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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/08/2025 has been entered.
Claim Status
1. The amendment filed 12/08/2025 has been entered. Claims 1, 5, 18, 20, 32, 33, and new claims 35 – 37 are pending and are under consideration. Claims 2 – 4, 6, 7, 19, and 23 – 25 have been canceled.
Election/Restrictions
2. Applicant’s election without traverse of Group I (claims 1 – 9 and 32 – 34) in the reply filed on 12/19/2024 is acknowledged.
3. Upon further consideration, the Examiner has decided to rejoin Group II (claims 18 – 25) with the elected Group I (claims 1 – 9 and 32 – 34).
Priority
4. This application claims priority to U.S. Provisional Application No. 62/858,576 filed 06/07/2019 and U.S. Provisional Application No. 62/859,257 filed 07/10/2019.
Withdrawn Claim Rejections
5. The rejection of claim 4 under 35 U.S.C. 103 is rendered moot in view of Applicant’s cancellation of the claim.
6. The rejection of claims 1, 5, and 32 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to the claims.
7. The rejection of claims 2 and 3 under 35 U.S.C. 103 is rendered moot in view of Applicant’s cancellation of the claims.
8. The rejection of claim 6 under 35 U.S.C. 103 is rendered moot in view of Applicant’s cancellation of the claim.
9. The rejection of claim 7 under 35 U.S.C. 103 is rendered moot in view of Applicant’s cancellation of the claim.
10. The rejection of claims 23 – 25 under 35 U.S.C. 103 is rendered moot in view of Applicant’s cancellation of the claims.
11. The rejection of claim 18 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to the claims.
12. The rejection of claim 19 under 35 U.S.C. 103 is rendered moot in view of Applicant’s cancellation of the claim.
13. The rejection of claim 20 under 35 U.S.C. 103 is rendered moot in view of Applicant’s cancellation of the claim.
14. The rejection of claim 33 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to the claims.
Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
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.
15. Claims 1 and 36 are 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.
16. Claim 1 recites “substantially free of citrate and citric acid” in the last line. The term "substantially" in claim 1 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. Claims 5, 18, 20, 32, 33, and 36 – 37 are also rejected as they depend from claim 1 and do not clarify the grounds of rejection.
17. Regarding claim 36, recitation of “up to” and “about 42 days” lacks clarity because it is unclear if the storage duration is up to 42 days or could be more than 42 days because Applicant’s specification states that “about” encompasses variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, and ±0.1% from the specified amount as such variations are appropriate to perform the disclosed method (page 7, lines 1 – 6).
Claim Interpretation
18. For the purpose of applying prior art, “substantially free of citrate and citric acid” in claim 1 is interpreted as the red blood cell storage solution composition does not include added citrate or citric acid.
19. Claims 5 and 20 broadly recite “sodium phosphate”. For the purpose of applying prior art, “sodium phosphate” is interpreted to include disodium phosphate and trisodium phosphate (Na2HPO4, Na3PO4).
20. Claim 33 broadly recites “is suitable for direct infusion into a patient”. For the purpose of applying prior art, this limitation is interpreted as the suspension of red blood cells were stored at 4 °C for no more than 42 days based on Applicant’s specification at page 2, lines 1 – 3 and page 17, lines 5 – 6 and are sterile.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
21. Claim(s) 1, 5, 18, 20, 32, 33, and 35 – 37 is/are rejected under 35 U.S.C. 103 as being unpatentable over De Korte (De Korte, Dirk, et al. Transfusion 48.6 (2008): 1081-1089), hereinafter De Korte in view of Harmening (US-4112070-A; Filed 06/08/1977; Published09/05/1978), hereinafter Harmening in view of Fisher (FISHER, RACHEL A., et al. Annals of Human Genetics 37.3 (1974): 341-353.), hereinafter Fisher in view of Pendas (Pendas, J., et al. Colloids and Surfaces A: Physicochemical and Engineering Aspects 195.1-3 (2001): 259-262.), hereinafter Pendas which is cited on the IDS filed 06/15/2023.
