DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 14 July 2025 have been entered. Claims 1-13 were previously pending in the application. Claims 1-13 are currently pending in the application. Claims 1 and 13 are independent claims. 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 1-13 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.
Objection to Drawings under 37 CFR 1.121(d)
The objection to the drawings under 37 CFR 1.121(d) for the drawing identifiers for Figures 5, 5a, and 5b are not formatted in consecutive numerals, wherein figure panels are identified by the same number followed by a capital letter, as required under 37 CFR 1.84(u)(1), is withdrawn in view of Applicant’s replacement sheets which label the figure panels as Fig. 5a, 5b, and 5c.
Specification
The objection to the specification of the disclosure for the Brief Description of the Drawings does not contain a description of each figure panel individually; specifically, Figures 15a-15d, Figures 19-22, Figures 23 and 24, and Figures 25-28 are described in groups of panels and/or figures and are not individually described, is withdrawn in view of the amendment to the Brief Description of the Drawing specifically describing each figure/ figure panel.
Claim Objections
The objection to amended independent claims 1 and 13 for reciting “DCD” in claims 1 and 13, reciting “lys-plasminogen” and “lysplasminogen” in claims 1 and 13, and reciting “circirculating”, “and and”, and “read blood cells” in claim 13 is withdrawn in view of the amendment to claims 1 and 13 which remove “DCD”, add a “-” to lysplasminogen, and correct the typographical errors in claim 13.
Claim Rejections - 35 USC § 112(b)
The rejection of amended and previously presented 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:
Claims 1 and 13 reciting lists of method steps without indicating whether the method steps are included with an “and”, “or”, or “and/or” relationship;
Claims 1 and 13 reciting the term “hyperoncotic”, which is a relative term (e.g., “hyper”) without indicating what it is “hyper” relative to;
Claims 1 and 13 reciting “providing a [tPA] simultaneously or after providing lys-plasminogen”;
Claims 1 and 13 reciting “conventional criteria”;
Claims 2 and 3 reciting “for example”;
Claims 8, 10, 11, and 13 reciting “such as”;
Claims 3, 6, and 8 reciting “said second hyperoncotic fluid” (line 3 of claim 3), “the first and second hyperoncotic fluids” (lines 1-2 of claim 6), or “the first, second, third, and forth hyperoncotic fluids” (line 1-2 of clam 8);
Claim 11 reciting “wherein wherein”;
Claim 13 reciting “a fourth hyperoncotic fluid comprising read blood cells (RBC), albumin at a concentration of between 50 g/L and 120 g/L and electrolytes and a coagulation inhibitor” in lines 16-17;
is withdrawn in view of Applicant’s amendments to the claims such that:
Claims 1 and 13 now recite “and” to clarify the step relationships;
Claims 1 and 13 now recite “wherein the first, second, third, and fourth hyperoncotic fluid has a higher oncotic pressure than the surrounding tissue;
Claims 1 and 13 now recite “providing a tissue plasminogen activator (tPA) simultaneously with providing the lys-plasminogen” in lines 7-8 of claim 1 and “providing a tissue plasminogen activator (tPA) to the organ simultaneously with providing lys-plasminogen” in lines 8-9 of claim 13;
Claims 1 and 13 no longer recite “conventional criteria”;
Claims 2 and 3 no longer recite “for example”;
Claims 8, 10, 11, and 13 no longer recite “such as”;
Claim 1 has been amended to recite a first hyperoncotic fluid and a second hyperoncotic fluid.
Claim 11 reciting “wherein” without the duplication;
Claim 13 now recites “circulating through the organ a fourth hyperoncotic fluid at a temperature of between 29oC and 37oC, wherein the fourth hyperoncotic fluid comprises red blood cells (RBC); albumin at a concentration of between 50 g/L and 120 g/L; electrolytes; and a coagulation inhibitor”, such that the fourth hyperoncotic fluid comprises all four of red blood cells, albumin, electrolytes, and a coagulation inhibitor.
**The following new rejection is necessitated by amendments to the claims.**
Amended and previously presented claims 1-13 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.
Independent claims 1 and 13 newly recite the limitation, “the surrounding tissue” in lines 15 and 26, respectively. There is insufficient antecedent basis for this limitation in the claim. Amended claim 1 has no prior recitation of any surrounding tissue. As such, the metes and bounds of the claim cannot be determined.
Amended and previously presented claims 2-12 are included in this rejection due to their dependence on amended independent claim 1.
Independent claim 13 additionally newly recites the limitation "the first, second, third, and fourth hyperoncotic fluid" in line 25. There is insufficient antecedent basis for this limitation in the claim. Amended claim 13 has prior recitations of “a first hyperoncotic fluid”, “a third hyperoncotic fluid”, and “a fourth hyperoncotic fluid”. Additionally, claim 13 has a prior recitation of “a second fluid” in line 10 and “the second fluid” in line 11, but does not have a prior recitation of any second hyperoncotic fluid. As such, the metes and bounds of the claim cannot be determined.
