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 .
Priority
This application claims benefit to US provisional 63/514,240 (filed on 07/18/2023).
Claims Status
Claims 1-20 are pending and have been examined on the merits.
Claim Objections
Claims 7,11,18, and 19 are objected to because of the following informalities:
In claim 7, the full term ‘Glucocorticoid-Induced TNFR-Related protein’ should precede the first use of acronym “GITR” in line 2.
In claim 11, the full term ‘thymic epithelial progenitor cells’ should precede the first use of acronym “TEPCs” in line 3.
In claims 18 and 19, the full term ‘Granulocyte-Macrophage Colony-Stimulating Factor’ should precede the first use of acronym “GM-SCF” in line 2 and the full term ‘Nuclear factor kappa-light-chain-enhancer of activated B cells’ should precede the first use of acronym “NF-kappa B” in line 2 of claim 18 and line 1 of claim 19.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 8 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 8, the claim recites the limitation “said immature dendritic cell” in line 1. There is insufficient antecedent basis for this limitation in the claim. The claim is dependent on claim 6, which recites a functional limitation to the T regulatory cells generated by the method of claim 1. There are no immature dendritic cells to refer to within the method. Therefore, claim 8 refers to a cell population not established in the claims it depends on.
Appropriate correction or clarification is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 3,4,8,9,16 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claims 3 and 4, claim 3 recites ‘wherein the lymphoid progenitor stem cell is substituted with a lymphoid progenitor cell’, but a lymphoid progenitor stem cell does not fall under the umbrella of a pluripotent stem cell, as a lymphoid progenitor stem cell is a multipotent cell with limited directions for differentiation. Therefore, this substitution would be a different method than is claimed in claim 1, which claim 3 depends on. Claim 4 is dependent on claim 3 and is included in the rejection.
Regarding claims 8, the claim recites “immature dendritic cell is capable of’, referring to a cell population that stimulates T cells and recites limitations to a cell population not included in the method of claim 1. This does not further limit the method of claims 6, or 1, which it is dependent on.
Regarding claim 9, the claim refers to a cell population that is affected by the T regulatory cells generated and recites limitations to a cell population not included in the method of claims 6 or 1. This does not further limit the method of claim 1, which it is dependent on.
Regarding claim 16, the claims recites limitations on the tolerogenic dendritic cells which are added to the method in claim 15, which it is dependent on. Claim 16 recites “said antigen are determined by analysis of peptides capable of’, this is a not a limitation that further limits the method of claim 1, which they depend on.
Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-10, and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Haque et al (Journal of immunology, 2012) and evidenced by Vignali et al (Immunology, 2008), Famili et al (Future Science OA, 2017), Liu et al (J Exp Med, 2006), and Warner et al (Exp Hematol, 2012).
Regarding claims 1,2,10, and 20, Haque et al teaches a method to generate functional Treg cells from induced pluripotent stem cells (iPSCs) and determining the Treg cell potential as an immunotherapeutic (See, Abstract). This reads on, a method for generating T regulatory cells of claim 1.
Haque et al teaches the use of mouse iPSCs that were transduced with Foxp3 retrovirus and then cocultured with adult thymic organ cultures (See, p1229 col 2 paragraph 6). This reads on a) obtaining a pluripotent stem cell population of claim 1 and wherein said pluripotent stem cell is an inducible pluripotent stem cell (iPSC) of claim 2. The adult thymus lobes were procured from mice at 4-12 weeks of age, dissected, and culture on sponge support filter membrane and then the iPSCs were added and the coculture was incubated (See, p1229 col 1 paragraph 5-6). This reads on, wherein said thymic medullary epithelial cells are isolated from living or cadaveric donors of claim 10, as the adult thymus could have that cell population within. This also reads on, wherein said thymic medullary epithelial cells in the presence of a scaffold to facilitate such interaction of claim 20, as the sponge acts as the scaffold.
