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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed 05/06/2026.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/06/2026 has been entered.
Claims 1 , 11 and 12 have been amended, no claims have been canceled and no claims are newly added as set forth in the claim set filed 04/01/2026. Claims 1 and 11 are independent.
Therefore, claims 1, 11 and 12 are pending and have been considered on the merits.
Priority
This application is a 371 of PCT/JP2017/024246 filed 06/30/2017 which claims a foreign priority to JP2016-132075 filed 07/01/2016.
Therefore, the earliest possible priority date for the instant application is July 1, 2016.
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112
The rejection of claims 1, 11 and 12 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second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter is withdrawn.
Applicant’s arguments and amendments filed 04/01/2026 have been considered and are persuasive in light of the amendments made to specify the limitations which occur after the time of treatment.
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claim 1 remains rejected under 35 U.S.C. 103 as being unpatentable over Kaneko et al. (March 2015. Research Project for Control Measures for Hepatitis: 1-11; IDS Reference AM filed on 04/01/2019) as evidenced by Yoshida (U.S. Patent No. 9,844,570; previously cited in PTO-892) and Iseki (Cell Transplantation, Vol. 26, pp. 821–840, 2017; IDS Reference) in view of Wakao (Cells 2012, 1, 1045-1060; previously cited) and further view of Young et al. (US2013/0071357; previously cited in PTO-892).
This rejection has been modified in response to Applicant’s amendments filed 04/01/2026.
Regarding claims 1, Kaneko et al. administered Muse cells (i.e. SSEA-3+ CD105+ pluripotent stem cells obtained from mesenchymal tissue) into the tail vein (i.e. intravenously) of a mouse in a model of liver fibrosis in order to treat the organ. The study of the chronic liver fibrosis disorder demonstrated significant suppression of fibrosis (1st page of Translation).
As evidenced by Yoshida et al., Muse cells are SSEA-3 and CD-105 positive and show negative expression for CD117, CD146, NG2, CD34, vWF and CD271 (Col. 8, lines 18-44). Furthermore, Yoshida teaches the Muse cells inherently have low or absent telomerase activity, ability to differentiate into embryonic endoderm, ectoderm, and mesoderm germ layers, with absence of neoplastic proliferation; and (v) ability to self-renew (Claim 1; Col. 8, lines 45-54). These muse cells are not reprogrammed or induced pluripotent cells (i.e. created in vitro to induce pluripotency).
Regarding the limitation of regenerating the organ through lysis of fibrotic tissue, as evidenced by Iseki, Muse cells inherently produce matrix malloproteases (MMPs) which are involved in fibrolysis and/or suppression of fibrosis (p. 831, 1st column; p. 835, 2nd column). Therefore, lysis of fibrotic tissue is an inherent function of Muse cells themselves, rendering obvious treatment of fibrosis.
Wakao et al taught that some Muse cells, upon administration, were present “in the lung and spleen, but, interestingly, the majority of Muse cells integrated into damaged tissues and not into intact tissues” (p. 1053, para 4.). Muse cells naturally integrate into damaged tissues, as they are perceptive of damaged sites and contribute to tissue reconstruction via their ability to differentiate into tissue specific cells (p. 1053).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date that the Muse cells of Kaneko which treat liver fibrosis would be capable of treating disorders of damaged tissue present in organs such as the lung as taught by Wakao, with a reasonable expectation of success. An artisan would have been motivated to utilize Muse cells in damaged tissue of various organs (i.e. the lung) as Wakao teaches Muse cells naturally integrate into damaged tissues, Iseki teaches that Muse cells produce matrix malloproteases (MMPs) which are involved in fibrolysis and/or suppression of fibrosis, thus Muse cells are perceptive of damaged sites and contribute to tissue reconstruction via their ability to differentiate into tissue specific cells and cause fibrolysis via MMPs.
However, Kaneko, Wakao, Iseki and Yoshida do not teach the treatment of lung fibrosis.
Young et al. teaches administering pluripotent stem cells isolated from blood (i.e. mesenchymal tissue from a body) intravenously which have SSEA-3+ cell markers in order to treat pulmonary diseases such as Interstitial Pulmonary Fibrosis (IPF; i.e. lung fibrosis) (Abstract, para. 0017, 0064; claim 87). Young discloses that the pluripotent stem cells can be utilized to treat neuropathies, skeletal muscle injuries, disorders of the skin as well as lung conditions (para. 0064).
