Patent Application 17212296 - RED BLOOD CELL STORAGE SOLUTIONS SOLUTION

Title: RED BLOOD CELL STORAGE SOLUTIONS, SOLUTION ADDITIVES, AND METHODS FOR IMPROVING THE STORAGE OF RED BLOOD CELLS

Application Information

Invention Title: RED BLOOD CELL STORAGE SOLUTIONS, SOLUTION ADDITIVES, AND METHODS FOR IMPROVING THE STORAGE OF RED BLOOD CELLS
Application Number: 17212296
Submission Date: 2025-05-15T00:00:00.000Z
Effective Filing Date: 2021-03-25T00:00:00.000Z
Filing Date: 2021-03-25T00:00:00.000Z
National Class: 435
National Sub-Class: 002000
Examiner Employee Number: 96394
Art Unit: 1631
Tech Center: 1600

Rejection Summary

102 Rejections: 0
103 Rejections: 3

Cited Patents

No patents were cited in this rejection.

Office Action Text

DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/21/2025 has been entered.

Status of the Claims
Claims 15-31 are pending.
Claims 15 and 21-22 are newly amended.
Claims 23-31 are newly added.
Claims 15-31 have been examined on their merits.

Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The rejection of claims 15-19 under 35 U.S.C. 103 as being unpatentable over Hoehn et al., (Biol Chem, 2015, first published online on March 29, 2015, on IDS 07/09/2021) in view of Awojoodu et ai. (Blood, 2014, on IDS 07/09/2021), Belizaire et al. (J Am Coll Surg, 2012) and Valeri et al. (Transfusion, 2000, previously cited) as evidenced by Miller et al. (Concise Clinical Review, 2012) is withdrawn in order to incorporate Belizaire et al. (J Am Coll Surg, 2012) due to amendment of the claims.
The rejection of claim 20 under 35 U.S.C. 103 as being unpatentable over Hoehn et al., (Biol Chem, 2015, first published online on March 29, 2015, on IDS 07/09/2021) in view of Awojoodu et ai. (Blood, 2014, on IDS 07/09/2021), Belizaire et al. (J Am Coll Surg, 2012) and Valeri et al. (Transfusion, 2000) as evidenced by Miller et al. (Concise Clinical Review, 2012, previously cited) is withdrawn in order to incorporate Belizaire et al. (J Am Coll Surg, 2012) due to amendment of the claims.
The rejection of claims 21 and 22 under 35 U.S.C. 103 as being unpatentable over Hoehn et al., (Biol Chem, 2015, first published online on March 29, 2015, on IDS 07/09/2021) in view of Awojoodu et ai. (Blood, 2014, on IDS 07/09/2021) and Valeri et al. (Transfusion, 2000), as evidenced by Miller et al. (Concise Clinical Review, 2012), as applied to claim 17 above, and further in view of Deo et al. (Colloids and Surfaces B Biointerfaces, 2004), is withdrawn in order to incorporate Belizaire et al. (J Am Coll Surg, 2012) and Ozayar et al. (Toxicology International, 2012) due to amendment of the claims.

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.

