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
The amendment filed February 18, 2026 in response to the Office Action of November 19, 2025 is acknowledged and has been entered.
Claims 1 and 32 have been amended.
Claims 1, 3-8, 12-18, 32 and 33 are pending.
Claims 12-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.
Claims 1, 3-8, 32 and 33 are currently under consideration as drawn to the elected invention.
In view of claim amendments, the claim objection set forth in the previous Office Action of 11/19/2025 is hereby withdrawn.
Information Disclosure Statement
The Information Disclosure Statement filed on 12/22/2025 has been considered and entered by examiner.
MAINTAINED/MODIFIED REJECTION
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-8, 32 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Lee (Lee et al., WO 2016/201304 A1, Publication Date: 12/15/2016, of record) in view of Ramos (Ramos et al., Current Protocols in Cell Biology, A.3I.1-A.3L8, Publication Date: September 2014, of record).
Lee teaches a composition comprising the modified NK-92 cells and at least one antibody, for example alemtuzumab, rituximab, trastuzumab ([0013]). Lee teaches the NK-92 cells and antibody in the same formulation ([0113]). Lee teaches the NK-92 cells and antibody maybe stored in one container (e.g. one vial) in liquid form to enhance shelf-life. If in liquid form, the components may comprise additives such as stabilizers and/or preservatives such as proline, glycine, or sucrose or other additives that enhance shelf-life. ([0116], claims 37-40).
Lee teach methods of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of the composition ([0014]).
Lee teaches expressing the CD16 F158V high affinity form of CD16 in NK-92 cells which enhanced the killing of the NK-92 cells. See ([0010-0011]), Example 2, and Fig. 1. CD16 (also called FcγRIII-A) is a Fc receptor bind to IgG antibodies and activate ADCC ([0038]).
Lee teaches thawing and culturing the cells ([0118]).
Lee teaches that in some embodiments, NK-92 cells are administered in a composition comprising a medium that has been reconstituted from a cryopreserved sample (thereby in a frozen preparation comprising cryopreservation medium) ([0109]).
Lee teaches the pharmaceutical composition of claim 1 as set forth above. However, Lee does not explicitly teach a cryopreservation medium, e.g. CryoStor CS10 or the cryopreservation increases antibody binding to the haNK cells, or storage in less than -85 ̊C.
Ramos teaches that cryopreservation is the use of low temperature to preserve structurally intact living cells. The cells that survive the thermodynamic journey from the 37 ̊C incubator to the -196 ̊C liquid nitrogen storage tank are free from the influences of time. Thus, cryopreservation is a critical component of cell culture and cell manufacturing protocols (Abstract).
Ramos teaches the cells (purified from leukapheresis collection) to be frozen are pelleted and gently resuspended, by the gradual addition of a freezing medium (CryoStor CS10) containing a cryoprotectant. The cells are divided into aliquots into cryogenic vials, placed in a CoolCell controlled-rate freezing container, and transferred into a -80 ̊C freezer for at least 4 hr for initial freezing cycle prior to placement in a liquid nitrogen freezer for long-term storage (page A.3I.1, para. 2). Temperature of liquid nitrogen is below -85̊ C.
Ramos teaches the method can be used for T cells, B cells, monocytes, and NK cells (the bottom paragraph of page A.3I.2, and Table A.3I.1-CD56).
Ramos teaches the detailed steps, which includes using CryoStar CS10, cryogenic vials, and storing in liquid nitrogen (pages A.3I.2-A.3I.3).
Ramos teaches that the cryopreservation solutions are designed to buffer mechanisms of cell death and damage during the freeze-thaw process (A.3I.5, col. 2, para. 1).
Regarding “the cryopreservation increases antibody binding to the haNK cells”, it is suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to prepare a pharmaceutical composition comprising haNK cells (e.g. NK-92 cell expressing CD16 F158V) and a therapeutic antibody (e.g. Rituximab) in the form of a combined preparation as taught by Lee, and to use cryopreservation medium, such as Cryostor CS10, and to store the composition in less than -85 ̊C condition (e.g. liquid nitrogen), as taught by Ramos, because CryoStor CS10 containing medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A.3I.5, col. 1, para. 2), CryoStor CS10 has been widely used in preparation and storage for primary cells (such as NK cells), the cells prepared with CryoStor CS10 shows good recovery rate (Fig. A.3I.1), CryoStor CS 10 is commercially available by BioLife Solutions (page A.3I.1, § Materials), the protocol of using CryoStor CS10 is well-known in the art. Based on the teachings of references, one of ordinary skill in the art would have had a reasonable expectation the composition comprising a cryopreservation in a cryopreservation medium (such as CryoStor CS10) would help to preserve cell structure, viability and functionality of the composition, as recognized by Ramos. The motivation would be to use a well-tested and commercially available system to prepared the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles.
Regarding claim 3, Lee teaches the NK-92 cells further express a cytokine, for example, interleukin-2 ([0012], claims 7 and 8).
Regarding claim 4, Lee teaches that NK-92 cells are derived from NK cells, but lack the major inhibitory receptors that are displayed by normal NK cells, while retaining the majority of the activating receptors ([0057]). Although Lee does not teach that the NK-92 were genetically engineered, claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. See MPEP 2113 (I).
Regarding claim 5, Lee teaches that the modified NK-92 are irradiated prior to administration to the patient, as described in US Pat. No. 8,034,332 ([0092]). Although Lee does not teach the dose of radiation, it is noted that the recitation of “wherein the haNK cell is irradiated before administration at a radiation dose of at least 500 cGy.” is an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
Regarding claims 6-8, Lee teaches a composition comprising the modified NK-92 cells and at least one antibody, for example rituximab ([0013]). Lee teaches NK-92-CD16-CD19 cells in combination with rituximab can be used to treat leukemia (Example 1).
Regarding claims 32 and 33, Lee teaches pharmaceutical compositions with pharmaceutically acceptable carriers for the compositions of the invention ([0110]). Lee teaches a kit comprising the modified NK-92 cells and at least one monoclonal antibody ([0016], [0115]). Ramos teaches the cells (purified from leukapheresis collection) to be frozen are pelleted and gently resuspended, by the gradual addition of a freezing medium (CryoStor CS10) containing a cryoprotectant. The cells are divided into aliquots into cryogenic vials, placed in a CoolCell controlled-rate freezing container, and transferred into a -80 ̊C freezer for at least 4 hr for initial freezing cycle prior to placement in a liquid nitrogen freezer for long-term storage (page A.3I.1, para. 2). Temperature of liquid nitrogen is below -85̊ C.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to prepare a pharmaceutical composition comprising haNK cells (e.g. NK-92 cell expressing CD16) and a therapeutic antibody (e.g. Rituximab) in the form of a combined preparation as taught by Lee, and to use cryopreservation medium, such as Cryostor CS10, and to store the composition in less than -85 ̊C condition as a frozen composition (e.g. liquid nitrogen), as taught by Ramos. One of ordinary skill in the art would have had a reasonable expectation of success to reach the claimed invention because CryoStor CS10 containing medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A.3I.5, col. 1, para. 2, as set forth above this would increase antibody binding of the haNK cells), CryoStor CS10 has been widely used in preparation and storage for primary cells (such as NK cells), the cells prepared with CryoStor CS10 shows good recovery rate (Fig. A.3I.1), CryoStor CS 10 is commercially available by BioLife Solutions (page A.3I.1, § Materials), the protocol of using CryoStor CS10 is well-known in the art. The motivation would be to use a well-tested and commercially available system to prepared the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles.
Claim 5 is alternatively rejected under 35 U.S.C. 103 as being unpatentable over Lee (Lee et al., WO 2016/201304 A1, Publication Date: 12/15/2016, of record) in view of Ramos (Ramos et al., Current Protocols in Cell Biology, A.3I.1-A.3L8, Publication Date: September 2014, of record), as applied to claims 1, 3-8, 32 and 33 above, and further in view of Klingemann (Klingemann et al., Frontiers in Immunology, Vol. 7, Article 91, Publication Date: 03/14/2016, of record).
Examiner’s note: if the radiation is interpreted as causing a structure difference claim 5 is alternatively rejected below.
Lee teaches the pharmaceutical composition of claim 1 as set forth above. Lee also teaches NK cells are irradiated. However, Lee does not teach the dose of irradiation at least 500 cGY.
Klingemann teaches a NK-92 variant that expresses the high-affinity Fc receptor FcγRIIIa (158V) (haNK) in combination with IgG1 monoclonal antibodies (page 4, col. 1, para. 1, and Fig. 2).
Klingemann teaches that in vitro and in vivo studies have confirmed improved mAb efficacy with the combination (page 4, col. 1, para. 1).
Klingemann teaches that the rationale for a treatment that combines mAb treatment with haNK infusions is based on the number of retrospective studies demonstrating an improved overall survival benefit in patients expressing the high-affinity FcγRIIIa receptor upon treatment with mAbs, such as Rituxan (Rituximab). Since only 10% of the population is homozygous for the high-affinity FcγRIIIa receptor (V/V), there is a clear rationale for infusing haNK to those patients who carry the low- or intermediate-affinity FcγRIIIa receptor (90% of the population) (41) to maximize mAb efficacy (page 4, the paragraph bridging cols. 1-2).
