DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/24/2025 has been entered.
Applicant’s amendments to the claims filed on November 24, 2025 have been received and entered. Claims 1, 3 have been amended, while claims 2, 6, 12 and 14 have been canceled. Claims 17-18 are newly added. Claims 1, 3-5, 7-11, 13, 15-17 and 18 are under consideration.
Priority
This application is a 371 of PCT/US19/30564 filed on 05/03/2019, which claims priority from US provisional application no 62/666,807 filed on 05/04/2018.
Withdrawn -Claim Rejections - 35 USC § 103
Claims 1, 3-5, 7-11, 13, 15 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Ichim et al (US20100008992, dated 01/14/2010, art of record), Conte et al (Cellular Immunology, 2013, 285, 55-61, IDS) and Hutton et al (J. Leukoc. Biol. 85: 445–451; 2009, IDS). In view of Applicants’ amendment of base claim 1, introducing the limitation “ exposing fibroblast with one or more agents", the previous rejections of claims 1, 3-5, 7-11, 13, 15 and 16 are hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are however subject to new rejections over the prior art of record, as set forth below.
Claims 1, 8 are rejected under 35 U.S.C. 103 as being unpatentable over Ichim et al (US20100008992, dated 01/14/2010, art of record), Conte et al (Cellular Immunology, 2013, 285, 55-61, IDS), Hutton et al (J. Leukoc. Biol. 85: 445–451; 2009, IDS) as applied above and further in view of Crawford et al (Stem Cell Research & Therapy 2013, 4:65, 1-12)/ Ichim (US10842815) as evidenced by Denu et al (Acta Haematol. 2016; 136(2): 85–97). The rejection is withdrawn for the reasons discussed above.
Claims 1, 12 were rejected under 35 U.S.C. 103 as being unpatentable over Ichim et al (US20100008992, dated 01/14/2010, IDS), Conte et al (Cellular Immunology, 2013, 285, 55-61, IDS) , Hutton et al (J. Leukoc. Biol. 85: 445–451; 2009, IDS).as applied above and further in view of Attawia (US20040229786, 11/18/2004, IDS). The rejection is withdrawn for the reasons discussed above.
Claim Rejections - 35 USC § 112-new matter
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.
Claims 1, 3-5, 7-11, 13, 15-16 and 18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In the instant case, the recitation of limitation “..
(i) exposing fibroblasts to: one or more histone deacetylase inhibitors selected from the group consisting of:a) valproic acid: b) trichostatin A: c) phenylbutyrate ; d) vorinostat e) belinostat; f) LAQ824; g) panobinostat; h) entinostat; i) C1994; j) mocetinostat; k) sulforaphane; and 1) a combination thereof;one or more DNA methyltransferase inhibitors selected from the group consisting of: a) decitabine: b) 5-azacytidine c) Zebularine; d) RG-108; e) procaine hydrochloride: f) Procainamide hydrochloride g) Hydralazine hydrochloride h) Epigallocatechin gallate: i) Chlorogenic acid j) Caffeic acid; and h) a combination thereof; and/or 2%-8% oxygen”, step of (ii) culturing CD4+ T-regulatory cell progenitors in the presence of fibroblasts from (i) (claims 1 and 18), 2%-8% oxygen (claims 1, 18) step of culturing CD4+ T-regulatory cell progenitors in media consisting essentially of the fibroblasts resulting from (i) (claim 18) is considered new matter. Upon further review of the instant specification, examiner could not find support for exposing fibroblast cells with any agent as required by the claims. There is no explicit or implicit support for exposing fibroblast to claimed agent including in 2-8% oxygen. In fact, contrary to applicants' assertions, paragraph 62 of the instant application directly support to the dedifferentiated fibroblast cells may have been produced upon exposure to stem cells and/or cytoplasm from stem cells, including pluripotent stem cells selected from the group consisting of a) parthenogenic stem cells; b) embryonic stem cells; c) inducible pluripotent stem cells; d) somatic cell nuclear transfer derived stem cells; e) Stimulus-triggered acquisition of pluripotency (STAP); and f) a combination thereof. The de-differentiated fibroblasts may have been produced upon exposure to hypoxia; one or more histone deacetylase inhibitors or DNA methyltransferase inhibitor as set forth in claims. The specification fails to teaches an active step of exposing fibroblast with any of the agent or in 2-8% oxygen or any agent set forth in claims 1 and 18. It appears that de-differentiated fibroblasts is prepared by exposure to a stem cell (see para. 62 of the specification). There is no implicit or explicit support for exposing a fibroblast cell to any agent. Thus, at the time the application was filed, an Artisan of skill would not recognize from the disclosure that Applicant was in possession of exposing fibroblast with any one of the agents set forth in claim, as claimed. In case if applicants have evidence to support otherwise, applicants are invited to indicate page and line number for the written support specifically for exposing fibroblasts to: one or more agents or to 2-8% oxygen set forth in claims 1 and 18 of the instant application.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph-written description requirement”. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981). Claims 3-5, 7-11, 13, 15-16 are included in the rejection because they directly or indirectly depend from the rejected base claim. This is a new matter rejection.
