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 .
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 27 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. Claim 27 recites, “wherein the activation step involves alpha-galactosylceramide- loaded PBMCs, soluble anti-CD3/CD28+ PBMCs, and soluble anti-CD2/3/28+PBMCs.” Involves is not a definitive active methods step and provides no information on how the particular elements relate to each other, or the method from which it depends. For instance, are the recited elements used as the activating factors in the activation step, or do they serve a different function? For instance, are they used to activate/prime/prepare another independent activator such as another cell? Are they cultured separately and their medium is taken and used for activation? Are they used to activate cells via a transwell system, or, is there direct contact? Are they added all at once to culture, or is there an order to which they are added? These alternative interpretations leave the metes and bounds of the claim undefined. (MPEP 2173).
Claim 27 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. Claim 27 recites, “wherein the activation step involves alpha-galactosylceramide- loaded PBMCs, soluble anti-CD3/CD28+ PBMCs, and soluble anti-CD2/3/28+PBMCs.” The identity/definition/description of what “soluble anti-CD3/CD28+ PBMCs” and “soluble anti-CD2/3/28+PBMCs” are/represent is lacking. For instance, are they PBMCs that express CD2/CD3/CD28 together? Does it represent three different mABs or is it a single trispecific antibody? Are they PBMCs that have been activated by anti-CD2/CD3/CD28 antibodie(s) in a previous step? Do they represent separate compositions, wherein a solution of soluble anti-CD3/CD28 antibodie(s) and PBMCs is a single composition and another composition contains anti-CD2/CD3/CD28 antibodie(s) and PBMCs? These alternative interpretations leave the metes and bounds of the claim unclear. (MPEP 2173).
Claim 31 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. Claim 31 recites, “wherein the activation step involves soluble antibodies comprising anti-CD3 +, anti-CD28, anti-CD2/3/28, and anti-CD3/28.” Involves is not a definitive active methods step and provides no information on how the particular elements relate to each other, or the method from which it depends. For instance, how are the antibodies used in the activation step? Are they used to activate a separate population of cells under independent conditions and then the activated cells are isolated and used to activate the target population? Or is it the medium from the aforementioned example that is taken and used to activate the target cells? Are they used directly on the target population? Is there an order in which they are added? These alterative interpretations leave the metes and bounds of the claim unclear. (MPEP 2173)
Claim 31 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. Claim 31 recites, “wherein the activation step involves soluble antibodies comprising anti-CD3 +, anti-CD28, anti-CD2/3/28, and anti-CD3/28.” The identity, definition/description of what “anti-CD3 +, anti-CD28, anti-CD2/3/28, and anti-CD3/28” antibodie(s) represent is lacking. For instance, does “anti-CD2/3/28” represent a single antibody containing all three ligands, or does it represent three different monoclonal antibodies in combination (anti-CD2 AB/ anti-CD3 AB/ anti-CD28 AB). These alterative interpretations leave the metes and bounds of the claim unclear. (MPEP 2173)
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.
Claims 21-26, 28-30, 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 23 of copending Application No. 17965377. The limitations of Claim 21 and 22 of instant application fall entirely in the bounds of claim 23 of the copending application. They both claim a method comprising differentiation of HSC cells into a T-cell, activating the derived T-cells, and then administering them as treatment. Note the open claim language used in claim 21. Furthermore, the additional limitations imposed on claim22 by claims 23-24, 26, 28-30, 32 of the instant application also fall within the bounds of claim 23 of the copending application due to the broad nature of the claim language used (aka “activate the T-cell”) in the reference application claim 23. This can language includes the possibility of using any of the methods outlined in the instant application’s claims 23-24, 26, 28-30, 32. Furthermore, the additional limitations imposed on claim 22 by claim 25 of the instant application also fall within the bounds of claim 23 of the copending application because reference application claim 23 claim language includes the possibility for the activation phase to last 7 days or less.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 5 and 6 and 7 and 19 and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 and 8 and 12 and 13 of copending Application No. 18290259 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the limitations of claim 1 and claim 5 of the instant application fall within the bounds of claim 1 of the reference application. They both include a method of creating iNKT cells expressing a TCR, a CAR and another transgene from HSC cells. Claim 6 and claim 7 of the instant application apply the same limitations as claims 7 and claim 8 of the reference application. Additionally, claim 19 and claim 20 of the instant application apply the same limitations as claim 12 and claim 13 of the reference application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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, 3, 5, 9-10, 12-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Seet, S.C. et al. 2017 as evidenced by Anjos-Afonso F, et al. 2023.
