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 .
Election/Restrictions
Applicant’s election without traverse of Group III (Claims 1-3, 7, and 10; drawn to a process of administering a composition to the liver) in the reply filed on September 4, 2025, is acknowledged.
Claims 4-6 and 8-9 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups II, IV, and V), there being no allowable generic or linking claim.
DETAILED ACTION
The amended claims filed on January 13, 2026, have been acknowledged. Claim 11 was cancelled. Claim 1 was amended. In light of the Applicant’s elected invention, claims 4-6 and 8-9 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-3, 7, and 10 are pending and examined on the merits.
Priority
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d).The applicant claims foreign priority from TW109115466 filed on May 8, 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received December 30, 2022. While a certified copy of the foreign patent application TW109115466 is provided with the instant application, a certified English translation of said foreign patent application has not been provided.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claims 1-3, 7, and 10-11 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of Applicant’s amendments to the claims to recite “the composition comprises stem cells and mitochondria located outside of the stem cells”.
Withdrawn Claim Rejections - 35 USC § 102
The prior rejection of claims 1, 3, 7, and 10 under 35 U.S.C. 102(a)(1) as being anticipated by Lin et al. (Shock 39: 304-310. 2013), as evidenced by Huang et al. (Cell Transplantation 25: 913-927. 2016) and Uwaifo et al. (Biomed Biotechnol Res J 4:137-140. 2020) is withdrawn in light of Applicant’s amendments to claim to positively recite that the composition comprises stem cells and mitochondria outside of the stem cells.
The prior rejection of claims 1-3 under 35 U.S.C. 102(a)(1) as being anticipated by Salomone et al. (Stem Cell Research 11: 1037–1044. 2013) is withdrawn in light of Applicant’s amendments to claim to positively recite that the composition comprises stem cells and mitochondria outside of the stem cells.
The prior rejection of claims 1 and 3 under 35 U.S.C. 102(a)(1) as being anticipated by Shi et al. (Translational Medicine 196: 31-40. 2018) is withdrawn in light of Applicant’s amendments to claim to positively recite that the composition comprises stem cells and mitochondria outside of the stem cells.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 1 and 11 under 35 U.S.C. 103 as being unpatentable over Salomone et al. (Stem Cell Research 11: 1037–1044. 2013) as applied to claim 1 above, and further in view of Shi et al. (Translational Medicine 196: 31-40. 2018), as evidenced by Huang et al. (Cell Transplantation 25: 913-927. 2016) is withdrawn in light of Applicant’s amendments to claim 1 to recite a specific ratio of the mitochondria to the stem cells.
New 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 1-3, 7, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Lin et al. (Shock 39: 304-310. 2013) and further in view of United States Patent Application No. 20100119490 (Yoon) and Mahrouf-Yorgov et al. (Cell Death and Differentiation 24: 1224–1238. 2017), as evidenced by Huang et al. (Cell Transplantation 25: 913-927. 2016) and Uwaifo et al. (Biomed Biotechnol Res J 4:137-140. 2020). This is a new rejection made in response to Applicant’s amendments to claim. Any aspect of Applicant’s traversal that is relevant to the new rejection is addressed below.
Regarding claim 1, Lin teaches a method of intrasplenic administration of isolated mitochondria from Wistar rat liver (7.7 x 106 ± 1.5 x 106; i.e. exogenous mitochondria) to Wistar rats with partial liver ischemia-reperfusion (I/R) (i.e. liver damage). An intrasplenic infusion of viable mitochondria isolated from the donor before reperfusion significantly reduced I/R injury in the liver (abstract, page 304, column 2, paragraph 2-page 308, column 2, paragraph 1).
Lin does not teach administering the exogenous mitochondria with stem cells.
However, Yoon teaches a method for regenerating a tissue after reperfusion injury in a subject in need thereof, the method involves administering to the subject a CD31+ cell, such as a mesenchymal stem cells, increasing secretion of a paracrine factor or cytokine in a tissue of the subject, thereby repairing or regenerating the tissue. Yoon teaches that the reperfusion injury can occur in the liver (paragraphs 0007, 0027-0030, 0043, 0053, 0156-0160, and 0172 and claims 1-7).
