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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11-14-2025 has been entered.
Applicant's amendments to the claims and arguments filed on 11-14-2025 have been received and entered. Claims 1, 10, 15 have been amended. Claims 2-9 and 19-20 have been canceled. Claims 1, 10-18 are pending in the instant application. The 37 C.F.R. 1.132 declaration by Dr. KyuBum submitted
on 11-14-2025 is acknowledged and has been considered in full. The arguments presented therein are
discussed below in the Response to Arguments section of this action.
Election/Restrictions
Applicant's election with traverse of Group II (Claims 15-20) in the reply filed on 11-08-2024 is acknowledged. The traversal is on the ground(s) that the ground that unity of invention does exist between Groups 1-11 because there is a technical relationship that involves the same special technical feature and a search of all the claims would not impose a serious burden on the Office. This is not found persuasive because Group I-II lack unity of invention, and the inventions of these groups require the technical feature of magnetic particles of which at least one surface is bound with an activating receptor ligand, an inhibitory receptor ligand, a costimulatory receptor ligand, a cytokine, a cytokine receptor, an immune checkpoint ligand, a blocking antibody, or a combination thereof, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of Germeroth et al (Pub. No.: US 2019/0136186 Al, Provisional application No. 62/245,261, filed on Oct. 22, 2015). The discussion for the technical feature can be found in the preceding restriction requirement mailed on 09-10-2024 and the USC 103 rejections below. Additionally, the traversal is on the grounds that there in not a serious search burden on the Examiner to search invention of all group I-II. Applicant’s argument of search burden is not found persuasive, because instant application is a national stage filing under 35 U.S.C. 371 and according to MPEP 1893.03(d), whether or not a serious burden is required is not a proper basis of traversal in a national stage application.
The requirement is still deemed proper and is therefore made FINAL.
Claims 1-14 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. Applicant timely traversed the restriction (election) requirement in the reply filed on 11-08-2024. It is noted that claims 2-9 have been canceled.
Claims 15-18 are under consideration.
Priority
This application is a 371 of PCT/KR2020/006366 filed on 05/14/2020 that claims priority from foreign application KR 10-2019-0057136 filed on 05/15/2019.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)- (d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CPR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
New and Maintained in modified form - 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.
Claims 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Gong et al (Cellular & Molecular Immunology (2010) 7, 477–484; doi:10.1038/cmi.2010.41; published online 27 September 2010) in view of Hauskins et al (WO 2019/027850 A1, 07 February 2019).
Regarding to claim 15, Gong et al teach “Immobilized MHC class I chain-related protein A synergizes with IL-15 and soluble 4-1BB ligand to expand NK cells with high cytotoxicity ex vivo” (Title). Gong et al teach “Major histocompatibility complex (MHC) class I chain-related protein A (MICA), …… In this study, we showed that recombinant, immobilized MICA (iMICA) molecules coated on plastic wells weakly promote peripheral NK cell activation, secretion of interferon (IFN)-c and degranulation without inducing apoptosis. In addition, iMICA synergized with IL-15 and soluble 4-1BB ligand (s4-1BBL) to expand NK cells 25- to 42-fold in a 13-day culture, whereas NK cells stimulated only with IL-15 and s4-1BBL expanded 10- to 16-fold. In contrast to NK cells expanded by IL-15 and s4-1BBL stimulation, NK cells expanded long term in the presence of iMICA exhibited increased cytotoxicity against leukemia cells. These results suggest that large numbers of NK cells with high cytotoxicity can be generated by stimulation with IL-15 and s4-1BBL in the presence of iMICA and that these cells can be used for adoptive cancer immunotherapy” (Abstract). Gong et al stated that “in this study, we investigated whether immobilized MICA (iMICA) synergizes with soluble 4-1BBL (s4-1BBL) and IL-15 to expand NK cells efficiently” (Page 477, right column, 2nd para.). (For the preamble and the claimed: culturing natural killer cells in a medium comprising a composition for culturing natural killer cells, and For the claimed: wherein at least one surface of the magnetic particles is bound with a 4-1BB ligand and IL- l 5Rα).
Gong et al teach “Stimulation of PBMCs: PBMCs from healthy donors were isolated on a Ficoll gradient.” (Page 478, right column, 2nd para.), and “Expansion of PBMCs: PBMCs were seeded into 24-well tissue culture plates at a density of 1x104 cells/well and cultured alone or in the presence of 4 µg iMICA; 50 ng/ml IL-15 and 50 ng/ml s4-1BBL; or iMICA, IL-15 and s4-1BBL simultaneously.” (Page 479, left column, 2nd para.). (For the claimed: wherein the natural killer cells are comprised in peripheral blood mononuclear cells (PBMCs)).
