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 .
Applicant’s amendments to the claims and arguments filed on 02-13-2026 have been entered. Claims 14, 18-22 have been emended. Claim 1-13 and 15 have been canceled. Claims 14, 16-23 are pending.
Election/Restrictions
Applicant’s election without traverse of Group II, claims 14-23, drawn to a method of treating a
disease in the reply filed on 02-26-2024 is acknowledged.
Claims 1-13, 16-17, 19-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02-26-2024. It is noted that claim 1-13 have been canceled.
Applicant’s election without traverse of the species: a cancer, prostate carcinoma, a CRISPR/Cas9 gene editing construct, and the first treated with 5-fluorouracil in the reply filed on 02-26-2024 is acknowledged.
Upon further consideration, claims 16-17 have been rejoined with the elected claims because claims 16-17 encompass the elected species (e.g., where the subject has cancer). For example, while claims 16-17 further limit the choices available for the method of claim 14 regarding the condition the subject suffers from for non-cancerous aberrant cellular proliferation and infectious diseases, respectively, they don’t recite language that limits the claimed methods to treatment of those specific conditions and which excludes embodiments where the subject has cancer. As such, it is appropriate to rejoin claims 16-17 with claims 14-15, 18 and 23 and to examine them to the extent that they encompass embodiments directed to the elected species (i.e., where the subject suffers from cancer).
Claims 14, 16, 17, 18, 23 and the species: a cancer, prostate carcinoma, a CRISPR/Cas9 gene editing construct, first treated with 5-fluorouracil are under consideration.
Priority
This application is a CON of PCT/US2019/033670 filed on 05/23/2019 that claims priority from US provisional application 62/677,815 filed on 05/30/2018.
Withdrawn- Claim Rejections - 35 USC § 112
Claim 18 was 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. In view of Applicants' amendment of claim 18, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
Withdrawn- Claim Rejections - 35 USC § 112
Claims 14-15, 16, 17, 18, 23 were 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. In view of Applicants' amendment of base claim 14, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
New-Claim Rejections - 35 USC § 112- necessitated by amendments
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.
Claims 16-17 are 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 16 recites the limitation “non-cancerous aberrant cellular proliferation” in line 1-2, and claim 17 recites the limitation “infectious disease” in line 1. Since the base claim 14 has been amended to remove limitations “non-cancerous aberrant cellular proliferation” and “infectious disease”, there is insufficient antecedent basis for this limitation in the claim. Appropriate correction is required.
Maintained in modified form and New-Claim Rejections - 35 USC § 103 - necessitated by amendments
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 14 is rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal (Pub .No.: US 2018 /0186878 A1 Provisional application No. 62/ 327 ,954 , filed on Apr. 26 , 2016 .) in view of Saccani et al (Cancer Res 2006; 66: (23). December 1, 2006, doi:10.1158/0008-5472.CAN-06-1867) and Crittenden et al (PLoS ONE 7(6): e39295. doi:10.1371/journal.pone.0039295, June 2012), and da Silva et al (BMC Cell Biology 2014, 15:37, doi:10.1186/1471-2121-15-37).
Claim interpretation:
The specification of the claimed invention teaches that “Figures 1A-1B illustrate an embodiment of a method for making a synthetic hematopoietic immature myeloid cell population” ([0017], page 4). Thus, immature myeloid cell is interpreted as synthetic hematopoietic progenitor cells.
For the sake of compact prosecution, claim 23 is interpreted as expression of NF-KB p50 protein subunit in said cells is reduced through the use of a CRISPR/Cas9 gene editing construct, a zinc finger nuclease (ZFN), or a transcription activator like effector nuclease (TALEN).
Regarding to claim 14, Rosenthal teaches “the present disclosure relate to a method of preventing, reducing risk , or treating cancer in an individual in need thereof, comprising: (a ) obtaining a plurality of isolated innate immune cells; ….. administering to the individual a therapeutically effective amount of the plurality of isolated innate immune cells …” ([0018], page 4). Rosenthal teaches “in some embodiments, the innate immune cell is a myeloid cell. Myeloid cells are derived from hematopoietic stem cells in the bone marrow” ([0222], page 4).
