DETAILED ACTION
Claims 1, 4, 7, 10, 17, 19, 29, 32, 35-37, 47, 50-52, 55-59, 64, and 68-70 are pending and under examination in the instant application.
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 .
Claim Objections
Claims 1, 4, 19, 29, 35-37, 64, and 69 are objected to because of the following informalities:
Claim 1 recites the abbreviations HE, VEGFR.
Claims 4 and 7 recite the abbreviation BMP.
Claim 19 recites the abbreviation SCF.
Claim 29 recites the abbreviation HPCs.
Claim 35 recites the abbreviations FLT3, IGF-1, IL-3 and IL-6.
Claim 36 recites the abbreviations FLT3, IGF-1, IL-3, IL-6, and IL-7.
Claim 37 recites the abbreviations SHH, EPO.
Claim 64 recites the abbreviation TCR.
Claim 69 recites the abbreviation NKCR.
The full terms should precede these abbreviations at the first iteration. While all abbreviations are noted
above, the claims must only be amended to spell out the entire word before the first use of the abbreviation.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 59, 64, and 68-70 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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.
Regarding claim 59, it recites “introducing heterologous nucleic acid encoding an antigen receptor into the iPSCs, HECs, HPCs or progenitor T cells”. However, there is insufficient antecedent basis for “HPCs or progenitor T cells” in the claim. Claim 1, from which claim 59 depends, only recites “iPSCs” and “HECs” and there is no recitation of HPCs or progenitor T cells in the claim. See MPEP 2173.05(e). In view of the substantial issues of indefiniteness related to lack of antecedent basis for a number of terms recited in claim 59, the metes and bounds of the method recited in this claim cannot be determined. Claims 64, and 68-70, which depend directly or indirectly from claim 59, are similarly rejected.
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.
Claim(s) 1, 4, 7, 10, 17, 19, 29, 32, 35-37, 47, and 50-52 are rejected under 35 U.S.C. 103 as being unpatentable over Niwa et al. (WO2011115308A1, filed 03/18/2011, and published on 09/22/2011), as evidenced by Richter et al. (Richter et al., “BMP4 Promotes EMT and Mesodermal Commitment in Human Embryonic Stem Cells via SLUG and MSX2”. Stem Cells, Volume 32, Issue 3, March 2014, Pages 636–648), in view of Valamehr et al. (US20180072992A1, filed on 11/20/2017, and published on 03/15/2018) as evidenced by Lennartsson et al. (Lennartsson et al., “Stem Cell Factor Receptor/c-Kit: From Basic Science to Clinical Implications”. Physiological Reviews 2012 92:4, 1619-1649).
Regarding claim 1, Niwa et al. teaches differentiating a population of induced pluripotent stem cells (iPSCs) into mesoderm cells by culturing the iPSCs sequentially in first, second and third mesoderm induction media to induce differentiation into mesoderm cells (claims 1-6 of Niwa et al.). Niwa et al. further teaches that the cells can be maintained by subculturing using a culture medium supplemented with substances such as fibroblast growth factor (FGF) (paragraph 0029). This reads on that the second and the third mesoderm induction media has fibroblast growth factor (FGF) activity. Also, Niwa et al. teaches that the cells can be maintained by subculturing using a culture medium supplemented with substances such as leukemia inhibitory factor (LIF) (an inhibitor of glycogen synthase kinase-3β) (paragraphs 0029 and 0037). This reads on that the third mesoderm induction medium inhibits glycogen synthase kinase 3β.
Although Niwa et al. does not specifically teach that the first mesoderm induction medium stimulates SMAD1, SMAD5 and SMAD9 mediated signaling pathways, the second mesoderm induction medium stimulates SMAD1, SMAD5 and SMAD9 mediated signaling pathways, and the third mesoderm induction medium stimulates SMAD1, SMAD2, SMAD3, SMAD5 and SMAD9 mediated signaling pathways, Niwa et al. teaches using BMP4 in the mesoderm induction media (claims 1-6 of Niwa et al. and paragraph 0006).