Klingemann teaches that infusing cells of malignant origin may be counterintuitive, but a large body of evidence suggests that it is indeed safe as the cells are irradiated before infusion. Irradiation prevents in vitro proliferation while maintaining their ability to kill target cells and produce immune active cytokines. For NK-92, functional cytotoxicity is maintained after irradiation with 1000cGy, a dose that completely abrogates proliferation. Fifty patients who have been treated with repeated infusions of irradiated NK-92 cells without any short- or long-term complications (page 2, col. 2, para. 2).
It would have prima facie been obvious to make a pharmaceutical composition comprising haNK cells and a therapeutic antibody as taught by Lee and Ramos as set forth above, and to irradiate haNK cells before administration with a dose of at least 500 cGy (e.g. 1000 cGy), because this dose completely abrogates proliferation but maintain cytotoxicity, as taught by Klingemann. One of ordinary skill in the art would have been motivated to use the dosage for a safe and effective treatment. Given that the irradiation is widely used, as evidenced by Lee and Klingemann, one of ordinary skill in the art would have had a reasonable expectation of success to reach the claimed invention.
Response to Arguments
For the rejection of claims 1, 3-8, 32 and 33 under 35 U.S.C. 103, Applicant argues:
Paragraph [0034] of the Specification explains that the inventors unexpectedly found that
a CD16 receptor on cryopreserved haNK cells (CD16+ NK cells) serve as a docking platform for
soluble therapeutic antibodies and can induce ADCC when co-incubated with tumor target cells.
The claims reflect this unexpected finding.
It is respectfully submitted that the cited art does not teach or even hint at the unexpected advantage of antibody docking on cryopreserved haNK cells. Neither Lee nor Ramos, alone or in combination, teaches or suggests that cryopreserved haNK cells pre-loaded with therapeutic antibody retain Fc receptor functionality and induce ADCC upon thaw.
Applicant’s arguments have been fully considered but they are not persuasive. First, because CD16 is a Fc receptor, thus, NK cells expressing the CD16 F158V high affinity form of CD16 in NK-92 (taught by Lee) would be able to serve a docking platform for antibody with Fc domain (such as rituximab) and induce ADCC. Ramos teaches that cryopreservation in the proper medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A.3I.5, col. 1, para. 2). Thus, cryopreservation in the cryopreservation medium would help to keep the NK cell structure, yield, viability, and functionality. Because cryopreservation are widely used in the art, one of ordinary skilled in the art would have had a reasonable expectation that the NK cells and antibody would maintain their functionality for later application after thawing. For example, Lee teaches the NK-92 cells and antibody maybe stored in one container (e.g. one vial) in liquid form to enhance shelf-life. If in liquid form, the components may comprise additives such as stabilizers and/or preservatives such as proline, glycine, or sucrose or other additives that enhance shelf-life. ([0116], claims 37-40).
Regarding the argument, the references do not teach or suggests “cryopreserved haNK cells pre-loaded with therapeutic antibody retain Fc receptor functionality and induce ADCC upon thaw”. Contrary to the argument, as taught by Ramos, cryopreservation medium is designed to buffer mechanisms of cell death and damage during freeze-thaw process, thus one of ordinary in the art would have expected that the functional of protein (antibody) and cells would be maintained during thaw.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., cryopreserved haNK cells pre-loaded with therapeutic antibody retain Fc receptor functionality and induce ADCC upon thaw) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant further argues:
The combination of Lee and Ramos does not teach antibody pre-loading before
freezing, or that CD 16 and the therapeutic antibody remains functionally competent after freeze thaw, or that Fe-mediated docking survives cryogenic stress, or that ADCC is retained post-thaw.
In page 7 of the OA, the Examiner states "Ramos teaches that CryoStor CSI O containing medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A. 3I 5, col. I, para. 2). This would read on "increases antibody binding to the haNK cells" over long period of time." Respectfully, this reasoning is legally and scientifically insufficient. General preservation of viability does not inherently establish preservation of Fc receptor and antibody conformation, high-affinity IgG binding capacity, or downstream ADCC function. These are specific biochemical and functional properties that depend on membrane integrity, receptor orientation, and Fc interaction dynamics, each of which may be adversely affected by freeze-thaw cycles.
Applicant’s arguments have been fully considered but they are not persuasive. As haNK cells can bind Fc region of an antibody (such as rituximab), adding antibody to the haNK cells before freezing, would load the antibody to the haNK cells. As set forth above, Based on the teachings of references, one of ordinary skill in the art would have had a reasonable expectation cryopreservation in a proper medium (such as medium comprising CryoStor CS10) would help to preserve cell/protein structure, viability and functionality of the composition. The motivation would be to use a well-tested and commercially available system to prepared the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles. Because cryopreservation are widely used in the art, logically, one of ordinary skilled in the art would have had a reasonable expectation that the NK cells and antibody would maintain their functionality for later application after thawing.
Applicant further argues:
The unexpected result here is not that cells survive freezing. Rather, it is that cryopreserved haNK cells plus antibody retain the ability to function as an antibody docking platform and induce ADCC after thaw. That outcome is distinct from simple cell survival and is not suggested by the cited art.
Applicant’s arguments have been fully considered but they are not persuasive. First, as set forth above, based on the teachings of the references, one of ordinary skill in the art would have a reasonable expectation that “cryopreserved haNK cells plus antibody retain the ability to function as an antibody docking platform and induce ADCC after thaw”.
Second, the limitation of “cryopreserved haNK cells plus antibody retain the ability to function as an antibody docking platform and induce ADCC after thaw” is different from “the cryopreservation increases the antibody binding to the haNK cells” cited by the instant claims. Applicant does not provide any evidence for any cryopreservation process with the alleged activity (e.g. a direct comparison of antibody-binding to haNK cells with or without any cryopreservation). On the contrary, paragraph [0029] of the specification (shown below, also cited by applicant in the Remark filed 05/19/2025) indicates that premixed, cryopreservation preparation has comparable killing activity compared to the antibody was exogenously added to cryopreserved haNK cells in the assay. Thus, the results of cryopreservation are expected and unsurprising to an ordinary skill in the art.
Furthermore, Example 1 of the specification shows that “a post-thaw hold time of 10-30 minutes (or more in some instances) on ice or room temperature had a significant impact on the potency of ADCC function of the haNK cells. … Fig. 2A shows that results for cells that were cryopreserved (freezed), thawed, washed, and tested without any post-thaw incubation time and substantially no ADCC based cell killing was observed”. Thus, even with cryopreservation medium, the haNK cells and antibody mix does not have required activity without the specific step of 10-30 min incubation. Based on the results of Fig. 2A, one of ordinary skill in the art would draw a conclusion that the step of post-thaw incubation (not the cryopreservation step) may enhance or increase the functionality of haNK cells (e.g. antibody binding to haNK cells). Consistent with this, all the experiments shown by the Examples of the specification (see Figs 2B, 2C, 3A, 3B, 4A, 4B) comprise the post-thaw incubation step (30 min on ice) (see paragraphs [0022]-[0027] of the instant specification). Taken together, the cryopreservation does not bring unexpected/surprising advantages such as “increasing antibody binding to haNK cells” as applicant alleged.
Furthermore, the evidence of nonobviousness must be commensurate in scope with the claims to rebut the prima facie case of obviousness. See MPEP 716.02 (d). The specification only testes a specific cryopreservation medium (comprising CryoStor10) and a process comprising cryopreservation, X-ray irradiation and post-thaw incubation (see Example 1) on a single antibody (Rituxan). Thus the evidence is not sufficient to overcome the obviousness rejection because the claims are not limited to the cryopreservation medium (comprising CryoStor10) or the cryopreservation process of Example 1. Thus, in view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Thus, Applicant’s arguments are not found persuasive for the reasons set forth above and the rejection is maintained for the reasons of record.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
U.S. Patent No. 10,456,420
Claims 1, 3-8, 32 and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 10,456,420 (hereinafter Pat. 420, of record), in view of Lee (Lee et al., WO 2016/201304 A1, Publication Date: 12/15/2016, of record), Ramos (Ramos et al., Current Protocols in Cell Biology, A.3I.1-A.3L8, Publication Date: September 2014, of record), and Klingemann (Klingemann et al., Frontiers in Immunology, Vol. 7, Article 91, Publication Date: 03/14/2016, of record).
The claims of Pat. 420 teach a method for treating cancer in a subject in need thereof comprising administering to the subject a monoclonal antibody having a cytotoxic effect and genetically modified NK-92 cells, wherein the genetically modified NK-92 cells are genetically modified using a plasmid expression vector to generate stable NK-92 cells that express a CD16 polypeptide having a valine at position 158 of the mature form of the CD16 polypeptide; and express interleukin-2 (IL-2) targeted to the endoplasmic reticulum (ER); and further, wherein the expression vector comprises a transgene encoding the CD16 polypeptide and the IL-2 targeted to the ER comprising, in the 5′ to 3′ direction: a polynucleotide encoding the CD16 polypeptide, an IRES, and a polynucleotide encoding the IL-2 targeted to the ER (claim 1). As evidenced by the specification of Pat. 420, CD16 polypeptide having a valine at position 158 is a higher affinity form of CD16 (see col. 2, para. 1).