New-Claim Rejections - 35 USC § 103- necessitude by amendments
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.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Ichim et al (US20100008992, dated 01/14/2010, art of record), and Pinchuk et al (Gastroenterology. 2011;140:2019–2030).
With respect to claim 17, Ichim teaches a method of treating disc degenerative disease in a subject, comprising the step of administering to the subject an effective amount of a plurality of T-regulatory cells capable of inhibiting inflammatory responses in a manner allowing access of said cell capable of inhibiting inflammatory responses to substantially suppress inflammatory responses causative of pain and said disc degenerative disease (abstract, para. 24, 27 and claims 39, 44-45 of ‘992). It is further disclosed that intravenous infusion of CD4+ CD25+ cells followed by infusion of MSC led to improvement in both the Oswerty disability index and the visual analogue pain score (see para. 131-133). Ichim teaches that cells including CD4+CD25+ T regulatory cells are autologous or allogeneic (see para. 8, 19).
While Ishim teaches inflammatory stimuli of T-cells includes amongst other things an allogeneic stimulator cells, however, differs from claimed invention by not (i) not culturing CD4+ T-regulatory cell progenitors in media consisting essentially of de- differentiated fibroblasts; and co-culturing T-reg. progenitor in media comprising fibroblasts.
However, before the effective filing date of instant application, Pinchuk teaches co culturing of Colonic CD90+ mesenchymal myofibroblasts and fibroblasts (CMFs) (a colonic fibroblast) with naïve, resting, CD4+ T cells (a Treg. Progenitor) to produce CD4+ CD25high FoxP3+ Treg cells (see fig. 2). It is disclosed that the induction of iTreg from N-CMF–primed naïve CD4+ T cells depend on both cell-contact–mediated interactions and production of a soluble factor (PGE2) (see page 2026, col. 2, para. 1).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings to prior art to modify the method by providing the activated T-reg disclosed in Ichim using the T-reg produced from co culturing naïve CD4+ T cells (a Treg progenitor) with fibroblast cells as disclosed in Pinchuk, in the method of successfully treat the pain and degenerative disc disease by using T-reg cells, as instantly claimed, with a reasonable expectation of success, before the effective filing date of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so because prior art recognized that coculturing results in generation of primed Treg phenotype also induces the proliferation of a CD25+ FoxP3+T cells (abstract). One of ordinary skill in the art would be further motivated to do as fibroblasts is reported to be actively interact with T lymphocytes by both cell-contact–mediated interactions and production of a soluble factor (PGE2) thereby suggesting the importance of the CMF-derived PGE2 in the regulation of Treg cells and consequently effector T-cell behavior (see page 2026, col. 2, para. 1). One of skill in the art would have been expected to have a reasonable expectation of success because prior art successfully reported producing to produce CD4+ CD25high FoxP3+ Treg cells produced from coculture of naïve CD4+ T reg cell in presence of fibroblast cells as evident from the teaching of Pinchuk. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd07 1925 pdf).
Claims 1, 3-5, 7-11, 13, 15, 16 18, are rejected under 35 U.S.C. 103 as being unpatentable over Ichim et al (US20100008992, dated 01/14/2010, art of record), Pinchuk et al (Gastroenterology. 2011;140:2019–2030).and Falanga et al (Journal of Investigative Dermatology, 1991, 634-637).
