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
1. The amendment filed 12/10/2025 has been entered. Claims 1 and 3 – 29 remain pending.
Election/Restrictions
2. Applicant's election of Group I (claims 1 – 13) in the reply filed on 09/24/2024 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
3. Claims 14 – 29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
4. Claims 1 and 3 – 13 are under consideration.
Priority
5. This application claims priority to U.S. Patent Application No. 62/828384 filed on April 2, 2019 and to U.S. Patent Application No. 62/945290 filed on December 9, 2019.
Withdrawn Claim Rejections
6. The rejection of 1 and 3 – 9, 11-13 are rejected under 35 U.S.C. 112(a) is withdrawn in view of Applicant’s amendment to claim 1.
Maintained Claim Rejections
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.
7. Claim(s) 1, 5, 7, 8, and 10 – 12 remain rejected under 35 U.S.C. 103 as being unpatentable over Duijvestein (Duijvestein M, et. al. Gut 2010;59:1662-1669; previously cited), hereinafter Duijvestein as evidenced by Baumgart (Baumgart, D. C., et. al. The Lancet 380.9853 (2012): 1590-1605; previously cited), hereinafter Baumgart, Le Blanc (Le Blanc, K. et. al. Nature Reviews Immunology 12.5 (2012): 383-396; previously cited), hereinafter Le Blanc, Coutu (Coutu DL, et. al. J Biol Chem. 2008 Jun 27;283(26):17991-8001; previously cited), hereinafter Coutu, Rostovskaya (Rostovskaya M, et. al. PLoS One. 2012;7(12):e51221; previously cited) hereinafter Rostovskaya, and Majumdar (Majumdar, Manas K., et al. " Journal of cellular physiology 176.1 (1998): 57-66; previously cited), hereinafter Majumdar in view of Laukoetter (Laukoetter, Mike Georg, et al. Journal of Gastrointestinal Surgery 15.4 (2011): 576-583; previously cited), hereinafter Laukoetter in view of Babu (Suresh Babu, Sahana, et al. BMc cancer 14.1 (2014): 113; previously cited), hereinafter Babu in view of Torres (Torres, Sofia, et al. Clinical cancer research 19.21 (2013): 6006-6019; previously cited), hereinafter Torres in view of Kosaric (Kosaric, N. et. al. Plast. Reconstr. Surg. Glob. Open 5 (2017): 74; previously cited), hereinafter Kosaric. Although maintained, note that the rejection is revised in view of the amendment to claim 1.
Regarding claims 1 and 5, Duijvestein teaches administering autologous mesenchymal stromal cells (MSCs) from adult patients intravenously (“administering a composition comprising mesenchymal stromal cells into the T-cell producing tissue or fluid of the subject” and “autologous” of claim 1 and claim 5) to patients and thereby increasing regulatory T cells at week 6 compared to week 0 (Abstract; page 1662, left col. paragraph 3 – 4; page 1664, left col. paragraph 4; Figure 1; page 1666, right col. paragraph 1). Regarding “wherein the mesenchymal stromal cells express Periostin and Pdgfra” of claim 1, Duijvestein teaches MSCs were obtained from bone marrow (page 1663, left col. paragraph 4), and bone marrow MSCs express Periostin as evidenced by Coutu (page 17995, left col. paragraph 2; page 17998, left col. paragraph 3; page 18000, left col. paragraph 3) and Pdgfra as evidenced by Rostovskaya (Table 1; page 7, left col. paragraph 3; Figure 3B). Duijvestein does not teach the MSCs are genetically modified to not express CD248 and Cdh11 of claim 1.
Regarding claim 7, Duijvestein teaches the patients have Crohn’s disease, which is a T cell production disorder as evidenced by Baumgart (page 1594, right col. paragraph 1).
Regarding claim 8, Duijvestein teaches MSCs were obtained from bone marrow (page 1663, left col. paragraph 4), and bone marrow MSCs express Flt3 ligand and IL-15 as evidenced by Majumdar (page 17995, left col. paragraph 2; Figure 3).
Regarding claims 10 and 11, Duijvestein teaches the MSCs are autologous to the patient (page 1663, left col. paragraph 2). Duijvestein teaches MSCs were obtained from bone marrow (page 1663, left col. paragraph 4), which contains self-renewing progenitors as evidenced by Le Blanc (page 383, left col. paragraph 1) therefore meeting the limitations of claim 11.
