steps required to differentiate pluripotent stem cells to specific lineage in the presence of a mutagen.
In total, the art to date teaches in vitro modeling of cancer via “blast crisis in a dish” via ENU mutagen exposure (Telliam) and compositions comprising tissue-specific fetal cells generated from pluripotent cells that are differentiated in vitro and mutated in the presence of ENU (Griscelli). The art does not support the full breadth of the claims.
The amount of direction provided by the inventor and the existence of working examples
What is enabled by the working examples is narrow in comparison to the breadth of the claims. The working examples disclosed in the specification that exemplify the claimed method are limited to a single mutagen and single lineage differentiation. The specification does not provide any examples distilled to practice where the cell products are used as an antigenic source for dendritic cell vaccines
and thus does not provide enabling guidance for using the binding agents as broadly claimed in the methods.
In view of the lack of the predictability of the art to which the invention pertains, the lack of guidance and direction provided by applicant, and the absence of appropriate working examples commensurate with the scope of the claims, undue experimentation would be required to use the claimed invention.
The quantity of experimentation needed to make or use the invention
The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the nature of the invention is treatment of cancer with a theoretical vaccine composition, a person having ordinary skill in the art would have to perform multiple further in vivo experiments, in human clinical trials, or in animal models that are predictive of treatment using differentiated, mutated neoplastic-like cells. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully treating cancer. Therefore, claim 1 and dependent claims are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 5, 11-14, 16-17, 21-23, and 28 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Griscelli (WO2019/101956A1, published 05/31/2019, effectively filed 11/24/2017).
The disclosure of Griscelli is directed to a composition comprising a population of inactivated fetal cells obtained by a process of differentiation of pluripotent cells and exposure to a mutagenic agent during expansion (Pg. 3, Lines 3-22). Griscelli teaches it is favorable to be able to induce mutations in the pluripotent stem cells in order to increase the variability of neo-antigens in the composition (Pg. 34, Lines 1-3).
Regarding claim 1, pertaining to a method of preparing an immunological composition for treatment of cancer in an individual, comprising the steps of (a) generating pluripotent-like cells from fibroblasts or receiving pluripotent-like cells which have been dedifferentiated from fibroblasts; and (b) exposing the pluripotent-like cells to one or more mutagenic agents, wherein the mutagenic agents are not differentiation factors, and exposing the pluripotent-like cells to one or more differentiation factors, thereby producing differentiated neoplastic-like cells; wherein the differentiated neoplastic-like cells and/or lysates thereof are comprised in the immunological composition and/or are used as an antigenic source for antigen presenting cells for the individual, Griscelli teaches the following:
A vaccine composition comprising a population of inactivated fetal cells for use in treatment of cancer in a subject (Pg. 84, claim 1)
The fetal stem cells of the invention are obtained by differentiation of a population of pluripotent cells towards the pathway pertaining to the specific cancer of the patient, expansion of the cells thus differentiated, exposing the cells to a mutagenic agent during expansion to induce mutagenesis of genes in cells of said population (Pg. 84, claim 4)
A “fetal cell” as defined in the disclosure is a cell that has lost its pluripotency as it has engaged in a differentiation pathway (endoderm, mesoderm, ectoderm) (Pg. 8, Lines 23-27)
Fetal cells were derived from murine tail fibroblast-derived iPSCs (Pg. 76, Lines 16-17).
Regarding claim 2, wherein the neoplastic-like cells of claim 1 are expanded in culture prior to a use, Griscelli teaches expansion of the differentiated cells (Pg. 84, Claim 4b).
Regarding claim 5, wherein the pluripotent-like cells or the neoplastic-like cells of claim 1 are differentiated into cells having one or more markers of the same tissue as the tissue of the cancer, Griscelli teaches differentiation of the cells toward the pathway pertaining to the specific cancer of the patient (Pg. 84, claim 4a) and verification that the cells of the population express at least one tumor associated antigen or neoantigen that is present in the subject’s cancer cells (Pg. 84, claim 4e).
Regarding claim 11, wherein the pluripotent-like cells according to the method of claim 1 are generated from fibroblasts upon exposure of the fibroblasts to NANOG; OCT-4; SOX-2, Griscelli teaches the iPSC of the disclosure refers to pluripotent stem cell artificially derived from a non-pluripotent cell by a reprogramming procedure comprising expression of factors OCT4, NANOG and SOX2 (Pg. 29, Lines 6-15).
