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 12/16/2025 has been entered. Claims 1 – 3, 5 – 12, 17 – 21, 23, 25, 28, 31, 32, 34, 44 – 48 remain pending and are under consideration. Claim
Priority
2. This application claims the benefit of the filing date of U.S. Provisional Application Serial No.
62/801,284, filed on February 5, 2019.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on 12/16/2025 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Claim Rejections
4. The rejection of claim 21 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendment to the claim.
Claim Interpretation
5. For the purpose of applying prior art, “wherein the vascular composite allograft is not a solid organ” of claim 1 will be interpreted as “VCAs including multiple tissue types including blood vessels and other tissues such as adipose, skin, muscle, nerves, ligaments, and/or bone, e.g., osteomyocutaneous grafts, or any tissues that can be perfused through a vessel such as limbs and other vascular composite allografts. In some embodiments, the biological tissue sample can be a VCA including skin, fat, bone, muscle, ligament, tendon, artery, vein, nerve, cartilage or any combination thereof. In some embodiments, a VCA is a portion of a limb ( e.g., all or part of an upper extremity including all or part of one or more digits, hand, nails, forearm, elbow, and/or upper arm, or all or part of a lower extremity including legs, ankles, feet, and one or more toes), face (e.g., all or part of a face including eye, periorbital tissue/eyelids, ear, nose, and/or a lip or lips), larynx, trachea, abdominal wall, genitourinary tissue (e.g., labia, a penis and/or urethra), uterine tissue (e.g., endometrium), or any tissues that can be perfused through a vessel such as limbs and other vascular composite allografts or a combination thereof” (Applicant’s specification at page 4, lines 12 – 18; page 13, lines 16 – 32).
6. For the purpose of applying prior art, the amount of the “one or more oxygen carrier agents” of claim 21 will be interpreted as the concentration ranges from about 50 to about 250 g/L as described in Applicant’s specification on page 20, lines 22 – 24.
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, 2, 6 – 12, 17 – 20, 25, 28, 31, 32, 46, and 47 remain rejected under 35 U.S.C. 103 as being unpatentable over Lellouch (Lellouch, Alexandre G., et al. Plastic and Reconstructive Surgery–Global Open 4.9S (2016): 55-56; previously cited), hereinafter Lellouch as evidenced by Tolboom (Tolboom, Herman, et al. Journal of Surgical Research 175.1 (2012): 149-156; previously cited), hereinafter Tolboom which is cited on the IDS filed 08/29/2022, in view of Fontes (US20150230453A1; Filed 10/11/2013; Published 08/20/2015; previously cited), hereinafter Fontes which is cited on the IDS filed 08/29/2022 in view of Davies (Davies, M. G., et al. European journal of vascular and endovascular surgery 17.6 (1999): 493-500; previously cited), hereinafter Davies in view of Abdel-Rahman (Abdel-Rahman U et. al. J Surg Res. 2009 Aug;155(2):293-300; previously cited), hereinafter Abdel-Rahman in view of Kueckelhaus (Kueckelhaus, Maximilian, et al. Annals of Plastic Surgery 76.3 (2016): 355-360; previously cited), hereinafter Kueckelhaus which is cited on the IDS filed 08/29/2022 in view of Bruinsma (Bruinsma BG, et. al. Nat Protoc. 2015 Mar;10(3):484-94; previously cited), hereinafter Bruinsma, which is cited on the IDS filed 08/29/2022 in view of Berendsen (Berendsen TA, et. al. Nat Med. 2014 Jul;20(7):790-3; previously cited), hereinafter Berendsen which is cited on the IDS filed 08/29/2022 in view of Duraes (Duraes, E. F. R., et al. Microsurgery 38.2 (2017): 185-194; previously cited), hereinafter Duraes.
Regarding step (a) of claim 1 and 8, 9, 18, and 19, Lellouch teaches subnormothermic oxygenated machine perfusion (SNMP) of porcine forelimbs (“vascular composite allograft” and “not a solid organ” of claim 1; “pig” of claim 18; “limb” of claim 19) with a perfusion solution comprising insulin (“one or more growth factors”) (page 55, right col. paragraph 1 – 2). Lellouch teaches the SNMP temperature is 20 and 30 ◦C (“sub-normothermic temperature” of claim 1 step (a) and claims 8 and 9) (page 55, right col. paragraph 1) as evidenced by Tolboom (Abstract; page 150, right col. paragraph 2). Lellouch does not teach “hyperosmolar”, “one or more cryoprotective agents”, “one or more oxygen carrier agents” or “one or more vasodilators” of step (a) of claim 1.
Regarding claim 46, Lellouch teaches the perfusion solution does not comprise 3-OMG (page 55, right col. paragraph 2).
Lellouch does not teach “hyperosmolar”, “one or more cryoprotective agents”, “one or more oxygen carrier agents” or “one or more vasodilators” of step (a) or steps (b) – (d) of claim 1 or steps (e) – (g) of claim 2 or “preservation solution” or “hypothermic temperature” of claim 6 or “about 4 ◦C” of claim 7 or “normothermic temperature” of claim 10 and 11 or “subzero” of claim 12 or “the vascular composite allograft is a donor vascular composite allograft for vascular composite allograft transplantation” of claim 17 or “PEG”, “acellular oxygen carrier” or “prostaglandin” of claim 20 or “duration” of claim 25 or “more than 12 hours” of claim 28. However, Lellouch teaches an increase in ATP production following perfusion reflects successful resuscitation of the forelimb (page 55, right col. last paragraph). Lellouch teaches SNMP has the potential to both actively preserve and enhance overall preservation of forelimbs in a swine model and may provide the crucial enabling technology for tissue preservation, transport, and eventual transplantation of VCAs (page 56, left col. paragraph 1).
Regarding “hyperosmolar” and “one or more oxygen carrier agents” of step (a) of claim 1 and claim 31 and “acellular oxygen carrier” of claim 20, Fontes teaches solutions for use with ex vivo machine perfusion of composite tissue allografts (CTA) that includes a limb at a temperature of about 21 ◦C where the solution comprises acellular cross-linked hemoglobin that is an HBOC (“one or more oxygen carrier agents” of step (a) of claim 1 and “acellular” of claim 20 and 31 and “HBOC” of claim 32) in a physiologically acceptable medium at about 290 – 360 mOsm/kg (“hyperosmolar”) (page 1, 0006 – 0008; page 2, 0046 – 0047; page 3, 0053 – 0054). Fontes teaches the perfusion solution is particularly suitable for machine perfusion at sub-normothermic temperatures (page 3, 0053). Fontes teaches CTA perfusion with an HBOC solution in Example 9 at 21 ◦C (page 12, 0123 – 0124).
Regarding claim 17, Fontes teaches the composite tissue allograft is a construct that is transplanted from one individual (a donor) to another individual (a recipient) that may be a limb or extremity such as an arm, leg, hand, foot, finger or toe (page 2, 0046). Fontes teaches the solutions for perfusion can be used for organ preservation during manipulation, treatment, storage and/or transport of an organ for transplantation in a recipient (page 3, 0053; page 5, 0063).
Fontes does not teach “one or more cryoprotective agents”, or “one or more vasodilators” of step (a) or steps (b) – (d) of claim 1 or steps (e) – (g) of claim 2 or “preservation solution” or “hypothermic temperature” of claim 6 or “about 4 ◦C” of claim 7 or “normothermic temperature” of claim 10 and 11 or “subzero” of claim 12 or “PEG” or “prostaglandin” of claim 20 or “duration” of claim 25 or “more than 12 hours” of claim 28. However, Fontes teaches PEG-35 as an osmotic agent that may be added to the perfusion solution (page 4, 0059). Fontes teaches there is a need to develop improved devices, methods, and preservation solutions in order to improve the success rate of organ transplantation and to decrease discard rates of organs (page 1, 0004). Fontes teaches machine perfusion devices should be able to provide adequate levels of oxygenation and flow while perfusing the organ or tissue for longer periods of time (page 1, 0006). Fontes teaches sub-normothermic temperatures may provide particular advantages over hypothermic or normothermic temperatures as mitochondrial function is maintained at temperatures above about 12 ◦C allowing maintenance of cellar ATP stores (page 5, 0064). One would have been motivated to combine the teachings of Lellouch regarding a method of SNMP of forelimbs with the teachings of Fontes regarding SNMP with a hyperosmolar solution comprising an acellular oxygen carrier in a method to preserve a limb for transplantation as Fontes teaches there is a need to develop improved devices, methods, and preservation solutions in order to improve the success rate of organ transplantation and to decrease discard rates of organs.