Regarding claim 12, Duijvestein teaches MSCs were obtained from bone marrow (page 1663, left col. paragraph 4) and therefore it is inherent that MSCs would be derived from embryonic stem cells or progenitors thereof.
Duijvestein does not teach the MSCs are genetically modified to not express CD248 and Cdh11 of claim 1. However, Duijvestein teaches MSCs lowered CD4+ T cells and in general cytokine levels decreased in the mucosa indicating a decrease in intestinal inflammation (page 1666, right col. para. 1; page 1667, right col. para. 1). Duijvestein teaches MSCs have an immunosuppressive effects in in vitro and in experimental colitis (Abstract; page 1662, right col. last para.). Duijvestein teaches despite improvement in the management of inflammatory bowel diseases, remission often remains difficult to maintain and many patients suffer from a poor quality of life due to disease relapse, repeated surgeries, extra-intestinal manifestations and drug side-effects and therefore novel therapeutic approaches need to be explored (page 1662, left col. and right col. para. 1). Duijvestein teaches a concern in cell-based therapies with ex vivo expanded cells is the formation of tumors and previous work indicated that in mice, MSCs stimulate the growth of cancers and promote metastasis (page 1668, right col. last para.). Duijvestein teaches intravenous application of autologous bone marrow MSCs is feasible and well tolerated and produce clinical benefits in severe refractory Crohn’s disease and further studies should be designed to examine MSCs as a potential treatment for Crohn’s disease (page 1669, left col. paragraph 2).
Laukoetter teaches Crohn’s disease is a risk factor for colorectal cancer and small bowel carcinoma (page 579, right col. para. 1 – 2; page 580, left col. para. 7). Laukoetter teaches Crohn’s disease patients develop intestinal cancers about 20 years earlier than healthy individuals and are frequently present in advanced stages, are poorly differentiated, and have a poor prognosis (page 581, right col. para. 2). Laukoetter teaches the results are from studies where only very few patients received immunosuppressives and the effect of this therapy on cancer risk has to be analyzed as both an increase in cancer risk due to immunosuppression and a reduction due to better control of inflammation seem possible (page 581, right col. last para.).
Regarding MSCs that do not express CD248 of claim 1, Babu teaches that CD248 is associated with tumorigenesis and inflammation and increased expression is detected in stromal cells surrounding most tumors and high levels often correlate with a poor prognosis (page 5, right col. last para.; page 8, left col. para. 2). Babu teaches CD248 is expressed by MSCs (page 1, left col. last para.). Babu teaches CD248 is largely absent in normal tissues but is markedly upregulated in almost all cancers where highest expression is found in a subset of cancers that include colon cancers (page 1, right col. last para.). Babu does not teach “genetically modified” or “Cdh11” of claim 1.
Regarding MSCs that do not express Cdh11 of claim 1, Torres teaches expression of CDH11 is associated with poor survival in a colitis-associated colorectal cancer model (page 6007, left col. para. 2 and right col. para. 2 – 3; page 6015, left col. para. 3 – 4 and right col. para. 2; Figure 5D). Torres does not teach “genetically modified” of claim 1. One of ordinary skill in the art would be motivated to combine the teachings of Duijvestein regarding a method of increasing T cells in Crohn’s disease patients by administering mesenchymal stromal cells with the teachings of Laukoetter regarding Crohn’s disease patients are at risk for colorectal cancer and small bowel carcinoma with the teachings of Babu regarding CD248 is associated with tumorigenesis and inflammation and CD248 is highly expressed in colon cancers with the teachings of Torres regarding Cdh11 is expressed in colorectal cancer and is associated with poor survival to engineer MSCs to not express CD248 and Cdh11 for treatment of Crohn’s disease.
Regarding “genetically modified” of claim 1, Kosaric teaches genetically modifying human mesenchymal stromal cells using CRISPR/Cas9 (left col. para. 4, Purpose). Kosaric teaches MSCs are a promising source for cell therapy due to their proregenerative and immunomodulatory effects, which can be enhanced by engineering MSCs (left col. para. 4, Purpose). Kosaric teaches genetically modified MSCs enhanced wound healing suggesting MSCs can be engineered to increase their therapeutic potential (right col. para. 2).