Claims 15-19 and 23-30 are rejected under 35 U.S.C. 103 as being unpatentable over Hoehn et al., (Biol Chem, 2015, first published online on March 29, 2015, on IDS 07/09/2021, previously cited) in view of Awojoodu et ai. (Blood, 2014, on IDS 07/09/2021, previously cited), Belizaire et al. (J Am Coll Surg, 2012) and Valeri et al. (Transfusion, 2000, previously cited).
In regards to independent claim 15 and its dependent claims 16-19, Hoehn teaches methods for storing erythrocytes (red blood cells, RBCs in AS-3 solution at 4°C for at least 35 days, and that the RBCs can be packed (“pRBCs”) (Blood collection and storage, p3; Figure 1, p16).
While Hoehn does not explicitly teach that the storage solution also comprises one or more acid sphingomyelinase (Asm) inhibitors, Hoehn teaches that it is known that incubating RBCs with sphingomyelinase induces formation of ceramide-enriched platforms which results in decreased cell size, increased fragility, and increases in RBC-derived microparticles (MPs) (Sphingolipids, p5), which are characteristics of RBC storage lesions (Table 1, p17), and that increases in sphingomyelinase and storage lesions is associated with a variety of pathologies including inflammation (Erythrocyte storage lesion, p4; Sphingolipids, p5).
This is confirmed by Awojoodu who teaches that Asm (referred to as “acid SMase” by Awojooju) contributes to lipid microdomain formation (of which ceramide rafts are a type), membrane fragility, vesiculation, and inflammatory MP generation (Title, Abstract, p1941; Introduction, p1941; MPs are internalized and modulate cytokine production by monocytes, 1944-1945).
Additionally, as taught by Belizaire it is known in the art that stored packed RBCs contain increased numbers of RBC-derived MPs, and that after transfusion cause inflammatory responses such as neutrophil-induced lung injury (Title, Abstract, p1; Discussion, p7-9).
As further taught by Awojoodu, centrifuged (packed) RBCs with amitriptyline, a tricyclic antidepressant and Asm inhibitor, reduces MP generation in vitro and in vivo and might be used to mitigate inflammatory processes (Abstract, p1941; Methods, p1942; Figure 7, p1947).
A person of ordinary skill in the art would have been motivated to modify the method of Hoehn and specifically add an Asm inhibitor such as amitriptyline in order to reduce the generation of MPs which are known to be involved in RBC dysfunction and cause inflammation as a result of being stored and packed.
They would have been further motivated to include an Asm inhibitor because Hoehn explicitly cites Awojoodu as implicating the role of sphingolipid (sphingomyelinase breaks down the sphingolipid sphingomyelin) disfunction in RBCs (Sphingolipids, p5).
Furthermore, because Awojoodu teaches that packed RBCs may be effectively treated with amitriptyline to reduce MP generation (Abstract, p1941; Methods, p1942; Ex vivo RBC studies, p1942), and since Hoehn and Awojoodu are in the same technical field of treating RBCs, it could have been done with predictable results and a reasonable expectation of success.
In regards to the property of “reducing a risk of storage lesion in the packed cells”, it is noted that the claim does not actually require that the method reduce storage legions in the stored packed cells, but only indicates that the risk (the probability) of storage legions is reduced (of which the probability of risk reduction is unlimited).
However, as discussed above, Hoehn teaches that sphingomyelinase is associated with decreased cell size, increased cell fragility, and MP formation. Hoehn also teaches that these are characteristics of RBC storage lesions specifically (Table 1, p17)
However as above, Hoehn teaches that MP generation is a characteristic of RBC storage lesions (Table 1, p17), while Awojoodu teaches that treatment of packed RBCs with Asm inhibitor amitriptyline reduces at least MP generation (Abstract, p1941; Methods, p1942).
Therefore, since it was known in the art before the effective filing date that contacting packed RBCs with an Asm inhibitor reduced MP generation, the upregulation of which is also known to be associated with formation of storage lesions and pathology after transfusion, it would be expected that a method wherein the MP generation is reduced would reduce the risk of storage lesions in the stored packed RBCs.
In regards to the step of administering the stored packed RBCs, while Hoehn does explicitly teach a step of administering RBCs to subjects via transfusion, Hoehn teaches that anemia and hemorrhagic shock are leading causes of morbidity and mortality worldwide, and transfusion of human blood products is the ideal treatment for these conditions (Remarks, p1).
Therefore, a person of ordinary skill in the arts would have been motivated to administer the stored RBCs to a subject via transfusion in order to reduce morbidity and mortality associated with anemia and hemorrhagic shock. Furthermore, because Valeri teaches that RBCs stored at 4°C in AS-3 solution can be effectively transfused into patients (Abstract, p1341; in vivo measurements, p1343) it could have been done with predictable results and a reasonable expectation of success.
In regards to mitigating the risk of a medical complication associated with a transfusion of packed blood cells blood cells, similarly to as above, not only does the claim not require that medical complications are mitigated (only a risk of which the probability of mitigation is unlimited), Applicant should note that this is an intended use of the claim a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997) (see MPEP 2111.02).
In the instant case since Hoehn teaches that increases in MP generation is a characteristic of RBC storage lesions, which Hoehn and Awojoodu both teach is associated with inflammation (a medical complication), and which Belizaire teaches is associated with post-transfusion lung inflammation specifically, and since Awojoodu teaches that treatment of packed RBCs with Asm inhibitor amitriptyline reduces at MP generation, it suggests that the combined method would in fact reduce the risk of a medical complication associated with transfusion of packed RBCs in a subject.
In regards to independent claim 27 and its dependent claim 28, as above, Hoehn teaches methods for storing erythrocytes (red blood cells, RBCs in AS-3 solution at 4°C for at least 35 days, and that the RBCs can be packed (“pRBCs”) (Blood collection and storage, p3; Figure 1, p16). Hoehn also teaches that the RBCs can be obtained from donors (Blood collection and storage, p3).
In regards to amitriptyline, as discussed above, amitriptyline is a known Asm inhibitor.
Further as discussed above, while Hoehn does not explicitly teach that the storage solution also comprises the Asm inhibitor amitriptyline, Hoehn teaches that it is known that incubating RBCs with sphingomyelinase induces formation of ceramide-enriched platforms which results in decreased cell size, increased fragility, and increases in RBC-derived microparticles (MPs) (Sphingolipids, p5), which are characteristics of RBC storage lesions (Table 1, p17), and that increases in sphingomyelinase and storage lesions is associated with a variety of pathologies including inflammation (Erythrocyte storage lesion, p4; Sphingolipids, p5).
This is confirmed by Awojoodu who teaches that Asm (referred to as “acid SMase” by Awojooju) contributes to lipid microdomain formation (of which ceramide rafts are a type), membrane fragility, vesiculation, and inflammatory MP generation (Title, Abstract, p1941; Introduction, p1941; MPs are internalized and modulate cytokine production by monocytes, 1944-1945).
Additionally, as taught by Belizaire it is known in the art that stored packed RBCs contain increased numbers of RBC-derived MPs, and that after transfusion cause inflammatory responses such as neutrophil-induced lung injury (Title, Abstract, p1; Discussion, p7-9).
As further taught by Awojoodu, centrifuged (packed) RBCs with amitriptyline, a tricyclic antidepressant and Asm inhibitor, reduces MP generation in vitro and in vivo and might be used to mitigate inflammatory processes (Abstract, p1941; Methods, p1942; Figure 7, p1947).
A person of ordinary skill in the art would have been motivated to modify the method of Hoehn and specifically add an Asm inhibitor such as amitriptyline in order to reduce the generation of MPs which are known to be involved in RBC dysfunction and cause lung inflammation as a result of being stored and packed.
They would have been further motivated to include an Asm inhibitor because Hoehn explicitly cites Awojoodu as implicating the role of sphingolipid (sphingomyelinase breaks down the sphingolipid sphingomyelin) disfunction in RBCs (Sphingolipids, p5).
Furthermore, because Awojoodu teaches that packed RBCs may be effectively treated with amitriptyline to reduce MP generation (Abstract, p1941; Methods, p1942; Ex vivo RBC studies, p1942), and since Hoehn and Awojoodu are in the same technical field of treating RBCs, it could have been done with predictable results and a reasonable expectation of success.
In regards to the step of administering the stored packed RBCs, while Hoehn does explicitly teach a step of administering RBCs to subjects via transfusion, Hoehn teaches that anemia and hemorrhagic shock are leading causes of morbidity and mortality worldwide, and transfusion of human blood products is the ideal treatment for these conditions (Remarks, p1).
Therefore, a person of ordinary skill in the arts would have been motivated to administer the stored RBCs to a subject via transfusion in order to reduce morbidity and mortality associated with anemia and hemorrhagic shock. Furthermore, because Valeri teaches that RBCs stored at 4°C in AS-3 solution can be effectively transfused into patients (Abstract, p1341; in vivo measurements, p1343) it could have been done with predictable results and a reasonable expectation of success.
In regards to the effect of the preamble of “reducing risk of lung inflammation associated with transfusion of red blood cells in a patient in need”, and the clause “wherein the risk of lung inflammation in the subject is reduced”, it is noted that the claim does not require that the method reduce inflammation in a subject, but only indicates that the risk (the probability) of lung inflammation is reduced (of which the probability of risk reduction is unlimited).
As discussed above, since Hoehn teaches that increases in MP generation is a characteristic of RBC storage lesions, which Hoehn and Awojoodu both teach is associated with inflammation, and which Belizaire teaches is associated with post-transfusion lung inflammation specifically, and since Awojoodu teaches that treatment of packed RBCs with Asm inhibitor amitriptyline reduces at MP generation, it suggests that the combined method would in fact reduce the risk of lung injury.
In regards to claims 23-24 and 30, Hoehn teaches that RBCs can be stored for at least 35 days (Figure 1, p16), which overlaps with the ranges as in claims 23 and 24.
In regards to claim 25, Hoehn teaches that stored RBCs (pRBCs) can have a chronological age of 42 days to 162 days (p2, third paragraph) which overlaps with the range as in claim 25.
In regards to claims 26 and 29, Awojoodu teaches that the concentration of amitriptyline can be 100 µM (Ex vivo RBC studies, p1942; Figure 7, p1947). While less than a concentration of 125 µM, it is nonetheless close (see MPEP 2144.05, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)).
Furthermore, a person of ordinary skill in the art could have arrived at a concentration of 125 µM by routine optimization and the disclosure does not point to a criticality in this concentration (see MPEP 2144.05(II)(A), Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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)).
In the instant case because Awojoodu teaches that RBC can be contacted with a range of concentrations of amitriptyline, and demonstrates that MPs significantly decrease over time in time with higher concentrations of amitriptyline (Figure 7, p1947), a person of ordinary skill in the art could have arrived at a concentration of 125 µM by routine optimization with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Hoehn, Awojoodu, Belizaire, and Valeri renders the invention unpatentable as claimed.

Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Hoehn et al., (Biol Chem, 2015, first published online on March 29, 2015, on IDS 07/09/2021, previously cited) in view of Awojoodu et ai. (Blood, 2014, on IDS 07/09/2021, previously cited), Belizaire et al. (J Am Coll Surg, 2012) and Valeri et al. (Transfusion, 2000, previously cited) as applied to claim 15 above, and further in view of Kornhuber et al. (J Med Chem, 2008, on IDS 07/09/2021, previously cited).
In regards to claim 20, Hoehn, as modified by Awojoodu, Belizaire, and Valeri, does not explicitly teach that the Asm inhibitor is Fluoxetine. However, Kornhuber teaches amitriptyline is known in the literature to be an Asm inhibitor (Abstract, p219; Table 1, compound 6, p221) and teaches that fluoxetine is also a novel functional Asm inhibitor (Abstract, p219; Table 3, compound 104, p229). Furthermore, as taught by Awojoodu above, amitriptyline is an antidepressant, and it is well known in the art that fluoxetine (Prozac) is also an antidepressant.
Thus, amitriptyline and fluoxetine are art recognized equivalents for the same purpose (see MPEP 2144.06). A person of ordinary skill in the arts would have been motivated to substitute amitriptyline for fluoxetine because Kornhuber indicates that fluoxetine is a suitable functional Asm inhibitor. Furthermore, because Kornhuber indicates that amitriptyline and fluoxetine are art recognized equivalents for the same purpose, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Hoehn, Awojoodu, Belizaire, Valeri, and Kornhuber render the invention unpatentable as claimed.

