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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Acknowledgment is made of applicant's claim for foreign priority based on a Foreign Application No. EP16305607.0 on 05/25/2016.
This Application is a Div of US Application No. 16/303,705 filed 11/21/2018. Claimed domestic priority from this application is thereby acknowledged.
Application Status
Amendments to claims filed 02/13/2026 are hereby acknowledged. Claim 3 is cancelled. Claims 1, 4-8 and 10 are currently amended. Claims 24-26 are newly added. Claims 1-2, 4-26 are currently pending.
Claims 12-23 are withdrawn from consideration since they are drawn to an unelected invention. Therefore, claims 1-2, 4-11 and 24-26 are under examination in this application.
Any objection or rejection not reiterated herein has been overcome by amendments and is therefore withdrawn.
Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follows.
Drawings
Replacement sheets for Drawings filed 02/13/2026 are hereby acknowledged and are acceptable.
Specification
Replacement sheet for Abstract filed 02/13/2026 is hereby acknowledged and is acceptable.
Replacement copies for Specification filed 02/13/2026 are hereby acknowledged and are acceptable.
The following rejections are modified as necessitated by Applicant’s amendments, but maintained from Office Action dated 11/14/2025:
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1-2, 7-8, 10-11 and 26 are rejected under 35 U.S.C. §103 as being unpatentable over Park (Park, I-H. et al. “Generation of human-induced pluripotent stem cells”. Nature Protocols, Vol. 3 , No. 7 (2008), pp: 1180-1186), and Lerou (Lerou, P.H. et al. “Derivation and maintenance of human embryonic stem cells from poor-quality in vitro fertilization embryos”. Nature Protocols, Vol. 3 No. 5 (2008), pp: 923-933; previously cited), in view of Kretsovali (Kretsovali, A. et al. “ Histone Deacetylase Inhibitors in cell pluripotency, differentiation, and reprogramming”. Stem Cells International, Vol. 2012, (2012), p: 184154; previously cited) and Acquarone ( Acquarone, M. et al. “Mitomycin-treated undifferentiated embryonic stem cells as a safe and effective therapeutic strategy in a mouse model of Parkinson’s disease”. Frontiers in Cellular Neuroscience, Vol. 9 (2015), p:97; previously cited).
Regarding claim 1, Park teaches a method of producing a population of pluripotent cells (see title) comprising:
Expanding pluripotent cells under conditions that maintain pluripotent ability of the cells (see page 1185, steps 77-83; “Picking and expanding iPS cell colonies: 7d”). And,
Recovering and conditioning the expanded cells (see page 1181, right column, 2X iPS cell-freezing medium”), in 20% DMSO (vol/vol), 60% FBS (vol/vol) and 20% hES medium (vol/vol).
Park not only teaches the freezing of human dermal fibroblasts in Box 1, page 1182, but also teaches how to passage and freeze derived iPS cells (see page 1185, step 83 and reference 8 (Lerou, see below)).
Regarding claim 2, Park teaches that the selected population is induced pluripotent stem cells (iPS) (see title, and see steps 77-83, page 1185).
Regarding claims 10 and 11, Park teaches the recovery of cells (see steps 82-83, page 1185) and the use of specific buffer for freezing (see page 1181, right column, 2X iPS cell-freezing medium”) . Park also refers to Lerou for maintenance and conditioning of cells, i.e. freezing (reference 8).
Regarding claims 1, 10 and 11, Park refers to Lerou, stating “Once derived, iPS cells should be treated like hES cells. Instruction on how to passage, freeze and characterize these cells can be found in ref.8”.
Lerou teaches the washing and freezing and resuspension in an appropriate buffer, i.e. conditioning, of cells (see page 928, Box 2).
Regarding claims 1-2, 5, 7-8, 10-11 and 26, the combination of Park/Lerou does not teach an agent that induces MHC-I presentation of antigens in the cells during the expanding. Park/Lerou does not teach an inactivating agent that inactivated the expanded cells while maintaining cell envelope integrity.
The Instant Specification defines “Agent for MHC I antigen presentation” as “Such agents are known in the art and one can site, in particular histone deacetylase inhibitors (HDACis)” (see page 13, lines 5-16).