Seet, S.C. et al. 2017 discloses “This optimized artificial thymic organoid (ATO) system induced rapid and efficient T lineage commitment from cord clood-CD34+CD3- HSPCs…(paragraph 2, Results section). Additionally, “the appearance of CD4+CD3- immature single positive (CD4ISP) and CD4+CD8+ (DP) T cell precursors by week 2 (Fig. 1b).” (paragraph 2, Results section). Therefore, Seet, S.C. et al. 2017 has disclosed an in-vitro based method where a CD34+CD3- population of hematopoietic stem and progenitor cells (HSPCs) are differentiated into T-cells. Note that HSCs, defined as CD34+CD38-/lo, are a subset of CD34+CD3- HSPCs as supported by Anjos-Afonso F, et al. 2023. Therefore, they are present in the aforementioned HPSC population of Seet, S.C. et al. 2017. Importantly, the protocol lacks a T-cell activation step. (Note: See paragraphs “Artificial Thymic Organoid (ATO) cultures” and “T cell monolayer co-cultures” in the Methods section). This anticipates claim 1.
Additionally, they disclose, “Mature CD8SP or CD4SP cells from ATOs were isolated by magnetic negative selection using the CD8+ or CD4+ Isolation Kits (Miltenyi)…” (paragraph “T cell cytokine assays” in the Methods section). Therefore, they disclose the isolation/purification of T-cells from MS5-hDLL1 cells used in the ATO cultures. Importantly, MS5-hDLL1 cells are a mouse stromal cell line engineered to express hDDL1 as supported by Seet, S.C. et al. 2017. This anticipates claim 3
Furthermore, they disclose, “CB CD34+CD3- HSPCs were transduced with a lentiviral vector encoding codon optimized α and β chains of a HLA-A*02:01-restricted TCR... At 7 weeks, TCR-transduced ATOs showed…markedly increased CD3+TCRαβ+ T cells, the majority of which expressed the transduced TCR …” (paragraph “In vitro generation of naïve TCR-engineered T cells in ATOs” in Results section). Therefore, they disclose a method for generating TCR-transduced HSPCs, and their subsequent differentiation into T-cells. Note that HSCs are found within the HSPC population used as supported above. This anticipates claim 5.
Additionally, they disclose, “…ATO-derived T cells and precursors were defined…with the following phenotypes: total …double negative (DN; CD4-CD8-), CD4 immature single positive (CD4ISP; CD5+CD4+CD3-), double positive (DP; CD4+CD8+), CD8SP (CD3+TCRαβ+CD8+CD4-), CD4SP (CD3+TCRαβ+CD8-CD4+” (paragraph “Isolation of human thymocytes” in the Methods section). Therefore, they confirm the differentiation of HSPC’s (that contain HSCs) results in a population of double negative progenitor T-cells. This anticipates claim 9.
They go on to disclose, “ATO culture medium (“RB27”) composed of RPMI 1640…5 ng/ml rhFLT3L and 5 ng/ml rhIL-7 was made fresh weekly...6×105 MS5-hDLL1 cells were combined with 3×102–1×105 purified CD34+CD3- cells… To plate ATOs…the cell slurry was adjusted to 5 μl per ATO…plated by forming a drop at the end of the pipet tip which was gently deposited onto the cell insert…Medium was changed completely every 3–4 day by replacement with 1 ml with fresh RB27/cytokines.” (paragraph “Artificial Thymic Organoid (ATO) cultures” in the Methods section). Therefore, they disclose including a mixture of cytokines (rhIL-7) and growth factors (rhFLT3L) during the differentiation of HPSC/HSC cells. As outlined above, the formation of double negative (DN; CD4-CD8-) T-cells occurs during the differentiation of HPSC/HSC cells into T-cells. This anticipates claim 10
Furthermore, they observed “mature CD3+TCRαβ+ cells emerged as early as week 4 and increased over time…” (paragraph 2 of “Development of an optimized artificial thymic organoid system for in vitro human T cell differentiation” in the Results section). Therefore, they observed the generation of a t-cell population prior to 5 weeks. This anticipates claim 12.
