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 .
Priority
The instant application is a 371 of PCT/KR2021/005785 filed 05/10/2021, which claims priority to Korean Application 10-2020-0150118 filed 11/11/2020.
Claim Objections
Claims 1, 3, 5, and 6 are objected to because of the following informalities:
Claims 1, 5, and 6 recite the phrase “anti-CD56, anti-NKp46, and anti-NKp30” (e.g., claim 1, lines 5-6 and 8), but does not recite what these compositions are. For the purpose of examination, this phrase is interpreted as “anti-CD56, anti-NKp46, and anti-NKp30 antibodies.”
Claims 1, 5, and 6 recite the acronym “RPMI,” which is understood to refer to “RPMI culture medium” (claim 1, line 5) or “RPMI medium” (claim 1, line 7). RPMI is an acronym for Roswell Park Memorial Institute and is not a medium per se. For the sake of clarity, it is recommended that “RPMI” be amended to recite “RPMI medium.”
Claims 3, 5, and 6 recite the concentration of a composition, immediately following the composition (e.g., “plasma 2 ml, IL-2 20 ng/ml” in lines 4-5 of claim 5). For the sake of clarity, it is recommended that these phrases be amended to recite, for example, “2 mL of plasma, IL-2 at a concentration of 20 ng/mL,” or otherwise clarified in a similar manner.
Appropriate correction is required.
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 1-6 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 1 contains the trademark/trade name “ficoll” in line 3. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a density gradient medium and, accordingly, the identification/description is indefinite.
Claim 2 recites the phrase “wherein the cytokine of the Step 4) is treated with IL-2 + IL-15.” This phrase is indefinite because IL-2 and IL-15 are cytokines, and it is unclear what is meant by “wherein the cytokine is treated with cytokines.” For the purpose of examination, this phrase is interpreted as “wherein the cytokine of the Step 4) is IL-2 + IL-15.”
Claim 3 recites the phrase “wherein the cytokine of the Step 4) is treated with IL-2 20 ng/ml and IL-15 50 ng/ml.” This phrase is indefinite for the same reason as set forth above for claim 2. For the purpose of examination, this phrase is interpreted as “wherein the cytokine of the Step 4) is IL-2 at a concentration of 20 ng/ml and IL-15 at a concentration of 50 ng/ml.”
Claim 4 is drawn to the method of claim 1, but does not recite an active step. As written, the limitation in claim 4 merely poses a product-by-process limitation on a pellet of PBMC containing immune cells, as recited in lines 1-2 of claim 1. For the sake of compact prosecution, claim 4 is interpreted as “The culture method of NK cell according to claim 1, further comprising treating the pellet of PBMC containing immune cells with an RBC lysis buffer to remove red blood cells.”
Claim 5 is indefinite for the following reasons:
Claim 5 recites the limitation “wherein the culturing in the step 2) is carried out in a T25 flask coated with anti-CD16 antibody when the cell number is 3x107 or less and in a T75 flask coated with anti-CD16 antibody when the cell number is 3x107 or more” (lines 1-4). It is unclear whether a T25 or T75 flask is to be used when the cell number is 3x107. For the purpose of examination, it is interpreted that either a T25 or T75 flask may be used when the cell number is 3x107.
Claim 5 recites the limitation “suspending PBMC pellet in 10 ml RPMI and further adding the mixture” (lines 6-7). First, there is insufficient antecedent basis for “the mixture” in the claim. Furthermore, it is unclear what “the mixture” refers to, either in claim 1 or claim 5. For the purposes of examination, “the mixture” is interpreted as referring to 8mL of RPMI medium, 2 mL of plasma, 20 ng/mL of IL-2, 50 ng/mL of IL-15, 5 ng/mL of anti-CD56 antibody, 5 ng/mL of anti-NKp46 antibody, and 5 ng/mL of anti-NKp30 antibody in lines 4-6 of claim 5. Furthermore, it is unclear whether the recited concentrations of IL-2, IL-5, and the anti-CD56, anti-NKp46, and anti-NKp30 antibodies refer to the concentrations in the mixture, or in the final concentration in the culturing flask.