Although Gong et al teach immobilized MICA (Immobilized MHC class I chain-related protein A), Gong et al do not specifically teaches magnetic particles is coated with protein G. However, Hauskins et al cures the deficiency.
Hauskins et al teaches methods include ex vivo or in vitro stimulation, enrichment, expansion, and/or activation of cells by incubation with a particle, e.g., a bead particle, attached to a binding molecule, such as a polypeptide antigen or anti-idiotype antibody (Abstract). In some embodiments, the cells are natural killer (NK) cells ([0423], page 136). The particle contains a magnetic, paramagnetic, and/or superparamagnetic core that is covered by a surface functionalized coat or coating ([0137], page 38). The coat contains or includes a material that is or includes a protein that is an albumin (e.g., human serum albumin), Protein A, and Protein G ([0138], page 38). In certain embodiments, particles, e.g., bead particles, comprise a surface conjugated or otherwise attached binding molecule that binds or is recognized by an antigen-binding domain of a recombinant receptor ([0264], page 77). The one or more additional agent is 4-IBB (CD137), 4-IBBL, IL-15R ([0266], page 77).
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 Germeroth et al by using magnetic particles coated with protein G or protein A as taught by Hauskins 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 Hauskins et al provided improved strategies for stimulating or expanding cell populations ([0004], page 2) such as natural killer (NK) cells ([0423], page 136) that express a recombinant receptor, for example, when cells are incubated with the particles, the binding molecules of the particles, e.g., beads, directly bind to the recombinant receptor, thus resulting in a greater stimulation, activation, proliferation, and/or expansion in the cells expressing the recombinant receptor as compared to the cells that lack the receptor ([0113], page 30). Specifically, Hauskins et al teaches a binding molecule (a fusion domain) is bound to a bead particle ([0294], page 88) which can be magnetizable or magnetically responsive ([0352], page 110), and fusion domains such as protein A, protein G can be linked to an antigen in the provided binding molecules to confer a desired property ([0298], page 90), and the molecule can be bound by 4-IBB (CD137), and IL-15R ([0266], page 77). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Hauskins et al successfully generated and expanded cells by incubation with a bead particle attached to a binding molecule, and also provided detailed instructions with material and methods and working examples and data to support their conclusions.
It is noted that the combined prior art references teach all structural/functional limitations required by the claim 15 as described above. The specification of the claimed invention teaches that “As shown in FIG. 6, it was confirmed that the number of NK cells significantly increased, when cultured with magnetic particles to which specific molecules were bound, as compared with the other two controls.” (Page 18, 5th para.) and “Both the percentage and the number of NK cells significantly increased, when cultured with magnetic particles to which specific molecules were bound, indicating that, when PBMCs are cultured with magnetic particles to which specific molecules were bound, the environment inside PBMCs is induced to the NK cell dominant environment” (Page 19, 1st para and see Experimental Example 2 – Table 1 on page 19). Thus, as evidenced by applicants’ own disclosure, a proportion of the NK cells in PBMCs is increased when cultured with the magnetic particles compared to controls that do not include the magnetic (For the claimed: wherein environment in PBMCs upon the culturing is induced to the NK cell dominant environment such that a proportion of the NK cells in PBMCs is increased when cultured with the magnetic particles compared to controls that do not include the magnetic particles).
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Regarding to claim 16, Gong et al teach obtaining peripheral blood mononuclear cells (PBMCs): “Stimulation of PBMCs: PBMCs from healthy donors were isolated on a Ficoll gradient …..” (Page 478, right column, 2nd para.).
Regarding to claim 17, Hauskins et al teach “the particles, e.g., beads, comprising a binding molecule are removed from the output composition. In some embodiments, the particles, e.g., beads, are magnetizable or magnetically responsive e.g., paramagnetic or superparamagnetic particles, e.g., beads. In some embodiments, the particles, e.g., beads, are streptavidin oligomers. Methods for removing particles, e.g., beads, (e.g., bead particles, e.g., beads, or magnetizable particles) from cells are known.” ([0352], page 110)
Regarding to claim 18, Gong et al teach “Expansions of pure NK cells Purified total NK cells, CD56dimCD16bright or CD56brightCD16dim cells were cultured with IL-15 and s4-BBL or iMICA, IL-15 and s4-1BBL. On days 1, 4, 7, 10 and 13, the cells were counted by trypan blue exclusion.” (Page 479, left column, last para.). Gong et al teach “Compared with freshly isolated NK cells, NK cells expanded in culture by stimulation with iMICA, IL-15 and s4-1BBL maintained their degranulation capacity after 21 days of culture …. ” (Page 481, right column, 3rd para.)
