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 .
DETAILED ACTION
Claims 1, 3, 8, 10-11, 15-20, 22, and 24-25 are pending.
The Examiner for the instant application has changed to Examiner John Skoko.
Claim Objections and Rejections Withdrawn
The rejection to claim 21 are moot in view of claim cancellation.
The objection to claim 22 is withdrawn in view of cancellation of claim 21.
The objection to claim 20 is withdrawn in view of claim amendment.
The rejections to claims 10-11 is withdrawn in view of exosomes not being taught by COPIK ‘479.
The rejection to claims 1, 3, 8, 15-20, 22, and 24-25 are withdrawn in view of claim amendment.
Priority
Applicant' s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a national stage entry of PCT/US2020/018384 filed on the 14 February 2020 and claiming priority benefit of PRO application no. 62/805,359 filed on 14 February 2019. Receipt is acknowledged of certified copies of papers required by 37 CPR 1.55. Claims 1, 3, 8, 10-11, 15-22 and 24-25 have an effective filing date of 02/14/2019.
Claim Interpretation
Regarding instant claims 1, 3, 8, 10-11, 15-20, 22, and 24-25, exosomes are cell-derived vesicles between 30 and 100 nm as defined by the instant specification (page 16, [0057]).
Claim Rejections - 35 USC § 112(b)
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 15-19 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.
Regarding instant claim 15, step b of the claim is for selecting potent NK cells based on the amount of cytokine detected, but step 1 requires the method of claim 1 to be performed which includes a step of selecting an exosome-contacted NK cell that meets the cytokine potency level sufficient for a potent therapeutic NK cell. Thus, the claim is indefinite because two steps are required and perform the same function and it is unclear what the differences are for NK cell selection in the steps. Instant claims 16-19 are dependent on claim 15 and also include the rejected subject matter.
To promote compact prosecution, step (b) of claim 15 will be interpreted as deleted.
Claim Rejections - 35 USC § 103
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.
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, 8, 10, 15-17, 20, 22, and 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over COPIK et al. (US 2017/0333479 A1; of record now defined as COPIK ‘479), GOODWIN et al. (US 5569585 A; of record), AN X et al. (PLoS ONE 2017 12(8): 1-19 e0181904.), WENDEL M et al. (Cancer Res (2008) 68 (20): 8437–8445.), and WANG R et al. (J Leukoc Biol. 2012 Feb;91(2):299–309.)
COPIK ‘479, in the field of compositions and methods comprising natural killer (NK) cells (title), discloses methods for the in vivo or in vitro stimulation and expansion of NK cells (page 1-2, [0002] and [0012]), using exosomes comprising NK cell effector agents including IL-21 and 41BBL (page 1, [0009]). COPIK ‘479 taught NK cell-stimulating exosomes from K562-mb21-41 BBL cells, which express 4-1BBL and IL-21 (pages 1-3, [0011], [0016], [0023] and Fig. 2).
COPIK ‘479 taught an effective method of stimulating NK cells with exosomes isolated from culture of K562-mb21-41bbl cells (page 3, [0025] and Fig. 3), wherein the NK cells stimulated and expanded with exosomes are cytotoxic against K562 cancer cells (page 3, [0026] and Fig. 4). Regarding instant claims 3 and 8, COPIK ‘479 taught stimulated NK cells secrete cytokines such as INF-γ and TNF-α that not only inhibit tumors, but also signal invasion to other immune cells (page 8, [0066]). Regarding instant claims 1, 10, 15-17, 20, 22, 24, COPIK ‘479 taught a method of treating a cancer patient comprising: extracting autologous or allogenic PBMC from the patient or another patient that contains a population of NK cells, culturing and expanding the PBMCs with exosomes from K562-mb21-41bbl cells containing stimulatory ligands mbIL-21 and 41BBL, and administering the an effective amount of the pharmaceutical composition of expanded NK cells to the patient in need of NK cell immunotherapy (page 3, [0023] and Fig. 1).
Regarding instant claim 10, COPIK ‘479 taught administration of 35 ng/mL exosomes from K562-mb21-41bbl cells stimulated NK cell expansion and NK cytotoxicity against cancer cells, but cytotoxicity toward cancer cells was decreased in comparison to NK stimulated with 200 µg/mL K562-mb21-41bbl plasma membrane (PM21) particles (page 3, [0025], [0141] and Fig. 3A). Regarding instant claim 11, COPIK ‘479 taught kits comprising the materials described as other materials can be packaged together in any suitable combination as a kit useful for performing, or aiding in the performance of, the disclosed methods, wherein it is useful if the kit components in a given kit are designed and adapted for use together in the disclosed method (page12, [0117-0118]).