Regarding “one or more cryoprotective agents” of step (a) of claim 1 and “PEG” of claim 20, Davies teaches polyethylene glycol (PEG) is a cryopreservation agent which attenuates tissue immunogenicity and it has been suggested that PEG may reduce the immune response to allogeneic transplants (page 494, left col. paragraph 2). Davies teaches storing veins in a solution comprising 10% PEG and GSH (PEG/GSH) prior and shipping on wet ice prior to cryopreservation (page 495, left col. last paragraph). Davies teaches PEG/GSH treatment prior to cryopreservation maintained endothelial morphology (page 499, left col. paragraph 1). Davies teaches the use of PEG/GSH in media prior to cryopreservation may be beneficial as an adjuvant to transportation media (page 500, left col. paragraph 2). Davies does not teach “one or more vasodilators” of step (a) of claim 1 or steps (b) – (d) of claim 1 or steps (e) – (g) of claim 2 or “preservation solution” or “hypothermic temperature” of claim 6 or “about 4 ◦C” of claim 7 or “normothermic temperature” of claim 10 and 11 or “subzero” of claim 12 or “prostaglandin” of claim 20 or or “duration” of claim 25 or “more than 12 hours” of claim 28, however, Davies teaches the presence of an intact endothelium in a cryopreserved vein graft has been correlated with normal prostacyclin production (page 499, left col. paragraph 1). Davies teaches vein segments were stored in liquid nitrogen for 6 weeks in individual containers (page 495, left col. last paragraph). One would have been motivated to combine the teachings of Lellouch regarding a method of SNMP of forelimbs with the teachings of Fontes regarding SNMP with a hyperosmolar solution comprising an acellular oxygen carrier with the teachings of Davies regarding PEG is a cryopreservation agent that may reduce the immune response to allogeneic transplants in a method to preserve a limb for transplantation as Davies teaches the use of PEG/GSH in media prior to cryopreservation may be beneficial as an adjuvant to transportation media.
Regarding “one or more vasodilators” of step (a) of claim 1 and “prostaglandin” of claim 20, Abdel-Rahman teaches prostaglandin E1 (PGE1) may reduce ischemia-reperfusion injury in skeletal muscle (page 294, left col. paragraph 1). Abdel-Rahman teaches porcine limb ischemia followed by reperfusion with or without PGE1 (page 294, left col. paragraph 3 – 8 and right col.). Abdel-Rahman teaches perfusion with PGE1 is beneficial regarding blood flow, glucose consumption, and serum potassium regulation (page 299, left col. paragraph 3). Abdel-Rahman teaches adding PGE1 in controlled limb reperfusion reduces the local and global damage after ischemia-reperfusion injury (page 299, left col. last paragraph). Abdel-Rahman does not teach steps (b) – (d) of claim 1 or steps (e) – (g) of claim 2 or “preservation solution” or “hypothermic temperature” of claim 6 or “about 4 ◦C” of claim 7 or “normothermic temperature” of claim 10 and 11 or “subzero” of claim 12 or “duration” of claim 25 or “more than 12 hours” of claim 28. One would have been motivated to combine the teachings of Lellouch regarding a method of SNMP of forelimbs with the teachings of Fontes regarding SNMP with a hyperosmolar solution comprising an acellular oxygen carrier with the teachings of Davies regarding PEG is a cryopreservation agent that may reduce the immune response to allogeneic transplants with the teachings of Abdel-Rahman regarding PGE1 is beneficial in reducing local damage after ischemia-reperfusion injury in a method to preserve a limb for transplantation as Lellouch teaches SNMP has the potential to both actively preserve and enhance overall preservation of forelimbs in a swine model and may provide the crucial enabling technology for tissue preservation, transport, and eventual transplantation of VCAs.
Regarding step (b) of claim 1 and “hypothermic temperature” of claim 6, Kueckelhaus teaches perfusion of porcine limbs with an acellular solution at 10 ◦C to delay ischemic muscle damage prior to transplantation (Abstract; page 356, left col. last paragraph; page 357, left col. paragraph 2). Kuckelhaus teaches the limbs have metabolic function and the viability of isolated limbs can be preserved for extended periods (page 358, right col. paragraph 3). Kueckelhaus teaches a major restriction of allotransplantation for limb loss is irrecoverable muscle damage due to ischemia (Abstract; page 355, left col.). Kueckelhaus teaches once a donor limb is procured, the ischemic limbs must often be transported over long distances to reach the recipient (page 355, right col. paragraph 2). Kueckelhaus teaches ischemia-reperfusion injury (IRI) is a well-described autoimmune mediated event that occurs in tissues that are exposed to prolonged ischemia, followed by restoration of blood flow and skeletal muscle is particularly prone to IRI (page 355, right col. paragraph 3). Kueckelhaus teaches to address IRI, artificial perfusion has been used to preserve isolated limbs (page 355, right col. paragraph 3). Kueckelhaus does not teach “subzero non-freezing preservation solution comprising at least one or more cryoprotective agents” of step (b) of claim 1 or steps (e) – (g) of claim 2 or “about 4 ◦C” of claim 7 or “normothermic temperature” of claim 10 and 11 or “subzero” of claim 12 or “duration” of claim 25 or “more than 12 hours” of claim 28. One would have been motivated to combine the teachings of Lellouch regarding a method of SNMP of forelimbs with the teachings of Fontes regarding SNMP with a hyperosmolar solution comprising an acellular oxygen carrier with the teachings of Davies regarding PEG is a cryopreservation agent that may reduce the immune response to allogeneic transplants with the teachings of Abdel-Rahman regarding PGE1 is beneficial in reducing local damage after ischemia-reperfusion injury with the teachings of Kueckelhaus regarding perfusion at a hypothermic temperature in a method to preserve a limb for transplantation as Kueckelhaus teaches a major restriction of allotransplantation for limb loss is irrecoverable muscle damage due to ischemia.
Regarding “subzero non-freezing preservation solution comprising at least one or more cryoprotective agents” of step (b) of claim 1 and claim 47, Bruinsma teaches a supercooling solution comprising PEG (page 486, right col. paragraph 2). Bruinsma teaches placing an organ in a sealable sterile bag filled with supercooling solution, removing air from the bag before sealing it and cooling to -6 ◦C (page 490, steps 36 – 39). Bruinsma teaches tandem application of 3-OMG (3-OMG of claim 47) and PEG allowed for 100% freeze-avoidance in organs stored for multiple days at -6 ◦C (page 485, paragraph 2). Bruinsma teaches freezing can occur in both the intracellular liquid phase and the extracellular space and a cryoprotectant is needed to protect each (page 485, paragraph 2). Bruinsma teaches PEG is used for the intravascular space as it is a known ice modulator which directly inhibits ice crystallization and has added benefits to cellular membranes (page 485, paragraph 2). Bruinsma teaches their method prevents both intracellular and extracellular ice formation to protect against hypothermic injury (Abstract).
Regarding claim 7, Berendsen teaches perfusing a liver at 4 °C (hypothermic temperature of step (b) of claim 1, and claim 7) with UW solution comprising PEG (UW-PEG) (Figure 1; page 791, left col. paragraph 3).
Regarding step (c) of claim 1, Berendsen teaches transferring the liver to a sterile bag filled with UW-PEG and sealing the bag (page 794, right col. paragraph 2). As Berendsen teaches the sterile bag is filled with liquid, one or more liquid-air interfaces is eliminated thus meeting the limitations of step (c) of claim 1.
Regarding step (d) of claim 1 and claim 28, Berendsen teaches the liver in the sterile bag filled with UW-PEG was immersed in ice-cold antifreeze, transferred to a controlled-rate freezer and cooled to −6 °C (subzero temperature of step (d) of claim 1), and preservation was continued for up to 96 hours (claim 28) (page 794, right col. paragraph 2). Berendsen teaches optimizing organ preservation to improve transplantation outcome has the potential to increase the availability of organs (page 790, left col. paragraph 1).
Regarding step (e) of claim 2, Berendsen teaches warming the liver to 4 °C (page 794, right col. paragraph 3; Figure 1a).
Regarding step (f) of claim 2, Berendsen teaches perfusion of the liver with Williams’ Medium E at 21 °C (page 794, right col. paragraph 3; Figure 1a). Berendsen does not teach the perfusion solution comprises “one or more cryoprotective agents and one or more oxygen carrier agents”.
Regarding step (g) of claim 2 and claims 10, and 11, Berendsen teaches warming the tissue to 37 °C (normothermic temperature) for transplantation (Figure 1a). Berendsen teaches warming a liver to a normothermic temperature but does not teach warming a limb to a normothermic temperature.
Regarding claim 12, Berendsen teaches the liver in the sterile bag filled with UW-PEG was immersed in ice-cold antifreeze, transferred to a controlled-rate freezer and cooled to −6 °C (page 794, right col. paragraph 2).
Regarding claim 25, Berendsen teaches 1 hour of SNMP at 21 °C (sub-normothermic), followed by SNMP where the temperature was reduced to 4 °C (hypothermic) at a rate of -1 °C /min (approximately 17 minutes: 21 – 4 = 17 degrees @ -1 °C /min) and then to -6 °C at a rate of -0.1 °C/min (approximately 40 minutes of SNMP to hypothermic 0 °C) for a total of performing steps (a) and (b) of approximately 2 hours (1 hour and 57 minutes) (Figure 1a).
