DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Applicant’s Request for Continued Examination, Amendment and Arguments/Remarks received on 17 April 2026 have been entered. Claims 1-13 were previously pending in the application. Claims 1-2, 6-7, and 12 have been cancelled, and no new claims have been added by Applicant. Claims 3-5, 8-11, and 13 are currently pending in the application. Claim 13 is an independent claim.
The election of Group I, drawn to methods of recovering an organ harvested from a donor, for example from a circulation arrest donor (DCD) or a cardiac arrest donor (DCD), and a fluid for performing the method of recovering an organ harvested from a donor, remains in effect in the instant application. The following election of species remains in effect in the instant application:
Inhibitor: coagulation inhibitor.
Claims 3-5, 8-11, and 13 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/SE2020/050381, filed 12 April 2020, which claims priority to SWEDEN 1930123-3, filed 12 April 2019, and SWEDEN 1930125-8, filed 12 April 2019. Filing of a certified copies of the SWEDEN 1930123-3, filed 12 April 2019, and SWEDEN 1930125-8, filed 12 April 2019, is acknowledged.
Thus, the earliest possible priority for the instant application is 12 April 2019.
Information Disclosure Statement
The information disclosure statements filed 17 April 2026 and 19 May 2026 have been considered by the Examiner. Examiner notes the filing of IDS Size Fee assertions for the IDS filed 17 April 2026 and 19 May 2026, as required under 37 CFR 1.98, indicating that no IDS size fee is required under 37 CFR 1.17(v) at this time.
Specification
The use of the term “Tienam” on specification pg 16, Tables B-M, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b)
The rejection of amended, previously presented, and cancelled claims 1-13 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for reciting “the surrounding tissue” in claims 1 and 13 and “the first, second, third, and fourth hyperoncotic fluid” in claim 13 is withdrawn in view of Applicant’s amendments to the claims cancelling 1-2, 6-7, and 12 and removing the indefinite limitations from claim 13 and relevant dependent claims.
Amended and previously presented claims 3-5, 8-11, and 13 are newly rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Amended claims 3-5 and 8-11 are included in this rejection due to their dependence on amended independent claim 13.
Amended claim 13 recites, “evaluating the organ for suitability of transplantation to a living recipient”, which is indefinite because it is unclear which assessment parameters Applicant intends to encompass in the evaluating step and what criteria must be met to indicate suitability for transplantation.
The specification teaches that “the ability to concentrate creatinine is measured as an indication of function. A known amount of creatinine may be added to the solution as a marker of filtration capacity of the kidneys. In addition, the kidney is visually examined. If the kidney comprises (large) dark areas, it may be an indication of a failing kidney. In addition, kidney vascular resistance is evaluated.
If the kidney is considered suitable for transplantation, the kidney is transplanted directly or cooled down to a low temperature of 4 to 15°C and stored until transplantation.” [pg 11 ln 31- pg 12 ln 2].
The specification further teaches evaluating kidneys by:
“The kidneys are now evaluated under 32 to 37°C and a pressure of 70 to 90 mmHg for 15 minutes, noting vascular resistance, flow and visual appearance in regards to how well the kidney is perfused. The surgeon decides whether the kidney is well, moderate or poor perfused, moderate being several blue/black spots and poor being several large dark blue or black areas not perfused. Urine production is measured and flow is registered as ml/min and 100g kidney tissue.” [pg 15 ln 11-28].
Additionally, the specification teaches evaluating kidney function as follows:
“The kidney can now be evaluated, for example by measuring "blood" parameters, such as paO2, PaCO2, HCO3, oxygen saturation, Hb, Hct, Lactate, Glucose, pH etc. In addition, the kidney can be examined optically. The resistance can be calculated from pump data. Urine production can be examined, including creatinine concentration, if creatinine is added to the evaluation fluid. In this manner, the kidney is examined for suitability for transplantation.“ [pg 21 ln 13-29].
As such, the specification teaches a few different parameters (i.e., assessing urine production, assessing the ability to concentrate creatine, visually inspecting for the presence of dark blue/black areas, and measuring vascular resistance) which may be used to evaluate suitability of a kidney, but does not provide a limiting scope for “evaluating the organ for suitability of transplantation to a living recipient”. Additionally, the specification teaches that the various assessments can be used for evaluation, but does not indicate which parameter values other than a lack of macroscopic dark spots on the kidneys indicates suitability for transplantation.
