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 .
Claim 1 is pending and under consideration.
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.
A) Claim(s) 1 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kundu (J Am Heart Assoc. 2017;6:e005146; IDS) in view of Juang (Transplantation Proceedings, 37, 3479–3481 (2005) ; IDS) and further in view of Marrotte (J Clin Invest. 2010;120(12):4207-4219; IDS).
Claim 1 is drawn to a method of treatment comprising transplanting an endothelial progenitor cells (EPC) under at least one kidney capsule of a subject in need thereof, wherein the EPC is genetically modified to have both i) transiently reduced p53 expression and ii) increased expression of at least one mitochondrial antioxidant.
Kundu teaches administering endothelial progenitor cells (EPCs) genetically modified with TP53-shRNA, which transiently reduces p53 expression, to diabetic (subject in need thereof) mice by injection in the hindlimb muscle around the femoral artery. Kundu teaches the use of the TP53-shRNA EPCs to treat ischemic tissue.
Kundu teaches that Type I diabetes mellitus was induced by injection of streptozotocin (STZ), which leads to symptoms of diabetic kidney disease. Kundu teaches that the transient silencing is generally around 28 days (page 9, col. 2). Kundu taught the transplanted cells led to upregulation of vascular markers such as VEGF (page 6) and eNOS.
Kundu taught intramuscular administration of the cells and did not teach transplanting them under the kidney capsule, as is required by claim 1. Kundu also fails to teach a second genetic modification to increase expression of at least one mitochondrial antioxidant.
With regard to modes of administration of cell in treating diabetes, Juang compared subcutaneous, intramuscular and kidney capsule transplantation. Juang found transplant of cells under the kidney capsule to be superior. Juang taught that sparsely vascularized sites may be associated with absent or poor integration of cells while highly vascular sites, such as the kidney capsule may allow for better functional results (page 3479, col. 1). Juang taught that while hyperbaric oxygen is beneficial for islet grafts under the kidney capsule, it does not aid in engraftment of cells administered IM or subcutaneously. Juang concludes that while vasculature in muscle is better than subcutaneous tissue, it was inadequate to support engraftment.
Neither Kundu nor Juang taught additionally genetically modifying the cells to have transiently increased expression of the mitochondrial antioxidant. However, Marotte taught transient adenoviral-driven MnSOD expression in diabetic EPCs accelerated wound healing in diabetic mice when compared to EPCs that did not overexpress MnSOD. Marrotte states, “It is well known that ROS production is an important mediator of hyperglycemia-mediated endothelial cell damage” (page 4213, col. 2).
It would have been obvious at the time of filing to modify the teachings of Kundu who taught IM administration of the CD34+ EPCs with reduced p53 expression to locally treat an area of infarct in diabetic mice by transplanting the cells under the kidney capsule as taught by Juang, to arrive at the invention as claimed. It would also have been obvious at the time of filing to combine the teachings of Kundu who taught transplant of CD34+ EPCs with reduced p53 expression to treat a STZ-induced diabetic model with the teachings of Marrotte who taught transgenic overexpression of MnSOD in EPCs to treat STZ-induced diabetic mice. One would have been motivated to make such a substitution of transplant site as Juang taught the kidney capsule as a better site for engraftment of cells due to increased vasculature as compared to muscle and to treat any loss of vasculature of the kidney that results from diabetes. One would have been motivated to increase the expression of MnSOD in the EPCs of Kundu as Marrotte taught that ROS production is an important mediator of hyperglycemia-mediated endothelial cell damage that occurs with diabetes. One would have had a reasonable expectation of success in carrying out the substitution because all of the requisite technology for introduction of cells under the kidney capsule and for overexpression of MnSOD was known and accessible to the skilled artisan at the time of filing.
B) Claim(s) 1 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kundu (J Am Heart Assoc. 2017;6:e005146; IDS) in view of WO2014165663 (‘663; IDS) and Song (ILAR Journal, Volume 51, Issue 1, 2010, Pages 74–81; IDS) and further in view of Marrotte (J Clin Invest. 2010;120(12):4207-4219; IDS).
Claim 1 is drawn to a method of treatment comprising transplanting an endothelial progenitor cells (EPC) under at least one kidney capsule of a subject in need thereof, wherein the EPC is genetically modified to have both i) transiently reduced p53 expression and ii) increased expression of at least one mitochondrial antioxidant.
Kundu teaches administering endothelial progenitor cells (EPCs) genetically modified with TP53-shRNA, which transiently reduces p53 expression, to diabetic (subject in need thereof) mice by injection in the hindlimb muscle around the femoral artery. Kundu teaches the use of the TP53-shRNA EPCs to treat ischemic tissue.