With respect to claim 1, Ichim teaches a method of treating disc degenerative disease in a subject, comprising the step of administering to the subject an effective amount of a plurality of T-regulatory cells capable of inhibiting inflammatory responses in a manner allowing access of said cell capable of inhibiting inflammatory responses to substantially suppress inflammatory responses causative of pain and said disc degenerative disease (abstract, para. 24, 27 and claims 39, 44-45 of ‘992). It is further disclosed that intravenous infusion of CD4+ CD25+ cells followed by infusion of MSC led to improvement in both the Oswerty disability index and the visual analogue pain score (see para. 131-133). Ichim teaches that cells including CD4+CD25+ T regulatory cells are autologous or allogeneic (see para. 8, 19).
Regarding claims 3-5, It is further disclosed that the anti-inflammatory cells found in the bone marrow such as ... CD4+ CD25+ T regulatory cells (Treg) can also be used within the teachings of the present invention. Ichim further teaches cells expressing the CD4+ CD25+ phenotype and possessing T cell inhibitory function are purified from a group of sources consisting of: peripheral blood, cord blood, and bone marrow (see claim 46 of ‘992). It is further disclosed that cells could be mobilized through the administration of a growth factor capable of eliciting such effect, wherein the growth factors capable of mobilizing bone marrow progenitors include: G-CSF, GM-CSF (see para. 98).
With respect to claims 9-10, Ichim teaches cells expressing the CD4+ CD25+ phenotype and possessing T cell inhibitory function are expanded by stimulation with agents known to trigger proliferation, wherein said plurality of agents are selected from a group consisting of: IL-2, TGF-beta, IL-10, anti-CD3 antibodies, anti-CD28 antibodies, vasoactive intestinal peptide and anti-PD1 antibodies (see claims 47-48 of ‘992).
Regarding claim 13, 15-16, Ichim teaches cells, T-reg cells are administered are concurrently administered with angiogenesis stimulating cells such as mesenchymal stem cells (claim 39, 43-44-45, and 65 of 992). Ichim further teaches 27 out of 30 of the patients report a reduction in analgesic intake due to reduction in overall pain suggesting patient were on analgesic therapy for pain alleviation (see para. 133, example 5).
While Ishim teaches inflammatory stimuli of T-cells includes amongst other things an allogeneic stimulator cells, however, differs from claimed invention by not disclosing (A) (i) exposing fibroblasts to hypoxia (2%-8% oxygen) and (B) co-culturing T-reg. progenitor in media comprising fibroblasts.
Pinchuk teaches co culturing of Colonic CD90+ mesenchymal myofibroblasts and fibroblasts (CMFs) (a colonic fibroblast) with naïve, resting, CD4+ T cells (a Treg. progenitor) to produce CD4+ CD25 high FoxP3+ Treg cells (see fig. 2). It is disclosed that the induction of iTreg from N-CMF–primed naïve CD4+ T cells depend on both cell-contact–mediated interactions and production of a soluble factor (PGE2) (see page 2026, col. 2, para. 1). Pinchuk reported fibroblast Stabilize FoxP3 Expression in nTreg and Induce Their Proliferation in Presence of IL-2 (see page 2021, col. 1, para. 5). It is further disclosed that CMF-induced iTreg cells express moderate levels of the IL-10 and high levels of TGF-b1 (Figure 3C), indicating indicate that the CMF-induced iTreg cells have the elements needed to exert suppressive function (see page 2020, col. 1, para. 1). The combination of references differs from claimed from the claimed invention by not using fibroblast that is exposed to hypoxia.