Additionally, the specification teaches evaluation of livers by determining the presence of perfusion defects [pg 39 ln 25-26, Figure 25-26] and by assessing perfusion flow and resistance for clearance of the parenchyma [pg 40 ln 25-26, pg 42 ln 17-24, Figure 29]. The specification further teaches evaluation of liver such that: “Ex-vivo normothermic perfusion resulted in cleared parenchyma, with better flow and lower resistance than in control DCD livers. We noted bile production and lower lactate levels than in control animals after 6,5 hours perfusion and the livers looked well perfused without defects.” [pg 42 ln 21-24]. However, as for kidney evaluation, the specification does not teach a limiting definition for the metes and bounds of the methods for evaluating the liver for suitability of transplantation into a living recipient nor the criteria for determining whether or not a liver is suitable for transplantation into a living recipient.
As such, the metes and bounds of the claim cannot be determined.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Amended and previously presented claims 3-5, 8-11, and 13 are newly rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A method of recovering an organ harvested from a donor, comprising:
retrieving the organ from the donor four hours after circulatory death of the donor, wherein there is no circulation of fluid through the organ during said four hours;
providing from 5 to 100U lys-plasminogen to blood vessels of the organ after harvesting, wherein the lys- plasminogen is comprised in 5 to 20 mL of a first fluid comprising albumin at a concentration of between 50 g/L and 70 g/L and a coagulation inhibitor;
providing from 0.5 to 10 mg tissue plasminogen activator (tPA) to said blood vessels of the organ simultaneously with providing lys-plasminogen or after providing lys-plasminogen, wherein the tissue plasminogen activator is comprised in said first fluid if provided simultaneously with providing lys-plasminogen and in about 20 mL of a second fluid, if provided after providing lys-plasminogen, wherein the second fluid comprises albumin at a concentration of between 50 g/L and 70 g/L and a coagulation inhibitor;
after providing the lys-plasminogen and the tPA, in a first restoration step, circulating through the organ a third fluid having a temperature of between 5°C and 25°C under pressure wherein a circulation pressure is increased from 20 mmHg to between 70 mmHg and 90 mmHg at a rate of 5 mmHg per 5 minutes, wherein the third fluid comprises albumin at a concentration of between 50 g/L and 120 g/L and a coagulation inhibitor;
following the first restoration step, in a first perfusion step, circulating through the organ the third fluid having a temperature of between 5°C and 25°C under a circulation pressure of 20-30 mmHg for a duration of 2.5 hours;
following the first perfusion step, in a second perfusion step, circulating through the organ the third fluid having a temperature of from 28°C to 33°C at a circulation pressure of 20-30 mmHg for 30 minutes; and
following the second perfusion step, in a second restoration step, circulating through the organ a fourth fluid having a temperature of between 28°C and 37°C at a circulation pressure of 20-30 mmHg for 3-5 hours, wherein the fourth fluid comprises red blood cells, albumin at a concentration of between 50 g/L and 120 g/L and a coagulation inhibitor;
wherein the organ is a porcine kidney or a liver;
wherein the donor is a pig;
wherein the coagulation inhibitor in each of the first fluid, the second fluid, the third fluid, and the fourth fluid is 600, 800, 1000, 1200U ATIII, 1.5, 3, 12, 24 mg abciximab, and/or 4, 8, 16, or 32 mg argatroban;
wherein the first fluid and the second fluid each further comprise electrolytes, amino acids, hormones, vitamins, adenine, sugars, and antibiotics according to Table H:
PNG
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274
601
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Greyscale
;
and
wherein the third fluid and the fourth fluid each further comprise electrolytes, amino acids, insulin, vitamins, adenine, sugars, and antibiotics according to Table K when the organ is a kidney or according to Table M when the organ is a liver:
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287
628
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Greyscale
,
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285
630
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;
does not reasonably provide enablement for:
A method of recovering any organ harvested from any donor, comprising:
retrieving the organ from the donor, at least four hours after circulatory death of the donor, wherein there is no circulation of fluid through the organ during said at least four hours;
providing any concentration of lys-plasminogen to blood vessels of the organ after harvesting, wherein the lys- plasminogen is comprised in any volume of a first fluid comprising albumin at a concentration of between 50 g/L and 70 g/L and any coagulation inhibitor without further comprising electrolytes, amino acids, hormones, vitamins, adenine, sugars, and antibiotics according to Table H;
providing any concentration of a tissue plasminogen activator (tPA) to said blood vessels of the organ simultaneously with providing lys-plasminogen or after providing lys-plasminogen, wherein the tissue plasminogen activator is comprised in said first fluid if provided simultaneously with providing lys-plasminogen and in any volume of a second fluid, if provided after providing lys-plasminogen, wherein the second fluid comprises albumin at a concentration of between 50 g/L and 70 g/L and any coagulation inhibitor without further comprising electrolytes, amino acids, hormones, vitamins, adenine, sugars, and antibiotics according to Table H;
