DETAILED ACTION
Applicant’s response filed 6/15/2026 has been received and entered into the application file. All arguments have been fully considered. Claims 1-4 and 7-11 are currently pending. Claim 1 is currently amended. Claims 5-6 are cancelled.
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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/20/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The corrected drawing sheets are in compliance with 37 CFR 1.121(d). Therefore, the objection to the drawings is withdrawn.
Claim Objections -Withdrawn
Applicant’s amendment obviates the previous objection to claim 1. Therefore, the objection is withdrawn.
REJECTION(S) WITHDRAWN
Claim Rejections - 35 USC § 112
RE: Rejection of Claim 6 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement:
It is noted that claim 6 has been cancelled. However, the limitation regarding the HGF concentration is 50000 pg/mL or more is now recited in amended claim 1.
Applicants’ remarks are found persuasive regarding this limitation, in view of the specification at [0017]. Therefore, the previous rejection of record is withdrawn.
Claim Rejections - 35 USC § 102
RE: Rejection of Claim(s) 1-5 and 7-11 under 35 U.S.C. 102(a)(1) as being anticipated by Seetharaman:
The rejection is withdrawn in view of Applicant’s amendment submitted 6/15/2026.
RE: Rejection of Claim(s) 1-4 and 7-11 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by HERRERA SANCHEZ (“WO ‘001”):
The rejection is withdrawn in view of Applicant’s amendment submitted 6/15/2026.
RE: Rejection of Claim(s) 1-2, 4 and 6-11 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by BALASUBRAMANIAN (“WO ‘900”):
The rejection is withdrawn in view of Applicant’s amendment submitted 6/15/2026.
Claim Rejections - 35 USC § 103
RE: Rejection of Claim(s) 5 under 35 U.S.C. 103 as being unpatentable over WO ‘001; and
Rejection of Claim(s) 6 under 35 U.S.C. 103 as being unpatentable over WO ‘001 and Tajima, as evidenced by Soto-Gamez:
For the reasons discussed above, the anticipation rejection over WO ‘001 is withdrawn, and thus the obviousness rejection that is based on the same basis is likewise withdrawn. However, the amendment submitted ON 6/15/2026 has necessitated new grounds of rejection, as set forth below.
REJECTION(S) MAINTAINED
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
The rejection has been updated in view of Applicant’s amendment submitted 6/15/2026. Applicants’ amendment cancelled claims 5-6.
Claims 1-4 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
The rationale set forth below conforms to current Office practice for examination of claims under § 101.
These claims are analyzed for eligibility in accordance with their broadest reasonable interpretation.
Claims 1-4 are directed to a statutory category, e.g., a composition (Step 1: YES).
The next part of the analysis involves whether the claimed invention recites or is directed to one or more judicial exceptions (Step 2A, prong one).
Claim 1: Claim 1 is directed to a detoxified secretome extract of a culture supernatant of mesenchymal stem cells or progenitor cells derived from the mesenchymal stem cells, wherein the detoxified secretome extract comprises at least one of IGFBP, HGF, VEGF, PDGF, EGF, KGF (FGF-7), PDGFR, TGFα, and TGFβ secreted by the mesenchymal stem cells or the progenitor cells derived from the mesenchymal stem cells, and lactic acid and ammonia that are metabolic waste products caused by the mesenchymal stem cells or the progenitor cells derived from the mesenchymal stem cells are removed from the detoxified secretome extract.
It is noted the broadest reasonable interpretation of the claims as currently written encompasses an extract (i.e., isolated) of purified native proteins. Applicant’s specification recognizes said proteins are naturally produced by mesenchymal stem cells ([0008] and [0013]).
As previously discussed, CellSciences.com evidenced that vascular endothelial growth factor (VEGF) is a natural protein found in mammalian species including bovine and human (Discovery of vascular endothelial growth factor) and the protein is secreted by many cell types, e.g., macrophages, platelets, keratinocytes (Physiological functions).
As previously discussed, Custo et al further evidenced that VEGF, EGF (epidermal growth factor), HGF (hepatocyte growth factor) and TGF-β1 (transforming growth factor- β1) are natural products produced by platelets (Abstract).
