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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/09/2026 has been entered.
Status of the Claims
Claims 17, 19-28, and 31-33 are pending.
Claims 17, 19-20, and 32 are newly amended.
Claims 17, 19-28, and 31-33 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Withdrawn Objections & Rejections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 Any objections or rejections not specifically reiterated are hereby withdrawn.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 17, 19-20, 24-25, and 27-28, and 31 under 35 U.S.C. 102(a)(1) or 35 U.S.C. 102(a)(2) as being anticipated by Sinden et al. (US2015/0079046 A1, previously cited) as evidenced by Yang et al. (Journal of Dental Research, 2016, previously cited) is withdrawn to address the claims as amended.
The rejection of claims 21 and 26 under 35 U.S.C. 103 as being unpatentable over Sinden et al. (US2015/0079046 A1, previously cited), as evidenced by Yang et al. (Journal of Dental Research, 2016, previously cited), as applied to claim 17 above, and further in view of Kalluri et al. (WO2016201323A1, 2016, on IDS 09/13/2023, previously cited) is withdrawn to address the claims as amended.
The rejection of claims 22-23 are rejected 35 U.S.C. 103 as being unpatentable over Sinden et al. (US2015/0079046 A1, previously cited), as evidenced by Yang et al. (Journal of Dental Research, 2016, previously cited), as applied to claim 17 above, and further in view of Klimanskaya et al. (WO2010138517A1, 2010, previously cited) is withdrawn to address the claims as amended.
The rejection of claim 32 under 35 U.S.C. 103 as being unpatentable over Sinden et al. (US2015/0079046 A1, previously cited), as evidenced by Yang et al. (Journal of Dental Research, 2016, previously cited), as applied to claim 17 and 20 above, and further in view of Cheng et al. (Sains Malaysiana 2018, previously cited) is withdrawn to address the claims as amended.
The rejection of claim 33 under 35 U.S.C. 103 as being unpatentable over Sinden et al. (US2015/0079046 A1, previously cited), as evidenced by Yang et al. (Journal of Dental Research, 2016, previously cited), as applied to claim 17 and 24 above, and further in view of Zhu et al. (PLOS ONE, 2008, previously cited) is withdrawn to address the claims as amended.
Claim Interpretation
Claim 17 is limited to a culture of “de-differentiated fibroblasts”. This term is not explicitly defined in the disclosure.
As evidenced by Merriam-Webster (previously cited) “dedifferentiation” means “reversion of a specialized structure (such as cells) to a more generalized or primitive conditions often as a preliminary to major physiological or structural change”, and therefore, the term “dedifferentiated fibroblast” has been interpreted as “a fibroblast that has been reverted to a more generalized or primitive condition” (Remarks, p6).
Additionally, it is noted that the specification explicitly states, “In some embodiments, passaged cells are defined as ‘dedifferentiated’ if expression of OCT-4 is detected” (paragraph [0117]). Thus, any cell derived from a fibroblast that expresses OCT-4, is considered a de-differentiated fibroblast per se.
Claim 17 is also limited to “conditioned media”. This term is also not explicitly defined by the specification. The specification states, “In particular embodiments, the conditioned media may be generated by manipulation of fibroblast cells that may be any kind of fibroblast cells” (paragraph [0037]). However, claim 28 states that “the conditioned media does not comprise fibroblasts or dedifferentiated fibroblasts”. Therefore, the conditioned media does not necessarily require fibroblasts themselves but only the exosomes derived from the cells. Turning to the art, as defined by Cell Guidance System (Conditioning cell culture media, 2020, previously cited), “conditioned media” is simply “media containing components secreted by cells which are required by another set of cells” (second page, top paragraph), of which exosomes are a type. Therefore, the term “conditioned media” has been interpreted as any media that comprises exosomes secreted from dedifferentiated fibroblasts.
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 17, 19-20, 24-25, and 27-28, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Sinden et al. (US2015/0079046 A1, previously cited) in view of Cheng et al. (Cell Research, 2014) as evidenced by Sethumadhavan et al. (Plos One, 2017).