Rosenthal teaches “Certain aspects of the present disclosure provide methods of preventing, reducing risk , or treating cancer comprising administering to an individual in need thereof a therapeutically effective amount of an isolated cell…… colon cancer … melanoma …. pancreatic cancer, prostate cancer …… ” ([0274], page 30).
Rosenthal teaches “wherein the one or more standard or investigational anti-cancer therapies are selected from the group consisting of ……adoptive cell transfer (ACT) therapy …...” (see claim 61, page 71, right column).
Rosenthal teaches Example 17 : Delivery of Immature Dendritic Cells In Vivo: “A DC -enriched population is generated from bone marrow using methods know in the art …. Modified dendritic cells are then transfused. A catheter is inserted into the carotid artery and 2x106 dendritic cells are infused (0.3 mL over 1 minute ), 2.5x106 cells are injected over 1 minute, or vehicle ( 50 % RPMI 1640 /50 % complete media without cytokines ) is injected over 1 minute . After infusion , the catheter is removed , the artery sutured , and the wound closed” ([0359], page 39).
Rosenthal teaches “the cell further expresses one or more signaling factors that promote an M2 phenotype by inhibiting a TNF-alpha/NF-kappa B pathway” ([0015], page 3).
Although Rosenthal teaches inhibiting a NF-kappa B pathway, Rosenthal does not teach expression of NF-KB p50 protein subunit in said cells is reduced when compared to wild-type cells. Saccani et al cure the deficiency.
Saccani et al teach that Tumor-associated macrophages (TAM) isolated from p50-/- mice showed normal production of M1 cytokines, associated with reduced growth of transplanted tumors (Abstract). Saccani et al showed in p50 NF-κB–deficient mice, and in lethally irradiated mice transplanted with p50-/- bone marrow, reversion of the anergic phenotype, delayed tumor progression and increased survival (Page 11433, left column, 1st para.).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Rosenthal by using hematopoietic cells in p50-/- bone marrow as taught by Saccani et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Saccani et al teach that mice transplanted with p50-/- bone marrow, reversion of the anergic phenotype, delayed tumor progression and increased survival (Page 11433, left column, 1st para.). Saccani et al observed that “TAMs from p50-/- mice express higher level of the T-cell recruiting and IFN-inducible chemokine CXCL10 (22, 29, 46, 47), which correlates with increased infiltration of CD4+ and CD8+ T lymphocytes in tumors from p50-/- mice. This observation is in line with the established antitumor role of these cells as well as with inhibition of tumor growth and increased survival of p50-/- mice” (Page 11439, left column, 3rd para.). Also, tumor-associated macrophages (TAM) isolated from p50-/- mice showed normal production of M1 cytokines, associated with reduced growth of transplanted tumors (Abstract). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Saccani et al were successful in using p50-/- bone marrow cells to delay tumor progression and increase survival, with working examples and data.
Rosenthal and Saccani et al do not specially teach the method of obtaining hematopoietic progenitor cells as claimed. Crittenden et al cure the deficiency.
Crittenden et al teach that “Radiation therapy aims to kill cancer cells with a minimum of normal tissue toxicity …. in mice lacking NFkB p50, radiation therapy is more effective …” (abstract) and “in vivo radiation therapy is more effective in mice defective in M2 polarization though deletion of NFkB p50” (Page 2, left column, 1st para.). Crittenden et al teach “Preparation of Bone Marrow Macrophages: Bone marrow cells isolated from long-bones of mice were cultured for a total of 7 days in complete media containing 40 ng/ ml MCSF (Ebioscience), with additional growth media provided after 3 days of culture. Adherent cells were harvested and macrophage differentiation confirmed by flow cytometry for CD11b, F4/80, Gr1 and IA” (Page 2, right column, 5th para.).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Rosenthal and Saccani et al by using method of obtaining bone marrow containing hematopoietic cell as taught by Crittenden et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Crittenden et al teach that “Radiation therapy aims to kill cancer cells with a minimum of normal tissue toxicity …. in mice lacking NFkB p50, radiation therapy is more effective …” (abstract) and “in vivo radiation therapy is more effective in mice defective in M2 polarization though deletion of NFkB p50” (Page 2, left column, 1st para.). Crittenden et al stated that “our data showing that NFkB p50 deficient macrophages sustain M1 differentiation even in the presence of irradiated cancer cells is consistent with data from Saccani et al. with M2 tumor macrophages ….. we propose that sustaining M1 differentiation, or creating a non-resolving environment in the tumor will increase destruction at the inflammatory site. In cancer therapy, increased destruction at a focused target site could be considered a benefit.” (Bridging last para in right column on page 8 to left column on page 9). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Crittenden et al were successful in preparation of bone marrow cells with data and working examples.
