DETAILED ACTION
Claims 1, 6-15, 17-19, 23, 25-28 and 63-65 are currently pending. Claims 2-5, 16, 20-22, 24, 29-62, 66-68 are cancelled.
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 .
Election/Restrictions
Applicant’s election without traverse of invention Group 1, claims 1, 6-15, 17-19, 23, 25-28 and 63-65, and Group 1 species:
Anticoagulant solution is present (claim 10);
Quencher is a peptide of 3-6 amino acids, wherein at least one of the amino acids is cysteine (claim 15 part (b), claim 17);
Each of the pathogen-inactivating compound and the quencher is in a solution
comprising 7-12% dextrose (claim 19, part (d)); and
Adenine (claim 23), in the reply filed on 12/8/2025 is acknowledged.
Claim 11 is withdrawn.
Priority
This application claims benefit as a CON of 16/474,938 (filed 6/28/2019; ABN) which claims benefit from PCT/US2017/068689 (filed 12/28/2017) and claims benefit of 62/441,312 (filed 12/31/2016).
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9/19/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 1, 6-10, 12-15, 17-19, 23, 25-28, and 63-65 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Henschler et al (Transfusion Medicine and Hemotherapy 38(1):33-42; IDS 9/13/2023) (“Henschler”), in view of Stassinopoulos et al., (US 2003/0113704; see PTO-892) (“Stassinopoulos”) and Mufti et al., (US 2011/0286987; IDS 9/19/2023) (“Mufti”), as evidenced by TERUMOBCT (SAG-M Saline Adenine Glucose-Mannitol, Safety Data Sheet; PTO-892) (“TERUMOBCT”).
Henschler entitled "Development of the S-303 Pathogen Inactivation Technology for Red Blood Cell Concentrates" teaches that pathogen inactivation of blood donation products using compound S-303 (claim 1, (ii), claim 12) and glutathione GSH (i.e., quencher, claim 1, (iii); claims 15 and 17) as a quencher for blood transfusion was known in the art prior to the instant application's filing date and report on efficacy studies pertaining to S-303 treatment of donated blood, see entire document including the Summary.
S-303 is described as a nucleic acid targeted alkylator with three components: i) an acridine anchor that intercalates non-covalently in nucleic acids, ii) a bis-alkylator effector group that reacts with nucleophiles such as DNA and RNA bases, and iii) a small flexible carbon linker containing a labile ester bond that hydrolyzes at neutral pH to yield the non-reactive, negatively charged breakdown product, S-300, see Fig. 2 (claims 12-13). When S-303 is added to RBCs, the compound rapidly (within seconds to minutes) passes through membranes, including those of cells and viral envelopes, due to its amphipathic character and intercalates into helical regions of nucleic acids. The decomposition kinetics (Fig. 3) are rapid (half-life 20 minutes) at concentrations above 10 nmol/1 slowing considerably at lower S-303 concentrations (half-life greater than 6 h). See "Chemical Structure and Characteristics of S-303" and Fig. 3. Further, Henschler explains that glutathione (GSH), a known antioxidant quencher, is included in PI processing to minimize unwanted extracellular S-303 reactions with proteins. More specifically, the reference explains that S-303 PI technology "…has been designed to enable processing or RBC units in additive solution over a wide range of RBC volumes…" indicating that PI consists of three containers, a first container for mixing the PI reagents including RBCs, GSH and S-303, along with a diluent solution (claims 64-65), a second container for incubating the RBCs and reagents and a third for storage of the pathogen inactivated RBCs (claim 63). "…A RBC concentrate separated from whole blood or collected via apheresis and leukoreduced is transferred into the integrated processing set…" For each unit of RBCs, approximately 30 ml of GSH and S-303 in saline are mixed with the RBCs and 140 ml of a diluent solution in the first container to a final concentration of 20 mmol/1 GSH and 0.2 mmol/1 S-303. The RBCs and reagents in the first container are transferred to a second container to allow the pathogen inactivation process to occur, (that is nearly complete after 30 minutes), and for S-303 to decompose to the nonreactive byproduct S-300 (between 6 and 18 hours). Following the pathogen inactivation and S-303 decomposition, the RBC unit with reagents and byproducts is centrifuged, the supernatant is removed, and the pathogen inactivated RBC unit is suspended in additive solution and transferred to a storage container for refrigerated storage (claims 25 and 28) up to 35 days. See "Mechanisms and Principles of the S-303 Pathogen Inactivation System". Henschler recognizes that implementation of the S-303 IP technology will need to take into account differences in blood donation criteria to ensure consistent blood products treated via S-303 IP technology and that "…different blood donation volumes have to be taken into account (450 or 500 ml) as well as different RBC volumes and hemoglobin content…" See "Development and Implementation of S-303 Treatment System -- the Path Forward.
