Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Response to Amendments
Applicant’s amendments, Declaration submitted under 37 C.F.R. §1.132 by Joan Roselló-Catafau, Ph.D. and response filed Jun. 25, 2026 have been received and entered into the case.
Status of the Claims
Claims 1, 3, 6-7 and 10-24 are currently pending.
Claims 2, 4, 5, 8 and 9 are cancelled.
Claim 24 is new.
Claims 1, 3, 6-7 and 10-24 have been considered on the merits.
Claim Rejections - 35 USC § 112(a)
New claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ) have been added to address the claim amendments.
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.
Claim 24 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 24 recites a limitation of “wherein the aqueous solution is substantially free of calcium ions. The specification describes that “NO2- ions are provided by a nitrite salt, for example, sodium nitrite (NaNO2), calcium nitrate (Ca(NO2)2, or potassium nitrite (KNO2) (see 0085 of published application). This description only relates calcium ions to form of nitrite salt and is one of three options listed for providing nitrite. There is no statement that the salt is intended to provide calcium ions to the solution as well. The specification does not state/describe a solution clearly containing or not containing calcium ions. The MPEP 2173.05(i) states that any negative limitation or exclusionary proviso must have basis in the original disclosure and if alternative elements are positively recited in the specification, they may be explicitly excluded in the claims. However, there appears to be no basis in the original disclosure for the negative limitation of the aqueous solution being substantially free of calcium ions.
All other claims depend directly or indirectly from the rejected claim and are, therefore, also rejected under USC 112 for the reasons set forth above.
This is a new matter rejection.
Claim Rejections - 35 USC § 112(b)
New claim rejections under 35 USC § 112, (b) or second paragraph (pre-AIA ) have been added to address the claim amendments.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 24 is 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.
The term "substantially" in claim 24 is a relative term which renders the claim indefinite. The term "substantially" is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Appropriate correction is required.
Claim Rejections - 35 USC § 102
The claim rejections under 35 USC § 102 are withdrawn due to applicant’s arguments being persuasive.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are revised due to amendment. New claim rejections under 35 USC § 103 have been added to address the newly added claim 24.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 10-12, and 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Lopez et al. (US 2002/0068265 A1) (ref. of record) as evidenced by Wicomb et al. (WO 98/35551) and Pasut et al. (World Journal of Gastroenterology, 2016) in view of Jochmans et al. (American Journal of Transplantation, 2016) (ref. of record).
With respect to claim 1, Lopez teaches a method of preserving and rinsing organs in an aqueous solution (0001-0002 and 0028). Lopez teaches the aqueous solution containing sodium ions at a concentration of 30-250 mmol, specifically at 125 mmol (0017-0019 and Table 2). Lopez teaches the aqueous solution containing potassium ions at a concentration of 10-40 mmol, specifically at 25 mmol (0024-0026 and Table 2). Lopez teaches the aqueous solution containing polyethylene glycol with a molecular weight of 35,000 g/mol (PEG35000) at a concentration of 0.01 to 5 mmol ((0.35-175 g/L)), specifically at 25 mmol (1.02 g/L) (0020-0021 and Table 2). Lopez teaches the organ or tissue are washed of residual blood (rinsed) and that typically organs are rinsed after being removed (0002-0003 and 0007).
Although, the concentration range of PEG35000 (0.35-175 g/L) of Lopez is larger than the claimed concentration range of PEG35000 of 2-5 g/L as recited in claim 1, one of ordinary skill in the art would recognize that the concentration of PEG35000 in an organ preservation would be matter of routine optimization depending on such factors as the organ being preserved, environmental conditions of the organ, the preservation strategy/temperature, and the specific properties of colloid used and as evidenced by Wicomb. Wicomb reports an organ preservation solution containing a biologically effective amount of substantially linear polyethylene glycol (PEG) including PEG 35,000 (PEG35000) (pg. 7 lines 28-30, pg. 8 lines 1-4 and pg. 11 lines 13-16). Wicomb teaches that a “biologically effective amount” is meant to be a concentration of the component able to improve the ability of an OPS (organ preservation solution) to preserve organs or a concentration able to preserve or restore cell, tissue or organ function (pg. 18 lines 5-7). In further support, Pasut reports that the addition of PEG35 (PEG35000) at a concentration of 5 g/L to the preservation solution used in subnormothermia machine transfusion (SNMP) with a supercooling technique is necessary to achieve successful liver transplantation after six days of preservation (pg. 6505 Col. 1 para. 2). Furthermore, generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation" In re Aller, 220 F.2d 454,456, 105 USPQ 233,235 (CCPA 1955) -MPEP § 2144.05.
With respect to claim 1, Lopez teaches the method where the organ is perfused with the solution (preserving is dynamic) and teaches perfusing livers with the inventive solution of Table 2 (solution of Group C) (0035-0038 and 0055). It appears from these teachings that the limitation of dynamic preservation is taught by Lopez, however, if the limitation of dynamic preservation is shown not to be taught by Lopez, it would have been obvious to one of ordinary skill in the art to modify the method of Lopez to use the aqueous solution for dynamic preservation.
In support, Jochmans teaches in the beginning of transplantation technology that dynamic preservation was the only way to preserve deceased organs and currently dynamic preservation strategies are being used to optimize organ preservation, to allow for real-time graft viability assessment, and as mode for delivering condition agents to repair damaged organs (abstract and pg. 2546 Col. 1 para. 1). Jochmans teaches dynamic preservation strategies allow for improved organ quality and utilization (pg. 2546 Col. 1 para. 1). In further support, Lopez teaches the desire for one solution for preserving organs (0006-0015).
