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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April 13, 2026, has been entered.
DETAILED ACTION
The amended claims filed on April 13, 2026, have been acknowledged. Claims 4-6 and 8-9 were cancelled. Claim 1 was amended. Claims 1-3, 7, and 10 are pending and examined on the merits.
Notice of Non-responsive Amendment
The reply filed on April 13, 2026, is not fully responsive to the prior Office Action because of the following omission(s) or matter(s): the claims are not considered to be in compliance with 37 CFR § 1.121, recited here:
§ 1.121(c) Manner of making amendments in applications.
Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
(1) Claim listing. All of the claims presented in a claim listing shall be presented in ascending numerical order. Consecutive claims having the same status of "canceled" or "not entered" may be aggregated into one statement (e.g., Claims 1–5 (canceled)). The claim listing shall commence on a separate sheet of the amendment document and the sheet(s) that contain the text of any part of the claims shall not contain any other part of the amendment.
(c)(2) When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of “currently amended,” and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of “currently amended,” or “withdrawn” if also being amended, shall include markings. If a withdrawn claim is currently amended, its status in the claim listing may be identified as “withdrawn— currently amended.”
The claim amendment submitted April 13, 2026, does not list claim 11 which was a previously cancelled claim in the claims set from January 13, 2026 and does not list claim 12 which was a previously presented claim in the claim set from November 8, 2022. While it would be appropriate to reject entry of the present amendment for noncompliance with 37 CFR § 1.121, applicant is instead respectfully reminded to properly note the status of each and all claims previously presented in order to avoid the issuance of a Notice of Non-Compliant Amendment, which would delay prosecution and potentially have an adverse effect on any patent term adjustment should the claims proceed to issue.
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.
New 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 1-3, 7, and 10 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 1 recites the term “the composition comprises human adipose derived stem cells and mitochondria located outside of the human adipose derived stem cells, the mitochondria extracted from the human adipose derived stem cells”. It is not clear how the composition can comprise the human adipose derived stem cells and mitochondria extracted from the same human adipose derived stem cells. As identified in the specification, mitochondria extraction requires homogenization of the adipose derived stem cells. Therefore, the process of extracting the mitochondria requires destroying the adipose derived stem cells. As such, it is unclear how the same adipose derived stem cells can generate extracted mitochondria while remaining in the composition considering the method of extraction destroys the cells. Based on Applicant’s own extraction method, this suggests a different set of adipose derived stem cells are used to extract the mitochondria than the adipose derived stem cells that are in the composition with the extracted mitochondria.
Claims 2-3, 7, and 10 are also rejected because of their dependency on claim 1.
Claim 2 recites the limitation "said repairing liver damage" in line 1 and claim 3 recites “said liver damage” in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 1 recites repairing liver fibrosis and not liver damage. Therefore, it is unclear whether said liver damage refers to liver fibrosis or some other liver damage.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 3 is dependent on claim 1 which recites that the method is for repairing liver fibrosis. Claim 3, recites liver fibrosis as one option for the type of liver damage but also includes other alternative forms of liver damage that are not liver fibrosis. Therefore, claim 3 either fails to further limit if the liver damage is fibrosis or fails to include all the limitations of the claim upon which it depends if the liver damage is any other type of liver damage and not liver fibrosis.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 1-3, 7, and 10 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) is withdrawn in light of Applicant’s amendments to claim 1 to recite a method of repairing liver fibrosis using human adipose derived 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 are rejected under 35 U.S.C. 103 as being unpatentable over Ko et al. (J Cell Mol Med. 24:10088–10099. 2020), United States Patent Application No. 20160206661 (Fraser), Harn et al. (Cell Transplantation 21: 2753–2764. 2012), Konari et al. (Scientific Reports 9: 1-14. 2019), and Romanov et al. (Cell Technologies in Biology and Medicine 3: 138-143. 2005). This is a new rejection made in response to Applicant’s amendments to claim. Applicant’s traversal has been considered but is moot in response to the new rejection of record.