Although Crittenden et al teach “Preparation of Bone Marrow Macrophages: Bone marrow cells isolated from long-bones of mice were cultured for a total of 7 days in complete media containing 40 ng/ ml MCSF” (Page 2, right column, 5th para.), Rosenthal, Saccani et al and Crittenden et al do not specially teach “culturing the hematopoietic progenitor cells with at least one myeloid cytokine for 1-3 days” as claimed. da Silva et al cure the deficiency.
da Silva et al teach in vitro differentiation of murine bone marrow cells into macrophages (Title and abstract). da Silva et al teach treatment of bone marrow cells BMCs for 24, 48, 72 and 96 hours with 100 nM macrophage colony-stimulating factor (M-CSF) (page 2, right column, 2nd para.). da Silva et al teach Mononuclear cells constitute monocytes (cells with a small cytoplasmic area and nucleus in a horse-shoe shape) and macrophages (large nucleus and evident cytoplasm). A significant increase in the number of cells with macrophage characteristics was observed (Figure 2c) (see page 6, left column, 1 st para). Therefore, it is indicating that the culturing and treating of bone marrow cells BMCs for differentiation of murine bone marrow cells (including hematopoietic progenitor cells) with myeloid cytokine such as M-CSF was recognized in the prior art to be a result-effective variable. A person of ordinary skill in the art would have been motivated to perform the culturing and treating of bone marrow cells BMCs with M-CSF a plurality of times with different duration such as 24, 48, 72 and 96 hours out of the course of routine optimization.
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Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of the above references by culturing bone marrow cells for 24, 48, 72 and or hours as taught by da Silva et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because da Silva et al teach “Macrophages are important for maintaining an efficient innate immune response, having the ability to migrate to the site of invasion, recognizing the aggressor, phagocytosing and eliminating the pathogen” (Page 2, left column, 1st para.). da Silva et al teach “During the differentiation of monocytes into macrophages, several cellular changes are observed, such as increased cell size, increased number of organelles and the induction of the autophagic process” (Page 1, right column, 1st para.). da Silva et al teach “A significant increase in the number of cells with macrophage characteristics was observed in the cultures treated with AEPa (8% ± 3) for 96 hours, when compared to the control group (Figure 2c)” (Page 6, left column, 1st para.). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because da Silva et al were successful in differentiation of murine bone marrow cells into macrophages with working example and data.
Claims 18 is rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal (Pub .No.: US 2018 /0186878 A1 Provisional application No. 62/ 327 ,954 , filed on Apr. 26 , 2016 .) in view of Saccani et al (Cancer Res 2006; 66: (23). December 1, 2006, doi:10.1158/0008-5472.CAN-06-1867) and Crittenden et al (PLoS ONE 7(6): e39295. doi:10.1371/journal.pone.0039295, June 2012), and da Silva et al (BMC Cell Biology 2014, 15:37, doi:10.1186/1471-2121-15-37). as applied to claim 14 above, and further in view of Vincent et al (Cancer Res; 70(8) April 15, 2010, doi: 10.1158/0008-5472.CAN-09-3690) and van Os et al (Blood, Vol 89, No 7 (April 1), 1997: pp 2376-2383).
The teachings of Rosenthal, Saccani et al, Crittenden et al and da Silva et al above are incorporated herein in their entirety.
Rosenthal, Saccani et al, Crittenden et al and da Silva et al do not teach 15-150 mg/kg 5-fluorouracil for 1-5 days and administered 1x 105 to 5 x 109 synthetic hematopoietic progenitor cells every 2 to 10 days. Vincent et al and van Os et al cure the deficiency.
Regarding to claim 18, Vincent et al teach 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced t cell–dependent antitumor immunity (Title). Vincent et al teach “in vivo chemotherapeutic treatments ……. 5FU (50 mg/kg) …...” (Page 3053, left column, 4th para.) and “Five days after injection of the cytotoxic agent, we observed that only gemcitabine and 5FU were able to significantly decrease the number of MDSC in both the spleen and tumor bed (Fig. 1A; see Supplementary Fig. S1)” (Page 3054, left column, last para.). Myeloid-derived suppressor cells (MDSC) have been identified as a population of immature myeloid cells with the ability to suppress T-cell activation in humans and mice (Page 3052, left column, 1st para.).