Additionally, they disclose, “Purified T cell populations were plated… Cells were stained for CD3, CD4, and CD8…and intracellular staining with antibodies against IFNγ, TNFα, IL-2, IL-4, or IL-17A.” (paragraph “T cell cytokine assays” in Methods section). Therefore, they disclose an additional step of analyzing differentiated T-cells for expression of specific proteins. This anticipates claim 13. Furthermore, they also disclose, “Both immature and mature naïve T cell subsets co-expressed CD62L” (paragraph “Recapitulation of thymopoiesis and naïve T cell development in ATOs” in the Results section). This anticipates claim 14.
Claims 1-2, 4, 11, 15-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by EP 3247792 B1 as evidenced by Song. L et al. 2009 and Fowlkes, B et al. 1987.
EP 3247792 B1 discloses, “Human bone marrow-derived HSCs were isolated and differentiated in vitro as follows.” (paragraph 0056). “Fresh bone marrow aspirate is obtained from donors. CD34+ Lineage- …progenitor cells or HSCs are isolated with flow cytometric cell sorting. If required, HSCs will be transfected with Lenti-Tet1…5 × 103 cells…are seeded…per 10-cm dish of 80%-90% confluent OP9 or OP9-DL1 cells...Add 5ng/mL GM-CSF, 5ng/mL IL-3 and 2ng/mL IL-2 for NKT cell differentiation.” (paragraph 0057). Furthermore, “5 days later…Resuspend the cells in 10 mL of OP9 medium…containing cytokines, and seed the cells onto 10-cm dishes of 80%-90% confluent fresh OP9 or OP9-DL1 cells. Measure NKT…by FSCS 6 weeks after coculture.” (paragraph 0058). Therefore, they have disclosed an in-vitro method of differentiating HSC cells into T-cells, as evidenced by NKT cell generation. This anticipates claim 1.
Additionally, they disclose, “The use of NKT and γδ T cells derived from Tetl overexpressing HSCs in cancer immunotherapy...we will generate and purify NKT and γδ T cells in the in vitro co-culture system and inject them into NSG humanized mice which would have been implanted with human colorectal tumors… Furthermore, we will determine the capacity of these NKT and γδ T cells to recognize and eliminate cancer cells in vitro.” (paragraph 0075). Therefore, they have disclosed a method wherein they differentiate HSCs into NKT cells in-vitro without activation, followed by direct injection into a tumor-bearing mouse wherein they become activated by antigen bearing tumor cells via CD1d interactions as supported by Song. L et al. 2009. This anticipates claim 2.
Furthermore, they disclose “The methods include an obtained first population comprising hematopoietic stem cells (HSC); engineering the HSC to express (i.e., overexpress) Ten eleven translocation (Tet)1; maintaining the Tetl-overexpressing HSC in culture under conditions and for a time sufficient for at least some of the HSC to differentiate into NKT and/or γδ T cells.” Importantly, the next sentence reads as follows, “and optionally purifying the NKT and/or γδ T cells, thereby providing a population of NKT and/or γδ T cells.” (paragraph 0005). Therefore, they disclosed the method of generating a T-cell from differentiating an HSC cell in culture, and provided the option to purify the differentiated cells or not. This anticipates claim 4.
Importantly, they also disclose that once NKT cells are produced from HSCs, “The cells can be maintained in culture until a desired number of cells, e.g., of HSC or NKT and γδ T cells, is obtained, and then harvested for use or freezing.” (paragraph 0039). Therefore, they have disclosed that after the generation of NKT cells, they can either be maintained in culture for the purpose of expansion, or they can be frozen down for long-term storage. This anticipates claim 11 and claim 15.
During differentiation of Tet1 transduced/expressing HSCs, the authors phenotyped the population of cells that resulted from the differentiation. Importantly, they note “the overexpression of Tetl in HSCs from WT or ApoE-/-mice resulted in 6-10-fold increase in the differentiation towards NKT cells…” (paragraph 0063, and refer to figures 1d, 1g, and 1i). The figures show CD1d+/Tet1+ co-expression as clear populations are generated from the differentiation process. Importantly, CD1dTeT co-expression is a marker for invariant NKT cells (iNKT cells) in this study. This anticipates claim 16. Importantly, the alpha/beta (TCR) is the only subunit combination expressed in iNKT cells as supported by Fowlkes, B et al. 1987. This anticipates claim 17.
Claims 1, and 18-20, 23, 25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2020252303 A1.
