DETAILED ACTION
Claims 1-11 are currently pending.
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 .
Priority
Acknowledgement is made of the instant application being a national stage entry under 35 USC 371 of international application PCT/JP20217/032402, filed September 3, 2021. Acknowledgment is further made of applicants' claim for foreign priority to JP application 2020-148193, filed 9/3/2020. A certified copy of the foreign priority document is present in the application file.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 6/2/2023, 12/6/2024, 5/9/2025, 7/18/2025, 8/15/2025 and 10/20/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because the drawings are indicated by “Figure” rather than “FIG.” as required by 37 C.F.R § 1.84 (u)(1) (see also MPEP § 608.02 (V)). The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation “FIG.” Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation “FIG.” must not appear.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
It is additionally noted there is text in FIG. 6 that is not legible.
Claim Objections
Claim 1 is objected to because of the following informalities: abbreviations.
The abbreviations IGFBP, HGF, VEGF, PDGF, EGF, KGF (FGF-7), PDGFR, TGFα, and TGFβ should first be spelled out upon first usage in a claim. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 6 is rejected 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 6 recites the limitation “…the HGF concentration is 50000 pg/mL or more.”
Upon review of the specification, the specification shows that Applicants have not provided sufficient description of the invention to support they were in possession of a detoxified secretome extract wherein the HGF concentration is 50000 pg/mL or more. Possession of an invention may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998).
In the instant case the only references in the specification to the concentrations of HGF are directed to culturing ASCs in 6% O2, seeded at a cell density of 3.5 x 104/o.2 mL (i.e., 1.75 x 105/ mL), culture supernatant was collected on days 3, 6, 8 and 11 (without FBS) and day 8 and 11 HGF levels were approximately 1.25 x 104 pg/mL (i.e. 1250 pg/mL) and 1.0 x 104 pg/mL (1000 pg/mL), respectively (see FIG. 5) (Specification at [0074]-[0075], page 27). The specification, at [0081] (page 29), discloses seeding ASCs at a density of 2 x 104 cells/cm2 and culturing at 1% O2, 6% O2 or 21% O2 and thereafter measuring the HGF levels (FIG. 8). The greatest quantity of HGF, approximately 1000 pg/mL, was produced at Day 17 (D17) and Day 21 (D21) cultures at 6% O2. FIG. 9 further shows HGF concentrations that do not exceed 15,000 pg/mL for cultures up to 9 days. FIG. 15 further shows HGF concentrations achieved when culturing in the present of 5% HPL, wherein the HGF concentration is no greater than 2500 pg/mL. FIG. 16 shows HGF levels that do not exceed 600 pg/mL.
Thus, a review of the specification shows that Applicants have not provided sufficient description of the invention to support they were in possession of a detoxified secretome extract wherein the HGF concentration is 50000 pg/mL or more.
Accordingly, the claims are considered to lack sufficient written description and are properly rejected under 35 USC 112, first paragraph.
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.
Claims 1-6 are 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 1-6 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 of native proteins. Applicant’s specification recognizes said proteins are naturally produced by mesenchymal stem cells ([0008] and [0013]).
CellSciences.com (see PTO-892) evidences 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).
Custo et al (see PTO-892) further evidences 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 1-6 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. 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 claims 4 and 6, it is noted the limitations directed to concentration of the extracted protein do 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.
Further regarding claim 5 and the limitation regarding the source of the extracted proteins, i.e., are adipose-derived stromal/stem cells or adipose-derived vascular endothelial progenitor cells, said limitation 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).
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-5 and 7-11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Seetharaman et al., (Case Reports in Dermatological Medicine, Vol. 2019, Article ID 8309103, 5 pages, published 2 May 2019; see PTO-892) (“Seetharaman”).
Seetharaman is directed to treating psoriasis vulgaris by administering mesenchymal stem cell conditioned medium (MSC-CM). Seetharaman specifically notes that the numerous growth factors and cytokines that are secreted by the MSCs into the culture medium are very likely to be the active agents that play a role in skin regeneration (Abstract).
Regarding claims 1, 3-5 and 7-9, it is noted Seetharaman (at page 2, 2.2 Preparation of MSC-Conditioned Media) exemplifies collecting adipose tissue via liposuction and isolating MSCs from the adipose tissue (as recited in claim 5 and as disclosed in the specification at [0058]). The isolated MSCs were cultured in DMEM (i.e., a culture solution), with media changes every 3 days. Passage 2 MSCs were seeded at a concentration of 5 x 106 per T175 (n=10) and once cells attained 90% confluence (i.e., a proliferative phase, claim 8) the culture media were replaced with serum-free DMEM, the culture was incubated 72 hours and the resulting MSC-CM was collected, centrifuged at 2000 rpm for 5 min to remove the cell debris (i.e., concentrating an active ingredient from the culture supernatant), filtered through 0.22-μm filter (i.e., concentrating an active ingredient from the culture supernatant), and thereafter further concentrated 10 times (i.e., detoxified) by ultrafiltration (i.e., 1.2 times or more concentrated, claim 4) using Amicon® Ultra-15 centrifugal filtering units with a molecular weight cut-off value of 3 kDa, as disclosed in the specification at [0040] and [0052], which reads on purifying by removing metabolic waste products from the concentrated culture supernatant).