It would have been obvious prior to the effective filing date of the invention as claimed for the person or ordinary skill in the art to combine the teachings of Duijvestein regarding a method of increasing T cells in Crohn’s disease patients by administering mesenchymal stromal cells with the teachings of Laukoetter regarding Crohn’s disease patients are at risk for colorectal cancer and small bowel carcinoma with the teachings of Babu regarding CD248 is associated with tumorigenesis and inflammation and CD248 is highly expressed in colon cancers with the teachings of Torres regarding Cdh11 is expressed in colorectal cancer and is associated with poor survival with the teachings of Kosaric regarding genetically modifying MSCs using CRISPR/Cas9 to arrive at the claimed method where mesenchymal stromal cells express Periostin and Pdgfra and are genetically modified to not express CD248 and Cdh11. One would have been motivated to combine the teachings of Duijvestein, Laukoetter, Babu, Torres, and Kosaric in a method to increase T cells in Crohn’s disease patients as Duijvestein teaches novel therapeutic approaches need to be explored and a concern in cell-based therapies with ex vivo expanded cells is the formation of tumors and previous work indicated that in mice, MSCs stimulate the growth of cancers and promote metastasis, and Laukoetter teaches Crohn’s disease is a risk factor for colorectal cancer and small bowel carcinoma, and Babu teaches CD248 is associated with tumorigenesis and Torres teaches Cdh11 is expressed in colorectal cancer and associated with poor survival. One would have a reasonable expectation of success in combining the teachings as Duijvestein teaches MSCs increased regulatory T cells in Crohn’s disease patients and Kosaric teaches MSCs can be genetically modified and this modification produces MSCs with desired therapeutic properties.
8. Claim(s) 3 and 4 remain rejected under 35 U.S.C. 103 as being unpatentable over Duijvestein (Duijvestein M, et. al. Gut 2010;59:1662-1669; previously cited), hereinafter Duijvestein as evidenced by Baumgart (Baumgart, D. C., et. al. The Lancet 380.9853 (2012): 1590-1605; previously cited), hereinafter Baumgart, Le Blanc (Le Blanc, K. et. al. Nature Reviews Immunology 12.5 (2012): 383-396; previously cited), hereinafter Le Blanc, Coutu (Coutu DL, et. al. J Biol Chem. 2008 Jun 27;283(26):17991-8001; previously cited), hereinafter Coutu, Rostovskaya (Rostovskaya M, et. al. PLoS One. 2012;7(12):e51221; previously cited) hereinafter Rostovskaya, and Majumdar (Majumdar, Manas K., et al. " Journal of cellular physiology 176.1 (1998): 57-66; previously cited), hereinafter Majumdar in view of Laukoetter (Laukoetter, Mike Georg, et al. Journal of Gastrointestinal Surgery 15.4 (2011): 576-583; previously cited), hereinafter Laukoetter in view of Babu (Suresh Babu, Sahana, et al. BMc cancer 14.1 (2014): 113; previously cited), hereinafter Babu in view of Torres (Torres, Sofia, et al. Clinical cancer research 19.21 (2013): 6006-6019; previously cited), hereinafter Torres in view of Kosaric (Kosaric, N. et. al. Plast. Reconstr. Surg. Glob. Open 5 (2017): 74; previously cited), hereinafter Kosaric as applied to claims 1, 5, 7, 8, and 10 – 12 above, and further in view of Manna (Manna S, et. al. Intrathymic Injection. Methods Mol Biol. 2016;1323:203-9; previously cited), hereinafter Manna as evidenced by Hsieh (Hsieh, CS., et. al. Nat Rev Immunol 12, 157–167 (2012); previously cited) hereinafter Hsieh in view of Xie (Xie, M., et al. Digestive diseases and sciences 62 (2017): 115-123; previously cited), hereinafter Xie.
Duijvestein in view of Laukoeeter, Babu, Torres, and Kosaric make obvious the limitations of claim 1 as set forth above. Duijvestein, Laukoeeter, Babu, Torres, and Kosaric do not teach thymus (claim 3) or lymphopoietic tissue (claim 4). However, Duijvestein teaches administering MSCs increases regulatory T cells (page 1664, left col. paragraph 4; Figure 1; page 1666, right col. paragraph 1). Duijvestein teaches MSCs from adipose tissue induced healing in Crohn’s disease patients (page 1663, left col. paragraph 1).