in a first restoration step, circulating through the organ a third fluid having a temperature of between 5°C and 25°C under pressure wherein a circulation pressure is increased from 20 mmHg to between 70 mmHg and 90 mmHg over any duration, wherein the third fluid comprises albumin at a concentration of between 50 g/L and 120 g/L; electrolytes; and any coagulation inhibitor without further comprising the additional components outlined in Table K or Table M;
in a second restoration step, circulating through the organ a fourth fluid having a temperature of between 28°C and 37°C for any duration, wherein the fourth fluid comprises red blood cells; albumin at a concentration of between 50 g/L and 120 g/L; electrolytes; and any coagulation inhibitor without further comprising the additional components outlined in Table K or Table M;
and any step of evaluating the organ for any suitability of transplantation to any living recipient without any defined criteria for suitability.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The specification comprises five (5) different issues: 1) the absence of an enabling disclosure for recovering any organ other than a kidney or liver from a pig; 2) the absence of an enabling disclosure for recovering an organ retrieved more than 4 hours after circulatory death of the donor; 3) the absence of an enabling disclosure for providing lys-plasminogen at any concentration other than 5 to 100U lys-plasminogen per organ in any volume other than 5 to 20 mL, providing tPA at any concentration other than 0.5 to 10 mg per organ in any volume other than about 20 mL, for first and second fluids to have any additional compositions other than that recited in Table H, for the third and fourth fluids to have any additional compositions other than that recited in Table K when the organ is a kidney or Table M when the organ is a liver, and for the coagulation inhibitors to be other than 600, 800, 1000, 1200U ATIII, 1.5, 3, 12, 24 mg abciximab, and/or 4, 8, 16, or 32 mg argatroban; 4) the absence of an enabling disclosure for recovering an organ retrieved from a donor 4 hours after circulation arrest of the donor without the steps of following the first restoration step, in a first perfusion step, circulating through the organ the third fluid having a temperature of between 5°C and 25°C under a circulation pressure of 20-30 mmHg for a duration of 2.5 hours; and following the first perfusion step, in a second perfusion step, circulating through the organ the third fluid having a temperature of from 28°C to 33°C at a circulation pressure of 20-30 mmHg for 30 minutes; and circulating the fourth fluid for a duration of 3-5 hours; 5) the absence of an enabling disclosure for evaluating the organ for suitability of transplantation.
These issues were identified by the Office after analysis of the disclosure provided by the specification. The Office has analyzed the specification in direct accordance to the factors outlined in In re Wands, namely 1) the nature of the invention, 2) the state of the prior art, 3) the predictability of the art, 4) the amount of direction or guidance present, and 5) the presence or absence of working examples, and presented detailed scientific reasons supported by publications from the prior art for the finding of a lack of enablement for the scope of the instant methods. The Wands analysis and supporting specific evidence are presented below for each of the identified issues.
As a first issue (1), the specification does not provide an enabling disclosure for recovering any organ other than a kidney or a liver from a pig using Applicant’s claimed methods. The broadest independent claim, amended claim 13, recites a method of recovering an organ harvested from a donor comprising retrieving the organ from the donor at least four hours after circulatory death of the donor, wherein the organ has blood vessels and is evaluated for suitability of transplantation to a living recipient. Note that the actual suitability of the organ is not required. Claims 3-5 and 8-11 depend from amended independent claim 13 and do not provide any further limitations as to the structure, identity, nor source of the organ itself beyond an ability to undergo the particular methodological limitations in any condition that allows the final evaluation of suitability for transplantation into a living recipient without requiring the actual suitability. Therefore, the claims encompass any organ from any species having blood vessels capable of having a fluid circulate through them.
The specification discloses generally that “The present invention is useful in transplantation of any organ, such as liver, kidney, pancreas, pancreatic islets, uterus, small intestine, multivisceral transplant” [page 9 lines 3-4].
However, the working examples and drawings are limited to teaching only pig kidneys and livers to optimize the retrieval method, wherein the specification teaches, “In order to verify the recondition process, kidneys from pigs exposed to warm ischemia during 4 hours or more have been used for experimental purposes” [page 9 lines 16-17].
The specification also teaches that “In humans, more than one artery per kidney can be seen in more than 30% of all kidneys. With the suggested techniques, this will not be any problem” [page 13 lines 25-27], which is the only specific recitation of “human”. Further, the specification references patients in contexts which imply a human source of organs, such as “In addition, kidneys exposed to ischemia for one hour or less may also, more or less, benefit from the process, thus including kidneys from brain dead donors (BDD) considered marginal either by extended warm or cold ischemia time or other cofounding factors, such as age, hypertension, diabetes, hypotension, time in the intensive care unit (ICU), anuria, elevated laboratory values, poorly perfused kidneys on the backtable or any other cause for not primarily accepting the donor for transplantation” [page 9 lines 19-24]. As such, the specification suggests using the instantly claimed method for humans, but does not provide any examples or data to support the use of the method with human organs or human recipients.