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to utilize the Muse cells of Kaneko, Yoshida and Wakao for the purpose of treating lung fibrosis with a reasonable expectation of success. An artisan would be motivated to do so as Young teaches SSEA-3+ pluripotent stem cells are utilized in methods of treating additional fibrotic disorders such as Interstitial Pulmonary Fibrosis.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 11 and 12 remain rejected under 35 U.S.C. 103 as being unpatentable over Kaneko et al. (March 2015. Research Project for Control Measures for Hepatitis: 1-11; IDS Reference AM filed on 04/01/2019) as evidenced by Yoshida (U.S. Patent No. 9,844,570; previously cited in PTO-892) and Iseki (Cell Transplantation, Vol. 26, pp. 821–840, 2017; IDS Reference) in view of Wakao (Cells 2012, 1, 1045-1060; previously cited)
This rejection has been necessitated by Applicant’s amendments filed 04/01/2026.
Regarding claims 11 and 12, Kaneko et al. teaches administered Muse cells (i.e. SSEA-3+ CD105+ pluripotent stem cells obtained from mesenchymal tissue) into the tail vein (i.e. intravenously) of a mouse in a model of liver fibrosis in order to treat the organ. The study of the chronic liver fibrosis disorder demonstrated significant suppression of fibrosis (1st page of Translation).
As evidenced by Yoshida et al., Muse cells are SSEA-3 and CD-105 positive and show negative expression for CD117, CD146, NG2, CD34, vWF and CD271 (Col. 8, lines 18-44). Furthermore, Yoshida teaches the Muse cells inherently have low or absent telomerase activity, ability to differentiate into embryonic endoderm, ectoderm, and mesoderm germ layers, with absence of neoplastic proliferation; and (v) ability to self-renew (Claim 1; Col. 8, lines 45-54). These muse cells are not reprogrammed or induced pluripotent cells (i.e. created in vitro to induce pluripotency).
Regarding the limitation of regenerating the organ through lysis of fibrotic tissue, as evidenced by Iseki, Muse cells inherently produce matrix malloproteases (MMPs) which are involved in fibrolysis and/or suppression of fibrosis (p. 831, 1st column; p. 835, 2nd column). Therefore, lysis of fibrotic tissue is an inherent function of Muse cells themselves.
However the combined teachings of Kaneko, Yoshida and Iseki do not teach the treatment of fibrosis utilizing pluripotent stem cells wherein the fibrosis is skin fibrosis.
Wakao teaches that MSCs comprising the Muse cells (i.e. pluripotent stem cells) naturally home to damaged sites and naturally differentiate into hepatocytes and keratinocytes or epidermal cells, integrating and contributing to tissue repair (p. 1046, 2nd-3rd paragraphs). Wakao further teaches that upon administration, the cells naturally home to damaged sites (i.e. sites of fibrosis) and can integrate as functional cells into damaged tissue and differentiate into endodermal or ectodermal according to the site of integration (p. 1053, Tissue Repairing Function of Muse Cells). This is particularly reduced to practice in the animal model of Figure 4 wherein the Muse cells are administered via tail vein (i.e. intravenous administration) for internal disorders and locally for skin injury models.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to have modified the method taught by Kaneko, Yoshida and Iseki with the method of Wakao al to arrive at the instantly claimed method with a reasonable expectation of success. The ordinary artisan would have been motivated to make the modification because said modification would have resulted in a method having the added advantage of treating skin fibrosis or skin injury as explicitly taught by Wakao. In addition, it would have been obvious to the ordinary artisan that the known techniques of Wakao et al could have been applied to the method of Kaneko, Yoshida and Iseki et al with predictable results because the known techniques of Wakao et al predictably results in methods useful treatment of for skin injury.
Regarding the limitations of the patient having claim 11 recites “wherein skin collagen content is decreased in the skin of the patient” and claim 12 recites “wherein dermal thickness is decreased in the skin of the patient,” as these are interpreted to be results of the active method steps of claim 11, they are rendered obvious by the combination of Keneko and Wakao. Each and every method step is taught and therefore, the same method steps yield the same predictable results with a reasonable expectation of success.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Applicants’ Arguments as they apply to rejection under 35 USC § 103 in relation to the teachings of Keneko, Wakao, Young, Yoshida and Iseki,
Applicant argues Kaneko teaches administering “Muse cells into the tail vein (i.e., intravenously) of a mouse in a liver fibrosis model resulted in significant suppression of fibrosis. However, Kaneko does not suggest reversal of existing fibrotic tissue, much less any therapeutic effect in lung tissue. In contrast, the present invention relates specifically to the treatment of fibrotic lung tissue.” (Applicant’s Remarks, p. 5). Applicant additionally states that suppression does not encompass the lysis of existing fibrotic tissue.