Haque et al teaches that coculturing Foxp3 transduced iPSCs with adult thymic organ cultures for 2 weeks results in CD4+CD25+Foxp3+ Treg cells (See, p1230 col 2 paragraph 1 and Figure 1). This reads on, b) exposing said pluripotent stem cell population to a population of thymic medullary epithelial cells, c) culturing the populations of “a” and “b” together, d) providing conditions to differentiation of said pluripotent stem cel into T regulatory cells and e) further providing conditions for expansion of T regulatory cells. Haque et al teaches that the coculture goes for 2 weeks implying the necessary conditions are provided.
Haque et al also teaches that he CD4+CD25+Foxp3+ T reg cells produced by the method produce suppressive cytokines similar to functional mature T reg cells (See, p1230 col 2 paragraph 1).
Regarding claims 3, following the discussion above, claim 3 is included in the rejection above because during the differentiation process from pluripotent stem cell to Treg cell, the cell must become a lymphoid progenitor cell, evidenced by Famili et al.
Famili et al teaches that hematopoietic stem cells (HSCs) are able to self-renew and differentiate into various blood system cell types, including B cells and T cells (See, p 1 col 1-2). Famili et al teaches that HSC, a pluripotent stem cell, differentiates to a common lymphoid progenitor cell and then to various T cells populations (See, p2 and Figure 1).
Therefore, a lymphoid progenitor cell is a part of the method and included in the rejection above.
Regarding claim 4, following the discussion above, the claim recites inherent properties of lymphoid progenitor cell, evidenced by Warner et al and Liu et al. Warner et al teaches lymphoid progenitors express CD127 and can efficiently differentiate in vitro into T cells (See, Abstract). Liu et al teaches CD127 is downregulated in FoxP3+ T cells (Tregs) (See, Abstract).
Therefore, a lymphoid progenitor cell would have higher expression of CD127 than a Treg cell and claim 4 is included in the rejection above.
Regarding claims 5-7, following the discussion above, the claims recite inherent properties of Treg cells, including suppressing proliferation of peripheral blood mononuclear cells… and suppressing dendritic cell maturation in a manner independent of GITR. These assertions are evidenced by Vignali et al and hold true because Haque et al confirms the Tregs generated from the method are functional.
Vignali et al teaches that Treg cells have four modes of actions, suppression of inhibitory cytokines such as (IL-35, IL10 and TFGβ), cytolysis, metabolic disruption, and targeting dendritic cells (DCs) by inhibiting their maturation and certain functions (See, p 524 col 1 paragraph 1 and Figure 1). Vignali et al teaches that Treg cell and DC interaction attenuate effector T-cell activation through cytotoxic T-lymphocyte antigen 4 (CTLA4), which is constitutively expressed on Treg cells (See, p527 col 2 paragraph 2). Vignali et al also teaches that Treg cells can condition DC cells to express indoleamine 2,3 dioxygenase (IDO), a molecule induces the production of apoptotic metabolites to suppress effector T cells through a mechanism dependent on interactions between CTLA4, CD80 and or CD86 (See, p527 col 2 paragraph 2). CTLA4 ligates CD3, IDO ligates CD28 through CD80 and or CD86, and LFA-1, which is expressed on the Treg cell ligates ICAM-1.
Regarding claims 8 and 9,the claims are dependent on claims 1 and 6 and do not recite limitations that further limit the method of claims 6 or 1 and thus are included in the rejection above.
Therefore, claims 1-10, and 20 are anticipated by Haque et al and evidenced by Vignali et al.
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.
Claims 11-14 are rejected under 35 U.S.C. 103 as being unpatentable over Haque et al (Journal of immunology, 2012) as applied to claims 1,2,5-7,10, and 20 above, and further in view of Reis et al (Frontiers in Immunology, 2021) and de Pedro et al (International journal of molecular sciences, 2021).
The teachings of Haque et al are set forth above.
Regarding claims 11-13, Haque et al does not teach that the thymic epithelial cells are derived by contacting the cels with a t least one thymic epithelial cell promoting agent, and then allowing the TEPCs to differentiate nor that the promoting agent is mesenchymal stem cell conditioned media.