Richter et al. provides evidence that BMP4 induces mesodermal differentiation through the BMP4-SMAD Pathways, such as SMAD1, SMAD2, SMAD3, SMAD5 and SMAD9 (Abstract, page 636, column 2, paragraph 2, and page 639, column 1, paragraph 5). Therefore, culturing the cells with BMP4 to induce mesoderm differentiation, inherently and necessarily results into stimulating SMAD mediated signaling pathways. Accordingly, the mere recitation of its presence in the instant claims is not sufficient to distinguish the instant claims from prior art. “When the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent.” See MPEP 2112.01 or In re Best, 195 USPQ 430, 433 (CCPA 1997).
Also, Niwa et al. as evidenced by Richter et al. fails to teach differentiating the mesoderm cells into HECs by culturing the mesoderm cells sequentially in first and second HE induction media to induce differentiation into HECs.
However, Valamehr et al. teaches contacting mesodermal cells with a composition comprising FGF, VEGF, to obtain mesodermal cells having definitive hemogenic endothelium (HE) potential and contacting the mesodermal cells having definitive HE potential with a composition comprising FGF, VEGF, and SCF, to obtain definitive hemogenic endothelium cells (HECs) (claims 1-2 of Valamehr et al. and paragraphs 0012-0013).
Although Valamehr et al. does not specifically teach that the second HE induction medium stimulates cKIT receptor (CD 117; KIT receptor tyrosine kinase) mediated signaling pathways, Valamehr et al. teaches that the second HE induction medium comprises SCF (claim 3 of Valamehr et al.)
Lennartsson et al. provides evidence that Stem cell factor (SCF) is a molecule that exerts its biological functions by binding to and activating the receptor tyrosine kinase c-Kit ((CD 117; KIT receptor tyrosine kinase)). (Abstract). Therefore, culturing the cells with SCF to induce HEC differentiation, inherently and necessarily results into stimulating cKIT mediated signaling pathways. Accordingly, the mere recitation of its presence in the instant claims is not sufficient to distinguish the instant claims from prior art. “When the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent.” See MPEP 2112.01 or In re Best, 195 USPQ 430, 433 (CCPA 1997).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have modified the production method of Niwa et al. to have further cultured the resulting mesodermal cells into a first induction medium comprising FGF, VEGF and into a second induction medium comprising FGF, VEGF, and SCF with a reasonable expectation of success. One would have been motivated to have done so to in order to obtain definitive hemogenic endothelium cells (HECs) as taught by Valamehr et al.
Regarding claim 4: Following discussion of claim 1 above, Niwa et al. teaches that the first mesoderm induction medium comprises BMP4 (claims 1-3 of Niwa et al.).
Regarding claim 7: Following discussion of claim 1 above, Niwa et al. teaches that the second mesoderm induction medium comprises FGF (paragraph 0029).
Regarding claim 10: Following discussion of claim 1 above, Niwa et al. teaches that the third mesoderm induction medium comprises activin, BMP, FGF, and leukemia inhibitory factor (LIF) (an inhibitor of glycogen synthase kinase-3β) (claims 1-6 and 12 of Niwa et al. and paragraphs 0029 and 0037).
Regarding claim 17: Following discussion of claim 1 above, Valamehr et al. teaches that the first HE induction medium comprises FGF and VEGF (claims 1-2 of Valamehr et al. and paragraphs 0012-0013).
Regarding claim 19: Following discussion of claim 1 above, Valamehr et al. teaches that the second HE induction medium comprises SCF, FGF and VEGF (claims 1-2 of Valamehr et al. and paragraphs 0012-0013).
Regarding claim 29 and 32: Following discussion of claim 1 above, Valamehr et al. teaches differentiating the HECs into HPCs by culturing the population of HECs in a haematopoietic induction medium to induce differentiation into HPCs, wherein the haematopoietic induction medium comprising SCF and VEGFR (claim 3 of Valamehr et al.). As noted above under the discussion of claim 1, SCF actually stimulates cKIT signaling pathways.
Regarding claims 35 and 36: Following discussion of claim 32 above, Valamehr et al. teaches that the haematopoietic induction medium comprises VEGF, SCF, Thrombopoietin (TPO), Flt3 ligand (Flt3L), IGF-1, IL-3, IL-6, and IL-7 (claim 3 and 12 of Valamehr et al. and paragraph 0012).
Regarding claims 37: Following discussion of claim 32 above, while Valamehr et al. does not explicitly teach that the haematopoietic induction medium is devoid of angiotensin II and losartan, absent evidence to the contrary considers the culture medium to be devoid of these components.
