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
The instant application, filed on 02/22/2023, claims priority to the US Provisional Application No. 63/313,313 filed on 02/24/2022, and will be examined with an effective filing date of 02/24/2022.
Status of the Claims/Application
Claims 1-20 are currently pending and are under examined on the merits herein.
Claim Objections
Claim 1 is objected to because of the following informalities: The claim recites the same limitation of the “quantification of induced growth factor production” twice in methods (b) and (d). Appropriate correction is required.
Claim 16 is objected to because of the following informalities: The claim recites an incorrect spelling for “Mushashi”, instead “Musashi”. Appropriate correction is required.
Claim 19 is objected to because of the following informalities: The claim recites the same limitation of the “…where in HGH-1 assessed is assessed subsequent to the culture of said regenerative immunotherapy population…”, the claim is missing a comma (,) after the “first assessed” making the claim as writing indefinite. The examiner will examine the claim in view that there is a comma after the “first assessed” and to mean that HGF-1 is only measured after the regenerative immunotherapy population is cultured with anti-CD3 and anti-CD28 antibodies bound to beads. 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 2 recites the limitation "said immunologically based immunotherapy" in line 1. There is insufficient antecedent basis for this limitation in the claim. The examiner will interpret the recitation as to mean “immunologically based regenerative medicine therapy” as recited in claim 1 line 1.
Claim 20 contains the trademark/trade name “DynaBeads”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe “uniform magnetic beads for stimulating regenerative immunotherapy cells” and, accordingly, the identification/description is indefinite.
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 1-8 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Aggarwal et al. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105 (4): 1815–1822, as evidenced by Pan et al. IL-4 expressing cells are recruited to nerve after injury and promote regeneration. Exp Neurol. 2022 Jan;347:113909, Wurster et al. Interleukin-4-mediated protection of primary B cells from apoptosis through Stat6-dependent up-regulation of Bcl-xL. J Biol Chem. 2002 Jul 26;277(30):27169-75 and Goh et al. Eosinophils secrete IL-4 to facilitate liver regeneration, Proc. Natl. Acad. Sci. U.S.A. 110 (24) 9914-9919, herein after referred to as Aggarwal, Pan, Wurster and Goh respectively.
Regarding claims 1-8, Aggarwal teaches of immune cells including dendritic cells (DCs), naïve and effector T cell (Th1 and Th2) and natural killer (NK) cells that were induced with anti-inflammatory or tolerant phenotype when the cells where cocultured with mesenchymal stem cells (MSCs) (Aggarwal Abstract and pg. 1821 col. 2 para 1). Aggarwal also teaches an increase in IL-10 secretion in a DCs/MSCs coculture (Aggarwal pg. 1817 col 2 para 3 and Fig. 1B), a significant increase in IL-4 secretion in naïve T cells that were activated to differentiate into TH2 effector cells in the presence of hMSCs (Aggarwal pg. 1818 col 1 para 3 and Fig. 2B), as well as an increased in CD4+CD25+ TReg population when naïve cell where cocultured with hMSCs Aggarwal Fig. 2C-D) and TNF-α and IFN-γ were decreased in immune cell/hMSCs cocultures (Aggarwal Fig. 4B). Furthermore, Aggarwal teaches that MSC can mediate the immunomodulatory effects of immune cells by interacting with the cells from both innate or adaptive immunity systems, which will skew the immune response of the immune cells towards an anti-inflammatory/tolerant phenotype which can be accomplished by direct cell-cell contact as well as by secreted factors such as IL-10, IL-4, TGF-ß etc. (Aggarwal pg. 1820 Fig. 6). As evidenced by Pan (in the Abstract and pg. 9 col 2 para 2), IL-4 secretion by the t-cells upon interaction with MSCs are indicators for neurogenic and angiogenic properties, further, Pan also showed that IL-4 plays a role in tissue regeneration (Pan Abstract) and has anti-inflammatory properties (Pan pg. 9 Sec 4 para 2). Wurster and Goh showed that IL-4 plays a role in antiapoptotic activities (Wurster Abstract), and cell proliferation (mitogenic) (Goh Abstract) respectively.