COPIK ‘479 does not teach: 1) Measuring and detecting secretion of a plurality of cytokines that include IFN-γ from a population of multiple NK cells to determine the potency of each NK cell with an immunoassay after 4 hours of exosome treatment; 2) Comparing the level of NK secreted IFN-γ to a population of cells with a cytokine potency level required for use in exosome-contacted NK cell immunotherapy, then selecting the NK cells that are potent enough to secrete IFN-γ over the therapeutic threshold level for an effective NK cell therapeutic; 3) stimulate NK cells with 200 µg/mL of exosomes isolated from K562-mb21-41bbl cells to measure cytokine secretion; but this is obvious in view of GOODWIN, AN, WENDEL, and WANG.
Regarding instant claims 1, 3, 8, 10-11, 15-20, 22, and 24-25, GOODWIN, in the field of assays measuring the degree of immune cell activation (see title), teaches methods of detecting and quantifying the in vitro activity (e.g., cytokine production) of stimulated immune cells, wherein the level of immune cell activity is evaluated for clinical outcomes for the therapeutic use of the activated cells (abstract). The method of GOODWIN uses peripheral blood mononuclear cells (PBMCs), which are heterogenous population of white blood cells including NK cells; GOODWIN further specifies that the assay is amenable for assaying NK cells (column 7, beginning line 19). GOODWIN teaches that the resting or in-active cells are stimulated with exogenous molecules (such as phorbol myristate acetate (PMA)) (beginning column 8, line 58). GOODWIN further establishes that the immune cells should be incubated with stimulating agent for a time sufficient for immune cell stimulation to have reached a maximal effect, from 0.5 to 150 hours (column 9, lines 38-46). GOODWIN explicitly states that the primary use of the assay is to correlate the degree of activity of non-resting immune cells as stimulated by the stimulant with in vivo potency in a clinical outcome for a particular therapy. GOODWIN taught by assaying the degree of activation of a sample of activated immune cells prior to infusion of the cells into a patient, it is possible to predict the clinical outcome of ex vivo therapy using the primed immune cells (column 5, lines 32-35). GOODWIN taught a standard can be ascertained which represents the minimum activity levels of stimulated, primed immune cells which correlates with an acceptably favorable clinical outcome (column 5, lines 36-39). GOODWIN taught the activation level of a particular sample of ex vivo activated cells compared to the previously determined standard value representing clinical efficacy; based on the comparison, appropriate decisions could be made as to whether or not to infuse the cells into the patient or whether to further process the cells (column 5, lines 39-45). GOODWIN taught assayed immune cells that do not meet the established standard for minimum activity levels, may be retreated or stimulated according to the protocol for that therapy to activate the cells or replaced and the replacement cells then treated or primed according to protocol (column 5, lines 46-59). Therefore, GOODWIN teaches a method of assaying the potency of a natural killer (NK) cell by contacting the NK cell with an effective amount of an exogenous stimulating factor for more than 4 hours, followed by measuring the amount of cytokine in said cell using an immunoassay and comparing the amount of cytokine produced in said NK cell to the amount of cytokine required for use in cellular immune therapy and selecting said potent NK cell based on the potency requirements. While the working examples of GOOWIN are primarily drawn to a mixed population of immune cells (e.g., see column 17, example 5 titled ‘Phenotypic Characterization of Ex Vivo Activated (EVA) Cells’) GOODWIN discloses that the assay is amenable to specific subsets of the immune cell population, including NK cells (column 7, line 18-23). It is clear that the central purpose of the GOODWIN assay is to administer therapeutically effective immune cells based on cytokine potency. Additionally, the GOODWIN method includes the detection of a plurality of cytokines, including IFNγ, GM-CSF, TNFα, TNFβ and IL-6 following NK cell stimulation (see column 16, lines 34-41; table 1).
