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 .
Amendments
In the reply filed on 11/24/2025, Applicant has amended claims 55, 58, 89 and 98, newly canceled claims 88 and 94.
Claim Status
Claims 1-6, 8-9, 12-14, 18-22, 51-52, 55, 58, 63, 70-71, 87, 89-93 and 95-101 are pending.
Claims 1-6, 8-9, 12-14, 18-22, 51-52, 63, and 70-71 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/17/2025.
Claims 55, 58, 87, 89-93 and 95-101 are considered on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/24/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. The corresponding signed and initialed PTO form 1449 has been mailed with this action.
Withdrawn Claim Objections
The prior objection to claims 55, 58, 92 and 98 because of typographic errors is withdrawn in light of Applicant’s amendment.
New Claim Objections
Claims 55 and 58 are objected to because of the following informalities:
Claim 55 and claim 58 recite “wherein low therapeutic potency cells” and “high potency cells” in the last wherein clause. Since high potency cells and low therapeutic potency cells have been recited in the prior limitations in the claims, it is suggested to change them to “wherein the low therapeutic potency cells” and “the high potency cells”.
Maintained 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 55, 58, 87, 89-93 and 95-101 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.
Claims 55 and 58 recite the “low therapeutic potency cells are cardiosphere-derived cells (CDCs) that express less than 30 ng/µL β-catenin, and high potency cells are CDCs that express 30 ng/µL or more β-catenin”. A claim may be rendered indefinite by reference to term of an object that is variable (see MPEP 2173.05(b), II). Specifically, Applicant uses protein levels of β-catenin to define low or high potency cells, however, the protein levels are variable depending on the cell number, source of material (e.g., supernatant or cell lysate), type of lysis buffer, buffer volume, and detection method, etc., which renders the claims indefinite. The specification does not provide a standard for ascertaining the requisite degree (see specification, [0135] and [0137] for lacking at least buffer volume), and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. For examination purposes, the “low potency” cells are interpreted as CDCs expressing a level of β-catenin, and the “high potency” cells are interpreted as CDCs expressing higher levels of β-catenin than the low potency cells. Claims 87, 89-93 and 95-101 are rejected as being directly or indirectly dependent from claim 55 or claim 58 but not resolving the ambiguity.
Withdrawn Claim Rejections - 35 USC § 102
The prior rejection of claim 55 under 35 U.S.C. 102 (a)(1) as being anticipated by Shang et al., (prior art of record) is withdrawn in light of Applicant’s amendment to claim 55 to recite new limitation that the cells are CDCs, which is not taught by Shang.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 55 and 87 under 35 U.S.C. 103 as being unpatentable over Shang et al., (prior art of record) in view of Jung et al., (prior art of record) is withdrawn in light of Applicant’s amendment to claim 55 to recite new limitation that the cells are CDCs, which is not taught by Shang or Jung.
The prior rejection of claims 55, 58, 89-93 and 95-101 under 35 U.S.C. 103 as being unpatentable over Aminzadeh, Shang, Liu and Jung is withdrawn in light of Applicant’s amendment to claims 55 and 58 to recite new limitation that the CDCs express a level of β-catenin, which is not taught by Aminzadeh, Shang, Liu and Jung.
New Claim Rejections - 35 USC § 103
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 55 and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Aminzadeh et al., (Stem Cell Reports. March 13, 2018; 10: 942-955. Cited in IDS 06/20/2022) in view of Nakamura et al., (Biochem Biophys Res Commun. 2017; 487(3): 653-659) and Shang et al., (Acta Pharmacologica Sinica. 2016; 37: 873-881. Prior art of record).
With respect to independent claims 55 and 58, Aminzadeh teaches a method of improving cardiac and skeletal myopathy in the mdx mouse model of Duchenne muscular dystrophy (abstract), thus teaches a method of treating dystrophic skeletal muscle in a subject with muscular dystrophy in the preamble of claims 55 and 58.
Aminzadeh teaches cardiosphere-derived cells (CDCs) are injected into left ventricular myocardium (e.g., p. 952, right col, para 1), thus teaches the method comprises administering to the subject CDCs in claim 55.
Aminzadeh teaches exosomes are collected from CDCs and are injected into myocardium, soleus muscles or left ventricular cavity (e.g., p. 952, right col, para 1 and p. 948, left col), thus teaches the method comprises administering to the subject exosomes that are prepared by (a) preparing therapeutic cells CDCs (see e.g., p. 952, last full para), and (b) collecting exosomes from the therapeutic cells CDCs (i.e., CDC exosomes, see e.g., p. 952, last para-p. 953, 1st para) in claim 58.