In regards to claim 17, Sinden teaches a conditioned medium comprising microparticles, which can be exosomes specifically (paragraphs [0010-0011, 0023]). Sinden teaches that the microparticles (exosomes) are derived from neural stem cells produced from somatic cells such as fibroblasts (paragraph [0058]) and are thus are de-differentiated fibroblasts as defined above.
In regards to whether the de-differentiated fibroblasts were produced from fibroblasts exposure to a composition consisting essentially of valproic acid (VPA) and were produced under hypoxic conditions, Applicant should note that this is a product-by-process step.
In regards to product-by-process claims, while the structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product (See, e.g., In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979)), and even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production (see MPEP 2113).
In the instant case, the claims explicitly do not express MHC 1, thus process steps appear to impart distinctive structural characteristics to the final product.
Indeed, as demonstrated in the Declaration under 37 CFR 1.132 on 04/09/2026, fibroblasts dedifferentiated in a combination of VPA and hypoxia demonstrate only negligible levels of MHC I (Exhibit 2 Figure, p33).
However, while Sinden does not specifically teach de-differentiating fibroblasts in a hypoxic media comprising VPA, Sinden gives an example of de-differentiating fibroblasts where Oct 4 is “strictly limited” (paragraph [0058]).
As demonstrated by Applicant in the Declaration under 37 CFR 1.132 on 04/09/2026, OCT4 reprogramming results in high expression of MHC 1. Thus, since in the method as taught by Sinden strictly limits OCT4, the method of Sinden would not result in high levels of MHC 1 expression.
Furthermore, methods of de-differentiating fibroblasts to neural stem cells were known in the art before the effective filing date. Specifically, Cheng teaches that fibroblasts can be re-programmed (de-differentiated) to neural progenitor (stem) cells in media comprising VPA and under hypoxic conditions (Abstract, p665). Additionally, Cheng teaches that utilizing chemical reprogramming with VPA is desirable because other methods (specifically, Yamanaka factor-induced reprogramming, as used in the example as taught by Sinden above) require exogenous reprogramming factors of which there are questions regarding their clinical safety (Introduction, p665-666).
In regards to hypoxic conditions, Cheng teaches that hypoxic conditions better mimic physiological conditions than ambient levels and is one of the key beneficial niche features for stem cells in vivo (Discussion, p676).
Therefore, a person of ordinary skill in the art would have been motivated to de-differentiate fibroblasts in hypoxic media comprising VPA because it would be most suitable for clinical application and better mimic . Furthermore, because Sinden teaches that the microparticles (exosomes) are specifically for use in therapy (Abstract), because Cheng teaches that fibroblasts can be de-differentiated to neural stem/progenitor cells in hypoxic media comprising VPA, and because Sinden and Cheng are in the same technical field of utilizing neural stem/progenitor cells from fibroblasts, it could have been done with predictable results and a reasonable expectation of success.
In regards to a lack of expression of MHC 1, the claims and Applicant’s declaration indicate that the lack of MHC 1 expression on exosomes is an inherent quality of de-differentiating fibroblasts in hypoxic media comprising VPA, and since the exosomes as taught by Sinden and as produced by the method of Cheng would also inherently not express MHC 1. Moreover, as evidenced by Sethumadhvan, hypoxia itself is sufficient to downregulate MHC 1 molecules when cells are cultured in 3D in vitro (Abstract, p1; Results, p2-5; Fig. 5, 7; it is noted that Cheng carries out reprogramming in Matrigel (Generation of ciNPCs, p676). Therefore, since Applicant’s declaration indicates that this is an inherently property of deprogramming in hypoxic media comprising VPA, since Sethumadhvan indicates that hypoxic conditions result in decreased MHC 1 expression, and since Sinden as modified by Cheng carries out these steps, the method of Sinden as modified would result in de-differentiated cells lacking MHC 1 expression absent evidence to the contrary.
In regards to claims 19 and 31, Sinden teaches that the exosomes may express NCAM (paragraph [0353]), which is the same as CD56.
In regards to claim 20, Sinden teaches that the media can comprise at last McCoy’s 5A (paragraph [0159]), which is known in the art to contain ascorbic acid (vitamin C).
In regards to claim 24, Sinden teaches that the media may comprise VEGF (paragraph [0254]).
