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 .
DETAILED OFFICE ACTION
This Office Action is in response to the papers filed on 20 April 2026.
CLAIMS UNDER EXAMINATION
Claims 1, 3-5 and 7-8 have been examined on their merits.
PRIORITY
Foreign Priority document TW112101219, filed on 11 January 2023, is acknowledged. A certified translation has not been provided.
WITHDRAWN REJECTIONS
The previous rejections have been withdrawn due to claim amendment.
REJECTIONS
New grounds of rejection have been made to address amended claims 1 and 5.
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 5 and 7-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yu et al. (previously cited; TSP-1 Secreted by Bone Marrow Stromal Cells Contributes to Retinal Ganglion Cell Neurite Outgrowth and Survival. Stem Cells And Development Volume 25 (21) 2016 pages 1681-1690) as evidenced by Li et al. (previously cited; The Therapeutic Potential of ADSC-Secreted LEFTY2 in Treating Alzheimer’s Disease. J. Mol. Sci, 2025, 26, 3382 pages 1-20).
Yu et al. co-culture bone marrow stromal cells (i.e., mesenchymal stem cells) with retinal ganglion cells in a “complete medium” (Abstract; see page 3, left column, section titled “Assay of BMSC and RGC survival and neurite outgrowth”). The stem cells secrete factors that promote neural recovery and survival (page 2, left column, first paragraph). TSP-1 is secreted by said stem cells into the culture medium (see page 3, right column, second paragraph; see Figure 3E; see page 6, left column). As evidenced by the post-filing reference Li et al., mesenchymal stem cells secrete exosomes containing LEFTY2 (see page 13, third paragraph; see Figure 2C). Therefore TSP-1 and LEFTY would be present in Yu’s culture medium because they are secreted by said stem cells. Yu teaches the stem cells differentiated into neural cells with neurite-like outgrowth, displaying primary and secondary branching (see page 5, left column, first paragraph; see page 8, left column, first paragraph). A neurite is defined as a cell growth from a neuron (nerve) body. Therefore the art teaches differentiation to a nerve cell. Because the claimed method is anticipated, it would inherently promote proliferation of cells differentiated from stem cells as recited in claim 5. Because the claimed method is anticipated, it would inherently reduce expression of anti-inflammatory factors as recited in claims 7-8.
Therefore Applicant’s Invention is anticipated as claimed.
RESPONSE TO APPLICANT’S ARGUMENTS
The arguments made in the response filed on 20 April 2026 are acknowledged.
Argument 1: The Applicant alleges Yu discloses at the last paragraph of the left column on page 6 to the last paragraph of the right column on page 7 that TSP1 does not affect bone marrow stromal cells and retinal ganglion cells survival. Yu discloses that when TSP-1 expression was decreased with siRNA silencing, the bone marrow stem cells had no impact on retinal ganglion cell survival (see abstract). The Applicant states these teachings demonstrate the effect of TSP1 and other components present in the culture medium is to maintain survival at best, and Yu's data does not support the assertion that LEFTY2, which allegedly is present in the culture, inherently promotes proliferation of cells differentiated from stem cells.
Response: Claim 5 requires culturing in a medium comprising TSP1 and LEFTY 2. As set forth above, TSP-1 and LEFTY2 are secreted by MSCs. Because the prior art anticipates the claimed medium and method step, it would inherently promote proliferation of cells differentiated from stem cells as claimed. The Applicant has not provided evidence demonstrating culturing stem cells by the claimed method does not promote proliferation. Therefore the argument is not persuasive.
Argument 2: The Applicant argues the evidentiary references do not teach LEFTY2 is present at a level sufficient to promote proliferation of cells differentiated from stem cells. The Applicant argues the evidentiary references Li and Khalkhali-Ellis demonstrate Lefty is merely one of the numerous factors present in the culture and exosomes secreted by stem cells. The Applicant states exosomes contain myriad microRNAs, DNA, and other proteins capable of affecting cell viability and morphology. On the other hand, Li clearly shows that LEFTY2 was only identified and studied after numerous differentially expressed proteins between the cell culture medium derived from the Ts21 neuron co-culture with ADSCs and Ts21 neurons-only groups were quantified using LC-MS/MS and screened.
Response: While the Applicant argues LEFTY2 is not present at a level which can promote proliferation, claim 5 does not recite any amounts of TSP-1 or LEFTY2. Because the prior art anticipates the claimed medium and method step, it would promote proliferation of cells differentiated from stem cells under the principles of inherency.
The Applicant argues the exosomes secreted by MSCs contain factors in addition to LEFTY. Claim 5 does not exclude any additional components from the claimed culture medium. Yu explicitly teaches TSP-1 is secreted by said stem cells into the culture medium. As evidenced by Li et al., said stem cells secrete exosomes containing LEFTY2. Therefore the claim is anticipated.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1 and 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al. in view of Li et al. (previously cited; Synergistic Protection of N-Acetylcysteine and Ascorbic Acid 2-Phosphate on Human Mesenchymal Stem cells Against Mitoptosis, Necroptosis and Apoptosis. Sci Rep 5, 9819 (2015) as evidenced by Li et al. (The Therapeutic Potential of ADSC-Secreted LEFTY2 in Treating Alzheimer’s Disease. J. Mol. Sci, 2025, 26, 3382 pages 1-20).