Claim Interpretation
It is noted that although amended independent claims 1 and 13 both recite “providing lys-plasminogen to the organ” and “providing a tissue plasminogen activator (tPA)” to the organ, neither claim requires “circulating” of either the first or second hyperoncotic solution through the organ, such as under pressure and/or via perfusion/reperfusion.
Claims 1-3 and 6-13 are interpreted without limitation to the organ temperature, while the temperature of the third hyperoncotic fluid must be between 5-25°C and the temperature of the fourth hyperoncotic fluid must be between 30-37°C, for example at least as the fluids enter the organ for circulation.
Regarding the order of method steps, claim 9 is interpreted to mean the fluid(s) is passed through a leucocyte-filter either before entering the kidney or, if not, before it reenters the kidney, e.g., during a repeated circulation. Similarly, in claims 10 and 11, the respective “contacting” step is interpreted to occur prior to the circulating of the fluid(s) or, if not, before it reenters the kidney, i.e., during recirculation.
Claim Rejections - 35 USC § 103
The rejection of amended and previously presented claims 1-2, 4-5, and 8 under 35 U.S.C. 103 as being unpatentable over Hosgood (Hosgood et al., Br J Surg 102: 1433-40 (2015)) in view of Eibl (US 5,520,912 A), Kaths (Kaths et al., J Vis Exp 101: e52909 (2015)), Steen (US20140007961A1), Scalea (Scalea et al., Am J Transplant 17: 191-200 (2016)), Hosgood2 (Hosgood et al., BMJ Open 6: e012237 (2017)), and Bjork (Bjork & Lindahl 1982, Molecular & Cellular Biochemistry, 48, 161-182), is withdrawn in view of Applicant’s amendment to claim 1 reciting “wherein the first, second, third, and fourth hyperoncotic fluid has a higher oncotic pressure than the surrounding tissue” in lines 14-15. None of the cited references teach the oncotic pressure of the surrounding tissue.
The rejection of amended and previously presented claims 1-8 under 35 U.S.C. 103 as being unpatentable over Hosgood (Hosgood et al., Br J Surg 102: 1433-40 (2015)) in view of Eibl (US 5,520,912 A), Kaths (Kaths et al., J Vis Exp 101: e52909 (2015)), Steen (US20140007961A1), Scalea (Scalea et al., Am J Transplant 17: 191-200 (2016)), Hosgood2 (Hosgood et al., BMJ Open 6: e012237 (2017)), and Bjork (Bjork & Lindahl 1982, Molecular & Cellular Biochemistry, 48, 161-182), as applied to claims 1-2, 4-5, and 8 above, and further in view of Caraceni (Caraceni et al., Blood Transfus Suppl 4: s18-25 (2013)) and Mangino (US 9,399,027 B2), is withdrawn in view of Applicant’s amendment to claim 1 reciting “wherein the first, second, third, and fourth hyperoncotic fluid has a higher oncotic pressure than the surrounding tissue” in lines 14-15. None of the cited references teach the oncotic pressure of the surrounding tissue.
The rejection of amended and previously presented claims 1-2, 4-5, and 8-9 under 35 U.S.C. 103 as being unpatentable over Hosgood (Hosgood et al., Br J Surg 102: 1433-40 (2015)) in view of Eibl (US 5,520,912 A), Kaths (Kaths et al., J Vis Exp 101: e52909 (2015)), Steen (US20140007961A1), Scalea (Scalea et al., Am J Transplant 17: 191-200 (2016)), Hosgood2 (Hosgood et al., BMJ Open 6: e012237 (2017)), and Bjork (Bjork & Lindahl 1982, Molecular & Cellular Biochemistry, 48, 161-182), as applied to claims 1-2, 4-5, and 8 above, and further in view of Roman (Roman et al., Transplantation 96: 509-18 (2013)), is withdrawn in view of Applicant’s amendment to claim 1 reciting “wherein the first, second, third, and fourth hyperoncotic fluid has a higher oncotic pressure than the surrounding tissue” in lines 14-15. None of the cited references teach the oncotic pressure of the surrounding tissue.
The rejection of amended and previously presented claims 1-2, 4-5, 8, and 10-11 under 35 U.S.C. 103 as being unpatentable over Hosgood (Hosgood et al., Br J Surg 102: 1433-40 (2015)) in view of Eibl (US 5,520,912 A), Kaths (Kaths et al., J Vis Exp 101: e52909 (2015)), Steen (US20140007961A1), Scalea (Scalea et al., Am J Transplant 17: 191-200 (2016)), Hosgood2 (Hosgood et al., BMJ Open 6: e012237 (2017)), and Bjork (Bjork & Lindahl 1982, Molecular & Cellular Biochemistry, 48, 161-182), as applied to claims 1-2, 4-5, and 8 above, and further in view of Brady (US20020197252A1), is withdrawn in view of Applicant’s amendment to claim 1 reciting “wherein the first, second, third, and fourth hyperoncotic fluid has a higher oncotic pressure than the surrounding tissue” in lines 14-15. None of the cited references teach the oncotic pressure of the surrounding tissue.