In light of Example 3 in the Specification (para 43), the limitation in lines 4-6 of claim 5 is interpreted as “culturing the isolated PBMC in an anti-CD16 antibody-coated incubator in a solution comprising 18 mL of RPMI culture medium, 2 mL of plasma, 20 ng/mL of IL-2, 50 ng/mL of IL-15, 5 ng/mL of anti-CD56 antibody, 5 ng/mL of anti-NKp46 antibody, and 5 ng/mL of anti-NKp30 antibody.”
Claim 6 is indefinite for the following reasons:
Claim 6 contains the limitation “wherein the subculturing in the Step 3) is preferably carried out by… in secondary subculture” (lines 1-9), which is set forth as a preferable embodiment. See Application of Collier, 397 F.2d 1003 (C.C.P.A. 1968), which states claims are considered indefinite when “things which may be done are not required to be done.” Specifically, it is unclear whether the claimed method may be infringed if the recited limitation does not occur. For the sake of compact prosecution, prior art is applied to the limitations of claim 6. However, as currently written, the entirety of claim 6 is an optional embodiment.
Furthermore, claim 6 recites the limitation "the cell culture suspension" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim Interpretation
Claim 1 recites the step of “treating the subcultured PBMC in a medium composition based on RPMI to which anti-NKp30, anti-NKp46 and anti-CD56 antibodies are added with a cytokine selected from a cytokine group consisting of IL-2, IL-15, and IL-2 + IL-15 to activate NK cells” (step 4, lines 9-12). The specification does not define how activation of NK cells is measured. The Examples in the specification use interferon-gamma (INF-γ) levels as a proxy for NK activity (e.g., Example 3, starting on p 10, para 42). In view of the specification, any increase in INF-γ levels relative to a control is understood to read on activation of NK cells. Furthermore, lines 9-10 of claim 1 are interpreted as “treating the subcultured PBMC in a composition comprising RPMI medium, anti-NKp30 antibody, anti-NKp46 antibody, and anti-CD56 antibody.”
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.
Claim(s) 1-2 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Baek (WO 2016/209021 A1), in view of Warren (The Journal of Immunology, 1999, 162(2): 735-742; cited in IDS filed 08/13/2024), Romagne (US 2008/0063717 A1), Lee (KR 101760764, cited in IDS filed 05/11/2023), and Shin (US 2023/0203444 A1).
Citations to Baek and Lee are to the WIPO machine translations, which are provided in this Office Action.
Regarding claim 1: Baek teaches a method for proliferating NK cells (para 1) comprising IL-12, IL-15, and an anti-Nik46 antibody (para 22). Baek teaches isolating PBMC from a human patient blood sample using Ficoll and centrifugation (para 88) (reads on lines 1-3), then culturing the PBMCs in a culture flask coated with fibronectin and gamma globulin (para 102-107).
Baek teaches that the cell culture may be performed in steps to maximally proliferate NK cells (para 30). Baek teaches an embodiment of the method comprising three culturing steps (para 40-41). In the first culturing step, PBMCs are cultured in a medium comprising IL-2, IL-15, anti-NKp46 antibody, and plasma (para 35) (corresponds to step 2). The second step of culture comprises transferring the culture of the first step to a new container (reads on subculturing), then culturing in a medium comprising IL-2, IL-15, anti-NKp46 antibody, and plasma (reads on albumin) (para 37-38) (corresponds to step 3). The third step of culture comprises IL-2 (para 40-41) (corresponds to step 4). Baek teaches that “each culture step may have the same or different culture medium components, culture vessels, and culture periods” (para 30). Therefore, steps 2-3 of the embodiment may comprise the same culture medium as the medium used in step 1, which comprises IL-12, IL-15, anti-NKp46 antibody, and plasma. Baek further teaches that RPMI 1640 may be used as the culturing medium (para 22) (reads on RPMI culture medium of steps 2-4).
Baek does not teach culturing the isolated PBMCs in an anti-CD16 antibody-coated incubator in step 2, a medium comprising anti-NKp30 antibody (steps 2-4), or a medium comprising anti-CD56 antibody (step 2).