Working Examples 1-16 disclose the retrieval of kidneys from pigs after circulatory arrest to various recovery variables [pg 24 lines 4-11, pg 25 lines 15-19, pg 26 lines 19-20, pg 27 lines 8-12, pg 28 lines 12-13, pg 28 line 36- pg 29 line 1, pg 29 lines 32-37, pg 30 lines 24-26, pg 31 lines 13-18, pg 32 lines 26-27, pg 33 lines 21-31, pg 34 lines 20-23, pg 35 lines 21-24, pg 36 lines 4-17, pg 37 lines 25-29, and pg 38 lines 15-17]. Working Examples 17-18 teach the retrieval of livers from pigs, wherein Example 17 resulted in perfusion defects and Example 18 resulted in livers that looked well perfused without defects [pg 38 lines 26-30, pg 39 lines 28-32, pg 42 lines 13-24].
The specification does not teach any examples using any organ other the kidneys or livers retrieved from pigs. The specification does not provide any teachings for using the method for the retrieval of organs from any organisms other than pigs.
The art at the time of filing teaches that only kidney, liver, pancreas, lung, and recently, heart, donation are eligible for controlled donation after circulatory death (cDCD) and only kidneys, livers, and lungs have successfully been transplanted to date for uncontrolled DCD (uDCD) [Smith et al. 2019, Intensive Care Medicine, 45, 310-321, published 06 February 2019, cited in a prior action, pg 311 col 1 ¶ 2].
Additionally, Manara teaches that liver, pancreas, and lungs have lower tolerance for warm ischemia than do kidneys, and that whereas DCD kidney transplantation can tolerate a functional warm ischemia time, which includes time prior to circulation arrest, of 2 hours plus up to an additional 2 hours in select donors (4 hours total functional warm ischemia time), liver is limited to 30 minutes, lung to 60 minutes, and pancreas to 30 minutes for DCD organ retrieval [Manara et al. 2012, British Journal of Anaesthesia, 108(S1), i108-i121, abstract, pg i108 col 2 ¶ 2, Table 2]. Therefore, the ordinarily skilled artisan at the time of filing would have considered methods which allow for extending the organ retrieval time for kidneys to 4 hours after circulatory death as highly unpredictable for extending the organ retrieval time to at least 4 hours for other organs which have lower tolerance for warm ischemia than do kidneys, such as the pancreas, liver, and lung.
Neither the specification nor the art at the time of filing teaches recovery of organs at least four hours after circulatory death of a human nor recovery of organs other than kidneys or lungs retrieved from a pig at least four hours after circulatory death of the donor, wherein there is no circulation of fluid through the organ during the at least four hours. Thus, in view of the limited number of organs with any suitability for donation after circulatory death, the different tolerances to warm ischemic time of the various organs with potential suitability for DCD, the limitation of the working examples to porcine kidney and liver recovery, and the breadth of the claims, the ordinarily skilled artisan would have considered practicing the instantly claimed method for recovering any organ harvested from any donor after circulatory death other than kidneys or livers retrieved from pigs as highly unpredictable. As such, it would have required undue experimentation to practice the scope of Applicant’s invention as claimed.
As a second issue 2), the specification does not provide an enabling disclosure for recovering an organ retrieved more than 4 hours after circulatory death of the donor. The broadest independent claim, amended claim 13, recites a method of recovering an organ harvested from a donor comprising retrieving the organ from the donor at least four hours after circulatory death of the donor without an upper limit to the time at which retrieval of the organ commences following circulatory death.
The specification teaches “In order to verify the recondition process, kidneys from pigs exposed to warm ischemia during 4 hours or more have been used for experimental purposes. There is evidence that kidneys exposed to ischemia during 6 hours, 8 hours, 10 hours, 12 hours or more can be recondition.” [pg 9 ln 16-19]. The specification also teaches, “The kidneys are harvesting as soon as possible, while it is unknown how long time the kidney has been exposed to ischemia because of circulatory arrest or other causes, but the ischemic time is more than 2 hours, such as about 3 hours or 4 hours or longer.“ [pg 12 ln 33-35]. However, the examples in the specification do not provide any data for recovering an organ retrieved later than 4 hours following death/circulatory arrest of the donor.
Example 1 teaches retrieval of kidneys from pigs starting at 3 hours after circulatory arrest [pg 24 ln 10-11]. Examples 2-6, 8, 12-13 teach retrieval of kidneys from pigs starting at 4 hours after death [pg 25 ln 19, pg 26 ln 19, pg 27 ln 12, pg 28 ln 12-13, pg 29 ln 1, pg 30 ln 27, pg 34 ln 23, pg 35 ln 22]. Examples 17-18 teach the retrieval of a porcine liver starting 4 hours after death [pg 38 ln 30, pg 39 ln 32]. Examples 7, 9-10, and 14-16 teach warm ischemia times (WIT) of 4 to 5 hours, which can include time prior to circulatory death, and do not teach retrieval times after circulatory death [pg 29 ln 37, pg 31 ln 18, pg 32 ln 27, pg 36 ln 17, pg 37 ln 28-29, pg 38 ln 16-17].