The rejection of amended and previously presented claims 1-8 and 12-13 under 35 U.S.C. 103 as being unpatentable over Hosgood (Hosgood et al., Br J Surg 102: 1433-40 (2015)) in view of Eibl (US 5,520,912 A), Kaths (Kaths et al., J Vis Exp 101: e52909 (2015)), Steen (US20140007961A1), Scalea (Scalea et al., Am J Transplant 17: 191-200 (2016)), Hosgood2 (Hosgood et al., BMJ Open 6: e012237 (2017)), Bjork (Bjork & Lindahl 1982, Molecular & Cellular Biochemistry, 48, 161-182), Caraceni (Caraceni et al., Blood Transfus Suppl 4: s18-25 (2013)), and Mangino (US 9,399,027 B2), as applied to claims 1-8 above, and further in view of Smith et al. 2019, Intensive Care Medicine, 45, 310-321, published 06 February 2019, is withdrawn in view of Applicant’s amendment to claims 1 and 13 reciting “wherein the first, second, third, and fourth hyperoncotic fluid has a higher oncotic pressure than the surrounding tissue” in lines 14-15 and 25-26, respectively, and the amendment to claim 13 . None of the cited references teach the oncotic pressure of the surrounding tissue.
**The following new rejection is necessitated by amendments to the claims.**
Amended and previously presented claims 1-13 are newly rejected 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).
The claims are interpreted as explained in a previous section. In addition, the preamble phrase “recovering an organ” is considered to imply nothing more than the method produces an organ suitable for any downstream process from the harvested organ, and thus, the method of claim 1 is performed under conditions not contrary to providing such a suitable organ. Specifically, the method is not limited to providing only organs suitable for transplantation to a living recipient. Furthermore, the “evaluating suitability of transplantation” step of claim 1 does not imply any limitation not recited in the claim, such as an implied structural or functional characteristic(s) of the recovered organ, in that the suitability for transplantation is evaluated, but suitability for transplantation itself is not required by the claim language.
Hosgood teaches the recovery of an organ harvested from a cardiac arrest donor after circulatory death [column 1 ¶ 1, column 6 ¶ 3, Table 4]. Hosgood teaches methods of perfusing a harvested organ (e.g., kidney), obtained from donation after circulatory death (DCD) donor, ex vivo (e.g., ex vivo normothermic perfusion (EVNP)) and evaluating retrieved kidneys, the methods including a restoration step (pg. 1433, right col., last para., to pg. 1434, left col., 2nd para.) comprising circulating through the kidney a solution comprising physiological electrolytes (Ringer’s solution) and oxygenated red blood cells (RBC) at near body temperature (e.g., ~36°C), such as prior to transplantation to increase oxygenation of kidney tissues, reduce ischemic reperfusion injury, and improve graft function (pg. 1434, left col., 4th para., to right col., last para.; pg. 1435, left col., 4th para.; Abstract). Hosgood teaches using the evaluating step criteria to produce an overall assessment score (Table 1) useful in assessing kidney quality and decisions regarding suitability for transplantation (Abstract; pg. 1434, right col., last para.; pg. 1434, left col., para. 1-2).
Regarding claim 1, Hosgood does not teach (1) providing to the kidney a hyperoncotic solution specifically comprising lys-plasminogen and/or a tissue plasminogen activator (tPA); (2) a first restoration step of circulating through the kidney a hyperoncotic solution comprising albumin and electrolytes at a temperature between 5-25°C; (3) that the first, second, third, and fourth hyperoncotic fluids have a higher oncotic pressure than a surrounding tissue; or (4) that the organ is retrieved from the donor at least two hours after circulation arrest of the organ.
Regarding (1), Eibl teaches both lys-plasminogen and tissue plasminogen activator (t-PA) treatments provide protective effects to organs damaged by ischemia and reperfusion (col. 6, lines 49-58; col. 8, lines 4-11), and lys-plasminogen treatment is useful in the preservation of organs for transplant by minimizing ischemic damage (col. 5, lines 30-43; col. 7, 60-3). Eibl teaches administering both lys-plasminogen along with t-PA may improve vascular flow via fibrinolysis, e.g., of blood clots (col. 8, lines 4-11; col. 4, lines 20-56). Eibl teaches the administration specifically for protecting the organ to be transplanted from ischemia, including administration locally into an artery supplying the organ or tissue, such that the lys-plasminogen and tPA circulate through the organ [column 5 ¶ 6, column 10 ¶ 1-4]. As such, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to treat a retrieved organ with both lys-plasminogen and t-PA to provide protective effects to organs damaged by ischemia and reperfusion and to preserve the organ for transplant. An ordinarily skilled artisan at the time of filing would also have a reasonable expectation of success given the teachings of Hosgood of ex vivo perfusion in light of the teachings of Eibl of the beneficial effects of lys-plasminogen and tPA treatment on donor organs.