Regarding the anti-CD16 antibody-coated incubator:
Baek teaches culturing the PBMCs in a culture flask coated with fibronectin and gamma globulin (para 102-107), but does not specify that the gamma globulin is an anti-CD16 antibody.
Warren teaches that culturing NK cells on plastic coated with purified anti-CD16 antibody (i.e., CD16 ligation) stimulates NK cell activation (p 736, col 2, para 2). In contrast to NK cells grown in control cultures, NK cells growth on anti-CD16 antibody-coated plates showed a heterogeneous pattern of fluorescence indicative of asynchronous cell division (p 740, col 2, para 3). Warren teaches that “These data demonstrate unequivocally that CD16 ligation stimulates NK cell division” (p 740, col 2, para 3).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Baek by culturing the NK cells on an anti-CD16 antibody-coated incubator, as taught by Warren. One of ordinary skill in the art would have been motivated to make this modification because Warren teaches that the data taught therein “demonstrate unequivocally that CD16 ligation stimulates NK cell division” (p 740, col 2, para 3). One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Warren teaches that NK cells can be grown on an anti-CD16 antibody-coated incubator.
Regarding the medium comprising anti-NKp30 antibody (steps 2-4):
Baek teaches that the composition for proliferation taught therein may include other carriers or adjuvants for PBMC culture and NK cell proliferation (para 70), but does not specify the inclusion of an anti-NKp30 antibody.
Romagne teaches a method for stimulating the proliferation of NK cells (Abstract). Romagne teaches resuspending PBMCs in complete medium comprising RPMI 1640 and 10% fetal calf serum (reads on plasma and albumin) (para 93), and adding interleukins and antibodies to establish a primary cell culture (para 97). The interleukins are a combination of IL-2 and IL-15 (para 94, 17), and the antibodies are anti-NKp46, anti-NKp30, or a combination of both (para 17). Romagne teaches that the combination of anti-NKp46 and anti-NKp30 gives the best enrichment of NK cells, compared to either antibody alone (para 148).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Baek by culturing isolated PBMCs in a medium comprising an anti-NKp30 antibody. One of ordinary skill in the art would have been motivated to make this modification because Romagne teaches that the combination of anti-NKp46 and anti-NKp30 gives the best enrichment of NK cells, compared to either antibody alone (para 148). One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Romagne teaches that PBMCs can be cultured in a medium comprising an anti-NKp30 antibody in addition to IL-2, IL-15, and an anti- NKp46 antibody.
Regarding the medium comprising anti-CD56 antibody (step 2):
Baek teaches that the composition for proliferation taught therein may include other carriers or adjuvants for PBMC culture (para 70), but does not specify the inclusion of an anti-CD56 antibody.
Lee teaches a culture method for mass proliferation of NK cells, comprising culturing PBMCs in an anti-CD16-antibody coated vessel in a medium containing IL-2, anti-CD335 (anti-NKp46) antibody, and anti-CD56 antibody (p 1, Means for Solving the Problem, para 1).
Shin teaches that NK cells stably proliferate at a higher rate when pre-stimulated with an anti-CD56 antibody (para 58). Shin CDteaches that culturing lymphocytes in the presence of an anti-CD16 antibody or an anti-CD56 antibody, which performs a similar function to the anti-CD16 antibody, causes signal transduction in NK cells, resulting in the expression of transferrin receptors or the production of TNF or IFN-γ (para 72).
It would have been prima facie obvious for a person of ordinary skill before the effective filing date of the claimed invention to have modified the method of Baek by culturing NK cells in the presence of an anti-CD56 antibody, as taught by Lee. One of ordinary skill in the art would have been motivated to make this modification because Shin teaches that culturing lymphocytes in the presence of an anti-CD56 antibody causes signal transduction in NK cells, resulting in the expression of transferrin receptors or the production of TNF or IFN-γ (para 72). One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Lee teaches that PBMCs can be cultured in the presence of an anti-CD56 antibody and IL-2.