However, Aminzadeh is silent on the CDCs initially expressing a level of β-catenin (i.e., the low therapeutic potency cells) and the CDCs expressing a higher level of β-catenin (i.e., the high potency cells) after being treated with a modulator of β-catenin expression in claims 55 and 58.
Nakamura teaches isolating CDCs from heart failure patients of various ages and treating the CDCs with exogenous Wnt3A protein (see e.g., abstract and Fig 1). Nakamura teaches the CDCs express Wnt ligands such as Wnt3A (see Fig 1A) and express a level of β-catenin (see Fig 1B, left panel, without Wnt3A treatment “(-)”). Nakamura teaches that after being treated with Wnt ligand Wnt3A, the CDCs express a higher level of β-catenin (see Fig 1B, left panel, with Wnt3A treatment “(+)” in which there is reduced phosphorylated β-catenin (that is to be degraded) and a higher level of total β-catenin). Thus, Nakamura teaches the CDCs initially express a level of β-catenin (i.e., the low therapeutic potency cells), and express a higher level of β-catenin (i.e., the high potency cells) after being treated with a modulator of β-catenin expression (i.e., Wnt3A) in claims 55 and 58.
Shang teaches a method of treating mdx mice (the same mouse model used by Aminzadeh) by transplanting mesenchymal stem cells (MSCs) (see abstract and e.g. Fig 1). Shang teaches the MSCs are pre-treated with Wnt3A-conditioned medium before transplantation (see e.g., p. 874, last para.), and teaches Wnt3a-MSCs demonstrate a significantly higher regenerative capacity after transplantation compared to control MSCs evidenced by decrease of the adipose and connective tissue area (see p. 876, last para, and Fig 2C) and higher percentage of the dystrophin-positive and MyoD-positive muscle fibers (see e.g., p. 877 and Figs 3 and 6).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating cardiac and skeletal myopathy by administering CDCs or exosomes collected from CDCs disclosed by Aminzadeh, by combining treating the CDCs with Wnt3A before transplantation or before collecting exosomes as suggested by Nakamura and Shang with a reasonable expectation of success. Since Aminzadeh aims to treat muscular dystrophy by transplanting CDCs or exosomes from CDCs (abstract), and since Shang teaches treating therapeutic cells with Wnt3A results in a significantly higher regenerative capacity compared to control cells (p. 877, Figs 3 and 6, and p. 876, last para, Fig 2C), one of ordinary skill in the art would have had a reason to combine treating CDCs with Wnt3A as suggested by Nakamura and Shang in the method of Aminzadeh in order to achieve better therapeutic effect.
Furthermore, since Nakamura teaches the CDCs initially express a level of β-catenin, and express a higher level of β-catenin after being treated with a modulator of β-catenin expression (i.e., Wnt3A), one of ordinary skill in the art would have immediately expected that the CDCs of Aminzadeh are equivalent to the claimed low therapeutic potency cells, and the Wnt3A-treated CDCs of Aminzadeh in view of Nakamura and Shang are equivalent to the claimed high potency cells.
Finally, regarding a reasonable expectation of success, Nakamura suggests Wnt3A treatment promotes CDC proliferation and reduces senescence (Fig 1C) while treating with Wnt antagonist sFRP1 induces senescence and IL-6 and IL1β secretion from CDCs (see Fig 4, it is noted that both IL-6 and IL1β are involved in fibrosis), thus suggests Wnt3A treatment would likely reduce secretion of pro-fibrotic cytokines IL-6 and IL1β from CDCs. Shang teaches Wnt3A-treated MSCs demonstrate a significantly higher regenerative capacity evidenced by decrease of the adipose and connective tissue area (see p. 876, last para, and Fig 2C), suggesting Wnt3A-treated MSCs better suppress fibrosis. Aminzadeh teaches one mechanism of transplanting CDCs is to suppress fibrosis (e.g., Fig 3D and 5G). Therefore, one of ordinary skill in the art would have had a reasonable expectation of success in treating CDCs with Wnt3A to reduce their secretion of pro-fibrotic cytokines so as to better suppress fibrosis to improve treating cardiac and skeletal myopathy.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 11/24/2025 are acknowledged.
Applicant’s argument regarding Shang not teaching the amended limitation of CDCs in the prior 102 rejection and 103 rejection (Remarks, p. 9), is persuasive. Therefore, the prior rejection over Shang has been withdrawn.
Regarding the rejection over Aminzadeh, Applicant’s argument that (1) the cited references fail to teach the expression levels of β-catenin in CDCs (Remarks, p. 11, section 1), has been fully considered and is persuasive. Therefore, the prior rejection over Aminzadeh is withdrawn. However, as necessitated by amendment, a new ground of rejection has been made over Aminzadeh in view of Nakamura and Shang. Specifically, Nakamura teaches CDCs express β-catenin, and express a higher level of β-catenin after Wnt3A treatment (see above for claim interpretation and rejection).