Additionally, van Os et al stated that “ we studied the ability of KL and 5-FU to allow stable donor engraftment of congenically marked marrow in a C57BL/6 (B6) mouse model. ….. Animals then received three injections of 107 congenic B6-Gpi-1a-donor bone marrow cells at 24, 48, and 72 hours after the second 5-FU dose. A separate group of animals received a single dose of either 1 x 107 or 3x 107 donor marrow cells 24 hours after the last 5-FU dose. The level of engraftment was measured from Gpi-phenotyping at 1, 3, 6, and 8 months in red blood cells (RBCs) and at 8 months by phenotyping cells from the thymus, spleen, and marrow. Percent donor engraftment in RBCs appeared stable after 6 months” (Abstract). Thus, it is indicating that the administration of bone marrow cells in a subject 24, 48, and 72 hours after treatment with 5-fluorouracil was recognized in the prior art to be a result-effective variable. A person of ordinary skill in the art would have been motivated to perform the administration of bone marrow cells in a subject 24, 48, and 72 hours after treatment with 5-fluorouracil out of the course of routine optimization.
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of the above references by using 5FU (50 mg/kg) for 5 days to decrease the number of MDSC that would enhance T Cell–Dependent Antitumor Immunity as taught by Vincent et al and performing the administration of bone marrow cells in a subject 24, 48, and 72 hours after treatment with 5-fluorouracil as taught by van Os et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Vincent et al stated that “The elimination of MDSC by 5FU increased IFN-γ production by tumor-specific CD8(+) T cells infiltrating the tumor and promoted T cell–dependent antitumor responses in vivo. Altogether, these findings suggest that the antitumor effect of 5FU is mediated, at least in part, by its selective cytotoxic action on MDSC ”(Abstract), and “these data show that cyclophosphamide and 5FU could exert a T-dependent synergistic antitumor effect and could lead to the cure of some animals bearing large tumors” (Page 3059, right column, 2nd para). Additionally, van Os et al teach that “An increase in the number of BM cells to 3x107 given in one single injection at 24 hours after 5-FU / KL (2 cycles) led to a level of engraftment comparable to three separate injections of 1x107 BM cells on three consecutive days after 5FU + KL (P = .46)” (Page 2378, left column, 2nd para.), and van Os et al teach that BM cells are stimulated when cultured in the presence of cytokines. KL has been shown to synergize with erythropoietin, IL-3, IL-6, IL-12, G-CSF, and granulocyte-macrophage (GM)-CSF to increase the size and numbers of erythroid, granuloid, and macrophage colonies derived from murine or human BM (Page 2380, bridging left column 2nd para. to right column.). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Vincent et al successfully demonstrated the use of 5FU (50 mg/kg) for 5 days and van Os et al were successful in engraftment of BM cells 24, 48, and 72 hours after treatment with 5-fluorouracil, with data and working examples.
Claims 23 is rejected under 35 U.S.C. 103 as being unpatentable over Rosenthal (Pub .No.: US 2018 /0186878 A1 Provisional application No. 62/ 327 ,954 , filed on Apr. 26 , 2016 .) in view of Saccani et al (Cancer Res 2006; 66: (23). December 1, 2006, doi:10.1158/0008-5472.CAN-06-1867) and Crittenden et al (PLoS ONE 7(6): e39295. doi:10.1371/journal.pone.0039295, June 2012), and da Silva et al (BMC Cell Biology 2014, 15:37, doi:10.1186/1471-2121-15-37). as applied to claims 14 above, and further in view of Ray et al (Bioconjugate Chem. 2018, 29, 445−450, DOI: 10.1021/acs.bioconjchem.7b00768, Published: January 3, 2018).
The teachings of Rosenthal, Saccani et al, Crittenden et al and da Silva et al above are incorporated herein in their entirety.
Rosenthal, Saccani et al, Crittenden et al and da Silva et al do not teach “wherein the gene for SIRPα was genetically deleted through the use of: a CRISPR/Cas9 gene editing construct, a zinc finger nuclease (ZFN), or a transcription activator like effector nuclease (TALEN).”. Ray et al cure the deficiency.