Regarding claim 2: Baek teaches that “each culture step may have the same or different culture medium components, culture vessels, and culture periods” (para 30). Therefore, step 3 of the method taught in Baek, which corresponds to step 4 of instant claim 1, may comprise the same culture medium as the medium used in step 1 the method taught in Baek (corresponding to step 2 of instant claim 1), which comprises IL-2 and IL-15 (para 35).
Regarding claim 4: Baek teaches preparing PBMC from a patient blood sample using Ficoll and centrifugation (para 88). Baek teaches resuspending precipitated cells (reads on immune cell pellet) in 5 mL of RBC lysis buffer to remove red blood cells (para 90).
Claim(s) 3 is rejected under 35 U.S.C. 103 as being unpatentable over Baek (WO 2016/209021 A1; citations are to the WIPO machine translation), in view of Warren (The Journal of Immunology, 1999, 162(2): 735-742; cited in IDS filed 08/13/2024), Romagne (US 2008/0063717 A1), Lee (KR 101760764, cited in IDS filed 05/11/2023), Shin (US 2023/0203444 A1), and CN105219713A.
Citations to Baek and CN105219713A are to their respective WIPO machine translations, which are provided in this Office Action.
Baek, in view of Warren, Romagne, Lee, and Shin, renders obvious claim 1.
Regarding claim 3:
Baek teaches that the concentration of IL-15 (i.e., the second interleukin in the composition) may be 30 to 100 ng/mL or 50 to 100 ng/mL (para 66).
Baek does not teach that the concentration of IL-2 is 20 ng/mL. Although Baek teaches that the concentration of IL-2 may be 500-5000 IU/mL (para 65), because Baek does not disclose the manufacturer or catalogue number of IL-2 used in the disclosure, the concentration of IL-2 disclosed therein cannot be reliably converted into units of ng/mL.
CN105219713A teaches a method for in vitro expansion of NK cells, comprising culturing PBMCs in a cell culture flask coated with anti-CD16 antibody in a solution comprising IL-2 with a concentration of 20-50 ng/mL and IL-15 with a concentration of 20-50 ng/mL (p 1, Summary of the Invention, steps 1-3).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Baek, in view of Warren, Romagne, Lee, and Shin, by culturing PBMCs in a solution comprising 20 ng/mL of IL-2, as taught in CN105219713A. One of ordinary skill in the art would have been motivated to make this modification because CN105219713A teaches that culturing NK cells in a solution comprising 20-50 ng/mL of IL-2 results in NK cells with high proliferation and killing force (p 1, Summary of the Invention, para 1). One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because CN105219713A teaches that IL-2 can be used at a concentration of 20-50 ng/mL to culture NK cells.
Claim(s) 5 is rejected under 35 U.S.C. 103 as being unpatentable over Baek (WO 2016/209021 A1), in view of Warren (The Journal of Immunology, 1999, 162(2): 735-742; cited in IDS filed 08/13/2024), Romagne (US 2008/0063717 A1), Lee (KR 101760764, cited in IDS filed 05/11/2023), Shin (US 2023/0203444 A1), CN105219713A, and ThermoFisher (Useful Numbers for Cell Culture, 2020).
Citations to Baek, Lee, and CN105219713A are to their respective WIPO machine translations, which are provided in this Office Action.
Baek, in view of Warren, Romagne, Lee, and Shin, renders obvious claim 1.
Regarding claim 5:
As set forth above in the 112(b) rejection, lines 4-6 of claim 5 is interpreted as “culturing the isolated PBMC in an anti-CD16 antibody-coated incubator in a solution comprising 18 mL of RPMI culture medium, 2 mL of plasma, 20 ng/mL of IL-2, 50 ng/mL of IL-15, 5 ng/mL of anti-CD56 antibody, 5 ng/mL of anti-NKp46 antibody, and 5 ng/mL of anti-NKp30 antibody” in light of Example 3 in the Specification (para 43).