In regards to claim 25, Sinden teaches that the composition is sterile (paragraph 0163]).
In regards to claim 27, Sinden teaches that the composition can be stably manufactured (paragraph [0206] and stored for extended periods (paragraph [0169]).
In regards to claim 28, Sinden teaches that the composition may be isolated from cells (paragraph [0010, 0023].
Therefore, the combined teachings of Sinden and Cheng renders the invention unpatentable as claimed.
Claims 21 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Sinden et al. (US2015/0079046 A1, previously cited) in view of Cheng et al. (Cell Research, 2014) as evidenced by Sethumadhavan et al. (Plos One, 2017), as applied to claim 17 above, and further in view of Kalluri et al. (WO2016201323A1, 2016, on IDS 09/13/2023, previously cited).
In regards to claims 21 and 26, Sinden teaches that composition can comprise a pharmaceutically acceptable carrier (paragraph [0025]), which suggests coating the composition. However, Sinden does not explicitly teach that the composition is coated with lecithin (as in claim 26), specifically.
However, a person of ordinary skill in the arts would have been motivated to coat the compound with lecithin because, as taught by Kalluri, exosomes for the use of the treatment of diseases (Abstract) can be coated with lecithin for administration (paragraph [00112]). Furthermore, because Kalluri indicates that lecithin is a suitable coating for pharmaceutically acceptable carries of exosomes (Abstract; paragraph [00122]), and Sinden teaches that that composition can comprise a pharmaceutically acceptable carrier, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Sinden, Cheng, and Kalluri render obvious the invention as claimed.
Claims 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over Sinden et al. (US2015/0079046 A1, previously cited) in view of Cheng et al. (Cell Research, 2014) as evidenced by Sethumadhavan et al. (Plos One, 2017) as applied to claim 17 above, and further in view of Klimanskaya et al. (WO2010138517A1, 2010, previously cited).
In regards to claims 22-23, Sinden does not explicitly teach that the composition comprised an enzyme inhibitor, or specifically the inhibitors as in claim 23.
However, a person of ordinary skill in the arts would have been motivated to include an enzyme inhibitor such as Trasylol (aprotinin) because as taught by Klimanskaya, media comprising aprotinin promotes nuclear envelope dissolution and chromatin condensation in fibroblasts (paragraph [00612]), which allow them to be remodeled to an undifferentiated state (thus, de-differentiated) (paragraph [00614]).
Furthermore, because Klimanskaya teaches methods of treating fibroblasts in media (thus coating) comprising aprotinin (paragraph [00612]), and Sinden teaches that stem cells may be derived from fibroblasts, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Sinden and Klimanskaya render obvious the invention as claimed.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Sinden et al. (US2015/0079046 A1, previously cited) in view of Cheng et al. (Cell Research, 2014) as evidenced by Sethumadhavan et al. (Plos One, 2017) as applied to claim 17 and 20 above, and further in view of Cheng et al. (Sains Malaysiana 2018, previously cited, hereafter “Cheng 2”).
In regards to claim 32, Sinden does not explicitly teach that the composition comprises gallic acid.
However, a person of ordinary skill in the art would have been motivated to add gallic acid to the composition because Cheng 2 teaches that gallic acid has anti-proliferative activities against cancer cells (Abstract, p1209; p1210, column 2); that gallic acid treated neural stem (progenitor) cells migrate towards glioblastoma cells which significantly reduces the number of these glioblastoma cells; and suggests that neural stem cells can act as a vehicle to deliver gallic acid (Abstract, p1209). Furthermore, because Cheng demonstrates that cells that can be de-differentiated fibroblasts can be used as vehicles for delivering gallic acid and because Sinden teaches that the composition can be used for therapeutic purposes (paragraph [0001]; claim 19), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Sinden, Cheng, and Cheng 2 render the invention unpatentable as claimed.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Sinden et al. (US2015/0079046 A1, previously cited), in view of Cheng et al. (Cell Research, 2014) as evidenced by Sethumadhavan et al. (Plos One, 2017), as applied to claim 17 and 24 above, and further in view of Zhu et al. (PLOS ONE, 2008, previously cited).
