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 .
Status of the Claims
Claims 1-4, 10, and 13-15 responsive to communications on are pending.
Claims 1-4 and 13-14 are newly amended.
Claims 1-4, 10, and 13-15 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The rejection of claims 1, 3-6, 11-12, and 14-15 under 35 U.S.C. 102(a)(1) or 35 U.S.C. 102(a)(2) as being anticipated by de la Rosa et al. (US20170121685A1, 2017, on IDS 07/13/2023) is withdrawn in order to address the claims as amended.
The rejection of claim 2 under 35 U.S.C. 103 as being unpatentable over de la Rosa et al. (US20170121685A1, 2017, on IDS 07/13/2023) in view of Dos Santos et al. (Stem Cell Rev and Rep, 2017) is withdrawn in order to address the claims as amended.
The rejection of claim 7 under 35 U.S.C. 103 as being unpatentable over de la Rosa et al. (US20170121685A1, 2017, on IDS 07/13/2023) in view of Ma et al. (Aging, 2019) is withdrawn due to cancellation of the claim.
The rejection of claim 8 under 35 U.S.C. 103 as being unpatentable over de la Rosa et al. (US20170121685A1, 2017, on IDS 07/13/2023) in view of Glustafsson et al. (Journal of Cellular Biochemistry, 2006) is withdrawn due to cancellation of the claim.
The rejection of claim 9 under 35 U.S.C. 103 as being unpatentable over de la Rosa et al. (US20170121685A1, 2017, on IDS 07/13/2023) in view of Zhang et al. (Journal of Cellular Physiology, 2018) is withdrawn due to cancellation of the claim.
The rejection of claim 10 under 35 U.S.C. 103 as being unpatentable over de la Rosa et al. (US20170121685A1, 2017, on IDS 07/13/2023) in view of Ludwig et al. (International Journal of Molecular Science, 2019) and Hoang et al., Frontiers in Molecular Biosciences, 2020 is withdrawn in order to address the claims as amended.
The rejection of claim 13 under 35 U.S.C. 103 as being unpatentable over de la Rosa et al. (US20170121685A1, 2017, on IDS 07/13/2023) in view of Shpall et al. (WO2019099927, on IDS 05/06/2024) is withdrawn in order to address the claims as amended.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over de la Rosa et al. (US20170121685A1, 2017, on IDS 07/13/2023, previously cited) in view of Ma et al. (Aging, 2019, previously cited) and Zhang et al. (Journal of Cellular Physiology, 2018, previously cited).
In regards to claims 1 and 14, de la Rosa teaches a medium for culturing MSCs (animal cells) to derive exosomes (a type of extracellular vesicle) comprising DMEM (a basal medium) (paragraph [0093]; claim 7).
De la Rosa does not explicitly teach that the medium comprises insulin-like growth factor.
However, a person of ordinary skill in the art would have been motivated to include insulin-like growth factor (IGF) because Ma teaches that exosomes produced in media supplemented with IGF demonstrate anti-inflammatory and anti-apoptotic effects and in particular, inhibit neuroinflammation and have neuroprotective effects (Abstract, p12278; Fig. 2, p12280; Figure 3, p12282-12283).
Furthermore, because Ma teaches that stem cells can be cultured in media comprising IGF (Preparation and characterization of IGF-Exo, p12279) and that it is known in that MSC-derived exosomes promote neurovascular reshaping and functional recovery after stroke (Introduction, p12278), it could have been done with predictable results and a reasonable expectation of success.
De la Rosa does not explicitly teach that the medium comprises TGF-β.
However, a person of ordinary skill in the art would have been motivated to include TGF-β in the media because Zhang teaches that exosomes derived MSCs stimulated with TGF-β promotes Treg differentiation (Title, Abstract, p6832; Preparation of conditioned medium, p6834; Fig. 6, p6837).
Furthermore, because Zhang teaches methods for producing media comprising TGF-β for culturing MSCs (Preparation of conditioned medium, p6834) and de la Rosa and Zhang are in the same technical field of deriving exosomes from MSCs, it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 15, de la Rosa teaches methods for producing extracellular vesicles (Claim 7; paragraph [0093]).
