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 .
1. Claims 17, 20, 24 – 27, 29 – 34, 36 – 40, and 42 – 43 remain pending and are under examination.
New Claim Objection
2. Claim 17 is objected to because of the following informalities: claim 31 recites “the first and fourth steps” but claim 17 does not explicitly recite step 1, step 2, step 3, or step 4. Therefore, claim 17 should be amended to label each of the four steps recited in claim 31 for clarity.. Appropriate correction is required.
Withdrawn Claim Rejections
3. The rejections of claims 44 and 45 under 35 U.S.C. 112(b) is rendered moot in view of Applicant’s cancellation of these claims.
4. The rejection of claims 17, 20, 24 – 27, 29 – 34, 36 – 40, and 42 – 43 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendment to claim 17.
5. The rejection of claims 44 and 45 under 35 U.S.C. 103 is rendered moot in view of Applicant’s cancellation of these claims.
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.
6. Claim(s) 17, 29 – 34, 42, and 43 remain rejected under 35 U.S.C. 103 as being unpatentable over Kaths (Kaths, J. Moritz, et al. American Journal of Transplantation 17.10 (2017): 2580-2590; previously cited), hereinafter Kaths in view of Nilsson (Nilsson, B., et. al. Molecular Immunology (2017) ; previously cited, hereinafter Nilsson as evidenced by Ekdahl (Ekdahl KN, et. al. Immunobiology, Volume 221, Issue 10, 2016, Page 1184; previously cited), hereinafter Ekdahl which is cited in the IDS filed on 05/26/2021 in view of Miura (Miura S, et. al. Biomaterials. 2006 Dec;27(34):5828-35; previously cited), hereinafter Miura, which is cited on the IDS filed 05/26/2021.
Regarding “ex vivo infusing an organ preservation solution into a vascular system of the organ” and “wherein the organ preservation solution does not contain any unfunctionalized” PEG-phospholipid molecules of claim 17, Kaths teaches resection of a kidney, cannulating artery, vein, and ureter, and flushing with HTK solution (“into a vascular system of the organ”) (page 2581, right col. para. 3).
Kaths does not teach “ex vivo infusion a solution comprising from 0.25 mg/mL to 5 mg/mL unfunctionalized PEG-phospholipid molecules consisting of PEG-phospholipids into the vascular system of the organ” and “wherein unfunctionalized PEG-phospholipid molecules bind to at least a portion of the endothelial lining” of claim 17.
Regarding “ex vivo incubating” of claim 17, 29, 30, and 32 – 34, Kaths teaches submerging the kidney in 4°C HTK (“at a temperature above 0°C but below 8°C” of claim 17 and “a temperature above 0°C but below 6°C” of claim 29) in a sterile organ bag and placing the bag on ice (“a temperature above 0°C but below 4°C” of claim 30) for 8 hours (“from 10 minutes up to 48 hours” of claim 32; “from 20 minutes up to 36 hours” of claim 33; “from 30 minutes up to 24 hours” of claim 34) (page 2581, right col. para. 4). Kaths does not teach the solution comprises from 0.25 mg/mL to 5 mg/mL of PEG-phospholipid molecules.
Regarding “ex vivo infusion an organ preservation solution into the vascular system to flush away” of claim 17, Kaths teaches normothermic ex vivo kidney perfusion with a solution followed by flushing with HTK (page 2581, right col. last para.; Table 1; page 2582, left col. para. 1).
Regarding claim 31, Kaths teaches HTK solution (page 2581, right col. para. 3; page 2582, left col. para. 1).
Regarding claim 42 and 43, Kaths teaches kidney (page 2581, right col. para. 3). Kaths does not teach coating of claim 43.