Manna teaches intrathymic injection (claim 3) is used in T cell-associated immunological studies to deliver cells directly into the thymus (Abstract). Manna teaches the thymus is the essential organ for differentiation and selection of immunocompetent T lymphocytes (“lymphopoietic tissue” of claim 4) (Abstract). Manna teaches two intrathymic injection procedures in a mouse (page 2 – 4).
Manna teaches intrathymic injection is used to study questions of cell transplantation and T cell development in mice (page 1, paragraph 2). Regulatory T cells are generated in the thymus as evidenced by Hsieh (page 157, left col. paragraph 2).
Xie teaches a mouse model of Crohn’s disease and administration of MSCs to determine their therapeutic effect (Abstract; page 117, left col. paragraph 3 – 4). Xie teaches administration of adipose-derived and bone marrow-derived MSCs and both significantly reduce the clinical activity of Crohn’s disease and increase survival (page 119, left col. paragraph 1; page 119, right col. paragraph 1; page 121, right col. paragraph 2; Figure 6). Xie teaches adipose derived- MSCs are emerging as a good alternative to bone marrow derived MSCs for cellular therapy because it is easier to obtain and can be collected with less injury (page 116, left col. para. 2; page 122, left col. paragraph 1). Xie teaches the pathogenesis of Crohn’s disease remains to be determined and its etiology remains unknown (page 115, right col. para. 2).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Duijvestein regarding a method of increasing T cells in Crohn’s disease patients by administering mesenchymal stromal cells with the teachings of Laukoetter regarding Crohn’s disease patients are at risk for colorectal cancer and small bowel carcinoma with the teachings of Babu regarding CD248 is associated with tumorigenesis and inflammation and CD248 is highly expressed in colon cancers with the teachings of Torres regarding Cdh11 is expressed in colorectal cancer and is associated with poor survival with the teachings of Kosaric regarding genetically modifying MSCs using CRISPR/Cas9 with the teachings of Manna regarding intrathymic injection is used to study questions of cell transplantation and T cell development in mice with the teachings of Xie regarding treating a mouse model of Crohn’s disease MSCs to arrive at the claimed method where MSCs expressing Periostin and Pdgfra and genetically modified to no express CD248 and Cdh11 are administered into the thymus. One would have been motivated to combine the teachings of Duijvestein, Laukoetter, Babu, Torres, Kosaric, Manna, and Xie to study the etiology of Crohn’s disease and if MSCs injected into the thymus increase regulatory T cells as Manna teaches intrathymic injection is used to study questions of T cell development in mice and Xie teaches the pathogenesis of Crohn’s disease remains to be determined and its etiology remains unknown. One would have a reasonable expectation of success in combining the teachings as Duijvestein teaches administering MSCs increases regulatory T cells and Xie teaches administration of MSCs significantly reduced the clinical activity of Crohn’s disease and increased survival.
9. Claim(s) 6 remains rejected under 35 U.S.C. 103 as being unpatentable over Duijvestein (Duijvestein M, et. al. Gut 2010;59:1662-1669; previously cited), hereinafter Duijvestein as evidenced by Baumgart (Baumgart, D. C., et. al. The Lancet 380.9853 (2012): 1590-1605; previously cited), hereinafter Baumgart, Le Blanc (Le Blanc, K. et. al. Nature Reviews Immunology 12.5 (2012): 383-396; previously cited), hereinafter Le Blanc, Coutu (Coutu DL, et. al. J Biol Chem. 2008 Jun 27;283(26):17991-8001; previously cited), hereinafter Coutu, Rostovskaya (Rostovskaya M, et. al. PLoS One. 2012;7(12):e51221; previously cited) hereinafter Rostovskaya, and Majumdar (Majumdar, Manas K., et al. " Journal of cellular physiology 176.1 (1998): 57-66; previously cited), hereinafter Majumdar in view of Laukoetter (Laukoetter, Mike Georg, et al. Journal of Gastrointestinal Surgery 15.4 (2011): 576-583; previously cited), hereinafter Laukoetter in view of Babu (Suresh Babu, Sahana, et al. BMc cancer 14.1 (2014): 113; previously cited), hereinafter Babu in view of Torres (Torres, Sofia, et al. Clinical cancer research 19.21 (2013): 6006-6019; previously cited), hereinafter Torres in view of Kosaric (Kosaric, N. et. al. Plast. Reconstr. Surg. Glob. Open 5 (2017): 74; previously cited), hereinafter Kosaric as applied to claims 1, 5, 7, 8, and 10 – 12 above, and further in view of Cassinotti (Cassinotti A, et. al. Gut. 2008 Feb;57(2):211-7; previously cited), hereinafter Cassinotti.