Accordingly at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method of Lopez so that the exposing of the organ includes dynamic preservation for the benefit of improving the organ quality as taught by Jochmans. It would have been obvious to one of ordinary skill in the art to modify the method of Lopez so that the exposing of the organ includes dynamic preservation, since dynamic preservation was well-known in the art at the time and was known for the benefits of optimizing organ preservation, allowing for real-time graft viability assessment, and as a mode for delivering condition agents to repair damaged organs as taught by Jochmans. It would have been obvious to one of ordinary skill in art to use the preservation solution taught by Lopez in dynamic preservation, since Lopez teaches the desire for one solution and Jochmans teaches the benefits of dynamic preservation. One of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to Lopez, since dynamic preservation was known in the art in methods of exposing organs intended for transplantation to an aqueous solution to preserve the organ as taught by Jochmans.
With respect to claim 3, Lopez teaches the method where the aqueous solution is maintained at a temperature between 2 to 10°C, and specifically at a temperature of 4°C (0029). With respect to claims 10 and 11, Lopez teaches the method where the organ intended to be transplanted or preserved is liver, kidney and heart (0074 and Example II). With respect to claim 12, Lopez teaches the method where the aqueous solution contains glutathione at a concentration of 1-6 mmol, specifically at 3 mmol (0026 and Table 2). With respect to claim 15, Lopez the method where the aqueous solution has a pH between 6.5 and 8, specifically a pH of 7.4 (0024-0025 and 0032). With respect to claim 16, Lopez teaches the method where the solution further comprises an impermeant anion, a sugar, a membrane-stabilizing agent, a buffer solution, an anti-free radical agent and an energy source (0022).
With respect to claim 17, Lopez teaches the method where the aqueous solution contains raffinose at a concentration of 20-40 mmol, specifically at 30 mmol (0026 and Table 2). Lopez teaches allopurinol at a concentration of 0.5-5 mmol, specifically at 1 mmol (0026 and Table 2).
With respect to claim 18, Lopez teaches the method where the aqueous solution contains lactobionic acid at a concentration of 70-140 mmol, specifically at 100 mmol (0026 and Table 2). Lopez teaches the solution with MgSO4 (sulphate ions) at a concentration of 1-10 mmol, specifically at 5 mmol (0026 and Table 2). Lopez the solution with teaches H2PO4 (phosphate ions) at a concentration of 10-40 mmol, specifically at 25 mmol (0026 and Table 2). Lopez teaches the solution with adenosine at a concentration of 1-10 mmol specifically at 5 mmol (0026 and Table 2).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 6 and 7 are rejected under 35 U.S.C. 103(a) as being unpatentable over Lopez in view of Jochmans (as applied to claims 1, 3, 10-12, and 15-18 above), and in further view of Fontes et al. (US 2015/0230453 A1) (ref. of record).
The teachings of Lopez and Jochmans can be found in the previous rejection above.
Lopez is silent as where the perfusing is continuous or pulsatile as recited in claims 6 and 7, respectively. However, Fontes teaches a similar method of exposing an organ to be transplanted to an aqueous solution (0002 and 0008). Fontes teaches the method where the exposing of the organ to the aqueous solution is by perfusing (0007-0008). Fontes further teaches the perfusion can be pulsatile or continuous to mimic either arterial blood flow or venous blood flow (0052). Accordingly at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method of Lopez so that the perfusion of the organ was either continuous or pulsatile for the benefit of mimicking the appropriate blood flow conditions for the organ as taught by Fontes. It would have been obvious to one of ordinary skill in the art to modify the method of Lopez to use known perfusion techniques in the art as demonstrated by Fontes. One of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to Lopez, since continuous and pulsatile perfusion was known in the art in methods of exposing organs intended for transplantation to an aqueous solution to preserve the organ as taught by Fontes.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 13 and 17 are rejected under 35 U.S.C. 103(a) as being unpatentable over Lopez in view of Jochmans (as applied to claims 1, 3, 10-12, and 15-18 above), and in further view of Ostróżka-Cieślik et al. (Acta Biochimica Polonica, 2018) (ref. of record) as evidenced by Doorscholdt et al. (US 2008/0187901 A1) and Nydegger et al. (Transplant Immunology, 2002) (ref. of record).
The teachings of Lopez and Jochmans can be found in the previous rejection above.
Lopez does not teach the method where the aqueous solution contains zinc ions at a concentration between 0.08-0.210 mmol.L-1 as recited in claim 13. However, Ostróżka-Cieślik teaches organ preservation solutions which are modified to include micronutrients to help improve the function of the organs when stored and where the micronutrient is zinc. Accordingly, at the effective time of filing one of ordinary skill in the art would have been motivated to modify the method of Lopez to include zinc in the aqueous composition for the benefit of improving the function of the organ as taught by Ostróżka-Cieślik. It would have been obvious to one of ordinary skill in the art to include zinc in the aqueous solution for preserving and rinsing an organ of Lopez, since it was known in the art to be included in such solutions for the same purpose as taught by Ostróżka-Cieślik. For this reason as well, one of ordinary skill in the art would have had a reasonable expectation of success in including zinc in the aqueous solution of Lopez.
Although Ostróżka-Cieślik is silent with respect to the concentration of zinc in the aqueous solution, one of ordinary skill in the art would recognize that the concentration of zinc is a result effective variable and that the amount of zinc would be matter of routine optimization depending on such factors as the organ being preserved as evidenced by Doorscholdt. Doorscholdt reports optimizing the balance of amino acids, vitamins, anti-oxidants, high molecular weight additives and buffering capacity of organ preservation solutions (abstract and 0006). Additionally, Doorscholdt teaches providing sufficient amount of vitamins and nutrients in the organ preservation and perfusion solution (0027-0028). Furthermore, generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation" In re Aller, 220 F.2d 454,456, 105 USPQ 233,235 (CCPA 1955) -MPEP § 2144.05.