Regarding claims 47: Following discussion of claim 29 above, Valamehr et al. teaches differentiating the population of HPCs into progenitor T cells, by a method comprising culturing the population of HPCs in a a composition comprising one or more growth factors and cytokines selected from the group consisting of SCF, Flt3L, IL7, IL2, IL3, and IL6; a BMP activator to obtain the progenitor T cells (claims 12-13 of Valamehr et al.).
Regarding claims 50-52: Following discussion of claim 47 above, Valamehr et al. teaches maturing the progenitor T cells to produce a population of double positive CD8+ CD4+ T cells (paragraph 0080 and 0298). Also, FIG. 10 shows single positive CD4 and CD8 cells.
Claim(s) 1, 4, 7, 10, 17, 19, 29, 32, 35-37, 47, 50-52, 55-59, 64, and 68-70 are rejected under 35 U.S.C. 103 as being unpatentable over Niwa et al. (WO2011115308A1, filed 03/18/2011, and published on 09/22/2011), as evidenced by Richter et al. (Richter et al., “BMP4 Promotes EMT and Mesodermal Commitment in Human Embryonic Stem Cells via SLUG and MSX2”. Stem Cells, Volume 32, Issue 3, March 2014, Pages 636–648), in view of Valamehr et al. (US20180072992A1, filed on 11/20/2017, and published on 03/15/2018) as evidenced by Lennartsson et al. (Lennartsson et al., “Stem Cell Factor Receptor/c-Kit: From Basic Science to Clinical Implications”. Physiological Reviews 2012 92:4, 1619-1649) as applied to claims 1, 4, 7, 10, 17, 19, 29, 32, 35-37, 47, and 50-52 above, and further in view of Minagawa et al. (Minagawa et al., “Enhancing T Cell Receptor Stability in Rejuvenated iPSC-Derived T Cells Improves Their Use in Cancer Immunotherapy”. Cell Stem Cell, Volume 23, Issue 6, 2018, Pages 850-858).
Regarding claims 1, 4, 7, 10, 17, 19, 29, 32, 35-37, 47, and 50-52, the teachings of Niwa et al., Richter et al., Valamehr et al., and Lennartsson et al. are set forth in detail above.
Regarding claims 55-59, 64, and 69-70, Minagawa et al. reports induced pluripotent stem cells derived from antigen-specific T cells (T-iPSCs) have a pre-rearranged T cell receptor (TCR) gene in the genome that originated from antigen-specific CD8 T cells (pg. 850, second column). The CD8+ T cells derived from human iPSCs lose their antigen specificity through additional rearrangement of the T cell receptor (TCR) a chain gene during the CD4/CD8 double positive stage of in vitro differentiation (Abstract). Therefore, Minagawa et al. teaches the T cell derived iPSCs, as taught by Niwa et al., have a pre-rearranged T cell receptor (TCR) that binds to a target antigen. Minagawa et al. also teaches introducing heterologous nucleic acid encoding an antigen receptor into the iPSCs, HECs, HPCs, or progenitor T cells wherein it states, “iPSCs … were transduced with an antigen-specific TCR” (Abstract) and “exogenous TCR gene transduction in iPSCs and other pluripotent stem cells can prevent the TCRbeta rearrangement to obtain antigen-specific T cells” (page. 851, second full paragraph).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have modified the production method of Niwa et al., in view of Valamehr et al. and have obtained the iPSCs from T cells that are specific for a target antigen and further introduced a nucleic acid encoding TCR or CAR into the cells with a reasonable expectation of success. One would have been motivated to have done so such that these cells have a pre-determined TCR with a binding specificity for a particular target antigen, which helps maintaining the affinity and avidity of specific TCR, suggesting improved anti-tumor effects as taught by Minagawa et al.
Regarding claims 68: Following discussion of claim 64 above, Minagawa et al. teaches that TCR binds specifically to an MHC displaying a peptide fragment of a target antigen expressed by cells. Minagawa states: “The CD8b ectodomain of CD8ab increases the binding affinity between the TCR and peptide/MHC complex and acts as a co-receptor of TCR signaling” (page. 851, first full paragraph).
Conclusion
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Hanan Isam Abuzeineh
/H.I.A./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633