Applicant further argues that (2) the combination of the cited references would change the principle of operation because Shang relies on MSCs’ physically contributing to muscle cells while Aminzadeh teaches the effect of CDCs are paracrine and not related to differentiation and integration (Remarks, p. 10 and section 2 of p. 11).
Applicant’s arguments have been fully considered but they are not persuasive.
As a first matter, Shang uses rat MSCs in a mouse disease model (p. 874, left col, para. “Animals and MSC preparation”), but none of Shang’s experiments identifies the new muscle fibers are physically derived from the transplanted rat MSCs. Shang instead teaches Wnt3a-MSC transplantation leads to decrease of the adipose and connective tissue area (p. 876, last para and Figure 2C), which is very likely due to an indirect effect. Therefore, Applicant’s argument, that Shang relies on MSCs’ physically contributing to muscle cells, is not supported by Shang.
Furthermore, in order to complete the art of record and rebut Applicant’s arguments, reference Gorecka et al., (Stem Cell Research & Therapy. 2018; 9: 195, p. 1-12) regarding MSCs’ physical contribution to muscle cells has been attached. Gorecka evidences that adipose-derived stem cells (ADSCs, one type of MSCs) “transplantation into acute damaged skeletal muscle significantly improves functional muscle tissue regeneration without direct participation in muscle fiber formation” (e.g., abstract), and “ADSC act via direct cell-cell or paracrine mechanisms by secreting factors involved in transient acceleration of skeletal muscle repair” (p. 10, left col, para “Conclusions”). Thus, Gorecka discloses that it was well known before the filing date of the claimed invention that transplanted MSCs may not physically contribute to muscle cells, but may instead act via paracrine mechanisms by secreting factors to the host muscle cells.
Applicant further argues that (3) there is no reasonable expectation of achieving the goal and there is no rational basis to combine Shang, related to MSCs, with Aminzadeh, related to CDCs, as the biological mechanisms are distinct (Remarks, p. 12, section 3).
Applicant’s arguments have been fully considered but they are not persuasive. As discussed above in the new ground of rejection necessitated by amendment, Nakamura suggests Wnt3A treatment promotes CDC proliferation and reduces senescence (Fig 1C) while treating with Wnt antagonist sFRP1 induces senescence and IL-6 and IL1β secretion from CDCs (see Fig 4, it is noted that both IL-6 and IL1β are involved in fibrosis), thus suggests Wnt3A treatment would likely reduce secretion of pro-fibrotic cytokines IL-6 and IL1β from CDCs. Shang teaches Wnt3A-treated MSCs demonstrate a significantly higher regenerative capacity evidenced by decrease of the adipose and connective tissue area (see p. 876, last para, and Fig 2C), suggesting Wnt3A-treated MSCs better suppress fibrosis in damaged muscle. Aminzadeh teaches one mechanism of transplanting CDCs is to suppress fibrosis (e.g., Fig 3D and 5G). Therefore, one of ordinary skill in the art would have had a reasonable expectation of success in treating CDCs with Wnt3A to reduce their secretion of pro-fibrotic cytokines so as to better suppress fibrosis to improve treating cardiac and skeletal myopathy.
Applicant further argues that (4) the Office impermissibly relies on non-analogous art because Shang pertains stem cell therapy while the invention involves in non-integrative therapeutic effects (Remarks, p. 12, section 4).
Applicant’s arguments have been fully considered but they are not persuasive. As discussed above in the response to Applicant’s second argument, Shang does not demonstrate MSCs’ physically contributing to muscle cells but instead teaches Wnt3a-MSC transplantation leads to decrease of the adipose and connective tissue area, and it was well known before the filing date of the claimed invention that transplanted MSCs may not physically contribute to muscle cells, but instead acts via paracrine mechanisms by secreting factors that involves in non-integrative therapeutic effects as evidenced by Gorecka. Thus, Shang is indeed an analogous art.
Applicant finally argues that (5) there are unexpectedly superior properties such as CDCs not showing differentiating into myoblasts, CDCs not showing integrating into muscle tissue, CDC not showing contributing to dystrophin restoration. The present application discloses working examples showing non-integrative, paracrine-mediated therapeutic effects, not stem cell-based tissue regeneration. The technical effect of the claimed invention is surprisingly superior to Aminzadeh and fundamentally different from that of Shang (Remarks, p. 12, section 5 - p. 13).
Applicant’s arguments have been fully considered but they are not persuasive.