The specification further teaches that “If the time from cardiac arrest to harvesting is more than 1 hour, the organs are normally not suitable for transplantation” [pg 1 ln 16-17].
The art at the time of filing teaches that liver, pancreas, and lungs have lower tolerance for warm ischemia than do kidneys, and that whereas donation after circulatory death (DCD) kidney transplantation can tolerate a functional warm ischemia time, which includes time prior to circulation arrest, of 2 hours plus up to an additional 2 hours in select donors (4 hours total functional warm ischemia time), liver is limited to 30 minutes, lung to 60 minutes, and pancreas to 30 minutes for DCD organ retrieval [Manara et al. 2012, British Journal of Anaesthesia, 108(S1), i108-i121, abstract, pg i108 col 2 ¶ 2, Table 2].
Manara also teaches that ischemic injury is measured as functional warm ischemic time, which begins when the patient’s systolic arterial pressure decreases below 50 mmHg and/or the arterial oxygen saturation decreases below 70% and ends with cold perfusion [pg i111 col 2 ¶ 2]. Manara further teaches that ischemic injury increases the risks of primary graft failure, delayed graft function, and other ischemic complications (e.g., biliary structures), and is a considerable concern to retrieval and implantation teams, such that organ retrieval may not occur if the time interval from withdrawal of treatment (or onset of functional warm ischemia) to asystole is prolonged [pg i111 col 2 ¶ 2- pg i112 col 1 ¶ 1]. Manara additionally teaches that reducing the time interval between the diagnosis of death and organ retrieval is an intervention that mighty prevent ischemic injury [pg i112 col 1 ¶ 1].
Neither the specification nor the art at the time of filing teaches recovery of organs more than four hours after circulatory death. Thus, in view of the well-known risks associated with ischemic injury resulting from prolonged functional warm ischemia time, the different tolerances to warm ischemic time of the various organs with potential suitability for DCD, the art teachings that kidneys have a maximum WIT of 4 hours and livers have a maximum WIT of 20-30 minutes, the teachings in the prior art that reducing the time interval between diagnosis of death and organ retrieval may help to prevent ischemic injury, the limitation of the working examples to porcine kidney and liver recovery starting at 3 or 4 hours after circulatory death, and the breadth of the claims, the ordinarily skilled artisan would have considered practicing the instantly claimed method for recovering any organ harvested from any donor more than 4 hours after circulatory death as highly unpredictable. As such, it would have required undue experimentation to practice the scope of Applicant’s invention as claimed.
As a third issue 3), the specification does not provide an enabling disclosure for providing lys-plasminogen at any concentration other than 5 to 100U lys-plasminogen per organ in any volume other than 5 to 20 mL, providing tPA at any concentration other than 0.5 to 10 mg per organ in any volume other than about 20 mL, for first and second fluids to have any additional compositions other than that recited in Table H, for the third and fourth fluids to have any additional compositions other than that recited in Table K when the organ is a kidney or Table M when the organ is a liver, and for the coagulation inhibitors to be other than 600, 800, 1000, 1200U ATIII, 1.5, 3, 12, 24 mg abciximab, and/or 4, 8, 16, or 32 mg argatroban.
Example 9 is the first example to teach the addition of lys-plasminogen and tPA, wherein 10 U lys-plasminogen and 1 mg tPA are added within 20 mL solutions each according to Table I. However, transplantation of the organs processed in Example 9 resulted in all three pigs displaying delayed graft function [page 32 ln 7-24, Figure 13-14]. Examples 10 teaches to include 10U lys-plasminogen and 2 mg tPA in solutions according to Table H and demonstrated improved recovery compared to the organs processed according to Example 9 [pg 32 ln 28- pg 33 ln 19, Figure 15]. Examples 12-15 do not indicate in which solution the lys-plasminogen and tPA were introduced, but do indicate that 10U, 15U, 20U, and 30 U lys-plasminogen and 2 mg, 3 mg, 4 mg, and 6 mg tPA were added in Examples 12-15, respectively. Organs processed according to Example 16, which utilized the same recovery protocol as Examples 14 and 15, were transplanted in recipient pigs which survived and were monitored for 3 months following transplantation [pg 38 ln 15-24, Figure 19-24].
Examples 17-18 teach recovery of livers, wherein Example 18 modeled the optimized protocol identified for kidneys, wherein livers were treated with 60U lys-plasminogen and 12 mg tPA.