Regarding instant claims 1, 3, 8, 15, 20, and 25, AN taught that both the amount and rate of IFN-γ secretion from individual NK cells were donor-dependent (abstract). Regarding instant claims 1, 3, 8, 15, 20, and 25, AN taught an effective method of measuring and detecting NK cell secretion of IFN-gamma with a bead-based immunoassay, wherein activation of a population of NK cells has a heterogenous IFN-γ secretion pattern for individual cells, and wherein secretion of IFN-γ reached a plateau at 4 hours (Fig. 4c). Regarding instant claims 1, 3, 8, 15, 20, and 25, AN taught it is straightforward to expand the number of analytes secreted by individual cells simultaneously. AN taught the secretion of the pro-inflammatory cytokine IFN-γ is an important mechanism of defense mediated by lymphocytes, wherein IFN-γ secretion has a profound influence on all cells within the microenvironment via multiple mechanisms (page 2, second paragraph).
Regarding instant claims 1, 3, 8, 15, 20, and 25, WENDEL taught IFN-γ predominantly from NK cells as a prerequisite for NK cell infiltration into tumors and exploiting strategies to augment NK cell accumulation in the tumor might lead to the development of effective antitumor therapies (abstract and page 8443, right column, Discussion first paragraph).
Regarding instant claims 1, 3, 8, 15, 20, and 25, WANG taught IFN-γ and TNF-α synergistically enhance NK cell cytotoxicity (abstract). WANG taught IFN-γ and TNF-α have been shown to be essential in tumor clearance and productions of IFN-γ and TNF-α by NK cells are functionally linked to their cytolytic activities (page 299, right column, first paragraph).
Regarding instant claims 1, 3, 8, 10, 15-16, 20, 22, and 24-25, it would have been obvious for a person having ordinary skill in the art to modify the method of COPIK ‘479 of treating a cancer patient comprising: extracting autologous or allogenic PBMC from the patient or another patient that contains a population of NK cells, culturing and expanding the PBMCs with exosomes from K562-mb21-41bbl cells containing stimulatory ligands mbIL-21 and 41BBL, and administering an effective amount of the pharmaceutical composition of expanded NK cells to the patient in need of NK cell immunotherapy
– to:
Measure and detect secretion of the cytokine IFN-γ from a population of multiple NK cells contacted with exosomes from K562-mb21-41bbl cells to determine the potency of each exosome contacted NK cell with an immunoassay after 4 hours of exosome treatment in view of GOODWIN, AN, WENDEL, and WANG;
Compare the level of secreted IFN-γ from each exosome contacted NK cell of a population to a threshold population of cells with a cytokine potency level required for use in exosome-contacted NK cell immunotherapy, then selecting the exosome contacted NK cells that are potent enough to secrete IFN-γ over the therapeutic threshold level for an effective NK cell therapeutic in view of GOODWIN, AN, WENDEL, and WANG;
Further measure NK secretion of TNF-α to select a population of NK cells in view of AN and WANG;
Stimulate NK cells with 200 µg/mL of exosomes isolated from K562-mb21-41bbl cells to measure cytokine secretion in view of COPIK ‘479; and
Further expand the NK cells that are selected as potent NK cells prior to administering a therapeutically effective amount of the potent NK cells in view of AN.
This is obvious because:
1-2a) GOODWIN taught methods of detecting and quantifying the in vitro activity (e.g., cytokine production) of stimulated immune cells, wherein the level of immune cell activity is evaluated for clinical outcomes for the therapeutic use of the activated cells, wherein the assay is amenable for assaying NK cells, and wherein immune cells should be incubated with stimulating agent for a time sufficient for immune cell stimulation to have reached a maximal effect, wherein the use of the assay is compared to an effective standard to correlate the degree of activity of immune cells as stimulated by the stimulant with in vivo potency in a clinical outcome for a particular therapy. Further, GOODWIN taught the assay as useful in characterizing the identity, purity and potency of therapeutic cell products to comply with FDA and other regulatory agency regulations. Thus, evaluation of stimulated immune cell activation in vitro for clinical outcome has been previously taught and useful to comply with regulatory agency regulations for characterizing potency of the therapeutic cell products;
1-2b) AN taught: i) an effective method of measuring NK cell secretion of IFN-gamma with a bead-based immunoassay to determine the potency of each NK cell, wherein activation of a population of NK cells has a heterogenous IFN-γ secretion pattern for individual cells, and wherein secretion of IFN-γ reached a plateau at 4 hours: ii) that both the amount and rate of IFN-γ secretion from individual NK cells were donor-dependent; iii) the secretion of the pro-inflammatory cytokine IFN-γ is an important mechanism of defense mediated by lymphocytes, wherein IFN-γ secretion has a profound influence on all cells within the microenvironment via multiple mechanisms. Thus, measurement and heterogeneity of NK cell secretion IFN-γ is known and further known to reach a plateau level at 4 hours.