Therefore, the combined teachings of de la Rosa, Ma, and Zhang render obvious the invention as claimed.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over de la Rosa et al. (US20170121685A1, 2017, on IDS 07/13/2023, previously cited) in view of Ma et al. (Aging, 2019, previously cited) and Zhang et al. (Journal of Cellular Physiology, 2018, previously cited) as applied to claim 1 above, and further in view of Dos Santos et al. (Stem Cell Rev and Rep, 2017, previously cited).
In regards to claim 2, de la Rosa teaches that the medium comprises glutamine (L-glutamine) (paragraph [0093]).
In regards to the concentration, it is noted that as above in claim 1, if the embodiment comprises L-glutamine, then the claimed concentration is 5mM. To this regard, de la Rosa teaches that the concentration of L-glutamine is 2mM (paragraph [0093]). While less than a concentration of 5mM or more, it is nonetheless close, and according to MPEP 2144.05(I), a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).
Furthermore, a person of ordinary skill in the art could have arrived at a concentration of 5 mM or greater and the disclosure does not point to a criticality in this concentration.
In regards to routine optimization, MPEP 2144.05(II)(A), generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
In the instant case because do Santos teaches that MSCs can be cultured in a range of concentrations including at least 10 mM L-glutamine (Abstract, p482; Fig. 1, p485), which overlaps with the range of at least 5 mM L-glutamine, a person of ordinary skill in the art could have arrived at a concentration of 5 mM or greater by routine optimization with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of de la Rosa, Ma, Zhang, and Dos Santos render obvious the invention as claimed.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over de la Rosa et al. (US20170121685A1, 2017, on IDS 07/13/2023, previously cited) in view of Ma et al. (Aging, 2019, previously cited) and Zhang et al. (Journal of Cellular Physiology, 2018, previously cited) as applied to claim 1 above, and further in view of Glustafsson et al. (Journal of Cellular Biochemistry, 2006, previously cited).
In regards to claim 3, de la Rosa discloses that the medium comprises at least insulin, transferrin and selenium (selenious acid) (paragraph [0093]).
De la Rosa does not explicitly teach that the medium comprises serotonin.
However, a person of ordinary skill in the art would have been motivated to include serotonin in the media because Glustafsson teaches that serotonin supplementation promotes proliferation of MSCs (Abstract, p139; Fig. 7, p147).
Furthermore, because Glustafsson teaches that serotonin can be added to media for culturing MSCs (Proliferation Assays, 142; Fig. 7, p147).) and de la Rosa are in the same technical field culturing MSCs, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of de la Rosa, Ma, Zhang, and Glustafsson render obvious the invention as claimed.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over de la Rosa et al. (US20170121685A1, 2017, on IDS 07/13/2023, previously cited) in view of Ma et al. (Aging, 2019, previously cited), Zhang et al. (Journal of Cellular Physiology, 2018, previously cited), and Dos Santos et al. (Stem Cell Rev and Rep, 2017, previously cited) as applied to claims 1 and 2 above, and further in view of Glustafsson et al. (Journal of Cellular Biochemistry, 2006, previously cited).
In regards to claim 4, de la Rosa discloses that the medium comprises at least insulin, transferrin and selenium (selenious acid) (paragraph [0093]).
De la Rosa does not explicitly teach that the medium comprises serotonin.
However, a person of ordinary skill in the art would have been motivated to include serotonin in the media because Glustafsson teaches that serotonin supplementation promotes proliferation of MSCs (Abstract, p139; Fig. 7, p147).