Regarding (2), Kaths teaches a traditional method of maintaining a harvested kidney is based on static cold storage or hypothermic machine perfusion, and an updated method comprises circulating through the organ a hyperoncotic fluid (STEEN solution) comprising albumin and physiological electrolytes to keep oncotic pressure and osmolarity within a physiological range (pg. 12, 2th para.). As evidenced by Steen, a STEEN solution may comprise albumin at 50 g/L (5%) with the solution used at a temperature between 5°C and 25°C, e.g., 10° C or less (hypothermic) ([0103]; [0106]).
Regarding (3), Kaths teaches that circulating a hyperoncotic fluid keeps pressure and osmolarity within a physiological range to maintain a harvested kidney [pg. 12 ¶ 2]. Specifically, Kaths teaches that it is important to keep oncotic pressure and osmolarity of the perfusate within a physiological range, and that a low oncotic pressure will result in an unphysiologically high urine production with significant kidney edema and increasing markers of kidney injury [pg. 12 ¶ 2]. Kaths also teaches that the perfusion and urine replacement solution should represent physiological values for blood oncotic pressure [page 4 ¶ 2].
Steen teaches the perfusion fluid comprises an oncotic agent exerting an oncotic pressure larger than about 30 mmHg [0007].
Mangino teaches that the term “oncotic agent” refers to a molecule that exerts oncotic pressure, or colloid osmotic pressure, that pulls fluid into the circulatory system [column 5 ¶ 2], thereby teaching at “oncotic pressure” and “colloid osmotic pressure” are synonyms. Mangino further teaches that an oncotic agent is the opposing force to capillary filtration pressure and interstitial colloidal osmotic pressure that balances out the tendency for fluid to leak out of the capillaries, such that the oncotic pressure tends to pull fluid into the capillaries and a loss of oncotic pressure and an increase in filtration across the capillary results in cell swelling and excess fluid buildup in the tissues [column 5 ¶ 2].
Levenbrown teaches that normal human plasma colloid osmotic pressure/oncotic pressure is 28 mmHg and the average colloid osmotic interstitial pressure is about 8 mmHg [page 1 ¶ 1-2 of excerpt]. Therefore, the teaching of Kaths to keep the oncotic pressure of the perfusate within the physiologic range is a teaching to keep the oncotic pressure in a range about 28 mmHg (e.g., a STEEN solution of greater than 30 mmHg, as taught by Steen), which is higher than the oncotic pressure of a surrounding tissue, e.g., the oncotic pressure of the interstitial fluid within the tissues of the organ (e.g., about 8 mmHg).
Regarding (4), Scalea teaches harvesting kidneys after circulatory death (DCD) at 1-2 hours after treatment withdraw (TTD), which occurs after circulation arrest and agonal time, e.g., removal of life support machine and induced coma, does not affect outcomes of kidney transplantation based on timing (pg. 191, 1st para.; Abstract; Fig. 4, 6). Scalea teaches evaluating donor kidney function after transplantation by a criterion of the medical need for hemodialysis as a proxy for inferior renal function, such as time to next hemodialysis treatment of the recipient (i.e., delayed graft function (DGF)) (pg. 191, 1st para.; 192, left col., 2nd para.). Additionally, Scalea states, “we would propose that a majority of [organ procurement organizations] move toward a standardized policy of allowing 2 h from agonal time (e.g., time at which systolic blood pressure drops below 80 mmHG and/or SpO2 drops below 80%) for stand-down time for kidneys” [column 13 ¶ 1, column 17 ¶ 3], thereby teaching to wait up to 2 hours after circulation arrest of the organ prior to retrieval of the organ from the donor. Scalea goes on to teach that waiting 2 additional hours (4 hours after withdrawal of treatment) would capture an additional 12.5% of potential donors, and that waiting as long as 12 h after withdrawal of treatment, as many as 50% of otherwise unsuccessful DCD donations could be converted to successful DCD donations [column 18 ¶ 4]. Therefore, Scalea teaches the retrieval of the organ from the donor at least two hours after circulation arrest of the organ, and provides motivation to retrieve organs at least 2 hours after circulation arrest of the organ to increase the number of viable transplantable kidneys retrieved while providing excellent outcomes to patients on the wait-list [column 18 ¶ 1].
Additionally, Smith teaches in situ organ preservation such that the maximum time from a witnessed cardiac arrest/ circulation arrest is 150 minutes, after which in situ preservation of abdominal organs can occur by in situ cooling, normothermic regional perfusion (nRP), or hypothermic regional perfusion (hRP) for a maximum of 180 minutes for in situ cooling or a maximum of 240 minutes for nRP or hRP [column 12 ¶ 2, Figure 3]. Therefore, Smith teaches the retrieval of an organ from the donor up to 6.5 hours following circulation arrest of the organ.