Kaths does not teach “ex vivo infusion a solution comprising from 0.25 mg/mL to 5 mg/mL unfunctionalized PEG-phospholipid molecules consisting of PEG-phospholipids into the vascular system of the organ” or “wherein unfunctionalized PEG-phospholipid molecules bind to at least a portion of the endothelial lining” of claim 17 and 43 or the solution comprises from 0.25 mg/mL to 5 mg/mL of PEG-phospholipid molecules of claims 17, 29, 30, 32 – 34 and 43 or coating of claim 43. However, Kaths teaches kidney transplantation has become the standard of care for end-stage renal disease and to shorten the recipients’ waiting list, grafts of lower quality are increasingly used for transplantation (page 2580, right col.). Kaths teaches prolonged hypothermic preservation times induce nonphysiologic cold ischemia and result in increased rates of primary nonfunction, delayed graft function, and reduced long-term outcomes, especially in grafts of lower quality (page 2581, left col. para. 1; page 2584, right col. para. 2). Kaths teaches normothermic machine perfusion (NMP) can be performed following static cold storage shortly prior to transplantation and NMP in kidney transplantation most likely will include hypothermic transportation periods (page 2581, left col. para. 2 – 3). Kaths teaches following hypothermic storage, normothermic ex vivo kidney perfusion (NEVKP) improved postoperative kidney function after transplantation (page 2582, left col. para. 2; Figure 1; page 2584, left col. para. 1 and right col. para. 1). Kaths teaches hypothermic storage, either statically or perfused, is the current standard of care in renal graft preservation (page 2584, right col. para. 2). Kaths teaches that because the model was autotransplantation rather than allotransplantation, the study excludes alloimmune responses and graft rejection (page 2587, right col.).
Regarding “ex vivo infusion a solution comprising from 0.25 mg/mL to 5 mg/mL unfunctionalized PEG-phospholipid molecules consisting of PEG-phospholipids into the vascular system of the organ” of claim 17 and 43 or “wherein unfunctionalized PEG-phospholipid molecules bind to at least a portion of the endothelial lining” of claim 17 or the solution comprises from 0.25 mg/mL to 5 mg/mL of PEG-phospholipid molecules of claims 17, 29, 30, 32 – 34 and 43 and “coating” of claim 43, Nilsson teaches a method of storing kidneys in HTK solution at 4°C, followed by treating the kidneys with PEG-lipid before transplantation, followed by washout and transplantation (left col. last para.). Nilsson teaches the method was to explore replacement of the glycocalyx (“wherein unfunctionalized PEG-phospholipid molecules bind to at least a portion of the endothelial lining” of claim 17) after ischemia with unconjugated PEG-linker (interpreted as PEG-lipid where the PEG portion is unfunctionalized because it is the PEG-lipid that Nilsson teaches regulators of complement are conjugated to at left col. para. 3 and the PEG portion can be functionalized with various ligands as evidenced by Ekdahl, left col. para. 3 – 4) (“unfunctionalized PEG-phospholipid molecules”) (left col. para. 3). Nilsson teaches that thromboinflammation resulting from porcine aortic endothelial cells coming into contact with human blood can be attenuated by PEG-lipid molecules to which regulators of complement and platelets were conjugated where the PEG-lipid spontaneously inserts into a cell membrane (left col. para. 3). Nilsson does not teach the concentration of the PEG-phospholipid. However, Nilsson teaches the coating technique (“coating” of claim 43) with PEG-lipid coatings is very successful in lowering the innate immune response during allogeneic transplantation in large animal models (right col. para. 2). One would have been motivated to combine the teachings of Kaths and Nilsson in a method of kidney preservation for allotransplantation where following kidney resection and flushing with HTK in the vascular system of Kaths, a PEG-phospholipid solution of Nilsson is infused into the vascular system of the kidney followed by incubating the kidney in a solution comprising the PEG-phospholipid of Nilsson because Nilsson teaches the coating technique with PEG-lipid coatings is very successful in lowering the innate immune response during allogeneic transplantation in large animal models and because Kaths’ model is for autotransplantation and not allotransplantation and Kaths teaches kidney transplantation has become the standard of care for end-stage renal disease and will most likely include hypothermic transportation periods and Kaths teaches hypothermic storage, either statically or perfused, is the current standard of care in renal graft preservation.