Lopez does not teach the method where the aqueous solution contains mannitol at a concentration between 40-80 mmol.L-1 as recited in claim 17, or where the aqueous solution contains mannitol at a concentration between 40-80 mmol.L-1 and histidine at a concentration between 25-35 mmol.L-1 as recited in claim 17. However, Ostróżka-Cieślik teaches organ preservation solution, Celsior, intended for the storage of thoracic organs such as hearts, lungs and organs of the abdominal cavity such as kidneys, livers and pancreas under hypothermic conditions and which contains mannitol as an antiedematous substance and histidine as a free radical scavenger (pg. 10 Col. 2 last para.). Celsior contains 60 mmol mannitol and 30 mM histidine as evidenced by Nydegger (Table 2). Accordingly, at the effective time of filing one of ordinary skill in the art would have been motivated to modify the method of Lopez to include mannitol and histidine in the aqueous composition for the benefit of acting as an antiedematous substance and as a free radical scavenger, respectively, as taught by Ostróżka-Cieślik. It would have been obvious to one of ordinary skill in the art to include mannitol and histidine in the aqueous solution for preserving and rinsing an organ of Lopez, since these were known in the art to be included in such solutions for the same purpose as taught by Ostróżka-Cieślik. For this reason as well, one of ordinary skill in the art would have had a reasonable expectation of success in including mannitol and histidine in the aqueous solution of Lopez.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 14 is rejected under 35 U.S.C. 103(a) as being unpatentable over Lopez in view of Jochmans (as applied to claims 1, 3, 10-12, and 15-18 above), and in further view of Li et al. (Journal of Transplantation, 2012) (ref. of record).
The teachings of Lopez and Jochmans can be found in the previous rejection above.
Lopez does not teach the method where the aqueous solution contains nitrite ions at a concentration between 5-100 nmol.L-1 as recited in claim 14. However, Li teaches a method of preserving organs for transplantation where the aqueous solution is supplemented with nitrite (abstract and pg. 2 Col. 1 para. 1). Li further teaches that the nitrite supplementation protected liver hepatocytes from apoptosis post-transplantation (abstract and pg. 2 Col. 1 para. 1). Li teaches the method where 0.25-1000 µM is used, and specifically teaches embodiments of the method using concentrations of 25 µM and 250 µM (25,000-250,000 nmol). Li notes that the protective effects of nitrite were dose dependent (pg. 4 Col. 1 para. 3).
Accordingly, at the effective time of filing one of ordinary skill in the art would have been motivated to modify the method of Lopez to include nitrite in the aqueous composition for the benefit of protecting the cells from apoptosis as taught by Li. It would have been obvious to one of ordinary skill in the art to include nitrite in the aqueous solution for preserving and rinsing an organ of Lopez, since it was known in the art to be included in such solutions for the same purpose as taught by Li. For this reason as well, one of ordinary skill in the art would have had a reasonable expectation of success in including nitrite in the aqueous solution of Lopez.
Although Li does not teach the claimed range of nitrite as recited in claim 14, one of ordinary skill in the art would recognize that the concentration of nitrite is a result effective variable as evidenced by Li and that the amount of nitrite would be matter of routine optimization depending on such factors as the organ being preserved and environmental conditions of the organ. Furthermore, generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation" In re Aller, 220 F.2d 454,456, 105 USPQ 233,235 (CCPA 1955) -MPEP § 2144.05.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 13, 14, 17, and 19-21 are rejected under 35 U.S.C. 103(a) as being unpatentable over Lopez in view of Jochmans (as applied to claims 1, 3, 10-12, and 15-18 above), and in further view of Ostróżka-Cieślik et al. (Acta Biochimica Polonica, 2018) (ref. of record) as evidenced by Nydegger et al. (Transplant Immunology, 2002) (ref. of record) and Li et al. (Journal of Transplantation, 2012) (ref. of record).
The teachings of Lopez and Jochmans can be found in the previous rejection above.
Lopez does not teach the method where the aqueous solution contains zinc ions at a concentration between 0.08-0.210 mmol.L-1 as recited in claim 13, or zinc ions at a concentration of 0.191 mmol.L-1 as recited in claims 19-21. However, Ostróżka-Cieślik teaches organ preservation solutions which are modified to include micronutrients to help improve the function of the organs when stored and where the micronutrient is zinc. Accordingly, at the effective time of filing one of ordinary skill in the art would have been motivated to modify the method of Lopez to include zinc in the aqueous composition for the benefit of improving the function of the organ as taught by Ostróżka-Cieślik. It would have been obvious to one of ordinary skill in the art to include zinc in the aqueous solution for preserving and rinsing an organ of Lopez, since it was known in the art to be included in such solutions for the same purpose as taught by Ostróżka-Cieślik. For this reason as well, one of ordinary skill in the art would have had a reasonable expectation of success in including zinc in the aqueous solution of Lopez.
Although Ostróżka-Cieślik is silent with respect to the concentration of zinc in the aqueous solution, one of ordinary skill in the art would recognize that the concentration of zinc is a result effective variable and that the amount of zinc would be matter of routine optimization depending on such factors as the organ being preserved. Furthermore, generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation" In re Aller, 220 F.2d 454,456, 105 USPQ 233,235 (CCPA 1955) -MPEP § 2144.05.
Lopez does not teach the method where the aqueous solution contains mannitol at a concentration between 40-80 mmol.L-1 as recited in claim 17, where the aqueous solution contains mannitol at a concentration between 40-80 mmol.L-1 and histidine at a concentration between 25-35 mmol.L-1 as recited in claim 17, where the aqueous solution contains mannitol at a concentration of 60 mmol.L-1 as recited in claim 20, or where the aqueous solution contains mannitol at a concentration of 60 mmol.L-1 and histidine at a concentration of 30 mmol.L-1 as recited in claim 21. However, Ostróżka-Cieślik teaches organ preservation solution, Celsior, intended for the storage of thoracic organs such as hearts, lungs and organs of the abdominal cavity such as kidneys, livers and pancreas under hypothermic conditions and which contains mannitol as an antiedematous substance and histidine as a free radical scavenger (pg. 10 Col. 2 last para.). Celsior contains 60 mmol mannitol and 30 mM histidine as evidenced by Nydegger (Table 2). Accordingly, at the effective time of filing one of ordinary skill in the art would have been motivated to modify the method of Lopez to include mannitol and histidine in the aqueous composition for the benefit of acting as an antiedematous substance and as a free radical scavenger, respectively, as taught by Ostróżka-Cieślik. It would have been obvious to one of ordinary skill in the art to include mannitol and histidine in the aqueous solution for preserving and rinsing an organ of Lopez, since these were known in the art to be included in such solutions for the same purpose as taught by Ostróżka-Cieślik. For this reason as well, one of ordinary skill in the art would have had a reasonable expectation of success in including mannitol and histidine in the aqueous solution of Lopez.