WO 2020252303 A1 discloses, “TCR gene-modified HSCs are then differentiated into TARGET cells in a differentiation medium over a period of 4-10 weeks without feeders.” (paragraph 0202). Importantly, the differentiation process does not include an activation step/condition. Furthermore, the second stage of the procedure beings with the phrase, “In some embodiments, differentiated TARGET cells are stimulated…” (paragraph 0204). The use of the terminology “in some embodiments” indicates the second step is optional and therefore, TARGER cells can be generated and used without activation. They go on to disclose, “FIGS. 57A-57C. Generation of IL-15-enhanced BCAR-iTARGET (IL-15 BCAR-iTARGET) cells. (A) Experimental design to generate the IL15BCAR-iTARGET cell product…(C) FACS plots showing the detection of IL15BCAR-iTARGET (hTCRβ+6B11+) cells in cell culture over time.” (paragraph 0125, see figure 57). Importantly, it is imperative to note that there is no activation step detailed/disclosed in the method outlined. The cells are generated and then immediately frozen. Therefore, they disclose a process to differentiate TCR/IL15 transgenic HSC cells into TCR-armed Gene-Engineered T (TARGET) cells without any activation step. This anticipates claim 1 (TCR+/IL15+ transgenetic HSC->T cell without activation), claim 18 (HSC transduced with transgene), claim 19 (transgene is a cytokine), and claim 20 (the cytokine is IL15).
However, there are some embodiments where TARGET cell creation includes an activation step. For instance, they disclose, “In some embodiments, differentiated TARGET cells are stimulated with…non-specific TCR stimulatory reagents (anti-CD3/anti-CD28 antibodies … and expanded for up to 1 month in T cell culture media.” (paragraph 208). Therefore, they have disclosed the activation of TARGET cells using media supplemented with activation antibodies, and specify activation should not occur for more than 1 month. The disclosure of “less than a month” includes the possibility of less than 7 days. This anticipates claim 23 (antibodies in media), and Claim 25 (activation step no more than 7 days).
Claims 21-22, 24, 26, 30, 32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2020252303 A1.
WO 2020252303 A1 discloses, “CD34+ HSC cells were transduced with lentivirus carrying iNKT-TCR vector... MS5-DLL4 cells were mixed with…transduced HSCs per ATO aggregate” (paragraph 0649). The method continues with, “Allo HSC-iNKT cells were harvested from ATO aggregates, processed into single mononuclear cells, and pooled together… Healthy donor-derived PBMCs were loaded with αGC… then mix withAllo HSC-iNKT cells at ratio 1:1… These cells were cultured in C10 medium supplemented with human IL-7 (10 ng/ml) and IL-15 (10 ng/ml) for 10-14 days.” (paragraph 650). Furthermore, they disclose, “A human mouse xenograft model was used in in vivo studies to demonstrate the efficacy of Allo HSC-iNKT cells against AML.” (paragraph 0736). Their disclose of an in-vitro-based method to differentiate HSCs into T-cells (specifically iNKT cells), activating the resulting HSC-iNKT cells using a coculture containing αGC-loaded PBMCs and IL7 and IL15, and then using the HSC-iNKT cells as an in-vivo treatment of AML. These disclosures anticipate claim 21 (method of HSC-T-cell with activation and treatment), claim 22 (only one activation step), claim 24 (no activating antibodies) and claim 32 (activation media contains IL7 and IL15). Furthermore, as disclosed above, after culture/differentiation in ATOs containing MS5-DLL4 cells (aka feeder cells), single mononuclear cells are isolated and pooled and then mixed with αGC-loaded PBMCs. This anticipates claim 26 (PBMC activation), and claim 30 (feeder-free activation).
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 6, 7, 8 are rejected under 35 U.S.C. 103 as being unpatentable over Seet, S.C. et al. 2017 as applied to claim 1 above, and further in view of Ratajczak, J et al. 2011 as supported by Kim K et al. 2010.
Seet, S.C. et al. 2017 anticipates claim 1. However, It does not disclose that the HSC cells used in claim 1 be derived from a progenitor cell. It also does not disclose that the progenitor cells be pluripotent. It also does not disclose that the progenitor cells come from a body fluid.
Ratajczak, J et al. 2011 discloses, “…we found that UCB-derived VSELs (aka umbilical cord blood-derived very small embryonic-like stem cells) not only differentiate over OP9 stroma into clonogenic hematopoietic progenitors but also into HSCs…” (paragraph 6, Discussion section). Importantly, VSEL cells from umbilical cord blood come from a body fluid (claim 8), they are pluripotent (claim 7), and are progenitors of HSC cells (claim 6).