Therefore, Henschler teaches mixing RBCs collected via apheresis with a PI being S-303 which is a PI having a functional group which is an electrophilic group and a quencher in a processing solution, replacing the solution used during treatment with an additive solution and transferring to a storage container. Scaling up such a process with IP treatment with S-303/glutathione on multiple, donated units of RBCs is obvious and predictable (MPEP 2144.04(V)) and separating the IP treated RBCs into readily usable transfusion bags, each containing a unit of RBCs is obvious and predictable since the IP treated RBCs are slated for transfusion and are therefore "suitable for infusion into a subject." (claim1 and 27). Thus, the separating limitation of claim 1(c) and claim 26 reads on aliquoting the final PI RBCs into units contained within separate blood bags or separate IV bags and can contain units suitable for either a large adult or a small child/infant since humans of all ages and sizes are subject in need of RBC transfusion. Therefore, claim 1, part (c) and claim 26, which indicates that the pathogen inactivated RBCs are separated into at least two units of pathogen inactivated RBCs wherein each unit is contained in an individual container is an obvious variation which flows predictably from the prior art. "A person of ordinary skill is also a person of ordinary creativity, not an automaton" KSR 127S. CT. at 1742.
The claims differ from Henschler in that Henschler does not further teach the quencher is in a solution comprising about 5% to about 12% dextrose or that the packed red blood cell volume is about 75% to about 95%.
As to the limitation the quencher is in a solution comprising about 5% to about 12% dextrose, it is noted Stassinopoulos entitled "Method for Inactivation of Pathogens in Biological Materials" teaches that conventional RBC storage solutions may interfere/effect pathogen inactivation and opines that, "…there is a need to find a suitable method of pathogen inactivation, with an appropriate additive solution, which gives optimal bacterial inactivation without substantially affecting the utility of the blood or blood products," see paragraph 7. Stassinopoulos teaches an updated, modified PI blood processing method utilizing hypotonic additive solutions of known blood products such as PRBCs to yield improved inactivation of certain pathogens such as gram negative bacteria including S. typhomurium and Y. entercolitica to increase the log of pathogen inactivation, see paragraph 8 and 29. A most preferred PIC is N-(acridin-9-yl), 2-[bis(2-chloroethyl)amino]ethyl ester; i.e. PIC S-303 in paragraph 45 which is utilized as the PIC in all of Examples 1-3 (claim 14). According to Stassinopoulos inclusion of an additive solution which is hypotonic, i.e. "…a solution having a lower osmolarity than cellular cytoplasm" by using dextrose which is a compound that can readily equilibrate (in paragraph 26) results in greater pathogen inactivation as evidenced by the data presented therein, see paragraph 81. In paragraph 37 "In one embodiment of the present invention, the additive solution is hypotonic, such that it will induce the movement of water into the intracellular compartment of cells in additive solution. A hypotonic additive solution is less than about 325 mOsmolar, more preferably less than about 300 mOsmolar. A hypotonic solution may be hypotonic due to the total ion and solute concentrations. Alternatively, a solution may be effectively hypotonic when the formal tonicity based on the ion and solute concentrations is above 325 mOsmolar but some of the components readily traverse the cell membranes. This result is an extracellular medium which is effectively hypotonic. Such solutions, in which the effective hypotonicity is based on ion and solute concentrations of those ions and solutes that do not traverse the cell membranes, are encompassed by the present invention.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to provide the claimed dextrose solution with a RBC volume of at least about 220 mL because Stassinopoulos provides several testing examples for their modified S-303 IP treatment of RBCs including Example 3 in paragraph 74, directed toward pathogen inactivation of a full unit of PRBC, 300 ml (claim 1(a)(i) and claim 7) was treated. 300 ml of PRBCs meets the limitation of claim 1(a)(i) because PRBCs are obtainable via apheresis and because 300 mL is squarely within the boundaries of "at least about 220 ml" as claimed. In these examples, PRBC units were mixed with a solution having S-303 and glutathione in either 10.05% of dextrose (E1) or 4.5% dextrose (A1) (claim 1 and 19). Note that the solution containing S-303 and the additives are present in an "additive solution" i.e. S-303/glutathione +additive with dextrose equals components in an "additive solution" as indicated by claim 1. Both of these formulations meet the limitation "…at least one of the pathogen inactivating compound and the quencher is in a solution comprising about 5% to about 12% of dextrose as claimed because both the PIC and the quencher are present in a 4.5% dextrose additive (whereby 4.5% dextrose is about 5% dextrose as claimed). And a 10.05% dextrose additive which falls completely within "about 5% to about 12% of dextrose" as claimed. Note that Table 3 presents log inactivations using both dextrose solutions to create hypotonicity and both formulations inactivate pathogens although the log inactivation is higher using the 4.5% dextrose solution. This document further indicates that RBC undergoing IPC treatment with hypotonic solutions may be tested for RBC function/viability using conventional testing (to test for hemolysis, pH, hematocrit, glucose/hemoglobin levels, etc.) and preferably have a less than 2% hemolysis after 28 days of storage, see paragraphs 64-65. Thus, the addition of at least the quencher or PIC whereby at least one of the quencher or PIC is contained in a solution containing about 5% to about 12% of dextrose is obvious is commensurate with the teachings within the prior art. The prior art already recognized the benefit of RBC pathogen inactivation within a hypotonic environment, expressly teaching mixing RBCs with glutathione (quencher) and PIC (S-303) in a solution containing 4.5% dextrose and 10% dextrose. Each of these RBC compositions is demonstrated as having the ability to inactivate pathogens associated with RBCs, and the quencher/PIC in a 4.5% dextrose solution (4.5% dextrose reading on "about 5% dextrose" as claimed) increased the log inactivation of RBC pathogens, see Table 2, E1 = .42 log increase of Y. enterocolitica inactivation.
