DETAILED ACTION
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 .
This action is in response to the papers filed 12/23/2025.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/23/2025 has been entered.
No new claims have been added, claim 1 has been amended, and no claims have been canceled as set forth in the claim set filed 12/23/2025.
Therefore, claims 1, 2, 6 and 10-17 are pending in the application and examined on the merits.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/JP2017/028328 filed August 03, 2017.
Applicant’s claim for the benefit of a prior-filed foreign Japanese applications 2016-153264 filed August 03, 2016 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is August 03, 2016.
Response to arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim objections
The objection of Claim 1 is withdrawn due to the amendments made to claim 1 of the claim set filed 12/23/2025 which define each acronym within the claim.
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claims 1-2, 6, 10, and 15-17 remain rejected and claims 11-14 are newly rejected under 35 U.S.C. 103 as being unpatentable over Young (WO2014100806A1; of record) in view of Lu (EXPERIMENTAL AND THERAPEUTIC MEDICINE 10: 2131-2137, 2015; of record), and Kinoshita (STEM CELLS TRANSLATIONAL MEDICINE 2015;4:146–155).
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 12/23/2025.
Regarding claim 1 and 11, Young teaches muse cells which are pluripotent stem cells which are positive for cell markers CD105 and SSEA-3 which are isolated from mesenchymal tissue or cultured mesenchymal cells (p. 3-4, multi-lineage stress enduring (Muse) Cells. Young further teaches that the pluripotent cells have properties such as low or absent telomerase activity, ability to differentiate into embryonic endoderm, ectoderm, and mesoderm germ layers, absence of neoplastic proliferation; and ability to self-renew (p. 3-4, Muse Cells). Additionally, Young further teaches said cells are CD34-negative, CD117-negative, CD146-negative, CD271-negative, NG2-negative, vWF-negative, Sox10-negative, Snail-negative, Slug-negative, Tyrp1-negative and Dct-negative (p. 3-4, Muse Cells). Young discloses that when the morphology of cells was examined in Example 3 resembled those of fibroblasts (page 22, lines 19-28). These cells are administered via intravenous injection into a living body wherein the pluripotent stem cells are capable of surviving and differentiating into organs (p. 12, 2nd to last paragraph). Young discloses that these cells can be utilized to treat conditions and disorders such as those of the lung (p. 13, last paragraph ). Young teaches that there are about 30% or more MUSE cells in the MUSE cell fraction/ population and that can be about 66% enrichment of SSEA3+ MUSE cells in the expanded population (p. 14, 1-8). Furthermore, Young teaches that in order to increase the yield and the percentages of MUSE cells, conditions can be optimized by repeating the culture steps (p. 2, lines 25-26). This is shown in Examples 2 and 3, where steps are repeated to increase the yield of MUSE cells in culture by about tenfold, from about 6% to 66% (p. 20). Young discloses that MUSE cells are limited in number, showing a need for methods for high yield production of MUSE cells (p. 1, lines 20-22).
However, Young does not teach that the Muse cells are administered in amounts between 1x104 to 1x106 cells nor that the disorder of the lung is specifically ischemia-reperfusion lung injury.
Lu teaches administering MSCs (i.e. pluripotent stem cells) from bone marrow via injection of 1x106 cells per individual intravenously to treat models of acute ischemia reperfusion lung injury (IRI ) in rats (Abstract, p. 2132, 2nd column). Lu teaches that the administration of MSCs results in a significant preservation of the arterial oxygen pressure (PaO2)/fraction of inspired oxygen (FiO2) (Figure 3) as well as reduction in tissue damage (p. 2137, last paragraph), this is interpreted as an improvement from the subjects which were not administered MSCs. Lu states that the results suggest that BMSC (Bone marrow mesenchymal stem cells) infusion exerts protective effects against pulmonary IRI by alleviating inflammation and that the findings provide experimental evidence for the treatment of pulmonary IRI using BMSC cell therapy (Abstract, p. 2137, last paragraph). Lu further discloses Ischemia-reperfusion injury (IRI) following lung transplantation is the main concern of the paper (Abstract).
Based on such teachings, it would have been obvious to one of ordinary skill in the art to utilize the MUSE cells of Young isolated from mesenchymal tissue or cultured mesenchymal cells in the method of Lu with a reasonable expectation of success and observe an improvement in at least one pulmonary function such as P/F ratio in a subject of ischemia reperfusion injury when administered. As taught by Lu, BMSC administration to individuals with pulmonary IRI results in improvement the P/F ratio than that of those without said administration and (Figure 3). Young teaches that the MUSE cells isolated from mesenchymal tissue can be used for treating inflammation and disorders of the lung (p. 13, last paragraph). Furthermore, Lu teaches that MSCs suppress inflammatory responses in IRI (Abstract, p. 2135, 2nd column). Therefore, an artisan would be motivated to utilize the MUSE cells isolated from mesenchymal tissue for a treatment of IRI resulting in the improvement of at least one pulmonary function as Lu teaches MSCs suppresses pulmonary inflammation and preserves lung functions (Figure 3, Abstract, p. 2135, 2nd column).