In regards to claim 33, Sinden does not explicitly teach that the composition comprises an anti-CD45RB antibody.
However, a person of ordinary skill in the art would have been motivated to include an anti-CD45RB antibody because Zhu teaches that LPS-induced microglial activation occurs in Alzheimer’s disease, but that treatment of microglial cells with agonist CD45 antibodies (including CD45RB antibodies specifically, a species of anti-CD45RB antibody) results in significant inhibition of LPS-induced microglial cytokine release, augmentation of microglial phagocytosis of amyloid, and therefore recommends this treatment for patients with Alzheimer’s disease because such treatments may be more effective with less potential to produce systemic side-effects than therapeutics which induce non-specific, systemic down-regulation of inflammation (Abstract, p1).
Furthermore, because Zhu demonstrates that microglia can be effectively treated with anti-CD45RB antibodies (Abstract, p1; Fig. 1, p3, etc.; Microglial phagocytosis assays, p10, etc.), and because Sinden teaches that the composition can be used for therapeutic purposes (paragraph [0001]; claim 19), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Sinden and Zhu renders the invention unpatentable as claimed.
Double Patenting
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claim 17 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 19/448,785 in view of Zhai et al. (Experimental Cell Research, 2015).
Claims 19-28, and 31-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 19/448,785 in view of Zhai et al. (Experimental Cell Research, 2015) as applied to claim 17 above, and further in view of Sinden et al. (US2015/0079046 A1, previously cited).
Claims 21 and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 19/448,785 in view of Zhai et al. (Experimental Cell Research, 2015) as applied to claim 17 above, and further in view of Kalluri et al. (WO2016201323A1, 2016, on IDS 09/13/2023, previously cited).
Claims 22-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 19/448,785 in view of Zhai et al. (Experimental Cell Research, 2015) as applied to claim 17 above, and further in view of Klimanskaya et al. (WO2010138517A1, 2010, previously cited).
Claim 32 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 19/448,785 in view of of Zhai et al. (Experimental Cell Research, 2015) and Sinden et al. (US2015/0079046 A1, previously cited) as applied to claims 17 and 20 above, and further in view of Cheng et al. (Sains Malaysiana 2018, previously cited, hereafter “Cheng 2”).
Claim 33 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 19/448,785 in view of Zhai et al. (Experimental Cell Research, 2015) and Sinden et al. (US2015/0079046 A1, previously cited) as applied to claims 17 and 24 above, and further in view of Zhu et al. (PLOS ONE, 2008, previously cited).
In regards to claim 17, while instant claims and the claims of the co-pending application are not identical, they are not patentably distinct because they are both drawn to conditioned media comprising exposomes that are produced from fibroblasts cultured under hypoxic conditions and a histone deacetylase (HDAC) inhibitor (of which VPA is a well-known type; and are thus de-differentiated fibroblasts). It would have been predictably obvious to use VPA as an HDAC inhibitor because as taught by Zhai, VPA is well-established HDAC inhibitor known for its ability to promote pluripotency (Title, Abstract, Introduction, p61).
In regards to not expressing MHC 1, as discussed above, and as demonstrated by Applicant (see declaration under 37 CFR 1.132 filed 04/09/2026, Exhibit 2), this is an inherent property of exosomes from fibroblasts de-differentiated under hypoxic conditions with VPA.
In regards to the embodiments of claims 19-28, and 31-33, these embodiments were all known in the art before the effective filing date.
In particular, Sinden teaches that the exosomes from de-differentiated fibroblasts may express NCAM (paragraph [0353]), which is the same as CD56; that exosome media may comprise at last McCoy’s 5A (paragraph [0159]), which is known in the art to contain ascorbic acid (vitamin C); that the media may comprise VEGF (paragraph [0254]); be sterile (paragraph 0163]); stably manufactured (paragraph [0206] and stored for extended periods (paragraph [0169]); and isolated from cells (paragraph [0010, 0023].
A person of ordinary skill in the art would have been motivated to use these conditions because Sinden teaches that they are suitable for use in therapeutic application (paragraph [0020]. Furthermore, because these are all known media conditions for exosomes from de-differentiated fibroblasts, as taught by Sinden above, it could have been done with predictable result and a reasonable expectation of success.