Examiner disagrees. “Treatment” can encompass a suppression of fibrosis when dealing with fibrotic lung tissue. Additionally, the reference of Kaneko is being argued individually in a 103 obviousness rejection which relies on other art as well. As the combination of Kaneko with Wakao and Young teach on each step of obtaining Muse cells and administering them to a patient in need thereof regarding lung fibrosis, the results would be the same with a reasonable expectation of success. Applicant has not provided evidence as to how the combination of references would not obtain the same results. Moreover, evidentiary references such as Yoshida and Iseki are utilized in order to demonstrate that Muse cells produce matrix malloproteases (MMPs) which are involved in fibrolysis and/or suppression of fibrosis and markers as well as their functional properties such as lysis of fibrotic tissue and thereby reversal of fibrosis are inherent to the cell structure itself absent of evidence to the contrary.
Applicant argues that Yoshida discloses that Muse cells were effective in preventing or treating myocardial infarction when administered intravenously 24 hours after reperfusion following 30 minutes of ischemia, however it is silent on the technical feature of treating fibrosis through lysis of fibrotic tissue.
Examiner reiterates that Yoshida is an evidentiary reference as indicated in the 103 rejection to describe the features of Muse cells and is not utilized in the 103 rejection to teach methods of treatment.
Applicant argues that Wakao discloses that a portion of Muse cells were captured in and supplemented to the lungs and spleen. Wakao further teaches that the majority of Muse cells fused with damaged tissue. Wakao does not disclose selective supplementation in the lungs and is silent on pulmonary fibrosis.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Wakao demonstrates that Muse cells have the ability to engraft into the lungs and spleen, further supporting teaching, suggestion and motivation to combine references for the treatment of lung diseases. Pulmonary fibrosis is disclosed by Young.
Applicant argues that Young merely states that stem cell transplantation into animal models for tissue repair includes "intravenous injection", and para. 0064 further includes the embodiments of "pulmonary diseases (COPD, IPF (idiopathic pulmonary fibrosis), bronchitis, emphysema, asthma, cystic fibrosis, etc.), gastrointestinal diseases (i.e., Celiac disease, Crohn's disease, etc.)". Moreover, Applicant submits that what Young isolated a CD105- negative cell and is substantially distinct from Muse cells claimed herein, which are CD105-positive.
Regarding Iseki, Applicant argues Iseki was published in Cell Transplant. 2017 May 9;26(5):821- 840 (doi: 10.3727/096368916X693662), and was electronically published on November 2, 2016, making it a post filing article.
Examiner agrees that the reference is not prior art. However, Iseki is an evidentiary reference to demonstrate inherent properties of Muse cells and not provided as a secondary reference to establish teaching, suggestion and motivation. Iseki shows that lysis is an inherent feature of Muse cells.
Regarding the rejection of claims 11 and 12, Applicant reiterates the arguments above and additionally submits that the skin fibrosis targeted by the present invention is a condition that is treated by reducing collagen in the skin. Applicant submits Wakao’s repair is typically through secretion of collagen by fibroblasts does not and the repair is through the secretion of collagen into the injury site.
As discussed above, “animal model of Figure 4 wherein the Muse cells are administered via tail vein (i.e. intravenous administration) for internal disorders and locally for skin injury models” does not indicate that lung or skin fibrosis is treated explicitly, however skin injury as evidenced, is accompanied by skin fibrosis. Though the methods in the cited references within Wakao for review are for skin regrowth and defect, the suggestion of “skin injury” would encompass that of skin fibrosis. There is suggestion to apply to the skin, the treatment or lysis of fibrosis would be another result of the treatment of skin injury. The evidentiary reference of Iseki teaches that Muse cells inherently produce matrix malloproteases (MMPs) which are involved in fibrolysis and/or suppression of fibrosis (p. 831, 1st column; p. 835, 2nd column). Therefore, lysis of fibrotic tissue is an inherent function of Muse cells themselves which is effective in treating organ fibrosis.
While Wakao does not explicitly teach that the lysis is present, Wakao and the other references provide all method steps recited with the exact same cells claimed. Therefore, an artisan would have a reasonable expectation of success in treating skin injury/fibrosis absent to evidence of the contrary wherein the treatment method is distinct from what is found in the art. As the claims currently stand, they are broadly encompassing subject matter and are not distinct from what has been cited in Wakao and the secondary references.
Conclusion
No claims are allowed.
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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634 /MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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