The Ratajczak, J et al. 2011 disclosure results in a person of ordinary skill in the art, before the effective filing date, finding it obvious to combine the following elements. The methods of Ratajczak, J et al. for the isolation and differentiation of UCB-derived VSELs into HSC cells and combining it with the methods of Seet, S.C. et al. 2011 to differentiate HSC cells into a population of T-cells without an activation step. The rationale for this this combination is as follows. Using VSELs to create HSC cells keeps the epigenetic landscape of the HSC cells more developmentally naïve, results in more broadly open chromatin structure at the development loci, and more intact developmentally naive imprinting patterns. This is in contrast to creating HSC cells from iPSC cells or harvesting HSC cells themselves from bone marrow or cord blood for the following reasons. iPSCs have been epigenetically reprogramed to a naiver state, however the reprograming is incomplete, limiting differentiation potential and hindering the ability to differentiate into cells that contain all the features/abilities that a naturally derived cell would as supported by Kim K et al. 2010. Direct harvest of HSC cells is inferior because natural HSC cells have modified their epigenetic landscape in response to their surrounding environment and other stimuli. Therefore, they are not truly naïve HSC cells and their epigenetic landscape differs from an HSC cell that’s just been born. Newly created HSCs have never sensed/responded to stimuli and signals which would result in epigenetic changes that curtail their differentiation potential. Therefore, claims 6-8 are obvious.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2020252303 A1 as applied to claim 21 above, and further in view of Webb, T et al. 2009
WO 2020252303 A1 discloses method of differentiating an HSC cell into an HSC-T-cell with a single activation step and subsequently using them as a therapeutic treatment. It does not disclose the activation step use aAPCs.
Webb, T et al. 2009 discloses, “Here we report a novel technique that facilitates the growth and analysis of NKT cells through the use of CD1d-expressing aAPC. CD1d-based aAPC can effectively propagate both canonical (iNKT cells) and noncanonical (Vα14−) NKT cells” (Abstract).
It would be obvious to a person of ordinary skill in the art, before the effective filing date, to use the method of aAPC-based activation of iNKT cells disclosed in Webb, T et al. 2009, in place of the aGalCer-loaded PBMC-based activation step disclosed in WO 2020252303 A1. This is a case of combining known elements to achieve predictable results. aAPC activation can be done using manufactured beads wherein they are designed to present large amounts of the main activating signal (aGalCer-loaded CD1d), and the necessary co-stimulatory molecules. The uniform manufacture of aAPCs (in terms of which/how many costimulatory/primary activation molecules are on each aAPC), provides a more uniform, reproducible, and tunable activation compared to aGalCer-loaded PBMCs. PBMC expression of primary/secondary signals is more variable and uncontrollable. This leads to variability and gives no control over how strong/what type of activation results. This renders claim 28 (activation using aAPCs) obvious.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Sun, W et al. 2015, and further in view of WO 2020252303 A1.
Sun, W et al. 2015 discloses, “Purified human HSC (3–6 × 104) were plated in 10cm Petri dishes containing either OP9-DL1 cells or OP9-GFP control cells...After three weeks, the expanded population was stained for iNKT cells (aGC-tet+CD3+ or iNKT+CD3+), and the remaining cells were stimulated biweekly with aAPC.” (paragraph titled, “2.3. In vitro T cell expansion” in the Methods section). Importantly, they disclose, “Here, we have demonstrated that CD1d-Ig based aAPC, made by covalent coupling of CD1d-Ig and potential co-stimulatory molecules to magnetic beads, can be used as a standardized method for the propagation of NKT cells. ” (1st paragraph in Discussion section). Therefore, these disclosures are a method to differentiate HSC cells into iNKT cells and then to activate them with aAPC-CD1d cells without aGalCer. They do not disclose using the use of the activated HSC-iNKT cells as a treatment.
WO 2020252303 A1 discloses a method of using αGC-loaded PBMC activated HSC-iNKT cells as an in-vivo treatment of AML. (see above rejections for details).
Therefore, it would be obvious to one of skill in the art, prior to the effective filling date, to use the aAPC-CD1d activated HSC-iNKT cells of Sun, W et al. 2015 as the therapeutic agent in the method of AML treatment outlined in US 2022257655. The rationale for this is as follows. This combination merely amounts to nothing more than substitution of known equivalents which produces expected results. This amounts to swapping out one known method of activation (PBMC-based) for another known method of activation (CD1d-aAPC), and both methods result in iNKT cell activation. This renders claim 29 (use of aAPC-activated HSC-iNKT cells)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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638
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