The combined teachings of Young and Lu do not explicitly teach MUSE cells administered within the range of 1x104 to 1x106 cells.
Kinoshita teaches isolating a Muse population of cells via applying a cell solution containing said Muse cells twice in a magnetic column at a very slow speed to obtain a “muse-rich” population from adipose tissue (p. 147, 2nd column). This muse-rich population contains 77.1% +/- 14.35% cells positive for SSEA3+ (p. 150, 2nd column). The muse-poor population contained 1.20% +/- 0.6% SSEA3+ cells (p. 150, 2nd column). Kinoshita further states that the MUSE cells can be achieved in large amounts with minimal morbidity and could be a practical tool for a variety of stem cell-depleted or ischemic conditions of various organs and tissues (Abstract).
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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Based on the teachings of Kinoshita, it would have been obvious to one of ordinary skill in the art to routinely optimize the culturing parameters of Young in order to obtain 70% or more MUSE cells in the cell fraction with a reasonable expectation of success. In doing so, it is filling the need described by Young, to have methods of high yield production of MUSE cells and avoiding expensive costs of utilizing other means such as magnetic nanobeads and columns (p. 1, lines 20-22; p. 7, lines 1-6, p. 11, lines 12-18). Although the method of Kinoshita involves nanobeads and columns, it demonstrates a desire to use and make a population comprising 70% or more SSEA3+ MUSE cells to be utilized in cell therapy. In light of Kinoshita’s teachings, it would be obvious to optimize Lu’s 1 x 106 BM-MSC administered to have 70% MUSE cells, this would result in 7 x 105 MUSE cells administered which is within the range of the claimed 1x104 to 1x106 cells.
Furthermore, regarding the limitation of the pluripotent stem cells migrate and engraft in lung tissues having ischemia-reperfusion induced lung injury, this is an inherent property of the MUSE cells themselves.
Regarding claim 2, the combined references of Young, Lu, and Kinoshita make obvious claim 1. Moreover, Young teaches that the pluripotent stem cells positive for SSEA-3 have been concentrated by external stress stimulation (p. 10, lines 25-30; p. 3, Muse Cells).
Regarding claim 6, the combined references of Young, Lu, and Kinoshita make obvious claim 1. Young teaches that said cells are CD34-negative, CD117-negative, CD146-negative, CD271-negative, NG2-negative, vWF-negative, Sox10-negative, Snail-negative, Slug-negative, Tyrp1-negative and Dct-negative (p. 4, 3rd paragraph).
Regarding claim 10, the combined references of Young, Lu, and Kinoshita make obvious claim 1. Young teaches that the pluripotent stem cells are obtained from cultured mesenchymal stem cells (Claim 1).
Regarding claims 12-14, the combined references of Young, Lu, and Kinoshita make obvious claim 1. Moreover, Lu teaches the rats utilized with their 106 cells are 250-275 g (p. 2132, 1st column). Therefore the dosage of cells/kg that Lu utilizes is 106/275g (or 3.6 x 106 cells/kg) to 106/250g (or 4 x 106 cells per kg) rat. When taking into account the 7 x 105 cells made obvious by the combination of references and the calculations of Lu, 7 x 105/275g (or 1.9 x 105 cells/kg) to 7 x 105/250g (or 1.7 x 105 cells per kg) rat. This is within the claimed range of 105 cells/kg to 106 cells/kg
Regarding claim 15-17, the combined references of Young, Lu, and Kinoshita make obvious claim 1. Young teaches that the external stress is being trypsin exposed (p. 8, lines 10-30).
The invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
In response to the 103 rejections of claims 1, 2, 6, and 10-17 over the combination of Young, Lu, and Kinoshita,
Applicant's arguments filed 12/23/2025 regarding the 103 rejection previously set forth have been considered, however they are not persuasive.
First, Applicant restates the deficiencies of Young already acknowledged in the 103 rejection which form the basis of the 103 rejection. This does not provide an argument, and merely restates Examiner’s own words which are then cured by the combination of references within the rejection..
Second, Applicant argues that MSCs are a mysterious cell group. Applicant argues that the reference of Denu in 2016 states that the MSCs are “completely indistinguishable from fibroblasts” (p. 6 of Remarks) and the website references show the “fibroblast-like morphology.” Applicant utilizes this argument to highlight that Muse cells have an “almost spherical shape” (p. 7 of Remarks).