Regarding “a solution comprising from 0.25 mg/mL to 5 mg/mL unfunctionalized PEG-phospholipid molecules” of claims 17, 29, 30, 32 – 34, and 43, Miura teaches PEG-phospholipids spontaneously incorporated into the surface of human embryonic kidney cells after adding the PEG-lipids at 1, 10, 100, or 1000 µM followed by incubation (page 5829, left col. para. 3 and right col. para. 1 – 2; page 5830, left col. para. 1; Scheme 1; Figure 1). Given that Miura teaches PEG 5000 and DPPE in the synthesis of the PEG-lipid shown in Scheme 1a (page 5829, left col. para. 1 – 2; page 5829, right col. last para.; page 5830, left col. para. 1), 100 µM PEG-lipid meets the limitation of “from 0.25 mg/mL to 5 mg/mL”. Miura teaches the encapsulation of living cells with semi-permeable membranes has been studied as a safe and simple technique for cell transplantation without the need for immunosuppressive therapy (page 5828, left col.). Miura teaches PEG-lipids have been widely used for the surface modification of liposomes to improve biocompatibility and prolong the circulation time in vivo (page 5828, right col. para. 2). Miura teaches PEG-lipid modification did not exert toxicity on living cells (page 5831, right col. last para.; page 5832, left col. para. 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 Kaths regarding a method of kidney preservation comprising resection of a kidney, cannulating artery, vein, and ureter, and flushing with HTK solution, followed by submerging the kidney in 4°C HTK in a sterile organ bag and placing the bag on ice, followed by normothermic ex vivo kidney perfusion with a solution followed by flushing with HTK prior to transplantation with the teachings of Nilsson regarding a method of reducing ischemic reperfusion injury in kidney transplantation comprising storing kidneys in HTK solution at 4°C, followed by treating the kidneys with unfunctionalized PEG-lipid molecules before transplantation, followed by washout and transplantation with the teachings of Miura regarding PEG-phospholipids spontaneously incorporated into the surface of human embryonic kidney cells after adding the PEG-lipids at 1, 10, 100, or 1000 µM followed by incubation to arrive at the claimed method comprising ex vivo infusing an organ preservation solution into a vascular system of the organ or the part of the organ, wherein the organ preservation solution does not contain any unfunctionalized poly(ethylene glycol)-phospholipid (PEG-phospholipid) molecules; ex vivo infusing a solution comprising from 0.25 mg/mL to 5 mg/mL unfunctionalized PEG-phospholipid molecules consisting of PEG-phospholipids into the a vascular system of the organ or the part of the organ; and ex vivo incubating the solution comprising from 0.25 mg/mL to 5 mg/mL unfunctionalized PEG-phospholipid molecules in the vascular system to enable coating of at least a portion of the endothelial lining of the vascular system with the unfunctionalized PEG-phospholipid molecules, wherein unfunctionalized PEG-phospholipid molecules bind to at least a portion of the endothelial lining, while keeping the organ or the part of the organ submerged in an organ preservation solution comprising from 0.25 mg/mL to 5 mg/mL unfunctionalized PEG-phospholipid molecules and at a temperature above 0°C but below 8°C; and ex vivo infusing an organ preservation solution into the vascular system to flush away non-bound unfunctionalized PEG-phospholipid molecules from the vascular system. One would have been motivated to combine the teachings of Kaths, Nilsson, and Miura in a method of kidney preservation for transplantation as Kaths teaches kidney transplantation has become the standard of care for end-stage renal disease and to shorten the recipients’ waiting list, grafts of lower quality are increasingly used for transplantation and Kaths teaches hypothermic storage, either statically or perfused, is the current standard of care in renal graft preservation and Miura teaches the encapsulation of living cells with semi-permeable membranes has been studied as a safe and simple technique for cell transplantation without the need for immunosuppressive therapy. One would have a reasonable expectation of success in combining the teachings as Nilsson teaches the coating technique with PEG-lipid coatings is very successful in lowering the innate immune response during allogeneic transplantation in large animal models and Miura teaches PEG-lipid modification did not exert toxicity on living cells.
7. Claim(s) 20 remains rejected under 35 U.S.C. 103 as being unpatentable over Kaths (Kaths, J. Moritz, et al. American Journal of Transplantation 17.10 (2017): 2580-2590; previously cited), hereinafter Kaths in view of Nilsson (Nilsson, B., et. al. Molecular Immunology (2017) ; previously cited), hereinafter Nilsson as evidenced by Ekdahl (Ekdahl KN, et. al. Immunobiology, Volume 221, Issue 10, 2016, Page 1184; previously cited), hereinafter Ekdahl which is cited in the IDS filed on 05/26/2021 in view of Miura (Miura S, et. al. Biomaterials. 2006 Dec;27(34):5828-35; previously cited), hereinafter Miura, which is cited on the IDS filed 05/26/2021 as applied to claims 17, 29 – 34, 42, and 43 above, and further in view of Kaths-2015 (Kaths JM, et. al. J Vis Exp. 2015 Jul 15;(101):e52909; previously cited), hereinafter Kaths-2015.