The specification does not teach to add any amount of lys-plasminogen or tPA outside of the ranges of 5 to 100U lys-plasminogen per organ and 0.5 to 10 mg tPA per organ, and does not teach successful recovery using a solution other than a solution according to Table H.
Examples 14-16 additionally teach inclusion of coagulation inhibitors comprising 600U ATIII within the first and second solutions and 1000U ATIII + 1.5 or 3 mg abciximab + 4 mg or 8 mg argatroban within the fourth fluid [pg 36 ln 18- pg 37 ln 20].
Example 18 teaches the inclusion of 1200U ATIII in the first and second fluids, 12 mg abciximab and 16 mg of argatroban in the third fluid, and 24 mg abciximab + 32 mg argatroban in the fourth fluid.
The art at the time of filing does not teach any conditions for reconditioning organs which have been harvested 4 hours following circulation arrest of the donor.
Neither the specification nor the art at the time of filing teaches to successfully recover an organ harvested 4 hours after circulation arrest of the donor by any protocol other than as a method comprising providing 5 to 100U lys-plasminogen per organ in 5 to 20 mL; providing tPA at 0.5 to 10 mg per organ in about 20 mL; a first and second fluids having additional compositions as recited in Table H; a third and fourth fluids having additional compositions as recited in Table K when the organ is a kidney or Table M when the organ is a liver; and coagulation inhibitors of: ATIII at 600, 800, 1000, or 1200U; abciximab at 1.5, 3, 12, or 24 mg; and/or argatroban 4, 8, 16, or 32 mg. Thus, in view of the art recognized unpredictability in recovering organs at 4 hours after circulatory arrest of the donor, the limitation of the working examples to specific solution compositions and specific concentrations of the lys-plasminogen, tPA, and coagulation inhibitors, and the breadth of the claims, the ordinarily skilled artisan at the time of filing the instant application would have considered performing the instantly claimed method using any solution compositions, any concentrations of lys-plasminogen, any concentrations of tPA, and any concentrations of any anticoagulants as highly unpredictable. As such, it would have required undue experimentation to practice the scope of Applicant’s invention as claimed.
As a fourth issue 4), the specification does not provide an enabling disclosure for recovering an organ retrieved from a donor 4 hours after circulation arrest of the donor without the steps of following the first restoration step, in a first perfusion step, circulating through the organ the third fluid having a temperature of between 5°C and 25°C under a circulation pressure of 20-30 mmHg for a duration of 2.5 hours; and following the first perfusion step, in a second perfusion step, circulating through the organ the third fluid having a temperature of from 28°C to 33°C at a circulation pressure of 20-30 mmHg for 30 minutes; and circulating the fourth fluid for a duration of 3-5 hours.
Examples 14-15 each teach additional perfusion steps including following the first restoration step, in a first perfusion step, circulating through the organ the third fluid having a temperature of between 5°C and 25°C under a circulation pressure of 20-30 mmHg for a duration of 2.5 hours; and following the first perfusion step, in a second perfusion step, circulating through the organ the third fluid having a temperature of from 28°C to 33°C at a circulation pressure of 20-30 mmHg for 30 minutes; and circulating the fourth fluid for a duration of 3-5 hours [pg 37 ln 1-21, pg 37 ln 34- pg 38 ln 10]. Example 18 teaches similar perfusion steps [pg 40 ln 14-24].
The art at the time of filing does not teach any conditions for reconditioning organs which have been harvested 4 hours following circulation arrest of the donor.
Neither the specification nor the art at the time of filing teaches to successfully recover an organ harvested 4 hours after circulation arrest of the donor by any protocol other than a protocol comprising steps of, following the first restoration step, in a first perfusion step, circulating through the organ the third fluid having a temperature of between 5°C and 25°C under a circulation pressure of 20-30 mmHg for a duration of 2.5 hours; and following the first perfusion step, in a second perfusion step, circulating through the organ the third fluid having a temperature of from 28°C to 33°C at a circulation pressure of 20-30 mmHg for 30 minutes; and circulating the fourth fluid for a duration of 3-5 hours. Thus, in view of the art recognized unpredictability in recovering organs at 4 hours after circulatory arrest of the donor, the limitation of the working examples to specific perfusion protocols as described above, and the breadth of the claims, the ordinarily skilled artisan at the time of filing the instant application would have considered performing the instantly claimed method without the perfusion steps identified above as highly unpredictable. As such, it would have required undue experimentation to practice the scope of Applicant’s invention as claimed.
As a fifth issue 5), the specification does not provide an enabling disclosure for evaluating the organ for suitability of transplantation.