The claims of Pat. 420 teach the method of claim 1, wherein the monoclonal antibody is a naked monoclonal antibody of an IgG subtype that induces ADCC (claim 7), e.g. rituximab (claim 8).
The claims of Pat. 420 teach The method of claim 1, wherein the monoclonal antibody and the genetically modified NK-92 cells are administered simultaneously to the subject (claim 9).
The claims of Pat. 420 teach a method of treating cancer with a combination therapy (e.g. NK cells-CD16 v158-IL-2 + rituximab). However, the claims of Pat. 420 do not explicitly teach a pharmaceutical composition or kit as instantly claimed, or the cryopreservation increases antibody binding to the haNK cells, or irradiation step.
Lee, Ramos and Klingemann teach as set forth above. In particular, Lee teaches compositions and kit comprising NK cells-CD16v158 and antibody (e.g. rituximab), Ramos teaches materials and methods for preparation of NK cells in cryopreservation medium comprising CryoStor CS10, Klingemann teaches that irradiation of NK-92 cells with a dose of at least 500cGy can inhibit cell proliferation and maintain cytotoxicity, combination of haNK cell with antibody can enhance efficacy of antibody therapy.
Regarding “the cryopreservation increases antibody binding to the haNK cells”, it is suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat cancers with a combination therapy (e.g. NK cells-CD16 v158-IL-2 + rituximab) as taught by the claims of Pat. 420, and to make a pharmaceutical composition and kits comprising NK cells-CD16 v158-IL-2 + rituximab, for streamlining the treatment and improved efficacy, as taught by Lee and Kligemann, and to use cryopreservation medium, such as Cryostor CS10, and to store the composition in less than -85 ̊C condition (e.g. liquid nitrogen), as taught by Ramos, because CryoStor CS10 containing medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A.3I.5, col. 1, para. 2), CryoStor CS10 has been widely used in preparation and storage for primary cells (such as NK cells), the cells prepared with CryoStor CS10 shows good recovery rate (Fig. A.3I.1), CryoStor CS 10 is commercially available by BioLife Solutions (page A.3I.1, § Materials), the protocol of using CryoStor CS10 is well-known in the art, and to use an irradiation dose of 1000 cGy to treat haNK cells, because this dose completely abrogates proliferation but maintain cytotoxicity. One of ordinary skill in the art would have had a reasonable expectation the composition comprising a cryopreservation medium (such as CryoStor CS10) would help to preserve cell structure, viability and functionality of the composition. The motivation would be to use a well-tested and commercially available system to prepared the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles.
U.S. Patent No. 10,736,921
Claims 1, 3-8, 32 and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 10,736,921 (hereinafter Pat. 921, of record) in view of Lee (Lee et al., WO 2016/201304 A1, Publication Date: 12/15/2016, of record), Ramos (Ramos et al., Current Protocols in Cell Biology, A.3I.1-A.3L8, Publication Date: September 2014, of record), and Klingemann (Klingemann et al., Frontiers in Immunology, Vol. 7, Article 91, Publication Date: 03/14/2016, of record).
The claims of Pat. 921 teach a pharmaceutical composition comprising a population of engineered NK-92 cells and a monoclonal antibody having a cytotoxic effect, wherein the engineered NK-92 cells are genetically modified to express a nucleic acid construct comprising a polynucleotide that encodes a CD16 polypeptide having a valine at position 158 of the mature form of the CD16 polypeptide, and a polynucleotide that encodes an interleukin-2 (IL-2) targeted to the endoplasmic reticulum (ER), wherein the nucleic acid construct is a bicistronic construct comprising the polynucleotide that encodes the CD16 polypeptide and the polynucleotide that encodes the IL-2 targeted to the ER. As evidenced by the specification of Pat. 921, CD16 polypeptide having a valine at position 158 is a higher affinity form of CD16 (see col. 2, para. 1). Thus, the pharmaceutical composition of Pat. 921, reads on the components of instant claims 1-3.
The claims of Pat. 921 teach the pharmaceutical composition of claim 1, wherein the monoclonal antibody is a naked monoclonal antibody of an IgG subtype that induces ADCC (claim 11)
The claims of Pat. 921 teach the pharmaceutical composition of claim 11, wherein the monoclonal antibody is alemtuzumab, rituximab, trastuzumab, avelumab, daratumumab or elotuzumab (claim 12). This reads on antibodies of claims 6-8 of the instant application.
The claims of Pat. 921 teach a pharmaceutical composition comprising haNK cells and rituximab, as set forth above. However, the claims of Pat. 921 do not explicitly teach a pharmaceutical composition comprising a cryopreservation medium or kit as instantly claimed, e.g. the cryopreservation ncrease antibody binding to the haNK cells, or irradiation step.
Lee, Ramos and Klingemann teach as set forth above. In particular, Lee teaches kit comprising NK cells-CD16v158 and antibody (e.g. rituximab), Ramos teaches materials and methods for preparation of NK cells in cryopreservation medium comprising CryoStor CS10, Klingemann teaches that irradiation of NK-92 cells with a dose of at least 500cGy can inhibit cell proliferation and maintain cytotoxicity, combination of haNK cell with antibody can enhance efficacy of antibody therapy.
Regarding “the cryopreservation increases antibody binding to the haNK cells”, it is suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a combination therapy (e.g. NK cells-CD16 v158-IL-2 + rituximab) as taught by the claims of Pat. 921, and to make a pharmaceutical kits comprising NK cells-CD16 v158-IL-2 + rituximab, for streamlining the treatment and improved efficacy, as taught by Lee and Klingemann, and to use cryopreservation medium, such as Cryostor CS10, and to store the composition in less than -85 ̊C condition (e.g. liquid nitrogen), as taught by Ramos, because CryoStor CS10 containing medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A.3I.5, col. 1, para. 2, thus, cryopreservation in the cryopreservation medium would help to keep the NK cell structure, yield, viability, and functionality), CryoStor CS10 has been widely used in preparation and storage for primary cells (such as NK cells), the cells prepared with CryoStor CS10 shows good recovery rate (Fig. A.3I.1), CryoStor CS 10 is commercially available by BioLife Solutions (page A.3I.1, § Materials), the protocol of using CryoStor CS10 is well-known in the art, and to use an irradiation dose of 1000 cGy to treat haNK cells, because this dose completely abrogates proliferation but maintain cytotoxicity. One of ordinary skill in the art would have had a reasonable expectation the composition comprising a cryopreservation medium (such as CryoStor CS10) would help to preserve cell structure, viability and functionality of the composition. The motivation would be to use a well-tested and commercially available system to prepared the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles.
U.S. Patent No. 10,738,279
Claims 1, 3-8, 32 and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,738,279 (hereinafter Pat. 279, of record) in view of Lee (Lee et al., WO 2016/201304 A1, Publication Date: 12/15/2016, of record), Ramos (Ramos et al., Current Protocols in Cell Biology, A.3I.1-A.3L8, Publication Date: September 2014, of record), and Klingemann (Klingemann et al., Frontiers in Immunology, Vol. 7, Article 91, Publication Date: 03/14/2016, of record).
The claims of Pat. 279 teach a method of treating a B-cell malignancy in a patient in need thereof, the method comprising administering to the patient an effective amount of an NK-92 cell line comprising modified NK-92 cells, wherein the modified NK-92 cells are modified to each express at least one Fc receptor and at least one chimeric antigen receptor (CAR), such that the at least one Fc receptor and the at least one CAR are displayed on the cell surface of the modified NK-92 cells, wherein the CAR comprises the amino acid sequence as defined in SEQ ID NO:9 (claim 1).
The claims of Pat. 279 teach the method of claim 1, wherein the Fc receptor is FcγRIII-A (CD16) or a CD16 polypeptide having a valine at position 158 of the mature form of the CD16. As evidenced by the specification of Pat. 279, CD16 polypeptide having a valine at position 158 is a higher affinity form of CD16 (see col. 2, lines 53-67). Thus, the modified NK cells are haNK cells.
The claims of Pat. 279 teach the method of claim 1, wherein the modified NK-92 cells are further modified to express a cytokine (claim 6), wherein the cytokine can be IL-2 (claim 7).
The claims of Pat. 279 teach the method of claim 1, further comprising administering to the patient an effective amount of at least one monoclonal antibody (claim 16), wherein the antibody can be rituximab (claim 16).
Thus, the claims of Pat. 279 teach a method of treating B-cell malignancy with a combination of haNK cells (e.g. NK92-CD16V158-IL-2) and antibody (e.g. rituximab) as set forth above. However, the claims of Pat. 279 do not explicitly teach a pharmaceutical composition in combination with an antibody e.g. Rituximab, or kit as instantly claimed, e.g. the cryopreservation increase antibody binding to the haNK cells, or irradiation step.