Regarding warming a limb to a normothermic temperature, Duraes teaches ex-situ normothermic porcine forelimb perfusion at 39 ◦C for 12 hours to preserve the viability and function of porcine limbs (Abstract; page 2, left col. paragraph 3 and right col. paragraph 1 – 3). Duraes teaches hand transplantation has become a feasible therapeutic option for traumatic limb loss but tissue damage caused by prolonged ischemia and reperfusion injury remains a limiting factor for the success of transplantation (page 1, right col.).
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 Lellouch regarding a method of SNMP of forelimbs with the teachings of Fontes regarding SNMP with a hyperosmolar solution comprising an acellular oxygen carrier with the teachings of Davies regarding PEG is a cryopreservation agent that may reduce the immune response to allogeneic transplants with the teachings of Abdel-Rahman regarding PGE1 is beneficial in reducing local damage after ischemia-reperfusion injury with the teachings of Kueckelhaus regarding perfusion of porcine limbs with an acellular solution at 10 ◦C to delay ischemic muscle damage prior to transplantation with the teachings of Bruinsma regarding a supercooling solution comprising PEG with the teachings of Berendsen regarding hypothermic perfusion and organ preservation with the teachings of Duraes regarding normothermic temperature for forelimb preservation of viability and function to arrive at the claimed method where the vascular composite allograft is a limb, a cryoprotective agent is PEG, an oxygen carrier is HBOC, a growth factor is insulin, and a vasodilator is PGE1. One would have been motivated to combine the teachings of Lellouch, Fontes, Davies, Abdel-Rahman, Kueckelhaus, Bruinsma, Berendsen, and Duraes in a method to preserve a limb for transplantation as Fontes teaches there is a need to develop improved devices, methods, and preservation solutions in order to improve the success rate of organ transplantation and to decrease discard rates of organs and Kueckelhaus teaches a major restriction of allotransplantation for limb loss is irrecoverable muscle damage due to ischemia and Berendsen teaches optimizing organ preservation to improve transplantation outcome has the potential to increase the availability of organs. One would have a reasonable expectation of success in combining the teachings as Lellouch teaches an increase in ATP production following SNMP reflects successful resuscitation of the forelimb and that the SNMP method is based on SNMP to resuscitate livers, Fontes teaches the perfusion solution is particularly suitable for machine perfusion at sub-normothermic temperatures, Davies teaches polyethylene glycol (PEG) is a cryopreservation agent which attenuates tissue immunogenicity and it has been suggested that PEG may reduce the immune response to allogeneic transplants, Kueckelhaus teaches to address IRI, artificial perfusion has been used to preserve isolated limbs, and Duraes teaches limbs at normothermic temperatures can preserve limb viability for 12 hours.
8. Claim(s) 3 remains rejected under 35 U.S.C. 103 as being unpatentable over Lellouch (Lellouch, Alexandre G., et al. Plastic and Reconstructive Surgery–Global Open 4.9S (2016): 55-56; previously cited), hereinafter Lellouch as evidenced by Tolboom (Tolboom, Herman, et al. Journal of Surgical Research 175.1 (2012): 149-156; previously cited), hereinafter Tolboom which is cited on the IDS filed 08/29/2022, in view of Fontes (US20150230453A1; Filed 10/11/2013; Published 08/20/2015; previously cited), hereinafter Fontes which is cited on the IDS filed 08/29/2022 in view of Davies (Davies, M. G., et al. European journal of vascular and endovascular surgery 17.6 (1999): 493-500; previously cited), hereinafter Davies in view of Abdel-Rahman (Abdel-Rahman U et. al. J Surg Res. 2009 Aug;155(2):293-300; previously cited), hereinafter Abdel-Rahman in view of Kueckelhaus (Kueckelhaus, Maximilian, et al. Annals of Plastic Surgery 76.3 (2016): 355-360; previously cited), hereinafter Kueckelhaus which is cited on the IDS filed 08/29/2022 in view of Bruinsma (Bruinsma BG, et. al. Nat Protoc. 2015 Mar;10(3):484-94; previously cited), hereinafter Bruinsma, which is cited on the IDS filed 08/29/2022 in view of Berendsen (Berendsen TA, et. al. Nat Med. 2014 Jul;20(7):790-3; previously cited), hereinafter Berendsen which is cited on the IDS filed 08/29/2022 in view of in view of Duraes (Duraes, E. F. R., et al. Microsurgery 38.2 (2017): 185-194; previously cited), hereinafter Duraes as applied to claims 1, 2, 6 – 12, 17 – 20, 25, 28, 31, 32, 46, and 47 above, and further in view of Ge (Ge, Liangpeng, et. al. Skin Grafts-Indications, Applications and Current Research. IntechOpen, 2011; previously cited), hereinafter Ge, which is cited on the IDS filed 05/09/2025 in view of Pouliot (Pouliot, R. J. Dermatol. Cosmetol 1 (2017): 24-31; previously cited), hereinafter Pouliot.
Lellouch, Fontes, Davies, Abdel-Rahman, Kueckelhaus, Bruinsma, Berendsen, and Duraes make obvious the limitations of claim 1 as set forth above but do not teach “removing hair” of claim 3.
Ge teaches skin tissue possesses a mixed commensal population of bacteria and fungi that lives primarily in or around the hair and sebaceous follicles (page 162, paragraph 2). Ge teaches even the commensal bacterial may damage the skin if subsequently allowed to grow during the skin storage period and therefore it is important to try to eliminate or minimize the microbial population of skin before retrieval (page 162, paragraph 2). Ge teaches removing the hair and sterilizing the skin prior to skin harvesting (page 163, paragraph 4 – 5). Ge teaches a non-freeze complex cryoprotectants comprising PEG to avoid ice crystal formation when skin is stored at subzero temperatures (page 164, last paragraph).
Pouliot teaches cryopreservation causes ice crystal formation which could perturb the integrity of skin and ice crystals are probably formed on keratins which are known as hygroscopic molecules (page 29, 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 Lellouch regarding a method of SNMP of forelimbs with the teachings of Fontes regarding SNMP with a hyperosmolar solution comprising an acellular oxygen carrier with the teachings of Davies regarding PEG is a cryopreservation agent that may reduce the immune response to allogeneic transplants with the teachings of Abdel-Rahman regarding PGE1 is beneficial in reducing local damage after ischemia-reperfusion injury with the teachings of Kueckelhaus regarding perfusion of porcine limbs with an acellular solution at 10 ◦C to delay ischemic muscle damage prior to transplantation with the teachings of Berendsen regarding hypothermic perfusion and organ preservation with the teachings of Duraes regarding normothermic temperature for forelimb preservation of viability and function with the teachings of Ge regarding removal of hair on skin prior to skin harvest with the teachings of Pouliot regarding ice crystals form on kerating to arrive at the claimed method where prior to step (a), hair is removed from the forelimb to avoid ice crystal formation within the forelimb and to minimize microorganism contamination. One would have been motivated to combine the teachings of Lellouch, Fontes, Davies, Abdel-Rahman, Kueckelhaus, Berendsen, Duraes, Ge and Pouliot in a method to preserve a limb for transplantation as Fontes teaches there is a need to develop improved devices, methods, and preservation solutions in order to improve the success rate of organ transplantation and to decrease discard rates of organs and Ge teaches even the commensal bacterial may damage the skin if subsequently allowed to grow during the skin storage period. One would have a reasonable expectation of success in combining the teachings as Ge teaches removing hair and a non-freeze complex cryoprotectants comprising PEG to avoid ice crystal formation when skin is stored at subzero temperatures.
9. Claim(s) 5, 44, and 45 remain rejected under 35 U.S.C. 103 as being unpatentable over Lellouch (Lellouch, Alexandre G., et al. Plastic and Reconstructive Surgery–Global Open 4.9S (2016): 55-56; previously cited), hereinafter Lellouch as evidenced by Tolboom (Tolboom, Herman, et al. Journal of Surgical Research 175.1 (2012): 149-156; previously cited), hereinafter Tolboom which is cited on the IDS filed 08/29/2022, in view of Fontes (US20150230453A1; Filed 10/11/2013; Published 08/20/2015; previously cited), hereinafter Fontes which is cited on the IDS filed 08/29/2022 in view of Davies (Davies, M. G., et al. European journal of vascular and endovascular surgery 17.6 (1999): 493-500; previously cited), hereinafter Davies in view of Abdel-Rahman (Abdel-Rahman U et. al. J Surg Res. 2009 Aug;155(2):293-300; previously cited), hereinafter Abdel-Rahman in view of Kueckelhaus (Kueckelhaus, Maximilian, et al. Annals of Plastic Surgery 76.3 (2016): 355-360; previously cited), hereinafter Kueckelhaus which is cited on the IDS filed 08/29/2022 in view of Bruinsma (Bruinsma BG, et. al. Nat Protoc. 2015 Mar;10(3):484-94; previously cited), hereinafter Bruinsma, which is cited on the IDS filed 08/29/2022 in view of Berendsen (Berendsen TA, et. al. Nat Med. 2014 Jul;20(7):790-3; previously cited), hereinafter Berendsen which is cited on the IDS filed 08/29/2022 in view of in view of Duraes (Duraes, E. F. R., et al. Microsurgery 38.2 (2017): 185-194; previously cited), hereinafter Duraes as applied to claims 1, 2, 6 – 12, 17 – 20, 25, 28, 31, 32, 46, and 47 above, and further in view of Ho (Ho, Andrew TV, et al. Proceedings of the National Academy of Sciences 114.26 (2017): 6675-6684; previously cited), hereinafter Ho.