Regarding claims 12 and 13, wherein the pluripotent-like cells are generated from fibroblasts upon exposure of the fibroblasts to valproic acid, Griscelli teaches use of valproic acid to improve reprogramming and quality of iPSCs (Pg. 29, Lines 30-31).
Regarding claim 14, wherein the pluripotent-like cells are generated from fibroblasts upon exposure of the fibroblasts to the methyltransferase inhibitor decitabine, Griscelli teaches the use of DNA methyltransferase inhibitors as activators of MHC expression in the iPSC cells (Pg. 55, Lines 20-21), specifically use of DNA methyltransferase inhibitor decitabine (Pg. 55, Lines 30-32)
Regarding claim 16, wherein an effective amount of the immunological composition is provided to the individual, Griscelli teaches a vaccine composition comprising a population of mutagenized fetal stem cells (Pg. 85, claims 11, 12) for use in treatment of cancer of a subject (Pg. 86, claim 13)
Regarding claim 17, wherein the method according to claim 16 further comprises administration of an adjuvant, Griscelli teaches combined administration of the population of inactivated fetal cells with HDACi (Pg.84, claim 1), the HDACi used as an adjuvant for increasing the immune response against the vaccine composition (Pg. 21, Lines 1-2).
Regarding claim 21, wherein the individual of claim 16 is the individual from which the fibroblasts and/or dendritic cells were obtained, Wang teaches autologous vaccination in a preclinical mouse model (Pg. 76, Example 5)
Regarding claims 22-23, wherein the neoplastic-like cells of the immunological composition are mitotically inactivated prior to delivery to an individual (claim 22) and wherein the neoplastic-like cells are mitotically inactivated by exposure to irradiation, one or more alkylating agents, treatment with mitomycin C, or a combination thereof, Griscelli teaches inactivation of the fetal cells in order for the cells to lose their availability to divide (Pg. 84, claim 4f) and discloses the cells are mitotically inactivated by exposure to chemical agents and/or irradiation (Pg. 32, Lines 17-20).
Regarding claim 28, wherein the mutagenic agent is hydrogen peroxide, Griscelli teaches a preferred mutagenic agent is H202 (Pg. 36, Lines 13-15).
Claim Rejections - 35 USC § 103
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.
Claims 1-14, 16-17, 19-23, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Griscelli (WO2019/101956A1, published 05/31/2019, effectively filed 11/24/2017) as applied to claims 1, 2, 5, 11-14, 16-17, 21-23, and 28 above, and further in view of Wang (US2017/0191034, published 07/06/2017, PTO-892 11/25/2024).
The disclosure of Griscelli teaches the generation of a composition comprising iPSC-derived cells that are differentiated and exposed to a mutagen in vitro (Pg. 84, claims 1-4).
The disclosure of Griscelli does not teach (1) the cell culture comprises fibroblast feeder cells, (2) ex vivo exposure of the cultured cells to produce antigen-loaded dendritic cells in the presence of dendritic cell activators, (3) wherein the antigen-loaded dendritic cells are co-cultured with T lymphocytes to produce antigen-specific T cells, or (4) wherein the method of administering to an individual comprises providing one more tumor endothelial antigens selected from Flt-3 ligand,TEM-1, NANOG, SOX2, CD133, and a combination thereof.
These deficiencies are taught by Wang.
The disclosure of Wang is directed to cancer therapy comprising cancer antigen-loaded dendritic cell therapy produced by pulsing autologous dendritic cells with cancer stem cell antigens, the cancer stem cells having been obtained by reverting tumor cells to an undifferentiated stem cell state ([0008, Lines 1-7 and [0010], Lines 1-8).
Regarding claims 3 and 4, wherein the culture of claim 2 comprises feeder cells (claim 3) and wherein the feeder cells are fibroblast cells (claim 4), Wang discloses the transduced induced pluripotent cancer cells were seeded in culture with a feeder layer of mouse embryonic fibroblasts ([0085], Lines 19-22).
Regarding claims 6 and 7, wherein the neoplastic-like cells and/or derivatives and/or lysates thereof of claim 1 are exposed to dendritic cells to produce antigen-loaded dendritic cells (claim 6) and wherein the exposure occurs ex vivo (claim 7), Wang discloses exposing the induced pluripotent cancer cells to heat shock treatment and pulsing dendritic cells with the lysate in culture ([0107], 18-23).