1-2c) WENDEL taught IFN-γ predominantly from NK cells as a prerequisite for NK cell infiltration into tumors and exploiting strategies to augment NK cell accumulation in the tumor might lead to the development of effective antitumor therapies. Thus, selection of NK cells that secrete IFN-γ at an effective therapeutic threshold would lead to effective therapies;
1-2d) WANG taught: i) IFN-γ and TNF-α have been shown to be essential in tumor clearance; and ii) productions of IFN-γ and TNF-α by NK cells are functionally linked to their cytolytic activities. Thus, IFN-γ is known to be linked to cytolytic function and tumor clearance and selection of NK cells at a therapeutic threshold would be obvious with a reasonable expectation of success;
1-2e) COPIK ‘479 taught stimulated NK cells secrete cytokines such as INF-γ and TNF-α that not only inhibit tumors, but also signal invasion to other immune cells. Thus COPIK ‘479 taught the importance of NF-γ and TNF-α.
3a) AN taught it is straightforward to expand the number of analytes secreted by individual cells simultaneously. Thus, other cytokines can be measured.
3b) WANG taught: i) IFN-γ and TNF-α synergistically enhance NK cell cytotoxicity; ii) IFN-γ and TNF-α have been shown to be essential in tumor clearance and productions of IFN-γ and TNF-α by NK cells are functionally linked to their cytolytic activities; Thus, TNF-α is known to be linked to cytolytic function and tumor clearance and selection of NK cells at a therapeutic threshold would be obvious with a reasonable expectation of success.
4) COPIK ‘479 taught administration of 35 ng/mL exosomes from K562-mb21-41bbl cells stimulated NK cell expansion and NK cytotoxicity against cancer cells, but cytotoxicity toward cancer cells was decreased in comparison to NK stimulated with 200 µg/mL K562-mb21-41bbl plasma membrane (PM21) particles. Thus, exosome concentrations can be further increased for higher levels of NK cell stimulation and increasing the concentration of exosomes to 200 µg/mL would be obvious with a reasonable expectation of success for higher stimulation; and
5) AN showed NK cell heterogeneity in IFN-γ secretion and it would be obvious with a reasonable expectation of success to expand a population of the highly potent IFN-γ secreting cells that are most therapeutically effective to obtain a larger population of potent and effective NK cells for therapy.
There is a reasonable expectation of success because:
1-2a) GOODWIN taught methods of detecting and quantifying the in vitro activity (e.g., cytokine production) of stimulated immune cells, wherein the level of immune cell activity is evaluated for clinical outcomes for the therapeutic use of the activated cells, wherein the assay is amenable for assaying NK cells, and wherein immune cells should be incubated with stimulating agent for a time sufficient for immune cell stimulation to have reached a maximal effect, wherein the use of the assay is compared to an effective standard to correlate the degree of activity of immune cells as stimulated by the stimulant with in vivo potency in a clinical outcome for a particular therapy. Further, GOODWIN taught the assay as useful in characterizing the identity, purity and potency of therapeutic cell products to comply with FDA and other regulatory agency regulations. Thus, evaluation of stimulated immune cell activation in vitro for clinical outcome has been previously taught and would be expected to allow a cell product be produced that is effective while meeting requirements to comply with regulatory agency regulations for characterizing potency of the therapeutic cell products;
1-2b) AN taught: i) an effective method of measuring NK cell secretion of IFN-gamma with a bead-based immunoassay, wherein activation of a population of NK cells has a heterogenous IFN-γ secretion pattern for individual cells, and wherein secretion of IFN-γ reached a plateau at 4 hours: ii) that both the amount and rate of IFN-γ secretion from individual NK cells were donor-dependent; iii) the secretion of the pro-inflammatory cytokine IFN-γ is an important mechanism of defense mediated by lymphocytes, wherein IFN-γ secretion has a profound influence on all cells within the microenvironment via multiple mechanisms. Thus, measurement and heterogeneity of NK cell secretion IFN-γ is known and further known to reach a plateau level at 4 hours.
1-2c) WENDEL taught IFN-γ predominantly from NK cells as a prerequisite for NK cell infiltration into tumors and exploiting strategies to augment NK cell accumulation in the tumor might lead to the development of effective antitumor therapies. Thus, selection of NK cells that secrete IFN-γ at an effective therapeutic threshold would lead to effective therapies;
1-2d) WANG taught: i) IFN-γ and TNF-α have been shown to be essential in tumor clearance; and ii) productions of IFN-γ and TNF-α by NK cells are functionally linked to their cytolytic activities. Thus, IFN-γ is known to be linked to cytolytic function and tumor clearance and selection of NK cells at a therapeutic threshold would be obvious with a reasonable expectation of success.