As stated supra, Shang does not demonstrate MSCs’ physically contributing to muscle cells, but instead reduces adipose and connective tissue area, and it was well known before the filing date of the invention that MSC transplantation may not physically contribute to muscle cells, but instead acts by secreting factors that involves in non-integrative, paracrine-mediated therapeutic effects, as evidenced by Gorecka.
Furthermore, as Applicant has stated in Remarks, page 10,
“Aminzadeh, on the other hand, discloses that "[m]ultiple lines of evidence now indicate that most of the beneficial effects of CDCs are indirect," and that injected CDCs do not persist in the implanted mdx hearts but the "CDC-induced improvement in EF persisted beyond the point at which no surviving CDCs were detectable in mdx hearts (3 weeks after CDC delivery)," (Aminzadeh at pp. 943 and 945). Thus, the effects of CDCs are paracrine and not related to cellular differentiation of stem cells and integration of differentiated myocytes in the recipient”.
Therefore, Aminzadeh’s CDC transplantation shows non-integrative, paracrine-mediated therapeutic effects, not stem cell-based tissue regeneration. The technical effect of the claimed invention is thus expected by the teaching of Aminzadeh.
Claims 89-90 and 95-96 are rejected under 35 U.S.C. 103 as being unpatentable over Aminzadeh et al., (Stem Cell Reports. March 13, 2018; 10: 942-955. Cited in IDS 06/20/2022) in view of Nakamura et al., (Biochem Biophys Res Commun. 2017; 487(3): 653-659) and Shang et al., (Acta Pharmacologica Sinica. 2016; 37: 873-881. Prior art of record), as applied to claims 55 and 58 above, and further in view of Liu et al., (US Patent No. 7,566,567. Published July 2009. Prior art of record).
Claims 89 and 95 are directed to immortalized CDCs. Claims 90 and 96 are directed to the CDCs being immortalized using SV40 large and small antigens.
However, both Aminzadeh and Nakamura teach the CDCs are derived from primary tissues, but do not teach the CDCs are immortalized, nor teach the CDCs are immortalized using SV40 large and small antigens in claims 89-90 and 95-96.
Liu teaches a method of immortalizing human cells derived from a normal primary human cell (abstract). Liu teaches the method comprises transfecting cells with immortalization gene SV40 large T and small t antigens (TAg) (e.g., col 4, lines 29-34 and col 9, section “Immortalized Human Hepatocyte Cell Lines”), thus teaches claims 89-90 and 95-96. Liu teaches this strategy was chosen because transfection of human cells with SV40 TAg can result in cell lifespan extension and in nontumorigenic immortalization since the cells are semipermissive to viral infection (col 9, lines 48-51) and teaches the immortalized cells have the ability to proliferate in a serum-free media, are nontumorigenic, and are capable of producing endogenous plasma proteins (abstract and col 9, lines 17-19).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating cardiac and skeletal myopathy by administering Wnt3A-treated CDCs or exosomes collected from Wnt3A-treated CDCs that are derived from primary tissues suggested by Aminzadeh in view of Nakamura and Shang, by substituting the primary CDCs with immortalized cells made by SV40 large and small antigens as taught by Liu with a reasonable expectation of success. Since Liu teaches the immortalized cells made by SV40 large T and small t antigens have the ability to proliferate in serum-free media, are nontumorigenic, and are capable of producing proteins (abstract and col 9), one of ordinary skill in the art would have had a reason to immortalize the cells with SV40 large T and small t antigens as taught by Liu in the method of Aminzadeh in view of Nakamura and Shang in order to obtain immortalized nontumorigenic CDCs that are capable of proliferating in serum-free media and producing proteins to reduce the cost of preparation, to overcome the limitation of cell sources, and to facilitate exosome collection from the serum-free media.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 11/24/2025 are acknowledged and have been discussed above.
Claims 87, 91-92, 93 and 97-101 are rejected under 35 U.S.C. 103 as being unpatentable over Aminzadeh et al., (Stem Cell Reports. March 13, 2018; 10: 942-955. Cited in IDS 06/20/2022) in view of Nakamura et al., (Biochem Biophys Res Commun. 2017; 487(3): 653-659), Shang et al., (Acta Pharmacologica Sinica. 2016; 37: 873-881. Prior art of record) and Liu et al., (US Patent No. 7,566,567. Published July 2009. Prior art of record), as applied to claims 55, 58, 89 and 95 above, and further in view of Jung et al., (Biochem. J. 2011; 436: 263-269. Prior art of record).
Claims 87 and 93 are directed to the high potency cells being prepared by downregulating expression of mest. Claims 91 and 97 are directed to mest expression being downregulated using a shRNA.