Regarding claim 8, wherein the exposure of the lysate and/or cell fragments to dendritic cells according to the method of claim 6 occurs in the presence of one or more dendritic cell activators, Wang discloses that heat shock treatment of the induced pluripotent cancer stem cells releases heat shock proteins that induce the maturation of DCs ([0106], Lines 5-10) and that DCs primed with the heat shocked cell supernatant produced greater antigen-specific T cell responses compared to DCs primed with non-heat shocked lysate ([0106], Lines 32-38).
Regarding claim 9, wherein the antigen-loaded dendritic cells according to the method of claim 6 are co-cultured with T lymphocytes to produce antigen-specific T cells, Wang teaches co-culture of antigen-pulsed DCs with T cells to produce cancer stem cell antigen-specific cytotoxic T lymphocytes ([0106], Lines 24-41).
Regarding claim 10, wherein the dendritic cells and the fibroblast cells according to the method of claim 6 are from the same individual, Wang teaches that the tumor cell, i.e. the original cell before pluripotency is induced, and the antigen presenting cell are autologous ([0048], Lines 1-4).
Regarding claims 19 and 20, wherein in the method according to claim 16 one or more tumor endothelial antigens are provided to the individual (claim 19), and wherein the tumor endothelial antigens are selected from the group disclosed in claim 20, Wang teaches the reprogrammed cells used to pulse the DC cells expressed cancer-specific antigens and were able to present the antigens to T cells and produce antigen-specific T cell responses against Sox2 and other cancer stem cell antigens ([0106], Lines 11-41).
It would have been obvious to one having ordinary skill in the art to modify the method of Griscelli with the teachings of Wang by (1) culturing the cell with fibroblast feeder cells and (2) exposing the cultured cells ex vivo to dendritic cells in the presence of dendritic cell activators to produce antigen-loaded dendritic cells, (3) co-culturing the antigen loaded dendritic cells with T lymphocytes to produce antigen-specific T cells, or (4) providing the individual with endothelial antigens present on the cells used to pulse DCs. One would have been motivated to do so because Wang teaches (1) successful growth of cancer stem cells with the support of a fibroblast feeder layer, (2) successful conditions for generation of antigen loaded dendritic cells, and (3) successful generation of antigen-specific T cells after exposure do the loaded dendritic cels of the disclosure, and (4) administration of endothelial antigens that represent the cancer that is being treated. There would be an expectation of success in modifying the methods of Griscelli with the teachings of Wang because Wan distills to practice a method of generating cancer-specific cells for cancer vaccination and subsequent successful anti-cancer treatment with the methods.
Claims 1, 2, 5, 11-17, 21-23, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Griscelli (WO2019/101956A1, published 05/31/2019, effectively filed 11/24/2017) as applied to claims 1, 2, 5, 11-14, 16-17, 21-23, and 28 above, and further in view of Yamanaka (US2011/0039338A1, published 02/17/2011, PTO-892 11/25/2024).
The disclosure of Griscelli teaches the generation of a composition comprising iPSC-derived cells that are differentiated and exposed to a mutagen in vitro (Pg. 84, claims 1-4).
The disclosure of Griscelli does not teach that the de-differentiated fibroblasts are exposed to the disclosed percentages of oxygen of claim 15 ranging from 2-8%.
This deficiency is taught by Yamanaka.
The disclosure of Yamanaka is directed to a method of improving the efficiency of the establishment of induced pluripotent stem cells, comprising culturing cells under hypoxic conditions during the reprogramming step (see Abstract).
Regarding claim 15, wherein the de-differentiated fibroblasts are exposed to 2-8% oxygen, Yamanaka teaches hypoxic conditions for the maintenance of the undifferentiated state of pluripotent cells ([0005], Lines 1-3) and discloses their reprogramming culture methods include oxygen concentration in the ambient atmosphere between 1-10% or 1-5% ([0022], Lines 1-8).
It would have been obvious to one having ordinary skill in the art to modify the methods of Griscelli by reprogramming the pluripotent cells at the disclosed percentages of oxygen ranging from 2-8%. It would have been obvious to do so because Yamanaka teaches culturing the cells in hypoxic conditions helps maintain pluripotency. Yamanaka provides a proven means of generating pluripotent cells from fibroblasts and provides evidence that culturing pluripotent cells in hypoxic environment improves the efficiency of known pluripotency reprogramming methods.
Claims 1, 2, 5, 11-14, 16-18, 21-23, 25-26 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Griscelli (WO2019/101956A1, published 05/31/2019, effectively filed 11/24/2017) as applied to claims 1, 2, 5, 11-14, 16-17, 21-23, and 28 above, and further in view of Chiang (Semin Immunol. 2010 Jun;22(3):132-43, PTO-892 11/25/2024).