Duijvestein in view of Laukoeeter, Babu, Torres, and Kosaric make obvious the limitations of claim 1 as set forth above. Duijvestein, Laukoeeter, Babu, Torres, and Kosaric do not teach hematopoietic stem cell transplantation. However, Duijvestein teaches one patient (patient 10) in the study was in the mobilization phase of hematopoietic stem cell transplantation (Table 1) and patient 10 only experienced taste and smell of DMSO as an adverse event (Table 2; page 1665, right col. paragraph 1). Duijvestein teaches a trend of higher regulatory T cells at week 6 (page 1666, right col. paragraph 1). Duijvestein teaches systemic infusion of MSCs ameliorated the clinical and histopathological severity of experimental colitis and induced healing in patients with Crohn’s disease (page 1662, right col. paragraph 2; page 1663, left col. paragraph 1).
Cassinotti teaches hematopoietic stem cell transplantation (HSCT) in patients with Crohn’s disease (Abstract; page 212, left col. paragraph 1). Cassinotti teaches HSCT appears to be safe and can induce and maintain remission in previously refractory Crohn’s disease (Abstract).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Duijvestein regarding a method of increasing T cells in Crohn’s disease patients by administering mesenchymal stromal cells with the teachings of Laukoetter regarding Crohn’s disease patients are at risk for colorectal cancer and small bowel carcinoma with the teachings of Babu regarding CD248 is associated with tumorigenesis and inflammation and CD248 is highly expressed in colon cancers with the teachings of Torres regarding Cdh11 is expressed in colorectal cancer and is associated with poor survival with the teachings of Kosaric regarding genetically modifying MSCs using CRISPR/Cas9 with the teachings of Cassinotti regarding HSCT in patients with Crohn’s disease to arrive at the claimed method where a composition comprising MSCs derived from embryonic stem cells that express periostin and Pdgfra and are genetically modified to not express CD248 and Cdh11 are administered to a subject that has undergone HSCT. One would have been motivated to combine the teachings of Duijvestein, Laukoetter, Babu, Torres, Kosaric, and Cassinotti in a method to increase regulatory T cells in Crohn’s disease patients as Duijvestein teaches novel therapeutic approaches need to be explored and a concern in cell-based therapies with ex vivo expanded cells is the formation of tumors and previous work indicated that in mice, MSCs stimulate the growth of cancers and promote metastasis. One would have a reasonable expectation of success in combining the teachings as Duijvestein teaches a trend of higher regulatory T cells at week 6 of MSC treatment, Duijvestein teaches one patient (patient 10) in the study was in the mobilization phase of hematopoietic stem cell transplantation (Table 1) and patient 10 only experienced taste and smell of DMSO as an adverse event, and Cassinotti teaches HSCT appears to be safe and can induce and maintain remission in previously refractory Crohn’s disease.
10. Claim(s) 9 remains rejected under 35 U.S.C. 103 as being unpatentable over Duijvestein (Duijvestein M, et. al. Gut 2010;59:1662-1669; previously cited), hereinafter Duijvestein as evidenced by Baumgart (Baumgart, D. C., et. al. The Lancet 380.9853 (2012): 1590-1605; previously cited), hereinafter Baumgart, Le Blanc (Le Blanc, K. et. al. Nature Reviews Immunology 12.5 (2012): 383-396; previously cited), hereinafter Le Blanc, Coutu (Coutu DL, et. al. J Biol Chem. 2008 Jun 27;283(26):17991-8001; previously cited), hereinafter Coutu, Rostovskaya (Rostovskaya M, et. al. PLoS One. 2012;7(12):e51221; previously cited) hereinafter Rostovskaya, and Majumdar (Majumdar, Manas K., et al. " Journal of cellular physiology 176.1 (1998): 57-66; previously cited), hereinafter Majumdar in view of Laukoetter (Laukoetter, Mike Georg, et al. Journal of Gastrointestinal Surgery 15.4 (2011): 576-583; previously cited), hereinafter Laukoetter in view of Babu (Suresh Babu, Sahana, et al. BMc cancer 14.1 (2014): 113; previously cited), hereinafter Babu in view of Torres (Torres, Sofia, et al. Clinical cancer research 19.21 (2013): 6006-6019; previously cited), hereinafter Torres in view of Kosaric (Kosaric, N. et. al. Plast. Reconstr. Surg. Glob. Open 5 (2017): 74; previously cited), hereinafter Kosaric as applied to claims 1, 5, 7, 8, and 10 – 12 above, and further in view of Middel (Middel P, et. al. Gut. 2006 Feb;55(2):220-7; previously cited), hereinafter Middel.