Regarding claims 1, 5, and 35, De Korte teaches a packed red blood cell storage solution (PAGGG-M) comprising monosodium phosphate (NaH2PO4) at 8 mM (“one or more electrolytes comprising monosodium phosphate (NaH2PO4) at a concentration of about 1 mM to about 5 mM” of claim 1), adenine (claim 1), glucose (“dextrose” of claim 1) that is free of citrate and citric acid and further comprises 8 mM Na2HPO4 (“sodium phosphate” of claim 5) with a pH of 8.2 (claim 35) (Abstract; Table 1; page 1082, left col. para. 4 and right col. para. 1; page 1088, left col. para. 3). De Korte does not teach the storage solution comprises “tetrasodium pyrophosphate at a concentration of about 10 mM to about 30 mM” of claim 1.
Regarding claims 18, 20, 36, and 37, De Korte teaches storing packed red blood cells in PAGGG-M (claim 18) that comprises 8 mM Na2HPO4 (“sodium phosphate” of claim 20) for 42 days (“for a storage duration” of claim 18 and claim 36) at 4 °C (claim 37) (page 1082, right col. para. 1; Table 1; page 1084, right col. para. 1; Figure 3; page 1088, left col. para. 3). De Korte does not teach the storage solution comprises “tetrasodium pyrophosphate at a concentration of about 10 mM to about 30 mM” of claim 1.
Regarding claim 32, De Korte teaches a suspension of red blood cells (RBCs) comprising PAGGG-M (page 1084, right col. para. 1; Figure 3; page 1088, left col. para. 3). De Korte does not teach the storage solution comprises “tetrasodium pyrophosphate at a concentration of about 10 mM to about 30 mM” of claim 1.
Regarding claim 33, De Korte teaches the RBCs stored in PAGGG-M for 42 days at 4 °C without washing showed a degree of hemolysis that is below 0.2% which is below the maximum of 0.8% as set in the European guidelines (page 1082, right col. para. 1; page 1085, right col. para. 1; Figure 4; Table 2). De Korte teaches the PAGGG-M was sterilized by filtration prior to the addition of RBCs (page 1082, right col. para. 1). De Korte teaches at the end of storage, all RBCs were tested on sterility by culturing and no units were found positive (page 1082, right col. para. 1; page 1087, left col. para. 1; page 1088, left col. para. 3). De Korte does not teach the storage solution comprises “tetrasodium pyrophosphate at a concentration of about 10 mM to about 30 mM” of claim 1.
De Korte does not teach the storage solution comprises “tetrasodium pyrophosphate at a concentration of about 10 mM to about 30 mM” of claim 1. However, De Korte teaches during storage of whole blood and RBCs, intracellular 2,3-DPG is rapidly depleted and that the level of 2,3-DPG is important for the regulation of oxygen delivery by hemoglobin (Hb) in RBCs (page 1086, right col. para. 2). De Korte teaches that several studies have focused on improved maintenance of 2,3-DPG during RBCs storage but the problem with these studies is that 2,3-DPG was only maintained during a relatively short period and/or that the 2,3-DPG level was maintained at the expense of ATP and for optimal results, the RBCs had to be subjected to laborious washing (page 1086, right col. para. 2). De Korte teaches after transfusion, low levels of 2,3-DPG will increase in vivo, although it takes at least 24 hours before normal levels are reached in normal volunteers whereas in patients even slower recoveries are described (page 1086, right col. para. 3). De Korte teaches in critically ill patients, in which often also the microcirculation is compromised, one may want an immediate effect of the RBC transfusion and it can be argued that RBCs with low levels of 2,3-DPG have an impaired capacity to deliver oxygen to the tissues, especially under critical conditions (page 1086, right col. para. 3). De Korte teaches in Figure 3B that the levels of 2,3-DPG of unwashed RBCs stored in PAGGG-M increased until day 21 where it began to decline but the levels of 2,3-DPG of washed RBCs stored in PAGGG-M increased until day 35 and only slightly decreased at day 42. De Korte teaches the higher initial internal pH of washed RBCs may be responsible for the increased 2,3-DPG levels compared to unwashed RBCs (Figure 5; page 1086, left col. para. 2 and right col. para. 1; page 1088, left col. para. 2).
