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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 response filed October 6, 2025 has been received and entered into the application file. All arguments have been fully considered.
Claims 1-4, 7-17, 19 and 27 of the claim set filed October 6, 2026 are pending. Claims 19 and 27 are withdrawn. Claims 5-6, 18, 20-26, and 28-32 are cancelled. Claims 1-4, and 7-17 are being examined on the merits herein.
Examiner notes the claim set filed October 6, 2025 states claims “5-6. (Cancelled)” as well as claims “4-5. (Previously Presented)”. Examiner notes claim 4 is “previously presented” and claims 5-6 have been cancelled.
OBJECTION(S)/REJECTION(S) MAINTAINED
Drawings
RE: The drawings are objected to because Fig. 1 contains shading that causes the different types of cells to be undecipherable. For example, the shading is the same for NK cells as it is for CD8 cells. Examiner suggests the use of different symbols rather than shading due to the Figure being in black and white.
Examiner notes Applicant stated a replacement Figure 1 has been filed but no figure has been submitted. Thus, the objection is maintained.
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.
RE: Claims 1-13 and 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Battista, in view of Kim and Agha. Claim 14 is rejected as being unpatentable over Battista, in view of Kim and Agha, as evidenced by Willson.
Applicant amended claim 1 to now require the ß-adrenergic receptor agonist (ß-AR) to be isoproterenol. Examiner respectfully notes said amendment was previously discussed in both the Non-Final OA filed 12/10/2024 (p6, top of the page) and the Final OA filed 6/4/2025 (p5, 2nd paragraph). Both office actions noted in the rejection of claim 1: “Battista teaches the adrenergic receptor may be a beta-adrenergic receptor such as isoproterenol [0028].”
Applicant further amended claim 1 to now require “when said stem cells are introduced into a recipient.” Examiner respectfully notes said amendment was previously discussed in the rejection of claim 1 in the final OA filed 12/10/2024 (p6, 1st paragraph): “Specifically, Kim teaches of obtaining stem cells from donor mice and performing allogeneic hematopoietic stem cell transplantation (allo-HSCT). As discussed supra, Kim teaches CGVHD is a serious complication of allo-HSCT. Kim teaches after transplantation, roflumilast (i.e., a PDE-4 inhibitor) was administered to the mice. Control mice did not receive roflumilast. Kim teaches treatment with roflumilast reduced graft versus host disease [i.e., relative to control mice] (p333, 1st column, 1st-2nd paragraph; Abstract). As is well known in the art and as a POSITA will appreciate, when collecting stem cells from the peripheral blood, a stem cell mobilization agent is used. Thus, Kim teaches treatment with PDE-4 caused the stem cells to exhibit reduced graft versus host disease relative to stem cells mobilized by a stem cell mobilization agent alone [and not administered PDE-4].” Thus, Examiner respectfully notes Kim teaches of reduced graft versus host disease relative to stem cells mobilized by stem cell mobilization agent alone (i.e., when said stem cells are introduced into a recipient).
Thus, the amendments to claim 1 are de minimis and not sufficient to overcome the previous rejection of record. Therefore, the previously filed rejection of claim 1 is upheld and likewise the previously filed rejections of the dependent claims are upheld.
Examiner notes claims claim 5-6 and 18 have been cancelled via Applicant amendment, thus making the rejection of said claims moot.
RESPONSE TO APPLICANT REMARKS
Re: REJECTIONS UNDER 35 USC 103
Applicant remarks state:
Applicant submits that the Examiner has failed to demonstrate prima facie obviousness under 35 U.S.C. 103 because the cited references do not provide a motivation to combine the references with a reasonable expectation of success in order to arrive at the presently claimed invention.