Smith also teaches that a continuing shortage of deceased donor organs for transplantation and the limited number of potential donors after brain death has led to a resurgence of interest in donation after circulatory death (DCD), and that new techniques of in situ organ preservation have contributed to minimizing the threat from warm and cold ischemia processes which threaten the viability of DCD organs [abstract, column 1 ¶ 1]. Smith further teaches that the in situ organ preservation method as taught in Figure 3 is initiated when an EMS attends a witnessed, unexpected cardiac arrest in a patient in whom resuscitation is unsuccessful despite advanced cardiopulmonary resuscitation (aCPR), and that efforts for preserving organ viability accompany any further efforts to restore life to the potential donor in case of ultimate resuscitation failure [column 10 ¶ 4- column 11 ¶ 1]. As such, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to retrieve an organ from such a donor for which at least 3 or 4 hours has passed (in which time was allotted for appropriate resuscitation methods and in situ organ preservation), when suitability of the donor has been established, for subsequent transplantation into a recipient.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to modify the method of Hosgood to comprise providing a hyperoncotic solution comprising both lys-plasminogen and t-PA simultaneously as taught by Eibl. One of ordinary skill in the art would be motivated to minimize ischemic damage and blood clotting to increase kidney functionality and transplantation suitability. Furthermore, one of ordinary skill in the art would be motivated to use the evaluating step of the ex vivo perfusion method of Hosgood to decide whether an individual kidney was suitable for transplantation using kidney quality criteria (e.g., macro-appearance, blood flow, and urine output (Table 1)), which meets the plain language meaning of the phrase “evaluating the kidney for suitability of transplantation.”
Moreover, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to include in the procedure of Hosgood before its restoration step a conventional EVP step of circulating through the kidney a hypothermic hyperoncotic solution comprising albumin and electrolytes, wherein the hyperoncotic solution has a higher oncotic pressure than a surrounding tissue, as taught by Kaths, Steen, Mangino, and Levenbrown. One of ordinary skill in the art would be motivated to keep oncotic pressure and osmolarity of an organ within a physiological range (e.g., such that the perfusate oncotic pressure is higher than the tissue interstitial pressure), and to obtain donated kidneys, many of which are subjected to this step already.
Additionally, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to perform the method of Hosgood as modified by Eibl, Kaths, Steen, Mangino, and Levenbrown wherein the kidney is retrieved at least two hours after circulation arrest due to cardiac arrest in view of Scalea and Smith because one would be motivated to obtain as many viable transplantable kidneys as possible to subject to restoration/preservation, especially kidneys often excluded by standard donor kidney procurement practices, to better meet the medical demand.
Regarding claim 2, Hosgood teaches maintaining an ex vivo perfusion pressure of 70-75 mmHg (mean arterial pressure), which constitutes a circulation pressure increase to a native kidney, and Steen teaches the albumin concentration in the perfusate solution is approximately 50 g/L (5%).
Regarding claim 3, the combination of Hosgood, Eibl, Kaths, Steen, Mangino, Levenbrown, Scalea, and Smith does not teach the RBC solution comprises albumin, such as at a concentration between 50-120 g/L.
Mangino teaches albumin is an oncotic agent that creates colloid osmotic pressure in the circulatory system thereby expanding the volume of circulating vascular fluids by maintaining oncotic hemostasis to prevent excessive fluid loss at capillaries and also useful as a clinical volume expander during blood loss (col. 5, lines 9-26 and 46-51).
Additionally, Caraceni teaches the naturally occurring albumin concentration in blood of a healthy human is between 35-50 g/L (3.5-5 g/dL) and acts as the main agent of oncotic pressure in plasma (contributing up to 80%) and modulator of fluid distribution in the body, being at 14 g/L in the interstitium (s18, para. 1-4).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to perform the procedure of Hosgood as modified by Eibl, Kaths, Steen, Mangino, Levenbrown, Scalea, and Smith, wherein any of the hyperoncotic perfusates (e.g., the RBC solution) comprise albumin at a concentration greater than 50 g/L, a naturally neutral level as taught by Caraceni, to exert a positive oncotic pressure on the kidney during ex vivo perfusion to prevent excessive fluid loss at capillaries and thereby to help preserve the viability of the organ.
Regarding claims 4-5, although Hosgood teaches hypothermic storage of the restored kidney after EVNP with the fourth oncotic fluid (second restoration step) in a 4°C kidney preservation fluid with the kidney on ice (pg. 1435, 4th para.), Hosgood does not teach the preservation fluid is circulated through the kidney at a pressure below 30 mmHg for a time of between one hour and 7 hours.
However, Steen teaches storing an organ ex vivo in a perfusion machine at a hypothermic temperature between 4-16°C (10° C or less) while circulating a preservation fluid (STEEN solution) through the organ at a pressure below 30 mmHg (at least 15 mmHg) for a duration of 1-7 hours, e.g., 4 or 6 hours on battery power for transport by airplane to any medical site within Europe ([0103]; [0106]-[0107]; [0007]).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to perform the method of Hosgood, as modified by Eibl, Kaths, Steen, Mangino, Levenbrown, Scalea, and Smith, wherein after the final restoration step the kidney is stored and transported via hypothermic machine perfusion with STEEN solution at 15 mmHg for 1-6 hours for delivery of the restored kidney to a transplant recipient.
