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 .
Applicant’s election without traverse of species group I (claims 13-16) in the reply filed on 4/6/2026 is acknowledged.
In regards to applicant’s submission of claim 21 (new) in response to the restriction requirement; support for claim 21 is found in Specification paragraph 0081, specifically, “In one study, scientists have used solid-phase anti-CD3 antibodies for TIL activation followed by culture in reduced concentrations of IL-2 to reactivate TIL previously grown in high concentrations of rIL2.”
Claims 17-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species group II there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/6/2026.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3,6,8,21 are rejected under 35 U.S.C. 103 as being unpatentable over Carreno, JL et al. 2010, Yamazaki, S et al 2007, Jiao, X et al 2021, Churlauda, G et al. 2014 and Peng, Q et al. 2020.
Carreno, JL et al. 2010 discloses, “Our findings suggest novel approaches to enhance DC [dendritic cell] capacity to induce self-tolerance and reduce the severity of autoimmune disorders. Specifically, we have shown, both in vitro and in vivo, that NF-κB blockade on DCs by andrographolide or rosiglitazone can significantly enhance the tolerogenic capacity of DCs” (abstract). It does not disclose the use of immature DC cells from bone marrow to enhance/expand Tregs, or to include IL-2 in the co-culture. It also does not disclose the use of the cocultured Tregs as a treatment for women suffering from POI characterized by ovarian over-expression of TNFa and IL-6.
Peng, Q et al. 2020 discloses, “We observe that PD-L1 on DC plays a critical role in limiting T cell responses… Blocking PD-L1 in established tumors promotes re-activation of tumor-infiltrating T cells for tumor control.” (abstract).
Yamazaki, S et al 2007 discloses, “At 5 days, we observed the TGF-β–dependent induction of Foxp3+ T cells by both immature and mature DCs (Figure 1A) and an expansion in total numbers of Foxp3+ cells (Figure 1B, compare closed to open symbols) …DCs induce Foxp3+T regs and also indicate that both immature and mature forms of DCs can be active.” (paragraph 1 results section). Importantly, “[Figure 1](D)…freshly isolated CD25+CD4+T cells from DO11.10 RAG+/+ mice (2 × 104, > 90% Foxp3+) were cultured with immature or mature BM-DCs…in the presence or absence of TGF-β (2 ng/mL) or IL-2 (100 U/mL). [Figure 1] (E)…freshly isolated CD25+CD4+T cells from DO11.10 RAG+/+mice were cultured with immature or mature BM-DCs (2 × 104). Geometric mean fluorescence intensity (MFI) for Foxp3 within the circle is shown in the bottom of the plots.” (Description of Figure 1). Importantly, this figure shows increased FoxP3+ expression in Tregs when cultured with immature BM-DC cells in the presence of IL-2. Finally, “Bone marrow DCs (BM-DCs) were derived with GM-CSF.” (paragraph 1, T cells and DCs paragraph in the materials and methods section).
Jiao, X et al 2021 discloses, “Here we showed that patients with POI had augmented T helper 1 (TH1) responses and regulatory T (Treg) cell deficiency in both the periphery and the ovary compared to the control women.” (abstract). Furthermore, “Flow cytometry analysis in ovaries revealed substantially increased infiltration of IFN-γ-and TNF-α-producingTH1 cells and a marked decrease of CD4+Foxp3+Treg cells in the anti-CD25 antibody group (Figure4F)…significantly increased mRNA expression of the proinflammatory cytokines Ifng and Tnf (Figure4E).” (paragraph titled, “Treg cell depletion exacerbates ovarian insufficiency by increasing TH1 cells in the ovary” in the results section).
Therefore, it would be obvious to a person of ordinary skill in the art, before the effective filing date, to combine the method of inhibiting maturation of dendritic cells (DC) by blocking Nf-kB signaling as disclosed in Carreno, JL et al. 2010, then ensuring those immature DC cells express PD-L1 as disclosed in Peng, Q et al, 2020, and subsequently using those PD-L1 expressing immature DCs to expand and enhance the population of FoxP3+ Treg cells in the presence of IL-2 as disclosed by Yamazaki, S et al 2007 and furthermore, using those FoxP3+ Tregs to treat women suffering from Premature Ovarian Insufficiency (POI) (aka premature ovarian failure) characterized by increased INF-6 and TNFa expression in the ovary as disclosed by Jiao et al. 2021. inducing the expansion of FoxP3+ Tregs WITH Nf-kB- blocked immature DC cells instead of immature DC cells harvested from the bone marrow is simply substituting one known element for another to achieve predictable outcomes. It’s well known that immature DC cells can be harvested/generated from either method (as outlined in the prior art above), and culturing immature DC cells with T-cells in the presence of IL-2 results in the predictable and documented enhancement and expansion of FoxP3+ Tregs, as supported by Churlauda, G et al. 2014. Furthermore, ensuring that the immature DC cells express PD-L1 is obvious due to its well-known and documented ability to repress traditional T-cell activation and expansion (aka Th1 responses), thereby preventing counteraction of Treg generation/activation (Th2). Additionally, Jiao, X et al 2021 provides a suggestion/motivation to administer the FoxP3+ Tregs as treatment for women suffering from POI characterized by increased expression of IL6 and TNFa from the ovary because they show one of primary features is the lack/depletion of FoxP3+ Tregs. This renders claims 1-3,6,8, 21 obvious.
Claims 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Carreno, JL et al. 2010, Yamazaki, S et al 2007, Jiao, X et al 2021, Churlauda, G et al. 2014 and Peng, Q et al. 2020 as applied to claim 1 above, and further in view of JA Sokoloski, et al. 1993, Sindhu, A et al. 2012 and NCBI’s MeSH definition of Gene Silencing 2000.