Lee, Ramos and Klingemann teach as set forth above. In particular, Lee teaches compositions and kit comprising NK cells-CD16v158 and antibody (e.g. rituximab), Ramos teaches materials and methods for preparation of NK cells in cryopreservation medium comprising CryoStor CS10, Klingemann teaches that irradiation of NK-92 cells with a dose of at least 500cGy can inhibit cell proliferation and maintain cytotoxicity, combination of haNK cell with antibody can enhance efficacy of antibody therapy.
Regarding “the cryopreservation increases antibody binding to the haNK cells”, it is suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a haNK cell line as taught by the claims of Pat. 279 for treating B-cell malignancy, and to make a pharmaceutical composition and kits for treating cancers comprising NK cells-CD16 v158-IL-2-CAR + rituximab, for treating cancers and streamlining the treatment and improved efficacy, as taught by Lee and Klingemann, and to use cryopreservation medium, such as Cryostor CS10, and to store the composition in less than -85 ̊C condition (e.g. liquid nitrogen), as taught by Ramos, because CryoStor CS10 containing medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A.3I.5, col. 1, para. 2, thus, cryopreservation in the cryopreservation medium would help to keep the NK cell structure, yield, viability, and functionality), CryoStor CS10 has been widely used in preparation and storage for primary cells (such as NK cells), the cells prepared with CryoStor CS10 shows good recovery rate (Fig. A.3I.1), CryoStor CS 10 is commercially available by BioLife Solutions (page A.3I.1, § Materials), the protocol of using CryoStor CS10 is well-known in the art, and to use an irradiation dose of 1000 cGy to treat haNK cells, because this dose completely abrogates proliferation but maintain cytotoxicity, as taught by Klingemann. One of ordinary skill in the art would have had a reasonable expectation the composition comprising a cryopreservation medium (such as CryoStor CS10) would help to preserve cell structure, viability and functionality. The motivation would be to use a well-tested and commercially available system to prepared the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles.
U.S. Patent No. 10,774,310
Claims 1, 3-8, 32 and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 10,774,310 (hereinafter Pat. 310, of record) in view of Lee (Lee et al., WO 2016/201304 A1, Publication Date: 12/15/2016, of record), Ramos (Ramos et al., Current Protocols in Cell Biology, A.3I.1-A.3L8, Publication Date: September 2014, of record), and Klingemann (Klingemann et al., Frontiers in Immunology, Vol. 7, Article 91, Publication Date: 03/14/2016, of record).
The claims of Pat. 310 teach population of modified NK-92 cells having antibody-dependent cell-mediated cytotoxicity (ADCC) comprising a polypeptide sequence with at least 90% identity to CD16 (SEQ ID NO:4) and a polypeptide sequence with at least 90% identity to IL-2 (SEQ ID NO:6), wherein greater than 90% of the cells in the population of cells express CD56, CD16, CD54, and NKp30 and less than 5% of the cells in the population of cells express CD3 and wherein the cells further comprise SEQ ID NO:1 on chromosome 17 (claim 1).
The claims of Pat. 310 teach the cells of claim 1, wherein the cells secrete IL-2 at a concentration of 10 to 60 pg/hour per million cells (claim 5).
The claims of Pat. 310 teach the cells of claim 1, wherein the cells are irradiated cells (claim 6).
The claims of Pat. 310 teach the cells of claim 1, wherein the cells have reduced downregulation of expression of CD16 compared to a control (claim 7). Thus, the modified NK-cell lines have higher CD16 expression which read on haNK cells.
The claims of Pat. 310 teach a kit comprising the population of cells of claim 1 (claim 9), wherein the kit further comprising an antibody (claim 10).
Thus, the claims of Pat. 310 teach a haNK-cell expressing CD16, IL-2, and a kit comprising the haNK cells and antibody. However, the claims of Pat. 310 do not explicitly teach the pharmaceutical composition and kit as instantly claimed, e.g. the cryopreservation increases antibody binding to the haNK cells, or irradiation step.
Lee, Ramos and Klingemann teach as set forth above. In particular, Lee teaches compositions and kit comprising NK cells-CD16v158 and antibody (e.g. rituximab), Ramos teaches materials and methods for preparation of NK cells in cryopreservation medium comprising CryoStor CS10, Klingemann teaches that irradiation of NK-92 cells with a dose of at least 500cGy can inhibit cell proliferation and maintain cytotoxicity, combination of haNK cell with antibody can enhance efficacy of antibody therapy.
Regarding “the cryopreservation increases antibody binding to the haNK cells”, it is suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a haNK cell line as taught by the claims of Pat. 310, and to make a pharmaceutical composition and kits for treating cancers comprising NK cells-CD16 v158-IL-2 + rituximab, for streamlining the treatment and improved efficacy, as taught by Lee and Klingemann, and to use cryopreservation medium, such as Cryostor CS10, and to store the composition in less than -85 ̊C condition (e.g. liquid nitrogen), as taught by Ramos, because CryoStor CS10 containing medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A.3I.5, col. 1, para. 2, thus, cryopreservation in the cryopreservation medium would help to keep the NK cell structure, yield, viability, and functionality), CryoStor CS10 has been widely used in preparation and storage for primary cells (such as NK cells), the cells prepared with CryoStor CS10 shows good recovery rate (Fig. A.3I.1), CryoStor CS 10 is commercially available by BioLife Solutions (page A.3I.1, § Materials), the protocol of using CryoStor CS10 is well-known in the art, and to use an irradiation dose of 1000 cGy to treat haNK cells, because this dose completely abrogates proliferation but maintain cytotoxicity, as taught by Klingemann. One of ordinary skill in the art would have had a reasonable expectation the composition comprising a cryopreservation medium (such as CryoStor CS10) would help to preserve cell structure, viability and functionality of the composition. The motivation would be to use a well-tested and commercially available system to prepared the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles.
U.S. Patent No. 11,000,550
Claims 1, 3-8, 32 and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,000,550 (hereinafter Pat. 550, of record), in view of Lee (Lee et al., WO 2016/201304 A1, Publication Date: 12/15/2016, of record), Ramos (Ramos et al., Current Protocols in Cell Biology, A.3I.1-A.3L8, Publication Date: September 2014, of record), and Klingemann (Klingemann et al., Frontiers in Immunology, Vol. 7, Article 91, Publication Date: 03/14/2016, of record).
The claims of Pat. 550 teach a composition comprising a plurality of engineered NK-92 cells from an engineered NK-92 cell line, wherein the engineered NK-92 cell line is genetically modified with a bicistronic nucleic acid construct that comprises a polynucleotide that encodes a CD16 polypeptide having a valine at position 158 of the mature form of the CD16 polypeptide, and a polynucleotide that encodes an interleukin-2 (IL-2) polypeptide targeted to the endoplasmic reticulum (ER), and wherein the engineered NK-92 cell line exhibits enhanced ADCC activity in combination with a monoclonal antibody (claim 1).
The claims of Pat. 550 teach the composition of claim 1, further comprising an antibody (claim 2), wherein the antibody is a mAb that induces ADCC (claim 8); wherein the monoclonal antibody can be rituximab (claim 9).
As evidenced by the specification of Pat. 550, CD16 polypeptide having a valine at position 158 is a higher affinity form of CD16 (see col. 2, para. 2).
The claims of Pat. 550 teach a pharmaceutical composition of comprising an antibody (e.g. rituximab) and haNK cells, as set forth above. However, the claims of Pat. 550 do not explicitly teach a pharmaceutical composition comprising cryopreservation medium or kit as instantly claimed, e.g. the cryopreservation increase antibody binding to the haNK cells, or irradiation step.
Lee, Ramos and Klingemann teach as set forth above. In particular, Lee teaches kit comprising NK cells-CD16v158 and antibody (e.g. rituximab), Ramos teaches materials and methods for preparation of NK cells in cryopreservation medium comprising CryoStor CS10, Klingemann teaches that irradiation of NK-92 cells with a dose of at least 500cGy can inhibit cell proliferation and maintain cytotoxicity.
Regarding “the cryopreservation increases antibody binding to the haNK cells”, it is suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a combination therapy (e.g. NK cells-CD16 v158-IL-2 + rituximab) as taught by the claims of Pat. 550, and to make a pharmaceutical kits comprising NK cells-CD16 v158-IL-2 + rituximab, for streamlining the treatment and improved efficacy, as taught by Lee and Klingemann, and to use cryopreservation medium, such as Cryostor CS10, and to store the composition in less than -85 ̊C condition (e.g. liquid nitrogen), as taught by Ramos, because CryoStor CS10 containing medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A.3I.5, col. 1, para. 2, thus, cryopreservation in the cryopreservation medium would help to keep the NK cell structure, yield, viability, and functionality), CryoStor CS10 has been widely used in preparation and storage for primary cells (such as NK cells), the cells prepared with CryoStor CS10 shows good recovery rate (Fig. A.3I.1), CryoStor CS 10 is commercially available by BioLife Solutions (page A.3I.1, § Materials), the protocol of using CryoStor CS10 is well-known in the art, and to use an irradiation dose of 1000 cGy to treat haNK cells, because this dose completely abrogates proliferation but maintain cytotoxicity. One of ordinary skill in the art would have had a reasonable expectation the composition comprising a cryopreservation medium (such as CryoStor CS10) would help to preserve cell structure, viability and functionality of the composition. The motivation would be to use a well-tested and commercially available system to prepared the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles.