However, Aminzadeh, Nakamura, Shang and Liu are silent on the immortalized CDCs being prepared by downregulating mest expression using a shRNA in claims 55, 58, 87, 91, 93 and 97.
Jung teaches Mest inhibits Wnt/β-catenin pathway induced by Wnt3a-conditioned medium through blocking the maturation and plasma membrane localization of Wnt co-receptor LRP6 and enhancing the ubiquitination of β-catenin (abstract, see e.g. Figs 1-2), and teaches knocking-down Mest by short hairpin RNA (shRNA) enhances Wnt signaling and augments the levels of total β-catenin and the active form of β-catenin (end of p. 267-p. 268, 1st para, see e.g. Fig 5C). Jung teaches Mest is an imprinted gene that is highly expressed in the mesoderm (p. 263, right col, para 1). Thus, Jung teaches downregulating expression of Mest using a shRNA enhances Wnt signaling and augments the levels of β-catenin, related to claims 55, 58, 87, 91, 93 and 97.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating cardiac and skeletal myopathy by administering Wnt3a-treated CDCs or exosomes collected from Wnt3a-treated CDCs suggested by Aminzadeh in view of Nakamura, Shang and Liu, by combining downregulating Mest expression in the cells using a shRNA as taught by Jung with a reasonable expectation of success. Since Jung teaches Mest inhibits Wnt/β-catenin pathway induced by Wnt3a and teaches knocking-down Mest by shRNA enhances Wnt signaling and augments the levels of total β-catenin and the active form of β-catenin (end of p. 267-p. 268, 1st para, Fig 5C), one of ordinary skill in the art would have had a reason to combine knocking-down Mest using a shRNA in the immortalized CDCs of Aminzadeh in view of Nakamura, Shang and Liu in order to further enhance Wnt/β-catenin signaling to obtain high potency cells for administering or collecting high potency exosomes to treat muscular dystrophy. Furthermore, since Jung teaches Mest is highly expressed in the mesoderm (p. 263, right col, para 1. It is noted that CDCs are derived from mesoderm thus likely express Mest), one of ordinary skill in the art would have had a reasonable expectation of success in knocking-down Mest expression in the CDCs by shRNA.
With respect to claims 92 and 98 directed to β-catenin protein levels being maintained in the immortalized CDCs with shRNA-mediated Mest knockdown, it must be noted that this wherein clause does not recite an active step in the claimed method, but only the results of the step of knocking-down Mest by shRNA in the immortalized CDCs in the method suggested by Aminzadeh in view of Nakamura, Shang, Liu and Jung. MPEP 2111.04 (I) states a whereby clause (or a wherein clause) “in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Therefore, this wherein clause does not provide any patentable weight in determining patentability of the claimed method. Claims 92 and 98 are rejected in the same way as claims 91 and 97.
With respect to claims 99-101 directed to the amount of exosomes administered to the subject, Aminzadeh performs dose-response studies to identify effective doses of exosomes (p. 953, 1st para) and uses 6 x 108 exosomes for intramyocardial injection (p. 953, 1st para), 10 x 109 exosomes for intraventricular injection, and 20 x 107 exosomes for intramuscular injection (p. 952, right col, para 1). Thus, Aminzadeh teaches a range of exosome dosage from 2 x 108 to 10 x 109, which overlaps or encompasses the claimed range and doses of 1 x 105 to about 1 x 109 in claim 99, 3 x 109 in claim 100 and 4 x 109 in claim 101.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have administered the claimed dose of exosomes in the method of treating cardiac and skeletal myopathy as suggested by Aminzadeh with a reasonable expectation of success. Applicant is reminded 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. It is a routine procedure to optimize component amounts to arrive at an optimal method 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. See M.P.E.P. §2144.05.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 11/24/2025 are acknowledged and have been discussed above.
Withdrawn Double Patenting Rejections
The prior rejections of claims on the ground of nonstatutory double patenting or provisional nonstatutory double patenting as being unpatentable over claims of the following US patents and applications in view of Aminzadeh, Shang, Liu and Jung are withdrawn in light of Applicant’s amendment to claims 55 and 58 to recite new limitation that the CDCs express a level of β-catenin, which is not taught by the patents, applications, Aminzadeh, Shang, Liu and Jung.
New Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 55, 58, 87, 89-93 and 95-101 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims of the following US patents: 9,828,603; 10,457,942; 11,220,687; 11,253,551; 11,351,200; 11,357,799; 11,541,078; 11,660,317; 11,759,482; 11,872,251; 12,146,137, in view of Aminzadeh et al., (Stem Cell Reports. March 13, 2018; 10: 942-955. Cited in IDS 06/20/2022), Nakamura et al., (Biochem Biophys Res Commun. 2017; 487(3): 653-659), Shang et al., (Acta Pharmacologica Sinica. 2016; 37: 873-881. Prior art of record), Jung et al., (Biochem. J. 2011; 436: 263-269. Prior art of record) and Liu et al., (US Patent No. 7,566,567. Published July 2009. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
The patented claims recite a preparation of cardiosphere-derived cells (CDCs), or exosomes collected from CDCs, or methods of administering CDCs or exosomes collected from CDCs to a subject in need thereof for treating skeletal muscle myopathy, heart failure, age-related stiffness of a heart, ventricular tachycardia, heart failure secondary to muscular dystrophy, or diseased or damaged cardiac tissue.
However, the patented claims do not specifically recite a method of treating dystrophic skeletal muscle comprising administering high potency CDC cells that are prepared from low potency CDCs and that the high potency CDCs have higher levels of β-catenin, nor recite the CDCs being prepared by treating with a modulator of β-catenin expression or by downregulating mest expression by shRNA, the CDCs being immortalized using SV40 large and small antigens.
Aminzadeh teaches a method of improving cardiac and skeletal myopathy in the mdx mouse model of Duchenne muscular dystrophy (DMD) by administering cardiosphere-derived cells (CDCs) or exosomes collected from CDCs (e.g., abstract), and teaches local administration of CDCs or exosomes has remote effects in improving function of dystrophic skeletal muscles (p. 945, right col, -p. 948, left col). Aminzadeh teaches exosomes secreted by human CDCs reproduce the benefits of CDCs (abstract) and teaches a range of exosome dosages in local and system administration (p. 952, right col, para 1-p. 953, 1st para).
Nakamura teaches the CDCs isolated from patients express Wnt ligands such as Wnt3A (see Fig 1A) and express a level of β-catenin (see Fig 1B, left panel, without Wnt3A treatment “(-)”). Nakamura teaches that after being treated with Wnt ligand Wnt3A, the CDCs express a higher level of β-catenin (see Fig 1B, left panel, with Wnt3A treatment “(+)” in which there is reduced phosphorylated β-catenin (that is to be degraded) and a higher level of total β-catenin). Nakamura suggests Wnt3A treatment promotes CDC proliferation and reduces senescence (Fig 1C) while treating with Wnt antagonist sFRP1 induces senescence and IL-6 and IL1β secretion from CDCs (see Fig 4, it is noted that both IL-6 and IL1β are involved in fibrosis), thus suggests Wnt3A treatment would likely reduce secretion of pro-fibrotic cytokines IL-6 and IL1β from CDCs.
Shang teaches a method of treating mdx mice (the same DMD mouse model used by Aminzadeh) by transplanting mesenchymal stem cells (MSCs) (see abstract and e.g. Fig 1). Shang teaches the MSCs are treated with Wnt3a-conditioned medium before transplantation (see e.g., p. 874, last para), and teaches Wnt3a-treated MSCs demonstrates a significantly higher regenerative capacity after transplantation compared to control MSCs evidenced by the higher percentage of the dystrophin-positive and MyoD-positive muscle fibers (see e.g., p. 877 and Figs 3 and 6).
Jung teaches Mest inhibits Wnt/β-catenin pathway induced by Wnt3a-conditioned medium through blocking the maturation and plasma membrane localization of Wnt co-receptor LRP6 and enhancing the ubiquitination of β-catenin (abstract, see e.g. Figs 1-2), and teaches knocking-down Mest by short hairpin RNA (shRNA) enhances Wnt signaling and augments the levels of total β-catenin and the active form of β-catenin (end of p. 267-p. 268, 1st para, see e.g. Fig 5C). Jung teaches Mest is highly expressed in the mesoderm (p. 263, right col, para 1. It is noted CDCs are derived from mesoderm thus likely express Mest).