The broadest independent claim, amended claim 13, broadly recites a step of “evaluating the organ for suitability of transplantation to a living recipient” without specifying any particular evaluation procedures or criteria for determining suitability. None of the dependent claims further limit the evaluation step.
The specification teaches evaluating kidneys, wherein:
“Normally, the kidney starts to produce urine and the ability to concentrate creatinine is measured as an indication of function. A known amount of creatinine may be added to the solution as a marker of filtration capacity of the kidneys. In addition, the kidney is visually examined. If the kidney comprises (large) dark areas, it may be an indication of a failing kidney. In addition, kidney vascular resistance is evaluated.
If the kidney is considered suitable for transplantation, the kidney is transplanted directly or cooled down to a low temperature of 4 to 15°C and stored until transplantation.” [pg 11 ln 31- pg 12 ln 2].
The specification further teaches evaluating kidneys by:
“In an evaluation step, the same solution from the perfusion step may be used … a red blood cell suspension (RBC) is added … The circulation proceeds during 1 to 4 hours with a pressure of 30 mmHg until the kidney is determined to be usable for transplantation purpose. The kidneys are now evaluated under 32 to 37°C and a pressure of 70 to 90 mmHg for 15 minutes, noting vascular resistance, flow and visual appearance in regards to how well the kidney is perfused. The surgeon decides whether the kidney is well, moderate or poor perfused, moderate being several blue/black spots and poor being several large dark blue or black areas not perfused. Urine production is measured and flow is registered as ml/min and 100g kidney tissue.” [pg 15 ln 11-28].
Additionally, the specification teaches evaluating kidney function on page 21:
“The kidney can now be evaluated, for example by measuring "blood" parameters, such as paO2, PaCO2, HCO3, oxygen saturation, Hb, Hct, Lactate, Glucose, pH etc. In addition, the kidney can be examined optically. The resistance can be calculated from pump data. Urine production can be examined, including creatinine concentration, if creatinine is added to the evaluation fluid. In this manner, the kidney is examined for suitability for transplantation.“ [pg 21 ln 13-29].
The specification does not indicate which parameter values other than a lack of macroscopic dark spots on the kidneys indicates suitability for transplantation.
The art at the time of filing teaches evaluating kidneys for suitability for transplantation by methods including macroscopic assessment of appearance during perfusion, mean renal blood flow, and total urine output during 60 minutes of ex vivo normothermic perfusion (EXNP) [Hosgood et al. 2015, British Journal of Surgery, 102, 1433-1440, cited in a prior action, pg 1434 col 2 ¶ 2]. Hosgood also teaches the derivation of a normothermic perfusion assessment score based on a combination of macroscopic (including pink, patchy, or mottled and purple/black appearance) and functional (including renal blood flow and urine output) parameters, wherein kidneys with a score of 1-4 are considered suitable for transplantation [abstract, pg 1434 col 2 ¶ 3, Table 1].
Miret-Alomar provides a review of kidney transplantation functional predictors, wherein the predictors of functionality include the donor risk indices, the calculation of the renal functional weight or the assessment of the nephronic mass, the measurement of vascular resistances during perfusion in hypothermia, the measurement of the donor’s biomarkers in urine and in the perfusion liquid, the measurement of functional and reperfusion parameters in normothermia, and the measurement of morphological parameters (microscopic and macroscopic) of the target organ [Miret-Alomar et al. 2018, Actas Urologicas Espanolas, 42(4), 218-226, abstract]. Miret-Alomar further teaches that tools are needed that are able to predict the short and long-term renal function in order to decide which kidneys will be implanted eventually or in which recipients they will be implanted, such that the most useful tool should be one that could be used before the implant, is easy and quick to apply, and has little variability among observers [pg 224 col 1 ¶ 2]. Miret-Alomar also teaches that the perfusion in normothermia can be a new useful tool in the prediction of functionality prior to implant as well as in the preservation of the graft [pg 223 col 1 ¶ 2]. However, Miret-Alomar teaches that of all the tools they reviewed, only the preimplantation biopsy and donor risk nomogram have an acceptable predictive capacity, but with limitations; that the macroscopic evaluation of the implant is not standardized and no prospective studies have been carried out in this regard; and that molecular diagnosis and ex vivo perfusion offer promising results but are not yet applicable [pg 224 col 1 ¶ 3- col 2 ¶ 2]. Therefore, Miret-Alomar teaches that the determination of suitability of kidneys for transplantation is not standardized and is unpredictable given the assessment tools available at the time of filing.
The specification teaches evaluating livers by determining the presence of perfusion defects [pg 39 ln 25-26, Figure 25-26] and by assessing perfusion flow and resistance for clearance of the parenchyma [pg 40 ln 25-26, pg 42 ln 17-24, Figure 29]. The specification further teaches evaluation of liver such that: “Ex-vivo normothermic perfusion resulted in cleared parenchyma, with better flow and lower resistance than in control DCD livers. We noted bile production and lower lactate levels than in control animals after 6,5 hours perfusion and the livers looked well perfused without defects.” [pg 42 ln 21-24].