U.S. Patent No. 11,058,723
Claims 1, 3-8, 32 and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 11,058,723 (hereinafter Pat. 723, of record) in view of Lee (Lee et al., WO 2016/201304 A1, Publication Date: 12/15/2016, of record), Ramos (Ramos et al., Current Protocols in Cell Biology, A.3I.1-A.3L8, Publication Date: September 2014, of record), and Klingemann (Klingemann et al., Frontiers in Immunology, Vol. 7, Article 91, Publication Date: 03/14/2016, of record).
The claims of Pat. 723 teach a method of treating a cancer or reducing cancer metastasis in a subject, the method comprising: administering to the subject a therapeutically effective amount of natural killer-92 (NK-92) cells transfected with a recombinant quadricistronic nucleic acid, wherein the NK-92 cells have American Type Culture Collection (ATCC) deposit number CRL-2407, wherein the recombinant quadricistronic nucleic acid includes a sequence encoding a cluster of differentiation 19-chimeric antigen receptor (CD19-CAR), a C-C chemokine receptor type 7 (CCR7), a cluster of differentiation 19 (CD16) 158V variant having an amino acid sequence of SEQ ID NO:12, and an endoplasmic reticulum directed Interleukin-2 (erIL-2), and expresses CD19-CAR, the CCR7, the CD16 158V variant, and the erIL-2, wherein the sequence encoding the CD19 CAR comprises the nucleotide sequence of SEQ ID NO:25,
wherein surface expression of the CCR7 enables the recombinant NK-92 cell to migrate towards CCL21 and/or CCL19; and wherein administration treats the cancer, or reduces cancer metastasis in the subject (claim 1). As evidenced by Pat. 723, CD16 polypeptide having a valine at position 158 is a higher affinity form of CD16 (see col. 4, lines 19-32). The recombinant NK-cell is a haNK cell.
Thus, the claims of Pat. 723 teach a haNK-cell expressing CD16V158, IL-2. However, the claims of Pat. 310 do not explicitly teach the pharmaceutical composition (e.g. in combination with an antibody) and kit as instantly claimed, e.g. the cryopreservation increase antibody binding to the haNK cells, or irradiation step.
Lee, Ramos and Klingemann teach as set forth above. In particular, Lee teaches compositions and kit comprising NK cells-CD16v158 and antibody (e.g. rituximab), Ramos teaches materials and methods for preparation of NK cells in cryopreservation medium comprising CryoStor CS10, Klingemann teaches that irradiation of NK-92 cells with a dose of at least 500cGy can inhibit cell proliferation and maintain cytotoxicity, combination of haNK cell with antibody can enhance efficacy of antibody therapy.
Regarding “the cryopreservation increases antibody binding to the haNK cells”, it is suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a haNK cell line as taught by the claims of Pat. 723, and to make a pharmaceutical composition and kits for treating cancers comprising NK cells-CD16 v158-IL-2 + rituximab, for treating CD20 expressing cancer, streamlining the treatment and improved efficacy, as taught by Lee and Klingemann, and to use cryopreservation medium, such as Cryostor CS10, and to store the composition in less than -85 ̊C condition (e.g. liquid nitrogen), as taught by Ramos, because CryoStor CS10 containing medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A.3I.5, col. 1, para. 2, thus, cryopreservation in the cryopreservation medium would help to keep the NK cell structure, yield, viability, and functionality), CryoStor CS10 has been widely used in preparation and storage for primary cells (such as NK cells), the cells prepared with CryoStor CS10 shows good recovery rate (Fig. A.3I.1), CryoStor CS 10 is commercially available by BioLife Solutions (page A.3I.1, § Materials), the protocol of using CryoStor CS10 is well-known in the art, and to use an irradiation dose of 1000 cGy to treat haNK cells, because this dose completely abrogates proliferation but maintain cytotoxicity, as taught by Klingemann. One of ordinary skill in the art would have had a reasonable expectation the composition comprising a cryopreservation medium (such as CryoStor CS10) would help to preserve cell structure, viability and functionality of the composition. The motivation would be to use a well-tested and commercially available system to prepared the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles.
U.S. Patent No. 11,129,850
Claims 1, 3-8, 32 and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 11,129,850 (hereinafter Pat. 850, of record) in view of Lee (Lee et al., WO 2016/201304 A1, Publication Date: 12/15/2016, of record), Ramos (Ramos et al., Current Protocols in Cell Biology, A.3I.1-A.3L8, Publication Date: September 2014, of record), and Klingemann (Klingemann et al., Frontiers in Immunology, Vol. 7, Article 91, Publication Date: 03/14/2016, of record).
The claims of Pat. 850 teach a recombinant NK-92 cell, comprising a recombinant quadricistronic nucleic acid that includes a sequence encoding a CCR7 homing receptor, a CD19CAR, a CD16.158V, and erIL-2, wherein the recombinant NK-92 cell expresses the CCR7 homing receptor, the CD19CAR, the CD16.158V, and the erIL-2 wherein surface expression of the CCR7 enables the recombinant NK-92 cell to migrate towards CCL21 and/or CCL19, wherein the NK-92 cell has American Type Culture Collection (ATCC) deposit number CRL-2407, and wherein the sequence encoding the CCR7 comprises the nucleotide sequence of SEQ ID NO:1 (claim 1). As evidenced by Pat. 850, CD16 polypeptide having a valine at position 158 is a higher affinity form of CD16 (see col. 6, lines 19-24). Thus, the recombinant NK-cell is a haNK cell.
The claims of Pat. 850 teach the recombinant NK-92 cell of claim 1, wherein the cell is contained in a medium for administration (claim 2).
The claims of Pat. 850 teach the cells of claim 1, wherein the cells are irradiated cells (claim 6).
The claims of Pat. 850 teach the recombinant NK-92 cell of claim 1, wherein the cell is cryopreserved (claim 4).
Thus, the claims of Pat. 850 teach a haNK-cell expressing CD16V158, IL-2. However, the claims of Pat. 310 do not explicitly teach the pharmaceutical composition (e.g. in combination with an antibody) and kit as instantly claimed, e.g. the cryopreservation increase antibody binding to the haNK cells, or irradiation step.
Lee, Ramos and Klingemann teach as set forth above. In particular, Lee teaches compositions and kit comprising NK cells-CD16v158 and antibody (e.g. rituximab), Ramos teaches materials and methods for preparation of NK cells in cryopreservation medium comprising CryoStor CS10, Klingemann teaches that irradiation of NK-92 cells with a dose of at least 500cGy can inhibit cell proliferation and maintain cytotoxicity, combination of haNK cell with antibody can enhance efficacy of antibody therapy.
Regarding “the cryopreservation increases antibody binding to the haNK cells”, it is suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a haNK cell line as taught by the claims of Pat. 850, and to make a pharmaceutical composition and kits for treating cancers comprising NK cells-CD16 v158-IL-2 + rituximab, for treating CD20 expressing cancer, streamlining the treatment and improved efficacy, as taught by Lee and Klingemann, and to use cryopreservation medium, such as Cryostor CS10, and to store the composition in less than -85 ̊C condition (e.g. liquid nitrogen), as taught by Ramos, because CryoStor CS10 containing medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A.3I.5, col. 1, para. 2, thus, cryopreservation in the cryopreservation medium would help to keep the NK cell structure, yield, viability, and functionality), CryoStor CS10 has been widely used in preparation and storage for primary cells (such as NK cells), the cells prepared with CryoStor CS10 shows good recovery rate (Fig. A.3I.1), CryoStor CS 10 is commercially available by BioLife Solutions (page A.3I.1, § Materials), the protocol of using CryoStor CS10 is well-known in the art, and to use an irradiation dose of 1000 cGy to treat haNK cells, because this dose completely abrogates proliferation but maintain cytotoxicity, as taught by Klingemann. One of ordinary skill in the art would have had a reasonable expectation the composition comprising a cryopreservation medium (such as CryoStor CS10) would help to preserve cell structure, viability and functionality of the composition. The motivation would be to use a well-tested and commercially available system to prepared the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles.
U.S. Patent No. 11,230,699
Claims 1, 3-8, 32 and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 11,230,699 (hereinafter Pat. 699, of record) in view of Lee (Lee et al., WO 2016/201304 A1, Publication Date: 12/15/2016, of record), Ramos (Ramos et al., Current Protocols in Cell Biology, A.3I.1-A.3L8, Publication Date: September 2014, of record), and Klingemann (Klingemann et al., Frontiers in Immunology, Vol. 7, Article 91, Publication Date: 03/14/2016, of record).
The claims of Pat. 699 teach a genetically modified NK cell transfected with one or more recombinant nucleic acids encoding and expressing (i) …; (ii) a recombinant CD16; (iii) an autocrine growth stimulating cytokine (claim 1).
The claims of Pat. 699 teach the genetically modified NK cell of claim 1 wherein the NK cell is an NK-92 cell (claim 2).
The claims of Pat. 699 teach the genetically modified NK cell of claim 1 wherein the recombinant CD16 is a CD16158V mutant (claim 3). As evidenced by Pat. 699, CD16 polypeptide having a valine at position 158 is a higher affinity form of CD16 (see col. 8, lines 3-11). Thus, the recombinant NK-cell is a haNK cell.