3a) AN taught it is straightforward to expand the number of analytes secreted by individual cells simultaneously. Thus, other cytokines can be measured.
3b) WANG taught: i) IFN-γ and TNF-α synergistically enhance NK cell cytotoxicity; ii) IFN-γ and TNF-α have been shown to be essential in tumor clearance and productions of IFN-γ and TNF-α by NK cells are functionally linked to their cytolytic activities; Thus, TNF-α is known to be linked to cytolytic function and tumor clearance and selection of NK cells at a therapeutic threshold would be obvious with a reasonable expectation of success;
4) COPIK ‘479 taught administration of 35 ng/mL exosomes from K562-mb21-41bbl cells stimulated NK cell expansion and NK cytotoxicity against cancer cells, but cytotoxicity toward cancer cells was decreased in comparison to NK stimulated with 200 µg/mL K562-mb21-41bbl plasma membrane (PM21) particles. Thus, exosome concentrations can be further increased for higher levels of NK cell stimulation and increasing the concentration of exosomes to 200 µg/mL would be obvious with a reasonable expectation of success for higher stimulation; and
5) AN showed NK cell heterogeneity in IFN-γ secretion and it would be obvious with a reasonable expectation of success to expand a population of the highly potent IFN-γ secreting cells that are most therapeutically effective to obtain a larger population of potent and effective NK cells for therapy.
This would produce a method of treating a cancer patient comprising:
Extracting autologous or allogenic PBMC from the patient or another patient that contains a population of NK cells (instant claim 22), which have not been assayed for potency yet (instant claim 16),
culturing and expanding the PBMCs with exosomes from K562-mb21-41bbl cells containing stimulatory ligands mbIL-21 and 41BBL;
administering 200 µg/mL (instant claim 10) exosomes which comprise membrane bound IL-21 and 4-1BBL from K562-mb21-41bbl cells to the population of NK cells and after 4 hours measuring and detecting secretion of the cytokines IFN-γ (instant claim 3) and TNF-α (instant claim 8) from the population of multiple NK cells contacted with 200 µg/mL exosomes from K562-mb21-41bbl cells to determine the potency of each NK cell with a bead-based immunoassay (instant claim 25);
compare the level of NK secreted IFN-γ and TNF-α from the exosome contacted NK cells to a population of cells with a cytokine potency level threshold required for use in exosome-contacted NK cell immunotherapy;
selecting the NK cells that are potent enough to secrete IFN-γ over the therapeutic threshold level for an effective NK cell therapeutic;
expanding the NK cells that are selected as potent NK cells (instant claims 17 and 24); and
administering the pharmaceutical composition of expanded NK cells to the cancer patient in need of immunotherapy.
This further meets the claim limitation of instant claims 1, 15, and 20.
Regarding instant claim 11, COPIK ‘479 taught kits comprising the materials described as other materials can be packaged together in any suitable combination as a kit useful for performing, or aiding in the performance of, the disclosed methods, wherein it is useful if the kit components in a given kit are designed and adapted for use together in the disclosed method. Thus, it is obvious with a reasonable expectation of success to manufacture a kit for assaying potency of natural killer cells of the method above, wherein the kit comprises a container including 200 µg/ml of a K562-mb21-41bbl derived exosome comprising membrane-bound IL-21
and membrane-bound 4-lBBL and a culture medium suitable for NK cells that is used in the method above because it is useful if the kit components in a given kit are designed and adapted for use together in the method.
Response to Arguments
Applicant has amended claims 1 and 20.
The updated rejection is above.
Applicant notes that exosomes originate from the internal endosomal compartment within a cell, and that the contents of an exosome include a unique lipid composition enriched with cholesterol, sphingomyelin, glycosphingolipids, and phosphatidylserine compared to the plasma membrane (Skotland et al. "Exosomal lipid composition and the role of ether lipids and phosphoinositides in exosome biology" Journal of Lipid Research. Vol 60. Issue 1, January 2019, pages 9-18). Applicant asserts that Goodwin does not disclose contacting NK cells with K562-derived exosomes. Applicant further asserts that Copik does not remedy the deficiencies of Goodwin. Therefore, it would not have been obvious to expect stimulation of NK cells in contact with K562-derived exosomes.