Regarding “tetrasodium pyrophosphate” of claim 1, Harmening teaches a blood preservation composition to maintain 2,3-DPG levels past the third week of storage comprising a phosphate source to maintain sufficient 2,3-DPG and ATP levels suitable for transfusion where the phosphate source may be inorganic pyrophosphate (col. 3, lines 1 – 9; col. 6, lines 66 – 68; col. 7, lines 10 – 19). While Harmening teaches “inorganic pyrophosphate”, Harmening does not teach the sodium salt of pyrophosphate or a concentration of about 10 mM to about 30 mM required by claim 1. However, Harmening teaches pH regulation plays a key role in blood preservation and alkaline liquid preservatives results in generally good 2,3-DPG maintenance but ATP levels rapidly decline while acid liquid preservatives result in good ATP maintenance but 2,3-DPG levels are rapidly depleted (col. 5, lines 24 – 32). Harmening teaches the need to regulate an adequate pH range for preserved red blood cells stems from the fact that pH can modify the rate at which the numerous array of enzymes associated with glucose metabolism function (col. 5, lines 32 – 35). Harmening teaches the transfused red cell, totally depleted of 2,3-DPG can regain half the normal level within about 24 hours but this reconditioning may not be rapid enough to be effective in a severely ill patient and it is not known whether the rate of resynthesis of 2,3-DPG in the donor cells given to critically ill patients is comparable to that observed in normal recipients (col. 1, lines 62 – 68). Harmening teaches blood with nearly normal hemoglobin-oxygen affinity is thus preferable for use in massive transfusions (col. 2, lines 6 – 9). One would have been motivated to combine the teachings of De Korte and Harmening because both teach phosphate containing red blood cell storage solutions to increase 2,3-DPG and ATP levels to that which are suitable for transfusion.
Regarding “tetrasodium pyrophosphate” of claim 1, Fisher teaches RBCs have an inorganic pyrophosphatase that catalyzes the hydrolysis of inorganic pyrophosphate to inorganic phosphate (page 341, para. 1 and 3; page 351, para. 5). Fisher teaches tetrasodium pyrophosphate (10 mM) is a substrate for the pyrophosphatase from RBCs (page 344, para. 4 – 5; page 345, para. 1). Fisher does not teach a concentration of tetrasodium pyrophosphate of about 10 mM to about 30 mM of claim 1. One would have been motivated to combine the teachings of De Korte, Harmening, and Fisher because De Korte and Harmening teach phosphate containing red blood cell storage solutions and Harmening teaches inorganic pyrophosphate may be used as a metabolizable phosphate in RBC storage solutions to maintain sufficient 2,3-DPG and ATP levels suitable for transfusion and Fisher teaches tetrasodium pyrophosphate is a substrate for pyrophosphatase found in RBCs.
Regarding a concentration of tetrasodium pyrophosphate of “about 10 mM to about 30 mM” of claim 1, Pendas teaches a RBC preservation solution comprising dextrose, phosphate buffer, and 10 mM tetrasodium pyrophosphate (page 261, left col. para. 1 – 3; Figure 1; page 262, left col. para. 1 – 2). Pendas teaches the decreasing viability and in vivo survival of RBCs observed in blood bank storage are due to alterations in their rheologic properties and metabolic status (Abstract; page 259, left col. and right col. para. 