Claims 21-22 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Hoehn et al., (Biol Chem, 2015, first published online on March 29, 2015, on IDS 07/09/2021, previously cited) in view of Awojoodu et ai. (Blood, 2014, on IDS 07/09/2021, previously cited), Belizaire et al. (J Am Coll Surg, 2012) and Valeri et al. (Transfusion, 2000, previously cited) as applied to claims 15 or 27 above, and further in view of Ozayar et al. (Toxicology International, 2012).
In regards to claims 21-22 and 31, as above, Hoehn teaches that stored RBCs can washed prior to transfusion (Microparticles, p7), and teaches filtration methods (p.3, 1st para.). However, Hoehn, as modified by Awojoodu, Belizaire, and Valeri, does not explicitly teach removing the Asm inhibitor (which is specifically amitriptyline as taught by Awojoodu as discussed above) prior to administration, and by filtration specifically.
However, as taught by Ozayar tricyclic antidepressant overdose (of which amitriptyline is a type) is one of the most common causes of serious drug poisoning, can be lethal, and that and amitriptyline intoxication can be difficult to treat with standard treatments (Abstract, p319). Continuing, Ozayar teaches that ultrafiltration can be used to eliminate amitriptyline from blood (Abstract, p319; Introduction, p319). Therefore, a person of ordinary skill in the art would have been motivated to remove or filter amitriptyline prior to administration in order to remove the drug and reduce the likelihood of drug poisoning, intoxication, or lethality. They would have specifically been motivated to filter amitriptyline because Ozayar indicates that ultrafiltration can eliminate amitriptyline from blood.
Furthermore, because Ozayar teaches ultrafiltration can remove amitriptyline from blood (Introduction, p319), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Hoehn, Awojoodu, Belizaire, Valeri, and Ozayar renders the invention unpatentable as claimed.