As acknowledged by the Examiner, Battista does not teach the use of at least one additional agent selected from the group consisting of a PDE-4 inhibitor and a beta-AR antagonist. The Examiner cites Kim and Agra to allegedly address the deficiencies of Battista. However, Kim is directed to the effect of roflumilast on pulmonary legions in mice and is silent as the effect of roflumilast or any other PDE4 inhibitor on properties of mobilized stem cells. Contrary to the Examiner's assertion, there is no evidence in Kim that a PDE4 inhibitor would have any effect on stem cells after mobilization.
In response, Examiner respectfully submits that Kim teaches the effect of a PDE4 inhibitor on stem cells after transplantation, i.e., Kim teaches the effect of a PDE-4 inhibitor on stem cells after mobilization. Examiner notes that in order to obtain stem cells from a donor to use for transplantation, said stem cells must first be mobilized. Further, Kim teaches said PDE-4 inhibitor reduces CGVHD, which is a known complication after allo-HSCT, i.e., which is a known complication after mobilization of stem cells which are then used for transplantation. Additionally, Kim teaches said PDE-4 inhibitor reduces pro-inflammatory and profibrotic cytokines. Thus, Examiner respectfully submits that Kim provides the motivation to administer a PDE-4 inhibitor. Thus, Applicant’s remarks have been carefully considered but have not been found persuasive.
Applicant remarks state:
One of ordinary skill in the art would not have been motivated to add the agents of Kim to Battista with a reasonable expectation of success because Kim is not directed to stem cell mobilization or the effect of the combination of a stem cell mobilization agent, isoproterenol, and a receptor antagonist and/or a PDE4 inhibitor on graft-versus tumor effect, viral reactivation, graft-versus-host-disease, and lymphoproliferative disease.
In response, Examiner respectfully submits that Kim need not teach the effect of the combination of a stem cell mobilization agent, a ß-AR, and a PDE-4 inhibitor on graft-versus tumor effect, viral reactivation, graft-versus-host-disease, and lymphoproliferative disease. Examiner notes first, the language of claim 1 does not require the stem cells to exhibit an effect on graft-versus tumor effect, viral reactivation, graft-versus-host-disease, AND lymphoproliferative disease, but rather the language of claim 1 states “wherein said stem cells exhibit one or more properties selected from…” Thus, the teachings of Kim are used to teach of stem cells which are mobilized and used for transplantation and exhibit reduced graft versus host disease. Examiner notes second that Kim need not teach the effect of the combination of a stem cell mobilization agent, a ß-AR, and a PDE-4 inhibitor. Kim is relied upon for the obviousness of using a PDE-4 inhibitor. Kim need not teach the features already disclosed by Battista and Agra. Thus, in response to Applicant’s remarks against Kim 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).
Thus, Applicant’s remarks have been carefully considered but have not been found persuasive.
Applicant remarks state:
Likewise, Agra is directed to the impact of bisoprolol on exercise-induced mobilization of HSCs. Agra is silent as the effect of bisoprolol on properties of stem cells mobilized via administering a stem cell mobilization agent, a ß-adrenergic receptor agonist (ß-AR), and a ß-AR antagonist.
One of ordinary skill in the art would not have been motivated to add the agents of Agra to Battista with a reasonable expectation of success because Agra is not directed to the effect of bisoprolol alone on stem cell mobilization or the effect of the combination of a stem cell mobilization agent, isoproterenol, and a -AR antagonist on graft-versus tumor effect, viral reactivation, graft-versus-host-disease, and lymphoproliferative disease in a recipient of the stem cells.
In response, Examiner respectfully submits that Agra need not teach the effect of bisoprolol on properties of stem cells mobilized via administering a stem cell mobilization agent, a ß-adrenergic receptor agonist (ß-AR), and a ß-AR antagonist. Agra is relied upon for the obviousness of administering bisoprolol (i.e., a ß-AR antagonist). As Agra teaches the number of CD34+ HSCs [in the peripheral blood] increases after donors are given bisoprolol, a ß1-AR antagonist, suggesting that ß2-AR signaling mediates the mobilization of CD34+ cells, Agra thus makes obvious administering a ß-AR antagonist.
