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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed December 01, 2025.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 submission filed on December 01, 2025 has been entered.
Claims 1-2, 4-9, and 11-34 are pending in the application. Claim 1 has been amended, no claims are newly added and claim 35 is canceled as set forth in the claim set filed December 01, 2025.
Claims 12-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/30/2023.
Claims 1-2, 4-9, 11, and 32-34 are examined on the merits.
Claim Interpretation
Claim 2 is interpreted as either the inflammation inducing cells are isolated from the inflammation site of the subject or the inflammation inducing cells are from an alternative source and cultured with a substance which causes inflammation before being administered to the subject.
Response to arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Objections
The objection of claim 1 is withdrawn because the typographical error has been corrected in the claim set filed 12/01/2025.
Claim Rejections - 35 USC § 112 (d)
The rejection of claim 35 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends is withdrawn.
Applicant’s arguments and amendments filed 12/01/2025 cancel claim 35 rendering the rejection and all arguments moot.
Claim Rejections - 35 USC § 103
The rejection of claim(s) 1, 2, 4, 5 and 11 under 35 U.S.C. 103 as being unpatentable over Zhang (2014. Stem Cells 2014;32:1616–1628) as evidenced by Heron (Clin Exp Immunol. 2012, 167(3): 523–531) in view of Abreu (STEM CELLS TRANSLATIONAL MEDICINE 2019;8:301–312; previously cited) is withdrawn.
Applicant’s arguments and amendments filed 12/01/2025 been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
The rejection of claim 6 under 35 U.S.C. 103 as being unpatentable over Zhang (supra) in view of Abreu (supra) as applied to claims 1, and 4, above, and further view of Lamkhioued (Am J Respir Crit Care Med Vol 162. pp 723–732, 2000; previously cited in PTO-892) is withdrawn.
Applicant’s arguments and amendments filed 12/01/2025 been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
The rejection of claims 7-9 under 35 U.S.C. 103 as being unpatentable over Zhang (supra) in view of Abreu (supra) as applied to claims 1 and 4 above, and in further view of Li (2018. INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 41: 2629-2639; previously cited in PTO-892) is withdrawn.
Applicant’s arguments and amendments filed 12/01/2025 been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
The rejection of claims 32 and 35 under 35 U.S.C. 103 as being unpatentable over Topoluk (J Tissue Eng Regen Med. 2018;12:1097–1110) in view of Maumus (2016, Front. Immunol. 7:392) is withdrawn.
Applicant’s arguments and amendments filed 12/01/2025 been considered and are persuasive. The rejection has been revised after further consideration. In particular, Smith and Manferdini have been added in order to better address the effects of exposure of ASCs to soluble factors which results in increased homing.
The rejection of claim 34 under 35 U.S.C. 103 as being unpatentable over Topoluk (supra) in view of Maumus (supra) as applied to claim 32, and further view of Saldana (Stem Cell Research & Therapy (2019) 10:58) is withdrawn.
Applicant’s arguments and amendments filed 12/01/2025 been considered and are persuasive. The rejection has been revised after further consideration. In particular, Smith has been added in order to better address the effects of exposure of ASCs to soluble factors which results in increased homing.
The rejection of claims 32 and 33 under 35 U.S.C. 103 as being unpatentable over Zeng (MOLECULAR MEDICINE REPORTS 14: 3887-3893, 2016) in view of Maumus (2016, Front. Immunol. 7:392) and further view of Lowin (2020, Scientific Reports, 10:780) is withdrawn.
Applicant’s arguments and amendments filed 12/01/2025 been considered and are persuasive. The rejection has been revised after further consideration. In particular, Zeng has been replaced by Manferdini to demonstrate an adipose stem cell co-culture with synovial fibroblasts.
New objections/ Rejections in response to Applicants’ arguments or amendments
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.
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.
Claim 1, 2, 4-5, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Manferdini (Osteoarthritis and Cartilage, Volume 25, Issue 7, July 2017, Pages 1161-1171) in view of Maumus (2016, Front. Immunol. 7:392).
