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 .
All previous objections and rejections not reiterated herein were overcome by claim amendments and arguments, filed December 31st, 2025 have been fully considered and found persuasive. As such all objections and rejections not reiterated herein have been withdrawn.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Li et. al. ((2012), Mesenchymal stem cells are injured by complement after their contact with serum, Blood, 120, 3436 – 3443; cited in the office action dated July 2nd, 2025).
Regarding claims 1 and 9, Li et. al. teach that mesenchymal stem cells (MSCs) are adult stem cells that can differentiate into many types of cells, and they are strongly immunosuppressive (page 3436 column 1 paragraph 1). Additionally, Li et. al. teach that there have been approximately 150 MSC-based clinical trials registered in the www.clinicaltrials.gov website alone for the treatment of different diseases, including graft-versus-host disease (GVHD), Crohn disease, diabetes, multiple sclerosis (MS), myocardial infarction, and allograft rejection (page 3436 column 1 paragraph 1). Furthermore, Li et. al. teach that one possible explanation for these disappointing results is that immediately after systemic infusion, these MSCs are recognized and injured by the host, leading to severely reduced activity in vivo (page 3436 column 1 paragraph 1). Thus Li et. al. suggest that a potential strategy for improving the activity of MSCs is by protecting the MSCs from injury.
Moreover, Li et. al. teach that primary bone marrow-derived human MSCs (claim 1) from healthy donors were provided by the MSC Core Facility at the National Center for Regenerative Medicine (NCRM) of Case Western Reserve University, and by Tulane University Center of Gene Therapy (page 3436 column 2 paragraph 1). Furthermore, Li et. al. teach that to up-regulate CD55 expression levels on MSCs (claim 1), a human CD55-expressing, and a mouse CD55 (Daf1)–expressing recombinant adenovirus with a green fluorescence protein (GFP) marker, that is as an active agent (claim 1), were constructed using an AdEasy kit (Stratagene) following protocols provided by the manufacturer was added (page 3437 column 2 paragraph 2).
Additionally, Li et. al. teach that after MSCs were incubated with the human CD55-expressing adenovirus or empty adenovirus (MOI: 1:10) for 48 hours, then the human CD55 levels on cell surface were assessed (claim 9) by flow cytometry using mouse anti–human CD55 IgG (clone 2H6; BD Bioscience) and APC-labeled goat anti–mouse IgG (Invitrogen) (page 3437 column 2 paragraph 2). Moreover, Li et. al. teach that transfecting MSCs with the CD55-expressing adenovirus significantly increased the levels of CD55 protein on the cell surface (page 3440 column 2 paragraph 2 and page 3441 Figure 7C). Additionally, Li et. al. teach that correlated with these flow cytometry results, in the cytotoxicity assays, the MSCs with up-regulated CD55 levels showed reduced cytotoxicity compared with MSCs transfected with the control adenovirus (page 3440 column 2 paragraph 2 and page 3441 Figure 7D).
Thus Li et. al. teach that by transfecting MSCs with CD55-expressing adenovirus, we demonstrated that up-regulating CD55 levels on MSCs helped to reduce the severity of MSCs injury after their contact with serum both in vitro and in vivo (page 3442 column 1 paragraph 3). Moreover Li et. al. teach that that statins (claim 1), a group of FDA-approved drugs for cardiovascular diseases, up-regulate CD55 and CD59 expression on human umbilical vein endothelial cells, and therefore protect these cells from complement mediated attack (page 3442 column 1 paragraph 3). Lastly, Li et. al. teach that up-regulating expression levels of cell surface complement regulators on MSCs by genetic engineering, or by treating the cells/patients with appropriate reagents such as statins, would help to preserve MSC function after their infusion (claim 1) (page 3442 column 2 paragraph 1).
However, Li et. al. fails to recite whether the cultured human MSCs with up-regulated CD55 levels were harvested for transplantation (claim 1).
Nonetheless, Li et. al. does suggest the possibility of infusing genetically engineered human MSCs in treatment therapies (page 3442 column 2 paragraph 1 and page 3436 column 1 paragraph 1). Thus it would have been obvious to one of ordinary skill in the art that in order to use the genetically engineered human MSCs in treatment they would need to be administered or transplanted in a subject.
Therefore it would have been obvious before the effective filing date of the instant application to modify the teaching of Li et. al. for a method comprising culturing hMSC with an active agent, such as a CD55-expressing adenovirus or small molecule statin, that can upregulate expression levels of cell surface complement regulators such as CD55. One of ordinary skill in the art would have been motivated to make the modification because in the cytotoxicity assays, the MSCs with up-regulated CD55 levels showed reduced cytotoxicity compared with MSCs transfected with the control adenovirus. Additionally, one of ordinary skill in the art would have had a reasonable expectation of success because transfecting MSCs with the CD55-expressing adenovirus significantly increased the levels of CD55 protein on the cell surface and because statins, a group of FDA-approved drugs for cardiovascular diseases, up-regulate CD55 and CD59 expression on human umbilical vein endothelial cells, and therefore protect these cells from complement mediated attack.
Claims 2 and 6 – 7 are rejected under 35 U.S.C. 103 as being unpatentable over Li et. al. ((2012), Mesenchymal stem cells are injured by complement after their contact with serum, Blood, 120, 3436 – 3443; cited in the office action dated July 2nd, 2025) as applied to claims 1 and 9 above, and further in view of Borriello et.al. ((2017), Tyrosine kinase inhibitors and mesenchymal stromal cells: effects on self-renewal, commitment and functions, Oncotarget, 8, 5540-5565; cited in the office action dated November 18th, 2024).
The teaching of Li et. al. as it relates to claims 1 and 9, from which claims 2 and 6 – 7 depend, are given previously in this office action and are fully incorporated here.