Regarding to claim 23, Ray et al teach “an integrated nanotechnology/biology strategy for cancer immunotherapy that uses arginine nanoparticles (ArgNPs) to deliver CRISPR-Cas9 gene editing machinery into cells to generate SIRP-α knockout macrophages. The NP system efficiently co-delivers single guide RNA (sgRNA) and Cas9 protein required for editing to knock out the “don’t eat me signal” in macrophages that prevents phagocytosis of cancer cells. Turning off this signal increased the innate phagocytic capabilities of the macrophages by 4-fold. This improved attack and elimination of cancer cells makes this strategy promising for the creation of “weaponized” macrophages for cancer immunotherapy.” (Abstract)
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of treating cancer of the above references by using CRISPR/ Cas gene editing system to knock out SIRP-α as taught by Ray et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Ray et al teach generating SIRP-α knockout in macrophages can increase the innate phagocytic capabilities of the macrophages by 4-fold, and this improved attack and elimination of cancer cells makes this strategy promising for the creation of “weaponized” macrophages for cancer immunotherapy (Abstract). Also, Ray et al stated that “we have created an integrated nanotechnology/ biology approach to engineer macrophages in vitro into therapeutic tools to fight cancer. We have utilized a protein-based approach to deliver CRISPR-Cas9 into macrophages to knockout the SIRP-α gene that governs macrophage interactions with CD47 on cancer cells to prevent phagocytosis. Knocking out SIRP-α weaponizes the macrophages, greatly enhancing their ability to phagocytose tumor cells, providing a new immunotherapeutic strategy for cancer therapy” (Page 449, left column, 3rd para.). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Ray et al were successful in knocking out SIRP-α to weaponize the macrophages, greatly enhancing their ability to phagocytose tumor cells with working examples and data.
Response to Arguments
Applicant's arguments filed 02-13-2026 have been fully considered but they are not persuasive. The new 35 USC § 103 rejections necessitated by amendments have been rewritten as described above. Relevant arguments are addressed below:
1. Applicants argue that
“The specification supports that this process results in the formation of "immature myeloid cells" (IMCs), which are characterized as myeloid progenitor cells which have the potential to generate mature granulocytes, monocytes, macrophages, and dendritic cells in vivo (specification at paragraph [0010] and Abstract) …..The claimed method recites administration of IMCs in which expression of NF-KB p50 protein subunit is reduced (e.g., "p50-IMCs"). An unexpected advantage of these cells is that they promote formation of different cell types, e.g., macrophages and granulocytes, that are localized to tumor sites.” (Remark, page 7).
Response to Arguments:
It appears that Applicant is arguing that the cited references do not expressly suggest the claimed invention. However, it is well established in case law that a reference must be considered not only for what it expressly teaches, but also for what it fairly suggests. In re Burkel, 201 USPQ 67 (CCPA 1979). Furthermore, in the determination of obviousness, the state of the art as well as the level of skill of those in the art are important factors to be considered. The teaching of the cited references must be viewed in light of these factors. It also appears that applicant is attempting to attack each reference individually. However, in a 35 USC § 103 rejections rejection the references must be considered as a whole.
In the instant case, Rosenthal teaches treating cancers by administering to the individual a therapeutically effective amount of the plurality of isolated innate immune cells ([0018], page 4). Rosenthal teaches the innate immune cell is a myeloid cell, and myeloid cells are derived from hematopoietic stem cells in the bone marrow” ([0222], page 4). It is noted that Rosenthal teaches “Myeloid cells are derived from hematopoietic stem cells in the bone marrow …. Exemplary myeloid cells include, without limitation , macrophages, monocytes …” ([0222], page 24), and bone marrow -derived myeloid precursor cells expressing pro-repair SMART receptors ([0317], page 35). Rosenthal teaches “Increased presence of myeloid cells can be identified by typical markers, including CD11b and CD40” ([0360], page 40), and “Monocytes are obtained by positive magnetic bead-based selection of CD14 + cells” ([0305] page 33). As an example, Monocytes (Myeloid cells) are CD11b positive cell and capable of differentiation into macrophages as evidenced by Yang et al (Biomarker Research 2014, 2:1, doi:10.1186/2050-7771-2-1) (This reference is cited as evidence without relying on the rejection). Yang et al teach monocyte subsets are grouped as Ly6C+ and Ly6C- monocytes which are CD11b+CD115+ (page 2, right column, 1st para), and Ly6C+ monocytes differentiate into Ly6C- monocytes in the circulation (page 2, right column, 2nd para), and Ly6C- monocytes can differentiate into M2 macrophages (Page 3, left column, 1st para.), and “CD14++ classical monocytes leave bone marrow and differentiate into CD14++CD16+ intermediate monocytes and sequentially to CD14+CD16++ nonclassical monocytes in peripheral blood circulation” (Page 6, right column, 2nd para.). Therefore, myeloid cells such as monocyte can differentiate to be more mature monocyte or macrophages which fit exactly in the definition of applicant above for “immature myeloid cells”.