Reis et al teaches that treating medullary thymic epithelial cells (mTECs) with mesenchymal cell-derived extracellular vesicles (MEx) restores thymic medullary architecture, shows an enrichment of antigen presentation (See, Abstract).
Reis et al teaches a method of isolating umbilical cord Whartons Jelly mesenchymal stromal cells (MSCs), culturing them, and isolating WJ-MSC exosomes (MEx) from the conditioned media after 36 hours (See, p2-3 col 2 – col 1). This reads on, wherein said promoting agent is mesenchymal stem cell (MSC) conditioned media of claim 12. This also reads on, wherein the MSC is perinatal tissue derived, as the umbilical cord WJ is perinatal tissue.
Reis et al exposed newborn mice at postnatal day 1 (PN1) to PN7 to hyperoxia (HYRX) or normoxic (NRMX) conditions and then returned them to room air from PN7 to P14. At PN4 the mouse pups were injected via IV with MEx and for experimental control, human foreskin fibroblast cells exosomes (HDF) (See, p7 col 1 and Figure 2, p2 col 2 paragraph 2).
Reis et al teaches that HYRX+MEx groups at PN14 had their thymus collected and assessed for FoxP3 expression by immunofluorescence (IF) and flow cytometry, to determine the population of regulatory T Cells (Tregs) in the thymus. Figure 4 of Reis et al shows that compared to NRMX and the HYRX group, the HYRX-MEx thymi had an increased FoxP3+ T cell population; indicating MEx treatment restores levels of FoxP3+ T cells lost during HYRX exposure (See, p8 col 1 paragraph 2).
Reis et al also teaches that MEx treatment promotes the maturation of SP4 thymocytes (See, p7 col 2 – p8 col 1, and Figure 3).
Overall, Reis et al teaches that a single dose of MEx improved thymic medullary architecture, restored thymocyte counts, regulatory T cell numbers, and promoted thymocyte differentiation into CD4+ T cells (See, p15 col 2).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of Haque et al to comprise using thymic epithelial cells derived from contacting cells with a thymic epithelial cell promoting agent of mesenchymal stem cell conditioned media, and allowing the TEPCs (or thymocytes) to differentiate, as taught in Reis et al. This conclusion of obviousness is based on teaching suggestion motivation rationale. One would have been motivated to make this modification to further promote the generation of Tregs cells in the method and maintain the thymic medullary architecture during co-culture, as taught by Reis et al. While Reis et al isolated the EVs from the conditioned media and injected that, contacting the conditioned media to coculture would have a similar effect, as the EVs are present in the media. One would have had a reasonable expectation of success because Reis et al had success in vivo and ex vivo culture would provide successful results.
Regarding claims 14, following the discussion above, Haque et al nor Reis et al teach that the MSC is activated with TNFα and Interferon-γ (IFNγ).
de Pedro et al teaches that that priming mesenchymal stromal cells with interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα) is optimal due to its production of synergistic and additive effect to immune related molecule expression (See, Abstract).
de Pedro et al further teaches that priming MScs with IFNγ and TNFα in vitro produces extracellular vesicles with heightened immunomodulatory potential, which enhances Tregs (See, p 2 paragraph 3).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of Reis et al to further comprise priming the MSCs used in the method with IFNγ and TNFα, then use then in the method of Haque et al as described above. This conclusion of obviousness is based on teaching suggestion motivation rationale. One would have been motivated to make this modification to further promote the generation of Tregs cells in the method, as Lee et al teaches that in vitro priming of MSCs changes the EVs produced in the conditioned media which would enhance the Tregs. One would have had a reasonable expectation of success evidenced by de Pedro et al and Reis et al.
Therefore, claims 11-14 are rendered obvious over Haque et al in view of Reis et al and de Pedro et al.