Lopez does not teach the method where the aqueous solution contains nitrite ions at a concentration between 5-100 nmol.L-1 as recited in claim 14, or at a concentration of 50 nmol.L-1 as recited in claims 19-21. However, Li teaches a method of preserving organs for transplantation where the aqueous solution is supplemented with nitrite (abstract and pg. 2 Col. 1 para. 1). Li further teaches that the nitrite supplementation protected liver hepatocytes from apoptosis post-transplantation (abstract and pg. 2 Col. 1 para. 1). Li teaches the method where 0.25-1000 µM is used, and specifically teaches embodiments of the method using concentrations of 25 µM and 250 µM (25,000-250,000 nmol). Li notes that the protective effects of nitrite were dose dependent (pg. 4 Col. 1 para. 3).
Accordingly, at the effective time of filing one of ordinary skill in the art would have been motivated to modify the method of Lopez to include nitrite in the aqueous composition for the benefit of protecting the cells from apoptosis as taught by Li. It would have been obvious to one of ordinary skill in the art to include nitrite in the aqueous solution for preserving and rinsing an organ of Lopez, since it was known in the art to be included in such solutions for the same purpose as taught by Li. For this reason as well, one of ordinary skill in the art would have had a reasonable expectation of success in including nitrite in the aqueous solution of Lopez.
Although Li does not teach the claimed range and concentration of nitrite as recited in claims 14 and 19-21, one of ordinary skill in the art would recognize that the concentration of nitrite is a result effective variable as evidenced by Li and that the amount of nitrite would be matter of routine optimization depending on such factors as the organ being preserved and environmental conditions of the organ. Furthermore, generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation" In re Aller, 220 F.2d 454,456, 105 USPQ 233,235 (CCPA 1955) -MPEP § 2144.05.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 22 and 23 are rejected under 35 U.S.C. 103(a) as being unpatentable over Lopez in view of Jochmans (as applied to claims 1, 3, 10-12, and 15-18 above), and in further view of Olausson (US 2022/0183272 A1, priority to Apr. 12, 2019) (ref. of record) and Heron (EP 1997374 A2) (EPO machine translation) (ref. of record).
The teachings of Lopez and Jochmans can be found in the previous rejection above.
Lopez does not explicitly teach the step of exposing further comprising a reconditioning of the organ in the aqueous solution as recited in claim 22 and where the aqueous solution is at a temperature between 2 to 10°C as recited in claim 23. However, Olausson teaches reconditioning organs after harvesting so that there are more organs available for transplantations (0009, 0058 and 0073). Olausson teaches that during perfusion the chemistry of the kidney is restored and toxic products are removed (0117). In further support, Heron teaches a method preparing an organ for transplantation with conditioning the organ for transplantation (0008 and 0011). Heron teaches the conditioning is performed by the steps of rinsing and preserving the organ in the solution (0008).
Accordingly, at the effective time of filing one of ordinary skill in the art would have been motivated to modify the method of Lopez to include a step of reconditioning the organ for the benefit of obtaining more organs available for transplantation as taught by Olausson. It would have been obvious to one of ordinary skill in the art to include a step of reconditioning the organ at a temperature between 2 to 10°C in the method of Lopez, since reconditioning and conditioning organs in the preservation solution was known in the art and within the claimed temperature as taught by Olausson and Heron. For these reasons as well, one of ordinary skill in the art would have had a reasonable expectation of success a step of reconditioning the organ where the aqueous solution is at a temperature between 2 to 10°C in the method of Lopez. Additionally, it is noted the teachings of Heron and Olausson suggest that reconditioning might be inherent to practicing the method of Lopez, since the reconditioning steps involve perfusion of the organ with an aqueous solution and there is no clear definition of what reconditioning encompasses.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 24 is rejected under 35 U.S.C. 103(a) as being unpatentable over Lopez in view of Jochmans (as applied to claims 1, 3, 10-12, and 15-18 above), and in further view of Stern et al. (US 5,552,267).
The teachings of Lopez and Jochmans can be found in the previous rejection above.
Neither Lopez nor Jochmans explicitly teach the method where the aqueous solution is free of calcium ions as recited in claim 24.
However, Stern teaches Stern teaches an organ preservation solution not containing calcium ions (Col. 3 lines 4-5). Stern teaches that calcium accumulation within a cardiac myocytes can be injurious or lethal followed reperfusion and preventing calcium overload into myocytes can prevent myocyte death during and after perfusion, therefor, an organ preservation or maintenance solution without calcium is desired (Col. 16 lines 31-37).
Accordingly, at the effective time of the claimed invention, one of ordinary would have been motivated to modify the method taught by the combined teachings of Lopez and Jochmans so that the organ preservation solution does not containing calcium ions for the benefit of preserving a heart as taught by Stern. It would have been obvious to one of ordinary skill in the art to remove calcium from the preservation solution depending on the organ or tissue being preserved and whether calcium is detrimental to that particular organ or tissue as taught by Stern. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to the combined teachings of Lopez and Jochmans, since Stern teach a method of organ preservation where calcium is not included in the organ preservation solution.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed Jun. 25, 2026 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 102, Applicant argues that Lopez does not teach PEG 35000 at the claimed concentration of 2-5 g/L and teaches a concentration of 1.015 g/L (Remarks pg. 6-7 bridging para.). This argument was persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new grounds of rejection is made in view of Lopez.