Kundu teaches that Type I diabetes mellitus was induced by injection of streptozotocin (STZ), which leads to symptoms of diabetic kidney disease. Kundu teaches that the transient silencing is generally around 28 days (page 9, col. 2). Kundu taught the transplanted cells led to upregulation of vascular markers such as VEGF (page 6) and eNOS.
Kundu taught intramuscular administration of the cells and did not teach transplanting them under the kidney capsule, as is required by claim 1. Kundu also fails to teach a second genetic modification to increase expression of at least one mitochondrial antioxidant.
With regard to modes of administration of cell in treating diabetes, ‘663 taught kidney capsule as a site transplantation of both beta cells and EPCs in the treatment of diabetes (see para 189-191). ‘663 references Song, who teaches “Sites for transplantation include the peritoneal cavity, the portal vein (which introduces islets into the low pressure hepatic perfusion system), and a hollow space created between the kidney capsule and the kidney parenchyma” (page 78, col. 2).
None of Kundu, ‘663 or Song taught additionally genetically modifying the cells to have transiently increased expression of the mitochondrial antioxidant. However, Marotte taught transient adenoviral-driven MnSOD (mitochondrial antioxidant) expression in diabetic EPCs accelerated wound healing in diabetic mice when compared to EPCs that did not overexpress MnSOD. Marrotte states, “It is well known that ROS production is an important mediator of hyperglycemia-mediated endothelial cell damage” (page 4213, col. 2).
It would have been obvious at the time of filing to modify the teachings of Kundu who taught IM administration of the CD34+ EPCs with reduced p53 expression to locally treat an area of infarct in diabetic mice by transplanting the cells under the kidney capsule as taught by ‘663 and Song, to arrive at the invention as claimed. It would also have been obvious at the time of filing to combine the teachings of Kundu who taught transplant of CD34+ EPCs with reduced p53 expression to treat a STZ-induced diabetic model with the teachings of Marrotte who taught transgenic overexpression of MnSOD in EPCs to treat STZ-induced diabetic mice. One would have been motivated to make such a substitution as ‘663 and Song taught the space under the kidney capsule is “…a confined, accessible area for transplantation while also permitting adequate blood and nutrient supply to the newly transplanted tissue” (page 78, col. 2). One would also be motivated to make the modification to treat any decreased vasculature of the kidney that results from diabetes. One would have been motivated to increase the expression of MnSOD in the EPCs of Kundu as Marrotte taught that ROS production is an important mediator of hyperglycemia-mediated endothelial cell damage that occurs with diabetes. One would have had a reasonable expectation of success in carrying out the substitution because all of the requisite technology for introduction of cells under the kidney capsule and for overexpression of MnSOD was known and accessible to the skilled artisan at the time of filing.
C) Claim(s) 1 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 10,016,458 (Sen; IDS) in view of Jiang (The FASEB Journal. 2021;35:e21198; IDS) and Juang (Transplantation Proceedings, 37, 3479–3481 (2005); IDS) further in view of Marrotte (J Clin Invest. 2010;120(12):4207-4219; IDS).
Claim 1 is drawn to a method of treatment comprising transplanting an endothelial progenitor cells (EPC) under at least one kidney capsule of a subject in need thereof, wherein the EPC is genetically modified to have both i) transiently reduced p53 expression and ii) increased expression of at least one mitochondrial antioxidant.
Claim 1 is drawn to a method of treatment comprising transplanting an endothelial progenitor cells (EPC) under at least one kidney capsule of a subject in need thereof, wherein the EPC is genetically modified to have both i) transiently reduced p53 expression and ii) increased expression of at least one mitochondrial antioxidant.
Sen teaches administering endothelial progenitor cells (EPCs) genetically modified with TP53-shRNA (see Col. 7, lines 10-20), which transiently reduces p53 expression, to diabetic (subject in need thereof) mice by injection in the hindlimb muscle around the femoral artery (Figure 10). Sen teaches the use of the TP53-shRNA EPCs to treat ischemic tissue. Sen teaches, “The methods of the invention are useful in treating ischemia and its effects in diabetic subjects by reducing peripheral vascular disease in such subjects or reducing the effects of peripheral vascular disease in such subjects.” (col. 2, lines 46-49). Sen taught the transplanted cells led to upregulation of vascular markers such as VEGFR2.
Sen taught intramuscular administration of the cells and did not teach transplanting them under the kidney capsule, as is required by claim 1. However, Sen does teach that the invention offers a therapeutic benefit of apoptosis resistant (TP53-shRNA) local delivery to improve circulation in peripheral vascular disease and diabetes. Sen does not point to the kidney as a tissue affected by diabetes and peripheral vascular disease. Sen also fails to teach a second genetic modification to increase expression of at least one mitochondrial antioxidant.