Kretsovali also teaches that HDACis have been used to facilitate induced pluripotent stem cell derivation by ectopic expression of pluripotency factors (see abstract section). Kretsovali teaches that HDACis increase self-renewal and interfere with differentiation (see page 3, left column, section 4.1, third paragraph). Therefore, it is interpreted that adding a HDACi in the culture medium will facilitate iPSC production and increase the expanding of the cells.
Kretsovali teaches that somatic cell reprogramming to pluripotency are mainly epigenetic and that epigenetic regulator agents such as HDACis can be added (see page 2, left column, third paragraph).
Regarding claim 1, Kretsovali also teaches that Azacytidine can be used as an epigenetic regulator agent (see page 3, left column, section 4.1).
Regarding claim 5, Kretsovali teaches that the mutagenic agent during expansion can be a base analog, i.e. 5-azacytidine, an inhibitor of DNA methylation (see page 3, section 4.1, first paragraph).
Regarding claims 7 and 26, Kretsovali teaches that the HDACi can be Valproic acid (VPA) (see page 3, right column, first paragraph).
Regarding claim 8, Kretsovali teaches that application of epigenetic regulators such as inhibitors of DNA methylation (5-Azacytidine) and HDAC inhibitors may be valuable tools for stem cell interventions (see page 3, section 4.1, first paragraph).
Acquarone teaches that Mitomycin-treated undifferentiated embryonic stem cells is a safe way to obtain inactivated stem cells in an effective therapeutic strategy (see title). Acquarone teaches that Mitomycin is an alkylating agent (see abstract section), that triggers mitotic inactivation of undifferentiated embryonic stem cells (see page 2, right column, “Mitomycin C treatment and apoptosis assay” section).
Acquarone teaches that using Mitomycin C avoids formation of teratoma (see Figure 2). Acquarone teaches that exposure of the cells to be used in transplantation with Mitomycin is more safe (see title).
Acquarone teaches integrity of cell membrane by testing for apoptosis and caspase 3 positive cells by flow cytometry (see page 2, right column, “Mitomycin C treatment and apoptosis assay” section).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined the teachings of Park and Lerou, with the teachings of Kretsovali and Acquarone. It would have been obvious to have modified the method of inducing and expanding the pluripotent cells as taught by Park/Lerou and adding an agent that promotes MHC-I presentation of antigens in the cells, i.e. Valproic acid, as taught by Kretsovali, and inactivating the cells with Mitomycin C as taught by Acquarone. One with ordinary skills in the art, motivated in a higher self-renewal capability of the pluripotent stem cells would have performed this modification and add Valproic acid to the culture medium during expansion. One with ordinary skills in the art, also motivated in abrogating teratomas formation and obtaining a safe product for cell transplantation, would have further modified the protocol taught by Park/Lerou modified by Kretsovali, by adding a mitotic inactivation step of the cells, as taught by Acquarone, before freezing. One with ordinary skills in the art, would have performed these modifications with a reasonable expectation of success and arrived at the claimed invention.
Claims 4 and 9 are rejected under 35 U.S.C. §103 as being unpatentable over Park (Park, I-H. et al. “Generation of human-induced pluripotent stem cells”. Nature Protocols, Vol. 3 , No. 7 (2008), pp: 1180-1186) and Lerou (Lerou, P.H. et al. “Derivation and maintenance of human embryonic stem cells from poor-quality in vitro fertilization embryos”. Nature Protocols, Vol. 3 No. 5 (2008), pp: 923-933; previously cited), in view of Kretsovali (Kretsovali, A. et al. “ Histone Deacetylase Inhibitors in cell pluripotency, differentiation, and reprogramming”. Stem Cells International, Vol. 2012, (2012), p: 184154; previously cited) and Acquarone ( Acquarone, M. et al. “Mitomycin-treated undifferentiated embryonic stem cells as a safe and effective therapeutic strategy in a mouse model of Parkinson’s disease”. Frontiers in Cellular Neuroscience, Vol. 9 (2015), p:97; previously cited) as applied to claim 1 above and in further view of Roy (Roy, A. et al. “Increased efficiency of Ɣ-irradiated versus Mitomycin C-treated feeder cells for the expansion of normal human cells in long-term cultures”. Journal of Hematotherapy & Stem Cell Research, Vol. 10 (2001), pp: 873-880; previously cited) and Burt (US 2013/0243739 A1, published September 19, 2013; previously cited).