Regarding claims 6-7, the combination of Hosgood, Eibl, Kaths, Steen, Mangino, Levenbrown, Scalea, Smith, and Caraceni does not explicitly teach the hyperoncotic solution(s) comprising lys-plasminogen and/or t-PA also comprises albumin, such as at a concentration between 50-120 g/L.
However, as mentioned above, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to perform the procedure of Hosgood as modified by Eibl, Kaths, Steen, Levenbrown, Mangino, Scalea, Smith, and Caraceni, wherein any of the hyperoncotic perfusates comprise albumin at a concentration greater than 50 g/L, a naturally neutral level, to exert a positive oncotic pressure on the kidney during perfusion to prevent excessive fluid loss at capillaries and thereby to help preserve organ viability/function.
Regarding claim 8, the combination of Hosgood as modified by Eibl, Kaths, Steen, Mangino, Levenbrown, Scalea, Smith, and Caraceni, does not teach wherein at least one of the hyperoncotic solution perfusates comprises a coagulation inhibitor.
However, Hosgood2 teaches methods of perfusing a kidney ex vivo (EVNP) including a restoration step comprising circulating through the kidney a solution comprising red blood cells (RBC) and a coagulation inhibitor (heparin) at near body temperature (e.g., 35-36°C), such as prior to transplantation to increase oxygenation in the kidney tissues (pg. 2, left col., 2nd para.; pg. 3, left col., 1st para., to pg. 4, left col., 2nd para.). Additionally, Bjork teaches that heparin is an anticoagulant (title, pg. 161 ¶ 1).
Further, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to modify the method of Hosgood to include heparin in the RBC solution perfusate as taught by Hosgood2 and Bjork. One of ordinary skill in the art would be motivated to minimize coagulation and clotting (e.g., within the perfusion circuit) to help maintain perfusion flow and to preserve the kidney for future use/transplantation.
Regarding claim 9, the combination of Hosgood, Eibl, Kaths, Steen, Mangino , Levenbrown, Scalea, Smith, Caraceni, Hosgood2, and Bjork does not teach either the Steen albumin solution or RBC solution is circulated through a leucocyte-filter.
However, Roman teaches filtering organ perfusion fluids using leukocyte filters (leukocyte depletion filter) is beneficial in reducing alloimmune reactivity by removing donor-derived immune cells, e.g., by reducing/preventing the presence of monocytes, inflammatory macrophages and/or dendritic cells in the organ that can release proinflammatory cytokines and promote organ rejection (pg. 515, left col., 2nd para.; pg. 513, right col., para. 4).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to include in the procedure of Hosgood, as modified by Eibl, Kaths, Steen, Mangino, Levenbrown, Scalea, Smith, Caraceni, Hosgood2, and Bjork, a leukocyte-depletion filter in any perfusion step to filter any of the perfusates, especially the penultimate solution, to remove potentially dangerous donor-derived immune cells prior to transplanting the kidney into a recipient. One of ordinary skill in the art with the goal of preparing the kidney for medical transplantation use would be motivated by safety reasons (e.g., to reduce autoimmune reactivity) to do so as taught by Roman.
Regarding claims 10-11, the combination of Hosgood, Eibl, Kaths, Steen, Mangino, Levenbrown, Scalea, Smith, Caraceni, Hosgood2, Bjork, and Roman does not teach either the Steen albumin solution or RBC solution is contacted by a cytokine adsorber or endotoxin adsorber.
However, Brady teaches methods of removing unwanted factors from a body fluid or organ for transplantation by selective adsorption ([0035]-[0036]; [0031]), including cytokines and LPS endotoxin ([0037]; FIG. 15; [0179]-[0181]; FIG. 13), e.g., by exposure of a circulating fluid to a cytokine adsorption medium ([0038]) or endotoxin adsorption medium ([0179]). Brady teaches it is desirable to remove excessive inflammatory cytokines and inflammatory endotoxin, which can cause significant tissue injury and even death, such as via septic shock during allotransplantation ([0005]; [0008]-[0010]; [0021]).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to include in the procedure of Hosgood, as modified by Eibl, Kaths, Steen, Mangino, Levenbrown, Scalea, Smith, Caraceni, Hosgood2, Bjork, and Roman, contacting the Steen albumin solution and/or RBC solution to a cytokine adsorber or endotoxin adsorber to remove potentially dangerous inflammatory factors to prevent tissue injury and/or death. One of ordinary skill in the art with the goal of preparing the organ for medical transplantation use would be motivated by safety reasons (e.g., avoiding death) to do so as taught by Brady to avoid detrimental inflammatory responses.