Mahrouf-Yorgov teaches that mesenchymal stem cells (MSCs) protect tissues against cell death induced by ischemia/reperfusion insults. This therapeutic effect seems to be controlled by physiological cues released by the local microenvironment following injury. Recent lines of evidence indicate that MSC can communicate with their microenvironment through bidirectional exchanges of mitochondria. In particular, in vitro and in vivo studies report that MSCs rescue injured cells through delivery of their own mitochondria. By using a co-culture system consisting of MSC and distressed somatic cells such as cardiomyocytes or endothelial cells, they showed that mitochondria from suffering cells acted as danger-signaling organelles that triggered the anti-apoptotic function of MSC. They demonstrated that foreign somatic-derived mitochondria were engulfed and degraded by MSC, leading to induction of the cytoprotective enzyme heme oxygenase-1 (HO-1) and stimulation of mitochondrial biogenesis. As a result, the capacity of MSC to donate their mitochondria to injured cells to combat oxidative stress injury was enhanced. They found that similar mechanisms – activation of autophagy, HO-1 and mitochondrial biogenesis – occurred after exposure of MSC to exogenous mitochondria isolated from somatic cells, strengthening the idea that somatic mitochondria alert MSC of a danger situation and subsequently promote an adaptive reparative response (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the method of administering mitochondria to treat reperfusion injury of the liver of Lin with the method of delivering stem cells to treat reperfusion injury of Yoon to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to combine with a reasonable expectation of success because Lin and Yoon show that their methods are beneficial for treating reperfusion injury in the liver. Furthermore, Mahrouf-Yorgov teaches that foreign exogenous somatic mitochondria alert MSC of a danger situation and subsequently promote an enhanced adaptive reparative response from the MSCs for treating ischemia/reperfusion insults though induction of the cytoprotective enzyme heme oxygenase-1 (HO-1) and stimulation of mitochondrial biogenesis. Therefore, it would have been obvious to combine the administration of mitochondria and stem cells to improve the efficacy of the treatment of reperfusion injury of the liver. Furthermore, MPEP 2144.06 states "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).
Regarding the ratio of the mitochondria to the stem cells, Huang evidences that they isolated mitochondria from BHK-21 cells and that 75 μg mitochondria corresponded to 1.2 x 106 mitochondria particles (page 914, column 1, paragraph 2-column 2, paragraph 3). Although Huang isolated their mitochondria from BHK-21 cells and Lin isolated their mitochondria from Wistar rat liver, both mitochondria are isolated from rodent cells and the data from Huang provides a close approximation of the weight of the mitochondria in Lin. Using the approximation of Huang, the 6.2 x 106-9.2 x 106 mitochondria would equate to ~375 μg-~600 μg of mitochondria. Yoon teaches that the quantity of cells to be administered can be between 106-108 and specifically identifies 3 x 107 stem cells as a possible dosage (paragraph 0218).
Taking these amounts into account, ~375 μg-~600 μg of mitochondria and 3 x 107 stem cells, this equates to a ratio of 1 microgram of mitochondria per 5 x 104-8 x 104 stem cells.
Regarding claim 2, Yoon, as stated supra, teaches that administration of their stem cells can regenerate the liver tissue after reperfusion injury (paragraphs 0007, 0027-0030, 0043, 0053, 0156-0160, and 0172 and claims 1-7). Therefore, administering a combination of stem cells and mitochondria would also have a regenerative effect.
Regarding claim 3, Lin teaches that a wide array of functional alterations in mitochondria develops during reperfusion injury of liver (1), including the excessive generation of reactive oxygen species (ROS) and intracellular Ca2+ overload, which result in mitochondrial permeability transition (MPT) (2) and subsequent cytochrome c release related cell death (page 304, column 1, paragraph 1). Excessive ROS generation and cell death are known to cause inflammation. Therefore, the ischemia-reperfusion injury of Lin would cause liver damage that comprises inflammation.