Kaths in view of Nilsson and Miura make obvious the limitations of claim 17 as set forth above. Kaths, Nilsson, and Miura do not teach ex vivo infusing comprises ex vivo clamping one of an artery and a vein, ex vivo infusing, and ex vivo clamping the other of the artery and the vein. However, Kaths teaches ex vivo infusion of HTK into the kidney and submerging the kidney in HTK solution (page 2581, right col. para. 3) and Nilsson teaches treating the kidney with PEG-lipid for coating where the glycocalyx is coated with PEG-lipid (left col. para. 3 – 4 and right col. para. 2).
Kaths-2015 teaches a method comprising steps of: cannulate the aorta with an organ flush line and tie the ligatures at the aorta and left renal artery ex vivo (“vein” of “ex vivo clamping one of an artery and a vein of the vascular system”); flush the kidney with HTK solution (“artery” of “ex vivo infusing” and “into the other of the artery and the vein”); clamp the thoracic cava; close the cranial part of the aorta with a tie and cannulate (“artery” of “ex vivo clamping the other of the artery and the vein”); cannulate the renal vein, and place the kidney on ice (page 3, steps 7 – 9 of “Surgical Procedure”; page 3, steps 1 – 3 of “Back Table Preparation of the Kidney Graft for the Perfusion”). Kaths-2015 teaches for patients suffering from end-stage renal disease, kidney transplantation offers better life expectancy and improved quality of life when compared to dialysis (page 1, paragraph 1 of “Introduction”). Kaths-2015 teaches the persisting organ shortage represents a severe problem in the field of transplant medicine and the median wait time for a deceased donor kidney transplant is up to 5 years (page 1, paragraph 1 of “Introduction”; Table 1). Kaths-2015 teaches the outcome of kidney transplantation is negatively affected by the waiting time which has triggered interest in marginal kidney grafts as an additional donor source (page 1, last paragraph). Kaths-2015 teaches cold anoxic kidney preservation is associated with ongoing graft injury and does not allow graft assessment because of the lack of metabolism and urine production where marginal kidney grafts tolerate cold storage poorly resulting in significant kidney injury and high rates of delayed graft function (page 2, paragraph 2). Kaths-2015 teaches ex vivo kidney perfusion represents an alternative method for the preservation, assessment, and repair of organs (page 2, paragraph 3). Kaths-2015 teaches during ex vivo perfusion the kidneys demonstrated stable perfusion parameters, active renal metabolism, homeostasis, and minimal renal injury (page 12, 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 Kaths regarding a method of kidney preservation comprising resection of a kidney, cannulating artery, vein, and ureter, and flushing with HTK solution, followed by submerging the kidney in 4°C HTK in a sterile organ bag and placing the bag on ice, followed by normothermic ex vivo kidney perfusion with a solution followed by flushing with HTK prior to transplantation with the teachings of Nilsson regarding a method of reducing ischemic reperfusion injury in kidney transplantation comprising storing kidneys in HTK solution at 4°C, followed by treating the kidneys with unfunctionalized PEG-lipid molecules before transplantation, followed by washout and transplantation with the teachings of Miura regarding PEG-phospholipids spontaneously incorporated into the surface of human embryonic kidney cells after adding the PEG-lipids at 1, 10, 100, or 1000 µM followed by incubation with the teachings of Kaths-2015 regarding surgical procedures and preparation of a kidney graft for perfusion to arrive at the claimed method comprising ex vivo clamping the renal vein of a kidney graft; ex vivo infusing a solution comprising unfunctionalized PEG-phospholipids into the vascular system of a kidney through the aorta; and ex vivo clamping the aorta. One would have been motivated to combine the teachings of Kaths, Nilsson, Miura, and Kaths-2015 to develop a kidney preservation method for marginal kidneys to increase the number of donor kidneys for transplantation as Kaths-2015 teaches there is interest in marginal kidney grafts as an additional donor source but marginal kidney grafts tolerate cold storage poorly resulting in significant kidney injury and high rates of delayed graft function. One would have a reasonable expectation of success in combining the teachings as Kaths-2015 teaches during ex vivo perfusion the kidneys demonstrated stable perfusion parameters, active renal metabolism, homeostasis, and minimal renal injury.