Regarding claims 1 and 3, Ko teaches a method of treating acute liver ischemia-reperfusion injury by administering 10 mg of melatonin-pretreated allogeneic mitochondria isolated from the liver of donor rats to protect the liver. Figure 4 shows that mitochondria administration limited the development of liver fibrosis but did not prevent fibrosis from occurring. Ko found that melatonin-pretreated mitochondrial therapy effectively protects the liver from acute IRI mainly through inhibiting the generation of oxidative stress, inflammation, apoptosis, fibrosis and DNA damage (whole document).
Ko does not teach co-administering adipose derived stem cells to treat liver fibrosis.
However, Fraser teaches a method of treating liver fibrosis resulting from ischemia-reperfusion injury comprising administering autologous adipose derived stem cells. Fraser teaches that around 1 x 108 to 1 x 109 adipose derived stem cells can be administered to the patient to treat fibrosis (paragraphs 0087, 0147-0149, 0164-0169, and 0195).
Harn teaches a method of treating liver fibrosis comprising administering 1 x 106 adipose derived stem cells in normal saline and injected into the liver of the subject. Harn teaches that following ADSC transplantation, the high blood levels of GOT and GPT associated with induction of liver fibrosis decreased to near-normal values 7 days after ADSC transplantation and continued to drop at days 14 and 28 post transplantation. Furthermore, ADSC transplantation led to reduced fibrosis scores. The biochemical liver function index revealed that transplantation of human ADSCs led to the regeneration of hepatocyte-like cells, the production of albumin, a recovery of prothrombin time, a decrease in bilirubin, and a general restoration of liver function (page 2754, column 1, paragraph 1-page 2755, column 1, paragraph 4, page 2756, column 1, paragraph 4-page 2759, column 1, paragraph 2, and Tables 3-4).
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 and limit the development of liver fibrosis of Ko with the method of delivering adipose derived stem cells to treat liver fibrosis caused by reperfusion injury of Fraser 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 Ko and Fraser are both interested in treating reperfusion injury and limiting/treating liver fibrosis after reperfusion injury. Furthermore, Ko (administering exogenous mitochondria) and Harn (administering ADSCs) show that their methods are beneficial for treating and limiting the development of fibrosis in the liver and Harn identifies that administering ADSCs led to the regeneration of hepatocyte-like cells, the production of albumin, a recovery of prothrombin time, a decrease in bilirubin, and a general restoration of liver function. 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 as exogenous mitochondria help limit the development of fibrosis after reperfusion injury (i.e. short term benefits), but does not fully prevent fibrosis development, and adipose derived stem cells show a regenerative affect after fibrosis development that led to the regeneration of hepatocyte-like cells, the production of albumin, a recovery of prothrombin time, a decrease in bilirubin, and a general restoration of liver function (i.e. long term benefits). 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). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the ratio of the mitochondria to the stem cells, as stated supra, Ko administers 10 mg of mitochondria and Fraser teaches that between 1 x 108 to 1 x 109 adipose derived stem cells can be administered. This range encompasses 6.7 x 108 stem cells. This equates to a ratio of 1 microgram of mitochondria per 6.7 x104 adipose derived stem cells. MPEP 2144.05(I) states that in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See also In re Bergen, 120 F.2d 329, 332, 49 USPQ 749, 751-52 (CCPA 1941) (The court found that the overlapping endpoint of the prior art and claimed range was sufficient to support an obviousness rejection, particularly when there was no showing of criticality of the claimed range). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the mitochondria being extracted from human adipose derived stem cells, Ko does not teach this as they extract their mitochondria from liver cells.
However, Konari teaches that mitochondria can be extracted from bone marrow mesenchymal stem cells and that these isolated mitochondria enhanced the expression of mitochondrial superoxide dismutase 2 and Bcl-2 expression and inhibited reactive oxygen species (ROS) production in vitro. Moreover, isolated Mt directly injected under the renal capsule of STZ rats improved the cellular morphology of STZ-PTECs, and the structure of the tubular basement membrane and brush border in vivo (abstract and page 9, paragraph 1-page 10, paragraph 2).