Carreno, JL et al. 2010, Yamazaki, S et al 2007, and Jiao, X et al 2021 disclose the use of Nf-kB inhibited bone marrow-derived DC cells co-cultured with a population of Tregs as a treatment for POI in women. It does not disclose NF-kB inhibition is achieved by antisense molecules targeting NF-kB.
JA Sokoloski, et al. 1993 discloses, “The p65 antisense phosphorothioate oligomer abolished p65 mRNA expression…” (paragraph 3 in the results section. See also Fig 2A). It is known that the NF-kB protein is composed of two subunits; p50 and p65, as supported by JA Sokoloski, et al. 1993.
Therefore, it would be obvious to a person of ordinary skill in the art, before the effective filing date, to use the p65 antisense phosphorothioate oligomers disclosed in JA Sokoloski, et al. 1993 to inhibit NF-kB in immature DC cells used in the method of Treg activation/expansion and treatment disclosed by Carreno, JL et al. 2010, Yamazaki, S et al 2007, and Jiao, X et al 2021. JA Sokoloski, et al. 1993 provides a teaching/suggestion to suppress NF-kB activity via an antisense molecule targeting NF-kB because it shows this method is effective and efficient (see Fig 2A). To reiterate, it is known that the NF-kB protein is composed of two subunits; p50 and p65, as supported by JA Sokoloski, et al. 1993. This renders claim 13 obvious. It also renders claims 14-16 obvious because it is known that inducing RNAi, administration of decoy oligonucleotides, and gene editing of NF-kB are multiple known options that achieve the same goal of gene silencing as supported by Sindhu, A et al. 2012 and NCBI’s MeSH definition of Gene Silencing 2000. Selection of known and functionally similar alternatives to achieve the same outcome is obvious. (See: In re Merck & Co. 800 F.2d1091 (Fed. Cir. 1986)).
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Carreno, JL et al. 2010, Yamazaki, S et al 2007, Jiao, X et al 2021, Churlauda, G et al. 2014 and Peng, Q et al. 2020 as applied to claim 6 above, and further in view of Zhang, J et al. 2022.
Carreno, JL et al. 2010, Yamazaki, S et al 2007, Jiao, X et al 2021, Churlauda, G et al. 2014 and Peng, Q et al. 2020 disclose the use of Nf-kB inhibited bone marrow-derived DC cells co-cultured with a population of Tregs as a treatment for POI in women. It does not disclose the use of an additional cell therapy administered in combination with the Tregs.
Zhang, J et al. 2022 discloses, “In this study, we have demonstrated that Treg+MSC combination therapy mitigates the neuroinflammatory response to TBI in vivo and in vitro and that combination therapy may confer increased potency and ability to modulate neuro- and systemic inflammatory responses compared to both Treg and MSC monotherapies.” (paragraph 1, discussion section). Furthermore, “As demonstrated in Figure 3, nearly all of the Treg+MSC combinations decreased TNFα or IFNγ production compared to the respective Treg or MSC monotherapy.” (paragraph 2, discussion section).
Therefore, it would be obvious to a person of ordinary skill in the art, before the effective filing date, to take the method for treatment of POI using Treg expansion/ enhancement in vitro as disclosed by Carreno, JL et al. 2010, Yamazaki, S et al 2007, and Jiao, X et al 2021 and include the administration of MSC cells in combination with the Tregs as disclosed in Zhang, J et al. 2022. Zhang, J et al. 2022 provides a teaching/motivation to combine MSC cell therapy with the Treg therapy by showing that addition of MSC cell therapy decreased TNFa production and mitigates traditional inflammatory responses in traumatic brain injury. Importantly, suppression of TNFa production and inhibition of traditional inflammation are exactly the type of therapeutic outcomes desired why treating the POI conditions outlined above. Therefore, claim 20 is obvious.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Carreno, JL et al. 2010, Yamazaki, S et al 2007, Jiao, X et al 2021, Churlauda, G et al. 2014 and Peng, Q et al. 2020 as applied to claim 1 above, and further in view of Caplan HW, et al. 2021
Carreno, JL et al. 2010, Yamazaki, S et al 2007, and Jiao, X et al 2021 disclose the use of Nf-kB inhibited bone marrow-derived DC cells co-cultured with a population of Tregs as a treatment for POI in women. It does not disclose the use of mesenchymal stem cell exosomes to activate Tregs before they are administered as a therapy.
Caplan HW, et al. 2021 discloses, “Here in, we demonstrate that the capacity of expanded Hucb-Tregs [Human Umbilical Cord Blood, Hucb] to inhibit both polyclonal and allogeneic responses in vitro could be promoted by culturing them in complete MSC-CM [Mesenchymal Stem Cell – Culture Medium], containing exosomes or with isolated exosomes separated from MSC-CM. These functional improvements in Hucb-Tregs were associated with increased expression of key Tregs functional and/or activation markers, including FOXP3, CD25, CTLA-4, CD39, and PD1.” (paragraph 2, discussion section).
Therefore, it would be obvious to a person of ordinary skill in the art, before the effective filing date, to use MSC-derived exosomes to activate Treg cultures as disclosed in Caplan HW, et al. 2021 when conducting the method for Treg stimulation/activation and POI treatment disclosed in Carreno, JL et al. 2010, Yamazaki, S et al 2007, and Jiao, X et al 2021. Caplan HW, et al. 2021 provides a motivation/suggestion to activate Tregs using the MSC-exosomes because they show this coculture enhanced Treg activation (increased CTLA-4 and FoxP3 expression), and by showing it is a possible clinically-applicable strategy to protect and maintain long-term Tregs function. Therefore, claim 19 is obvious.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Adam M Smith whose telephone number is (571)272-7517. The examiner can normally be reached Monday- Friday 10:30AM-5PM.
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/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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