In addition, Applicant argues that they maintain that Lopez does not teach dynamic preservation with their inventive solution which is only used for static preservation at 4°C while KREBS was used for all reperfusion/evaluation (Remarks pg. 7 para. 2). This argument was not found to be persuasive and is addressed with arguments addressing the rejections under 35 U.S.C. § 103.
With respect to the rejections under 35 U.S.C. § 103, Applicant argues that Lopez’s inventive solution of Lopez disclosed in Table 2 was only used for static preservation at 4°C while KREBS was used for all reperfusion/evaluation and Lopez’s experimental protocol in para. 0034-0038 clearly establish a two-step process with a first step of static preservation at 4°C where organs in Group C were preserved in Lopez’s inventive solution and then a second step of reperfusion and function evaluation at 37°C performed in KREBS-Henseleit solution for all groups (Remarks pg. 8 para. 2). However, this argument is still not found to be persuasive, since the Lopez does not clearly state in the document that all of the organs were perfused with KREPS after static preservation. For instance, in para. 0034, it is unclear from the text if the technique used in the Examples requires perfusion with KREPS-Henseleit bicarbonate solution or whether this is an exemplary artificial solution used in known techniques. This is especially unclear given the prior paragraph states that the performance of the inventive solution is being compared with the Belzer-Viaspan solution in para. 0033. Additionally, Lopez states perfusing liver with their inventive solution in para. 0055. Even if Lopez does not clearly teach perfusion of their inventive solution, it would have been obvious to one of ordinary skill in the art to perfuse with preservation solution of Lopez, since perfusion or dynamic preservation was well-known at the effect time of filing as taught by Jochmans and explained in the rejections under 35 U.S.C. § 103.
Applicant argues that this is further confirmed in para. 0055 where the final sentence comparing Group A and Group C results compares KREBS reperfusion outcomes and not perfusion with the inventive solution and Lopez does not suggest substituting their inventive solution for the perfusion buffer (Remarks pg. 8 para. 2). However, this argument was not found to be persuasive, since in 0055 of Lopez it states: “The livers perfused with the solution of Group B (the intracellular type) release more ASAT and ALAT than the livers preserved in the solution of the subject invention of the extracellular type (Group C)…Finally, it is observed that there is no difference in cellular lysis between the liver perfused with the solution of Group A compared with the liver perfused with the solution of Group C.” From these statements it appears that the livers are perfused with the inventive solution, Group C.
Applicant argues that a person of ordinary skill in the art based on the disclosure of Lopez would understand that the inventive solution taught by Lopez was designed for static preservation and this interpretation is for explained in the present Declaration under 37 CFR §1.132 (Remarks pg. 8 para. 2). However, this argument was not found to be persuasive, since there is no clear indication in Lopez that the inventive solution was intended solely for the purpose of static preservation. Instead, Lopez appears to use the inventive solution for both static and perfusion preservation as described in Example II.
Applicant argues that it is not obvious optimize the concentration of PEG in Lopez to arrive at the claimed PEG concentration of 2-5 g/L, since the range disclosed in Lopez spans nearly three orders of magnitude (0.35-175 g/L) and the preferred concentration of 1.05 g/L is below the claimed range (Remarks pg. 8 last para. to pg. 9 para. 2). However, this argument was not found to be persuasive, and it is maintained that it would have been obvious to optimize the concentration of PEG35000 in an organ preservation solution. As explained in the present rejection, one of ordinary skill in the art would recognize that the concentration of PEG35000 in an organ preservation solution would be matter of routine optimization depending on such factors as the organ being preserved, environmental conditions of the organ, the preservation strategy/temperature, and the specific properties of colloid used. This is supported by Wicomb and Pasut. Wicomb reports an organ preservation solution containing a biologically effective amount of substantially linear polyethylene glycol (PEG) including PEG 35,000 (PEG35000) (pg. 7 lines 28-30, pg. 8 lines 1-4 and pg. 11 lines 13-16). Wicomb teaches that a “biologically effective amount” is meant to be a concentration of the component able to improve the ability of an OPS (organ preservation solution) to preserve organs or a concentration able to preserve or restore cell, tissue or organ function (pg. 18 lines 5-7). In further support, Pasut reports that the addition of PEG35 (PEG35000) at a concentration of 5 g/L to the preservation solution used in subnormothermia machine transfusion (SNMP) with a supercooling technique is necessary to achieve successful liver transplantation after six days of preservation (pg. 6505 Col. 1 para. 2). The evidence presented in Wicomb and Pasut demonstrate that the concentration of PEG35000 in the preservation solution was known to be adjusted to be effective for the particular organ preservation method.
Applicant argues that one of ordinary skill in the art would not have been motivated to increase the PEG concentration of Lopez, since it is well established that increasing PEG concentration increases viscosity which would be unsuitable for dynamic perfusion as is explained in the enclosed Declaration (Remarks pg. 9 para. 3). However, this argument was not found to be persuasive, since no evidence has been present demonstrating that the claimed amounts would be predicted by one of ordinary skill in the art to have a viscosity unsuitable for dynamic perfusion.
Applicant argues that Lopez does not recognize PEG concentration as a result effective variable or the role of PEG concentration in relation to viscosity, perfusability or any other functional parameters (Remarks pg. 9 para. 4). However, this argument was not found to be persuasive, since even though Lopez does not explicitly state that PEG concentration is a result effective variable or recognizes its relation to viscosity, perfusability or any other functional parameters, one of ordinary skill in the art would have readily recognized it as result effective variable as evidenced by Wicomb and Pasut and explained in the present rejection.
Applicant argues typically HES (hydroxyethyl starch) not PEG is used as a colloid in dynamic hypothermic perfusion in the art as shown in Jochmans (Remarks pg. 9 para. 5). However, this argument was not found to persuasive, since no evidence has been presented supporting that HES is typically used in dynamic hypothermic perfusion over PEG. Furthermore, PEG was known in the art to be used in machine perfusion of organs. For instance, Bessems et al. (Transplantation Proceedings, 2005) states that they developed Polysol, a machine perfusion (MP) preservation solution based on a colloid and the necessary nutrients for the liver where HES is substituted with PEG (abstract and pg. 329 para. 1). Bessem reports that PEG has been used in organ preservation solution for its osmotic capacities (pg. 330 last para.). Additionally, Bessems reports that HES is expensive, difficult to obtain, and causes microvasculatory obstruction (pg. 329 para. 1) whereas PEG has protective effects against lipid peroxidation, its enhancement of ATP restoration during reperfusion, its prevention of osmotic swelling and the decrease incidence of rejection in clinical and experimental heart transplantations (pg. 330 last para.).