Romanov teaches that stem cells from adipose tissue are more easily isolated than bone marrow MSCs and exhibit similar characteristics (whole document).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have extracted mitochondria from adipose derived mesenchymal stem cells instead of liver cells to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to extract mitochondria from adipose derived mesenchymal stem cells instead of liver cells with a reasonable expectation of success because Konari teaches that mitochondria can be extracted from mesenchymal stem cells to counteract and inhibit oxidative stress, inflammation, and DNA damage which was also shown by Ko. Furthermore, it is significantly easier to isolate mitochondria from adipose derived stem cells using lipoaspirate than from liver cells (used by Ko) and bone marrow mesenchymal stem cells (used by Konari) for allogeneic or autologous administration of the mitochondria. Isolating mitochondria from liver cells requires resection of the liver and isolation of bone marrow derived stem cells is known to have technological and medical difficulties, as identified by Romanov, that are not associated with lipoaspirate. Therefore, isolating mitochondria from adipose derived stem cells represents a simpler procedure that allows for a higher yield of adipose derived stem cells and can be readily adjusted based on the availability of autologous and allogeneic adipose derived stem cells that would not be as easily reproducible with bone marrow stem cells and liver cells considering the increased difficulty of isolating these cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the use of saline for direct injection, Harn, as stated supra, specifically identifies that they placed their adipose derived stem cells in a saline solution before injecting the cells into the liver (page 2754, column 1, paragraph 1-page 2755, column 1, paragraph 4) and although Ko does not specifically state that their mitochondria are in a saline solution before injection, the controls infuse saline. Therefore, it would be reasonable to conclude that the mitochondria are also in saline to match the control group. As such, it would have been well understood that the mitochondria and adipose derived stem cells could be in a saline solution for injection.
Regarding claim 2, Harn, as stated supra, teaches that administration of adipose derived stem cells reduces GOT index, GPT index, and regenerative effect (paragraph 4, page 2756, column 1, paragraph 4-page 2759, column 1, paragraph 2, and Tables 3-4).
Claims 1, 7, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Ko et al. (J Cell Mol Med. 24:10088–10099. 2020), United States Patent Application No. 20160206661 (Fraser), Harn et al. (Cell Transplantation 21: 2753–2764. 2012), Konari et al. (Scientific Reports 9: 1-14. 2019), and Romanov et al. (Cell Technologies in Biology and Medicine 3: 138-143. 2005) as applied to claim 1 above and further in view of 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). This is a new rejection made in response to Applicant’s amendments to claim. Applicant’s traversal has been considered but is moot in response to the new rejection of record.
The teachings of Ko, Fraser, Harn, Konari, and Romanov are as discussed above.
The combined teachings of Ko, Fraser, Harn, Konari, and Romanov do not teach using mitochondria at a ratio of 0.5 micrograms to 1000 micrograms per gram of liver nor wherein the weight of the mitochondria is 1 microgram to 1000 micrograms.
However, Lin teaches a method of intrasplenic administration of isolated mitochondria from Wistar rat liver (7.7 x 106 ± 1.5 x 106) to Wistar rats with partial liver ischemia-reperfusion (I/R). 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, and Figures 1-7).
As can be seen in Lin and Ko, both reduce ALT levels after reperfusion injury (Figure 3 and 1, respectively), both reduce liver injury score (Figure 4 of both), and both reduce cytochrome-c levels (Figure 6 and 3, respectively). Therefore, although Ko used 10 mg of isolated mitochondria, Lin shows that 7.7 x 106 ± 1.5 x 106 mitochondria is an effective amount for treating reperfusion injury. Therefore, it would have been obvious that 7.7 x 106 ± 1.5 x 106 mitochondria could have also been used instead of the 10 mg of mitochondria used by Ko.
Ko teaches administering 10 mg of mitochondria through portal vein injection in rats (page 10090, column 1, paragraph 3), Harn teaches administering their adipose derived stem cells through liver injection in Wistar rats (page 2754, column 1, paragraph 1-page 2755, column 1, paragraph 4), and Lin teaches intrasplenic administration of their mitochondria (page 304, column 2, paragraph 2-page 308, column 2, paragraph 1). 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 of Lin 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) and Harn used Wistar rats) had a liver weight of ~5 grams (Tables 2-3). This would equate to ~75-120 μg of mitochondria per gram of liver.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631
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