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.
Claims 9-14 are rejected under 35 U.S.C. 103 as being unpatentable over Aggarwal as applied to claim 1-4 above, and further in view Lee et al. Interleukin-4 inhibits the vascular endothelial growth factor- and basic fibroblast growth factor-induced angiogenesis in vitro. Mol Cells. 2002 Aug 31;14(1):115-21, as evidenced by Pan, Wurster and Goh, herein after referred to as Lee respectively.
Regarding claims 9-14, and incorporating the analysis of claim 1, 2, 3 and 4 above, Aggarwal teaches quantification of IL-4 (an angiogenic cytokine) that was stimulated by a coculture of hMSC and naïve T cells stimulated with phytohemagglutinin (PHA) (Aggarwal pg. 1861 col 2 para 7 and Fig. 2B).
Aggarwal does not specifically teach that the potency of the cells is measured by the quantification of a cytokine that stimulates angiogenesis in vitro after stimulation of the cells, where the in vitro assay is the migration of human umbilical vein endothelial cells.
Lee teaches that angiogenesis begins with the stimulation of endothelial cells, and cells will then begin to migrate and proliferate (Lee pg. 115 col 2 para 1). Lee also teaches that the migration of HUVEC was assayed in an in vitro platform, in which VEGF was placed in the lower wells and IL-4 was place in the upperwell together with the HUVECs and the number of HUVECs that migrated towards the lower well was then counted. The results showed that IL-4 inhibits HUVEC chemotaxis induced by VEGF (Lee pg. 117 col 2 para 3 and Fig. 3).
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify teachings of Aggarwal in view of Lee with a reasonable high degree of predictable outcome to assess the potency of the cells by in an in vitro assay the migration of HUVEC in response to the IL-4 other cytokines and/or growth factors that is secreted by the reprogrammed immune cell. Also as indicated by Lee other paracrine secretions or cytokines such as VEGF can be quantified measure potency. Therefore, a skilled artisan would have been able to modify the teachings of Aggarwal in view of Lee to measure the level of migration of HUVECs in an in vitro assay in response to IL-4 secreted by the reprogramed immune cells (which is a mitogen stimulant for endothelial cells (Lee pg. 119 col 2 para 3)) as one MoA for the quantification the potency of the regenerative immune cell therapy.
Claims 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Aggarwal as applied to claim 1-3 and 5 above, and further in view Bhattarai et al. IL4/STAT6 Signaling Activates Neural Stem Cell Proliferation and Neurogenesis upon Amyloid-β42 Aggregation in Adult Zebrafish Brain. Cell Rep. 2016 Oct 18;17(4):941-948, Imai et al. The neural RNA-binding protein Musashi1 translationally regulates mammalian numb gene expression by interacting with its mRNA. Mol Cell Biol. 2001 Jun;21(12):3888-900 and MacNicol et al. Neural stem and progenitor cell fate transition requires regulation of Musashi1 function. BMC Dev Biol. 2015 Mar 18;15:15, as evidenced by Pan, Wurster and Goh, herein after referred to as, Bhattarai, Imai and MacNicol respectively.
Regarding claims 15-16, and incorporating the analysis of claims 1-3 and 5 above, Aggarwal does not specifically teach that the neurogenic potential of the cell is assessed by measuring the cells ability to stimulate proliferation of neuronal progenitors.
Bhattarai teaches that IL-4 is activated primarily in neurons and microglia/macrophages in response to Aß42 and is sufficient to increase neural stem/progenitor cells (NSPCs proliferation and neurogenesis via STAT6 phosphorylation through the IL-4 receptor in NSPCs (Bhattarai Abstract).