The examiner acknowledges the physical differences in the MSCs obtained and Muse cells. However, as set forth in the 103 rejection, Young used as the primary reference utilizes Muse cells (p. 3-4, Muse Cells). Young discloses that SSEA-3 Muse cells are negative for the following makers: CD34-negative, CD117-negative, CD146-negative, CD271-negative, NG2-negative, vWF-negative, Sox10-negative, Snail-negative, Slug-negative, Tyrp1-negative and Dct-negative (p. 4, 3rd paragraph). These are the same makers that are required for the SSEA-3 pluripotent cells isolated from mesenchymal tissue as required in claims 1 and 6. Young teaches that “MUSE cells are stress tolerant morphologically indistinguishable from general mesenchymal cells in adhesion culture (resemble fibroblasts) page 6, lines 10-15:”[emphasis added] ). The spherical formation as demonstrated in Applicant’s remarks are from suspension cultures, whereas adherently, MUSE cells are morphologically indistinguishable from general mesenchymal cells. Young further teaches that Muse cells are known in the art to be capable of surviving and differentiating into organs upon being administered via intravenous injection (p. 12, 2nd to last paragraph). Young discloses that these cells can be utilized to treat conditions and disorders such as those of the lung (p. 13, last paragraph). Applicant highlights the physical difference between the cells of Young and Lu, but does not state the art shows that they have functionally different characteristics in terms of therapeutic effect.
Third, Applicant argues against the predictability of the combination of Young and Lu with Kinoshita. Applicant cites de Perrot and argues that Kinoshita treats a different disease and mechanism than that of Young and Lu. Applicant argues as “Lu’s treatment was performed with MSCs there was no motivation to administer Muse cells in the first place,” (Remarks p. 9). Additionally, Applicant argues that claim 1 associates the lung injury specifically with organ transplantation Moreover, Applicants argue that “is no motivation/reason to increase the concentration of Muse cells in Lu's MSCs with a reasonable expectation of success, as Muse cells are not recognized as an active ingredient in the first place.” Examiner disagrees with this line of reasoning. Kinoshita is not required to have the same disease or mechanism. Kinoshita provides prior art which demonstrates motivation for obtaining a Muse cell population which is 70% of the BM-MSCs of Lu, therefore, in light of Kinoshita’s teachings, it would be obvious to optimize Lu’s 1 x 106 BM-MSC administered to have 70% MUSE cells, this would result in 7 x 105 MUSE cells administered which is within the range of the claimed 1x104 to 1x106 cells regardless of if the main intention of Lu is to use the BM-MSC or Muse cell population, this then is applied to the Muse cells of Young. This shows the ability as well as the motivation to optimize to dosages claimed. Kinoshita in combination with Lu’s teachings are overall modifying the Muse cells of Young. Furthermore, Young alone teaches that in order to increase the yield and the percentages of MUSE cells, conditions can be optimized by repeating the culture steps (p. 2, lines 25-26). This is shown in Examples 2 and 3, where steps are repeated to increase the yield of MUSE cells in culture by about tenfold, from about 6% to 66% (p. 20). Young discloses that MUSE cells are limited in number, showing a need for methods for high yield production of MUSE cells (p. 1, lines 20-22). Regarding the lung transplantation limitation, Lu further discloses Ischemia-reperfusion injury (IRI) following lung transplantation is the main concern of the paper (Abstract).
In relation to Applicants’ arguments related to a reasonable expectation of success, as Muse cells are not recognized as an active ingredient in the first place, the examiner notes that claim 1 requires intravenous administering of the cell preparation “such that the pluripotent stem cells administered migrate and engraft in lung tissues having ischemia reperfusion-induced lung injury” . The claims don't require any astounding levels of efficacy: all that is required under 103 is what KSR has told us. Young teaches that Muse cells are administered via intravenous injection into a living body wherein the pluripotent stem cells are capable of surviving and differentiating into organs and treating disorder of lung (p. 12, 2nd to last paragraph; p. 15, line 30). Lu further discloses treatment of Ischemia-reperfusion injury (IRI) following lung transplantation by administration of MSCs (i.e. pluripotent stem cells). As Muse cells are within the MSC fraction and are essentially a type of MSC administration of Muse cells should be reasonably expected to treat IRI following lung transplantation, for the same reason Lu’s MSC do.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
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/ALEXANDRA F CONNORS/ Examiner, Art Unit 1634
/MARIA G LEAVITT/ Supervisory Patent Examiner, Art Unit 1634