The disclosure of Griscelli teaches the generation of a composition comprising iPSC-derived cells that are differentiated and exposed to a mutagen in vitro (Pg. 84, claims 1-4). Griscelli teaches the composition can be formulated with any adjuvant known in the art (Pg. 22, Lines 1-2).
The disclosure of Griscelli does not teach (1) that the adjuvant provided to the subject is one or more toll like receptors agonists or (2) that the individual is provided one or more agents that causes local accumulation of antigen presenting cells, further defined as local administration of GM-CSF.
These deficiencies are taught by Chiang.
The disclosure of Chiang is a review of approaches for the preparation of whole tumor cell vaccines, useful as a source of tumor associated antigens and able induce simultaneous CTLs and CD4+ T helper cell activation (see Abstract).
Regarding claim 18, wherein the adjuvant provided to the individual comprises one or more toll-like receptors agonist adjuvants, Chiang teaches the use of TLR agonist CpG as an adjuvant to a tumor lysate vaccine and teaches that the addition of CpG to the vaccination increased the number of T cells and activated DCs in the draining lymph nodes compared to lysate vaccine alone (Pg. 143, Left column, Full paragraph 2, Lines 9-14).
Regarding claims 25 and 26, wherein the individual is provided one or more agents that causes local accumulation of antigen presenting cells (claim 25), further defined as local administration of GM-CSF to the individual (claim 26), Chiang teaches genetically modified tumor cell vaccines that secrete GM-CSF at the site of vaccination and maximize recruitment of DCs to the site (Pg. 135, Left column, Full paragraph 1, Lines 8-11).
It would have been obvious to one having ordinary skill in the art to modify the methods of Griscelli by (1) providing to the subject one or more toll like receptor agonists and (2) providing to the individual one or more agents that causes local accumulation of antigen presenting cells, further defined as local administration of GM-CSF as taught by Chiang. It would have been obvious to do so because (1) Chiang teaches administration of TLR agonist CpG recruits T cells and DCs in the lymph nodes that drain the vaccine and (2) that local administration of GM-CSF causes recruitment of DCs to the vaccination site. There would be an expectation of success in modifying the methods of Griscelli with the teachings of Chiang because Chiang teaches cancer vaccine methods that are routinely used in the field and cites evidence of their efficacy in pre-clinical and clinical studies.
Claims 1, 2, 5, 11-14, 16-17, 21-24, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Griscelli (WO2019/101956A1, published 05/31/2019, effectively filed 11/24/2017) as applied to claims 1, 2, 5, 11-14, 16-17, 21-23, and 28 above, and further in view of Giavridis (Nat Med. 2018 Jun;24(6):731-738, PTO-892 11/25/2024).
The disclosure of Griscelli teaches the generation of a composition comprising iPSC-derived cells that are differentiated and exposed to a mutagen in vitro (Pg. 84, claims 1-4).
The disclosure of Griscelli does not teach that the individual is provided an effective amount of one or more immune suppressive factors.
This deficiency is taught by Giavridis.
The disclosure of Giavridis is directed to investigating therapeutic intervention for severe cytokine release syndrome (CRS) that occurs after CAR T cell administration. Giavridis teaches that blocking inflammatory cytokine IL-1 prevents the occurrence of cytokine release syndrome (Pg. 734, Right column, Full paragraph 2, Lines 16-18).
Regarding claim 24, wherein the individual is provided an effective amount of one or more immune suppressive factors prior to, during, and/or after providing the immunological composition, Giavridis teaches that IL-1 blockade by anakinra, an IL-1 receptor antagonist, abrogates CRS-related mortality in a pre-clinical model (Pg. 734, Right column, Full paragraph 2, Lines 16-18, Fig. 4c).
It would have been obvious to modify the method Griscelli with the addition of an immunosuppressive agent such as IL-1 antagonist as taught by Giavridis. It would have been obvious to do so because Giavridis teaches that immunosuppression through blocking IL-1 prevents mortality from immunotherapy-induced cytokine release syndrome in pre-clinal studies. There would be an expectation of success in modifying the methods of Griscelli with administration of an anti-inflammatory agent as taught by Giavridis because anakinra is an immune regulator drug routinely administered to patients and Giavridis shows that when administered in conjunction with an inflammatory cellular vaccine it prevents cytokine release syndrome.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROL ANN CHASE whose telephone number is (571)270-0934. The examiner can normally be reached Monday-Friday 9:00am-6:00pm.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646