As to claims 1, 3, and 4 and the limitation the detoxified secretome extract comprising at least one, or all, of the recited factors, e.g., one of IGFBP, HGF, VEGF, PDGF, EGF, KGF (FGF-7), PDGFR, TGFα, and TGFβ, although Seetharaman discusses specific growth factors found in bone marrow derived MSCs (BMMSCs), including VEGF, IGF, FGF, EGF, KGF, Seetharaman does not further discuss the growth factors secreted by the adipose-derived MSCs. However, given that Seetharaman employs the same MSCs as disclosed in the specification at [0058], means that any and all results of the method of Seetharaman, whether recognized at the time of publication or not, were inherently achieved by the reference method.
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 the limitation that lactic acid and ammonia are removed from the detoxified secretome extract (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 Seetharaman employs the same ultrafiltration step as disclosed in the instant specification at [0040] and [0052]. i.e., ultrafiltration using Amicon Ultra-15 centrifugal filtering units with 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 above, “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).” MPEP 2112.01.
Thus, the teaching of Seetharaman anticipates claims 1, 3-5 and 7-9.
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.
Further regarding claims 10 and 11, Seetharaman discloses purification by ultrafiltration using Amicon® Ultra-15 centrifugal filtering units with a molecular weight cut-off value of 3 kDa, thus anticipating claims 10 and 11.
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 et al., (WO 2011/070001; IDS 12/6/2024) (“WO ‘001”).
WO ‘001 is directed to adult stem cell derived conditioned medium derived from a human liver stem cell (HLSC-CM) (Abstract).
WO ‘001 teaches the human adult non-oval liver stem/progenitor cells (HLSCs) express both mesenchymal and embryonic stem cell markers and have multipotent differentiation abilities and regenerative properties (page 2), thus the disclosed HLSCs are considered mesenchymal stem cells.
Regarding claims 1, 3-4 and 7-9, WO ‘001 (pages 11-12) teaches the human liver stem cells (HLSCs) were cultured in a-MEM/EBM (3:1) (i.e., obtaining a culture supernatant by culturing mesenchymal stem cells in a culture solution, claim 7), supplemented with 10% fetal bovine serum, 100 μg/ml penicillin and 100 μg/ml streptomycin. EBM was reconstituted with hEGF (human Epithelial Growth Factor), Hydrocortisone, GA (gentamicin), BBE (Brain Bovine Extract).
The cell free conditioned medium (CM) from HLSCs was prepared by collecting the cell culture medium by centrifugation after 24 hours of culture (i.e., concentrating an active ingredient from the culture supernatant, claim 7; i.e., a culture supernatant is obtained from a culture of the mesenchymal stem cells that are in a proliferation phase, claim 8). The experiments were performed with a cell mass of 2 x 106 cells. The medium was ultracentrifuged and concentrated, at approximately 25-fold (i.e., is 1.2 times or more concentrated, claim 4), by centrifugation at 2700 g for 75 minutes, using Amicon® Ultra centrifugal ultrafiltration units having a 3 kDa molecular weight cut-off, as disclosed in the specification at [0040] and [0052], which reads on purifying by removing metabolic waste products from the concentrated culture supernatant).
The cell-free conditioned medium (CM), concentrated by ultrafiltration using a 3 kDa molecular weight cut-off reads on “A detoxified secretome extract”.
Thus, the method disclosed by WO ‘001 anticipates the method of claim 7.
As to claims 1, 3, and 4 and the limitation the detoxified secretome extract comprising at least one, or all, of the recited factors, e.g., one 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 anticipating claims 1, 3 and 4.
Further regarding the limitation that lactic acid and ammonia are removed from the detoxified secretome extract (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 ‘001 employs the same ultrafiltration step as disclosed in the instant specification at [0040] and [0052]. i.e., ultrafiltration using Amicon Ultra centrifugal filtering units with a molecular weight cut-off value of 3 kDa, thus, absent evidence to the contrary, 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).” MPEP 2112.01.
Thus, the teaching of WO ‘001 anticipates claims 1, 3-4 and 7-9.
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.
Further regarding claims 10 and 11, WO ‘001 discloses purification by ultrafiltration using Amicon Ultra centrifugal filtering units with a molecular weight cut-off value of 3 kDa, thus anticipating claims 10 and 11.
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 et al., (WO 2015 028900; IDS 6/2/2023) (“WO ‘900”).
Regarding claims 1, 4, 7-11, WO ‘900 is directed to a conditioned medium comprising bioactive factors secreted by bone marrow-derived mesenchymal cells (BM-MSCs) (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) (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 (secretome extract) 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 as recited in claim 1, specifically
Further regarding the limitation that lactic acid and ammonia are removed from the detoxified secretome extract (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).”