8. Claim(s) 24 remains rejected under 35 U.S.C. 103 as being unpatentable over Kaths (Kaths, J. Moritz, et al. American Journal of Transplantation 17.10 (2017): 2580-2590; previously cited) hereinafter Kaths in view of Nilsson (Nilsson, B., et. al. Molecular Immunology (2017) ; previously cited), hereinafter Nilsson as evidenced by Ekdahl (Ekdahl KN, et. al. Immunobiology, Volume 221, Issue 10, 2016, Page 1184; previously cited), hereinafter Ekdahl which is cited in the IDS filed on 05/26/2021 in view of Miura (Miura S, et. al. Biomaterials. 2006 Dec;27(34):5828-35; previously cited), hereinafter Miura, which is cited on the IDS filed 05/26/2021 as applied to claims 17, 29 – 34, 42, and 43 above, and further in view of Teramura (2011) (Teramura Y, et. al. Transplantation. 2011 Feb 15;91(3):271-8; previously cited), hereinafter Teramura (2011) which is cited on the IDS filed 05/26/2021.
Kaths in view of Nilsson and Miura make obvious the limitations of claim 17 as set forth above. Miura teaches PEG-phospholipids spontaneously incorporated into the surface of human embryonic kidney cells after adding the PEG-lipids at 1, 10, 100, or 1000 µM followed by incubation (page 5829, left col. para. 3 and right col. para. 1 – 2; page 5830, left col. para. 1; Scheme 1; Figure 1). Given that Miura teaches PEG 5000 and DPPE in the synthesis of the PEG-lipid shown in Scheme 1a (page 5829, left col. para. 1 – 2; page 5829, right col. last para.; page 5830, left col. para. 1), 100 µM PEG-lipid would correspond to about 0.5 – 0.6 mg/mL and 1000 µM PEG-lipid would correspond to about 5 – 6 mg/mL. Miura does not teach 2 mg/mL.
Teramura (2011) teaches surface modification of islets using 2 mg/mL of a PEG-lipid solution followed by transplantation into mice (page 277, left col. paragraph 6). Teramura (2011) teaches the hydrophobic lipid portion of the PEG-lipid was spontaneously incorporated into the lipid bilayer of the cells of the islets (Figure 1 legend). Teramura (2011) teaches PEG-lipid can be easily immobilized onto cells through hydrophobic interaction (page 277, left col. paragraph 3). Teramura (2011) teaches less ischemic areas were observed after transplantation with PEG-lipid modified cells compared to native cells (page 273, left col. last paragraph; page 275, left col. last paragraph; page 276, right col. paragraph 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 Kaths regarding a method of kidney preservation comprising resection of a kidney, cannulating artery, vein, and ureter, and flushing with HTK solution, followed by submerging the kidney in 4°C HTK in a sterile organ bag and placing the bag on ice, followed by normothermic ex vivo kidney perfusion with a solution followed by flushing with HTK prior to transplantation with the teachings of Nilsson regarding a method of reducing ischemic reperfusion injury in kidney transplantation comprising storing kidneys in HTK solution at 4°C, followed by treating the kidneys with unfunctionalized PEG-lipid molecules before transplantation, followed by washout and transplantation with the teachings of Miura regarding PEG-phospholipids spontaneously incorporated into the surface of human embryonic kidney cells after adding the PEG-lipids at 1, 10, 100, or 1000 µM followed by incubation with the teachings of Teramura (2011) regarding 2 mg/mL PEG-lipids spontaneously insert into the cell membrane to arrive at the claimed method comprising ex vivo infusing a solution comprising 2 mg/mL of unfunctionalized PEG-phospholipids into the vascular system of a kidney. One would have been motivated to combine the teachings of Kaths, Nilsson, Miura and Teramura (2011) in a method of kidney preservation for transplantation as Kaths teaches prolonged hypothermic preservation times induce nonphysiologic cold ischemia and result in increased rates of primary nonfunction, delayed graft function, and reduced long-term outcomes, especially in grafts of lower quality and Kaths teaches hypothermic storage, either statically or perfused, is the current standard of care in renal graft preservation and Teramura (2011) teaches PEG-lipid can be easily immobilized onto cells through hydrophobic interaction. One would have a reasonable expectation of success in combining the teachings as Nilsson teaches the coating technique with PEG-lipid coatings is very successful in lowering the innate immune response during allogeneic transplantation in large animal models and Miura teaches PEG-lipid modification did not exert toxicity on living cells and. Teramura (2011) teaches less ischemic areas were observed after transplantation with PEG-lipid modified cells compared to native cells.