In regards to claims 21 and 26, a person of ordinary skill in the arts would have been motivated to coat the compound with lecithin because, as taught by Kalluri, exosomes for the use of the treatment of diseases (Abstract) can be coated with lecithin for administration (paragraph [00112]). Furthermore, because Kalluri indicates that lecithin is a suitable coating for pharmaceutically acceptable carries of exosomes (Abstract; paragraph [00122]), it could have been done with predictable results and a reasonable expectation of success.
In regards to claims 22-23, a person of ordinary skill in the arts would have been motivated to include an enzyme inhibitor such as Trasylol (aprotinin) because as taught by Klimanskaya, media comprising aprotinin promotes nuclear envelope dissolution and chromatin condensation in fibroblasts (paragraph [00612]), which allow them to be remodeled to an undifferentiated state (thus, de-differentiated) (paragraph [00614]).
Furthermore, because Klimanskaya teaches methods of treating fibroblasts in media (thus coating) comprising aprotinin (paragraph [00612]), it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 32, a person of ordinary skill in the art would have been motivated to add gallic acid to the composition because Cheng 2 teaches that gallic acid has anti-proliferative activities against cancer cells (Abstract, p1209; p1210, column 2); that gallic acid treated neural stem (progenitor) cells migrate towards glioblastoma cells which significantly reduces the number of these glioblastoma cells; and suggests that neural stem cells can act as a vehicle to deliver gallic acid (Abstract, p1209). Furthermore, because Cheng demonstrates that cells that can be de-differentiated fibroblasts can be used as vehicles for delivering gallic acid it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 33, a person of ordinary skill in the art would have been motivated to include an anti-CD45RB antibody because Zhu teaches that LPS-induced microglial activation occurs in Alzheimer’s disease, but that treatment of microglial cells with agonist CD45 antibodies (including CD45RB antibodies specifically, a species of anti-CD45RB antibody) results in significant inhibition of LPS-induced microglial cytokine release, augmentation of microglial phagocytosis of amyloid, and therefore recommends this treatment for patients with Alzheimer’s disease because such treatments may be more effective with less potential to produce systemic side-effects than therapeutics which induce non-specific, systemic down-regulation of inflammation (Abstract, p1). Furthermore, because Zhu demonstrates that microglia can be effectively treated with anti-CD45RB antibodies (Abstract, p1; Fig. 1, p3, etc.; Microglial phagocytosis assays, p10, etc.) it could have been done with predictable results and a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant argues that the claims as amended are not anticipates under 35 USC 102 (Remarks, p4).
Applicant’s arguments, see p4, filed 04/09/2026 with regards to the rejection of the claims under 25 USC 102 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of over Sinden in view of Cheng as discussed above.
Applicant argues that the claims are not prima facie obvious under 35 USC 103 (Remarks, p4-5). Specifically, Applicant argues that none of the cited references teach conditioned media comprising exosomes from de-differentiated fibroblasts wherein the exosomes do not express MHC-1 (Remarks, p5). Additionally, Applicant argues that the media as taught by Sinden comprises MHC 1 antigens (Remarks, p5).
Applicant’s arguments filed 04/09/2026 have been fully considered but are not found persuasive.
In regards to Applicant’s argument that the exosomes of Sinden Express MHC 1, Sinden only teaches “Exosomes of the invention typically express specific integrins, tetraspanins, MHC Class I and/or Class II antigens, CD antigens and cell-adhesion molecules on their surfaces” (paragraph [0081]). Therefore, while the exosomes of Sinden may comprise MHC 1 antigens, it is not necessarily the case that they do.
Additionally, in regards to a conditioned media comprising exosomes from de-differentiated fibroblasts wherein the exosomes do not express MHC-1, as discussed above, Sinden teaches a conditioned medium comprising microparticles, which can be exosomes specifically (paragraphs [0010-0011, 0023]). Sinden teaches that the microparticles (exosomes) are derived from neural stem cells produced from somatic cells such as fibroblasts (paragraph [0058]) and are thus are de-differentiated fibroblasts as defined above.