Lellouch, Fontes, Davies, Abdel-Rahman, Kueckelhaus, Bruinsma, Berendsen, and Duraes make obvious the limitations of claim 1 as set forth above but do not teach “basic FGF” of claim 45.
Regarding skeletal muscle media of claims 5 and 44, Lellouch teaches the sub-normothermic perfusion solution consisted of William’s E medium enriched with dexamethasone, insulin, and heparin (right col. paragraph 2) but does not teach “skeletal muscle cell growth medium”.
Regarding “PEG” of claim 5, Davies teaches PEG is a cryopreservation agent which attenuates tissue immunogenicity and it has been suggested that PEG may reduce the immune response to allogeneic transplants (page 494, left col. paragraph 2). Davies does not teach “skeletal muscle cell growth media”.
Regarding “skeletal muscle cell growth medium” of claims 5 and 44 and basic FGF of claim 45, Ho teaches skeletal muscles harbor muscle-specific stem cells (MuSCs) capable of tissue regeneration (Abstract; page 6675, left col. paragraph 1). Ho teaches PGE2 leads to MuSC expansion and muscle regeneration by either endogenous of transplanted MuSCs (Abstract; page 6677, left col. paragraph 2 – 3 and right col. paragraph 1 – 2). Ho teaches culturing MuSCs in a culture medium supplemented with FBS, FGF2 (bFGF), and PGE2 and transplanting cultured MuSCs (page 6682, left col. paragraph 2 and 5). Ho teaches MuSCs are crucial to development and regeneration and their numbers dramatically increase in response to insults that damage the muscles (page 6679, right col. last paragraph). Ho teaches transplanted cultured MuSCs augments muscle regeneration (Figure 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 Lellouch regarding a method of SNMP of forelimbs with a perfusion solution with the teachings of Ho regarding culturing MuSCs in media comprising FBS, FGF2, and PGE2 to arrive at the claimed method where the sub-normothermic perfusion solution comprises PEG, HBOC, bFGF, PGE2, dexamethasone, insulin, and heparin. One would have been motivated to combine the teachings of Lellouch and Ho in a method to preserve a limb comprising MuSCs for transplantation as Fontes teaches there is a need to develop improved devices, methods, and preservation solutions in order to improve the success rate of organ transplantation and to decrease discard rates of organs and Ho teaches MuSCs are crucial to development and regeneration. One would have a reasonable expectation of success in combining the teachings as Ho teaches transplanted cultured MuSCs augments muscle regeneration.
10. Claim(s) 21, 23, and 48 remain rejected under 35 U.S.C. 103 as being unpatentable over Lellouch (Lellouch, Alexandre G., et al. Plastic and Reconstructive Surgery–Global Open 4.9S (2016): 55-56; previously cited), hereinafter Lellouch as evidenced by Tolboom (Tolboom, Herman, et al. Journal of Surgical Research 175.1 (2012): 149-156; previously cited), hereinafter Tolboom which is cited on the IDS filed 08/29/2022, in view of Fontes (US20150230453A1; Filed 10/11/2013; Published 08/20/2015; previously cited), hereinafter Fontes which is cited on the IDS filed 08/29/2022 in view of Davies (Davies, M. G., et al. European journal of vascular and endovascular surgery 17.6 (1999): 493-500; previously cited), hereinafter Davies in view of Abdel-Rahman (Abdel-Rahman U et. al. J Surg Res. 2009 Aug;155(2):293-300; previously cited), hereinafter Abdel-Rahman in view of Kueckelhaus (Kueckelhaus, Maximilian, et al. Annals of Plastic Surgery 76.3 (2016): 355-360; previously cited), hereinafter Kueckelhaus which is cited on the IDS filed 08/29/2022 in view of Bruinsma (Bruinsma BG, et. al. Nat Protoc. 2015 Mar;10(3):484-94; previously cited), hereinafter Bruinsma, which is cited on the IDS filed 08/29/2022 in view of Berendsen (Berendsen TA, et. al. Nat Med. 2014 Jul;20(7):790-3; previously cited), hereinafter Berendsen which is cited on the IDS filed 08/29/2022 in view of in view of Duraes (Duraes, E. F. R., et al. Microsurgery 38.2 (2017): 185-194; previously cited), hereinafter Duraes as applied to claims 1, 2, 6 – 12, 17 – 20, 25, 28, 31, 32, 46, and 47 above, and further in view of Brasile (US5599659; Filed 01/13/1995; Published 02/04/1997; previously cited), hereinafter Brasile which is cited on the IDS filed 08/29/2022 in view of Kurien (Kurien, JS., et al. International Surgery Journal 4.10 (2017): 3306-3310; previously cited), hereinafter Kurien in view of Ho (Ho, Andrew TV, et al. Proceedings of the National Academy of Sciences 114.26 (2017): 6675-6684; previously cited), hereinafter Ho.
Lellouch, Fontes, Davies, Abdel-Rahman, Kueckelhaus, Bruinsma, Berendsen, and Duraes make obvious the limitations of claim 1 as set forth above.
Regarding “between 50 mL and 200 mL of the one or more oxygen carrier agents per 500 mL” of claim 21 and “acellular oxygen carrier agent” of claim 48, Fontes teaches 3 – 10 g/dL of acellular hemoglobin (30 – 100 g/L) and the perfusion solution utilizes a low fraction of oxygen carrier compared to that found in blood but this amount as been found to provide adequate oxygen delivery and carbon dioxide removal for organ preservation at sub-normothermic temperatures (page 3, 0056).
Regarding “albumin” of claim 21, Fontes teaches albumin is an osmotic agent that contributes to the oncotic pressure exerted by a solution (page 3, 0050; page 4, 0059) but does not teach between 1 g and 20 g per 500 mL. Duraes teaches perfusion with albumin (page 2, right col. paragraph 2).
Regarding 35 kDa cryoprotective agent of claim 21 and “PEG” of claim 48, Fontes teaches the solution can comprise PEG-35 (page 4, 0059) and Davies teaches 10% PEG (page 495, left col. last paragraph).
Regarding vasodilator of claim 21 and “prostaglandin” of claim 48, Abdel-Rahman teaches 20 µg PGE1 (page 294, right col. last paragraph) but does not teach the flow rate.
Regarding between 1 g and 20 g albumin per 500 mL of claim 21, Brasile teaches a basal medium supplemented with albumin at 30 g/L (15 g/ 500 mL) to improve preservation of cells (col. 9, lines 21 – 29; Formula I of Table 2; col. 11, lines 30 – 35). Brasile teaches a solution which can support organs and tissues ex vivo without extreme hypothermia (col. 1, lines 16 – 21). Brasile teaches there is a need for a preservation solution as a tissue culture medium for supporting growth of vascular endothelial cells (col. 2, lines 45 – 48). Brasile teaches there will be a need of organ specific perfusates designed to support metabolism during preservation (col. 8, lines 49 – 51).
Regarding flow rate of claim 21, Kurien teaches PGE1 can increase blood flow in limbs and is used for the treatment of advanced critical limb ischemia (page 3306, right col. paragraph 2). Kurien teaches 100 µg of PGE1 was added to 500 mL and this was infused into patients with micro drip set at 50 micro drops/minute (page 3307, left col. last paragraph). Kurien teaches the use of PGE1 to treat limb ischemia as patients improved (page 3308, right col. paragraph 1).
Regarding “skeletal muscle cell growth medium” of claim 21, Ho teaches skeletal muscles harbor muscle-specific stem cells (MuSCs) capable of tissue regeneration (Abstract; page 6675, left col. paragraph 1). Ho teaches PGE2 leads to MuSC expansion and muscle regeneration by either endogenous of transplanted MuSCs (Abstract; page 6677, left col. paragraph 2 – 3 and right col. paragraph 1 – 2). Ho teaches culturing MuSCs in a culture medium supplemented with FBS, FGF2 (bFGF), and PGE2 and transplanting cultured MuSCs (page 6682, left col. paragraph 2 and 5). Ho teaches MuSCs are crucial to development and regeneration and their numbers dramatically increase in response to insults that damage the muscles (page 6679, right col. last paragraph). Ho teaches transplanted cultured MuSCs augments muscle regeneration (Figure 2).