The rejections of claim 1 is described above. The combination of references Park/Lerou, Kretsovali and Acquarone renders the elements of claim 1 obvious. However, the combination of references, Park/Lerou, Kretsovali and Acquarone does not teach a physical mutagen selected from ionizing radiation and UV radiation (claim 4). The combination of references does not teach an inactivating agent that is a lethal dose of radiation (claim 9).
However, regarding claim 4, Roy teaches Ɣ-irradiation of cells for obtaining a population of “feeder cells” (see title and abstract). It is therefore interpreted that those cells are needed in a state of mitotic inactivation, since Roy teaches that the “Feeder cells have to be somehow proliferation arrested to use them as nonreplicating viable support cells” (see page 873, right column). Roy teaches Ɣ-radiations, i.e. ionizing radiations (see page 874, “Materials and Methods” section).
Regarding claim 9, Roy teaches exposure to Ɣ-radiations in the amount of 75 Gy (see page 874, “Materials and Methods” section and Figure 2).
Burt teaches a method for preparing pluripotent stem cells for regenerating an repairing damaged or aged tissue or organs (see title and abstract). Burt teaches that pluripotent stem cells killed with either lethal doses of irradiation or converted into a powder by lyophilization retain the capability to repair damage organs or tissues (see page 1, § [0009] and see § [0024], [0108] and Figure 12). Burt teaches lethal doses from 25 Gy to 100 Gy (see Figure 12).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to modify the protocol/method of obtaining pluripotent cells taught by Park/Lerou, as modified by Kretsovali and Acquarone, with the mutagen taught by Roy modified by Burt. Roy teaches that Ɣ-irradiation is more efficient to arrest cells than Mitomycin C. One with ordinary skills in the art, motivated in a more efficient method of mitotically inactivate the pluripotent cells, would have substituted Mitomycin C with Ɣ-irradiation, as taught by Roy/Burt, with a reasonable expectation of success and arrived at the claimed invention.
Response to Arguments
Applicant's arguments filed 02/13/2026 have been fully considered but they are not persuasive.
In response, claim 1 is rejected under 35 U.S.C. §103 as being unpatentable over Park (Park, I-H. et al. “Generation of human-induced pluripotent stem cells”. Nature Protocols, Vol. 3 , No. 7 (2008), pp: 1180-1186; previously cited), and Lerou (Lerou, P.H. et al. “Derivation and maintenance of human embryonic stem cells from poor-quality in vitro fertilization embryos”. Nature Protocols, Vol. 3 No. 5 (2008), pp: 923-933; previously cited), in view of Kretsovali (Kretsovali, A. et al. “ Histone Deacetylase Inhibitors in cell pluripotency, differentiation, and reprogramming”. Stem Cells International, Vol. 2012, (2012), p: 184154; previously cited) and Acquarone ( Acquarone, M. et al. “Mitomycin-treated undifferentiated embryonic stem cells as a safe and effective therapeutic strategy in a mouse model of Parkinson’s disease”. Frontiers in Cellular Neuroscience, Vol. 9 (2015), p:97; previously cited).
Kretsovali teaches that Azacytidine can be used as an epigenetic regulator agent (see page 3, left column, section 4.1). Kretsovali teaches that the mutagenic agent during expansion can be a base analog, i.e. 5-azacytidine, an inhibitor of DNA methylation (see page 3, section 4.1, first paragraph).
According to Dapp (Dapp, M.J. et al. “5-Azacytidine can induce lethal mutagenesis in Human Immunodeficiency Virus type 1”. Journal of Virology, Vol. 83, No. 22 (2009), pp: 11950-11958), 5-Azacytidine is a mutagen capable of creating G-to-C transversion (see abstract), but also C-to-G mutations (see page 11953, left column), as well as Indel mutation (see table 1). Dapp teaches a mutation load in a reporter gene GFP that can be as high as 3.4 per GFP sequence (see Figure 4).