9. Claim(s) 25 – 27 remain rejected under 35 U.S.C. 103 as being unpatentable over Kaths (Kaths, J. Moritz, et al. American Journal of Transplantation 17.10 (2017): 2580-2590; previously cited), hereinafter Kaths in view of Nilsson (Nilsson, B., et. al. Molecular Immunology (2017) ; previously cited), hereinafter Nilsson as evidenced by Ekdahl (Ekdahl KN, et. al. Immunobiology, Volume 221, Issue 10, 2016, Page 1184; previously cited), hereinafter Ekdahl which is cited in the IDS filed on 05/26/2021 in view of Miura (Miura S, et. al. Biomaterials. 2006 Dec;27(34):5828-35; previously cited), hereinafter Miura, which is cited on the IDS filed 05/26/2021 as applied to claims 17, 29 – 34, 42, and 43 above, and further in view of Maathuis (Maathuis, Mark-Hugo J., et al. Annals of surgery 246.6 (2007): 982-991; previously cited), hereinafter Maathuis in view of Effros (Effros, Richard M., et al. Circulation research 20.2 (1967): 162-173; previously cited), hereinafter Effros.
Kaths in view of Nilsson and Miura make obvious the limitations of claim 17 as set forth above. Kaths teaches flushing the kidney with 300 – 500 mL of HTK solution (page 2581, right col. para. 3; page 2582, left col. para. 1) but does not teach “from 5 mL up to 250 mL” of claim 25 or “from 5 mL up to 100 mL” of claim 26, or “from 5 mL up to 50 mL” of claim 27.
Regarding claim 25, Maathuis teaches after procurement, pig kidneys were flushed with 250 mL of perfusion solution and autotransplanted (page 983, left col. paragraph 5 and last paragraph). Maathuis teaches ex vivo perfusion improved posttransplantation viability (page 987, right col. paragraph 2; Abstract). Maathuis teaches the increasing proportion of marginal and nonheart beating donors necessitates better preservation methods to maintain adequate graft viability (Abstract). Maathuis does not teach “from 5 mL up to 100 mL” of claim 26 or “from 5 mL up to 50 mL” of claim 27.
Regarding claims 26 and 27, Effros teaches average renal blood volume of 34.8 ± 3.1 mL for one normal kidney of man (Abstract; page 162, right col. paragraph 1). Effros teaches differences in renal volumes in individual subjects may indicate real differences in compartment size or may result for alterations in tissue perfusion or exchange (page 172, left 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 Kaths regarding a method of kidney preservation comprising resection of a kidney, cannulating artery, vein, and ureter, and flushing with HTK solution, followed by submerging the kidney in 4°C HTK in a sterile organ bag and placing the bag on ice, followed by normothermic ex vivo kidney perfusion with a solution followed by flushing with HTK prior to transplantation with the teachings of Nilsson regarding a method of reducing ischemic reperfusion injury in kidney transplantation comprising storing kidneys in HTK solution at 4°C, followed by treating the kidneys with unfunctionalized PEG-lipid molecules before transplantation, followed by washout and transplantation with the teachings of Miura regarding PEG-phospholipids spontaneously incorporated into the surface of human embryonic kidney cells after adding the PEG-lipids at 1, 10, 100, or 1000 µM followed by incubation with the teachings of Maathuis regarding ex vivo perfusing 250 mL perfusate with the teachings of Effros regarding the average blood volume of a normal kidney is 34.8 ± 3.1 mL to arrive at the claimed method where 40 mL of solution comprising 0.25 mg/mL to 5 mg/mL of unfunctionalized PEG-phospholipid is infused into the vascular system of the kidney ex vivo. One would have been motivated to combine the teachings of Kaths, Nilsson, Miura, Maathuis, and Effros in a method of kidney preservation for kidney transplantation as Kaths teaches hypothermic storage, either statically or perfused, is the current standard of care in renal graft preservation and Maathuis teaches the increasing proportion of marginal and nonheart beating donors necessitates better preservation methods to maintain adequate graft viability. One would have a reasonable expectation of success in combining the teachings as Nilsson teaches the coating technique with PEG-lipid coatings is very successful in lowering the innate immune response during allogeneic transplantation in large animal models and Miura teaches PEG-lipid modification did not exert toxicity on living cells and Maathuis teaches ex vivo perfusion improved posttransplantation viability.