In regards to whether the de-differentiated fibroblasts were produced from fibroblasts exposure to a composition consisting essentially of valproic acid (VPA) and were produced under hypoxic conditions, Applicant should note that this is a product-by-process step.
In regards to product-by-process claims, while the structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product (See, e.g., In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979)), and even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production (see MPEP 2113).
In the instant case, the claims explicitly do not express MHC 1, thus process steps appear to impart distinctive structural characteristics to the final product.
Indeed, as demonstrated in the Declaration under 37 CFR 1.132 on 04/09/2026, fibroblasts dedifferentiated in a combination of VPA and hypoxia demonstrate only negligible levels of MHC I (Exhibit 2 Figure, p33).
However, while Sinden does not specifically teach de-differentiating fibroblasts in a hypoxic media comprising VPA, Sinden gives an example of de-differentiating fibroblasts where Oct 4 is “strictly limited” (paragraph [0058]).
As demonstrated by Applicant in the Declaration under 37 CFR 1.132 on 04/09/2026, OCT4 reprogramming results in high expression of MHC 1. Thus, since in the method as taught by Sinden strictly limits OCT4, the method of Sinden would not result in high levels of MHC 1 expression.
Furthermore, methods of de-differentiating fibroblasts to neural stem cells were known in the art before the effective filing date. Specifically, Cheng teaches that fibroblasts can be re-programmed (de-differentiated) to neural progenitor (stem) cells in media comprising VPA and under hypoxic conditions (Abstract, p665). Additionally, Cheng teaches that utilizing chemical reprogramming with VPA is desirable because other methods (specifically, Yamanaka factor-induced reprogramming, as used in the example as taught by Sinden above) require exogenous reprogramming factors of which there are questions regarding their clinical safety (Introduction, p665-666).
In regards to hypoxic conditions, Cheng teaches that hypoxic conditions better mimic physiological conditions than ambient levels and is one of the key beneficial niche features for stem cells in vivo (Discussion, p676).
Therefore, a person of ordinary skill in the art would have been motivated to de-differentiate fibroblasts in hypoxic media comprising VPA because it would be most suitable for clinical application and better mimic . Furthermore, because Sinden teaches that the microparticles (exosomes) are specifically for use in therapy (Abstract), because Cheng teaches that fibroblasts can be de-differentiated to neural stem/progenitor cells in hypoxic media comprising VPA, and because Sinden and Cheng are in the same technical field of utilizing neural stem/progenitor cells from fibroblasts, it could have been done with predictable results and a reasonable expectation of success.
In regards to a lack of expression of MHC 1, the claims and Applicant’s declaration indicate that the lack of MHC 1 expression on exosomes is an inherent quality of de-differentiating fibroblasts in hypoxic media comprising VPA, and since the exosomes as taught by Sinden and as produced by the method of Cheng would also inherently not express MHC 1. Morever, as evidenced by Sethumadhvan, hypoxia itself is sufficient to downregulate MHC 1 molecules when cells are cultured in 3D in vitro (Abstract, p1; Results, p2-5; Fig. 5, 7; it is noted that Cheng carries out reprogramming in Matrigel (Generation of ciNPCs, p676). Therefore, since Applicant’s declaration indicates that this is an inherently property of deprogramming in hypoxic media comprising VPA, since Sethumadhvan indicates that hypoxic conditions result in decreased MHC 1 expression, and since Sinden as modified by Cheng carries out these steps, the method of Sinden as modified would result in de-differentiated cells lacking MHC 1 expression absent evidence to the contrary.
Applicant argues that there are unexpected results (Remarks, p5). Specifically, Applicant argues that as discussed in the Declaration under 37 CFR 1.132 filed 04/09/2026, fibroblasts that have been de-differentiated in hypoxic media comprising VPA do not expression MHC 1 and have two-fold greater regenerative properties (Declaration Exhibit 1), but that fibroblasts differentiated without these conditions do not (Remarks, p5-6).
Applicant’s arguments filed 04/09/2026 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 regarding regenerative properties of HUVECs.