One having the above cited references before them would have understood that this improved treatment would be advantageously used for any volume of RBCs and that adjustment of amounts of elements within the additive to account for varying RBC volumes would have been routine in order to optimize pathogen inactivation and viability/function of RBCs slated for transfusion. Notwithstanding the consideration that the prior art expressly teaches treatment of 300 ml of RBCs with this improved treatment with dextrose containing additives having PIC and glutathione admixed therein, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
As to the limitation that the packed red blood cell volume is about 75% to about 95% (claim 1) or about 80% to 90% (claim 6), it is noted that Henschler teaches a RBC (red blood cell) concentrate is separated from whole blood or collected via apheresis and leuko-reduced is transferred into the integrated processing set.
Henschler does not further comment on the concentration of the RBCs (red blood cells) having a packed red cell volume of 75% to 95%, or a volume of 80% to 90%.
However, Mufti is likewise directed to treating red blood cell compositions with pathogen inactivators to prepare the blood for infusion into humans (Abstract and paragraph 16) and specifically teaches using red blood cell concentrates that are described by their packed red blood cell (PRBC) volume or hematocrit (a measure of the red blood cells in the composition), wherein the concentrated RBC compositions have a hematocrit in the range of about 1% to 100%, more likely 10% to 90% (paragraph 32). Mayo Clinic further evidences that a hematocrit is a measure of the proportion of red blood cells (see Overview). Thus, Mufti, as evidenced by Mayo Clinic, has established it was well-known to employ a packed red blood cell volume ranging from 10%-90% in methods of treating a red blood cell composition with pathogen-inactivating compounds to prepare the blood for infusion to humans.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ a packed red blood cell volume ranging from 10%-90%.
The person of ordinary skill in the art would have been motivated to modify the method of Henschler to include a packed red blood cell volume of up to 90%, as taught by Mufti, for the predictable result of successfully maximizing pathogen-inactivation of red blood cells prior to transfusion to humans, thus meeting the limitation of claim 1.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Henschler and Mufti because each of these teachings are directed at methods of treating a red blood cell composition with pathogen-inactivating compounds to prepare the blood for infusion to humans.
Further regarding claims 9-10, it is noted that Henschler does not further comment on the red blood cell composition to be subjected to pathogen inactivation comprises less than about 5% plasma by volume (claim 9) or further comprises an anticoagulant solution (claim 10). However, Stassinopoulos, as set forth above, is also directed to methods for inactivation of pathogens in red blood cells and teaches the PRBC (packed red blood cells) were prepared from whole blood that contained an anticoagulant which was subsequently removed upon centrifugation and removal of the supernatant, which further reads on the red blood cell composition comprises less than about 5% plasma.
Thus, Stassinopoulos has established it was known in methods for inactivation of pathogens in red blood cells that the red blood cell composition comprises less than about 5% plasma by volume (claim 9) or further comprises an anticoagulant solution (claim 10).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that methods for inactivation of pathogens in red blood cells, the red blood cell compositions employed comprise an anticoagulant and less than about 5% plasma by volume.
The claimed limitations were known, as taught by Stasinopoulos, and one skilled in the art could have combined the claimed limitations without any change in promoting inactivation of pathogens in red blood cells since Stassinopoulos teaches the predictable result of for inactivation of pathogens in red blood cells, thus meeting the limitation of claims 9-10.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Stassinopoulos and Henschler because each of these teachings are directed at methods for inactivation of pathogens in red blood cells.
Further regarding claim 18, Henschler teaches the glutathione is monosodium salt (Table 1), thus meeting the limitation of claim 18.
Further regarding claim 23 directed to the processing solution comprising adenine, it is noted that Henschler teaches use of SAG-M (page 36, left col, last paragraph) and TERUMOBCT evidences that SAG-M comprises saline, adenine, glucose-mannitol, thus Henschler’s teaching meets the limitation of claim 23.
Conclusion
No claim is allowed. No claim is free of prior art.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/ Primary Examiner, Art Unit 1633