Further, Examiner additionally notes Agra need not teach the features already disclosed by Battista and Kim. Thus, in response to Applicant’s remarks against Agra 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).
Thus, Applicant’s remarks have been carefully considered but have not been found persuasive.
37 CFR 1.132 Declaration
The examiner acknowledges receipt of the Declaration under 37 CFR 1.132 by Richard Simpson submitted with Applicant’s reply of October 6, 2025 in response to the Office Action mailed June 4, 2025.
The Declaration under 37 CFR 1.132 submitted with Applicant’s reply of October 6, 2025 is insufficient to overcome the rejections of record because:
Examiner notes Applicant remarks (p8) state the declaration provides experimental data demonstrating that the combination of G-CSF and isoproterenol results in mobilized PBHCs that unexpectedly provide increased body weight and increased survival in mice receiving the PBHCs. Such unexpected results are neither taught nor suggested by the cited references, alone or in combination.
Examiner further notes that points 6-8 of the affidavit address results.
Point 6 states “Results are shown in Figure 1. Mice receiving G-CSF mobilized PBHCs exhibited a significant decline in body weight throughout the experiment, whereas those receiving G-CSF+ISO mobilized PBHCs maintained their body weight.”
Point 7 states: “In addition, overall survival using Kaplan-Meier analysis revealed a trend with 40% of the mice injected with G-CSF+ISO PBHCs remaining alive by day 100 and exhibiting minimal signs of GvHD, compared to only 10% survival in the G-CSF group.”
Point 8 states: “These results demonstrated that PBHCs mobilized with a combination of G-CSF+ISO have improved properties compared to those mobilized with only G-CSF.”
In response, Examiner notes said results are not commensurate in scope with the claims as currently written. Claim 1, as currently written, does not require an increased body weight nor an increased survival in mice. Further, the asserted unexpected results require G-CSF+ISO, but the claims as currently drafted only recite a generic stem cell mobilization agent. Examiner further respectfully notes that as taught in the affidavit, the isoproterenol has to be administered before and after the 5-day course of G-CSF. The claims as currently drafted are not commensurate in scope with the method and data provided with the affidavit. Additionally, it is unclear if the affidavit experimental data included the PDE-4 inhibitor and/or a ß-AR antagonist.
Additionally, Examiner respectfully notes the data in the Figure 1 filed with the affidavit is hard to decipher due to the labeling on the X and Y axis being out of focus and there not being any labels for the data on the first two graphs and being indistinguishable between the experimental and control groups on the last two graphs. Moreover, it appears some of the data is overlapping as indicated by the error bars.
In addition to the facts provided above, the examiner notes that the Affiant is the same as the Inventor of the instant application. Therefore, the Affiant has an interest in the outcome of the instant application. In assessing the weight to be given to expert testimony, the examiner may properly consider, among other things, the nature of the fact sought to be established, the strength of any opposing evidence, the interest of the expert in the outcome of the case, and the presence or absence of factual support for the expert’s opinion. See Ex parte Simpson, 61 USPQ2d 1009 (BPAI 2001), Cf. Redac Int’l. Ltd. v. Lotus Development Corp., 81 F.3d 1576, 38 USPQ2d 1665 (Fed. Cir. 1996), Paragon Podiatry Lab., Inc. v. KLM Lab., Inc., 948 F.2d 1182, 25 USPQ2d 1561, (Fed. Cir. 1993). Affidavits or declarations are provided as evidence and must set forth facts, not merely conclusions. In re Pike and Morris, 84 USPQ 235 (CCPA 1949).
Upon consideration of the facts taught by the prior art and the information submitted by the Affiant, the balance of evidence indicates that the prior art teaches the instantly claimed inventions.
Conclusion
No claims are allowable. No claims are free of the prior art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE R SMALL whose telephone number is (703)756-4783. The examiner can normally be reached Monday - Friday 8:30am-4pm.
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/KATHERINE R SMALL/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633