10. Claim(s) 36 – 40 remain rejected under 35 U.S.C. 103 as being unpatentable over Kaths (Kaths, J. Moritz, et al. American Journal of Transplantation 17.10 (2017): 2580-2590; previously cited), hereinafter Kaths in view of Nilsson (Nilsson, B., et. al. Molecular Immunology (2017) ; previously cited), hereinafter Nilsson as evidenced by Ekdahl (Ekdahl KN, et. al. Immunobiology, Volume 221, Issue 10, 2016, Page 1184; previously cited), hereinafter Ekdahl which is cited in the IDS filed on 05/26/2021 in view of Miura (Miura S, et. al. Biomaterials. 2006 Dec;27(34):5828-35; previously cited), hereinafter Miura, which is cited on the IDS filed 05/26/2021 as applied to claims 17, 29 – 34, 42, and 43 above, and further in view of Nilsson-2012 (Nilsson, Per H., et al. Biomaterials 34.4 (2013): 985-994; previously cited), hereinafter Nilsson-2012, which is cited on the IDS filed 05/26/2021 as evidenced by Teramura-2007 (Teramura Y, et. al. Biomaterials. 2007 Nov;28(32):4818-25; previously cited), hereinafter Teramura-2007, which is cited on the IDS filed 05/26/2021.
Kaths in view of Nilsson and Miura make obvious the limitations of claim 17 as set forth above. Nilsson teaches the method was to explore replacement of the glycocalyx after ischemia with unconjugated PEG-linker (interpreted as PEG-lipid where the PEG portion is unfunctionalized because it is the PEG-lipid that Nilsson teaches apyrase is conjugated to at left col. para. 3 and the PEG portion can be functionalized with various ligands as evidenced by Ekdahl, left col. para. 3 – 4) (left col. para. 3).
Regarding claim 36 – 40, Miura teaches a PEG-phospholipid where n and m are 14 (claims 36 – 38) and p is selected so that the PEG chain has an average molecular weight of 5000 Da (claims 36 and 39 – 40) (Scheme 1(a)); page 5829, left col. para. 2 – 3). While Miura teaches phospholipid structure of formula I of claim 36, Miura does not teach portion of formulas I or II connected to the carbonyl carbon in the PEG portion of the structures.
Regarding the PEG portion of formula I in claim 36, Nilsson-2012 teaches the structure of a PEG-lipid derivative in Figure 1c where m and n of claim 36 are 14 and p of claim 36 is selected so that the PEG chain has an average molecular weight of 5000 Da (page 987, right col. para. 2) as evidenced by Teramura-2007 (Abstract; page 4819, left col. last para and right col. para. 3). Nilsson-2012 teaches the PEG-lipid can be immobilized to cell membranes by hydrophobic interactions with the lipid bilayer membranes without cytotoxicity (page 986, left col. para. 3). Nilsson-2012 teaches preparation of methoxy-PEG conjugated phospholipid, Mal-PEG-conjugated phospholipid, and biotin-PEG-conjugated phospholipid were synthesized as described by Teraumra-2007 (page 987, 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 Kaths regarding a method of kidney preservation comprising resection of a kidney, cannulating artery, vein, and ureter, and flushing with HTK solution, followed by submerging the kidney in 4°C HTK in a sterile organ bag and placing the bag on ice, followed by normothermic ex vivo kidney perfusion with a solution followed by flushing with HTK prior to transplantation with the teachings of Nilsson regarding a method of reducing ischemic reperfusion injury in kidney transplantation comprising storing kidneys in HTK solution at 4°C, followed by treating the kidneys with unfunctionalized PEG-lipid molecules before transplantation, followed by washout and transplantation with the teachings of Miura regarding PEG-phospholipids spontaneously incorporated into the surface of human embryonic kidney cells after adding the PEG-lipids at 1, 10, 100, or 1000 µM followed by incubation with the teachings of Nilsson-2012 regarding the synthesis of PEG-phospholipids to arrive at the claimed method where the unfunctionalized PEG-phospholipid molecules have formula I or II. One would have been motivated to combine the teachings of Kaths, Nilsson, Miura, and Nilsson-2012 in a method of kidney preservation and transplantation that prevents innate immune response as Kaths teaches prolonged hypothermic preservation times induce nonphysiologic cold ischemia and result in increased rates of primary nonfunction, delayed graft function, and reduced long-term outcomes, especially in grafts of lower quality and Kaths teaches hypothermic storage, either statically or perfused, is the current standard of care in renal graft preservation. One would have a reasonable expectation of success in combining the teachings as Nilsson teaches the coating technique with PEG-lipid coatings is very successful in lowering the innate immune response during allogeneic transplantation in large animal models and Miura teaches PEG-lipid modification did not exert toxicity on living cells.