According to Bertoli (Bertoli, R. et al. “5-Azacytidine and decitabine induce C>G transversions in both murine and human cells”. Leukemia, Vol. 39 (2025), pp: 2112-2124), a single nucleotide mutation such as a C>G transversion can lead to amino acid substitutions, therefore non-sense mutations, in gene products such as Chd4 (R985X), Ikzf1 (R51) and Trp53 (R196X) (see Figure 3).
According to Nohmi (Nohmi, T. et al. “Molecular nature of intrachromosomal deletions and base substitutions induced by environmental mutagens”. Environmental and Molecular Mutagenesis, Vol. 45 (2005), pp: 150-161) Carbon-ion radiation, UVB and Mitomycin C induce large deletions of more than 1kb, base substitutions G:C[Wingdings font/0xE0]A:T transitions at pyrimidine sites and tandem base substitutions at GG sites (see abstract).
Therefore, the deletions and base substitutions can produce frameshift or splice-variant mutations in genes.
Therefore, 5-Azacytine and Mitomycin C qualify as agents that can induce “non-synonymous, nonsense, frameshift or splice-variant mutations in genes expressed by the pluripotent cells”, as recited in amended claim 1.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “deliberate introduction of sequence-level disruptive genomic mutations to increase antigen diversity for vaccine use’) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Regarding Applicant’s arguments on page 14, against Roy and Burt as references, stating that “Roy teaches away from lethal irradiation”, because “lethality would defeat Roy’s stated purpose”, and “Burt’s teachings are directed to regenerative medicine, …not cancer vaccination or immunotherapy”, Examiner would like to point out that the claims (claims 4 and 9) as written, do not state a required purpose nor end-result. Again, these elements, i.e., “cancer vaccination or immunotherapy” are not recited in the claims. Applicant does not state/claim in the claim that viability of cells are required.
Therefore, Roy and Burt were used as references to indicate that the technique of applying a lethal dose of radiation on stem cells is known in the art, and can be performed by a person of ordinary skills in the art. Copying what is already described in the art, one with ordinary skills could achieve the application of a lethal dose of radiation.
The following rejections are new as necessitated by Applicant’s amendments filed 02/13/2026:
Claims 6 and 25 are rejected under 35 U.S.C. §103 as being unpatentable over Park (Park, I-H. et al. “Generation of human-induced pluripotent stem cells”. Nature Protocols, Vol. 3 , No. 7 (2008), pp: 1180-1186) and Lerou (Lerou, P.H. et al. “Derivation and maintenance of human embryonic stem cells from poor-quality in vitro fertilization embryos”. Nature Protocols, Vol. 3 No. 5 (2008), pp: 923-933; previously cited), in view of Kretsovali (Kretsovali, A. et al. “ Histone Deacetylase Inhibitors in cell pluripotency, differentiation, and reprogramming”. Stem Cells International, Vol. 2012, (2012), p: 184154; previously cited) and Acquarone ( Acquarone, M. et al. “Mitomycin-treated undifferentiated embryonic stem cells as a safe and effective therapeutic strategy in a mouse model of Parkinson’s disease”. Frontiers in Cellular Neuroscience, Vol. 9 (2015), p:97; previously cited) as applied to claim 1 above and in further view of Roy (Roy, A. et al. “Increased efficiency of Ɣ-irradiated versus Mitomycin C-treated feeder cells for the expansion of normal human cells in long-term cultures”. Journal of Hematotherapy & Stem Cell Research, Vol. 10 (2001), pp: 873-880; previously cited), Mahmud (Mahmud, N. US 2013/0136722 A1, published May 30, 2013; cited on IDS filed 07/28/2022).
The rejections of claim 1 is described above. The combination of references Park/Lerou, Kretsovali and Acquarone renders the elements of claim 1 obvious. However, the combination of references, Park/Lerou, Kretsovali and Acquarone does not teach a mutagenic and alkylating agent exposed to the cell for a duration of at least 15 days (claim 6) or of at least 45 days (claim 25).
