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 .
Priority
This application is a national stage entry under 35 USC 371 of PCT/US20/049510 (filed 9/4/2020). Acknowledgement is made of Applicants’ claim for benefit of prior-filed US Provisional application 62/896360 (filed 9/5/2019).
Election/Restrictions
Applicant’s election without traverse of Group I, a method of making a stored red blood cell composition for drug delivery, in the reply filed on 11/21/2025 is acknowledged. Applicants have further elected the species of the method wherein the RBCs comprise a fusion protein, the RBCs with the fusion protein are treated with carbon monoxide (CO), and then the treated RBCs are stored in an atmosphere comprising CO. Claims 6-9, 13, 15, 21-26 read on the elected invention and species. Claims 16, 18 and 28-31 are withdrawn from consideration, as being drawn to non-elected inventions and/or non-elected species. Claims 6-9, 13, 15, and 21-26 have been considered on the merits.
Claim Objections
Claims 21 and 26 are objected to for minor informalities: In claim 21, line 2 the word “and” (in “a red blood cell comprising and pharmaceutical agent”) should read “said”.
In claim 26, line 2 the word “is” is missing (“fusion protein is selected from the group consisting of…”).
In claim 26, line 2, the abbreviation
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.
Claim 26 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.
Regarding claim 26: Claim 26 attempts to define the fusion protein that is the pharmaceutical agent present within the red blood cell. However claim 26 only discloses individual proteins, a fusion protein would comprise two proteins. The language either needs to be changed to recite actual fusion proteins, or to recite that the fusion protein comprises at least one of the recited proteins.
Furthermore, in claim 26 an extremely large number of “proteins” are listed, however numerous species are not recognized proteins. The following are identified as examples of unknown ‘proteins’, however Applicants must carefully review the list and remove or correct all mistyped or non-existent proteins.
-Arginase type 1 erythroid variant (arginase type 1 is a known urea cycle enzyme. It is unknown what “arginase type 1 erythroid variant” refers to)
-bA421I18.2
-probable ubiquitin E3 ligase C12orf51 (E3 ubiquitin ligase C is a known protein, the other details are unknown)
- Rh blood group SLC43A3 antigen
-DC 38 (CD38 is a known protein)
-enhancer protein
-all “Hypothetic proteins” listed
-protein band 3
- protein band 4.1
- protein band 4.1 (elliptocytosis 1, RH-linked) (it is unclear if the term in parenthesis is further limiting the species, or merely exemplary)
-protein band 4.1
-protein band 4.9 (dematin) (It is unclear if the term in parenthesis is further limiting the species, or merely exemplary)
-protein band 7.2b (stomatin) (It is unclear if the term in parenthesis is further limiting the species, or merely exemplary)
-tubulin alpha 1 (testis specific) (It is unclear if the term in parenthesis is further limiting the species, or merely exemplary)
-KIAA0340
Claim Rejections - 35 USC § 103
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.
Claims 6-9, 13, 15, and 21-26 are rejected under 35 U.S.C. 103 as being unpatentable over Villa et al (Blood Advances, Feb 2018), in view of Bitensky (US Patent 5476764).
Regarding claim 6: Villa et al teach RBCs are capable of being used as carriers to deliver drugs to a subject. Drugs can be encapsulated and/or surface coupled to RBCs. Villa et al teach surface coupling of drugs to RBCs is particularly useful in delivery of antithrombotic and anti-inflammatory drugs (See Villa et al, abstract and Pg 165-Pg 166, col. 1). Villa et al demonstrate the ability with representative antithrombotic and anti-inflammatory drug human thrombomodulin (hTM).
Villa et al create a fusion protein comprising hTM and nonhuman-primate single-chain antibody fragment (scFv) targeted to RhCE (Rh17/HR0 epitope) (hTM-aRh17) (See Villa et al, Pg 166, “Derivation and production of antibodies and fusion proteins”, Pg 167 “Binding of ligands and cargos to RBCs”). Villa et al further show that loading the hTM-aRh17 onto the RBCs did not cause any significant change in RBC membrane deformability, mechanical resistance, or osmotic resistance (See Villa et al, Pg 171, col. 2). The hTM-aRh17-carrying RBCs are able to successfully generate activated protein C (APC) in the presence of human protein C and thrombin (the expected enzymatic effect). In a microfluidic model, the hTM-aRh17-carrying RBCs significantly reduced fibrin deposition in response to TNFα activation (See Villa et al, Pg 170 “Therapeutic effectiveness of RBC cargoes” & paragraph spanning Pg 172-173).
Villa et al is comparable to the instant claims in that they are directed to red blood cell compositions for drug delivery. Specifically, they obtain a red blood cell comprising a pharmaceutical agent (the pharmaceutical agent being the hTM-aRh17 fusion protein).