Liu teaches a method of immortalizing human cells derived from a normal primary human cell (abstract). Liu teaches the method comprises transfecting cells with immortalization gene SV40 large T and small t antigens (TAg) (e.g., col 4, lines 29-34 and col 9, section “Immortalized Human Hepatocyte Cell Lines”). Liu teaches this strategy was chosen because transfection of human cells with SV40 TAg can result in cell lifespan extension and in nontumorigenic immortalization since the cells are semipermissive to viral infection (col 9, lines 48-51) and teaches the immortalized cells have the ability to proliferate in a serum-free media, are nontumorigenic, and are capable of producing endogenous proteins (abstract and col 9, lines 17-19).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method or preparation recited in the patented claims in the cited US patents, by combining the teaching of Aminzadeh, Nakamura, Shang, Jung and Liu to recite a method of treating dystrophic skeletal muscle comprising administering Wnt3a-treated or mest knockdown immortalized CDCs or administering an amount of exosomes collected from those CDCs with a reasonable expectation of success. Since Aminzadeh teaches local administration of CDCs or exosomes has remote effects in improving function of dystrophic skeletal muscles (p. 945, right col, -p. 948, left col) and one functional mechanism is to suppress fibrosis (e.g., Fig 3D and 5G), Nakamura suggests Wnt3A treatment would likely reduce secretion of pro-fibrotic cytokines IL-6 and IL1β from CDCs (see Fig 1C for Wnt3A reducing senescence and Fig 4 for Wnt antagonist inducing senescence and IL-6 and IL1β secretion), Shang teaches Wnt3A-treated MSCs demonstrate a significantly higher regenerative capacity evidenced by decrease of the adipose and connective tissue area (see p. 876, last para, and Fig 2C) thus suggests Wnt3A-treated MSCs better suppress fibrosis, one of ordinary skill in the art would have had a reason to treat CDCs with Wnt3A to reduce their secretion of pro-fibrotic cytokines so as to better suppress fibrosis to improve treating dystrophic skeletal muscle. Furthermore, since Jung suggests CDCs express Mest and teaches knocking-down Mest by shRNA enhances Wnt signaling and augments the levels of total β-catenin and the active form of β-catenin (end of p. 267-p. 268, 1st para, see e.g. Fig 5C), and Liu teaches immortalized cells have the ability to proliferate in a serum-free media, are nontumorigenic, and are capable of producing endogenous proteins (abstract and col 9, lines 17-19), one of ordinary skill in the art would have had a reason to recite the shRNA-mediated mest knockdown and to recite immortalized CDCs by T antigens as suggested by Jung and Liu in order to enhance Wnt signaling to obtain high potency CDCs and to reduce preparation cost.
Since the instant application claims are obvious over cited patent claims, in view of Aminzadeh, Nakamura, Shang, Jung and Liu, said claims are not patentably distinct.
Response to Traversal:
Applicant’s arguments filed on 11/24/2025 are acknowledged and have been discussed above.
New Provisional Double Patenting Rejections
Claims 55, 58, 87, 89-93 and 95-101 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims of the following Applications: 17/528,822; 17/537,005; 17/748,992; 17/906,464; 18/205,313; 18/601,773; 19/061,766, in view of Aminzadeh et al., (Stem Cell Reports. March 13, 2018; 10: 942-955. Cited in IDS 06/20/2022), Nakamura et al., (Biochem Biophys Res Commun. 2017; 487(3): 653-659), Shang et al., (Acta Pharmacologica Sinica. 2016; 37: 873-881. Prior art of record), Jung et al., (Biochem. J. 2011; 436: 263-269. Prior art of record) and Liu et al., (US Patent No. 7,566,567. Published July 2009. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims in the applications recite a preparation of cardiosphere-derived cells (CDCs), or exosomes collected from CDCs, or methods of administering CDCs or exosomes collected from CDCs to a subject in need thereof for treating skeletal muscle myopathy, improving heart function or cardiac performance, damaged cardiac tissue, reducing oxidative stress in a heart of a subject with muscular dystrophy, treating respiratory viral infection or tumor growth.
However, the copending claims do not specifically recite a method of treating dystrophic skeletal muscle comprising administering high potency CDC cells that are prepared from low potency CDCs and that the high potency CDCs have higher levels of β-catenin, nor recite the CDCs being prepared by treating with a modulator of β-catenin expression or by downregulating mest expression by shRNA, the CDCs being immortalized using SV40 large and small antigens.
Aminzadeh teaches a method of improving cardiac and skeletal myopathy in the mdx mouse model of Duchenne muscular dystrophy (DMD) by administering cardiosphere-derived cells (CDCs) or exosomes collected from CDCs (e.g., abstract), and teaches local administration of CDCs or exosomes has remote effects in improving function of dystrophic skeletal muscles (p. 945, right col, -p. 948, left col). Aminzadeh teaches a range of exosome dosages in local and system administration (p. 952, right col, para 1-p. 953, 1st para).