Regarding claim 12, as described above, Smith teaches in situ organ preservation such that the maximum time from a witnessed cardiac arrest/ circulation arrest is 150 minutes, after which in situ preservation of abdominal organs can occur by in situ cooling, normothermic regional perfusion (nRP), or hypothermic regional perfusion (hRP) for a maximum of 180 minutes for in situ cooling or a maximum of 240 minutes for nRP or hRP [column 12 ¶ 2, Figure 3]. Therefore, Smith teaches the retrieval of an organ from the donor up to 6.5 hours following circulation arrest of the organ, which includes no more than 3 hours of in situ cooling. Smith also teaches that in situ cooling of kidneys involves a double-balloon triple-catheter technique and that cooling of lungs involves the instillation of cold preservation fluid or saline serum [column 12 ¶ 2]. The methods taught by Smith do not include the use of topical cooling using cold saline, ice, or ice slush installed in the abdomen of the donor. As such, the Smith teaches the retrieval of the organ from the donor after the donor had circulation arrest for at least 3 hours, wherein the at least three hours included no more than two hours of topical cooling by cold saline, ice, or ice slush installed in the abdomen of the donor.
Smith also teaches that a continuing shortage of deceased donor organs for transplantation and the limited number of potential donors after brain death has led to a resurgence of interest in donation after circulatory death (DCD), and that new techniques of in situ organ preservation have contributed to minimizing the threat from warm and cold ischemia processes which threaten the viability of DCD organs [abstract, column 1 ¶ 1]. Smith further teaches that the in situ organ preservation method as taught in Figure 3 is initiated when an EMS attends a witnessed, unexpected cardiac arrest in a patient in whom resuscitation is unsuccessful despite advanced cardiopulmonary resuscitation (aCPR), and that efforts for preserving organ viability accompany any further efforts to restore life to the potential donor in case of ultimate resuscitation failure [column 10 ¶ 4- column 11 ¶ 1]. As such, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to retrieve an organ from such a donor for which at least 3 or 4 hours has passed (in which time was allotted for appropriate resuscitation methods and in situ organ preservation), when suitability of the donor has been established, for subsequent transplantation into a recipient.
Given the teachings and motivation taught by Smith to retrieve an organ from a cardiac arrest patient even after at least 3 to 4 hours have passed following circulation arrest, it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application to further modify the method of Hosgood, as modified by Eibl, Kaths, Steen, Mangino, Levenbrown, Scalea, Caraceni, Hosgood2, Bjork, Caraceni, Mangino, and Brady to retrieve the organ at least 3 or 4 hours after the donor had circulation arrest, with a reasonable expectation of success.
Regarding claim 13, note that most of the limitations of amended independent claim 13 have been addressed above in addressing claims 1-12.
Additionally, as described above for amended claim 2, Hosgood teaches maintaining an ex vivo perfusion pressure of 70-75 mmHg (mean arterial pressure), which constitutes a circulation pressure increase to a native kidney [column 3 ¶ 4].
Kaths teaches setting the arterial pressure to 75 mmHg [page 4 section 3.2.], and that perfusion is run with a constant physiological pressure of around 60-80 mmHg throughout the whole perfusion [page 4 ¶ 2, Figure 4].
Further, Steen teaches that the perfusion is performed at a pressure which is at least 15 mmHg and may be intermittent [0007], that the system may be operated with a substantially constant pressure or a substantially constant flow rate or any combination thereof [0068], and that total perfusion is believed to be present when the pressure is above a threshold pressure (e.g., about 10 mmHg, which depends on the organ to be perfused and the temperature of the perfused organ) [0069]. Steen further teaches that the circulation pump is operated to increase the pressure to the desired pressure value [0083].
Roman teaches perfusion of an organ in which the perfusion pressure was varied as the flow rate was gradually increased, such that the perfusion pressure is limited by a preset safe upper limit [column 9 ¶ 2, Figure 2].
Therefore, it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant to increase the pressure from an initial or threshold pressure (e.g., about 10 mmHg) to a desired pressure value, such as the pressure taught by Hosgood of 70-75 mmHg (e.g., between 70-90 mmHg). Given that the starting pressure prior to perfusion is 0 (not being perfused), the threshold pressure to get full perfusion is believed to be about 10 mmHg, and the desired pressure is 70-75 mmHg as taught by Hosgood and Kaths, increasing the pressure to the desired pressure necessarily requires passing through the value of 20 mmHg, and therefore increasing from 20 mmHg to the desired pressure between 70 mmHg and 90 mmHg.
Thus, it would have been prima facie obvious to one of ordinary skill in the art before the earliest effective filing date of the instant application to practice the claimed invention as a whole with a reasonable expectation of success.