Villa et al differs from the instant claims in that they do not teach storing the hTM-aRh17-carrying RBCs, much less storing under conditions to increase the shelf-life of the RBCs. Villa et al use the hTM-aRh17-carrying RBCs immediately in their trial run. However, one having ordinary skill in the art, as of the effective filing date, would recognize that the preparation of Villa et al is cost and labor intensive. Production of hTM-aRh17-carrying allogeneic RBCs in larger batches at a single facility, and then shipping the drug-loaded RBCs out to physicians for use at point of care facilities would be more cost and labor efficient than performing the drug loading on individual batches at the point of care facility for individual patients. Therefore, one would have been motivated to modify the method of Villa et al to produce larger batches of hTM-aRh17-carryign RBCs and then store the hTM-aRh17-carrying RBCs and ship to facilities for future use as hTM-carrying RBCs.
At the time the invention was made, it was known that red blood cells (RBCs) deteriorate during storage at 4oC (i.e. storage lesion). The extent and severity of changes is directly related to the duration of storage (See Bitensky, col. 1, ln 28-34). Therefore, storage lesion of hTM-aRh17-carrying RBCs would have been a concern. However, Bitensky teaches a method for prolonging the useful life (i.e. increasing the shelf life ) of refrigerated RBCs. The method comprises, inter alia, exposing cooled, packed RBCs to an environment fully saturated with CO, and then maintaining the RBCs in an environment saturated with CO (See Bitensky, col. 4, ln 37-67 & exemplified at col. 6, ln 55- col 7, ln 18). Though not specifically disclosed by Bitensky, when RBCs are exposed to CO, the hemoglobin in the RBCs forms stable carboxyhemoglobin (CO-Hb). This is an inherent chemical reaction.
Therefore, it would have been prima facie obvious to one having ordinary skill in the art, to have stored the hTM-aRh17-carrying RBCs via the protocol of Bitensky. Specifically, to have first produced the hTM-aRh17-carrying RBCs via the method of Villa et al (which reads on obtaining RBCs comprising a pharmaceutical agent comprising a fusion protein), treating the red blood cells containing the rTM-aRh17 fusion protein (pharmaceutical agent) with a chemical agent (CO) to prepare a red blood cell comprising a hemoglobin derivative (CO-Hb), and then storing said red blood cell composition comprising said hemoglobin derivative (CO-Hb) under a storage atmosphere (CO atmosphere) to prepare a stored RBC composition. This conclusion of obviousness is based on teaching, suggestion or motivation rationale. Specifically, one would have been motivated to store the hTM-aRh17-carrying RBCs under conditions that would increase their shelf-life in order to reduce storage lesion and product loss. One would have had a reasonable expectation of success because Bitensky teach that storage under CO atmospheres increases refrigerated RBC storage lifespan significantly (See Bitensky, col. 6, ln 17-36).
Regarding claim 7: Following the discussion of claim 6 above, Bitensky teaches storing the RBCs in pure CO, thus the oxygen pressure would be zero.
Regarding claim 8: Following the discussion of claim 6 above, Bitensky teaches storing the RBCs in pure CO. The storage conditions will necessarily create an ambient pressure. It is noted no specific numerical value is imparted by ‘ambient pressure’.
Regarding claim 9: Following the discussion of claim 6 above, the RBCs are treated with CO, and said hemoglobin derivative is CO-Hb.
Regarding claim 13: Following the discussion of claim 9 above, the RBCs are stored in a CO atmosphere.
Regarding claim 15: Following the discussion of claim 9 above, Bitensky teaches storage of RBCs in a CO atmosphere increases the shelf-life from about 6 weeks to about 6 months (See Bitensky col, 6, ln 17-36).
Regarding claims 21-22: These effects are considered inherent based on exposure of the cells to CO, and then storage in a 100% CO environment. This conclusion is based on the fact that Bitensky teaches the same method steps as in the instant specification that are disclosed as achieving these results.
Regarding claim 23: Following the discussion of claim 6 above, the method of Villa et al couples the hTM-aRh17 pharmaceutical agent on the cell surface of said RBC.
Regarding claims 24-25: Following the discussion of claim 6 above, the delivery of CO in the method of Bitensky reads on a rapid gas exchange (See Bitensky, col. 7, ln 10-18).
Regarding claim 26: Following the discussion of claim 6 above, the hTM-aRh17 is a fusion protein that includes thrombomodulin. Thrombomodulin is also known as CD141, which is one of the proteins listed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M FOX whose telephone number is (571)272-2936. The examiner can normally be reached M-F 10-6 EST.
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/ALLISON M FOX/Primary Examiner, Art Unit 1633