Response to Arguments
Applicant argues that Hoehn is a review article and provides, teaches a variety of storage solutions, including AS-3, but provides no guidance or suggestion whatsoever to modify the named storage solutions, to add an Asm inhibitor in order to mitigate medical complications associated with transfusion of stored packed RBCs (Remarks, p6).
Applicant argues that while Hoehn states that sphingolipid metabolism plays a role in erythrocyte structural changes that may occur in aging, Hoehn cites “Dinkla 2012” which Applicant argues only teaches “incubating” erythrocytes at 37°C with varying doses of sphingomyelinase, not storing RBCs at 4°C (Remarks, p6-7).
Continuing, Applicant argues that, while the Advisory Action on Jan. 21, 2025 assets that the specification does not distinguish between the terms “incubating” and “storing”, Applicant argues that word “incubate” is understood in the art to refer to maintaining a living system under conditions favorite for growth or development (Remarks, p7).
Therefore, Applicant concludes that a person of ordinary skill in the art would not have selected AS-3 from the list of possible storage solutions as taught by Hoehn to comprise an Asm inhibitor, and then store the blood at 4°C to mitigate the risks of medical complications in a subject receiving a transfusion of blood with any reasonable expectation of success (Remarks, p7).
Applicant's arguments filed 02/21/2025 have been fully considered but they are not persuasive.
As discussed above, Hoehn teaches that it is known that incubating RBCs with sphingomyelinase induces formation of ceramide-enriched platforms which results in decreased cell size, increased fragility, and increases in RBC-derived microparticles (MPs) (Sphingolipids, p5), which are characteristics of RBC storage lesions (Table 1, p17), and that increases in sphingomyelinase and storage lesions is associated with a variety of pathologies including inflammation (Erythrocyte storage lesion, p4; Sphingolipids, p5).
This is confirmed by both Belizaire and Awojoodu as discussed above.
As above, Awojoodu who teaches that Asm (referred to as “acid SMase” by Awojooju) contributes to lipid microdomain formation (of which ceramide rafts are a type), membrane fragility, vesiculation, and inflammatory MP generation (Title, Abstract, p1941; Introduction, p1941; MPs are internalized and modulate cytokine production by monocytes, 1944-1945), and Belizaire teaches that it is known in the art that stored packed RBCs contain increased numbers of RBC-derived MPs, and that after transfusion cause inflammatory responses such as neutrophil-induced lung injury (Title, Abstract, p1; Discussion, p7-9).
Therefore, the detrimental effects of the generation of MPs on RBC morphology, and resultant pathological effects (including inflammation), due to these MPs, is a known problem with stored packed RBCs.
As a result, a person of ordinary skill in the art would have been motivated to modify the method of Hoehn, which uses a well-known blood storage medium, and add an Asm inhibitor such as amitriptyline because as above, Awojoodu teaches that exposure of RBCs to amitriptyline reduces MP generation and therefore may be a solution to inflammation (Abstract, p1941; Methods, p1942; Figure 7, p1947).
Furthermore, as a above, Hoehn cites Awojoodu in their discussion of the effects of sphingolipids and sphingomyelinase. Therefore, a person of ordinary skill in the art would have been motivated to add Asm inhibitor such as amitriptyline, as taught by Awojoodu because Hoehn identifies Awojoodu as offering a solution to the known problem of MP generation, RBC dysfunction, and resultant inflammation as a result of RBC exposure to sphingomyelinase.
In regards to Dinkla 2012, this reference has not been cited in the Office Action. Furthermore, contrary to Applicant’s assertions, Dinkla 2012 provides further motivation to modify the method of Hoehn because Dinkla 2012 recognizes the deleterious effects of sphingomyelinase on RBCs.
In regards to a difference between “storing” and “incubating”, the disclosure does not distinguish between these terms. As evidenced by Oxford Language “store” merely means “a quantity or supply of something kept for use as needed” or to “keep or accumulate (something) for future use”. Cells that are “incubated” because they are being kept for a future use (at the end of incubation).
In regards to the difference between 4°C and 37°C and an effect it could have on an Asm inhibitor in solution, noted that “4°C” only refers to refrigeration temperature. At this temperature, cellular metabolism is lowed, but still active, and cells and solution do not freeze. Furthermore, as evidenced by Sigma-Aldrich, it is recommended that amitriptyline be stored between 2 to 8°C (Section 7, p4). Therefore, absent evidence to the contrary, amitriptyline would still be expected to have pharmacological activity at 4°C.
Moreover, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
As a result, as a above, because Awojoodu teaches that packed RBCs may be effectively treated with amitriptyline to reduce MP generation (Abstract, p1941; Methods, p1942; Ex vivo RBC studies, p1942), and since Hoehn and Awojoodu are in the same technical field of treating RBCs, a person of ordinary skill in the art could have modified the method of Hoehn to include amitriptyline, as taught by Awojoodu above, with predictable results and a reasonable expectation of success.