Applicant’s Arguments/ Response to Arguments
11. Applicant Argues: Applicant asserts that Kaths discloses very little of claim 17 yet asserts that Kaths teaches steps corresponding steps 2 and 4 of claim 17. Applicant asserts that Kaths fails to disclose all of step 1 of claim 17, “the unfunctionalized PEG-phospholipid molecules consist of PEG-phospholipids containing no functional groups” of steps 2 and 3, and “the organ preservation solution that does not contain any unfunctionalized PEG-phospholipid molecules” of step 4.
Response to Arguments: This is not found persuasive because Applicant is interpreting “an organ preservation solution that does not contain any unfunctionalized poly(ethylene glycol)-phospholipid (PEG-phospholipid) molecules” of steps 1 and 4 too narrowly. There are no exclusions to the organ preservation solution in steps 1 and 4 of claim 17 apart from it not containing unfunctionalized PEG-phospholipid molecules. As Kaths teaches ex vivo infusing with HTK, Kaths teaches ex vivo infusing and ex vivo incubating of steps 1 – 4 of claim 17 where the Kaths’ organ preservation solution meets the limitations of the organ preservation solution of steps 1 and 4.
Applicant Argues: Applicant asserts that Nilsson and Ekdahl fail to disclose how the treatment of the kidneys with the PEG-lipid were performed and that one of ordinary skill in the art would not have combined the teachings of Nilsson and Ekdahl that relate to allotransplantation with the protocol taught by Kaths, adapting it for allotransplantation rather than autotransplantation. Applicant asserts that Nilsson discloses that when the endothelial lining of the vascular system comes into contact with human blood, thromboinflammation is triggered which is due to the glycocalyx being deteriorated after ischemia and PEG-lipids are used to replace the glycocalyx and thereby obtain a protecting PEG-lipid coating on endothelial cells. Applicant asserts that there is no guidance in Kaths, Nilsson or Ekdahl or any combination for one of ordinary skill in the art to add the PEG-lipids to the HTK solution and one of ordinary skill in the art would not have considered this because both Nilsson and Ekdahl teach that the kidneys are treated with PEG-lipids after the end of SCS and prior to organ transplantation.
Response to Arguments: This is not found persuasive because one of ordinary skill in the art would have been motivated to combine the teachings of Nilsson and Ekdahl to adapt Kaths’ method for allotransplantation because Kaths teaches kidney transplantation has become the standard of care for end-stage renal disease (page 2580, right col.) and Nilsson teaches the coating technique with PEG-lipid coatings is very successful in lowering the innate immune response during allogeneic transplantation in large animal models (right col. para. 2). As Nilsson and Ekdahl disclose that coating the endothelial lining of the vascular system with PEG-phospholipids protects the endothelial cells and Kaths teaches infusing into the vascular system, one would be motivated to combine Kaths, Nilsson and Ekdahl to coat the kidney and the endothelial lining of the vascular system of the kidney by ex vivo infusing with the organ preservation solution of Kaths containing the PEG-phospholipids of Nilsson and Ekdahl and remove the PEG-phospholipids by ex vivo infusing the kidney with the HTK solution before allotransplantation.
Applicant Argues: Applicant asserts that the combination of Kaths, Nilsson and Ekdahl would teach ex vivo perfusing the vascular system of the kidney with unfunctionalized PEG-phospholipid molecules, however, this perfusion is performed at 37°C and not while keeping the organ submerged in any organ preservation solution comprising unfunctionalized PEG-phospholipid molecules.
Response to Arguments: This is not found persuasive because Applicant is reading limitations into step 2 of claim 17 that are not recited (temperature, submersion).
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
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