Thus, claims 1-4 recite at least one natural product.
There is no indication in the specification that combining the recited proteins provides any characteristics (structural, functional, or otherwise) that are not present in the individual parts. The combination does not improve or change in any way each components natural functioning. Thus, the claimed composition does not have markedly different characteristic from what occurs in nature and is a "product of nature" exception.
Further regarding claim 1, although the claim has been amended to recite “wherein the mesenchymal stem cells or the progenitor cells derived from the mesenchymal stem cells are adipose-derived stromal/stem cells or adipose-derived vascular endothelial progenitor cells”, it is noted this limitation is directed to the source of the proteins, i.e., the manner by which the growth factors have been produced, and said limitation does not further limit the purified growth factors in such a way to provide a markedly different characteristic from the natural counterpart.
As to claim 1 and the amended limitation directed to the concentration of lactic acid and ammonia, including zero, said limitation appears to indicate the removal of cell culture by-products and thus identify the purity of the claimed growth factor proteins. However, said limitation does not further limit the purified growth factors in such a way to provide a markedly different characteristic from the natural protein counterpart. The fact of purification or isolation alone is inadequate to demonstrate marked structural differences. See Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 106 U.S.P.Q. 2d 1972, 1979 (2013) (“separating [a] gene from its surrounding genetic material is not an act of invention”).
Further regarding claim 1 and the limitation directed to the concentration of HGF, said limitation does not limit the claimed protein in such a way that is markedly in structure from the natural counterpart.
Accordingly, the claims are directed to an exception (Step 2A, prong one: YES). Thus, the claims do not qualify as eligible subject matter and are rejected under 35 U.S.C. 101.
Further regarding claim 2, it is noted claim 2 recites limitations that are considered only to be directed to intended use. Such a limitation does not limit the claimed composition in such a way that is markedly different in structure or biological and/or pharmacological function from their natural counterparts.
Thus, the claimed composition does not have markedly different characteristics from what occurs in nature and is a "product of nature" exception. Thus, the claims do not qualify as eligible subject matter and are rejected under 35 U.S.C. 101.
Further regarding claim 4, it is noted the limitation directed to concentration of the extracted protein does not limit the claimed protein in such a way that is markedly different in structure or biological and/or pharmacological function from the natural counterpart.
The next part of the analysis involves whether the claimed invention recites additional elements that integrate the judicial exception into a practical application (Step 2A, prong two).
Given the claims are directed to a composition, the claims do not recite additional steps that integrate the judicial exception into a practical application (Step 2A, prong two: No).
The final part of the analysis involves whether the claimed invention, as a whole, recite something “significantly more” than the judicial exceptions (Step 2B).
In view of the above and considered as a whole, the claimed composition does not have markedly different characteristics from what occurs in nature and such elements discussed above are not significantly more than the indicated judicial exceptions. Thus, the claims do not qualify as eligible subject matter and are rejected under 35 U.S.C. 101 (Step 2B: NO).
NEW GROUND(S) OF REJECTION, NECESSITATED BY AMENDMENT
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 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(s) 1-4 and 7-11 are rejected under 35 U.S.C. 103 as being unpatentable over BALASUBRAMANIAN et al., (WO 2015 028900, previously cited; IDS 6/2/2023) (“WO ‘900”), in view of HERRERA SANCHEZ et al., (WO 2011/070001, previously cited; IDS 12/6/2024) (“WO ‘001”).
Regarding claims 1-2, 4, and 7-11, WO ‘900 is directed to a conditioned medium comprising bioactive factors secreted by bone marrow-derived mesenchymal cells (BM-MSCs) (i.e., secretome extract) (Abstract; page 1, lines 5-12; page 5, lines 7-15). The bioactive factors comprise growth factors, cytokines, chemokines, anti-oxidants and other factors that are known to function or mediate a biological process, wherein the biological process includes cell proliferation and cell migration (page 8, lines 13-17). WO ‘900 teaches the bioactive factors are selected from a group comprising VEGF, TGF-β, PGE-2, PDGF, GDNF, IGFBP, FGF, GCSF M-CSF, angiogenin, angiopoietin, KGF, FGF7, BMP6, IGF1, laminin, MMP1, MMP2, MMP9, TEVIP1 and TIMP2, HGF, SDF1 and LIF, IL-10, or any combination thereof (as recited in claims 1 and 4) (page 8, lines 19-22). WO ‘900 specifically teaches the concentration of HGF ranges from about 20 to about 200 ng/ml (i.e., 20000 to 200000 pg/ml, claimed range overlaps the prior art range) (page 9, lines 7-8).