Regarding claims 7 and 10, Lin, as stated supra, teaches intrasplenic administration of their mitochondria. As identified above, using the approximation of Huang, the 6.2 x 106-9.2 x 106 mitochondria would equate to ~375 μg-~600 μg of mitochondria. Uwaifo evidences that Wistar rats with a body weight of ~246 grams (Lin used male Wistar rats between 200-250 grams (page 304, column 2, paragraph 2)) had a liver weight of ~5 grams (Tables 2-3). This would equate to ~75-120 μg of mitochondria per gram of liver.
Response to Arguments
Applicant's arguments filed January 13, 2026, are acknowledged.
Applicant argues the experimental data in the specification (Table 3 of Experiment 2) demonstrate a synergistic effect that would not have been obvious from the cited references. Specifically, the combination of mitochondria and stem cells (Example 5: 75 g/mL mitochondria + 5 x 106 cells/mL ADSCs, yielding a weight-to-number ratio of 1 μg: 6.7x104 cells) produced superior improvements in liver function indices (GOT, GPT, albumin, prothrombin time, and total bilirubin) compared to Example 3 (75 pg/mL mitochondria alone), Example 4 (200 pg/mL mitochondria alone), or stem cells alone. Notably, the combination of mitochondria and stem cells (Example 5) outperforms even the higher mitochondrial dose of 200 g/mL (Example 4), demonstrating an unexpected synergistic effect that a person skilled in the art could not predict from the cited references (page 5, paragraph 4).
Applicant's arguments have been fully considered but they are not persuasive.
Although Applicant argues unexpected results, the claims are not commensurate in scope with the experimental results cited by the Applicant. MPEP 716.02(d) discloses that whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100°C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110°C and 130°C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60°C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100°C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
Regarding the claims at issue in the instant application, claim 1 encompasses performing the method with mitochondria from any cell type, any kind of stem cell, repairing any type of liver damage in any subject, and with a range of ratios of mitochondria to stem cells while the data cited by the Applicant identifies a single ratio of mitochondria to stem cells (Example 5: 75 g/mL mitochondria from human adipose derived stem cells (ADSCs) + 5 x 106 cells/mL human ADSCs, yielding a weight-to-number ratio of 1 μg: 6.7x104 cells) to treat liver damage/liver fibrosis caused by thioacetamide in rats (paragraphs 0024-0025 and Example 2). It is not clear that other ratios of mitochondria to stem cells would have a synergistic effect. Furthermore, it is not clear whether other combinations of mitochondria and stem cell sources and other types of liver damage in other subjects would have the same affect. Furthermore, although Applicant argues that the combination of mitochondria and stem cells (Example 5) outperforms even the higher mitochondrial dose of 200 μg/mL, the results between the two groups significantly overlap and do not appear statistically significant as the mean of both embodiments are well within the standard deviations of each group and each indices.
As such, the claims as written are not commensurate in scope with alleged unexpected results.
Additionally, it is not clear that these results would be unexpected as Mahrouf-Yorgov already identifies that incubating MSCs with foreign exogenous somatic mitochondria alert MSC of a danger situation and subsequently promote an enhanced adaptive reparative response from the MSCs for treating ischemia/reperfusion insults though induction of the cytoprotective enzyme heme oxygenase-1 (HO-1) and stimulation of mitochondrial biogenesis. As such, it was already known that incubating exogenous mitochondria and MSCs together would enhance the reparative properties of the MSCs. Therefore, it would have been expected that administering exogenous mitochondria and MSCs together would improve therapeutic efficacy for treating liver damage.
Note that unexpected results must be “really unexpected” in view of the prior art. “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.” (emphasis added). See MPEP §716.02.
In view of the foregoing, applicant’s arguments pertaining to unexpected results are not found persuasive.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEENAN A BATES whose telephone number is (571)270-0727. The examiner can normally be reached M-F 7:30-5:00.
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/KEENAN A BATES/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631