Claims 15-18 remained rejected under 35 U.S.C. 103 as being unpatentable over Germeroth et al (Pub. No.: US 2019/0136186 Al, Pub. Date: May 9, 2019) in view of Hauskins et al (WO 2019/027850 A1, 07 February 2019).
Regarding to claim 15, Germeroth et al teach methods that relate to the incubation or culturing, such as to induce stimulation of expansion (proliferation), activation, co-stimulation and/or survival, of a composition of cells, such as a population of lymphocytes (Abstract). Illustrative example of a suitable cell population includes natural killer cells (NK cells) which may for example be expanded with agents that bind to CD16 or CD56 ([0308], page 37). The incubation steps can include culture, cultivation, stimulation, activation, and/or propagation ([0477], page 56), and the conditions can include one or more of particular media, temperature, oxygen content, carbon dioxide content, time, agents ([0478], page 56) (For the preamble and the claimed: culturing natural killer cells in a medium comprising a composition for culturing natural killer cells).
Germeroth et al teach the cells are natural killer (NK) cells ([0438], page 53), and “the sample from which the cells are derived or isolated is blood or a blood-derived sample, or is or is derived from an apheresis or leukapheresis product. Exemplary samples include whole blood, peripheral blood mononuclear cells (PBMCs), ….” ([0442], page 53). (For the claimed: wherein the natural killer cells are comprised in peripheral blood mononuclear cells (PBMCs))
Germeroth et al teach the reagent is comprised on a support, such as a solid support or surface, e.g., bead, or a stationary phase ([0251], page 29), and any solid support (surface) can be used for the reversible immobilization of the reagent. Illustrative examples of solid supports on which the reagent can be immobilized include a magnetic bead ([0252], page 29). The magnetic particle or bead contains a magnetically responsive material bound to a specific binding member, such as an antibody or other binding partner ([0463], page 55). In some embodiments, the magnetically responsive particles are left attached to the cells that are to be subsequently incubated, cultured and/or engineered ([0467], page 55). (For the claimed: the composition comprising magnetic particles).
Germeroth et al teaches in some embodiments, the ligand is or includes 4-1BB ligand ([0327], page 39) Germeroth et al teaches the receptor-binding agent can include a ligand of a stimulatory receptor or other receptor capable of inducing a signal in the cell, such as an IL-15 ligand or a biologically active portion thereof ([0377], page 45) (For the claimed: wherein at least one surface of the magnetic particles is bound with a 4-1BB ligand and IL- l 5Rα,).
Although Germeroth et al teaches 4-IBB ligand ([0327], page 39), and IL-15R ([0377], page 45) and [0351], page 41), Germeroth et al do not specifically teaches magnetic particles is coated with protein G or protein A. However, Hauskins et al cures the deficiency.
Hauskins et al teaches methods include ex vivo or in vitro stimulation, enrichment, expansion, and/or activation of cells by incubation with a particle, e.g., a bead particle, attached to a binding molecule, such as a polypeptide antigen or anti-idiotype antibody (Abstract). In some embodiments, the cells are natural killer (NK) cells ([0423], page 136). The particle contains a magnetic, paramagnetic, and/or superparamagnetic core that is covered by a surface functionalized coat or coating ([0137], page 38). The coat contains or includes a material that is or includes a protein that is an albumin (e.g., human serum albumin), Protein A, and Protein G ([0138], page 38). In certain embodiments, particles, e.g., bead particles, comprise a surface conjugated or otherwise attached binding molecule that binds or is recognized by an antigen-binding domain of a recombinant receptor ([0264], page 77). The one or more additional agent is 4-IBB (CD137), 4-IBBL, IL-15R ([0266], page 77).