Nakamura teaches the CDCs isolated from patients express Wnt ligands such as Wnt3A (see Fig 1A) and express a level of β-catenin (see Fig 1B, left panel, without Wnt3A treatment “(-)”). Nakamura teaches that after being treated with Wnt ligand Wnt3A, the CDCs express a higher level of β-catenin (see Fig 1B, left panel, with Wnt3A treatment “(+)” in which there is reduced phosphorylated β-catenin (that is to be degraded) and a higher level of total β-catenin). Nakamura suggests Wnt3A treatment promotes CDC proliferation and reduces senescence (Fig 1C) while treating with Wnt antagonist sFRP1 induces senescence and IL-6 and IL1β secretion from CDCs (see Fig 4, it is noted that both IL-6 and IL1β are involved in fibrosis), thus suggests Wnt3A treatment would likely reduce secretion of pro-fibrotic cytokines IL-6 and IL1β from CDCs.
Shang teaches a method of treating mdx mice (the same DMD mouse model used by Aminzadeh) by transplanting mesenchymal stem cells (MSCs) (see abstract and e.g. Fig 1). Shang teaches the MSCs are treated with Wnt3a-conditioned medium before transplantation (see e.g., p. 874, last para), and teaches Wnt3a-treated MSCs demonstrates a significantly higher regenerative capacity after transplantation compared to control MSCs evidenced by the higher percentage of the dystrophin-positive and MyoD-positive muscle fibers (see e.g., p. 877 and Figs 3 and 6).
Jung teaches Mest inhibits Wnt/β-catenin pathway induced by Wnt3a-conditioned medium through blocking the maturation and plasma membrane localization of Wnt co-receptor LRP6 and enhancing the ubiquitination of β-catenin (abstract, see e.g. Figs 1-2), and teaches knocking-down Mest by short hairpin RNA (shRNA) enhances Wnt signaling and augments the levels of total β-catenin and the active form of β-catenin (end of p. 267-p. 268, 1st para, see e.g. Fig 5C). Jung teaches Mest is highly expressed in the mesoderm (p. 263, right col, para 1. It is noted CDCs are derived from mesoderm thus likely express Mest).
Liu teaches a method of immortalizing human cells derived from a normal primary human cell (abstract). Liu teaches the method comprises transfecting cells with immortalization gene SV40 large T and small t antigens (TAg) (e.g., col 4, lines 29-34 and col 9, section “Immortalized Human Hepatocyte Cell Lines”). Liu teaches this strategy was chosen because transfection of human cells with SV40 TAg can result in cell lifespan extension and in nontumorigenic immortalization since the cells are semipermissive to viral infection (col 9, lines 48-51) and teaches the immortalized cells have the ability to proliferate in a serum-free media, are nontumorigenic, and are capable of producing endogenous proteins (abstract and col 9, lines 17-19).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method or preparation recited in the copending claims in the cited applications, by combining the teaching of Aminzadeh, Nakamura, Shang, Jung and Liu to recite a method of treating dystrophic skeletal muscle comprising administering Wnt3a-treated or mest knockdown immortalized CDCs or administering an amount of exosomes collected from those CDCs with a reasonable expectation of success. Since Aminzadeh teaches local administration of CDCs or exosomes has remote effects in improving function of dystrophic skeletal muscles (p. 945, right col, -p. 948, left col) and one functional mechanism is to suppress fibrosis (e.g., Fig 3D and 5G), Nakamura suggests Wnt3A treatment would likely reduce secretion of pro-fibrotic cytokines IL-6 and IL1β from CDCs (see Fig 1C for Wnt3A reducing senescence and Fig 4 for Wnt antagonist inducing senescence and IL-6 and IL1β secretion), Shang teaches Wnt3A-treated MSCs demonstrate a significantly higher regenerative capacity evidenced by decrease of the adipose and connective tissue area (see p. 876, last para, and Fig 2C) thus suggests Wnt3A-treated MSCs better suppress fibrosis, one of ordinary skill in the art would have had a reason to treat CDCs with Wnt3A to reduce their secretion of pro-fibrotic cytokines so as to better suppress fibrosis to improve treating dystrophic skeletal muscle. Furthermore, since Jung suggests CDCs express Mest and teaches knocking-down Mest by shRNA enhances Wnt signaling and augments the levels of total β-catenin and the active form of β-catenin (end of p. 267-p. 268, 1st para, see e.g. Fig 5C), and Liu teaches immortalized cells have the ability to proliferate in a serum-free media, are nontumorigenic, and are capable of producing endogenous proteins (abstract and col 9, lines 17-19), one of ordinary skill in the art would have had a reason to recite the shRNA-mediated mest knockdown and to recite immortalized CDCs by T antigens as suggested by Jung and Liu in order to enhance Wnt signaling to obtain high potency CDCs and to reduce preparation cost.
Since the instant application claims are obvious over cited application claims, in view of Aminzadeh, Nakamura, Shang, Jung and Liu, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending applications have not in fact been patented.
Response to Traversal:
Applicant’s arguments filed on 11/24/2025 are acknowledged and have been discussed above.
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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631