Baek teaches culturing PBMCs in a T75 flask (para 101-107). Baek teaches that the total number of cells used in the initial culture was 3x107 (p 14, Table 3). Baek teaches that the culture of PBMCs is carried out in a normal cell culture condition, which is at about 37℃ in a CO2 incubator (para 29). Baek teaches that in the first culture step (corresponds to step 2 of instant claim 1), the PBMCs may be cultured for 3 days or 4 days (para 35).
Baek does not specify the use of a T25 flask when the cell count is less than 3x107.
ThermoFisher teaches that a T75 flask has a seeding density of 2.1x106 cells and requires approximately 8-15 mL of media, and a T25 flask has a seeding density of 0.7x106 cells and requires approximately 3-5 mL of media.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Baek, in view of Warren, Romagne, Lee, and Shin, by utilizing a T25 flask instead of T75 according to cell count. One of ordinary skill in the art would have been motivated to make this modification because a T25 flask accommodates a smaller number of cells compared to a T75 flask and requires fewer volume of medium. One of ordinary skill in the art would have had a reasonable expectation of making this modification because Baek teaches that the cell culture vessel may be dishes, flasks, plates, and bags (para 29), indicating that the method taught therein is not limited to a T75 flask.
Regarding the amounts of components in the culture medium:
Regarding 18 mL of RPMI: Baek teaches that RPMI 1640 may be used as the culturing medium (para 22). In a working example, Baek teaches that the amount of medium used in the culture is approximately 13.5 mL (para 111).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have optimized the amount of medium in the culturing solution based on factors such as duration of culture and desired number of cells at harvest to arrive at the claimed invention of using 18 mL of medium. See MPEP 2144.05(II)(A). As noted in In re Aller, 105 USPQ 233 at 235, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Regarding 2 mL of plasma: Baek teaches that the amount of plasma added to the culture is 1.5 mL (para 111).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have optimized the amount of plasma in the solution based on factors such as the total volume of culture medium to arrive at the claimed invention of using 2 mL of plasma. See MPEP 2144.05(II)(A). As noted in In re Aller, 105 USPQ 233 at 235, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Regarding 20 ng/mL of IL-2: Baek teaches that the concentration of IL-2 may be 500-5000 IU/mL (para 65). However, because Baek does not disclose the manufacturer or catalogue number of IL-2 used in the disclosure, the concentration of IL-2 disclosed therein cannot be reliably converted into units of ng/mL.
CN105219713A teaches a method for in vitro expansion of NK cells, comprising culturing PBMCs in a cell culture flask coated with anti-CD16 antibody in a solution comprising IL-2 with a concentration of 20-50 ng/mL and IL-15 with a concentration of 20-50 ng/mL (p 1, Summary of the Invention, steps 1-3).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Baek, in view of Warren, Romagne, Lee, and Shin, by culturing PBMCs in a solution comprising 20 ng/mL of IL-2, as taught in CN105219713A. One of ordinary skill in the art would have been motivated to make this modification because CN105219713A teaches that culturing NK cells in a solution comprising 20-50 ng/mL of IL-2 results in NK cells with high proliferation and killing force (p 1, Summary of the Invention, para 1). One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because CN105219713A teaches that IL-2 can be used at a concentration of 20-50 ng/mL to culture NK cells.
Regarding 50 ng/mL of IL-15: Baek teaches that the concentration of IL-15 (i.e., the second interleukin in the composition) may be 30 to 100 ng/mL of 50 to 100 ng/mL (para 66).
Regarding 5 ng/mL of anti-CD56 antibody: The instant claim recites the concentration of 5 ng/mL anti-CD56 antibody in 20 mL of solution (18 mL of RPMI medium and 2 mL of plasma), which amounts to 100 ng of anti-CD56 antibody. Lee teaches that 1 to 50,000 ng of anti-CD56 antibody can be used to culture PBMCs (p 1, Means for Solving the Problem, para 2).
Regarding 5 ng/mL of anti-NKp46 antibody: The instant claim recites the concentration of 5 ng/mL anti-NKp46 antibody in 20 mL of solution (18 mL of RPMI medium and 2 mL of plasma), which amounts to 100 ng of anti-NKp46 antibody. Lee teaches that 1 to 50,000 ng of anti-CD335 (anti-NKp46) antibody can be used to culture PBMCs (p 1, Means for Solving the Problem, para 2).