Insofar as applicant’s arguments apply to this new grounds of rejection, applicant argues that:
1) addition of a hyperoncotic fluid to the lys-plasminogen and tPA had an unexpected synergistic effect on the lysis process;
2) the present method is directed to removing microclot ischemic damage, not preventing such microclot ischemic damage;
3) Eibl relates to the addition of lys-plasminogen and tPA to a donor or recipient that is a living body (in vivo) and having blood circulation, such that applying the teachings of Eibl of in vivo therapies solely for the purpose of improving the organs to be transplanted would be ethically questionable, and that since Eibl doesn’t disclose using the method ex vivo, it would not be obvious to combine it with Hosgood;
4) Kaths does not disclose or suggest hyperoncotic fluids which have an oncotic pressure larger than the physiologic range as recited in the present claims;
5) Scalea discloses how DCD donors time-to-death affect recipient outcomes, which is a discussion of time before circulatory death while the claimed invention relates to time after circulatory death, that the presumption is that harvesting takes place as soon as possible after circulatory death such that there is no problem with coagulation after circulation arrest of the kidney, and that coagulation may start during agonal time, but the inventor could not find that such coagulation resulted in microclots;
6) Mangino teaches an organ preservation solution for in vivo use in a living patient, and other conditions may apply for a fluid to be used ex vivo during organ storage;
7) Smith discloses post-mortem organ preservation in which normothermic regional perfusion (nRP) is performed and there is no substantial time duration when there is no circulation in the organ, but the instant claims recite that the circulation arrest to the organ should be at least two hours before harvesting.
However, this is not agreed.
In response to applicant’s arguments against the references individually, it is noted that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In addition, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Specifically, regarding Applicant’s argument 1) that addition of a hyperoncotic fluid to the lys-plasminogen and tPA had an unexpected synergistic effect on the lysis process, note that the assertion of unexpected results was not accompanied by any evidentiary data, and as such amounts to arguments of counsel. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP § 716.01(c) for examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration. Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. MPEP 716.01(c). Attorney argument is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art.
It is also noted that any evidence of unexpected results must be commensurate in scope with the claimed invention, and that a greater, or greater than additive, effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected MPEP 716.02 (a) and (d). Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).
Note that Applicant’s arguments assert that organs harvested more than 4 hours after patient death and ensuing circulation arrest in the organs, which were treated with lys-plasminogen and tPA and subsequent normothermic treatment with a red blood cell suspension seemed to respond to the normothermic treatment. Additionally, Applicant asserts that such organs harvested more than 4 hours after patient death and ensuing circulation arrest in the organs which were exposed to a hyperoncotic fluid in addition to the lys-plasminogen and tPA and circulating fluid had a better response such that the hyperoncotic fluid had an unexpected synergistic effect on the lysis process. However, the instant claims recite that the organ is retrieved from the donor at least two hours after circulation arrest of the organ (not after cardiac arrest of the donor or patient death). Further, statements of “seemed to respond”, “response was even better”, and “a synergistic effect” in the absence of data do not provide support for a claim of unexpected results in that they do not provide a reference for evaluating the merits of the unexpected results assertion. Further, the statements provided are presented broadly and do not include details which would indicate that the referenced methods were performed consistently with the scope of the claims as written, such as performance of all method steps and limitations included therein as recited in claim 1.
Regarding Applicant’s argument 2) that the present method is directed to removing microclot ischemic damage, not preventing such microclot ischemic damage, note that the instant claims as written do not include any limitations reciting removing microclot ischemic damage. The claims are directed towards methods of “recovering an organ” harvested from a donor. The specification does not provide a limiting definition of the words “recover” or “recovering” nor the phrase “recovering an organ”. Hosgood teaches that “a measure of the organ’s ability to recover is also examined” [column 11 ¶ 4]. Scalea uses the term “organ recovery” to modify the team which is harvesting an organ [column 2 ¶ 2] and an “attempted recovery” to be an attempt to obtain an organ [column 3 ¶ 3]. Smith teaches “poor preservation is the main reason to discard abdominal organs once recovered” [column 13 ¶ 2]. Therefore, the phrase “recovering an organ” is not limited in the art to refer to improving the organ in some way.
As discussed in the prior action, the broadest reasonable interpretation of “recovering an organ” is considered to imply nothing more than the method produces an organ suitable for any downstream process from the harvested organ, and thus, the method of claim 1 is performed under conditions not contrary to providing such a suitable organ. Specifically, the method is not limited to providing only organs suitable for transplantation to a living recipient. Furthermore, the “evaluating the organ for suitability of transplantation” step of claim 1 does not imply any limitation not recited in the claim, such as an implied structural or functional characteristic(s) of the recovered organ, in that the suitability for transplantation is evaluated, but suitability for transplantation itself is not required by the claim language.
Note additionally that Applicant’s arguments assert the removal of microclots themselves, which contribute to the development of ischemic damage, and so it is unclear how Applicant is also asserting that the microclot ischemic damage itself is removed, in that the damaged tissues of the organ are not removed by the methods recited in the instant claims. It would appear that by removing the microclots, as a result of the instantly claimed methods, (further) ischemic damage is being prevented, which effect is consistent with teachings in the prior art for treating an organ to prevent ischemic damage.
Regarding Applicant’s argument 3), note that ethical considerations are not part of an evaluation of obviousness under 35 U.S.C. 103.
Note further that Eibl was cited for teaching that both lys-plasminogen and tissue plasminogen activator (t-PA) treatments provide protective effects to organs damaged by ischemia and reperfusion (col. 6, lines 49-58; col. 8, lines 4-11), and lys-plasminogen treatment is useful in the preservation of organs for transplant by minimizing ischemic damage (col. 5, lines 30-43; col. 7, 60-3). Although Eibl teac