Thus, WO ‘900 anticipates claims 1, 4, 7-11.
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.
Regarding claim 6, it is first noted as set forth above regarding claim 1, 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, absent evidence to the contrary, the lower molecular weight waste products, i.e., ammonia, would pass through the filtration device and be removed from the conditioned medium, and thus considered to have a concentration less than 20 µg/dL.
WO ‘900 specifically teaches the concentration of HGF ranges from about 20 to about 200 ng/ml (i.e., 20000 to 200000 pg/ml) (page 9, lines 7-8). It is noted the range disclosed in WO ‘900 is disclosed with sufficient specificity to constitute an anticipation. See MPEP 2131.03 (II)
Further regarding claims 10 and 11, WO ‘900 discloses purification by ultrafiltration using a molecular weight cut-off value of 3 kDa, thus anticipating claims 10 and 11.
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) 5 is rejected under 35 U.S.C. 103 as being unpatentable over WO ‘001 (set forth above), as applied to claims 1-4 and 7-11.
The teaching of WO ‘001 is set forth above and anticipates claims 1-4 and 7-11.
Regarding claim 5 and the 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 WO ‘001 exemplifies preparing conditioned medium from HLSCs, liver-derived mesenchymal stem cells, and does not further exemplify adipose-derived stem cells. However, WO ‘001, at page 6, teaches the adult stem cell is selected from the group consisting of a liver stem cell, a renal stem cell, an adipose stem cell, a mesenchymal stem cell, a perivascular multipotent progenitor cell, a dental pulp stem cell, an epithelial stem cell, a hematopoietic stem cell, a stem cell from exfoliated deciduous teeth and an umbilical cord stem cell. Thus, WO ‘001 does render obvious a cell-free conditioned medium composition obtained from adipose-derived stem cells, that is, WO ‘001 teaches the limitations required by the current claims and as all limitations are found in one reference it is held that a composition comprising cell-free conditioned medium composition is within the scope of the teachings of WO ‘001, and thus renders the invention of claim 5 prima facie obvious. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion to obtain a cell-free conditioned medium composition from adipose-derived mesenchymal stem cells. Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by WO ‘001.
Claim(s) 6 is rejected under 35 U.S.C. 103 as being unpatentable over WO ‘001 (set forth above), as applied to claims 1-4 and 7-11, and further in view of Tajima et al., (FEBS 10294, Vol 291, No. 2, 229-232, October 1991; see PTO-892), as evidenced by Soto-Gamez et al., (Radiotherapy and Oncology 190 (2024) 109984, pages 1-8; see PTO-892) (“Soto-Gamez”).
The teaching of WO ‘001 is set forth above an anticipates claims 1-4 and 7-11.
Regarding claim 6, it is first noted as set forth above regarding claim 1, WO ‘001 employs the same ultrafiltration step as disclosed in the instant specification at [0040] and [0052]. i.e., ultrafiltration using Amicon Ultra centrifugal filtering units with a molecular weight cut-off value of 3 kDa, thus, absent evidence to the contrary, the lower molecular weight waste products, i.e., ammonia, would pass through the filtration device and be removed from the conditioned medium, and thus considered to have a concentration less than 20 µg/dL.
Further regarding the limitation that the concentration of HGF is 50000 pg/mL or more, it is noted that WO ‘001 teaches 2 x 106 cells were seeded and cultured for 24 hours prior to conducting the densitometric analysis (antibody labeling) to determine the presence of factors expressed in the conditioned medium and indicates HGF at a level of 15.29. WO ‘001 does not further comment on the correlation to pg/mL of HGF. However, Soto-Gamez evidences that adipose-derived mesenchymal stem cells (ADSCs), seeded at a density of 5 x 103 cells/cm2 cultured for 7 days produce HGF at a concentration of approximately 2500 pg/mL (Fig. 1c and Co-culture experiments, page 2). Thus, the concentration of secreted growth factor is achieved as the result of cell concentration and culturing time.
Tajima further teaches that hepatocyte growth factor (HGF) has anti-proliferative activity in tumor cells at concentrations as low as 1-10 ng/ml (i.e., 1000-10000 pg/ml) (Abstract). Tajima’s Fig. 1 and Fig. 2 show that increasing concentrations of HGF, up to 30 ng/ml (i.e., 30000 pg/ml) have increased anti-tumor effects.
Therefore, given that WO ‘001 is directed to using the ADSC conditioned medium for anti-tumor therapy it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to modify the method of WO ‘001 to optimize the concentration of the expressed growth factors by optimizing the culturing time period or cell concentration to permit HGF levels of 50000 pg/mL or more since it has been shown by Tajima that HGF has anti-tumor activity.
One of ordinary skill in the art would have been motivated by routine practice to optimize the concentration of HGF with a reasonable expectation for successfully producing a therapeutic conditioned medium with anti-tumor properties; thus, meeting the limitation of claim 6.
Conclusion
No claim is allowed. No claim is free of prior art.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633