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 Germeroth et al by using magnetic particles coated with protein G or protein A as taught by Hauskins 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 Hauskins et al provided improved strategies for stimulating or expanding cell populations ([0004], page 2) such as natural killer (NK) cells ([0423], page 136) that express a recombinant receptor, for example, when cells are incubated with the particles, the binding molecules of the particles, e.g., beads, directly bind to the recombinant receptor, thus resulting in a greater stimulation, activation, proliferation, and/or expansion in the cells expressing the recombinant receptor as compared to the cells that lack the receptor ([0113], page 30). Specifically, Hauskins et al teaches a binding molecule (a fusion domain) is bound to a bead particle ([0294], page 88) which can be magnetizable or magnetically responsive ([0352], page 110), and fusion domains such as protein A, protein G can be linked to an antigen in the provided binding molecules to confer a desired property ([0298], page 90), and the molecule can be bound by 4-IBB (CD137), and IL-15R ([0266], page 77). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Hauskins et al successfully generated and expanded cells by incubation with a bead particle attached to a binding molecule, and also provided detailed instructions with material and methods and working examples and data to support their conclusions.
It is noted that the combined prior art references teach all structural/functional limitations required by the claim 15 as described above. The specification of the claimed invention teaches that “As shown in FIG. 6, it was confirmed that the number of NK cells significantly increased, when cultured with magnetic particles to which specific molecules were bound, as compared with the other two controls.” (Page 18, 5th para.) and “Both the percentage and the number of NK cells significantly increased, when cultured with magnetic particles to which specific molecules were bound, indicating that, when PBMCs are cultured with magnetic particles to which specific molecules were bound, the environment inside PBMCs is induced to the NK cell dominant environment” (Page 19, 1st para and see Experimental Example 2 – Table 1 on page 19). Thus, as evidenced by applicants’ own disclosure, a proportion of the NK cells in PBMCs is increased when cultured with the magnetic particles compared to controls that do not include the magnetic (For the claimed: wherein environment in PBMCs upon the culturing is induced to the NK cell dominant environment such that a proportion of the NK cells in PBMCs is increased when cultured with the magnetic particles compared to controls that do not include the magnetic particles).
Regarding to claim 16, Germeroth et al teach that the sample from which the cells are derived or isolated is blood or a blood-derived sample, or is or is derived from an apheresis or leukapheresis product. Exemplary samples include whole blood, peripheral blood mononuclear cells (PBMCs) …. ([0442], page 53).
Regarding to claim 17, Germeroth et al teach that, in some embodiments, the magnetizable or magnetically responsive particles are removed from the cells ….…([0467], page 55). Germeroth et al teach that the use of Dynabeads in which additional measures have to be taken to ensure that the final expanded T cell population is free of magnetic beads. Furthermore, in some embodiments, the use of a soluble multimerization agent makes it much easier to remove the same from the activated cell population (T cells, B cells or also natural killer cells) ([0210], page 22).
Regarding to claim 18, Germeroth et al teach that cells were incubated at 37° C. for a total of eight days ([1139], page 88).
Response to Arguments
Applicant's arguments and the 37 C.F.R. 1.132 declaration by Dr. KyuBum filed on 11-14-2025 have been fully considered but they are not persuasive.
1. The declaration on page 2-6 essentially stated that the claimed method provides unexpected, advantageous effects and therefore is not obvious:
(1) Additional experimental data
In the Declaration, new comparative data regarding the use of IL-l 5Ra alone is provided. This data demonstrates the superior synergistic effect of the claimed combination.
The new data, which evidences the unpredictable superior effect, is included as the revised Table 1 (as compared to Table 1 in the present specification). As shown in the revised Table 1 below, an addition of comparative data for IL-l 5Ra alone clearly demonstrates the true synergistic effect of the combination (4-lBBL + IL-l 5Ra), with a 6.08±2.20-fold increase (P<0.05) that is significantly superior to both the 4-lBBL alone (4.90±2.81) and IL-15Ra alone (1.98±1.01) conditions.
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That is, compared to 4-lBBL alone or IL-15Ra alone, the combination (4-lBBL + IL-15Ra) has a superior effect in creating an NK cell-dominant environment, resulting in an excellent synergistic effect. Alos see Experimental Example 2 on pages 16-18, Table 1 and the paragraph on page 18 under Table 1.
(2) Explanation of Results shown in the Figures in the present specification:
- Figure 1: Figure 1 is a representative image and the Combination group (d) formed the largest, densest, and most robust maximal aggregates.
- Figure 2 and 6: Any outliers are attributed to standard experimental variability, but the overall trend for the claimed combination remains superior.