Applicant argues that the specification demonstrates that the claimed PEG concentration unexpectedly does not substantially alter viscosity as shown in Table 2 (Remarks pg. 9-10 bridging para.). Applicant further argues that the unexpected results is not a matter of routine optimization and demonstrate that the claimed 2-5 g/L is critical with respect to viscosity behavior in dynamic perfusion which could not have been predicted from the broad range and static solution disclosed in Lopez (Remarks pg. 10 para. 1). Applicant argues that the enclosed Declaration confirms that the viscosity is a critical parameter in dynamic hypothermic perfusion; a PHOSITA would not have expected increasing the PEG concentration to 2-5 g/L would maintain acceptable viscosity for dynamic perfusion, historically PEG-based solutions were used for static preservation while HES-based solutions were used for dynamic use and Lopez’s broad range does not teach which concentrations would be suitable for dynamic perfusion (Remarks pg. 10 para. 2).
However, these arguments were not found to be persuasive, since at the time of the claimed invention organ preservation solutions containing higher amounts of PEG35000 were known to have lower viscosity than other solutions widely used in machine perfusion such as University of Wisconsin (UW) solution. In support, Schreinemachers et al. (Nephrology Dialysis Transplantation, 2009) teaches that Polysol has low viscosity, since one of its main components, PEG 35 kDA (PEG35000), is a low-molecular-weight colloid that does not increase viscosity like HES-containing solutions (pg. 816 Col. 2 para. 3). Additionally, Schreinemachers reports the viscosity of Polysol containing PEG-35 at a concentration of 20 g/L is 1.8 at 5°C (cP), whereas the viscosity of UW solution containing HES at a concentration of 50 g/L of is 5.7 at 5°C (cP) (Table 1). It is maintained that even though Lopez does not explicitly state that PEG concentration is a result effective variable or recognizes its relation to viscosity, perfusability or any other functional parameters, one of ordinary skill in the art would have readily recognized it as result effective variable as evidenced by Wicomb and Pasut and explained in the present rejection.
Applicant argues that the prior art does not establish that PEG concentration is result-effective variable for dynamic preservation, Lopez’s solution was designed only for static perfusion, the claimed range produces unexpected results and the breadth of Lopez’s range does not provide guidance for optimization (Remarks pg. 10 para. 3). As stated previously, this argument was not found to be persuasive, and it is maintained that it would have been obvious to optimize the concentration of PEG35000 in an organ preservation solution. As explained in the present rejection, one of ordinary skill in the art would recognize that the concentration of PEG35000 in an organ preservation solution would be matter of routine optimization depending on such factors as the organ being preserved, environmental conditions of the organ, the preservation strategy/temperature, and the specific properties of colloid used. This is supported by Wicomb and Pasut. Wicomb reports an organ preservation solution containing a biologically effective amount of substantially linear polyethylene glycol (PEG) including PEG 35,000 (PEG35000) (pg. 7 lines 28-30, pg. 8 lines 1-4 and pg. 11 lines 13-16). Wicomb teaches that a “biologically effective amount” is meant to be a concentration of the component able to improve the ability of an OPS (organ preservation solution) to preserve organs or a concentration able to preserve or restore cell, tissue or organ function (pg. 18 lines 5-7). In further support, Pasut reports that the addition of PEG35 (PEG35000) at a concentration of 5 g/L to the preservation solution used in subnormothermia machine transfusion (SNMP) with a supercooling technique is necessary to achieve successful liver transplantation after six days of preservation (pg. 6505 Col. 1 para. 2). The evidence presented in Wicomb and Pasut demonstrate that the concentration of PEG35000 in the preservation solution was known to be adjusted to be effective for the particular organ preservation method.
Applicant argues that the solution taught by Lopez requires calcium ions whereas the claimed aqueous does not require calcium ions and none of the compositions disclosed in specification require calcium ions as shown in Table 1 which sets forth the formulation of the inventive solution and the only possible source of calcium ions would be in the presence of calcium nitrite (Remarks pg. 10 last para.). The Applicant’s amendments adding new claim 24 which limits the solution to be free of calcium necessitated a new rejection under 35 U.S.C. §103. This new limitation is addressed in the new rejections.
Applicant argues that a person of ordinary skill in the art would have recognized that removing calcium from Lopez’s solution would alter its intended function, since Lopez teaches that calcium is important for preserving multiple organ types and there is no motivation to remove calcium from the solution (Remarks pg. 11 para. 2). The Applicant’s amendments adding new claim 24 which limits the solution to be free of calcium necessitated a new rejection under 35 U.S.C. §103. This new limitation is addressed in the new rejections. Briefly, one of ordinary skill in the art would have been motivated to remove the calcium ions from Lopez for the benefit of preserving a heart as taught by Stern. It would have been obvious to one of ordinary skill in the art to remove calcium from the preservation solution depending on the organ or tissue being preserved and whether calcium is detrimental to that particular organ or tissue as taught by Stern.
Applicant argues that Jochmans does not remedy the deficiencies of Lopez and is a review article that shows that HES-based solutions are historically used in dynamic perfusion instead of PEG-based solutions (Remarks pg. 11 last para.). However, this argument was not found to be persuasive, since the arguments with respect to the rejections over Lopez were not found to be persuasive as explained above.
