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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2/9/2026 has been entered.
Claims status
Claims 5, 6, 11, 12 and 14 is/are currently pending with claims 5, 6 is/are withdrawn. Claims 11, 12, 14 is/are under examination.
Claim Objections
Claim 11 is objected to because of the following informalities: Claim 11 recites culturing SSEA-4(-) cells separated from iPS cells to allow differentiation in to BxC stem cells, which are precursor cells. The claim also recites “wherein the precursor cells of the mesenchymal stem cells derived from induced pluripotent stem cells are SSEA-4(-) cells”. Using different terminology, the claim also recites that “the BxC stem cell is a progenitor cell of an induced pluripotent cell-derived mesenchymal stem cell”. Each of these are referring to the same cells and these limitations introduce verbosity to the claim language that do not appear to add anything to the claim but merely recite inherent features. Following claim language is recommended:
1. in line 6: “BxC stem cells
2. in line 18, the limitation is inherent to the BxC stem cell that differentiate into MSC i.e. inherently progenitors of MSC: “
3. in line 20: “wherein the BxC stem cells are SSEA-4(-) cells that do not express SSEA-4 protein in the cell surface”.
Appropriate corrections are required.
Claim Rejections - 35 USC § 112(b) - Maintained
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 11, 12, 14 remain 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 11 continues to recite an administration step wherein a subject is administered “a composition comprising exosomes”. Although the claim recites product-by-process limitations proceeding the administration step that result in isolation of exosomes from mesenchymal stem cells (MSCs), it is unclear if the “composition comprising exosomes” used in the administration step is the same as or different from the exosomes produced by the isolation step. For the purpose of compact prosecution, the claim(s) 11 is/are interpreted as “a composition comprising exosomes isolated in the isolation step”.
Claim 12-14 is/are rejected due their dependence on claim 11 because they do not clarify the 112b issue noted with claim 11.
Claim Interpretation - Reiterated
Claim 11 recites process steps for the generation of the product administered to the subject i.e. ‘the composition comprising exosomes isolated in the isolation step’. According to MPEP 2113, “Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps.” The process steps recited in claims are directed to differentiation of iPSCs into MSCs wherein the process comprises a step of selecting SSEA-4(-) cells that eventually differentiate into BxC cells and then finally into MSCs. An ordinary artisan recognizes that MSCs, including MSCs derived from iPSCs are mostly SSEA4-ve (Figure 1, Kim et al, Int. J. Mol. Sci. 2018, 19, 3119; ref of record). Thus, the process results in production of MSCs after the second culturing steps. These MSCs are pretreated with at least one of the agents recited in the pretreatment step, followed by continued culturing of MSCs to isolate exosomes from MSCs pre-treated with at least one of the recited agents. Claim 14 requires the agent to be hyaluronic acid. Therefore, the structure provided by the recited process steps to the composition is exosomes derived from MSCs pre-treated with at least one of the recited agents.
Regarding the “wherein the BxC stem cell” is a progenitor of the MSCs produced in the process steps, this clause is implicit to the process step since the steps already recite differentiating BxC stem cells in the MSCs i.e. the recited BxC stem cells are progenitor of the MSCs produced. Critically, this limitation does not provide any additional structure to the composition since exosomes are not derived from BxC stem cells.
Regarding the “precursor cells” are SSEA-4(-), this clause is also implicit to the process step since the steps already selects for SSEA4(-) cells. Critically, this limitation does not provide any additional structure to the composition since exosomes are not derived from precursor cells.
Claim Rejections - 35 USC § 112(a) - Withdrawn
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Rejection of Claim 11, 12, 14 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the scope of enablement requirement is withdrawn due to claim amendment.
Claim Rejections - 35 USC § 103 – Maintained
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.
Claim(s) 11, 12, 14 remain rejected under 35 U.S.C. 103 as being unpatentable over Vaskova et al (JACC, Vol 71, Issue 11, March 20, 2018; ref of record) in view of Kim et al (KR102123268, Published 2020/06/17; cited and machine translation provided in IDS 11/15/2022; pin citations below refer to machine translation; ref of record), Chen et al (Biochemical and Biophysical Research Communications 360 (2007) 1–6; ref of record) and Kwon et al (Tissue Eng Regen Med (2017) 14(5):595–604).