- Figure 3 & 5: The statistical markers indicate significance relative to the Day 0 control, rather than between the (c) and (d) groups.
- Figure 4: Figure 4 visually demonstrates the superior effect of the combination (f) in achieving a higher NK cell percentage CD3-, CD56+ than 4-lBBL alone (e)
- Figure 7~9: Although the killing ability (Figure 8) may not be significant between (c) and (d), an improvement in cytotoxic function is clearly observable, and the enhanced cytotoxic potential is strongly supported by the statistically significant functional synergy observed in the IFN-y production (Fig. 9).
- Figure 10 & 11: Figure 11 demonstrates (c) has the advantage of significantly increasing activating receptors NKG2D and CD69 compared to the control (a) or (b).
(3) Unexpected results presented in the Examples and Figures in the specification
The present Examples also confirmed the superior combination of advantageous effects discarded below achieved by combining the 4-lBB ligand and IL-l 5Ra through specific embodiments. Specifically, the specific examples described in the present specification confirmed that the experimental group comprising soluble IL-15 and magnetic particles attached with 4-lBBL_IgGlFc and IL-15Ra_IgG1Fc showed superior combinations of effects compared to other comparative groups.
The advantageous effects of the claimed invention shown in the Examples include better cell aggregation, increase in cell count, a higher NK cell proliferation effect, increase in a ratio of NK cells, improved apoptosis and enhanced cytotoxicity function on immune cells against K562 cells, high detection of INF-y in a culture supernatant, decreased inhibitory receptors and increased activating receptors on NK cells, and clinical application, to name a few. (see the declaration filed on 11-14-2025 on page 2-6).
Response to Arguments:
The combination (4-lBBL + IL-15Ra) has been reported in the prior art references; therefore, their effects are expected and not superior over prior arts in creating an NK cell-dominant environment, resulting in an excellent synergistic effect:
Gong et al (as described above) teach “NK cells stimulated only with IL-15 and s4-1BBL expanded 10- to 16-fold” and “iMICA synergized with IL-15 and soluble 4-1BB ligand (s4-1BBL) to expand NK cells 25- to 42-fold in a 13-day culture” (See the abstract). Thus, if NK cells stimulated only with IL-15 and s4-1BBL, the expansion is already 10- to 16-fold. Since the declaration stated that “synergistic effect of the combination (4-lBBL + IL-l 5Ra), with a 6.08±2.20-fold increase (P<0.05)”, synergistic effect of the combination (4-lBBL + IL-l 5Ra) of the claimed invention appears less effective than the Gong et al’s teachings.
Specifically, Gong et al teach “To confirm the ability of iMICA, IL-15 and s4-1BBL to expand NK cells in vitro, CD3-CD56+ cells were sorted to high purity and expanded by stimulation with iMICA, IL-15 and s4-1BBL or with IL-15 and s4-1BBL. After 13 days of stimulation, the numbers of NK cells increased 32-fold (range: 25- to 42-fold) when cultured with iMICA, whereas cells cultured with IL-15 and s4-1BBL increased 13-fold (range: 10- to 16-fold) (Figure 4a). In addition, NK cells stimulated with iMICA, IL-15 and s4-1BBL exhibited high cytotoxicity against K562, U937 and HL60 leukemia cells (67.4, 58.6 and 62.3%, respectively). Since the numbers of NK cells in expansion with IL-15 and s4-1BBL increased efficiently and significantly, it is inherent that there are more NK cells in the culture (e.g., bigger aggregates size etc.)
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Additionally, Hauskins et al teaches methods include ex vivo or in vitro stimulation, enrichment, expansion, and/or activation of cells by incubation with a particle, e.g., a bead particle, attached to a binding molecule, such as a polypeptide antigen or anti-idiotype antibody (Abstract). In some embodiments, the cells are natural killer (NK) cells ([0423], page 136). The particle contains a magnetic, paramagnetic, and/or superparamagnetic core that is covered by a surface functionalized coat or coating ([0137], page 38). The coat contains or includes a material that is or includes a protein that is an albumin (e.g., human serum albumin), Protein A, and Protein G ([0138], page 38). In certain embodiments, particles, e.g., bead particles, comprise a surface conjugated or otherwise attached binding molecule that binds or is recognized by an antigen-binding domain of a recombinant receptor ([0264], page 77). The one or more additional agent is 4-IBB (CD137), 4-IBBL, IL-15R ([0266], page 77). One of ordinary skill in the art would have been motivated to use magnetic particles coated with protein G or protein A because Hauskins et al provided improved strategies for stimulating or expanding cell populations ([0004], page 2) such as natural killer (NK) cells ([0423], page 136) that express a recombinant receptor, for example, when cells are incubated with the particles, the binding molecules of the particles, e.g., beads, directly bind to the recombinant receptor, thus resulting in a greater stimulation, activation, proliferation, and/or expansion in the cells expressing the recombinant receptor as compared to the cells that lack the receptor ([0113], page 30). Specifically, Hauskins et al teaches a binding molecule (a fusion domain) is bound to a bead particle ([0294], page 88) which can be magnetizable or magnetically responsive ([0352], page 110), and fusion domains such as protein A, protein G can be linked to an antigen in the provided binding molecules to confer a desired property ([0298], page 90), and the molecule can be bound by 4-IBB (CD137), and IL-15R ([0266], page 77).