Moreover, as discussed above, as demonstrated in the specification, the lack of expression of MHC 1 is an inherent property of reprogramming (de-differentiating) in hypoxic media, comprising VPA. Moreover, as evidenced by as evidenced by Sethumadhvan, hypoxia itself is sufficient to downregulate MHC 1 molecules when cells are cultured in 3D in vitro (Abstract, p1; Results, p2-5; Fig. 5, 7).
Furthermore, as discussed above, there is clear motivation in the art to dedifferentiate fibroblasts in hypoxic media comprising VPA.
As above, as taught by Cheng teaches that utilizing chemical reprogramming with VPA is desirable because other methods (specifically, Yamanaka factor-induced reprogramming, as used in the example as taught by Sinden above) require exogenous reprogramming factors of which there are questions regarding their clinical safety (Introduction, p665-666).
In regards to hypoxic conditions, Cheng teaches that hypoxic conditions better mimic physiological conditions than ambient levels and is one of the key beneficial niche features for stem cells in vivo (Discussion, p676).
Therefore, a person of ordinary skill in the art would have been motivated to de-differentiate fibroblasts in hypoxic media comprising VPA because it would be most suitable for clinical application and better mimic . Furthermore, because Sinden teaches that the microparticles (exosomes) are specifically for use in therapy (Abstract), because Cheng teaches that fibroblasts can be de-differentiated to neural stem/progenitor cells in hypoxic media comprising VPA, and because Sinden and Cheng are in the same technical field of utilizing neural stem/progenitor cells from fibroblasts, it could have been done with predictable results and a reasonable expectation of success.
Therefore, since Applicant’s declaration indicates that this is an inherently property of deprogramming in hypoxic media comprising VPA, since Sethumadhvan indicates that hypoxic conditions result in decreased MHC 1 expression (and again, it is noted that Cheng carries out reprogramming in 3D, and since Sinden as modified by Cheng carries out these steps, the method of Sinden as modified would result in de-differentiated cells lacking MHC 1 expression absent evidence to the contrary.
Declaration under 36 CFR 1.132
Applicant declares that experiments demonstrate that exosomes from fibroblasts that are dedifferentiated with Oct4 express MHC 1, while fibroblasts dedifferentiated with VPA under hypoxic conditions do not express MHC 1 (Paragraph 2, citing Exhibit 2).
The declaration under 37 CFR 1.132 filed 04/09/2026 is insufficient to overcome the rejection of claims 17, 19-28, and 31-33 based upon Sinden in view of Cheng as discussed above because: it does not establish facts which overcomes the rejection.
, in regards to a conditioned media comprising exosomes from de-differentiated fibroblasts wherein the exosomes do not express MHC-1, as discussed above, Sinden teaches a conditioned medium comprising microparticles, which can be exosomes specifically (paragraphs [0010-0011, 0023]). Sinden teaches that the microparticles (exosomes) are derived from neural stem cells produced from somatic cells such as fibroblasts (paragraph [0058]) and are thus are de-differentiated fibroblasts as defined above.
In regards to whether the de-differentiated fibroblasts were produced from fibroblasts exposure to a composition consisting essentially of valproic acid (VPA) and were produced under hypoxic conditions, Applicant should note that this is a product-by-process step.
In regards to product-by-process claims, while the structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product (See, e.g., In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979)), and even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production (see MPEP 2113).
In the instant case, the claims explicitly do not express MHC 1, thus process steps appear to impart distinctive structural characteristics to the final product.
Indeed, as demonstrated in the Declaration under 37 CFR 1.132 on 04/09/2026, fibroblasts dedifferentiated in a combination of VPA and hypoxia demonstrate only negligible levels of MHC I (Exhibit 2 Figure, p33).
However, while Sinden does not specifically teach de-differentiating fibroblasts in a hypoxic media comprising VPA, Sinden gives an example of de-differentiating fibroblasts where Oct 4 is “strictly limited” (paragraph [0058]).
As demonstrated by Applicant in the Declaration under 37 CFR 1.132 on 04/09/2026, OCT4 reprogramming results in high expression of MHC 1. Thus, since in the method as taught by Sinden strictly limits OCT4, the method of Sinden would not result in high levels of MHC 1 expression.