Also, the base claim 14 specify “hematopoietic progenitor cells …. express one or more cell surface markers selected from the group consisting of: CD11b, CD14 … ”. Thus, by the language of the claim, cells expressing markers such as CD11b encompass and satisfy the hematopoietic progenitor cells of the claimed invention. As described above, Rosenthal teaches without limitation any myeloid cells (mature or immature) derived from hematopoietic stem cells in the bone marrow ([0222], page 24). Thus, any myeloid cells (mature or immature progenitors ) derived from hematopoietic stem cells are encompassed by the teaching of Rosenthal
Furthermore, the cited prior art references provide proof of concept for reducing expression of NF-KB p50 in myeloid cells for cancer treatment: Rosenthal teaches “the cell further expresses one or more signaling factors that promote an M2 phenotype by inhibiting a TNF-alpha/NF-kappa B pathway” ([0015], page 3). Additionally, Saccani et al showed in p50 NF-κB–deficient mice, and in lethally irradiated mice transplanted with p50-/- bone marrow, reversion of the anergic phenotype, delayed tumor progression and increased survival (Page 11433, left column, 1st para.). Moreover, Crittenden et al teach that “Radiation therapy aims to kill cancer cells with a minimum of normal tissue toxicity …. in mice lacking NFkB p50, radiation therapy is more effective …” (abstract) and “in vivo radiation therapy is more effective in mice defective in M2 polarization through deletion of NFkB p50” (Page 2, left column, 1st para.), and Crittenden et al teach marrow cells isolated from long-bones of mice were cultured in complete media containing 40 ng/ ml MCSF and macrophage differentiation confirmed by flow cytometry for CD11b, F4/80, Gr1 and IA” (Page 2, right column, 5th para.).
2. Applicants argue that
Because Crittenden teaches differentiation of mature macrophages rather than immature myeloid populations (e.g. IMCs), Crittenden cannot teach cell populations exhibiting the unexpected advantages described above. For example, a skilled person would recognize that the mature macrophages obtained by Crittenden would be incapable of forming granulocytes in vivo.
The fact that the claimed subject matter is associated with unexpected results relative to the cited art, e.g., the cited art fails to teach the unexpected advantages for promoting formation of immune cell types at tumor sites outlined in the specification with respect to use of the claimed subject matter, is evidence of the nonobviousness of that subject matter (Remark, page 8).
Response to Arguments:
It is noted that the claim requires hematopoietic progenitor cells exposed to myeloid cytokine such as M-CSF and have cells expressing markers such as CD11b (marker for myeloid cells). In the instant case, Crittenden et al teach differentiation of bone marrow cells isolated from long-bones of mice in complete media containing 40 ng/ ml MCSF with the use of flow cytometry for confirmation of CD11b (Page 2, right column, 5th para.). It is well-known in the art that bone marrow cells encompass/comprise all hematopoietic progenitor cells that can be differentiated into all myeloid cells, and the art reference teach the use of CD11b as marker for presence of desired myeloid cells during the differentiation process which is the same as the claimed invention. Thus, a person of ordinary skill in the art would read the cited prior art references and expect that bone marrow cells comprising hematopoietic progenitor cells in medium containing Macrophage colony-stimulating factor (M-CSF) would differentiate to increase myeloid related cells expressing myeloid markers such as CD11b. As per MPEP 716.01(c) (II), Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHOA NHAT TRAN whose telephone number is (571)270-0201. The examiner can normally be reached M-F (9-5).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, PETER PARAS can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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