Regarding claim 6, Roy compares the effects of Ɣ-irradiation to exposure to Mitomycin-C , i.e. an alkylating agent on the feeder cells (see title). Roy teaches exposure for 4 hours (see page 874, “Materials and Methods” section).
Roy teaches growing cells to be used for therapy, i.e. during the expansion phase, in coculture with 4hour-Mitomycin-C inactivated feeder cells, over a duration of at least 30 days (see Figure 1).
Roy does not teach specifically the induced cells to be exposed directly to the agent for at least 30 days. However, Roy teaches long cultures of cells for at least 33 days.
Roy teaches that Mitomycin C, an alkylating agent, has the same functionality than Ɣ-irradiation, although irradiation is more efficient (see title).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined the teachings of Park/Lerou modified by Kretsovali, Acquarone, about a method of obtaining, expanding and inactivating pluripotent stem cells, with the teachings of Roy, substituting Ɣ-radiations to high level of Mitomycin C, over a longer period of time, i.e. 30 days culture as taught by Roy, and obtaining a composition of nonviable stem cells to be used as scaffold. One with ordinary skills in the art, motivated in avoiding high irradiation levels necessitating special equipment and biosafety precautions, could have made this substitution with a reasonable expectation of success, since the end-result would be the same, i.e. the killing of stem cells, and would arrived at the claimed invention.
Regarding claim 25, Mahmud teaches the expansion of progenitor cells ex vivo (see title and abstract). Mahmud teaches the use of valproic acid (VPA), a histone deacetylase inhibitor (HDACi) that according to Specification is capable of inducing MHC-I presentation of antigens in the cells (see page 13, lines 5-16), for eliciting an increase in expansion (see Figure 1B and [0017]). Mahmud also teaches a combination of HDACi and 5-Azacytidine or analogs (see Figure 1B and [0017], [0053]). Mahmud teaches that the combination 5aza analog and Trichostatin A (TSA) (an alternative Histone deacetylase inhibitor ([0056])) is more efficacious than VPA in expanding in vivo repopulating hematopoietic stem cells (see [0090]).
Mahmud teaches that the limitation of treating patients undergoing therapy with progenitor cells is overcome if the number of transplantable stem cells within a single unit to be administered were expanded (see [0040]).
Regarding claim 25, Mahmud teaches methods of stem cell expansion ([0058]-[0062]) and teaches calculation of the number of cells expanded is achieved through the long-term culture-initiating cell (LTCIC) assay, which is based on a limiting dilution analysis of the number of clonogenic cells produced in a stromal co-culture after 5-8 weeks (see [0060]).
In KSR Int 'l v. Teleflex, the Supreme Court, indicated that “The principles underlying [earlier] cases are instructive when the question is whether a patent claiming the combination of elements of prior art is obvious. When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability”. KSR Int'l v. Teleflex lnc., 127 S. Ct. 1727, 1740 (2007).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined the teachings of Park/Lerou modified by Kretsovali, Acquarone and Roy, about a method of obtaining, expanding and inactivating pluripotent stem cells, with the teachings of Mahmud, substituting high level of Mitomycin C with a combination of HDACi and 5-Azacytidine, over a longer period of time, i.e. 30 days culture as taught by Roy, and testing the number of transplantable of stem cells obtained after a culture of 5 to 8 weeks for a LTCIC assay, and optimized the length of culture time accordingly. One with ordinary skills in the art, motivated in obtaining an optimized number of expanded transplantable stem cells, could have made this substitution with a reasonable expectation of success, as taught by Mahmud, and would arrived at the claimed invention.