The claims of Pat. 699 teach a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the genetically modified NK cells of claim 1 thereby treating the cancer (claim 24).
The claims of Pat. 699 teach the method of claim 24 further comprising a step of administering at least one additional therapeutic entity selected from the group consisting of a viral cancer vaccine, a bacterial cancer vaccine, a yeast cancer vaccine, N-803, an antibody, a stem cell transplant, and a tumor targeted cytokine.
Thus, the claims of Pat. 699 teach a method of treating cancer with a combination of haNK cells (e.g. NK92-CD16V158) and antibody as set forth above. However, the claims of Pat. 699 do not explicitly teach a pharmaceutical composition in combination with an antibody e.g. Rituximab, or kit as instantly claimed, e.g. the cryopreservation increase antibody binding to the haNK cells, or irradiation step.
Lee, Ramos and Klingemann teach as set forth above. In particular, Lee teaches compositions and kit comprising NK cells-CD16v158 and antibody (e.g. rituximab), Ramos teaches materials and methods for preparation of NK cells in cryopreservation medium comprising CryoStor CS10, Klingemann teaches that irradiation of NK-92 cells with a dose of at least 500cGy can inhibit cell proliferation and maintain cytotoxicity, combination of haNK cell with antibody can enhance efficacy of antibody therapy.
Regarding “the cryopreservation increases antibody binding to the haNK cells”, it is suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a haNK cell line as taught by the claims of Pat. 699 for treating cancers in combination with an antibody, and to make a pharmaceutical composition and kits for treating cancers comprising the haNK cells + rituximab, for treating cancers and streamlining the treatment and improved efficacy, as taught by Lee and Klingemann, and to use cryopreservation medium, such as Cryostor CS10, and to store the composition in less than -85 ̊C condition (e.g. liquid nitrogen), as taught by Ramos, because CryoStor CS10 containing medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A.3I.5, col. 1, para. 2, thus, cryopreservation in the cryopreservation medium would help to keep the NK cell structure, yield, viability, and functionality), CryoStor CS10 has been widely used in preparation and storage for primary cells (such as NK cells), the cells prepared with CryoStor CS10 shows good recovery rate (Fig. A.3I.1), CryoStor CS 10 is commercially available by BioLife Solutions (page A.3I.1, § Materials), the protocol of using CryoStor CS10 is well-known in the art, and to use an irradiation dose of 1000 cGy to treat haNK cells, because this dose completely abrogates proliferation but maintain cytotoxicity, as taught by Klingemann. One of ordinary skill in the art would have had a reasonable expectation the composition comprising a cryopreservation medium (such as CryoStor CS10) would help to preserve cell structure, viability and functionality of the composition. The motivation would be to use a well-tested and commercially available system to prepared the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles.
U.S. Patent No. 11,207,350
Claims 1, 3-8, 32 and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,207,350 (hereinafter Pat. 350, of record), in view of Lee (Lee et al., WO 2016/201304 A1, Publication Date: 12/15/2016, of record), Ramos (Ramos et al., Current Protocols in Cell Biology, A.3I.1-A.3L8, Publication Date: September 2014, of record), and Klingemann (Klingemann et al., Frontiers in Immunology, Vol. 7, Article 91, Publication Date: 03/14/2016, of record).
The claims of Pat. 350 teach a cell line comprising engineered NK-92 cells genetically modified with a non-retroviral vector, wherein the engineered NK-92 cells comprise a bicistronic nucleic acid construct that comprises a polynucleotide that encodes a CD16 polypeptide having a valine at position 158 of the mature form of the CD16 polypeptide, and a polynucleotide that encodes an interleukin-2 (IL-2) polypeptide targeted to the endoplasmic reticulum (ER); and wherein genetic modification to obtain the engineered NK-92 cells comprises introducing the non-retroviral vector that comprises the bicistronic nucleic acid construct into NK-92 cells to be genetically modified (claim 1). As evidenced by the specification of Pat. 350, CD16 polypeptide having a valine at position 158 is a higher affinity form of CD16 (see col. 2, para. 2).
The claims of Pat. 350 teach a haNK cell line. However, the claims of Pat. 350 do not teach a pharmaceutical composition in combination with an antibody e.g. Rituximab, or kit as instantly claimed, e.g. the cryopreservation increase antibody binding to the haNK cells, or irradiation step.
Lee, Ramos and Klingemann teach as set forth above. In particular, Lee teaches compositions and kit comprising NK cells-CD16v158 and antibody (e.g. rituximab), Ramos teaches materials and methods for preparation of NK cells in cryopreservation medium comprising CryoStor CS10, Klingemann teaches that irradiation of NK-92 cells with a dose of at least 500cGy can inhibit cell proliferation and maintain cytotoxicity, combination of haNK cell with antibody can enhance efficacy of antibody therapy.
Regarding “the cryopreservation increases antibody binding to the haNK cells”, it is suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a haNK cell line as taught by the claims of Pat. 350, and to make a pharmaceutical composition and kits for treating cancers comprising NK cells-CD16 v158-IL-2 + rituximab, for streamlining the treatment and improved efficacy, as taught by Lee and Klingemann, and to use cryopreservation medium, such as Cryostor CS10, and to store the composition in less than -85 ̊C condition (e.g. liquid nitrogen), as taught by Ramos, because CryoStor CS10 containing medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A.3I.5, col. 1, para. 2, thus, cryopreservation in the cryopreservation medium would help to keep the NK cell structure, yield, viability, and functionality), CryoStor CS10 has been widely used in preparation and storage for primary cells (such as NK cells), the cells prepared with CryoStor CS10 shows good recovery rate (Fig. A.3I.1), CryoStor CS 10 is commercially available by BioLife Solutions (page A.3I.1, § Materials), the protocol of using CryoStor CS10 is well-known in the art, and to use an irradiation dose of 1000 cGy to treat haNK cells, because this dose completely abrogates proliferation but maintain cytotoxicity. One of ordinary skill in the art would have had a reasonable expectation the composition comprising a cryopreservation medium (such as CryoStor CS10) would help to preserve cell structure, viability and functionality of the composition. The motivation would be to use a well-tested and commercially available system to prepared the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles.
U.S. Patent No. 11,753,625
Claims 1, 3-8, 32 and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,753,625 (hereinafter Pat. 625, of record) in view of Lee (Lee et al., WO 2016/201304 A1, Publication Date: 12/15/2016, of record), Ramos (Ramos et al., Current Protocols in Cell Biology, A.3I.1-A.3L8, Publication Date: September 2014, of record), and Klingemann (Klingemann et al., Frontiers in Immunology, Vol. 7, Article 91, Publication Date: 03/14/2016, of record).
The claims of Pat. 625 teach a method of treating cancer in a subject in need thereof, the method comprising: (a) administering to the subject a population of modified NK-92 cells, wherein the modified NK-92 cells comprise a polypeptide with at least 90% identity to SEQ ID NO:4 (CD16) and a polypeptide with at least 90% identity to SEQ ID NO:6 (IL-2) and wherein the cells comprise SEQ ID NO:1 on chromosome 17, wherein greater than 90% of the cells in the population of cells express CD56, CD16, CD54, and NKp30 and wherein fewer than 5% of the cells in the population of cells express CD3; and (b) administering to the subject an antibody (claim 1).
The claims of Pat. 625 teach wherein the cells secrete IL-2 at a concentration of 10 to 60 pg/hour per million cells (claim 6).
The claims of Pat. 625 teach the method of claim 1, wherein the cells are irradiated cells (claim 7).
The claims of Pat. 625 teach wherein the antibody is a monoclonal antibody (claim 9).
The claims of Pat. 625 teach wherein the population of cells and the antibody are administered in the same formulation (claim 12).
The claims of Pat. 625 teach wherein the antibody is selected from the group consisting of alemtuzumab, bevacizumab, ibritumomab tiuxetan, ofatumumab, rituximab, and trastuzumab (claim 14).
Thus, the claims of Pat. 625 teach using a combination of modified NK-92 cells expressing CD16 or a variant and IL-2 and antibody (e.g. rituximab) to treat cancers. However, the claims of Pat. 625 do not teach that the modified NK-92 cells are haNK cells, or explicitly pharmaceutical composition and kit as instantly claimed, e.g. the cryopreservation increase antibody binding to the haNK cells, or irradiation step.
Lee, Ramos and Klingemann teach as set forth above. In particular, Lee teaches compositions and kit comprising NK cells-CD16v158 and antibody (e.g. rituximab), Ramos teaches materials and methods for preparation of NK cells in cryopreservation medium comprising CryoStor CS10, Klingemann teaches that irradiation of NK-92 cells with a dose of at least 500cGy can inhibit cell proliferation and maintain cytotoxicity, combination of haNK cell with antibody can enhance efficacy of antibody therapy.