In response, Applicant’s arguments, see page 8, filed 11/6/2025, with respect to exosomes and COPIK ‘072 have been fully considered and are persuasive. The rejection of claims 10 and 11 has been withdrawn. An updated claim rejection is above with COPIK ‘479, which teaches exosomes as indicated above.
Claims 1, 3, 8, 10, 15-20, 22, and 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over COPIK et al. (US 2017/0333479 A1; of record now defined as COPIK ‘479), GOODWIN et al. (US 5569585 A; of record), AN X et al. (PLoS ONE 12(8): 1-19 e0181904.), WENDEL M et al. (Cancer Res (2008) 68 (20): 8437–8445.), and WANG R et al. (J Leukoc Biol. 2012 Feb;91(2):299–309.) as applied to claims 1, 3, 8, 10, 15-17, 20, 22, and 24-25 above, and further in view of WO 2016/164370 (YU J et al.).
COPIK ‘479, GOODWIN, AN, WENDEL, and WANG are described above.
COPIK ‘479 did not teach: 1) Modify the NK cells to express a CAR but this is obvious in view of YU.
YU taught EGFR-CAR NK-92 cells that were transduced with an EGFR targeted chimeric antigen receptor to genetically alter a population of NK cells to present a CAR on the surface that effectively recognized, targeted and lysed EGFR positive breast cancer cells and secreted IFN-γ, and wherein NK-CAR cells from different donors secreted different levels of IFN-γ (pages 7-8, [0023-0024] and Fig. 7 and 13-14).
Regarding instant claims 18-19, it would have been obvious for a person having ordinary skill in the art to modify the method of COPIK ‘479, GOODWIN, AN, WENDEL, and WANG above – to:
Modify the NK cells to genetically alter a population of NK cells to present an EGFR-CAR on the surface that effectively recognized, targeted and lysed EGFR positive cancer cells before measuring cytokine levels in view of ‘370.
This is obvious because: 1) YU taught EGFR-CAR NK-92 cells that were transduced with an EGFR targeted chimeric antigen receptor to genetically alter a population of NK cells to present a CAR on the surface that effectively recognized, targeted and lysed EGFR positive cancer cells and secreted IFN-γ, and wherein NK-CAR cells from different donors secreted different levels of IFN-γ. Thus, an EGFR-CAR would be obvious to include in the method.
There is a reasonable expectation of success because: 1) Y U taught EGFR-CAR NK-92 cells that were transduced with an EGFR targeted chimeric antigen receptor to genetically alter a population of NK cells to present a CAR on the surface that effectively recognized, targeted and lysed EGFR positive cancer cells and secreted IFN-γ, and wherein NK-CAR cells from different donors secreted different levels of IFN-γ. Thus, EGFR-CAR NK are known to effectively kill cancer cells and secrete higher levels of IFN-γ and would be expected to be effective in the method.
This would produce a method of treating a cancer patient comprising:
Extracting autologous or allogenic PBMC from the patient or another patient that contains a population of NK cells, which have not been assayed for potency yet,
Modify the multiple NK cells to genetically alter a population of NK cells to present an EGFR-CAR on the surface that effectively recognized, targeted and lysed EGFR positive cancer cells, which direct the multiple NK cells to respond to an EGFR antigen (instant claims 18 and 19);
culturing and expanding the EGFR-CAR-NK cells with exosomes from K562-mb21-41bbl cells containing stimulatory ligands mbIL-21 and 41BBL;
measuring and detecting secretion of the cytokines IFN-γ and TNF-α from a population of multiple EGFR-CAR-NK cells to determine the potency of each EGFR-CAR-NK cell with a bead-based immunoassay 4 hours after administration of 200 µg/mL exosomes from K562-mb21-41bbl cells;
compare the level of EGFR-CAR-NK cell secreted IFN-γ and TNF-α to a population of cells with a cytokine potency level required for use in exosome-contacted NK cell immunotherapy;
selecting the EGFR-CAR-NK cells that are potent enough to secrete IFN-γ over the therapeutic threshold level for an effective NK cell therapeutic;
administering the pharmaceutical composition of expanded EGFR-CAR-NK cells to the cancer patient in need of immunotherapy.
Response to Arguments
Applicant has amended claims 1 and 20.
The updated rejection is above.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN J SKOKO III whose telephone number is (571)272-1107. The examiner can normally be reached M-F 8:30 - 5:00.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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