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 Status
Claims 1 – 15, 29, 32 – 34 and 36 are pending.
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.
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.
Claims 1 –6, 8 – 9 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Sato et al. (Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche, Nature Letters, Vol 459, (2009); Corresponds with US8642339 on the IDS; hereinafter Sato) in view of Xiao et al. (TGF-β1 protects intestinal integrity and influences Smads and MAPK signal pathways in IPEC-J2 after TNF-α challenge, Innate Immunity, Vo. 23(3) 276 – 284 (2017); cited on IDS, hereinafter Xiao) and Lombaert et al. (Epithelial Stem/Progenitor Cells in the Embryonic Mouse Submandibular Gland, Front. Oral. Biol.; 14: 90 – 106 (2010); cited on IDS, hereinafter Lombaert).
Regarding claims 1 – 2, 5 – 6, 8 – 9 and 14, Sato discloses that single epithelial Lgr5+ stem cells can initiate crypt-villus organoids (Abstract) when cultured in Matrigel (p. 265, Methods Summary). Sato does not explicitly disclose the use of TGF-β. However, It is well known that Standard Matrigel does contain TGF-β.
Xiao discloses a study on the effects of TGF-β1 in regard to intestinal integrity, in which the aim was to investigate the protective effects of TGF-β1 on intestinal epithelial barrier (Abstract). Xiao discloses the use of porcine small intestinal epithelial cells (IPEC-J2) for all experiments (p. 277, col. 1, para. 3). The cells were pre-incubated with TGF-β1 (10 ng/ml) in both the basal and apical culture media for 2 h (p. 277, col. 2, para. 1). Xiao further discloses (p. 281, col. 2, para. 1) that in this study, they found that TGF-β1 prevented epithelial barrier dysfunction caused by TNF-a in IPEC-J2, as evidenced by TGF-β1 alleviating both transepithelial electrical resistance (TER) decrease and paracellular permeability increase. They also report that pretreatment with TGF-β1 prevented the TNF-a-induced reductions in Occluding and Zo-1, which are thought of as the major integral membrane proteins in the barrier function. Xiao teaches all of the elements of the current invention as stated above except using intestinal stem cells or that the cell culture is an organoid culture.
However, Lombaert discloses/provides motivation in a study that focuses on how to induce autologous stem cells to regenerate damaged salivary tissue in a therapeutic context, the use of TGFβ1 (p. 8, Section 3. Basal cells are regulated by TGFβs) to regulate (increase stemness) stem/progenitor cell-related gene expression in E13 Submandibular gland (SMG) epithelium (Fig. 2). Lombaert discloses that the SMG involves interactions between mesenchymal and epithelial cells (Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Xiao and Lombaert for using TGFβ1 for cellular regeneration when preparing mammalian cell cultures for the organoid development of Sato and to substitute and/or add Lgr5+ intestinal stem cells with the IPEC-J2 cells of Xiao, in order to promote intestinal epithelial regeneration in the cultured organoid.
Regarding claims 3 – 4, Xiao discloses the use of IPEC-J2 cells and in IPEC-J2 cells, TGF-β1 signaling is mediated through its type II receptor (Tgfbr2).
Claims 10 – 11 are rejected under 35 U.S.C. 103 as being unpatentable over Sato, Xiao, and Lombaert as applied to claims 1 – 6, 8 – 9 and 14 above, and further in view of Wang et al. (Long-Term Culture Captures Injury-Repair Cycles of Colonic Stem Cells, Cell, 179, 1144 – 1159 (2019); cited on IDS, hereinafter Wang).
Regarding claim 10, Sato, Xiao, and Lombaert teach all of the elements of the current invention as stated above except wherein the epithelial regenerative cells comprise at least one of a Clusterin (Clu) and Stem cell antigen (Ly6a) biomarkers. However, Wang discloses in a study related to the long-term culture of colonic stem cells, that Ly6a is a biomarker of epithelial regenerative cells (p. 1150, col. 2, para. 1).
Regarding claim 11, Wang discloses/provides motivation for the concept of the spherical morphology of the organoid in instant claim 11 by utilizing mouse colonic spheroid lines (p. e4, Mouse colonic spheroid lines).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to recognize that Ly6a expression in the intestinal epithelial organoid of Sato, Xiao, and Lombaert would be a marker for regenerative epithelium, according to Wang. Also, it would have been obvious to use a spherical organoid to mimic “in vivo-like” conditions as Wang’s (motivation) system was designed to reenact the “homeostasis-injury-regeneration” cycle of epithelial alterations that occur in vivo.
Claims 12 – 13 are rejected under 35 U.S.C. 103 as being unpatentable over Sato, Xiao, and Lombaert as applied to claims 1 – 6, 8 – 9 and 14 above, and further in view of Magin et al. (U.S. Patent Application Publication No. 2020/0347359 A1; hereinafter Magin).
