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 19 December 2025.
ELECTION
Applicants’ election with traverse of Group I (Claims 1-8; drawn to a method of promoting proliferation) in the reply filed on 19 December 2025 is acknowledged. The Applicant argues both Inventions would require a search for TSP-1 and LEFTY2.
In response: Burden was established in the restriction mailed on 22 October 2025. Invention I is directed to a method of increasing proliferation in cells. Invention II is directed to a stem cell derivative encompassing secretory bodies, exosomes and extracellular vesicles. The claimed method can be used to prepare stems cells that express pluripotency factors (a materially different product). The requirement is still deemed proper and is therefore made FINAL. Claim 9 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
CLAIMS UNDER EXAMINATION
Claims 1-8 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.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7-8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 7 recites “the nerve cells”. There is a lack of antecedent basis for nerve cells in claim 5. Appropriate correction is required. Claim 8 is included in this rejection because it depends from claim 7.
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.
Claims 1 and 3-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yu et al. (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. (The Therapeutic Potential of ADSC-Secreted LEFTY2 in Treating Alzheimer’s Disease. J. Mol. Sci, 2025, 26, 3382 pages 1-20) and Khalkhali-Ellis (Lefty Glycoproteins in Human Embryonic Stem Cells: Extracellular Delivery Route and Posttranslational Modification in Differentiation. Stem Cells and Development Volume 25(21) 2016 pages 1681-1690).
Yu et al. co-culture bone marrow stromal cells (i.e., mesenchymal stem cells) with retinal ganglion cells (nerve cells) (Abstract; see page 3, left column, second paragraph). The art teaches TSP-1 is secreted into the culture medium (see page 3, right column, second paragraph); see Figure 3E). Yu teaches the stem cells differentiated into neural cells (hence, nerve cells; (see page 8, left column, second paragraph).
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).
As evidenced by Khalkhali-Ellis, cited by evidentiary refence Li as reference 14, LEFTY is a secreted protein (see page 1681, right column, first paragraph). As evidenced by Khalkhali-Ellis there are two Lefty proteins: LeftyA and LeftyB in human and their homologues Lefty 1 and Lefty2 in mice (see page 1681, left column, last paragraph). As evidenced by Khalkhali-Ellis, mesenchymal stem cells secrete exosomes containing LEFTY proteins (see Figure 5; see page 1688, left column, third and fourth paragraphs; see Figure 3A-LEFTY B).
As set forth above, Yu teaches a co-culture comprising stem cells. Yu teaches TSP-1 is secreted by cells into the media. As evidenced by Li and Khalkhali-Ellis, MSCs secrete exosomes containing Lefty-2. Because the claimed method is anticipated, it would inherently promote proliferation and expression of pluripotency factors of stem cells as recited in claim 1. See MPEP 2112.02 I. Claim 1 is anticipated as claimed.
Yu teaches mesenchymal stem cells (supra). Therefore claim 3 is rejected. Because the claimed method is anticipated, it would inherently promote expression of the pluripotency factors recited in claim 4. See MPEP 2112.02 I Claim 4 is anticipated.
Regarding independent claim 5:
The teachings of Yu are reiterated. Yu teaches MSCs differentiated to neural cells (cells differentiated from stem cells). Yu teaches TSP-1 is secreted by cells into the media. As evidenced by Li and Khalkhali-Ellis, MSCs secrete exosomes containing Lefty-2. Because the claimed method is anticipated, it would inherently promote proliferation of cells differentiated from stem cells as recited in claim 5. See MPEP 2112.02 I.
Therefore claim 5 is anticipated.
The neural cells taught by Yu are interpreted to read on nerve cells. Therefore claim 6 is included in this rejection.
Because the claimed culture medium is anticipated, it would inherently reduce expression of inflamation0related factors or increase expression of anti-inflammatory factors in the nerve cells. Therefore claim 7 is rejected. Claim 8 is rejected on the same grounds as claim 7.
Therefore Applicant’s Invention is anticipated as claimed.
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.
Claims 1 and 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over Belotti et al. (Thrombospondin-1 promotes mesenchymal stromal cell functions via TGFβ and in cooperation with PDGF. Matrix Biol. (2016) 55, 106-116) in view of Clarke et al. (Compositions and methods for modulating left-right differentiation factor (lefty) and bone morphogenic factor (bmp) US20210079400).
Belotti teaches thrombospondin-1 (TSP-1) induces proliferation in cultured mesenchymal stem cells (MSCs) (Abstract; page 107, right column, fourth paragraph; see Figure 1A; see Figure 2A).
Belotti does not teach culturing MSCs in LEFTY2.
Clarke et al. teach a method of promoting or maintaining the proliferation of stem cells comprising culturing the stem cells in the presence of a LEFTY protein or an agonist of a LEFTY protein ([0015]; [0047]; [0191]; see claim 32 of Clarke). Clarke teaches reference to a LEFTY factor or protein in the disclosure includes LEFTY1 or LEFTY2, or a combination of both LEFTY1 and LEFTY2 ([0021]). The stem cells can be mesenchymal stem ([0194]).
It would have been obvious to culture MSCs in a culture media comprising TSP-1 and LEFTY2. Belotti increasing MSC proliferation by culturing with TSP-1 and Clarke teaches culturing MSCs with LEFTY2 to induce proliferation. One would be motivated to culture with both components to provide increased MSC proliferation. Applicants are referred to In re Kerkoven (205 USPQ 1069) in which it was shown to be prima facia obvious to combine two compositions, each of which is taught by the prior art to be used for that very same purpose. Therefore, then, barring unexpected results, one would reasonably expect enhanced, additive, or synergistic activity to be observed by combining the compositions or materials. One would have had a reasonable expectation of success since the prior art teaches TSP-1 and LEFTY can induce proliferation. One would have expected similar results both references are directed to inducing proliferation in MSCs. Therefore claim 1 is rendered obvious. Belotti and Clarke teach 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.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Belotti in view of Clark as applied to claim 1 above, and further 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)).
Claim 1 is rejected on the grounds set forth . The teachings of the prior art are reiterated. Belotti and Clark teach culturing MSCs in a cell culture medium. The references do not teach the medium contains acetylcysteine and vitamin C.
Li teaches culturing MSCs with NAC and vitamin C to prevent cell death and injury of tissues 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. Therefore claim 2 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
Conclusion
No claims are allowed.
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) 270-8439.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NATALIE M MOSS/ Examiner, Art Unit 1653