Furthermore, because Glustafsson teaches that serotonin can be added to media for culturing MSCs (Proliferation Assays, 142; Fig. 7, p147).) and de la Rosa are in the same technical field culturing MSCs, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of de la Rosa, Ma, Zhang, Dos Santos, and Glustafsson render obvious the invention as claimed.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over de la Rosa et al. (US20170121685A1, 2017, on IDS 07/13/2023, previously cited) in view of Ma et al. (Aging, 2019, previously cited) and Zhang et al. (Journal of Cellular Physiology, 2018, previously cited) as applied to claim 1 above, and further in view of Ludwig et al. (International Journal of Molecular Science, 2019, previously cited) and Hoang et al., (Frontiers in Molecular Biosciences, 2020, previously cited).
In regards to claim 10, de la Rosa teaches that the medium comprises serum (paragraph [0093]).
However, Ludwig teaches that there are exosomes present in fetal bovine serum (FBS) itself and that they are biologically active and that that co-isolation may lead to interference in subsequent in vitro or in vivo studies; that FBS can have confounding effects on highly sensitive gene profiling technologies; and that not only FBS in culture supernatants but also proteins present in serum or plasma or any body fluid used as a source of extracellular vesicles can “contaminate” exosomes leading to artefactual data in downstream applications, especially in mass spectrometry (Medium Composition, p4-5). Therefore, a person of ordinary skill in the art would have been motivated to use serum free conditions in order avoid this contamination.
Furthermore, because Hoang teaches that MSCs can be specifically cultured in serum-free conditions for the derivation of exosomes (Title, Abstract, p1; Figure 4, p8), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of de la Rosa, Ma, Zhang, Ludwig and Hoang render obvious the invention as claimed.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over de la Rosa et al. (US20170121685A1, 2017, on IDS 07/13/2023, previously cited) in view of Ma et al. (Aging, 2019, previously cited), Zhang et al. (Journal of Cellular Physiology, 2018, previously cited), and Shpall et al. (WO2019099927, on IDS 05/06/2024).
In regards to claim 13, as discussed above, de la Rosa teaches a medium for culturing MSCs (animal cells) to derive exosomes (a type of extracellular vesicle) comprising DMEM (a basal medium) (paragraph [0093]; claim 7).
De la Rosa does not explicitly teach that the medium comprises insulin-like growth factor.
However, a person of ordinary skill in the art would have been motivated to include insulin-like growth factor (IGF) because Ma teaches that exosomes produced in media supplemented with IGF demonstrate anti-inflammatory and anti-apoptotic effects and in particular, inhibit neuroinflammation and have neuroprotective effects (Abstract, p12278; Fig. 2, p12280; Figure 3, p12282-12283).
Furthermore, because Ma teaches that stem cells can be cultured in media comprising IGF (Preparation and characterization of IGF-Exo, p12279) and that it is known in that MSC-derived exosomes promote neurovascular reshaping and functional recovery after stroke (Introduction, p12278), it could have been done with predictable results and a reasonable expectation of success.
De la Rosa does not explicitly teach that the medium comprises TGF-β.
However, a person of ordinary skill in the art would have been motivated to include TGF-β in the media because Zhang teaches that exosomes derived MSCs stimulated with TGF-β promotes Treg differentiation (Title, Abstract, p6832; Preparation of conditioned medium, p6834; Fig. 6, p6837).
Furthermore, because Zhang teaches methods for producing media comprising TGF-β for culturing MSCs (Preparation of conditioned medium, p6834) and de la Rosa and Zhang are in the same technical field of deriving exosomes from MSCs, it could have been done with predictable results and a reasonable expectation of success.
De la Rosa does not explicitly teach the composition as a kit.
However, a person of ordinary skill in the art would have been motivated to incorporate the composition into a kit because Shpall teaches that kits comprising compositions for deriving MSCs exosomes can be used to administer exosome compositions (paragraph [00176]). Furthermore, kits for media compositions are well-known in the art and it would have been obvious to combine components into a kit for the purpose of convenience and economy. Furthermore, because Shpall teaches that kits for preparing exosomes can be made (paragraph [00176]), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of de la Rosa, Ma, Zhang, and Shpall render obvious the invention as claimed.
Response to Arguments
Applicant argues that the exosomes of Ma derive from neural stem cells which are different from the MSCs as claimed (Remarks, p7).