Imai teaches that Musashi is an RNA-binding protein that is highly expressed in neuronal progenitors cells, including neural stem cells (Imai Abstract).
MacNicol teaches that elevated Musashi1 levels are associated with proliferation predisposition and loss of differentiation potential in a wide variety of tissue and cell types (MacNicol pg. 5 col 2 para 1).
Therefore, it would have been obvious before the effective filing date for an ordinary skilled artisan to modify the teachings of Aggarwal in view of Bhattarai, Imai and MacNicol with a reasonable degree of predictable success so as measure a cytokine such as IL-4 in other to assess the cells ability to stimulate the proliferation of neuronal progenitors that expresses Musashi. As indicated by Bhattarai, IL-4 plays a role in neuronal progenitor proliferation, and as thought by Imai, Musashi is expressed neuronal progenitors and at elevated levels it associated to neuronal progenitors proliferation. Therefore, a skilled artisan would have been able to modify the teachings of Aggarwal assess the cells ability to stimulate proliferation by measuring IL-4 and/or Musashi stimulation.
Claims 17 are rejected under 35 U.S.C. 103 as being unpatentable over Aggarwal as applied to claim 1-3 and 5, 15 above, and further in view Bhattarai et al. IL4/STAT6 Signaling Activates Neural Stem Cell Proliferation and Neurogenesis upon Amyloid-β42 Aggregation in Adult Zebrafish Brain. Cell Rep. 2016 Oct 18;17(4):941-948, Makela et al. (2010) Interferon-γ Produced by Microglia and the Neuropeptide PACAP Have Opposite Effects on the Viability of Neural Progenitor Cells. PLOS ONE 5(6): e11091, as evidenced by Pan, Wurster and Goh, herein after referred to as, Bhattarai and Makela respectively.
Regarding claim 17, and incorporating the analysis of claim 1-3 and 5 above, Aggarwal does not specifically teach that the neurogenic potential of the cell is assessed by measuring the cells ability to stimulate proliferation of neuronal progenitors that express IFNγ receptors.
Bhattarai teaches that IL-4 is activated primarily in neurons and microglia/macrophages in response to Aß42 and is sufficient to increase neural stem/progenitor cells (NSPCs proliferation and neurogenesis via STAT6 phosphorylation through the IL-4 receptor in NSPCs (Bhattarai Abstract).
Makela teaches that neuronal progenitors cells express interferon γ (IFNγ) receptors and that that NPCs labeled with BrdU showed IFNγR2 positive cells actively divide in culture (Makela pg. 1 col 2 col para 2 – pg. 2 col 1 papa 1). Makela also teaches that IFNγ reduces cell proliferation in NPCs by upregulation of the cell cycle protein p21 (Makela Abstract).
Therefore, it would have been obvious before the effective filing date for a skilled artisan to modify the teachings of Aggarwal in view of Bhattarai and Makela with a reasonable expectation of success to assess the ability of the cells to stimulate the proliferation of neuronal progenitors cells that expresses IFNγ receptors, as indicated by Makela, IFN inhibits the proliferation of NPCs. Therefore, a skilled artisan would have been able to know that assessing if the neurogenic progenitors express IFNγ receptor is an indicator that the cells would not proliferate when IFN (a known and critical cytokine produced by immune cells vital for coordinating innate and adaptive immunity) is introduced into the culture.
Claims 1, 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al Induction of immunomodulatory monocytes by human mesenchymal stem cell-derived hepatocyte growth factor through ERK1/2. Journal of Leukocyte Biology, 2014, 96: 295-303, and further in view of and Yen et al. Multipotent human mesenchymal stromal cells mediate expansion of myeloid-derived suppressor cells via hepatocyte growth factor/c-met and STAT3. Stem Cell Reports. 2013 Jul 25;1(2):139-51, and Kalamasz et al Optimization of human T-cell expansion ex vivo using magnetic beads conjugated with anti-CD3 and Anti-CD28 antibodies. J Immunother. 2004 Sep-Oct; 27(5):405-18, herein referred to as Chen, Yen and Kalamasz respectively.