Regarding claims 1 and 2, Manferdini teaches a co-culture of stimulated M1 macrophages with adipose mesenchymal stem cells (Summary). The M1 macrophages were obtained by culture of monocytes isolated from peripheral blood and activated via GM-CSF these M1 macrophages were then activated by interferon gamma culture (p.1162, 2nd column). Manferdini states that co-culture of m1 macrophages increases adipose stem cell migration towards cytokines (e.g, IL1b,TNFa, IL10 and CD163) produced by macrophages and that adipose stem cells have a specific role in therapeutic resolution of osteoarthritis (OA) synovial inflammation and also clearly provided evidence that IFNy activated-M1-like macrophages are a good cell model to test the efficacy/potency of ASC (p. 1165, 2nd column, p. 1169, 2nd column; p. 1164, 1st column “Both activated-M1-like and M2-like macrophages cells stimulated ASC migration (3 and 1.5 fold, respectively) compared to basal control, while synovial fibroblasts (SFs) did not induce ASC migration as compared to a positive control (þPDGFBB) and to basal control). Moreover, Manferdini discloses the presence of macrophages in synovial tissue (page 1162; cl. 1) where synovitis has shown a role on pathophysiology of Osteoarthritis (OA) (page 1161; col.1)
However, Manferdini does not teach a step of administering the co-cultured adipose stem cells to a subject in need thereof.
Maumus teaches priming adipose derived MSCs (AD-MSCs) through interferon gamma culture and administering the primed MSCs to a murine model of osteoarthritis through intra-articular injection (Objective, p. 2, 2nd column; p. 5, 2nd column). Administration of the inflammatory primed adipose mesenchymal stem cells resulted in significantly improved results (p. 5, 2nd column). Additionally, the inflammatory primed MSCs resulted in upregulating the expression of chemokines which contributed to anti-inflammatory properties as well as immunomodulatory properties, improving their efficiency in vivo (p. 8, 2nd column; p. 9, 1st column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to administer the adipose MSCs from the co-culture of the MSCs and IFN-y stimulated M1 macrophages as taught by Manferdini to a subject in need thereof as taught by Maumus with a reasonable expectation of success. An artisan would be motivated to do so as Maumus teaches that inflammatory primed adipose derived MSCs administered to a mouse model of arthritis resulted in upregulating the expression of chemokines which contributed to anti-inflammatory properties as well as immunomodulatory properties, improving their efficiency in vivo (p. 8, 2nd column; p. 9, 1st column) and Manferdini teaches migration of AD-MSCs towards cytokines produced by macrophages located in synovial tissue from OA patients.
Regarding claims 4 and 5, the combination of Manferdini and Maumus make obvious claims 1 and 2. Moreover, Manferdini teaches the M1 macrophages are activated by interferon gamma culture (i.e. inflammatory cytokine) (p.1162, 2nd column).
Regarding claim 11, the combination of Manferdini and Maumus make obvious claim 1. Moreover, Maumus teaches in order to induce the model of OA, right knee joints of mice were injected with 1 U type VII collagenase from Clostridium histolyticum (i.e. a pathogen) (p. 3, last paragraph).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Manferdini (supra) in view of Maumus (supra) as applied to claims 1, 2 and 4 above, and in further view of Smith (Stem Cells Transl Med. 2015 Feb 2;4(3):239–251)
As discussed above and incorporated herein in its entirety, the combination of Manferdini and Maumus render obvious a method of co-culturing adipose mesenchymal stem cells with activated M1 macrophages before administration to a patient with osteoarthritis. The M1 macrophages are activated with a proinflammatory cytokine, interferon gamma (INFy).
However, these references do not teach activation by a proinflammatory chemokine such as MCP-4.
Smith teaches enhancing the homing and migration of adipose mesenchymal stem cells by culturing them in conditioned media from neural cells which comprises INFy, TNFalpha and MCP-4 for the purpose of injection into a subject (p. 245, 2nd column; p. 247, 1st column).
It would have been obvious to one of ordinary skill in the art to utilize MCP-4 as taught by Smith in addition to INFy as taught by Manferdini and Maumus to activate the macrophages and culture them with adipose stem cells for the purpose of enhanced homing toward cytokines produced by macrophages located in the synovial tissue of OA patients with a reasonable expectation of success. An artisan would be motivated to do so as both MCP-4 and INFy are proinflammatory factors known in the art and are known to increase cell migration as well as homing.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 7-9 is rejected under 35 U.S.C. 103 as being unpatentable over Manferdini (supra) in view of Maumus (supra) as applied to claims 1, 2 and 4 above, and in further view of Saldana (Stem Cell Research & Therapy (2019) 10:58; previously cited)
As discussed above and incorporated herein in its entirety, the combination of Manferdini and Maumus render obvious a method of co-culturing adipose mesenchymal stem cells with activated M1 macrophages before administration to a patient with osteoarthritis. The M1 macrophages are activated with a proinflammatory cytokine, interferon gamma (INFy).
However, these references do not teach the macrophages are stimulated or activated by LPS.