Applicant’s arguments filed 05/04/2026 have been fully considered but are not found persuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., specific cells in the culture medium, such as MSCs) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues that while treatment with both TGFβ and IFNγ promotes Treg differentiation, treatment but TGFβ alone yields a lower effect (Remarks, p7). As a result, Applicant argues that Zhang does not provide a proper rationale (Remarks, p7).
Applicant’s arguments filed 05/04/2026 have been fully considered but are not found persuasive.
The culture medium as claimed “comprises” TGFβ and IGF and therefore, may allow other factors such as IFNγ.
Thus, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a medium that does not comprise IFNγ) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Moreover, as noted by Applicant, as taught by Zhang, TGFβ still yields an effect, and therefore, a person of ordinary skill in the art would still have been motivated to add TGFβ in order to obtain this effect.
Applicant argues that there is no rationale to combine IGF and TGFβ (Remarks, p7). Applicant argues that the references fail to disclose all the claim limitations and fail to provide a proper reason to combine (Remarks, p8-9).
Applicant’s arguments filed 05/04/2026 have been fully considered but are not found persuasive.
As discussed above, de la Rosa teaches a medium for culturing MSCs (animal cells) to derive exosomes (a type of extracellular vesicle) comprising DMEM (a basal medium) (paragraph [0093]; claim 7).
De la Rosa does not explicitly teach that the medium comprises insulin-like growth factor.
However, a person of ordinary skill in the art would have been motivated to include insulin-like growth factor (IGF) because Ma teaches that exosomes produced in media supplemented with IGF demonstrate anti-inflammatory and anti-apoptotic effects and in particular, inhibit neuroinflammation and have neuroprotective effects (Abstract, p12278; Fig. 2, p12280; Figure 3, p12282-12283).
Furthermore, because Ma teaches that stem cells can be cultured in media comprising IGF (Preparation and characterization of IGF-Exo, p12279) and that it is known in that MSC-derived exosomes promote neurovascular reshaping and functional recovery after stroke (Introduction, p12278), it could have been done with predictable results and a reasonable expectation of success.
De la Rosa does not explicitly teach that the medium comprises TGF-β.
However, a person of ordinary skill in the art would have been motivated to include TGF-β in the media because Zhang teaches that exosomes derived MSCs stimulated with TGF-β promotes Treg differentiation (Title, Abstract, p6832; Preparation of conditioned medium, p6834; Fig. 6, p6837).
Furthermore, because Zhang teaches methods for producing media comprising TGF-β for culturing MSCs (Preparation of conditioned medium, p6834) and de la Rosa and Zhang are in the same technical field of deriving exosomes from MSCs, it could have been done with predictable results and a reasonable expectation of success.
As argued by Applicant, the combination of IGF and TGFβ results in increased anti-inflammatory activity (Remarks, p8, citing Fig. 3 and paragraph [0049] of the instant specification). Applicant argues that these are unexpected results (Remarks, p9).
Applicant argues that none of de la Rosa, Ma, or Zhang discloses this advantageous effect (Remarks, p8).
Applicant’s arguments filed 05/04/2026 have been fully considered but are not found persuasive.
In regards to Applicant’s allegations of unexpected results, whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (see MPEP 716.02(d)).
In the instant case, the claims do not require any specific result.
Furthermore, according to MPEP 716.02(a), not only must the evidence relied upon should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength “are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration.”), but also, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (Evidence showing greater than additive sweetness resulting from the claimed mixture of saccharin and L-aspartyl-L-phenylalanine was not sufficient to outweigh the evidence of obviousness because the teachings of the prior art lead to a general expectation of greater than additive sweetening effects when using mixtures of synthetic sweeteners.).
In the instant case, even if the claims did require specific results, there is no indicated in the disclosure that the results were greater than those which would have been expected from the prior art to an unobvious extent or were even greater than additive effect.
Thus, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a specific effect on culturing cells) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Conclusion
No claims are allowed.
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 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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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
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