Vaskova teaches a method for treating ischemia-induced myocardial infarction (= ischemic heart disease required for claims 11, 12) by intramyocardially administration of exosomes derived from iPSC-derived MSC (iMSC) (required for claim 11 in part; see claim interpretation above; Methods, Results, Conclusion). Vaskova teaches hypoxia preconditioning of MSCs prior to exosome isolation (Methods). They teach that hypoxic conditioning resulted in greater quantity of exosomes produced (Results). They also teach that hypoxic conditioning of iMSCs resulted in exosomes with increased angiogenesis capability and cardiomyocyte viability in in vitro ischemia-models as well as improved cardiac function and viability in in vivo ischemia models (Results and Conclusion).
Although Vaskova teaches hypoxia pre-conditioning, Vaskova does not teach iPSC-derived MSC derived exosomes wherein iPSC-derived MSCs are treated with an agent, such as hyaluronic acid recited in claims 11 and 14.
Kim teaches exosomes derived from stem cells cultured with hyaluronic acid wherein stem cells are disclosed to be MSCs derived from iPSC (page 8, para 8; page 6, para 6). Kim teaches that culturing MSCs with hyaluronic acid increasing their proliferation and maintains their stemness (Experimental Example 1). Kim also teaches that culturing MSCs with hyaluronic acid increases the number of exosomes produced (Experimental Example 2). Kim suggests the use of their exosomes in the treatment of cardiovascular diseases such as myocardial infarction (page 8, para 6).
Similarly, Chen teaches that hyaluronic acid when added to MSC culture medium increases MSC proliferation and reduces their senescence (Figure 1, 2). Chen teaches that “the introduction of HA in a culture system may be useful for expanding adult stem cells in vitro without loss of their replicative and differentiation capacity.”(Discussion, last sentence).
Kwon teaches that hypoxia treatment also increases MSC proliferation, reduces senescence and maintains stemness (Abstract).
Therefore, it would be obvious to a person of ordinary skill in the art to treat the iPSC-derived MSCs of Vaskova with hyaluronic acid, as taught by Kim and Chen, in place of hypoxic condition. An ordinary artisan would be motivated to treat iPSC-derived MSCs of Vaskova with hyaluronic acid because, similar to the hypoxic conditioning, hyaluronic acid treatment would allow the cultured MSCs to remain proliferative without succumbing to senescence or loss of stemness. It would also allow for collection of more exosomes. Furthermore, treatment with hyaluronic acid would be considered simpler than hypoxia conditioning which requires specificized equipment of hypoxia chambers (such as taught by Kwon in 2.2 Hypoxic condition). An ordinary artisan would reasonably expect that that exosomes of iPSC-derived MSCs treated with hyaluronic acid in place of hypoxic preconditioning would be useful in treating heart disease because Vaskova teaches that exosomes of hypoxic preconditioned-iPSC-derived MSCs are efficacious for this method and hyaluronic acid treatment is expected to similarly maintain key MSCs properties such as proliferation, stemness and low senescence as hypoxic preconditioning.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Response to Arguments
Applicant's arguments filed 2/9/2026 regarding U.S.C. 103 rejection of the claims have been fully considered but they are not persuasive.
Applicant argue that “There is no reasonable expectation of success in view of the cited references.”. In support, Applicant allege that “the cited references do not teach or suggest treating ischemic heart disease by specifically administering exosomes derived from MSCs pretreated with hyaluronic acid.” (page 6-7, bridging para).
In response, Vaskova teaches “treating ischemic heart disease by specifically administering exosomes derived from MSCs”, and both Kim and Chen teach treating MSCs with hyaluronic acid while Kim specifically teaches deriving exosomes from MSCs with hyaluronic acid. Taken together the cited references teach and suggest treating ischemic heart disease by specifically administering exosomes derived from MSCs pretreated with hyaluronic acid. Furthermore, regarding reasonable expectation of success, Vaskova teaches that exosomes of hypoxic preconditioned-iPSC-derived MSCs are efficacious for treating ischemic heart disease and hyaluronic acid treatment is expected to similarly maintain key MSCs properties such as proliferation, stemness and low senescence as hypoxic preconditioning, as taught by Kim and Chen.