Duijvestein in view of Laukoeeter, Babu, Torres, and Kosaric make obvious the limitations of claim 1 as set forth above. Duijvestein teaches MSCs were obtained from bone marrow (page 1663, left col. paragraph 4), and bone marrow MSCs express Flt3 ligand and IL-15 as evidenced by Majumdar (page 17995, left col. paragraph 2; Figure 3) (“Flt3 ligand and IL-15” of claim 9). Duijvestein, Laukoeeter, Babu, Torres, and Kosaric do not teach MSCs express Ccl19 (claim 9).
Middel teaches colonic tissue affected by Crohn’s disease was characterized by an increased number of mature myeloid dendritic cells (DCs) forming clusters with proliferating T cells (Abstract; page 220, right col. para. 2; page 223, left col. para. 2). Middel teaches increased expression of CCL19 by the DCs was observed in Crohn’s disease thereby causing the matured DC to be trapped at the site of inflammation (Abstract; page 220, right col. para. 2; page 223, left col. para. 2). Middel teaches CCL19 is a chemokine (page 220, left col.). Middle teaches that the significantly increased expression of CCL19 observed in Crohn’s disease tissue implies a chemokine microenvironment normally observed in lymph nodes and CCL19 may favor homing and interaction of CCR7 expressing cells within the bowel wall instead of within regional lymph nodes (page 226, right col. last para.; page 227, left col. para. 1). Thus, Middel teaches CCL19 expressing cells home to colonic tissue in Crohn’s disease.
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Duijvestein regarding a method of increasing T cells in Crohn’s disease patients by administering mesenchymal stromal cells with the teachings of Laukoetter regarding Crohn’s disease patients are at risk for colorectal cancer and small bowel carcinoma with the teachings of Babu regarding CD248 is associated with tumorigenesis and inflammation and CD248 is highly expressed in colon cancers with the teachings of Torres regarding Cdh11 is expressed in colorectal cancer and is associated with poor survival with the teachings of Kosaric regarding genetically modifying MSCs using CRISPR/Cas9 with the teachings of Middel regarding CCL19 expressing cells home to colonic tissue in Crohn’s disease to arrive at the claimed method where the mesenchymal stromal cells express CCL19, Flit3 ligand, and IL-15. One would have been motivated to combine the teachings of Duijvestein, Laukoetter, Babu, Torres, Kosaric, and Middel in a method of increasing T cells in Crohn’s disease patients as Duijvestein teaches novel therapeutic approaches need to be explored and a concern in cell-based therapies with ex vivo expanded cells is the formation of tumors and previous work indicated that in mice, MSCs stimulate the growth of cancers and promote metastasis. One would have a reasonable expectation of success in combining the teachings as Middel teaches CCL19 expressing cells may favor homing to the bowel wall in Crohn’s disease and Duijvestein teaches administering MSCs increases regulatory T cells.