However, before the effective filing date of instant application, Falanga teaches exposing fibroblast in culture under hypoxic condition (see page 634, col. 1, para. 2). It is disclosed that low oxygen tension upregulates the synthesis of TGF-β1 by human dermal fibroblasts, and leads to increased secretion of TGFb (see abstract).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings to prior art to modify the method by providing the T-reg disclosed in Ichim using the T-reg produced from co culturing naïve CD4+ T cells (a Treg progenitor) with fibroblast cells as disclosed in Pinchuk, in the method of successfully treat the pain and degenerative disc disease by using primed T-reg cells, as instantly claimed, with a reasonable expectation of success, before the effective filing date of the instant invention. One of ordinary skill in the art would be motivated to do so because prior art recognized CMF-induced iTreg cells express moderate levels of the TGFbeta 1 suggesting presence of elements that exert suppressive function. It would be further obvious to one of ordinary skill in art to modify the method Ishim and Pinchuk by using fibroblast that is exposed under hypoxic conditions as suggested in Falanga to increase expression and secretion of TGFb1, with a reasonable expectation of success. One of skill in the art would have been expected to have a reasonable expectation of success in using T-reg produced from coculture of naïve CD4+ T reg cell in presence of fibroblast cells that is exposed to TGFb1 to produce T reg cells for cell therapy. . It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd07 1925 pdf).
Claims 1, 8 are rejected under 35 U.S.C. 103 as being unpatentable over Ichim et al (US20100008992, dated 01/14/2010, art of record), Pinchuk et al (Gastroenterology. 2011;140:2019–2030).and Falanga et al (Journal of Investigative Dermatology, 1991, 634-637)as applied above and further in view of Hutton et al (J. Leukoc. Biol. 85: 445–451; 2009, IDS) , Crawford et al (Stem Cell Research & Therapy 2013, 4:65, 1-12, art of record)/ Ichim (US10842815, IDS) as evidenced by Denu et al (Acta Haematol. 2016; 136(2): 85–97, art of record).
The teaching of Ishim, Pinchuk and Falanga have been described above and relied in same manner here. The combination of references differs from claimed invention by not disclosing media additionally comprises mesenchymal stem cells.
However, before the effective filing date of instant application, Crawford teaches producing CD4+CD25+ Foxp3+ T regulatory cell phenotype from or CD4+ activated cells induced in a coculture with mesenchymal stem cells under in vitro conditions (see page 5, col. 2, last para. and fig. 4). The combination of references differs from claimed invention by not disclosing medium comprising MSC and fibroblast. Likewise, Ichim teaches a method of stimulating an increase in perfusion of the lower back area comprising the steps of administering a population of T regulatory cells that have been activated by exposure to anti-CD3 and anti-CD28 antibodies into muscles surrounding the lower back area at a concentration and frequency sufficient to induce an angiogenic response, wherein said T regulatory cells are activated by culture with mesenchymal stem cells. obtained from a source selected from the group of tissues consisting of: a) adipose from the stromal vascular fraction; b) bone marrow; c) tooth pulp; d) hair follicle; e) endometrium; f) menstrual blood; g) peripheral blood; h) omentum; i) skin; j) cord blood; k) Wharton's jelly; l) placenta; and m) fallopian tube (see claims in 815).
Hutton teaches producing a population of CD4+CD25+ FoxP3+ T reg cells from a progenitor cell (abstract) in presence of hIL-2 (see page 446, col. 1, last para.). Hutton teaches that HPC derived CD4+CD25+ T cells are anergic T cells (see page 448, col. 2, para. 1). Denu provides evidence that MSCs are similar to fibroblasts and are capable of suppressing T cell proliferation and modulating the immunophenotype (abstract).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings to prior art to modify the method by providing the activated T-reg disclosed in Ichim using the T-reg produced is cocultured with fibroblast cells and IL-2 as disclosed in Pinchuk and/or cocultured with MSC as suggested in Crawford in view Hutton , in the method of successfully treat the pain and degenerative disc disease by using an activated T-reg cells, as instantly claimed, with a reasonable expectation of success, before the effective filing date of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to coculture CD4+ progenitor of Hutton in presence of fibroblast (Pinchuk) and mesenchymal stem cells (Crawford/Ishim) because prior art recognized that MSCs are similar to fibroblasts and are capable of function in same manner (See Denu abstract). One of skill in the art would have been expected to have a reasonable expectation of success in using T-reg coculture with MSC and/or fibroblast cells as both type of cell was known to function is same manner and it was routine in art to substitute mesenchymal for fibroblast or use together to have additive effect in producing T-reg cells for cell therapy purpose. In fact, Denu suggests that MSCs and fibroblasts could not be distinguished based on the commonly used phenotypic characterization methodologies and could likely represent the same cell type (see page 9, para. 2). It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd07 1925 pdf).
Conclusion
No claims allowed.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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