EXAMPLE 2 (pages 17-19) teaches seeding and proliferation of the BM-MSCs to passage 5 cultures in cell stacks, thereafter one of three cell culture medium change processes is conducted once cells achieve 45-50% confluency. Once the cells reach 80-90% confluency (i.e., culture supernatant is obtained from a culture of the mesenchymal stem cells that are in a proliferative phase, claim 8) conditioned medium is collected from the cell stacks. The production process for each of the three methods mentioned above requires about 10-15 days at the end of which the conditioned medium (CM) is collected for enrichment (i.e., obtaining a culture supernatant by culturing mesenchymal stem cells in a culture solution, claim 7).
EXAMPLE 4 (pages 20-22) teaches concentration of the conditioned medium by further concentration and enrichment by ultra-filtration/Tangential flow filtration (TFF) using defined molecular weight cut offs including by using molecular weight cutoffs of 1 kDa and 3 kDa and above, which reads on “concentrating an active ingredient from the culture supernatant; and purifying by removing metabolic waste products from the concentrated culture supernatant”, claim 7). The TFF concentration thus resulted in a conditioned medium which is 10 times concentrated when compared to the original conditioned medium prior to the TFF (i.e., 1.2 times or more concentrated, claim 4). Thus, the conditioned medium obtained is a 10 X concentrate. Once the ultrafiltration cycle is complete, diafiltration cycles are performed to enhance the purity of the final CM concentrate. In diafiltration process, Dulbecco's phosphate buffered saline is added into the feed tank in volumes equivalent to the CM retentate. Eight cycles of diafiltration are performed to obtain the final retentate with optimum purity.
Thus, WO ‘900 exemplifies culturing BM-MSCs to produce a BM-MSC conditioned culture medium that is subjected to concentrating and purifying by ultrafiltration and Tangential flow filtration, wherein the molecular weight cutoff is 3 kDa (as disclosed in the specification at [0040] and [0052]) and the conditioned medium comprises various growth factors (i.e., secretome extract) as recited in claim 1, specifically VEGF, TGF-β, PDGF, IGFBP, KGF, FGF7, and HGF.
Further regarding the limitation that lactic acid and ammonia are removed from the detoxified secretome extract and wherein the lactic acid concentration is 0.3 mM or less and the ammonia concentration is 20 µg/dL or less (claim 1); the limitation of purifying by removing metabolic waste products from the concentrated culture supernatant (claim 7); and the limitation the metabolic waste products removed in the purification are lactic acid and ammonia (claim 9), it is noted WO ‘900 employs the same ultrafiltration step as disclosed in the instant specification at [0040] and [0052]. i.e., ultrafiltration using a molecular weight cut-off value of 3 kDa, thus the lower molecular weight waste products of lactic acid and ammonia would pass through the filtration device and be removed from the conditioned medium.
As discussed at MPEP 2112.01, “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).”
Further regarding claim 1 and the amended limitation “wherein the mesenchymal stem cells or the progenitor cells derived from the mesenchymal stem cells are adipose-derived stromal/stem cells or adipose-derived vascular endothelial progenitor cells” it is noted that WO ‘900 teaches the mesenchymal stem cells are bone marrow-derived mesenchymal cells and does not further teach obtaining the conditioned medium from adipose-derived stromal/stem cells or adipose-derived vascular endothelial progenitor cells. However, WO ‘001 is directed to preparing purified conditioned medium from adult stem cells, e.g., human liver stem cell (HLSC-CM) (Abstract; pages 11-12). WO ‘001 teaches the human adult non-oval liver stem/progenitor cells (HLSCs) and are considered mesenchymal stem cells (page 2). WO ‘001, at page 6, further teaches the method can employ adipose stem cells. Thus, WO ‘001 has established it was known that cell-free conditioned medium compositions can be prepared from adipose-derived stem cells.