Furthermore, methods of de-differentiating fibroblasts to neural stem cells were known in the art before the effective filing date. Specifically, Cheng teaches that fibroblasts can be re-programmed (de-differentiated) to neural progenitor (stem) cells in media comprising VPA and under hypoxic conditions (Abstract, p665). Additionally, Cheng teaches that utilizing chemical reprogramming with VPA is desirable because other methods (specifically, Yamanaka factor-induced reprogramming, as used in the example as taught by Sinden above) require exogenous reprogramming factors of which there are questions regarding their clinical safety (Introduction, p665-666).
In regards to hypoxic conditions, Cheng teaches that hypoxic conditions better mimic physiological conditions than ambient levels and is one of the key beneficial niche features for stem cells in vivo (Discussion, p676).
Therefore, a person of ordinary skill in the art would have been motivated to de-differentiate fibroblasts in hypoxic media comprising VPA because it would be most suitable for clinical application and better mimic . Furthermore, because Sinden teaches that the microparticles (exosomes) are specifically for use in therapy (Abstract), because Cheng teaches that fibroblasts can be de-differentiated to neural stem/progenitor cells in hypoxic media comprising VPA, and because Sinden and Cheng are in the same technical field of utilizing neural stem/progenitor cells from fibroblasts, it could have been done with predictable results and a reasonable expectation of success.
In regards to a lack of expression of MHC 1, the claims and Applicant’s declaration indicate that the lack of MHC 1 expression on exosomes is an inherent quality of de-differentiating fibroblasts in hypoxic media comprising VPA, and since the exosomes as taught by Sinden and as produced by the method of Cheng would also inherently not express MHC 1. Moreover, as evidenced by Sethumadhvan, hypoxia itself is sufficient to downregulate MHC 1 molecules when cells are cultured in 3D in vitro (Abstract, p1; Results, p2-5; Fig. 5, 7; it is noted that Cheng carries out reprogramming in Matrigel (Generation of ciNPCs, p676). Therefore, since Applicant’s declaration indicates that this is an inherently property of deprogramming in hypoxic media comprising VPA, since Sethumadhvan indicates that hypoxic conditions result in decreased MHC 1 expression, and since Sinden as modified by Cheng carries out these steps, the method of Sinden as modified would result in de-differentiated cells lacking MHC 1 expression absent evidence to the contrary.
Applicant declares that the observation that exosomes from dedifferentiated fibroblasts treated with hypoxia and VPA lacking MHC I is completely counter intuitive (paragraph 3). Specifically, Applicant argues that this is because hypoxia VPA-treated dedifferentiated fibroblasts potentially stimulate HUVEC proliferation and because it is believed in the art that exosomes which possess mitogenic activity contain more “cargo”, which is associated with increased cellular stress, and which suggests enhanced MHC I expression because this molecule is needed to present antigens to T cells (Paragraph 3).
The declaration under 37 CFR 1.132 filed 04/09/2026 is insufficient to overcome the rejection of claims 17, 19-28, and 31-33 based upon Sinden in view of Cheng as discussed above because: it is not commensurate in scope with the claims and is not germane the rejection.
Specifically, the claims do not require steps of stimulating HUVEC proliferation, contacting T cells, inducing cellular stress, or exosomes with mitogenic activity.
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 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).
Furthermore, it is noted that MHC 1, is an immune system surveillance surface protein, and is not considered a mitogen (a substance that induces cells to undergo mitosis) and is therefore, not germane to Applicant’s arguments concerning the stimulating proliferation of HUVECs.
In response to applicant's argument that it would be counter intuitive to observe exosomes produced by de-differentiating fibroblasts under hypoxic conditions with VPA that are lacking MHC 1, again, as above, as evidenced by Sethumadhvan, hypoxia itself is sufficient to downregulate MHC 1 molecules when cells are cultured in 3D in vitro (Abstract, p1; Results, p2-5; Fig. 5, 7). Therefore, this was a known phenomenon, and would been the expected result when culturing in hypoxic conditions as discussed above.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH (PAUL) MIANO whose telephone number is (571)272-0341. The examiner can normally be reached Mon-Fri from 8:30am to 5:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Doug) Schultz can be reached at (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
Prosecution Insights