Applicant argues that Awojoodu fails to cure the deficiencies of Hoehn (Remarks, p8). In particular, Applicant argues that Awojoodu incubates RBCs at 37°C and in PBS supplemented with glucose not storage solution (Remarks, p8).
Continuing, Applicant argues that it is well-known in the art that PBS is commonly used to mimic physiological conditions rather than refrigerated blood storage conditions (Remarks, p8).
Applicant further argues that Awojoodu teaches that decreases in MP generation were only detected after 24 hours, and again, only at 37°C (Remarks, p8).
Continuing, Applicant argues that the question is not whether RBCs “can” be stored at 4°C and then transfused, but whether the data observed by Awojoodu at physiological temperatures and PBS would reasonably be expected to occur in cells stored at 4°C (Remarks, p8-9).
Applicant argues that there is no motivation to combine Hoehn, Awojoodu, and Valeri and that it could not have been done with predictable results and a reasonable expectation of success (Remarks, p9).
Applicant's arguments filed 02/21/2025 have been fully considered but they are not persuasive.
Applicant’s arguments in regards to a temperature of 37°C have been addressed in the previous response.
In regards to the use of PBS, similarly, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
As a result, as a above, because Awojoodu teaches that packed RBCs may be effectively treated with amitriptyline to reduce MP generation (Abstract, p1941; Methods, p1942; Ex vivo RBC studies, p1942), and since Hoehn and Awojoodu are in the same technical field of treating RBCs, a person of ordinary skill in the art could have modified the method of Hoehn to include amitriptyline, as taught by Awojoodu above, with predictable results and a reasonable expectation of success.
In regards to timings, it is noted that the independent claims do not require storing RBCs for any particular amount of time and do not indicate that a timing is critical for the application of an Asm inhibitor.