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute adipose-derived stem cells for the BM-MSCs since both cell types are known to be useful for preparing cell-free conditioned medium comprising secretome extracts. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of MSCs for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
The skilled artisan would have had a reasonable expectation of success in combining the teachings of WO ‘009 with WO ‘001 because each of these teachings are directed at preparing secretome extracts.
Regarding claim 2 and the limitation the detoxified secretome is used as a therapeutic agent for regenerative medicine, an immunosuppressant, an anti- inflammatory agent, or an antifibrotic agent, it is noted that claim 2 is directed to a composition, per se. Although claim 2 states that the composition is “used as a therapeutic agent for regenerative medicine, an immunosuppressant, an anti- inflammatory agent, or an antifibrotic agent”, this limitation is considered only to be directed to intended use which does not further define or limit the composition, per se. Compositions are defined by their physical, structural, and chemical properties, not by an intended use or application. Please note that it is well settled that “intended use” of a composition or product will not further limit claims drawn to a composition or product. See, e.g., Ex parte Masham, 2 USPQ2d 1647 (1987) and In re Hack 114, USPQ 161. See MPEP 2111.02.
As to claim 3 and the limitation the detoxified secretome extract comprising all of IGFBP, HGF, VEGF, PDGF, EGF, KGF (FGF-7), PDGFR, TGFα, and TGFβ, WO ‘001 teaches the cell-free, concentrated CM composition was analyzed by Raybio Biotin Label-Based Antibody Array and the expression levels of 507 human target proteins were detected (pages 12-13). The analysis shows the mesenchymal stem cells express each of IGFBP, HGF, VEGF, PDGF, EGF, KGF (FGF-7), PDGFR, TGFα, and TGFβ (Table spanning pages 13-29), thus meeting the limitation of claim 3.
Further regarding claims 10 and 11, WO ‘900 discloses purification by ultrafiltration using a molecular weight cut-off value of 3 kDa, thus meeting the limitations of claims 10 and 11.
Response to Remarks and Declaration under 37 CFR 1.132
Claim Rejections under 35 USC 101:
The examiner acknowledges receipt of the Declaration under 37 CFR 1.132 by Dr. Kotaro Yoshimura, filed on 6/15/2026.
The Declaration is insufficient to overcome the rejection of claims 1-4 under 35 USC 101 because, although the Declaration shows experimental data supporting the purified growth factor (removal of cell culture waste byproducts, i.e., detoxified) has improved cell proliferation characteristics, the Declaration does not provide experimental data to show that the claimed growth factor protein, HGF, has any structural or chemical properties that are markedly different from the natural counterpart. No evidence has been provided to show the claimed HGF has a markedly different amino acid sequence, as compared to the natural counterpart, or has a markedly different three-dimensional folded structure, as compared to the natural counterpart, or has a markedly different light-absorption characteristic, as compared to the natural counterpart.
It is again noted that the fact of purification or isolation alone is inadequate to demonstrate marked structural differences. See Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 106 U.S.P.Q. 2d 1972, 1979 (2013) (“separating [a] gene from its surrounding genetic material is not an act of invention”).
Claims Rejections under 35 USC 102:
As set forth above, the previous rejections of record have been withdrawn in view of Applicants’ amendment submitted 6/15/2026. New grounds of rejection are set forth above addressing the amendments to claim 1.
Claims Rejections under 35 USC 103:
As set forth above, the previous rejections of record have been withdrawn in view of Applicants’ amendment submitted 6/15/2026. Applicant’s remarks regarding previously cited Herrera Sanchez have been fully considered, but are not found persuasive for the reasons set forth above at the new grounds of rejection addressing the amendments to claim 1.
Conclusion
No claim is allowed. No claim is free of prior art.
Applicants’ 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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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