However, the specification does not teach any threshold values for “better flow and lower resistance”, any minimal amount of bile production, nor any threshold values for “lower lactate levels” that would indicate suitability for transplantation to a living recipient.
The art at the time of filing teaches functional assessment of livers during normothermic machine perfusion, wherein the viability criteria to assess the suitability of livers for transplantation includes lactate clearance, pH maintenance, bile production, vascular flow patterns, and liver macroscopic appearance, and wherein the criteria were used successfully to select and transplant viable livers from among livers originally discarded as declined for transplantation following retrieval [Mergental et al. 2018, Liver Transplantation, 24, 1453-1469, abstract, pg 1468 col 1 ¶ 3, col 2 ¶ 1]. Mergental teaches that the reasons for discard for the organs tested included extensive primary warm ischemic time and/or cold ischemic time [Table 2]. Mergental further teaches that it is still to be determined which parameters can best predict posttransplant outcomes [pg 1467 col 1 ¶ 3-4]. As such, Mergental teaches the unpredictability of evaluating livers for suitability of transplantation to a living recipient using any methods other than the full list of viability criteria (i.e., lactate clearance, pH maintenance, bile production, vascular flow patterns, and liver macroscopic appearance) as used in their study for the objective assessment of viability for livers originally declined for transplantation due to a variety of factors, including prolonged warm ischemic time after cardiac death.
Neither the specification nor the art at the time of filing teaches evaluating livers for suitability of transplantation to a living recipient without defined assessment protocols and defined suitability criteria. Thus, in view of the well-known risks associated with ischemic injury resulting from prolonged functional warm ischemia time which would contraindicate an organ for suitability for transplantation to a living recipient, the art recognized unpredictability in evaluating suitability of organs having prolonged ischemic times for transplantation into living recipients, the limitation of the working examples to general statements about evaluation without specific criteria or data defining suitability parameters, and the breadth of the claims, the ordinarily skilled artisan would have considered practicing the instantly claimed method for evaluating an organ for the suitability of transplantation to a living recipient in which the organ was harvested from a donor more than 4 hours after circulatory death of the donor as highly unpredictable. As such, it would have required undue experimentation to practice the scope of Applicant’s invention as claimed.
Claim Rejections - 35 USC § 103
The rejection of amended, previously presented, and cancelled claims 1-13 under 35 U.S.C. 103 as being unpatentable over Hosgood [Hosgood et al., Br J Surg 102: 1433-40 (2015), cited in a prior action); in view of Eibl (US 5,520,912 A, cited in a prior action); Kaths (Kaths et al., J Vis Exp 101: e52909 (2015) , cited in a prior action); Steen (US20140007961A1, cited in a prior action); Mangino (US 9,399,027 B2, cited in a prior action); Levenbrown (Levenbrown & Costarino 2012, Nephrology and Fluid/Electrolyte Physiology: Neonatology Questions and Controversies (Second Edition), Chapter 16: Edema, 267-284, excerpt retrieved on 22 October 2025 from the Internet: <https://www.sciencedirect.com/topics/immunology-and-microbiology/oncotic-pressure#:~:text=Thus%2C%20the%20average%20colloid%20osmotic,Costarino%20MD>); Scalea (Scalea et al., Am J Transplant 17: 191-200 (2016), cited in a prior action); Hosgood2 (Hosgood et al., BMJ Open 6: e012237 (2017), cited in a prior action); Bjork (Bjork & Lindahl 1982, Molecular & Cellular Biochemistry, 48, 161-182, cited in a prior action); Smith (Smith et al. 2019, Intensive Care Medicine, 45, 310-321, published 06 February 2019, cited in a prior action); Caraceni (Caraceni et al., Blood Transfus Suppl 4: s18-25 (2013), cited in a prior action); Roman (Roman et al., Transplantation 96: 509-18 (2013), cited in a prior action); and Brady (US20020197252A1, cited in a prior action); is withdrawn in view of Applicant’s cancellation of claims 1-2, 6-7, and 12 and amendments to the claims such that claim 13 now recites “retrieving the organ from the donor, at least four hours after circulatory death of the donor, wherein there is no circulation of fluid through the organ during said at least four hours” in independent claim 13. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Double Patenting
Applicant’s reply has overcome the Double Patenting rejection of claims 1-13 on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of copending Application No. 17/598,002 in view of Applicant’s terminal disclaimer filed 17 April 2026.
The terminal disclaimer filed 17 April 2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of any patent granted on U.S. Application No. 17/598,002 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Conclusion
No claim is allowed.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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