Regarding claim 12 – 13, Sato, Xiao, and Lombaert teach all of the elements of the current invention as stated above except a regenerative biomarker. However, Magin discloses that TGF-β is a soluble factor commonly used to induce profibrotic cellular activation in vitro. CTGF is considered to be a profibrotic gene (para. [0267]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the knowledge from Magin about the profibrotic gene induction capability of TGF-β in the intestinal epithelial organoid generation method of Sato, Xiao, and Lombaert. Doing so would reveal a difference in CTGF gene expression when comparing a TGF-β treated group to an untreated group. CTGF is a profibrotic gene that is induced with TGF-β treatment. Profibrotic genes help deposit extracellular matrix components like collagen, which stabilizes damaged tissue, restores structural integrity, and provides a scaffold for cell migration and regeneration.
Claims 7, 15, 29 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Sato, Xiao, and Lombaert as applied to claims 1 – 6, 8 – 9 and 14 above, and further in view of Germeroth (U.S. Patent Application Publication No. 2021/0284965 A1; hereinafter Germeroth).
Regarding claims 7, 15 and 33, Sato, Xiao, and Lombaert teach all of the elements of the current invention as stated above except engrafting the organoid into a subject. However, Germeroth discloses the non-immunogenic engineered tissue and methods of producing and using the same, in which mesenchymal stem cells (para. [0014]) are cultured in TGFβ1 (para. [0078]) in order to form the tissue. Germeroth further discloses the “robotic tissue” of the disclosed invention is an ideal candidate for graft versus host disease (para. [0048]). Geremeroth discloses (claim 42) a method of treating a disease condition, comprising administering to a subject in need thereof an effective amount of the engineered tissues.
Regarding claim 29, the pre-treated with TGFβ organoid would inherently have an increased number, size, or area of organoid colonies compared to the organoid that is not treated. It is well known that TGFβ signaling can promote organoid growth by enhancing stem cell pluripotency, stimulating proliferation, and inducing a regenerative state that supports tissue expansion.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the method of Germeroth and substitute in the mesenchymal stem cells for treating graft versus host disease with the tissue organoid of Sato, Xiao, and Lombaert.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Sato, Xiao, Lombaert, and Germeroth as applied to claims 7, 15, 29 and 33 above, and further in view of Hariri et al. (E.S. Patent Application Publication No. 2444548; hereinafter Hariri). The machine translation was used.
Regarding claim 32, Sato, Xiao, Lombaert, and Germeroth teach all of the elements of the current invention as stated above except a subject that was previously treated with chemotherapy or radiotherapy. Hariri discloses/provides the motivation by stating that TGFβ can induce the differentiation of stem or progenitor cells (“agent” p. 23, 3rd para.) and that embryonic-type stem cells can be administered to a patient to regenerate or restore tissues or organs that have been damaged as consequence of an illness, e.g., boost the immune system after chemotherapy or radiation (p. 28, middle of page “chemotherapy or radiation”).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the organoid generation method of Sato, Xiao, and Lombaert with the engraftment method of Germeroth in order to treat a subject after chemotherapy. Doing so could be vital to boosting the immune system after chemotherapy or radiation, according to Hariri.
Claims 34 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Sato, Xiao, Lombaert, and Germeroth as applied to claims 7, 15, 29 and 33 above, and further in view of Pezzella et al. (New Insights and Perspectives in Congenital Diarrheal Disorders, Curr Pediatr Rep 5:156 – 166 (2017); hereinafter Pezzella).
Regarding claims 34 and 36, Sato, Xiao, Lombaert, and Germeroth teach all of the elements of the current invention as stated above except the intestinal tissue damage being caused by a genetic disease or disorder. However, Pezzella discloses that SPINT2 encodes the transmembrane protein Kunitz-type 2 serine-protease inhibitor which is involved in epithelial regeneration, in the Nf-Kb and TGF-β signaling pathways. The inhibition of trypsin-family serine peptidases, which are encoded by SPINT2, abolishes the stimulation of apical Na+ transport by nonvoltage-gated sodium channel-1-alpha in polarized intestinal epithelial cells, which could contribute to secretory diarrhea (p. 161, Genotype section) and this is the possible mechanism for the syndromic form of congenital sodium diarrhea that is associated with SPINT2 mutations.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the “genetically corrected” organoid of Sato, Xiao, and Lombaert with the engraftment method of Germeroth in order to treat the congenital diarrhea of Pezzella. Doing so could potentially improve epithelial repair in certain congenital diarrhea models.
Conclusion
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/WALTER JACKSON III/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