Applicant argues that Valeri fails to overcome the deficiencies of Hoehn and Awojoodu since Valeri does not teach modifying a storage solution to include an Asm inhibitor and storing at 4°C that this would result in reduction of storage lesions (Remarks, p8). Applicant argues that there is no motivation to combine Hoehn and Valeri and that it could not have been done with predictable results and a reasonable expectation of success (Remarks, p9).
Applicant's arguments filed 02/21/2025 have been fully considered but they are not persuasive.
Valeri has not been relied upon to teach methods of storing RBC with an Asm inhibitor at 4°C, but rather to demonstrate that stored RBCs could have been administered to a patient with predictable results and a reasonable expectation of success.
As discussed above, in regards to the step of administering the stored packed RBCs, while Hoehn does explicitly teach a step of administering RBCs to subjects via transfusion, Hoehn teaches that anemia and hemorrhagic shock are leading causes of morbidity and mortality worldwide, and transfusion of human blood products is the ideal treatment for these conditions (Remarks, p1).
Therefore, a person of ordinary skill in the arts would have been motivated to administer the stored RBCs to a subject via transfusion in order to reduce morbidity and mortality associated with anemia and hemorrhagic shock. Furthermore, because Valeri teaches that RBCs stored at 4°C in AS-3 solution can be effectively transfused into patients (Abstract, p1341; in vivo measurements, p1343) it could have been done with predictable results and a reasonable expectation of success.

Applicant argues that there is no motivation to combine Hoehn, Awojoodu, and Valeri and that it could not have been done with predictable results and a reasonable expectation of success (Remarks, p9).
Applicant's arguments filed 02/21/2025 have been fully considered but they are not persuasive as addressed above.

In regards to claim 20, Applicant argues that Kornhuber does not teach modifying an AS-3 storage solution to comprise an Asm inhibitor (Remarks, p10).
Applicant's arguments filed 02/21/2025 have been fully considered but they are not persuasive.
Kornhuber has not been relied on to teach modifying an AS-3 storage solution to comprise an Asm inhibitor.
Rather as above, Kornhuber teaches amitriptyline is known in the literature to be an Asm inhibitor (Abstract, p219; Table 1, compound 6, p221) and teaches that fluoxetine is also a novel functional Asm inhibitor (Abstract, p219; Table 3, compound 104, p229). Furthermore, as taught by Awojoodu above, amitriptyline is an antidepressant, and it is well known in the art that fluoxetine (Prozac) is also an antidepressant.
Thus, amitriptyline and fluoxetine are art recognized equivalents for the same purpose (see MPEP 2144.06). A person of ordinary skill in the arts would have been motivated to substitute amitriptyline for fluoxetine because Kornhuber indicates that fluoxetine is a suitable functional Asm inhibitor. Furthermore, because Kornhuber indicates that amitriptyline and fluoxetine are art recognized equivalents for the same purpose, it could have been done with predictable results and a reasonable expectation of success.

In regards to claims 21-22, Applicant argues that Deo is variously deficient (Remarks, p10-13).
Applicant’s arguments with respect to claims 21-22 have been considered but are moot because the new ground of rejection does not rely on Deo for any teaching or matter specifically challenged in the argument.

Conclusion
No claims are allowed.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631 /ARTHUR S LEONARD/Examiner, Art Unit 1631