Saldana teaches priming MSCs with conditioned media from M1 macrophages stimulated with LPS (p. 5, Results). Factors originated from pro-inflammatory or anti-inflammatory macrophages enhance immunomodulatory properties of MSC as the MSC immunomodulation was enhanced by the CM from LPS stimulated M1 macrophages (p. 11, 1st column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to stimulate the M1 macrophages of Manferdini and Maumus with LPS instead of INFy as taught by Saldana with a reasonable expectation of success. An artisan would have been motivated to do so as Saldana teaches MSC immunomodulation is enhanced by the CM from LPS stimulated M1 macrophages (p. 11, 1st column).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 32 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Manferdini (Osteoarthritis and Cartilage, Volume 25, Issue 7, July 2017, Pages 1161-1171) in view of Maumus (2016, Front. Immunol. 7:392) and Lowin (2020, Scientific Reports, 10:780)
Manferdini teaches a co-culture of synovial fibroblasts (SFs) obtained from the synovium of an osteoarthritis patient with adipose mesenchymal stem cells (p. 1162-1163, bridging section).
However, Manferdini does not teach that the MSCs co-cultured with the fibroblasts are administered to a subject in need thereof.
Maumus teaches priming adipose derived MSCs (AD-MSCs) through interferon gamma culture and administering the primed MSCs to a murine model of osteoarthritis through intra-articular injection (Objective, p. 2, 2nd column; p. 5, 2nd column). Administration of the inflammatory primed adipose mesenchymal stem cells resulted in significantly improved results (p. 5, 2nd column). Additionally, the inflammatory primed MSCs resulted in upregulating the expression of chemokines which contributed to anti-inflammatory properties as well as immunomodulatory properties, improving their efficiency in vivo (p. 8, 2nd column; p. 9, 1st column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to administer the adipose MSCs from the co-culture of the MSCs and synovial fibroblasts from a rheumatoid arthritis source as taught by Manferdini to a subject in need thereof as taught by Maumus with a reasonable expectation of success. An artisan would be motivated to do so as Maumus teaches that inflammatory primed adipose derived MSCs administered to a mouse model of arthritis resulted in upregulating the expression of chemokines which contributed to anti-inflammatory properties as well as immunomodulatory properties, improving their efficiency in vivo (p. 8, 2nd column; p. 9, 1st column). Regarding the intended use limitation of enhancing the migration to a site, as each and every step is taught by the combination of references, the limitation would additionally be present to one of ordinary skill in the art.
In relation to claim 33, the combined teachings of Manferdini and Maumus do not teach that the synovial fibroblasts are stimulated with TNF-alpha.
Lowin teaches stimulating rheumatoid arthritis sourced synovial fibroblasts (obtained from rheumatoid arthritis patient site) with TNF-alpha (Abstract). The exposure increased proliferation of the fibroblasts and increased IL-6 and IL-8 production (Figure 4A and 3A).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to stimulate the synovial fibroblasts of Zeng and Maumus with LPS as taught by Lowin with a reasonable expectation of success. An artisan would have been motivated to do so as Lowin teaches the exposure increased proliferation of the fibroblasts and increased IL-6 and IL-8 production (Figure 4A and 3A).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Manferdini (supra) in view of Maumus (supra) and Lowin (supra) as applied to claim 32, and in further view of Saldana (Stem Cell Research & Therapy (2019) 10:58)
As applied to claim 32 and discussed above, the combination of Manferdini, Maumus and Lowin render obvious a method of enhancing the migration and homing to an osteoarthritis site by co-culturing adipose stem cells with osteoarthritis synovium derived M1 macrophages in order to prime the adipose stem cells.
However, these references do not teach that the macrophages are stimulated with LPS.
Saldana teaches priming MSCs with conditioned media from M1 macrophages stimulated with LPS (p. 5, Results). Factors originated from pro-inflammatory or anti-inflammatory macrophages enhance immunomodulatory properties of MSC as the MSC immunomodulation was enhanced by the CM from LPS stimulated M1 macrophages (p. 11, 1st column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to stimulate the M1 macrophages of Manferdini, Maumus and Lowin with LPS as taught by Saldana with a reasonable expectation of success. An artisan would have been motivated to do so as Saldana teaches MSC immunomodulation is enhanced by the CM from LPS stimulated M1 macrophages (p. 11, 1st column).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
Conclusion
No claims are allowed.
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/ALEXANDRA F CONNORS/ Examiner, Art Unit 1634
/MARIA G LEAVITT/ Supervisory Patent Examiner, Art Unit 1634