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of De Korte regarding a red blood cell storage solution (PAGGG-M) comprising monosodium phosphate (NaH2PO4) at 8 mM, adenine, and glucose that is free of citrate and citric acid that caused an increase in the levels of 2,3-DPG of unwashed RBCs until day 21 where it began to decline with the teachings of Harmening regarding the addition of a phosphate source that may be inorganic pyrophosphate to a red blood cell storage solution to maintain 2,3-DPG levels past the third week of storage with the teachings of Fisher regarding tetrasodium pyrophosphate is a substrate for the pyrophosphatase found in red blood cells with the teachings of Pendas regarding a red blood storage solution comprising dextrose, phosphate buffer, and 10 mM tetrasodium pyrophosphate to arrive at the claimed packed red blood cell storage solution comprising tetrasodium pyrophosphate at a concentration of about 10 mM to about 30 mM; one or more electrolytes comprising monosodium phosphate (NaH2PO4) at a concentration of about 1 mM to about 5 mM; adenine; and dextrose; wherein the storage solution is substantially free of citrate and citric acid. One would have been motivated to combine the teachings of De Korte, Harmening, Fisher, and Pendas in a packed red blood cell storage solution allowing storage of packed red blood cells that are suitable for transfusion to critically ill patients as De Korte teaches during storage of RBCs, intracellular 2,3-DPG is rapidly depleted and that the level of 2,3-DPG is important for the regulation of oxygen delivery by hemoglobin in RBCs and De Korte teaches in critically ill patients, one may want an immediate effect of the RBC transfusion and it can be argued that RBCs with low levels of 2,3-DPG have an impaired capacity to deliver oxygen to the tissues, especially under critical conditions and Harmening teaches the transfused red cell, totally depleted of 2,3-DPG can regain half the normal level within about 24 hours but this reconditioning may not be rapid enough to be effective in a severely ill patient and it is not known whether the rate of resynthesis of 2,3-DPG in the donor cells given to critically ill patients is comparable to that observed in normal recipients and Harmening teaches blood with nearly normal hemoglobin-oxygen affinity is thus preferable for use in massive transfusions. Further, it would be obvious to adjust the concentration of tetrasodium pyrophosphate and monosodium phosphate since it is a result-effective variable dependent on the desired pH of the storage solution as Harmening teaches pH regulation plays a key role in blood preservation and alkaline liquid preservatives results in generally good 2,3-DPG maintenance but ATP levels rapidly decline while acid liquid preservatives result in good ATP maintenance but 2,3-DPG levels are rapidly depleted and Harmening teaches the need to regulate an adequate pH range for preserved red blood cells stems from the fact that pH can modify the rate at which the numerous array of enzymes associated with glucose metabolism function and De Korte teaches the higher initial internal pH of washed RBCs may be responsible for the increased 2,3-DPG levels compared to unwashed RBCs. One would have a reasonable expectation of success in combining the teachings as De Korte teaches the levels of 2,3-DPG of unwashed RBCs stored in PAGGG-M increased until day 21 where it began to decline but the levels of 2,3-DPG of washed RBCs stored in PAGGG-M increased until day 35 and only slightly decreased at day 42 and Harmening teaches inorganic pyrophosphate may be the phosphate source to maintain sufficient 2,3-DPG and ATP levels suitable for transfusion and Pendas teaches a RBC storage solution comprising 10 mM tetrasodium pyrophosphate, dextrose, and phosphate buffer.
Applicant’s Arguments/ Response to Arguments
22. Applicant Argues: On page 6, paragraph 3 – 4, Applicant asserts that the combined references fail to teach or suggest all elements of amended claim 1. Applicant asserts that the ordinary skilled person would not have been motivated to combine Mazor and/or Hess with Parfentjev and Meyer to arrive at amended claim 1 and prima facie obvious ness of the claims has not been established.