However, while Li et. al. teach an active agent, such as a CD55-expressing adenovirus or a small molecule statin, that can upregulate expression levels of cell surface complement regulators such as CD55; Li et. al. fails to explicitly recite an EGFR inhibitor (claims 2 and 6) as the active agent.
Nevertheless, Borriello et. al. teach that few studies have sought to investigate how tyrosine kinase inhibitors (TKIs) effect mesenchymal stromal cells (MSCs) (page 5441 column 1 paragraph 2). Additionally, Borriello et. al. teach that the complex effects of TKIs on cell functions (embracing cell growth, differentiation and death) might strongly affect MSC outcomes (page 5541 column 1 paragraph 2). Furthermore, Borriello et. al. teach both gefitinib (claim 6) and erlotinib (claim 7) as 1st generation (TKIs) that are anti epidermal growth factor receptor(EGFR) inhibitors (claim 2) (page 5541 column 2 paragraph 4).
Borriello et. al. teach that mesenchymal stromal cells (MSCs) are useful in the area of tissue transplantation and regenerative medicine due to MSCs’ characteristics of self-renewal capacity, ability to migrate to the site of injury, potentiality to differentiate towards the major mesenchymal tissue phenotypes, and immunomodulatory and anti-inflammatory properties (page 5543 column 2 paragraph 3). Furthermore, Borriello et.al. teach that in an increasing number of studies, MSCs were able to statistically ameliorate the engraftment of hematopoietic staminal cell transplantation, and very importantly, to reduce the graft versus host disease (GVHD) (page 5553 column 1 paragraph 4). Additionally, Borriello et.al. teach that human BM-MSCs express immunoreactive EGFR and that treatment with gefitinib leads to a reduction of EGFR activation along with Akt down regulation (page 5556 column 1 paragraph 1). Moreover, Borriello et. al. teach that erlotinib was shown to modulate the interactions of MSCs with leukemic cells (page 5556 column 1 paragraph 2). Furthermore, Borriello et. al. teach that TKI inhibitors, that includes EGFR inhibitors, change MSCs favoring a specific differentiation of MSCs (page 5556 column 2 paragraph 2).
Therefore it would have been obvious before the effective filing date of the instant application to modify the teaching of Li et. al. for a method comprising culturing hMSC in view of Borriello et. al. for gefitinib or erlotinib to be used as an active agent, that can upregulate expression levels of cell surface complement regulators such as CD55. One of ordinary skill in that art would have been motivated to make this modification and have a reasonable expectation of success because TKI inhibitors, which includes EGFR inhibitors, change MSCs differentiating to a specific MSCs subpopulation.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Li et. al. ((2012), Mesenchymal stem cells are injured by complement after their contact with serum, Blood, 120, 3436 – 3443; cited in the office action dated July 2nd, 2025) and Borriello et.al. ((2017), Tyrosine kinase inhibitors and mesenchymal stromal cells: effects on self-renewal, commitment and functions, Oncotarget, 8, 5540-5565; cited in the office action dated November 18th, 2024) as applied to claims 2 and 6 – 7 above, and further in view of Borghese et. al. ((2013), Gefitinib Inhibits the Cross-Talk Between Mesenchymal Stem Cells and Prostate Cancer Cells Leading to Tumor Cell Proliferation and Inhibition of Docetaxel Activity, Journal of Cellular Biochemistry, 114, 1135 – 1144; cited in the office action dated November 18th, 2024)
The teachings of Li et. al. and Borriello et.al. as it relates to claims 2 and 6 – 7, from which claim 8 depends, are given previously in this office action and are fully incorporated here.
However, the prior art of Li et. al. and Borriello et. al. fail to teach the EGFR inhibitor erlotinib at a concentration between about 2 µM and 25 µM, inclusive (claim 8).
Nevertheless, Borghese et. al. teach that the phase contrast of human mesenchymal stem cell (hMSC) cultured with osteogenic or adipogenic medium alone and in the presence of 5 µM gefitinib (claim 8) (page 1139 Figure 3 A). Since the prior art of Borghese et. al. teach the use of gefitinib at 5 µM and that both gefitinib and erlotinib are EGFR inhibitors; one of ordinary skill in the art would have recognized the interchangeability of using either gefitinib or erlotinib.
Therefore, it would have been prima facie obvious before the effective filling date of the instant application to modify the teaching of Li et. al. and Borriello et. al. for a method comprising culturing hMSC with gefitinib or erlotinib in view of Borghese et. al. that is to use5 µM of either gefitinib or erlotinib to upregulate expression levels of cell surface complement regulators such as CD55. One of ordinary skill in that art would have been motivated to make this modification and have a reasonable expectation of success because TKI inhibitors, which includes EGFR inhibitors, change MSCs differentiating to a specific MSCs subpopulation.
Response to Arguments
Applicant’s arguments, see applicants argument and claims amendments, filed December 31st, 2025, with respect to the prior art rejections of claims 1 – 2 and 6 – 9 have been fully considered and are not persuasive.
Applicants argues that the reference of Li et. al. fails to teach that isolating and culturing hMSCs from other tissue sources would lead to increased efficacy over BM-hMSCs (see applicant’s remarks page 13 paragraph 5). Applicants argues that the reference of Li et. al. alone does not provide a reasonable expectation of success for preferentially selecting hMSCs from other sources than bone marrow (see applicant’s remarks page 13 paragraph 5).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., that isolating and culturing hMSCs from other tissue sources would lead to increased efficacy over BM-hMSCs) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Additionally, in response to applicant's arguments against the references 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).
Conclusion
Claims 1 – 2 and 6 – 9 are rejected.
THIS ACTION IS MADE FINAL. 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.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
/JULIET C SWITZER/Primary Examiner, Art Unit 1682