Regarding insulin, dexamethasone, and heparin of claim 23, Lellouch teaches the perfusion medium comprises insulin, dexamethasone, and heparin (right col. paragraph 2) but does not teach the recited volumes. Berendsen teaches subnormothermic perfusate of 500 mL contains the following: 2 U/l of insulin and supplementation with 750 U/l of insulin; 1000 U/L of heparin, 40,000 U/l of penicillin, 40,000 µg/L of streptomycin, 0.292 g/L of L-glutamine, and 10 mg/L hydrocortisone (page 794, left col. paragraph 3). Berendsen does not teach the volume of dexamethasone.
Regarding dexamethasone volume of claim 23, Bruinsma teaches a perfusion solution comprising L-glutamine (0.292 mg/liter), 4 ml of penicillin-streptomycin (5000 U/ml), 5 mg of hydrocortisone (10 mg/liter), 5000 U of heparin and 375 U of insulin to a 500 ml bottle of Williams’ medium E (page 486, paragraph 1). Bruinsma teaches a perfusion solution comprising 40 U of insulin and 16 mg of dexamethasone in 1 liter of UW solution and further comprising 5% PEG (page 486, 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 Lellouch regarding a method of SNMP of forelimbs with a perfusion solution comprising insulin, dexamethasone, and heparin with the teachings of Fontes regarding a perfusion solution comprising acellular hemoglobin, with the teachings of Berendsen regarding a perfusion solution comprising pen-strep, L-glutamine, and hydrocortisone with the teachings of Duraes regarding a perfusion solution comprising albumin with the teachings of Davies regarding a perfusion solution comprising PEG with the teachings of Abdel-Rahman regarding a perfusion solution comprising PGE1 with the teachings of Kurien regarding a flow rate of PGE1 with the teachings of Ho regarding culturing MuSCs in media comprising FBS, FGF2, and PGE2 with the teachings of Bruinsma regarding a perfusion solution comprising insulin, dexamethasone, and PEG to arrive at the claimed method where the sub-normothermic perfusion solution comprises HBOC, albumin, PEG, PGE1, PGE2, insulin, dexamethasone, heparin, penicillin-streptomycin, L-glutamine, and hydrocortisone One would have been motivated to combine the teachings of Lellouch, Fontes, Berendsen, Duraes, Abdel-Rahman, Kurien, Ho, and Bruinsma in a method to preserve limbs for transplant as Fontes teaches there is a need to develop improved devices, methods, and preservation solutions in order to improve the success rate of organ transplantation and to decrease discard rates of organs. One would have a reasonable expectation of success in combining the teachings as Fontes teaches the solution can be used for perfusion of a limb at sub-normothermic temperatures and Ho teaches transplanted cultured MuSCs augments muscle regeneration.
11. Claim 34 remains rejected under 35 U.S.C. 103 as being unpatentable over Lellouch (Lellouch, Alexandre G., et al. Plastic and Reconstructive Surgery–Global Open 4.9S (2016): 55-56; previously cited), hereinafter Lellouch as evidenced by Tolboom (Tolboom, Herman, et al. Journal of Surgical Research 175.1 (2012): 149-156; previously cited), hereinafter Tolboom which is cited on the IDS filed 08/29/2022, in view of Fontes (US20150230453A1; Filed 10/11/2013; Published 08/20/2015; previously cited), hereinafter Fontes which is cited on the IDS filed 08/29/2022 in view of Davies (Davies, M. G., et al. European journal of vascular and endovascular surgery 17.6 (1999): 493-500; previously cited), hereinafter Davies in view of Abdel-Rahman (Abdel-Rahman U et. al. J Surg Res. 2009 Aug;155(2):293-300; previously cited), hereinafter Abdel-Rahman in view of Kueckelhaus (Kueckelhaus, Maximilian, et al. Annals of Plastic Surgery 76.3 (2016): 355-360; previously cited), hereinafter Kueckelhaus which is cited on the IDS filed 08/29/2022 in view of Bruinsma (Bruinsma BG, et. al. Nat Protoc. 2015 Mar;10(3):484-94; previously cited), hereinafter Bruinsma, which is cited on the IDS filed 08/29/2022 in view of Berendsen (Berendsen TA, et. al. Nat Med. 2014 Jul;20(7):790-3; previously cited), hereinafter Berendsen which is cited on the IDS filed 08/29/2022 in view of in view of Duraes (Duraes, E. F. R., et al. Microsurgery 38.2 (2017): 185-194; previously cited), hereinafter Duraes as applied to claims 1, 2, 6 – 12, 17 – 20, 25, 28, 31, 32, 46, and 47 above, and further in view of Kravitz (US-20120148542-A1; previously cited), hereinafter Kravitz in view of Bruinsma2014 (Bruinsma BG, et. al. Am J Transplant. 2014 Jun;14(6):1400-9; previously cited), hereinafter Bruinsma2014, which is cited on the IDS filed 08/29/2022.
Lellouch, Fontes, Davies, Abdel-Rahman, Kueckelhaus, Bruinsma Berendsen, and Duraes make obvious the limitations of claim 1 as set forth above.
Berendsen teaches subnormothermic machine perfusion system comprising a pump, an oxygenator, a jacketed bubble trap, and perfusate reservoir (page 794, left col. paragraph 3). Berendsen does not teach a heat exchanger, a hollow fiber oxygenator, a pressure sensor, tubing, or a computer.
Regarding “computer”, “pressure sensor”, and “heat exchanger”, Kravitz teaches an organ perfusion apparatus where perfusion is controlled by a computer (page 3, 0027). Kravitz teaches the perfusion may be controlled by a microprocessor with connections to sensors, thermoelectric units, and pumps (page 4, 0032). Kravitz teaches the apparatus may be capable of perfusing organs at both normothermic and hypothermic temperatures (page 4, 0033). Kravitz teaches the apparatus may have reservoirs (page 4, 0034). Kravitz teaches pressure sensors may be provided (page 4, 0035). Kravitz teaches the perfusion solutions may be held in a reservoir with a thermoelectric unit in heat transfer communication with the reservoir or cooled using a cryogenic fluid heat exchanger (page 11, 0210). Kravitz teaches the computer can respond from a sensor or similar device disposed in a flow path such as in an end of tubing placed in a vessel of the perfused organ (page 3, 0027). Kravitz does not teach a hollow fiber oxygenator.
Regarding “hollow fiber oxygenator”, Bruinsma2014 teaches subnormothermic machine perfusion with a system comprising a hollow fiber oxygenator, a pump, a jacketed bubble trap, and pressure sensors (page 3, Ex vivo Subnormothermic Machine Perfusion). Bruinsma2014 teaches minimal injury was sustained during perfusion of livers and that subnormothermic machine perfusion effectively maintains liver function and sustains or improves various hepatobiliary parameters post-ischemia (Abstract). Bruinsma2014 teaches livers showed improved oxygen uptake. Lactate levels, and ATP content after perfusion (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 Berendsen and Kravitz regarding a perfusion apparatus comprising a pump, solution reservoir, heat exchanger, oxygenator, jacketed bubble trap, pressure sensor, tubing connecting the flow path to an organ, and a computer to control perfusion and substitute the oxygenator of Berendsen with the hollow fiber oxygenator of Bruinsma2014 to arrive at the claimed system for subzero preserving a biological tissue sample. One would have been motivated to combine the teachings and make the substitution because Kravitz teaches the perfusion solutions can be cooled using a cryogenic fluid heat exchanger and Bruinsma2014 teaches subnormothermic machine perfusion effectively maintains liver function and sustains or improves various hepatobiliary parameters post-ischemia. One would have a reasonable expectation of success in carrying out the combination and substitution because Bruinsma2014 teaches livers showed improved oxygen uptake. Lactate levels, and ATP content after perfusion.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
12. Claims 1 – 3, 5 – 12, 17 – 21, 23, 25, 28, 31 – 32, 34, and 44 – 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 – 20 of copending Application No. 18937740 in view of Lellouch (Lellouch, Alexandre G., et al. "Ex-vivo Subnormothermic Oxygenated Machine Perfusion of Swine Forelimbs Enables Prolonged Graft Preservation Prior to Transplantation." Plastic and Reconstructive Surgery–Global Open 4.9S (2016): 55-56.), hereinafter Lellouch.
Instant claim 1 is drawn to A method for preserving a vascular composite allograft, the method comprising: (a) perfusing the vascular composite allograft biological tissue sample with a
hyperosmolar sub-normothermic perfusion solution comprising one or more cryoprotective agents, one or more oxygen carrier agents, one or more growth factors, and one or more vasodilators, at a sub-normothermic temperature; (b) perfusing the vascular composite allograft biological tissue sample with a subzero non-freezing preservation solution comprising at least one or more cryoprotective agents at a hypothermic temperature; (c) placing the perfused vascular composite allograft biological tissue sample in a container, and removing sufficient air from the container to eliminate or reduce one or more liquid-air interfaces in the container, and sealing the container; and (d) cooling the vascular composite allograft biological tissue sample in the container to a subzero temperature without freezing the sample, thereby preserving the vascular composite allograft biological tissue sample at the subzero temperature.,_ wherein the vascular composite allograft is not a solid organ. Instant claim 34 is drawn to a system for subzero preserving a vascular composite allograft, the system comprising: a pump; a solution reservoir;
a heat exchanger; a hollow fiber oxygenator; a jacketed bubble trap; a pressure sensor; a tubing that serially connects the pump, the solution reservoir, the heat exchanger, the hollow fiber oxygenator, the jacketed bubble trap, and the pressure sensor; and a computer control unit that operates the system to perform any of the perfusion steps described in claim 1.