Regarding independent claim 1: The teachings of Yu as set forth above are reiterated. Yu cultures mesenchymal stem cells. The stem cells secrete factors that promote neural recovery and survival (page 2, left column, first paragraph). TSP-1 is secreted by said stem cells into the culture medium (supra). As evidenced by the post-filing reference Li et al., mesenchymal stem cells secrete exosomes containing LEFTY2 (supra). Therefore TSP-1 and LEFTY would be present in the culture medium because they are secreted by said stem cells.
While Yu teaches cells are cultured in complete media, the art is silent regarding the components of the media.
Li teaches culturing MSCs with NAC and vitamin C to prevent cell death due to oxidative stress (see page 10, right column “Cell Treatment” section; see page 7, first paragraph of Discussion section).
It would have been obvious to culture MSCs in a medium comprising NAC and vitamin C . One would have been motivated to use these components to prevent cell death, as taught by Li. One would have had a reasonable expectation of success since Li teaches MSCs can be cultured with NAC and vitamin C. One would have expected similar results since each of the references is directed to MSC culture. Because the claimed method is rendered obvious, it would be expected to promote proliferation and expression of pluripotency factors of stem cells as recited in claim 1. Claim 1 is rendered obvious.
Yu teaches mesenchymal stem cells (supra). Therefore claim 3 is rejected.
Claim 4 recites the factors promoted by the culturing step recited in the base claim. Because the claimed method is rendered obvious, it would be expected to promote expression of the pluripotency factors recited in claim 4. Claim 4 is rejected.
Therefore Applicant’s invention is rendered obvious as claimed.
Claims 1 and 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over Belotti et al. (previously cited; Thrombospondin-1 promotes mesenchymal stromal cell functions via TGFβ and in cooperation with PDGF. Matrix Biol. (2016) 55, 106-116) in view of Li et al. (Synergistic Protection of N-Acetylcysteine and Ascorbic Acid 2-Phosphate on Human Mesenchymal Stem cells Against Mitoptosis, Necroptosis and Apoptosis. Sci Rep 5, 9819 (2015)) as evidenced by Li et al. (supra).
Belotti cultures mesenchymal stem cells (MSCs) in thrombospondin-1 (TSP-1). The art teaches it induces proliferation in cultured (Abstract; page 107, right column, fourth paragraph; see Figure 1A; see Figure 2A). As evidenced by the post-filing reference Li et al., mesenchymal stem cells secrete exosomes containing LEFTY2 (see page 13, third paragraph; see Figure 2C). Therefore LEFTY2 would also be present in the culture medium because it is secreted by mesenchymal stem cells.
Belotti does not teach the medium contains acetylcysteine and vitamin C.
Li teaches culturing MSCs with NAC and vitamin C to prevent cell death and injury due to oxidative stress (see page 10, right column “Cell Treatment” section; see page 7, first paragraph of Discussion section).
It would have been obvious to use a medium comprising NAC and vitamin C to culture MSCs. One would have been motivated to use these components to prevent cell death, as taught by Li. One would have had a reasonable expectation of success since Li teaches MSCs can be cultured with NAC and vitamin C. One would have expected similar results since each of the references is directed to MSC culture. Because the claimed method is rendered obvious, it would be expected to promote proliferation and expression of pluripotency factors. Therefore claim 1 is rendered obvious.
Belotti teaches mesenchymal stem cells (supra). Therefore claim 3 is included in this rejection. Because the claimed method is rendered obvious, it would be expected to promote expression of the pluripotency factors recited in claim 4.
Therefore Applicant’s Invention is rendered obvious as claimed.
RESPONSE TO APPLICANT’S ARGUMENTS
The arguments made in the response filed on 20 April 2026 are acknowledged.
Argument 1: The arguments state Belotti is silent regarding the presence of LEFTY2, acetylcysteine and vitamin C. The Applicant argues Belotti does not each the effect of the cell culture medium. The arguments state Belotti neither teaches nor suggests that the claimed cell culture medium promotes stem cells proliferation while maintaining their stem cell characteristics and increasing their exosomes secretion.
Response: Belotti cultures MSCs in a medium comprising TSP-1. As evidenced by Li et al., said cells secrete LEFTY2 in culture medium. Belotti explicitly teaches cell proliferation is increased. The claims do not require increasing exosome secretion. The claims do not recite maintaining stem cell characteristics. Therefore this argument is not commensurate with the scope of claim 1.
The rejection acknowledges Belotti does not teach culturing in a medium comprising acetylcysteine and vitamin C. Li is relied upon because it teaches acetylcysteine and vitamin C have a cytoprotective effect. The arguments are not persuasive.
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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