11. Claim(s) 13 remains rejected under 35 U.S.C. 103 as being unpatentable over Duijvestein (Duijvestein M, et. al. Gut 2010;59:1662-1669; previously cited), hereinafter Duijvestein as evidenced by Baumgart (Baumgart, D. C., et. al. The Lancet 380.9853 (2012): 1590-1605; previously cited), hereinafter Baumgart, Le Blanc (Le Blanc, K. et. al. Nature Reviews Immunology 12.5 (2012): 383-396; previously cited), hereinafter Le Blanc, Coutu (Coutu DL, et. al. J Biol Chem. 2008 Jun 27;283(26):17991-8001; previously cited), hereinafter Coutu, Rostovskaya (Rostovskaya M, et. al. PLoS One. 2012;7(12):e51221; previously cited) hereinafter Rostovskaya, and Majumdar (Majumdar, Manas K., et al. " Journal of cellular physiology 176.1 (1998): 57-66; previously cited), hereinafter Majumdar in view of Laukoetter (Laukoetter, Mike Georg, et al. Journal of Gastrointestinal Surgery 15.4 (2011): 576-583; previously cited), hereinafter Laukoetter in view of Babu (Suresh Babu, Sahana, et al. BMc cancer 14.1 (2014): 113; previously cited), hereinafter Babu in view of Torres (Torres, Sofia, et al. Clinical cancer research 19.21 (2013): 6006-6019; previously cited), hereinafter Torres in view of Kosaric (Kosaric, N. et. al. Plast. Reconstr. Surg. Glob. Open 5 (2017): 74; previously cited), hereinafter Kosaric as applied to claims 1, 5, 7, 8, and 10 – 12 above, and further in view of Zhao (Zhao Q, et. al. Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):530-5; previously cited), hereinafter Zhao.
Duijvestein in view of Laukoeeter, Babu, Torres, and Kosaric make obvious the limitations of claim 1 as set forth above. Duijvestein, Laukoeeter, Babu, Torres, and Kosaric do not teach the MSCs are derived from iPS cells.
Zhao teaches bone marrow MSCs may promote cancer progression and have considerable donor variations and limited expandability which hinder the use of MSCs in therapeutic applications (Abstract). Zhao teaches derivation of MSCs from iPSCs (iPSC-MSCs) (Abstract; page 530, right col. paragraph 1). Zhao teaches iPSC-MSCs do not promote EMT, invasion, and stemness of cancer cells as is seen with bone marrow-derived MSCs (BM-MSCs) and iPSC-MSCs are a safe alternative to BM-MSCs (page 530, right col. paragraph 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Duijvestein regarding a method of increasing T cells in Crohn’s disease patients by administering mesenchymal stromal cells with the teachings of Laukoetter regarding Crohn’s disease patients are at risk for colorectal cancer and small bowel carcinoma with the teachings of Babu regarding CD248 is associated with tumorigenesis and inflammation and CD248 is highly expressed in colon cancers with the teachings of Torres regarding Cdh11 is expressed in colorectal cancer and is associated with poor survival with the teachings of Kosaric regarding genetically modifying MSCs using CRISPR/Cas9 with the teachings of Zhao regarding iPSC-derived MSCs to arrive at the claimed method where the mesenchymal stromal cells that express Periostin and Pdgfra and are genetically modified to not express CD248 and Cdh11 are derived from iPS cells. One would have been motivated to combine the teachings of Duijvestein, Laukoetter, Babu, Torres, Kosaric, and Zhao in a method of increasing T cells in a Crohn’s disease patient as Duijvestein teaches a concern in cell-based therapies with ex vivo expanded cells is the formation of tumors and that in mice, MSCs stimulate the growth of cancers and promote metastasis and Zhao teaches the benefits of iPSC-MSCs include that they do not promote EMT, invasion, and stemness of cancer cells as is seen with bone marrow-derived MSCs (BM-MSCs) and iPSC-MSCs are a safe alternative to BM-MSCs. One would have a reasonable expectation of success in combining the teachings Zhao teaches iPSC-MSCs are a safe alternative to BM-MSCs.
Applicant Arguments/ Response to Arguments
12. Applicant Argues: On page 7 – 10, Applicant asserts that the references fail to disclose or suggest a population of MSCs that express both periostin and PDGFRA and where the population of MSCs are genetically modified to not express CD248 and Cdh11 and provides no teaching or suggesting of genetically modifying a cell to knockdown expression of CD248 or CDH11.