Response to Arguments: The previous rejection of the claims citing the teachings of Parfentjev, Meyer, Mazor, and Hess have been withdrawn in view of Applicant’s amendment to claim 1. A new rejection of the claims is set forth above. In the new rejection De Korte teaches a packed red blood cell storage solution (PAGGG-M) that comprises monosodium phosphate at 8 mM, adenine, and glucose and the formulation does not contain citrate or citric acid (Abstract; Table 1; page 1082, left col. para. 4 and right col. para. 1; page 1088, left col. para. 3). De Korte does not teach the storage solution comprises “tetrasodium pyrophosphate at a concentration of about 10 mM to about 30 mM” of amended claim 1. However, De Korte teaches during storage of whole blood and RBCs, intracellular 2,3-DPG is rapidly depleted and that the level of 2,3-DPG is important for the regulation of oxygen delivery by hemoglobin (Hb) in RBCs (page 1086, right col. para. 2). De Korte teaches that several studies have focused on improved maintenance of 2,3-DPG during RBCs storage but the problem with these studies is that 2,3-DPG was only maintained during a relatively short period and/or that the 2,3-DPG level was maintained at the expense of ATP and for optimal results, the RBCs had to be subjected to laborious washing (page 1086, right col. para. 2). De Korte teaches in critically ill patients, one may want an immediate effect of the RBC transfusion and it can be argued that RBCs with low levels of 2,3-DPG have an impaired capacity to deliver oxygen to the tissues, especially under critical conditions (page 1086, right col. para. 3). De Korte teaches in Figure 3B that the levels of 2,3-DPG of unwashed RBCs stored in PAGGG-M increased until day 21 where it began to decline thereafter. Harmening teaches a blood preservation composition to maintain 2,3-DPG levels past the third week of storage comprising a phosphate source to maintain sufficient 2,3-DPG and ATP levels suitable for transfusion where the phosphate source may be inorganic pyrophosphate (col. 3, lines 1 – 9; col. 6, lines 66 – 68; col. 7, lines 10 – 19). While Harmening teaches “inorganic pyrophosphate”, Harmening does not teach the sodium salt of pyrophosphate or a concentration of about 10 mM to about 30 mM required by amended claim 1. Similar to De Korte’s teachings, Harmening teaches the transfused red cell, totally depleted of 2,3-DPG can regain half the normal level within about 24 hours but this reconditioning may not be rapid enough to be effective in a severely ill patient and it is not known whether the rate of resynthesis of 2,3-DPG in the donor cells given to critically ill patients is comparable to that observed in normal recipients (col. 1, lines 62 – 68). Harmening teaches blood with nearly normal hemoglobin-oxygen affinity is thus preferable for use in massive transfusions (col. 2, lines 6 – 9). Fisher teaches 10 mM tetrasodium pyrophosphate is a substrate for the enzyme pyrophosphatase found in red blood cells (page 344, para. 4 – 5; page 345, para. 1) and Pendas teaches a RBC preservation solution comprising dextrose, phosphate buffer, and 10 mM tetrasodium pyrophosphate (page 261, left col. para. 1 – 3; Figure 1; page 262, left col. para. 1 – 2). One would have been motivated to combine the teachings of De Korte, Harmening, Fisher, and Pendas to arrive at amended claim 1 in a packed red blood cell storage solution allowing storage of packed red blood cells that are suitable for transfusion to critically ill patients as De Korte teaches during storage of RBCs, intracellular 2,3-DPG is rapidly depleted and that the level of 2,3-DPG is important for the regulation of oxygen delivery by hemoglobin in RBCs and De Korte teaches in critically ill patients, one may want an immediate effect of the RBC transfusion and it can be argued that RBCs with low levels of 2,3-DPG have an impaired capacity to deliver oxygen to the tissues, especially under critical conditions and Harmening teaches the transfused red cell, totally depleted of 2,3-DPG can regain half the normal level within about 24 hours but this reconditioning may not be rapid enough to be effective in a severely ill patient and it is not known whether the rate of resynthesis of 2,3-DPG in the donor cells given to critically ill patients is comparable to that observed in normal recipients and Harmening teaches blood with nearly normal hemoglobin-oxygen affinity is thus preferable for use in massive transfusions. Further, it would be obvious to adjust the concentration of tetrasodium pyrophosphate and monosodium phosphate since it is a result-effective variable dependent on the desired pH of the storage solution as Harmening teaches pH regulation plays a key role in blood preservation and alkaline liquid preservatives results in generally good 2,3-DPG maintenance but ATP levels rapidly decline while acid liquid preservatives result in good ATP maintenance but 2,3-DPG levels are rapidly depleted and Harmening teaches the need to regulate an adequate pH range for preserved red blood cells stems from the fact that pH can modify the rate at which the numerous array of enzymes associated with glucose metabolism function and De Korte teaches the higher initial internal pH of washed RBCs may be responsible for the increased 2,3-DPG levels compared to unwashed RBCs. One would have a reasonable expectation of success in combining the teachings as De Korte teaches the levels of 2,3-DPG of unwashed RBCs stored in PAGGG-M increased until day 21 where it began to decline but the levels of 2,3-DPG of washed RBCs stored in PAGGG-M increased until day 35 and only slightly decreased at day 42 and Harmening teaches inorganic pyrophosphate may be the phosphate source to maintain sufficient 2,3-DPG and ATP levels suitable for transfusion and Pendas teaches a RBC storage solution comprising 10 mM tetrasodium pyrophosphate, dextrose, and phosphate buffer.