Applicant argues that Jochmans focuses on kidney preservation whereas the claimed method covers a broader range of transplantable organs (Remarks pg. 12 first para.). However, this argument was not found to be persuasive, since the teachings of Jochmans are still relevant to the claimed invention. Even though Jochmans focuses on the kidney and liver, Jochmans also addresses organ preservation in general (pg., 2545 para. to pg. 2547 Col. 1 last para. and pg. 2551 last para. to pg. 2552 para. 2).
Applicant argues hindsight reasoning was used to combine Lopez and Jochmans, since there is no motivation to combine the two reference, Lopez does not teach or suggest using its inventive solution for dynamic preservation and Jochmans teaches HES-based solutions are used for dynamic preservation (Remarks pg. 12 first para.). In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, 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). Furthermore, it is maintained that Lopez teaches the method where the organ is perfused with the solution (preserving is dynamic) and teaches perfusing livers with the inventive solution of Table 2 (solution of Group C) (0035-0038 and 0055). Even if this teaching is not clear in Lopez, it would have been obvious to one of ordinary skill in the art to modify the method of Lopez to use the aqueous solution for dynamic preservation based on the teachings in Jochmans. Jochmans teaches dynamic preservation strategies allow for improved organ quality and utilization (pg. 2546 Col. 1 para. 1). One of ordinary skill in the art would have been motivated to modify the method of Lopez so that the exposing of the organ includes dynamic preservation for the benefit of improving the organ quality as taught by Jochmans.
Applicant argues that neither Lopez nor Jochmans provide a rationale for increasing the PEG concentration to the claimed range of 2-5 g/L (Remarks pg. 12 para. 2). As explained in the present rejection, one of ordinary skill in the art would recognize that the concentration of PEG35000 in an organ preservation solution would be matter of routine optimization depending on such factors as the organ being preserved, environmental conditions of the organ, the preservation strategy/temperature, and the specific properties of colloid used. Furthermore, the range taught by Lopez includes higher concentrations than that claimed, 0.35-175 g/L (0020-0021 and Table 2).
Applicant argues Fontes does not remedy the deficiencies of Lopez and Jochmans, and one would not be motivated to combine these references in manner proposed by the Examiner, because one would be modifying the KREBS solution of Lopez which used in the dynamic perfusion method (Remarks pg. 12-13 bridging para.). However, this argument was not found to be persuasive, since as explained in the rejections Lopez teaches dynamic preservation and teaches perfusion of livers with the inventive solution (0055). Additionally, even if Lopez did not teach dynamic preservation with the inventive solution, it would have been obvious to modify Lopez to include dynamic preservation with the inventive solution in view of the benefits taught by Jochmans.
Applicant argues that there is no motivation in Lopez to include the additional components of zinc, mannitol or histidine, since Lopez’s solution is formulated for static preservation (Remarks pg. 13 para. 3). However, this argument was not found to be persuasive, since the motivation to combine is found in Ostróżka-Cieślik. Ostróżka-Cieślik teaches organ preservation solutions which are modified to include micronutrients to help improve the function of the organs when stored and where the micronutrient is zinc. It is maintained that one of ordinary skill in the art would have been motivated to modify the method of Lopez to include zinc, mannitol and histidine in the aqueous composition for the benefit of improving the function of the organ as taught by Ostróżka-Cieślik.
Applicant argues that Ostróżka-Cieślik cannot be used for routine optimization, since Ostróżka-Cieślik does not teach the claimed zinc concentration and it has not been shown that the claimed zinc concentration is a result-effective variable in Lopez’s static preservation solution (Remarks pg. 13 para. 3). However, this argument was not found to be persuasive, since Doorscholdt reports optimizing the balance of amino acids, vitamins, anti-oxidants, high molecular weight additives and buffering capacity of organ preservation solutions (abstract and 0006), and therefore the zinc concentration the preservation solution would be recognized as a result-effective variable.
Applicant argues that Li does not remedy the deficiencies of Lopez and Jochmans and there is no reason for adding the nitrate taught by Li for reducing cold ischemia-reperfusion injury and protecting hepatocytes from apoptosis post-transplantation to the solution used in the method of Lopez (Remarks pg. 14 para. 2). However, this argument was not found to be persuasive, since Li provides motivation to modify the method of Lopez. Li teaches that the nitrite supplementation protected liver hepatocytes from apoptosis post-transplantation (abstract and pg. 2 Col. 1 para. 1). Therefore, it is maintained that one of ordinary skill in the art would have been motivated to modify the method of Lopez to include nitrite in the aqueous composition or inventive solution for the benefit of protecting the cells from apoptosis as taught by Li.
Applicant further argues that Li cannot be used for routine optimization, since Li teaches nitrate levels many orders of magnitude higher than the claimed nanomolar range and it has not been shown that the claimed nitrate levels is a result-effective variable which would have been predictably led to the claimed range with an expectation of success (Remarks pg. 14 para. 2). However, this argument was not found to be persuasive, since Li teaches the protective effects of nitrate levels are dose dependent (pg. 4 Col. 1 para. 3) and, therefore, nitrate levels are a result-effective variable.
Applicant argues that Olausson is directed to a fundamentally different approach than from Lopez and is directed to organ regeneration at normothermic temperatures (28-37°C) which is different from the claimed method of hypothermic preservation of organs (Remarks pg. 14 para. 4). However, this argument was not found to be persuasive, since both Lopez and Olausson are directed to preserving organs for transplantation. Olausson teaches their “invention relates to harvesting organs and preservation and evaluation of organs”. Even though, Olausson focuses on reconditioning organs after harvesting and a method preparing an organ for transplantation with conditioning the organ for transplantation (0008-0009, 0011, 0058 and 0073) these methods are relevant to the claimed preservation method and the preservation method of Lopez.
Response to Evidentiary Declaration under 37 CFR §1.132
The declaration of Joan Roselló-Catafau, Ph.D. filed on Jun. 25, 2026 under 37 CFR §1.132 has been considered but is ineffective to overcome the rejections of claims 35 U.S.C. §103.