Claims 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Haque et al (Journal of immunology, 2012) as applied to claims 1,2,5-7,10, and 20 above, in view of Desreumaux et al (Gastroenterology, 2012) and evidenced by Scott et al (Immunity, 1998).
The teachings of Haque et al have been set forth above.
Regarding claims 15-16, Haque et al does not teach combining the pluripotent stem cells and mTECs with an antigen or that the antigen is capable of binding to HLA-2.
Desreumaux et al teaches a method of isolating PBMCs from patients, exposing them to ovalbumin (an antigen), to get T regulatory ovalbumin specific (ova-Tregs), and administering them intravenously (See, abstract). This reads on, wherein antigen are...capable of binding to HLA-2 of claim 16, as ovalbumin binds to HLA-2, evidenced by Scott et al teaching ovalbumin is responsible for 25-35% of T cell response in BALB/c mice immunized with whole ovalbumin and there that the peptide binding to MHC Class II (or HLA-2) and T cell activation (See, p319 col 2 paragraph 2).
Desreumaux et al teaches isolating the PBMCs from patients, culturing them with ovalbumin, an antigen, to expand ova-specific T cells. Ova-Tregs were selected through their production of IL-10 and expression of Foxp3 and CD25 (See, p1209 col 1 paragraph 1).
Desreumaux et al teaches that ova-Tregs have an antigen specific immunosuppressive effect to reduce the normal peripheral blood mononuclear cells (PBMCs) proliferative response to ovalbumin (See, p1215 col 1 paragraph 2).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of Haque et al add ovalbumin, an antigen, to the coculture of mTECs and pluripotent stem cells, as taught by Desreumaux et al. This conclusion of obviousness is based on teaching suggestion motivation rationale. One would have been motivated to make this modification to further promote the generation of Tregs cells in the method and give the Tregs antigen specific capabilities. One would have had a reasonable expectation of success evidenced by Desreumaux et al.
Therefore, claims 15-16 are rendered obvious over Haque et al in view of Desreumaux et al and evidenced by Scott et al.
Claims 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Haque et al (Journal of immunology, 2012) and Desreumaux et al (Gastroenterology, 2012) as applied to claims 15-16 above, and further in view of Lee et al (Scientific reports, 2017).
The teachings of Haque et al and Desreumaux et al are set forth above.
Regarding claims 17-19, Haque et al nor Desreumaux et al teach tolerogenic dendritic cells (tDCs) are pulsed with said antigens and administered to the three dimensional structure containing pluripotent stem cells and mTECs or that the tDCs are generated by culture of monocytes in GM-SCF and an NF-kappa B inhibitor, minocycline.
Lee et al teaches a method of generating tolerogenic dendritic cells (tDCs) by combining minocycline, dexamethasone, granulocyte colony-stimulating factor (GM-SCF) and IL-4 (See, Abstract).
Lee et al teaches that that DCs were generated by culturing mouse bone marrow in medium with GM-SCF, IL-4, and minocycline for 3 days. Then to generate tDCs minocycline and other factors were added to the culture after removing non-adherent cells on day 3. The tDCs were harvested on day 7 (See, p8 paragraph 1).
Lee et al teaches that coculture of ovalbumin (OVA) peptide pulsed minocycline DCs (mDCs) with CD4+ T cells induce the proportion of CD25+FoxP3+ T cells was higher in mDCs than other generated DCs in the method (See, p3-4 and Figure 4).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of Haque et al add tolerogenic dendritic cells generated by the culture of monocytes with GM-SCF and minocycline to the coculture of mTEC and pluripotent stem cells as taught by Lee et al. This conclusion of obviousness is based on teaching suggestion motivation rationale. One would have been motivated to make this modification to further promote the generation of Tregs cells in the method and generate a higher population during coculture. One would have had a reasonable expectation of success evidenced by Lee et al.
Therefore, claims 17-19 are rendered obvious over Haque et al and Desreumaux et al in further view of Lee et al.
Conclusion
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/CAROLINE M LARA/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
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