Regarding “the cryopreservation increases antibody binding to the haNK cells”, it is suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a modified cell line (NK-92-CD16-IL-2) as taught by the claims of Pat. 625, and to choose a CD16 variant CD16V158 and to make a pharmaceutical composition and kits for treating cancers comprising NK cells-CD16 v158-IL-2 + rituximab, for treating CD20 expressing cancer, streamlining the treatment and improved efficacy, as taught by Lee and Klingemann, and to use cryopreservation medium, such as Cryostor CS10, and to store the composition in less than -85 ̊C condition (e.g. liquid nitrogen), as taught by Ramos, because CryoStor CS10 containing medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A.3I.5, col. 1, para. 2, thus, cryopreservation in the cryopreservation medium would help to keep the NK cell structure, yield, viability, and functionality), CryoStor CS10 has been widely used in preparation and storage for primary cells (such as NK cells), the cells prepared with CryoStor CS10 shows good recovery rate (Fig. A.3I.1), CryoStor CS 10 is commercially available by BioLife Solutions (page A.3I.1, § Materials), the protocol of using CryoStor CS10 is well-known in the art, and to use an irradiation dose of 1000 cGy to treat haNK cells, because this dose completely abrogates proliferation but maintain cytotoxicity. One of ordinary skill in the art would have had a reasonable expectation the composition comprising a cryopreservation medium (such as CryoStor CS10) would help to preserve cell structure, viability and functionality of the composition. The motivation would be to use a well-tested and commercially available system to prepared the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles.
Patent No. 12,435,122
Claims 1, 3-8, 32 and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 12,435,122 (hereinafter Pat. 122, corresponding to previous Appl. 17/056,385 which is used in previous Double Patenting rejection) in view of Lee (Lee et al., WO 2016/201304 A1, Publication Date: 12/15/2016, of record), Ramos (Ramos et al., Current Protocols in Cell Biology, A.3I.1-A.3L8, Publication Date: September 2014, of record), and Klingemann (Klingemann et al., Frontiers in Immunology, Vol. 7, Article 91, Publication Date: 03/14/2016, of record).
The claims of Pat. 122 teach a genetically modified NK cell, comprising: a cytokine; a CD16; and a membrane bound chimeric antigen receptor (CAR)… (claim 1).
The claims of Pat. 122 teach wherein the NK cell is an NK-92 cell (claim 2).
The claims of Pat. 122 teach wherein the cytokine is IL-2 (claim 3).
The claims of Pat. 122 teach the genetically modified NK cell of claim 1, wherein the CD16 is a high-affinity CD16 variant having the amino acid sequence of SEQ ID NO: 35 and having a 158V mutation (claim 5).
The claims of Pat. 122 teach the genetically modified NK cell of claim 1, wherein the genetically modified NK cell comprises a tricistronic nucleic acid sequence comprising a sequence encoding the cytokine, a sequence encoding the CD16, and a sequence encoding the CAR (claim 6). Thus, the modified NK cells are haNK cells.
Thus, the claims of Pat. 122 teach modified NK-92 cells (haNK cells) expressing high affinity CD16 and IL-2. However, the claims of Pat. 625 do not teach explicitly pharmaceutical composition (e.g. further comprising antibody and cryopreservation medium) and kit as instantly claimed, e.g. the cryopreservation increase antibody binding to the haNK cells, or irradiation step.
Lee, Ramos and Klingemann teach as set forth above. In particular, Lee teaches compositions and kit comprising NK cells-CD16v158 and antibody (e.g. rituximab), Ramos teaches materials and methods for preparation of NK cells in cryopreservation medium comprising CryoStor CS10, Klingemann teaches that irradiation of NK-92 cells with a dose of at least 500cGy can inhibit cell proliferation and maintain cytotoxicity, combination of haNK cell with antibody can enhance efficacy of antibody therapy.
Regarding “the cryopreservation increases antibody binding to the haNK cells”, it is suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a modified cell line (NK-92-CD16-IL-2) as taught by the claims of Pat. 122, and to choose a CD16 variant CD16V158 and to make a pharmaceutical composition and kits for treating cancers comprising NK cells-CD16 v158-IL-2-CAR + rituximab, for treating CD20 expressing cancer, streamlining the treatment and improved efficacy, as taught by Lee and Klingemann, and to use cryopreservation medium, such as Cryostor CS10, and to store the composition in less than -85 ̊C condition (e.g. liquid nitrogen), as taught by Ramos, because CryoStor CS10 containing medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A.3I.5, col. 1, para. 2, thus, cryopreservation in the cryopreservation medium would help to keep the NK cell structure, yield, viability, and functionality), CryoStor CS10 has been widely used in preparation and storage for primary cells (such as NK cells), the cells prepared with CryoStor CS10 shows good recovery rate (Fig. A.3I.1), CryoStor CS 10 is commercially available by BioLife Solutions (page A.3I.1, § Materials), the protocol of using CryoStor CS10 is well-known in the art, and to use an irradiation dose of 1000 cGy to treat haNK cells, because this dose completely abrogates proliferation but maintain cytotoxicity. One of ordinary skill in the art would have had a reasonable expectation the composition comprising a cryopreservation medium (such as CryoStor CS10) would help to preserve cell structure, viability and functionality of the composition. The motivation would be to use a well-tested and commercially available system to prepared the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles.
Patent No. 12,384,852
Claims 1, 3-8, 32 and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,384,852 (hereinafter Pat. 852, corresponding to previous Appl. 17/530,211 which is used in previous Double Patenting rejection) in view of Lee (Lee et al., WO 2016/201304 A1, Publication Date: 12/15/2016, of record), Ramos (Ramos et al., Current Protocols in Cell Biology, A.3I.1-A.3L8, Publication Date: September 2014, of record), and Klingemann (Klingemann et al., Frontiers in Immunology, Vol. 7, Article 91, Publication Date: 03/14/2016, of record).
The claims of Pat. 852 teach a cell line comprising engineered NK-92 cells genetically modified to express: (i) a bicistronic nucleic acid construct encoded by a non-retroviral vector, wherein the bicistronic construct comprises a polynucleotide that encodes a CD 16 polypeptide having a valine at position 158 of the mature form of the CD16 polypeptide, and a polynucleotide that encodes an interleukin-2 (IL-2) polypeptide targeted to the endoplasmic reticulum (ER); and (ii) a safety system gene that allows the NK-92 cells to be killed by introduction of a selective agent (claim 1). As evidenced by paragraph [0008] of US 2022/0062343 A1, CD16 polypeptide having a valine at position 158 is a higher affinity form of CD16. Thus, the cell line of Pat. 852 is a haNK cell line.
The claims of Pat. 852 teach a haNK cell line. However, the claims of Pat. 852 do not teach a pharmaceutical composition in combination with an antibody e.g. Rituximab, or kit as instantly claimed, e.g. the cryopreservation increase antibody binding to the haNK cells, or irradiation step.
Lee, Ramos and Klingemann teach as set forth above. In particular, Lee teaches compositions and kit comprising NK cells-CD16v158 and antibody (e.g. rituximab), Ramos teaches materials and methods for preparation of NK cells in cryopreservation medium comprising CryoStor CS10, Klingemann teaches that irradiation of NK-92 cells with a dose of at least 500cGy can inhibit cell proliferation and maintain cytotoxicity, combination of haNK cell with antibody can enhance efficacy of antibody therapy.
Regarding “the cryopreservation increases antibody binding to the haNK cells”, it is suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a haNK cell line as taught by the claims of Pat. 852, and to make a pharmaceutical composition and kits for treating cancers comprising NK cells-CD16 v158-IL-2 -safety system gene+ rituximab, for treating CD20 expressing cancers, streamlining the treatment and improved efficacy, as taught by Lee and Klingemann, and to use cryopreservation medium, such as Cryostor CS10, and to store the composition in less than -85 ̊C condition (e.g. liquid nitrogen), as taught by Ramos, because CryoStor CS10 containing medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A.3I.5, col. 1, para. 2, thus, cryopreservation in the cryopreservation medium would help to keep the NK cell structure, yield, viability, and functionality), CryoStor CS10 has been widely used in preparation and storage for primary cells (such as NK cells), the cells prepared with CryoStor CS10 shows good recovery rate (Fig. A.3I.1), CryoStor CS 10 is commercially available by BioLife Solutions (page A.3I.1, § Materials), the protocol of using CryoStor CS10 is well-known in the art, and to use an irradiation dose of 1000 cGy to treat haNK cells, because this dose completely abrogates proliferation but maintain cytotoxicity. One of ordinary skill in the art would have had a reasonable expectation the composition comprising a cryopreservation medium (such as CryoStor CS10) would help to preserve cell structure, viability and functionality of the composition. The motivation would be to use a well-tested and commercially available system to prepared the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles.
Application No. 17/795,735
Claims 1, 3-8, 32 and 33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 13-16, 18-20, and 21-29 of copending Application No. 17/795,735 (hereinafter Appl. 735, US 2023/0172982 A1, of record) in view of in view of Lee (Lee et al., WO 2016/201304 A1, Publication Date: 12/15/2016, of record), Ramos (Ramos et al., Current Protocols in Cell Biology, A.3I.1-A.3L8, Publication Date: September 2014, of record), and Klingemann (Klingemann et al., Frontiers in Immunology, Vol. 7, Article 91, Publication Date: 03/14/2016, of record).