Further, Applicant argue that “the cited references do not indicate whether pretreating MSCs with hyaluronic acid would impact the therapeutic efficacy of the exosomes” (page 6-7, bridging para). Applicant point to Tables 12-17; summarized in Table 1 and Appendix 1 on page 8, and Figures 12a and 12b that allegedly show that exosomes isolated from MSCs pretreated with hyaluronic acid reduce cytokine levels and fibrosis markers in macrophage and fibroblast cultures in comparison to exosomes isolated from MSCs that are not pretreated with hyaluronic acid (page 7-9).
In response, at first it must be noted that although the arguments presented are specific to hyaluronic acid-pretreated MSCs, Claims 11 and 12 are not limited to this embodiment. Thus, the arguments presented are not commensurate in scope with claims 11 and 12. See MPEP 716.02(d) that states “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." The specification does not test the other pre-treatment reagents for their effect on cytokine levels or fibrosis markers.
Next, regarding the alleged superior effects of the exosomes derived from hyaluronic acid-pretreated MSCs, such as reduced cytokine levels and fibrosis, there is no evidence that these results are of a significant, practical advantage in a method of treating ischemic heart conditions in a subject in vivo. See MPEP 716.02(b) guides that “The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance."
The data for measuring cytokine levels was generated from cultured macrophages stimulated by LPS, a bacterial antigen, and treated with exosomes derived from MSCs and hyaluronic acid-pretreated MSCs (Tables 12-17; summarized in Table 1 and Appendix 1). The relevance of this assay to an ischemic heart disease is unclear since LPS, a bacterial antigen while inflammation in ischemic heart disease is due to hypoxia. Furthermore, it is not clear if the results shown have any statistical significance such that their practical significance could be gauged. There is no evidence that the alleged differences between exosomes derived from MSCs vs exosomes derived from hyaluronic acid-pretreated MSCs on cytokine levels would lend a practical therapeutic difference when exosomes are delivered to a subject.
Similar issue arises for the data for measuring fibrosis which was generated from cultured mouse embryonic fibroblasts stimulated by TGFb and treated with exosomes derived from MSCs and hyaluronic acid-pretreated MSCs (Figures 12a, b). The relevance of this assay to an ischemic heart disease is unclear since mouse embryonic fibroblasts are not relevant to this disease. Furthermore, it is not clear if the results shown have any statistical significance such that their practical significance could be gauged. There is no evidence that the alleged differences between exosomes derived from MSCs vs exosomes derived from hyaluronic acid-pretreated MSCs on fibrosis levels would lend a practical therapeutic difference when exosomes are delivered to a subject.
Finally, “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention.” See MPEP 2145 (II).
In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979) (Claims were directed to grooved carbon disc brakes wherein the grooves were provided to vent steam or vapor during a braking action. A prior art reference taught noncarbon disc brakes which were grooved for the purpose of cooling the faces of the braking members and eliminating dust. The court held the prior art references when combined would overcome the problems of dust and overheating solved by the prior art and would inherently overcome the steam or vapor cause of the problem relied upon for patentability by applicants. Granting a patent on the discovery of an unknown but inherent function (here venting steam or vapor) "would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art." 596 F.2d at 1022, 201 USPQ at 661.);
"The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.).
See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.").
In the instant case, Vaskova, Kim and Chen render the instantly claimed method wherein exosomes derived from hyaluronic acid-pretreated-MSC are administered to a subject for the treatment of ischemic heart disease prima facie obvious. The additional advantages alleged by the Applicant, such as reduced cytokine levels and fibrosis, are inherent to and flows naturally from the teachings and suggestion of the prior art. Thus, additional advantages allegedly associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention
Taken together, based on guidance from MPEP 716.02 and 2145(II), teachings from the prior art regarding the obviousness of the claimed invention and the lack of evidence that the results presented in the specification are in fact superior to either statistical or practical level, the allegation regarding unexpected/superior results are unpersuasive.
Conclusion
No claim is allowed.
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/MATASHA DHAR/Examiner, Art Unit 1632
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