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 May 12, 2026.
Claims 1-2, 4-9, and 11-34 are pending in the application. Claim 1 has been amended, no claims are newly added and no claims are canceled as set forth in the claim set filed May 12, 2026.
Claims 12-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 for autologous transplantation or the inflammation inducing cells are from an alternative source and cultured with a substance which causes inflammation.
Response to arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
The rejection of claim 1, 2, 4-5, and 11 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 Immunol. 7:392) is withdrawn.
Applicant’s arguments and amendments filed 05/12/2026 been considered and are persuasive regarding the narrowing the scope of the claims to only synovial fibroblasts and the evidence within Manferdini which demonstrates a lack of enhanced migration. The rejection has been revised after further consideration.
The rejection of claim 6 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as applied to claims 1, 2 and 4 above, and in further view of Smith (Stem Cells Transl Med. 2015 Feb 2;4(3):239–251) is withdrawn.
Applicant’s arguments and amendments filed 05/12/2026 been considered and are persuasive as discussed above, as the independent claim rejection is withdrawn, this rejection is additionally withdrawn.
The rejection of claims 7-9 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).
Applicant’s arguments and amendments filed 05/12/2026 been considered and are persuasive as discussed above, as the independent claim rejection is withdrawn, this rejection is additionally withdrawn.
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claims 32 and 33 remain 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 Manferedi and Maumus with TNFalpha 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
Claim 34 remains 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.
In response to Applicant’s arguments regarding the 103 rejections,
Applicant’s arguments and amendments filed 05/12/2026 have been considered and are persuasive regarding independent claim 1 as discussed above, however they are not persuasive regarding independent claim 32.
Claim 32 has not been amended in the same manner as claim 1 and includes macrophages, therefore rejections directed towards macrophages still stand in light of Manferdini’s results regarding macrophages.
Moreover, the rejection is based on known co-cultures of synovial fibroblasts and AD-MSC which is then modified to be stimulated with TNF-alpha. Therefore, the results of Manferdini is not indicative of the overall claimed invention wherein synovial fibroblasts are stimulated through the teachings of Lowin and then co-cultured with AD-MSCs which are then provided to the subject.
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.
Claims 1, 2, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Manferdini2 (Orthopaedic Research Society. J Orthop Res 38:336–347, 2020) in view of Maumus (2016, Front. Immunol. 7:392).
Regarding claims 1 and 2, Manferdini2 teaches a method of treating GMP-ASCs (i.e. adipose stem cells) with conditioned media from synoviocytes/synovial fibroblasts obtained from patients with osteoarthritis (Abstract, p.337, Cell Cultures). Manferdini2 found that ASCs treated with the conditioned media in both normoxic and hypoxic conditions resulted in a significantly higher increase in migration (p. 343, last paragraph). Manferdini2 likens the stimulation utilizing the conditioned media to an inflammatory stimulus such as interferon gamma, however, Manferdini2’s results are improved over that of TNF alpha and IFNy stimulated MSCs (p. 343, last paragraph; p. 345, 1st paragraph).
However, Manferdini2 does not teach a step of administering the conditioned media treated 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 stimulated by conditioned media from synovial cells in OA patients from Manferdini2 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 Manferdini2 teaches that conditioned media stimulated ASCs are an alternative to stimulus with INFy (p. 343, last paragraph).
Regarding claim 11, the combination of Manferdini2 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 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Manferdini2 (Orthopaedic Research Society. J Orthop Res 38:336–347, 2020) in view of Maumus (2016, Front. Immunol. 7:392) as applied to claims 1, 2, and 11 above, and in further view of Pretzel (Arthritis Research & Therapy 2009, 11:R25)
As discussed above and incorporated herein in its entirety, the combination of Manferdini2 and Maumus render obvious a method of co-culturing adipose mesenchymal stem cells with osteoarthritis synovial conditioned media to a patient with osteoarthritis.
Regarding claims 4 and 5, the combination of Manferdini2 and Maumus do not teach wherein synovial fibroblasts not isolated from the subject of the treatment are cultured with an inflammatory cytokine.
Pretzel teaches an in vitro model of rheumatoid arthritis which comprises stimulating continuously synovial fibroblasts with TNF alpha and/or Interleukin 1 beta (Methods). As this is an in vitro model, the stimulated cells are not administered to the same subject for autologous transplantation and are from separate subjects other than Manferedi2, therefore meeting the limitation of claim 2.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to stimulate synovial fibroblasts from alternative sources to obtain conditioned media as taught by Pretzel with TNF alpha and/or Interleukin 1 beta in place of the synovial fibroblast conditioned media from OA synovial fibroblast cells alone with a reasonable expectation of success. An artisan would be motivated to utilize cells from a different source as Pretzel demonstrates that alternative sources with cytokines are utilized for in vitro models of arthritis (Abstract). Therefore, the cell source is an alternative equivalent to obtain conditioned media for the stimulation of ASCs. Moreover, as the aim of Maumus’ study is a xenogenic transplant, xenogenic sources for other cell types would additionally be utilized with a reasonable expectation of success.
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 Manferdini2 (supra) in view of Maumus (supra) and Pretzel (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 Manferdini2, Maumus, and Pretzel render obvious a method of co-culturing adipose mesenchymal stem cells with osteoarthritis synovial conditioned media to a patient with osteoarthritis wherein the synovial cells utilized in the conditioned media are not isolated from the subject receiving treatment.
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 place of TNFalpha as taught by Manferdini2, Maumus. and Pretzel to activate the synovial fibroblasts for cell culture 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 TNFalpha 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 Manferdini2 (supra) in view of Maumus (supra) and Pretzel (supra) as applied to claims 1, 2 and 4 above, and in further view of Simonin (Am J Physiol Cell Physiol 282: C125–C133, 2002)
As discussed above and incorporated herein in its entirety, the combination of Manferdini2, Maumus, and Pretzel render obvious a method of co-culturing adipose mesenchymal stem cells with osteoarthritis synovial conditioned media to a patient with osteoarthritis wherein the synovial cells utilized in the conditioned media are not isolated from the subject receiving treatment.
However, these references do not teach the synovial fibroblasts are stimulated or activated by LPS.
Simonin teaches stimulating synovial fibroblasts with LPS (p. C126, 1st column; p. C125, 1st column). Simonin further demonstrates that LPS induces strong Interleukin 1 beta and TNF alpha expression as compared to the controls (p. C128, 1st column). The expression of these cytokines is linked to inducing cartilage degeneration in rheumatoid arthritis (p. C129, 2nd 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 synovial fibroblasts of Manferdini2, Maumus and Pretzel with LPS instead of TNFalpha as taught by Simonin with a reasonable expectation of success. An artisan would have substituted TNF alpha for LPS in stimulated synovial fibroblasts model rheumatoid arthritis as taught by Simonin as Pretzel’s TNFalpha stimulated synovial fibroblasts also model rheumatoid arthritis. Therefore, an artisan would be substituting two known equivalents for the stimulation of synovial fibroblasts in models of rheumatoid arthritis.
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.
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.
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/ALEXANDRA F CONNORS/ Examiner, Art Unit 1634
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631
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