Regarding claims 1 and 18-20, Chen teaches and immunomodulatory assay in which CD4+ T cells and CD14-depleted PBLs (all of which express CD3 and CD28) labelled with CFSE was stimulated with anti-CD3 and anti-CD28 was cocultured MSC culture medium or rhHGF. Chen teaches that after 72 hours the 5 X 105 labelled cells were harvested and analyzed for cell proliferation (Chen pg. 296 col 2 para 3). Chen also teaches that the HGF production by MSC and the IL-10 or TNF-α produced by the PBLs/monocytes/cell lines were measured by ELISA (Chen pg. 297 para 2). Chen also teaches that HGF about 20-30 ng of HGF was secreted by MSC in the co-culture with anti-CD3 and anti-CD28 PBLs (Chen Fig 1C). Chen further teaches that HGF induces CD14+ monocytes to produce IL-10 which is an essential anti-inflammatory cytokine as well as the reduction of TNF-α (a pro-inflammatory cytokine) (Chen pg. 299 col 2). Chen also teaches that when recombinant HGF was administered to CD14+ cells at various doses (1, 5, 10 and 50 ng/ml) the amount of IL-10 that was secreted by the cells increased compared to cell that did not receive rHGF (Chen Fig. 4). Chen also teaches that HGF secreted by MSC, act on CD14+ monocytes to modulate allogenic T cell function and enhance IL-10 expression via ERK1/2 (Chen pg. 300 col 2 para 2 and Fig. 5).
Chen does not specifically teach the release criteria for HGF-1 secretion by the regenerative immunotherapy cells wherein the criteria is the secretion of HGF-1 is 30 nanograms per 1 million cells stimulated with 10 million “Dynabeads” for 24 hours.
Yen teaches that the addition of recombinant HGF alone could result in the expansion of MDSCs, and this effect was dose dependent up to a concentration of 30 ng/ml, which is approximately the upper limit found in MSC-conditioned medium (Ye pg. 141 col 2 para 1). Ye teaches that assessment of the effect of HGF was done using a co-culture of anti-CD3 and anti-CD28 stimulated CFSE labelled PBLs and MSC-expanded MDSCs at a various effector-to-target ratio (Ye pg. 149 col 1 para 3) including 1:10 (Yen Fig. 2).
Kalamasz teach that the ratio of T cells to anti-CD3/anti-CD28 beads for T cell stimulation can be varied and will have different effects of the memory T cells compared to naïve T cells (Kalamasz pg. 410 col 2 para 1) and that the beads to cell ratio was varied from 10:1 to 1:10 at start of culture (Kalamasz pg. 411 col 1 para 1). Kalamasz teaches that a 1:1 beat-to-T cell ratio achieved maximal results (Kalamasz pg. 411 para 2).
Therefore, it would have been obvious before the effective filing date for a person with ordinary skill in the art to modify the teachings of Chen in view of Yen and Kalamasz with a reasonable expectation of success to assess the HGF secretion by the immunomodulatory assay of Chen whereby the effector-to-target ratio is adjusted as indicated by Yen in other to achieve a stimulated cell population that will produce 30 ng of HGF. As indicated by Yen, 30 ng of HGF is approximately the amount of HGF that can be secreted by a regenerative cell such as MSC and therefore a skilled artisan would have been motivated to adjust the immunomodulatory potency assay of Chen in view of Yen and Kalamasz to measure or assess the production of HGF as a determining factor for the release of the regenerative immunotherapy product.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMMANUEL LED YOUTCHOM PENDIE whose telephone number is (571)272-6313. The examiner can normally be reached Mon - Fri: 8AM - 5PM CST.
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/EMMANUEL LED YOUTCHOM PENDIE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647