Regarding 5 ng/mL of anti-NKp30 antibody: Romagne discloses an experiment to establish a titration curve of anti-NKp30 antibody to evaluate the amount of anti-NKp30 antibody necessary to obtain proliferation (Example 3, para 160, Fig 5). Romagne teaches that the effect of the anti-NKp30 antibody for induction of proliferation is saturable with a plateau effect at about 1 µg/mL, and that the dose to obtain 50% of maximum effect is below 0.1 µg/mL in this particular experiment (para 160). Romagne further teaches that “It should be noted that the characteristics of the curve may depend on the particular antibody used, and particularly of its affinity. The use of humanized anti NCR antibodies may also display a different titration curve” (para 161).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have optimized the concentration of the anti-NKp30 antibody based on aspects of the particular antibody used, as taught by Romagne, to arrive at the claimed invention. See MPEP 2144.05(II)(A). As noted in In re Aller, 105 USPQ 233 at 235, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Claim(s) 6 is rejected under 35 U.S.C. 103 as being unpatentable over Baek (WO 2016/209021 A1), in view of Warren (The Journal of Immunology, 1999, 162(2): 735-742; cited in IDS filed 08/13/2024), Romagne (US 2008/0063717 A1), Lee (KR 101760764, cited in IDS filed 05/11/2023), Shin (US 2023/0203444 A1), CN105219713A, and Arango (Autoimmunity: From Bench to Bedside, 2013, Chapter 45).
Citations to Baek, Lee, and CN105219713A are to their respective WIPO machine translations, which are provided in this Office Action.
Baek, in view of Warren, Romagne, Lee, and Shin, renders obvious claim 1.
Regarding claim 6: Baek teaches that in the second culturing step (corresponds to step 3 of instant claim 1), the culture of the first culturing step (corresponds to step 2 of instant claim 1) may be transferred to a new container (para 38). Baek teaches that in the second culture step, the cells may be cultured for 3 days to 6 days (para 39). Baek teaches that the culture of PBMCs is carried out in a normal cell culture condition, which is at about 37℃ in a CO2 incubator (para 29).
Regarding amounts of cell culture suspension from the first culture, RPMI, and plasma:
In a working example, Baek teaches that approximately 53 mL of medium and were added to 27 mL of the cell culture suspension from the primary culture (para 123), with the final culture solution comprising 9 mL of plasma (para 123).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have optimized the amount of cell culture suspension from the first culture, the amount of medium, and the amount of plasma in the culturing solution based on factors such as the desired number of cells at harvest, to arrive at the claimed invention. See MPEP 2144.05(II)(A). As noted in In re Aller, 105 USPQ 233 at 235, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
The limitations regarding the concentrations for IL-2, IL-15, and the anti-NKp30, anti-NKp46, and anti-CD56 antibodies are rendered obvious over Baek, in view of Warren, Romagne, Lee, Shin, and CN105219713A, as discussed for claim 5 above.
Baek does not teach a secondary subculturing step (lines 6-9).
Arango teaches that cells should be subcultured in a series of passages in order to keep the best condition for cell growth (p3, para 3).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Baek by subculturing the cells obtained in the second culturing step (corresponds to step 3 of instant claim 1). One of ordinary skill in the art would have been motivated to make this modification because Arango teaches that subculturing cells keeps the cells in the best condition for growth. One of ordinary skill in the art would have had a reasonable expectation of making this modification because Arango teaches that cells isolated from a tissue can be subcultured.
It would have been further prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have optimized the amount of cell culture suspension from the primary subculture, the amount of medium, and the amount of plasma in the culturing solution based on factors such as the desired number of cells at harvest, to arrive at the claimed invention. See MPEP 2144.05(II)(A). As noted in In re Aller, 105 USPQ 233 at 235, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Conclusion
No claims are allowed.
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/RISA TAKENAKA/ Examiner, Art Unit 1632
/TITILAYO MOLOYE/ Primary Examiner, Art Unit 1632