Claim 24 is rejected under 35 U.S.C. §103 as being unpatentable over Park (Park, I-H. et al. “Generation of human-induced pluripotent stem cells”. Nature Protocols, Vol. 3 , No. 7 (2008), pp: 1180-1186) and Lerou (Lerou, P.H. et al. “Derivation and maintenance of human embryonic stem cells from poor-quality in vitro fertilization embryos”. Nature Protocols, Vol. 3 No. 5 (2008), pp: 923-933; previously cited), in view of Kretsovali (Kretsovali, A. et al. “ Histone Deacetylase Inhibitors in cell pluripotency, differentiation, and reprogramming”. Stem Cells International, Vol. 2012, (2012), p: 184154; previously cited) and Acquarone ( Acquarone, M. et al. “Mitomycin-treated undifferentiated embryonic stem cells as a safe and effective therapeutic strategy in a mouse model of Parkinson’s disease”. Frontiers in Cellular Neuroscience, Vol. 9 (2015), p:97; previously cited), Roy (Roy, A. et al. “Increased efficiency of Ɣ-irradiated versus Mitomycin C-treated feeder cells for the expansion of normal human cells in long-term cultures”. Journal of Hematotherapy & Stem Cell Research, Vol. 10 (2001), pp: 873-880; previously cited), Mahmud (Mahmud, N. US 2013/0136722 A1, published May 30, 2013; cited on IDS filed 07/28/2022), as applied to claims 1 and 6 above and in further view of Cashman (Cashman, S. et al. “An ENU mutagenesis approach to dissect “self”-induced immune responses”. OncoImmunology, Vol. 1, No. 6 (2012), pp: 856-862) and Takeda (Takeda, J. et al. US 2008/0318804 A1, published December 25, 2008).
The rejections of claims 1 and 6 are described above. The combination of references Park/Lerou, Kretsovali and Acquarone renders the elements of claim 1 obvious. The combination of Park/Lerou, Kretsovali, Acquarone, and Roy/Mahmud renders elements of claim 6 obvious. However, the combination of references, Park/Lerou, Kretsovali, Acquarone, Roy and Mahmud does not teach a mutagenic and alkylating agent wherein the mutagenic agent is N-ethyl-N-nitrosourea (ENU) (claim 24).
Regarding claim 24, Cashman teaches that N-ethyl-N-nitrosourea (ENU) is used for mutagenesis approach to dissect “self”-induced immune responses (see title).
Cashman teaches that a functional immune system is usually capable of eliminating transformed cells. However, transformed cells do possess the ability to subvert and evade the immune system (“Introduction” section, page 856, left column). Cashman teaches that immunosurveillance, performed by innate immune effector cells (Natural Killer cells, NK cells), requires overcoming significant challenges as tumor cells normally represent self-tissue, therefore, an effective adaptive immune response need to break immunological tolerance (“Introduction” section, page 856, right column).
Cashman teaches obtaining insight into self-induced immune responses via (NK cell-mediated) cell death using ENU as a mutagen (see page 857, right column, second paragraph). Cashman teaches selecting cells, after mutations induced by ENU, with increased cell killing capabilities, lacking the “missing-self” targets (see Figure 2).
Takeda teaches the making of a library of mutated embryonic stem cells bearing mutations in both alleles, obtained by exposing the cells to a universal mutagen such as ENU (see [0001]-[0004] and Figure 3). Takeda teaches that these mutated cells can be prepared and induced to differentiate into various organs or tissues (see [0002]).
The teachings of Cashman and Takeda suggest that adding ENU to cells that are expanded for treatment, can be mutated with ENU to alter self-antigens or the capability to recognize self-antigens once the stem cells are administered and differentiated into NK cells in a target tissue.
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined the teachings of Park/Lerou modified by Kretsovali, Acquarone, Roy and Mahmud, about a method of obtaining, expanding and inactivating pluripotent stem cells, with the teachings of Cashman and Takeda, and tried combining HDACi with ENU instead of 5-Azacytidine, as taught by Cashman and Takeda, and tried optimizing the condition of cultures according to the phenotype of the differentiated stem cells. Both 5-Azacytidine and ENU are mutagenic agents; it would have been the substitution of one mutagen for another. One with ordinary skills in the art, motivated in obtaining an optimized number of expanded transplantable stem cells lacking self-antigens, or lacking self-antigen recognition once differentiated into NK cells, could have made this substitution with a reasonable expectation of success, as taught by Cashman and Takeda, and would arrived at the claimed invention.
Conclusion
No claim is allowed.
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.
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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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