Reference claim 1 recites a method for preservation of a biological sample, the method comprising: providing a system comprising: a pump; a reservoir having a reservoir volume configured to hold a fluidic solution and the biological sample; a chamber configured to hold the biological sample;
a heat exchanger; a hollow fiber oxygenator; a jacketed bubble trap; a pressure sensor; a tubing that serially connects the pump, the reservoir, the heat exchanger, the hollow fiber oxygenator, the jacketed bubble trap, and the pressure sensor; and a computer control unit operatively connected to and configured to control the system; placing the biological sample into the reservoir; causing the computer control unit to perform operations comprising: perfusing the biological sample at a first perfusion rate with a first loading solution comprising one or more cryoprotective agent(s); perfusing the biological sample at a second perfusion rate lower than the first perfusion rate with a second loading solution; and cooling the biological sample to a subzero temperature, thereby preserving the biological sample at the subzero temperature. Reference claim 1 lacks the biological tissue being a “vascular composite allograft”, however reference claim 20 recites “the method of claim 1, wherein the biological sample is an organ or tissue, and wherein the organ is a heart, liver, kidney, bone, lung, eye, ovary, pancreas or any tissues that can be perfused through a vessel such as limbs and other vascular composite allografts”.
Lellouch teaches subnormothermic oxygenated machine perfusion (SNMP) of forelimbs with successful resuscitation of the forelimbs (page 55, right col. paragraph 1 – 3). Lellouch teaches SNMP has the potential to both actively preserve and enhance overall preservation of forelimbs and may provide the crucial enabling technology for tissue preservation, transport, and eventual transplantation of VCAs (page 56, 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 preserve a vascular composite allograft with the method recited in reference claim 1 for transplantation as Lellouch teaches SNMP of forelimbs with successful resuscitation and SNMP has the potential to both actively preserve and enhance overall preservation of forelimbs and may provide the crucial enabling technology for tissue preservation, transport, and eventual transplantation of VCAs.
This is a provisional nonstatutory double patenting rejection.
13. Claims 1 – 3, 5 – 12, 17 – 21, 23, 25, 28, 31 – 32, 34, and 44 – 48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 19 and 21 – 28 of U.S. Patent No. 12167729 in view of Lellouch (Lellouch, Alexandre G., et al. "Ex-vivo Subnormothermic Oxygenated Machine Perfusion of Swine Forelimbs Enables Prolonged Graft Preservation Prior to Transplantation." Plastic and Reconstructive Surgery–Global Open 4.9S (2016): 55-56.), hereinafter Lellouch.
Instant claim 1 is drawn to A method for preserving a vascular composite allograft, the method comprising: (a) perfusing the vascular composite allograft biological tissue sample with a hyperosmolar sub-normothermic perfusion solution comprising one or more cryoprotective agents, one or more oxygen carrier agents, one or more growth factors, and one or more vasodilators, at a sub-normothermic temperature; (b) perfusing the vascular composite allograft biological tissue sample with a subzero non-freezing preservation solution comprising at least one or more cryoprotective agents at a hypothermic temperature; (c) placing the perfused vascular composite allograft biological tissue sample in a container, and removing sufficient air from the container to eliminate or reduce one or more liquid-air interfaces in the container, and sealing the container; and (d) cooling the vascular composite allograft biological tissue sample in the container to a subzero temperature without freezing the sample, thereby preserving the vascular composite allograft biological tissue sample at the subzero temperature.,_ wherein the vascular composite allograft is not a solid organ.
Patent claim 1 recites a method for preserving a biological sample, the method comprising: (a) perfusing the biological sample at a first perfusion rate with a first loading solution comprising one or more cryoprotective agent(s) at a hypothermic temperature between 0° C. and 12° C.; (b) perfusing the biological sample at a second perfusion rate lower than the first perfusion rate with a second loading solution comprising a higher concentration of at least one of the one or more cryoprotective agent(s) than in the first loading solution at a hypothermic temperature; (c) placing the perfused biological sample in a container; (d) removing air from the container to avoid ice crystal 20 formation in cells within the biological sample or the first and second loading solutions, and sealing the container; and (e) cooling the biological sample in the container to a subzero temperature, thereby preserving the biological sample at a subzero temperature. Patent claim 1 lacks the biological tissue being a “vascular composite allograft”, however patent claim 28 recites “the method of claim 16, wherein the organ is a heart, kidney, bone, lung, eye, ovary, pancreas or any tissues that can be perfused through a vessel such as limbs and other vascular composite allografts”.
Lellouch teaches subnormothermic oxygenated machine perfusion (SNMP) of forelimbs with successful resuscitation of the forelimbs (page 55, right col. paragraph 1 – 3). Lellouch teaches SNMP has the potential to both actively preserve and enhance overall preservation of forelimbs and may provide the crucial enabling technology for tissue preservation, transport, and eventual transplantation of VCAs (page 56, 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 preserve a vascular composite allograft with the method recited in reference claim 1 for transplantation as Lellouch teaches SNMP of forelimbs with successful resuscitation and SNMP has the potential to both actively preserve and enhance overall preservation of forelimbs and may provide the crucial enabling technology for tissue preservation, transport, and eventual transplantation of VCAs.
Applicant’s Arguments/ Response to Arguments
14. Applicant Argues: On page 10 para. 1 – 2, Applicant asserts that to prevent hindsight reconstruction the Office must show some suggestion or motivation before the invention itself to make the new combination and recognition of need alone does not render obvious the achievement that meets the need; and the Office relies on eight separate references to stitch together an obviousness rejection of independent claim as a whole.
Response to Arguments: In response to applicant's argument that the examiner has combined an excessive number of references, reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991).
In response to “hindsight reconstruction”, the MPEP (2145.X(A)) states that Applicants may argue that the examiner’s conclusion of obviousness is based on improper hindsight reasoning. However, "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." Applicants may also argue that the combination of two or more references is "hindsight" because "express" motivation to combine the references is lacking. However, there is no requirement that an "express, written motivation to combine must appear in prior art references before a finding of obviousness."
In the maintained rejection of the claims, a motivation to make the combination of references set forth above is because Fontes teaches there is a need to develop improved devices, methods, and preservation solutions in order to improve the success rate of organ transplantation and to decrease discard rates of organs and Kueckelhaus teaches a major restriction of allotransplantation for limb loss is irrecoverable muscle damage due to ischemia and Berendsen teaches optimizing organ preservation to improve transplantation outcome has the potential to increase the availability of organs . Soley to rebut Applicant’s argument that “need alone does not render obvious the achievement that meets the need”, the cited references show “some suggestion or motivation before the invention itself to make the new combination” based on the following previously cited teachings before the priority date of the claimed invention: (1) Lellouch (cited in the obviousness rejection of claim 1) teaches motivation to make the combination with the additional cited references because Lellouch teaches SNMP has the potential to both actively preserve and enhance overall preservation of forelimbs and it may provide the crucial enabling technology for tissue preservation, transport, and eventual transplantation of VCAs (page 56, left col. para. 1; previously cited and cited in Applicant’s arguments at page 11, para. 2); (2) Fontes provides motivation to make the combination of references because Fontes teaches machine perfusion devices should be able to provide adequate levels of oxygenation and flow while perfusing the organ or tissue for longer periods of time (page 1, 0006; previously cited); (3) Davies provides motivation to make the combination of references because Davies teaches the use of PEG/GSH in media prior to cryopreservation may be beneficial as an adjuvant to transportation media (page 500, left col. paragraph 2; previously cited) because Davies teaches PEG/GSH treatment prior to cryopreservation maintained endothelial morphology (page 499, left col. paragraph 1; previously cited) and the presence of an intact endothelium in a cryopreserved vein graft has been correlated with normal prostacyclin production (page 499, left col. paragraph 1; previously cited); (4) Abdel-Rahman provides motivation to make the combination of references because Abdel-Rahman teaches perfusion with PGE1 is beneficial regarding blood flow, glucose consumption, and serum potassium regulation (page 299, left col. paragraph 3; previously cited); (5) Kueckelhaus provides motivation to combine the references because Kueckelhaus teaches once a donor limb is procured, the ischemic limbs must often be transported over long distances to reach the recipient (page 355, right col. paragraph 2; previously cited); (6) Bruinsma provides motivation to make the combination of references because Bruinsma teaches PEG is used for the intravascular space as it is a known ice modulator which directly inhibits ice crystallization and has added benefits to cellular membranes (page 485, paragraph 2; previously cited) and Bruinsma teaches their method prevents both intracellular and extracellular ice formation to protect against hypothermic injury (Abstract; previously cited); (7) Berendsen provides motivation to make the combination of references because Berendsen teaches optimizing organ preservation to improve transplantation outcome has the potential to increase the availability of organs (page 790, left col. paragraph 1; previously cited).
