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 .
Applicants’ response of 6/19/2026 has been received and entered into the application file.
Election/Restrictions
Applicants previously elected Group I, a method of making a stored red blood cell composition for drug delivery, without traverse. Applicants 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 and 33-34 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 Claims 16, 18 and 28-31 are withdrawn from consideration, as being drawn to non-elected inventions and/or non-elected species.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, 21-26, 33 and 34 have been considered on the merits.
Status of Prior Rejections/Response to Arguments
RE: Objections to claims 21 and 26:
The amendments to the claims are effective to overcome the previous bases of objection. The objections are withdrawn.
RE: Rejection of claim 26 under 35 USC 112(b): The amendment to claim 26 is effective to overcome the previous basis of rejection. The rejection is withdrawn.
RE: Rejection of claims 6-9, 13, 15, and 21-16 under 35 USC 103 over Bitensky:
Applicants have traversed the rejection on three grounds. Each ground will be addressed in turn:
First, Applicants assert Villa and Bitensky fail to teach, suggest or otherwise provide for all claim elements. Applicants point out differences between each of Villa and Bitensky and the current claims.
This argument is not found persuasive because it argues deficiencies in each reference, individually. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The rejection acknowledged that Villa et al does not teach storage of the hTM-aRh17-carrying RBCs, but storage in 100% CO atmosphere was taught by Bitensky. It was concluded it would have been prima facie obvious to have stored the hTM-aRh17-carrying RBCs in the 100% CO atmosphere of Bitensky. The effects of this method on measurable outcomes including shelf-life stability, Heinz body formation and cell lysis rates of the modified RBCs would be inherent to this modified process.
Second, Applicants assert the Examiner has not established a reasonable expectation of success. Specifically, Applicants assert there was no reasonable expectation of successfully combining the erythrocyte carriers of Villa with the chemically modified red blood cells of Bitensky (Response at Pg 21).
In response, it is respectfully submitted that the rejection did not suggested combining the erythrocyte carriers of Villa et al with the RBCs of Bitensky et al. Rather, the rejection set forth that it would have been prima facie obvious to have subjected the hTM-aRh17-carrying RBCs of Villa et al to a 100% CO atmosphere because Bitensky teach that storage under CO atmospheres increases refrigerated RBC storage lifespan significantly (See Bitensky, col. 6, ln 17-36). Doing so would thus be expected to increase the shelf-life of the hTM-aRh17-carrying RBCs by reducing storage lesion. The rejection set forth the basis for reasonable expectation of success: Bitensky teach that storage under CO atmospheres increases refrigerated RBC storage lifespan significantly (See Bitensky, col. 6, ln 17-36).
Third, Applicants assert the recited methods yields unexpected results compared to the cited prior art references.
In response, it is respectfully submitted Applicants have not provided data or evidence to support this assertion of unexpected results. The cited portions of the specification fail to provide data that compares the claimed method to the closet prior art. Mere conclusions of unexpected results are not entitled to weight of conclusions accompanied by evidence (See MPEP 716.02(b)).
Ultimately, the arguments are not found persuasive. The rejection has been modified to address the new claim limitations.
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, 21-26 and 33-34 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 at 4oC (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), and then stored the red blood cells containing the rTM-aRh17 fusion protein in a 100% CO atmosphere at 4oC (which reads on 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 storing said red blood cell composition comprising said hemoglobin derivative (CO-Hb) under a storage condition comprising an oxygen pressure of less than 20 mmHg (100% CO atmosphere has oxygen partial pressure of zero) 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).
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). Thus, the limitation the shelf-life is increased by one or more weeks relative to a red blood cell composition comprising the pharmaceutical agent and oxyhemoglobin and having been stored under the same conditions will be achieved.
The effects on number of Heinz bodies and number of lysed cells 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 7: Following the discussion of claim 6 above, Bitensky teaches storing the RBCs in pure CO, thus the oxygen partial pressure would be zero. This reads on less than 10 mmHg.
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). This meets the limitation of the shelf-life improving by at least two weeks.
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.
Regarding claim 33: Following the discussion above, Bitensky teach storage in pure CO at 4oC.
Regarding claim 34: This effect is 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.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALLISON M FOX/Primary Examiner, Art Unit 1633
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