Dr. Roselló-Catafau notes that Lopez’s solution is different from the inventive solution, since has a different polyethylene glycol (PEG) concentration which is approximately 1.015 g/L, whereas the claimed concentration is between 2-5 g/L (Declaration para. 10). As stated in the response to the Remarks, this argument was persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new grounds of rejection is made in view of Lopez.
Dr. Roselló-Catafau states that PEG performs different roles in dynamic preservation and static storage. Specifically, in dynamic preservation PEG is carried through the organ’s vasculature keeping fluid intravascular, stabilizing cell membranes and influencing shear and ischemia reperfusion injury whereas in static storage PEG is used as a colloid and protective excipient in a non-flowing bath (Declaration para. 11). However, this argument was not found to be persuasive, since PEG was known to be used for dynamic perfusion at the effective time of filing of the claimed invention as explained in response to the Remarks above. Bessems et al. (Transplantation Proceedings, 2005) states that they developed Polysol, a machine perfusion (MP) preservation solution based on a colloid and the necessary nutrients for the liver where HES is substituted with PEG (abstract and pg. 329 para. 1). Furthermore, whether it plays different roles in dynamic preservation and static preservation does not overcome the obviousness of using it in a preservation solution during dynamic preservation.
Dr. Roselló-Catafau notes that it is well-known that viscosity plays a role in dynamic hypothermic perfusion and that excessive viscosity increases vascular resistance, impairs homogenous distribution of the perfusate within the organ parenchyma and may cause endothelial injury and UW solution is generally used due to its lower viscosity and absence of colloids. Dr. Roselló-Catafau states that a PHOSITA would understand increasing the concentration of macromolecular agents such as HES, albumin, dextran and PEG in a solution would increase its viscosity (Declaration para. 12). Dr. Roselló-Catafau states that it is their opinion that in view of this knowledge, it would not be obvious to increase the concentration of PEG to the claimed range of 2-5 g/L and maintain the appropriate viscosity for dynamic perfusion (Declaration para. 13). Dr. Roselló-Catafau argues that there is nothing in the prior art that increasing PEG concentration in a static solution could be suitable for dynamic perfusion, since historically PEG-based solutions are used for static organ preservation as a colloid and HES-based solutions are used in dynamic renal perfusion (Declaration para. 14).
However, these arguments were not found to be persuasive, as explained in the response to the Remarks, since at the time of the claimed invention organ preservation solutions containing higher amounts of PEG35000 were known to have lower viscosity than other solutions widely used in machine perfusion such as University of Wisconsin (UW) solution. In support, Schreinemachers et al. (Nephrology Dialysis Transplantation, 2009) teaches that Polysol has low viscosity, since one of its main components, PEG 35 kDA (PEG35000), is a low-molecular-weight colloid that does not increase viscosity like HES-containing solutions (pg. 816 Col. 2 para. 3). Additionally, Schreinemachers reports the viscosity of Polysol containing PEG-35 at a concentration of 20 g/L is 1.8 at 5°C (cP), whereas the viscosity of UW solution containing HES at a concentration of 50 g/L of is 5.7 at 5°C (cP) (Table 1). It is maintained that even though Lopez does not explicitly state that PEG concentration is a result effective variable or recognizes its relation to viscosity, perfusability or any other functional parameters, one of ordinary skill in the art would have readily recognized it as result effective variable as evidenced by Wicomb and Pasut and explained in the present rejection.
Dr. Roselló-Catafau argues that the concentration range of PEG taught by Lopez is not a teaching of which concentrations would work for dynamic perfusion and the upper end of about 175 g/L would be entirely incompatible with organ perfusion since the solution would be excessively viscous and likely to damage the tissue (Declaration para. 15). However, this argument was not found to be persuasive, since no evidence has been provided showing that 175 g/L would be detrimental to dynamic perfusion of an organ.
Dr. Roselló-Catafau further argues that Lopez does not explain the purpose of PEG in the solution or why to adjust the concentration to arrive at the claimed concentration of 2-5 g/L which improves organ protection in dynamic preservation (Declaration para. 15). Dr. Roselló-Catafau argues that it would not have been a matter of routine optimization, since Lopez teaches a cold-storage solution and does not provide any detail or data on PEG concentration, viscosity, temperature, or flow parameters that would permit (Declaration para. 15).
These arguments were not found to be persuasive, and it is maintained that it would have been obvious to optimize the concentration of PEG35000 in an organ preservation solution. As explained in the present rejection and in the response to the arguments, one of ordinary skill in the art would recognize that the concentration of PEG35000 in an organ preservation solution would be matter of routine optimization depending on such factors as the organ being preserved, environmental conditions of the organ, the preservation strategy/temperature, and the specific properties of colloid used. This is supported by Wicomb and Pasut. Wicomb reports an organ preservation solution containing a biologically effective amount of substantially linear polyethylene glycol (PEG) including PEG 35,000 (PEG35000) (pg. 7 lines 28-30, pg. 8 lines 1-4 and pg. 11 lines 13-16). Wicomb teaches that a “biologically effective amount” is meant to be a concentration of the component able to improve the ability of an OPS (organ preservation solution) to preserve organs or a concentration able to preserve or restore cell, tissue or organ function (pg. 18 lines 5-7). In further support, Pasut reports that the addition of PEG35 (PEG35000) at a concentration of 5 g/L to the preservation solution used in subnormothermia machine transfusion (SNMP) with a supercooling technique is necessary to achieve successful liver transplantation after six days of preservation (pg. 6505 Col. 1 para. 2). The evidence presented in Wicomb and Pasut demonstrate that the concentration of PEG35000 in the preservation solution was known to be adjusted to be effective for the particular organ preservation method.
Dr. Roselló-Catafau states that in their opinion that a PHOSITA reading Lopez would not have interpreted that the inventive PEG-containing solution was used for dynamic perfusion and would recognize that it is used only for cold storage and that dynamic perfusion is carried out with KREPS buffer (Declaration para. 20). However, it is the position of the examiner that a PHOSITA reading Lopez would have interpreted that the inventive PEG-containing solution was used for dynamic perfusion (0055).
Conclusion
No claims are allowed.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632