Applicant Argues: On page 11, paragraph 3, Applicant asserts that Lellouch fails to teach the sub-normothermic perfusion step using a solution as recited in claim 1 (step (a)) and doesn’t even hint at steps (b) – (d) of claim 1. Applicant asserts that a POSA would have had no reason to have modified Lellouch’s SNMP step in the manner suggested by the Office let alone gone on to carry out steps (b) – (d). Applicant asserts that even if there was a reason for a POSA to have made the combination as the Office suggests (there would not have been), a POSA would not have done so with a reasonable expectation of success at “preserving a vascular composite allograft” without undue experimentation. On page 11, last para. and page 12, para. 1 – 2 and 4; page 13, para. 2, Applicant asserts that without knowing that the claimed perfusion solution greatly reduced the formation of edema, a POSA would not have had any reason to make the specific combination, nor could a POSA have predicted the greatly reduced edema. On page 12, para. 3 – 5 – page 17, Applicant asserts that (1) nothing in the cited art would have given a POSA a reasonable expectation of success that preservation of organs other than VCAs could translate to successful preservation of a VCA; (2) a POSA would have no reason to include a cryoprotective agent; (3) the use of hindsight; (4) a POSA would not have had any reason to expect PGE1 would preserve a VCA; (5) liver preservation does not translate to VCA preservation.
Response to Arguments: In response, the rejections of the claims are maintained. However, solely to rebut Applicant’s arguments that a POSA would have no reason to modify Lellouch or have a reasonable expectation of success, the following response is provided. Lellouch teaches VCA preservation for 3 hours at subnormothermic temperature in William’s E medium containing dexamethasone, insulin, and heparin (page 55, right col. para. 2; previously cited). Lellouch teaches SNMP has the potential to both actively preserve and enhance overall preservation of forelimbs and it may provide the crucial enabling technology for tissue preservation, transport, and eventual transplantation of VCAs (page 56, left col. para. 1; previously cited and cited in Applicant’s arguments at page 11, para. 2). Fontes teaches hyperosmolar solutions containing HBOC for perfusion of a CTA and that the solutions can be used for organ preservation during manipulation, treatment, storage and/or transport of an organ for transplantation in a recipient and the perfusion solution is particularly suitable for machine perfusion at sub-normothermic temperatures (page 3, 0053; page 5, 0063; page 12, 0123 – 0124; page 3, 0053; previously cited). A POSA would be motivated to combine the teachings of Lellouch with the teachings of Fontes in a method to preserve a limb for transplantation as Fontes teaches there is a need to develop improved devices, methods, and preservation solutions in order to improve the success rate of organ transplantation and to decrease discard rates of organs. A POSA would have a reasonable expectation of success in combining the teachings as Fontes teaches machine perfusion devices should be able to provide adequate levels of oxygenation and flow while perfusing the organ or tissue for longer periods of time (page 1, 0006; previously cited) and Fontes teaches sub-normothermic temperatures may provide particular advantages over hypothermic or normothermic temperatures as mitochondrial function is maintained at temperatures above about 12 ◦C allowing maintenance of cellar ATP stores (page 5, 0064; previously cited) and Lellouch teaches an increase in ATP production reflects successful resuscitation of the forelimb (page 55, right col. last paragraph; previously cited). Thus Lellouch and Fontes teach VCA preservation at sub-normothermic temperatures. Lellouch and Fontes do not teach VCA preservation at hypothermic or subzero temperatures of steps (b) and (d) or a cryoprotective agent in perfusion solution of step (a) or in the preservation solution of step (b), or a vasodilator in the perfusion solution of step (a) or step (c). However, Lellouch teaches SNMP may provide the crucial enabling technology for tissue preservation, transport, and eventual transplantation of VCAs and Fontes teaches hyperosmolar solutions containing HBOC can be used for organ preservation during manipulation, treatment, storage and/or transport of an organ for transplantation in a recipient and Fontes teaches PEG-35 as an osmotic agent that may be added to the perfusion solution (page 4, 0059; previously cited).
Davies teaches PEG is a cryopreservation agent which attenuates tissue immunogenicity and it has been suggested that PEG may reduce the immune response to allogeneic transplants (page 494, left col. paragraph 2; previously cited). Davies teaches storing veins (which are VCAs based on Applicant’s specification at page 13, lines 15 – 21) in a solution comprising 10% PEG and GSH (PEG/GSH) prior and shipping on wet ice prior to cryopreservation (page 495, left col. last paragraph; previously cited). Davies teaches PEG/GSH treatment prior to cryopreservation maintained endothelial morphology (page 499, left col. paragraph 1; previously cited). Davies teaches the presence of an intact endothelium in a cryopreserved vein graft has been correlated with normal prostacyclin production (page 499, left col. paragraph 1; previously cited). Davies teaches the use of PEG/GSH in media prior to cryopreservation may be beneficial as an adjuvant to transportation media (page 500, left col. paragraph 2; previously cited). One would have been motivated to combine the teachings of Lellouch, Fontes, and Davies because Davies teaches the use of PEG/GSH in media prior to cryopreservation may be beneficial as an adjuvant to transportation media and as previously cited both here and in the maintained claim rejection, Lellouch teaches SNMP has the potential to both actively preserve and enhance overall preservation of forelimbs and it may provide the crucial enabling technology for tissue preservation, transport, and eventual transplantation of VCAs and Fontes teaches hyperosmolar solutions containing HBOC for perfusion of a CTA and that the solutions can be used for organ preservation during manipulation, treatment, storage and/or transport of an organ for transplantation in a recipient and the perfusion solution is particularly suitable for machine perfusion at sub-normothermic temperatures, and Fontes teaches PEG-35 can be added to the perfusion solution. Davies does not teach a vasodilator in the solution of steps (a) and (b) of claim 1 or perfusion at a hypothermic temperature of step (b) or steps (c) and (d) of claim 1. However, Davies teaches vein segments were stored in liquid nitrogen for 6 weeks in individual containers (page 495, left col. last paragraph; previously cited) and Davies teaches the presence of an intact endothelium in a cryopreserved vein graft has been correlated with normal prostacyclin production. A POSA in allograft preservation would know that prostacyclin is a potent vasodilator.
Abdel-Rahman teaches prostaglandin E1 (PGE1) may reduce ischemia-reperfusion injury in skeletal muscle (page 294, left col. paragraph 1; previously cited). Abdel-Rahman teaches porcine limb ischemia followed by reperfusion with or without PGE1 (page 294, left col. paragraph 3 – 8 and right col.; previously cited). Abdel-Rahman teaches perfusion with PGE1 is beneficial regarding blood flow, glucose consumption, and serum potassium regulation (page 299, left col. paragraph 3; previously cited). Abdel-Rahman teaches adding PGE1 in controlled limb reperfusion reduces the local and global damage after ischemia-reperfusion injury (page 299, left col. last paragraph; previously cited). One would have been motivated to combine the teachings of Lellouch, Fontes Davies, and Abdel-Rahman because Lellouch teaches SNMP has the potential to both actively preserve and enhance overall preservation of forelimbs in a swine model and may provide the crucial enabling technology for tissue preservation, transport, and eventual transplantation of VCAs. Therefore, Lellouch and Fontes teach SNMP for VCA preservation (step (a)), and Davies teaches PEG for VCA cryopreservation and the addition of PEG/GSH prior to cryopreservation maintained endothelial morphology and that the presence of an intact endothelium in a cryopreserved vein graft has been correlated with normal prostacyclin production, and Abdel-Rahman teaches perfusion with PGE1 is beneficial regarding blood flow. Thus the combined teachings of Lellouch, Fontes, Davies, and Abdel-Rahman make obvious SNMP of a VCA in a perfusion solution with PEG, HBOC, insulin, and PGE1 and cryopreservation of a VCA. Lellouch, Fontes, Davies, and Abdel-Rahman do not teach perfusion at a hypothermic temperature of step (b) steps (c) and (d) of claim 1.