However, Jiang teaches that STZ-induced diabetes leads to diabetic kidney disease as a result of microvascular complication (see Introduction). Additionally, Juang compared subcutaneous, intramuscular and kidney capsule transplantation. Juang found transplant of cells under the kidney capsule to be superior. Juang taught that sparsely vascularized sites may be associated with absent or poor integration of cells while highly vascular sites, such as the kidney capsule may allow for better functional results (page 3479, col. 1). Juang taught that while hyperbaric oxygen is beneficial for islet grafts under the kidney capsule, it does not aid in engraftment of cells administered IM or subcutaneously. Juang concludes that while vasculature in muscle is better than subcutaneous tissue, it was inadequate to support engraftment.
None of Sen, Jiang or Juang taught additionally genetically modifying the cells to have transiently increased expression of a mitochondrial antioxidant. However, Sen did teach that diabetes can be characterized by the presence of reactive oxygen species. Additionally, Marotte taught transient adenoviral-driven MnSOD expression in diabetic EPCs accelerated wound healing in diabetic mice when compared to EPCs that did not overexpress MnSOD. Marrotte states, “It is well known that ROS production is an important mediator of hyperglycemia-mediated endothelial cell damage” (page 4213, col. 2).
It would have been obvious at the time of filing to combine the teachings of Sen, who taught transplant of CD34+ EPCs with reduced p53 expression to treat a STZ-induced diabetic model, with the teachings of Jiang and Juang, regarding diabetic effects on kidneys and superor effects of kidney capsule transplantation of EPCs, with the teachings of Marrotte who taught transgenic overexpression of MnSOD in EPCs to treat STZ-induced diabetic mice, to arrive at the invention as claimed. One would have been motivated to increase the expression of MnSOD in the EPCs of Sen as both Sen and Marrotte taught that ROS production is an important mediator of hyperglycemia-mediated endothelial cell damage that occurs with diabetes. One would have had a reasonable expectation of success in carrying out the combination because all of the requisite technology for overexpression of MnSOD and kidney capsule transplantation of EPCs was known and accessible to the skilled artisan at the time of filing.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claim(s) 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3,6,9-10 ,14-16 of U.S. Patent No. 10,016,458 in view of Jiang (The FASEB Journal. 2021;35:e21198) and Marrotte (J Clin Invest. 2010;120(12):4207-4219).
Claim 1 is drawn to a method of treatment comprising transplanting an endothelial progenitor cells (EPC) under at least one kidney capsule of a subject in need thereof, wherein the EPC is genetically modified to have both i) transiently reduced p53 expression and ii) increased expression of at least one mitochondrial antioxidant.
‘458 claims administering endothelial progenitor cells (EPCs) genetically modified with TP53-shRNA (claim 5; see Col. 7, lines 10-20), which transiently reduces p53 expression, to a subject with diabetes (claim 1). ‘458 claims the use of the TP53-shRNA EPCs to treat ischemic tissue.
‘458 and did not teach transplanting them under the kidney capsule, as is required by claim 1. However, ‘458 does teach that the invention offers a therapeutic benefit of apoptosis resistant (TP53-shRNA) local delivery to improve circulation in peripheral vascular disease and diabetes. ‘458 does not point to the kidney as an tissue affected by diabetes and peripheral vascular disease.
However, Jiang teaches that STZ-induced diabetes leads to diabetic kidney disease as a result of microvascular complication (see Introduction).
‘458 did not claim additionally genetically modifying the cells to have transiently increased expression of the mitochondrial antioxidant (instant claim 11) MnSOD (instant claim 12). However, Marotte taught transient adenoviral-driven MnSOD expression in diabetic EPCs accelerated wound healing in diabetic mice when compared to EPCs that did not overexpress MnSOD. Marrotte states, “It is well known that ROS production is an important mediator of hyperglycemia-mediated endothelial cell damage” (page 4213, col. 2).
It would have been obvious at the time of filing to alter the claims of ‘458 who taught local administration of the CD34+ EPCs with reduced p53 expression to locally treat an area in need of vascularization with the teachings of Jiang who teaches that the kidney is an organ affected by microvasculature complication in diabetes and Marotte who taught addition of the MnSOD gene to reduce oxidative stress. One would have been motivated to make such a combination as Jiang taught the kidney as a local area in need of increased vascularization. One would have had a reasonable expectation of success in carrying out the substitution because all of the requisite technology for introduction of cells under the kidney capsule was known and accessible to the skilled artisan at the time of filing.
Conclusion
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/ Primary Examiner, Art Unit 1632