It is noted that the prior art references above teach all structural/functional limitations required by the claim 15 as described above. The specification of the claimed invention teaches that “As shown in FIG. 6, it was confirmed that the number of NK cells significantly increased, when cultured with magnetic particles to which specific molecules were bound, as compared with the other two controls.” (Page 18, 5th para.) and “Both the percentage and the number of NK cells significantly increased, when cultured with magnetic particles to which specific molecules were bound, indicating that, when PBMCs are cultured with magnetic particles to which specific molecules were bound, the environment inside PBMCs is induced to the NK cell dominant environment” (Page 19, 1st para and see Experimental Example 2 – Table 1 on page 19). Also, the table 1 of the declaration also demonstrates the synergistic effect of the combination a 4-1BB ligand and IL- l 5Ra. Thus, as evidenced by applicants’ own disclosure, a proportion of the NK cells in PBMCs is increased when cultured with the magnetic particles compared to controls that do not include the magnetic.
As per MPEP 2112 (II), inherent feature need not be recognized at the relevant time: There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention.").
2. The remarks on page 7 argue superior and unexpected effects of the combination of the 4-lBB ligand and IL-l 5Ra attached to magnetic particles, which is described and verified in the specific embodiments of the present Examples (i.e., magnetic particles attached with 4-lBBL_IgGlFc and IL-15Ra_IgG1Fc) (Remarks, page 7)
Response to Arguments:
The response for superior and unexpected effects of the combination of the 4-lBB ligand and IL-l5Ra attached to magnetic particles can be found above, and it will not be repeated here.
3. The remarks argue that Dl (Germeroth et al.) relates to a method for proliferating NK cells, but merely exemplifies the use of the 4-1BB ligand alone or in a limited combination with an antibody formulation. The claimed invention, however, confirmed the superior combination of advantageous effects discarded below achieved by combining the 4-lBB ligand and IL-15Ra through specific embodiments (Remarks, page 7-8).
Reference D1 merely lists the 4-IBB ligand as one of many examples and does not suggest any combination effect with IL-l 5Ra or the special synergistic effect brought about by this combination. Given that this synergy involves a structural combination of the claimed invention with substantial functional enhancement beyond a simple combination of elements, this effect is unpredictable by a person skilled in the art based on Reference D1 (Remarks, page 9).
Response to Arguments:
Germeroth et al teach methods that relate to the incubation or culturing, such as to induce stimulation of expansion (proliferation), activation, co-stimulation and/or survival, of a composition of cells, such as a population of lymphocytes (Abstract). The cells are natural killer (NK) cells ([0438], page 53), the ligand is or includes 4-1BB ligand ([0327], page 39), and the receptor-binding agent can include a ligand of a stimulatory receptor or other receptor capable of inducing a signal in the cell, such as an IL-15 ligand or a biologically active portion thereof ([0377], page 45). Also, Germeroth et al teach the reagent is comprised on a support, such as a solid support or surface, e.g., bead, or a stationary phase ([0251], page 29), and any solid support (surface) can be used for the reversible immobilization of the reagent. Illustrative examples of solid supports on which the reagent can be immobilized include a magnetic bead ([0252], page 29). The magnetic particle or bead contains a magnetically responsive material bound to a specific binding member, such as an antibody or other binding partner ([0463], page 55). Thus, Germeroth et al teach embodiments with combination of a 4-1BB ligand and IL- l 5Rα with a magnetic bead.
As per MPEP 2112 (II), inherent feature need not be recognized at the relevant time: There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention.").
Conclusion
No claim is allowed.
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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