Kueckelhaus teaches perfusion of porcine limbs with an acellular solution at 10 ◦C to delay ischemic muscle damage prior to transplantation where the limbs have metabolic function and the viability of isolated limbs can be preserved for extended periods (Abstract; page 356, left col. last paragraph; page 357, left col. paragraph 2; page 358, right col. paragraph 3; previously cited). Kueckelhaus teaches a major restriction of allotransplantation for limb loss is irrecoverable muscle damage due to ischemia (Abstract; page 355, left col.; previously cited). Kueckelhaus teaches once a donor limb is procured, the ischemic limbs must often be transported over long distances to reach the recipient (page 355, right col. paragraph 2; previously cited). Kueckelhaus teaches ischemia-reperfusion injury (IRI) is a well-described autoimmune mediated event that occurs in tissues that are exposed to prolonged ischemia, followed by restoration of blood flow and skeletal muscle is particularly prone to IRI (page 355, right col. paragraph 3; previously cited). Kueckelhaus teaches to address IRI, artificial perfusion has been used to preserve isolated limbs (page 355, right col. paragraph 3; previously cited). One would have been motivated to combine the teachings of Lellouch, Fontes, Davies, Abdel-Rahman and Kueckelhaus because Kueckelhaus teaches a major restriction of allotransplantation for limb loss is irrecoverable muscle damage due to ischemia and as previously cited both here and in the maintained claim rejection, Lellouch teaches SNMP has the potential to both actively preserve and enhance overall preservation of forelimbs and it may provide the crucial enabling technology for tissue preservation, transport, and eventual transplantation of VCAs and Fontes teaches hyperosmolar solutions containing HBOC for perfusion of a CTA and that the solutions can be used for organ preservation during manipulation, treatment, storage and/or transport of an organ for transplantation in a recipient and the perfusion solution is particularly suitable for machine perfusion at sub-normothermic temperatures, and Fontes teaches PEG-35 can be added to the perfusion solution. Therefore, Lellouch and Fontes teach SNMP for VCA preservation (step (a)), and Davies teaches PEG for VCA cryopreservation and the addition of PEG/GSH prior to cryopreservation maintained endothelial morphology and that the presence of an intact endothelium in a cryopreserved vein graft has been correlated with normal prostacyclin production, and Abdel-Rahman teaches perfusion with PGE1 is beneficial regarding blood flow, and Kueckelhaus teaches VCA perfusion at a hypothermic temperature. Thus the combined teachings of Lellouch, Fontes, Davies, Abdel-Rahman, and Kueckelhaus make obvious SNMP and hypothermic temperature perfusion of a VCA in a perfusion solution with PEG, HBOC, insulin, and PGE1 and cryopreservation of a VCA. Lellouch, Fontes, Davies, Abdel-Rahman, and Kueckelhaus do not teach steps (c) and (d) of claim 1. However, Davies teaches vein segments were stored in liquid nitrogen for 6 weeks in individual containers (page 495, left col. last paragraph; previously cited).
Bruinsma teaches placing an organ in a sealable sterile bag filled with supercooling solution, removing air from the bag before sealing it and cooling to -6 ◦C (page 490, steps 36 – 39; previously cited). Bruinsma teaches tandem application of 3-OMG and PEG allowed for 100% freeze-avoidance in organs stored for multiple days at -6 ◦C (page 485, paragraph 2; previously cited). Bruinsma teaches freezing can occur in both the intracellular liquid phase and the extracellular space and a cryoprotectant is needed to protect each (page 485, paragraph 2; previously cited). Bruinsma teaches PEG is used for the intravascular space as it is a known ice modulator which directly inhibits ice crystallization and has added benefits to cellular membranes (page 485, paragraph 2; previously cited). Bruinsma teaches their method prevents both intracellular and extracellular ice formation to protect against hypothermic injury (Abstract; previously cited). Thus the combined teachings of Lellouch, Fontes, Davies, Abdel-Rahman, Kueckelhaus, and Bruinsma make obvious SNMP and hypothermic temperature perfusion of a VCA in a perfusion solution with PEG, HBOC, insulin, and PGE1, and placing the VCA in a container, removing the air, and sealing it, and cryopreservation of a VCA. Lellouch, Fontes, Davies, Abdel-Rahman, Kueckelhaus, and Bruinsma do not teach step (d) of claim 1.
Berendsen teaches transferring a liver to a sterile bag filled with UW-PEG and sealing the bag (page 794, right col. paragraph 2; previously cited). Berendsen teaches the liver in the sterile bag filled with UW-PEG was immersed in ice-cold antifreeze, transferred to a controlled-rate freezer and cooled to −6 °C, and preservation was continued for up to 96 hours (page 794, right col. paragraph 2; previously cited). Berendsen teaches optimizing organ preservation to improve transplantation outcome has the potential to increase the availability of organs (page 790, left col. paragraph 1). Thus the combined teachings of Lellouch, Fontes, Davies, Abdel-Rahman, Kueckelhaus, Bruinsma, and Berendsen make obvious SNMP and hypothermic temperature perfusion of a VCA in a perfusion solution with PEG, HBOC, insulin, and PGE1, and placing the VCA in a container, removing the air, and sealing it, preserving a VCA at a subzero temperature. One would have been motivated to combine these teachings in a method to preserve a limb for transplantation as Fontes teaches there is a need to develop improved devices, methods, and preservation solutions in order to improve the success rate of organ transplantation and to decrease discard rates of organs and Kueckelhaus teaches a major restriction of allotransplantation for limb loss is irrecoverable muscle damage due to ischemia and Berendsen teaches optimizing organ preservation to improve transplantation outcome has the potential to increase the availability of organs. One would have a reasonable expectation of success in combining the teachings as Lellouch teaches an increase in ATP production following SNMP reflects successful resuscitation of the forelimb and that the SNMP method is based on SNMP to resuscitate livers, Fontes teaches the perfusion solution is particularly suitable for machine perfusion at sub-normothermic temperatures, Davies teaches polyethylene glycol (PEG) is a cryopreservation agent which attenuates tissue immunogenicity and it has been suggested that PEG may reduce the immune response to allogeneic transplants, and Kueckelhaus teaches to address IRI, artificial perfusion has been used to preserve isolated limbs.
Solely to rebut Applicant’s argument of “undue experimentation”, as Applicant points out in the Remarks on page 11, para. 2, Lellouch teaches that the use of SNMP for preservation of VCAs comes from its utility with livers (page 55, right col. para. 1). Therefore, a POSA would not have to perform undue experimentation with a reasonable expectation of success to preserve a VCA because a POSA could look to preservation methods of other vascular organs in the prior art. Solely to rebut Applicant’s argument regarding “undue experimentation”, Constantinescu (Constantinescu, Mihai A., et al. "Preservation of amputated extremities by extracorporeal blood perfusion; a feasibility study in a porcine model." Journal of Surgical Research 171.1 (2011): 291-299.), which is cited on the IDS filed 08/29/2022 teaches preservation of VCAs by extracorporeal blood perfusion and that extracorporeal blood perfusion has recently been demonstrated to be feasible in lung and liver and appears to be superior to cold storage in kidney preservation (Abstract; page 292, left col. para. 2; page 294, right col. para. 1). Constantinescu teaches the perfusion was with oxygenated blood (page 292, left col. para. 2), which obviously contains hemoglobin (oxygen carrier agent), growth factors, and vasodilators. Constantinescu teaches unlike visceral organs, extremities contain a particularly wide range of tissues, and while skin can be grafted after weeks of storage at 4 °C, muscle will irreversibly deteriorate within hours, and that continuous perfusion with oxygenated blood may offer a solution by supporting the survival of all the different types of tissues present in a whole limb (page 294, right col. para. 3). Constantinescu also provides a brief history of perfusion solutions leading to the choice of whole blood for perfusion with a clinically utilized heart-lung machine (page 294, right col. para. 4; page 295, para. 1 – 2). Thus, a POSA would not have undue experimentation to preserve a VCA based on the state of the prior art prior to the effective filing date of the claimed invention.
Regarding Applicant’s argument regarding a POSA would not have predicted greatly reduced edema, as previously cited, Lellouch teaches the perfusion solution contained dexamethasone (right col. paragraph 2), which a POSA would know reduces edema. Solely to rebut Applicant’s argument, Constantinescu teaches perfusion of the VCA with blood prevented edema with the VCA showing essentially no difference in weight pre- and post-perfusion (page 293, left col. para. 4; page 295, right col. para. 2; Figure 1).
Should claim 1 be amended to recite the method and solution compositions as shown in Applicant’s Figure 7 and described in Applicant’s specification at page 8, lines 14 – 25, the rejection of the claims over the cited prior art may be overcome upon further search and consideration.
Applicant Argues: On page 18 – 19, Applicant traverses the double patenting rejections. Applicant asserts that the cited claims in the ‘740 application nor the cited claims of Patent ‘729 do not render the present claims obvious because the claims of the ‘740 application fail to teach the claimed perfusion solution of instant claim 1.
Response to Arguments: In response, reference claim 1 of application ‘740 and Patent ‘729 claim 1 broadly recite “loading solution”, only requires the loading solution to comprise a cryoprotective agent, and does not exclude or limit the composition of the “loading solution” to not comprise the components of instant claim 1. Further, application claim 20 and Patent claim 28 recite that the biological sample may be a VCA. Therefore, the rejections are maintained.
Conclusion
No claims allowed.
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/Z.M.B./Examiner, Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632