Applicant Argues: On page 6, last paragraph and page 7, paragraphs 1 – 4 , Applicant asserts that the present Specification demonstrates the unexpected beneficial effects of storing pRBCs in a storage solution as presently claimed. Applicant asserts that Example 2 demonstrates that storing pRBCs in a storage solution as claimed for 42 days resulted in a reduction in microvesicle and cell-free hemoglobin release (Figs 1A – 1B), a reduction in susceptibility to osmotic stress, with reduced EC50 (Figs 2A – 2B), an increase in intracellular hemoglobin content (Figs 2C – 2D), increased ATP (Fig. 3A), and increased glucose metabolism compared to cell in citrate-containing AS-3 (Figs 3B, 6A – 6C). Applicant asserts that Example 3 demonstrates that pRBCs stored in PPi-3 exhibited improved quality after storage compared to citrate-containing storage solutions with reduced microvesicle accumulation and free hemoglobin concentration, maintenance of Band-3 expression and reduced phosphatidylserine expression of RBCs. Applicant asserts that the results presented in Applicant’s disclosure indicate storage of pRBCs in PPi-3 solution provides significant improvement in RBC quality compared to standard storage solutions, including AS-3 and CP2D, which lack tetrasodium pyrophosphate and contain citrate. Applicant asserts that Examples 4 – 5 demonstrate that administration of pRBCs stored in PPi-3 to an in vivo model yielded greater hemodynamic response compared to pRBCs stored in AS-3 additive solutions including and MLECs treated with pRBCs stored in PPi-3 demonstrated a reduced inflammatory response compared to pRBCs in AS-3. Applicant asserts that these benefits could not have been predicted based on the teachings of the cited art.
Response to Arguments: The previous rejections of the claims have been withdrawn in view of Applicant’s amendment to claim 1. In the new rejection set forth above, claim 1 is obvious over the combined teachings of De Korte, Harmening, Fisher, and Pendas where De Korte teaches the storage solution PAGGG-M that does not contain citrate or citric acid, and Pendas teaches the storage solution containing tetrasodium pyrophosphate does not contain citrate or citric acid. Therefore, none of the cited teachings in the new rejection set forth above teach AS-3, and it is AS-3 that Applicant’s PPi-3 is compared to in asserting the unexpected beneficial effects.
De Korte teaches that PAGGG-M showed no vesicle formation indicating high membrane integrity and free hemoglobin levels remained below 0.2% after 6 weeks (page 1087, right col. para. 2; Figure 4). De Korte teaches PAGGG-M has a low osmolarity and this and/or the high concentration of mannitol plays a role in maintaining the integrity of the membranes (page 1087, right col. para. 2). De Korte teaches the ATP levels after 42 days of storage were between 4 – 5 µmol/g Hb in Figure 3 (page 1085, left col. para. 2). De Korte teaches in Figure 3D glucose consumption during storage in PAGGG-M (page 1085, left col. para. 2). De Korte teaches washed RBCs stored in PAGGG-M for 42 days were of high quality showing high levels of 2,3-DPG, even up to twice the physiologic level, with ATP content between 5 and 6 µmol per g Hb (page 1086, right col. last para.; page 1087, left col. para. 1; page 1088, left col. para. 3). As Harmening teaches the addition of a phosphate source that may be inorganic pyrophosphate to maintain 2,3-DPG levels past the third week of storage comprising a phosphate source to maintain sufficient 2,3-DPG and ATP levels suitable for transfusion, the combine teachings of De Korte, Harmening, Fisher, and Pendas make obvious the claimed pRBC storage solution and therefore the beneficial effects of storing pRBCs in the claimed storage solution would be expected.
Conclusion
No claims allowed.
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/ZANNA MARIA BEHARRY/Examiner, Art Unit 1632