Response to Argument: In response, claim 1 requires that the MSCs express Periostin and Pdgfra and be genetically modified to not express CD248 and Cdh11. Therefore, the claims read on any MSCs from any source that express any genes except CD248 and Cdh11 by genetic modification. Duijvestein teaches administering autologous mesenchymal stromal cells (MSCs) from adult patients intravenously to patients and thereby increasing regulatory T cells at week 6 compared to week 0 (Abstract; page 1662, left col. paragraph 3 – 4; page 1664, left col. paragraph 4; Figure 1; page 1666, right col. paragraph 1). Duijvestein teaches MSCs were obtained from bone marrow (page 1663, left col. paragraph 4), and bone marrow MSCs express Periostin as evidenced by Coutu (page 17995, left col. paragraph 2; page 17998, left col. paragraph 3; page 18000, left col. paragraph 3) and Pdgfra as evidenced by Rostovskaya (Table 1; page 7, left col. paragraph 3; Figure 3B). Thus, Duijvestein teaches administering bone marrow-derived MSCs that express periostin and Pdgfra to the blood of patients suffering from Crohn’s disease increase T cells. Duijvestein does not teach the MSCs have been genetically modified to not express CD248 and Cdh11 as required by claim 1. However, Duijvestein teaches a concern in cell-based therapies with ex vivo expanded cells is the formation of tumors and previous work indicated that in mice, MSCs stimulate the growth of cancers and promote metastasis (page 1668, right col. last para.). Laukoetter teaches Crohn’s disease is a risk factor for colorectal cancer and small bowel carcinoma (page 579, right col. para. 1 – 2; page 580, left col. para. 7). Babu teaches CD248 is expressed by MSCs (page 1, left col. last para.), CD248 is associated with tumorigenesis and inflammation and high levels often correlate with a poor prognosis (page 5, right col. last para.; page 8, left col. para. 2), and CD248 is markedly upregulated in almost all cancers where highest expression is found in a subset of cancers that include colon cancers (page 1, right col. last para.). Torres teaches expression of CDH11 is associated with poor survival in a colitis-associated colorectal cancer model (page 6007, left col. para. 2 and right col. para. 2 – 3; page 6015, left col. para. 3 – 4 and right col. para. 2; Figure 5D). Because Duijvestein teaches MSCs as a therapy for Crohn’s disease by increasing T cells but MSCs can stimulate the growth of cancers, and Laukoetter teaches Crohn’s disease is a risk for colorectal cancer and Babu teaches MSCs express CD248 and CD248 is highly expressed in colon cancers, and Torres teaches expression of CDH11 is associated with poor survival in colitis-associated colorectal cancer, one would be motivated to administer MSCs that do not express CD248 or CDH11 to Crohn’s disease patients to treat the disease but not contribute to tumorigenesis/support cancer growth because these patients are at a high risk for colorectal cancer that has high level expression of CD248 and CD248 is expressed by MSCs. While one of ordinary skill in the art would be aware of methods to genetically modify MSCs to not express desired genes and that MSCs are therapeutic for various diseases including Crohn’s disease (as taught by Duijvestein), Kosaric teaches genetically modifying human mesenchymal stromal cells using CRISPR/Cas9 (left col. para. 4, Purpose). Kosaric teaches MSCs are a promising source for cell therapy due to their proregenerative and immunomodulatory effects, which can be enhanced by engineering MSCs (left col. para. 4, Purpose). Therefore, one would have been motivated to combine the teachings of Duijvestein, Laukoetter, Babu, Torres, and Kosaric in a method to increase T cells in Crohn’s disease patients as Duijvestein teaches novel therapeutic approaches need to be explored and a concern in cell-based therapies with ex vivo expanded cells is the formation of tumors and previous work indicated that in mice, MSCs stimulate the growth of cancers and promote metastasis, and Laukoetter teaches Crohn’s disease is a risk factor for colorectal cancer and small bowel carcinoma, and Babu teaches CD248 is associated with tumorigenesis and Torres teaches Cdh11 is expressed in colorectal cancer and associated with poor survival. One would have a reasonable expectation of success in combining the teachings as Duijvestein teaches MSCs increased regulatory T cells in Crohn’s disease patients and Kosaric teaches MSCs can be genetically modified and this modification produces MSCs with desired therapeutic properties.
Should applicant amend the claims to recite that the MSCs are thymic MSCs and/or the MSCs express Ccl19 (and/or Flt3L and IL-15) and/or the T cells increased are CD8+ TCTL cells (Applicant’s specification at page 25, para. 00125; Example 4 and 5 at page 28 – 29), the prior art rejections may be overcome upon further search and consideration.
Conclusion
No claims allowed.
THIS ACTION IS MADE FINAL. 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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/Z.M.B./Examiner, Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632