The claims of Appl. 735 teach a genetically modified NK cell, comprising: a recombinant nucleic acid encoding (i) a membrane bound recombinant chimeric antigen receptor (CAR) that comprises in a single polypeptide chain an extracellular binding domain, a hinge domain, a transmembrane domain, and a signaling domain, wherein the extracellular binding domain specifically binds to a BCMA receptor; (ii) a recombinant CD 16; (iii) an autocrine growth stimulating cytokine; and (iv) a TGF-beta trap, or a homing receptor (claim 13).
The claims of Appl. 735 teach the genetically modified NK cell of claim 13 wherein the NK cell is an NK-92® cell (claim 15).
The claims of Appl. 735 teach the genetically modified NK cell of claim 13 wherein the recombinant CD16 is a CD16158V mutant (claim 18). As evidenced by paragraph [0048] of US 2023/0172982 A1, CD16158V mutant is a high affinity variant of CD16. Thus, the NK cell of claim 13 of Appl. 735 is read on the haNK cells of the instant application.
The claims of Appl. 735 teach the genetically modified NK cell of claim 13 wherein the autocrine growth stimulating cytokine is IL-2 or IL-15 (claim 19).
The claims of Appl. 735 teach a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the genetically modified NK cells of claim 13, thereby treating the cancer (claim 26).
The claims of Appl. 735 teach the method of claim 26 further comprising a step of administering at least one additional therapeutic entity, e.g. antibody (claim 27).
The claims of Appl. 735 teach a haNK cell line and a method of using the haNK cell line in combination with an antibody to treat cancers. However, the claims of Appl. 735 do not teach a pharmaceutical composition in combination or kit as instantly claimed, e.g. the cryopreservation increase antibody binding to the haNK cells, or irradiation step.
Lee, Ramos and Klingemann teach as set forth above. In particular, Lee teaches compositions and kit comprising NK cells-CD16v158 and antibody (e.g. rituximab), Ramos teaches materials and methods for preparation of NK cells in cryopreservation medium comprising CryoStor CS10, Klingemann teaches that irradiation of NK-92 cells with a dose of at least 500cGy can inhibit cell proliferation and maintain cytotoxicity, combination of haNK cell with antibody can enhance efficacy of antibody therapy.
Regarding “the cryopreservation increases antibody binding to the haNK cells”, it is suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a haNK cell line as taught by the claims of Appl. 735, and to make a pharmaceutical composition and kits for treating cancers comprising NK cells-CD16 v158-IL-2 + rituximab, for treating CD20 expressing cancers, streamlining the treatment and improved efficacy, as taught by Lee and Klingemann, and to use cryopreservation medium, such as Cryostor CS10, and to store the composition in less than -85 ̊C condition (e.g. liquid nitrogen), as taught by Ramos, because CryoStor CS10 containing medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A.3I.5, col. 1, para. 2, thus, cryopreservation in the cryopreservation medium would help to keep the NK cell structure, yield, viability, and functionality), CryoStor CS10 has been widely used in preparation and storage for primary cells (such as NK cells), the cells prepared with CryoStor CS10 shows good recovery rate (Fig. A.3I.1), CryoStor CS 10 is commercially available by BioLife Solutions (page A.3I.1, § Materials), the protocol of using CryoStor CS10 is well-known in the art, and to use an irradiation dose of 1000 cGy to treat haNK cells, because this dose completely abrogates proliferation but maintain cytotoxicity, as taught by Klingemann. One of ordinary skill in the art would have had a reasonable expectation the composition comprising a cryopreservation medium (such as CryoStor CS10) would help to preserve cell structure, viability and functionality of the composition. The motivation would be to use a well-tested and commercially available system to prepared the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles.
This is a provisional nonstatutory double patenting rejection.
Application No. 18/195,588
Claims 1, 3-8, 32 and 33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/195,588 (hereinafter Appl. 588, US 2023/0381313 A1, of record) in view of in view of Lee (Lee et al., WO 2016/201304 A1, Publication Date: 12/15/2016, of record), Ramos (Ramos et al., Current Protocols in Cell Biology, A.3I.1-A.3L8, Publication Date: September 2014, of record), and Klingemann (Klingemann et al., Frontiers in Immunology, Vol. 7, Article 91, Publication Date: 03/14/2016, of record).
The claims of Appl. 588 teach a population of NK-92MI cells enriched in CD16+CD57+ NK-92MI cells that natively express CD16 and CD57 and that exhibits IL-2 independent growth, wherein the enriched population of NK-92MI cells contains more CD16+CD57+ NK-92MI cells that natively expresses CD16 and CD57 as compared to NK-92 MI cells having American Type Culture Collection (ATCC) Deposit No. CRL-2408 (claim 1). Since the cell population contains more CD16 receptors, the NK cells have higher affinity than ATCC CRL-2408 lines. Thus, the NK cells of claim 1 of Appl. 588 is a haNK cell line based on the instant specification.
The claims of Appl. 588 teach the cell of claim 1, wherein the cell has, post-thaw and expansion, maintained high expression of CD57, CD16, and NKG2D as compared to NK-92MI cells (claim 5).
The claims of Appl. 588 teach a method of treating a cancer, comprising: administering to an individual in need thereof a composition comprising a medium that contains a therapeutically effective quantity of cells according to claim 1 (claim 16)
The claims of Appl. 588 teach the method of claim 16, wherein the individual is a mammal, and/or wherein the cancer is a solid tumor (claim 17).
The claims of Appl. 588 teach the method of claim 16, further comprising a step of co-administering an antibody, a checkpoint inhibitor, an immune stimulant, a cancer vaccine, and/or metronomic low-dose chemotherapy (claim 20).
Thus, the claims of Appl. 588 teach a haNK cell line and a method of using the haNK cell line in combination with an antibody to treat cancers. However, the claims of Pat. 588 do not teach a pharmaceutical composition in combination or kit as instantly claimed, e.g. the cryopreservation increase antibody binding to the haNK cells, or irradiation step.
Lee, Ramos and Klingemann teach as set forth above. In particular, Lee teaches compositions and kit comprising NK cells-CD16v158 and antibody (e.g. rituximab), Ramos teaches materials and methods for preparation of NK cells in cryopreservation medium comprising CryoStor CS10, Klingemann teaches that irradiation of NK-92 cells with a dose of at least 500cGy can inhibit cell proliferation and maintain cytotoxicity, combination of haNK cell with antibody can enhance efficacy of antibody therapy.
Regarding “the cryopreservation increases antibody binding to the haNK cells”, it is suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a haNK cell line as taught by the claims of Appl. 588, and to make a pharmaceutical composition and kits for treating cancers comprising NK-92MI cells of Appl. 588 + rituximab, for treating CD20-expressing cancer and streamlining the treatment and improved efficacy, as taught by Lee and Klingemann, and to use cryopreservation medium, such as Cryostor CS10, and to store the composition in less than -85 ̊C condition (e.g. liquid nitrogen), as taught by Ramos, because CryoStor CS10 containing medium can entail use of ultra-low temperatures to preserve cell structure, yield, viability, and functionality (page A.3I.5, col. 1, para. 2, cryopreservation in the cryopreservation medium would help to keep the NK cell structure, yield, viability, and functionality), CryoStor CS10 has been widely used in preparation and storage for primary cells (such as NK cells), the cells prepared with CryoStor CS10 shows good recovery rate (Fig. A.3I.1), CryoStor CS 10 is commercially available by BioLife Solutions (page A.3I.1, § Materials), the protocol of using CryoStor CS10 is well-known in the art, and to use an irradiation dose of 1000 cGy to treat haNK cells, because this dose completely abrogates proliferation but maintain cytotoxicity, as taught by Klingemann. One of ordinary skill in the art would have had a reasonable expectation the composition comprising a cryopreservation medium (such as CryoStor CS10) would help to preserve cell structure, viability and functionality of the composition. The motivation would be to use a well-tested and commercially available system to prepared the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
For the Double Patenting rejections, Applicant argues:
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Applicant’s arguments have been fully considered but they are not persuasive because the claims of the instant application are still obvious in view of the patented or co-pending claims and a terminal disclaimer has not been filed. Therefore, the rejections above are maintained for the reasons of record.
NEW REJECTION
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-8, 32 and 33 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 recites the limitation "the cryopreservation" in the last line. There is insufficient antecedent basis for this limitation in the claim.
Claim 32 recites the limitation "the cryopreservation" in the line 4. There is insufficient antecedent basis for this limitation in the claim.
Claims 3-8 and 33 are also rejected because these claims depend on the rejected claims directly or indirectly.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-8, 32 and 33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a NEW MATTER rejection.
Claim 1 was amended after the filing date. The limitation of “wherein the cryopreservation increases antibody binding to the haNK cells” in claim 1 has no clear support in the specification as originally filed.
Similarly, Claim 32 was amended after the filing date. The limitation of “wherein the cryopreservation increases antibody binding to the haNK cells” in claim 32 has no clear support in the specification as originally filed.
Applicants argues that support for the limitation can be found throughout the application as originally filed. However, upon carefully examination, no such support has been found through the specification or claims as originally filed. In fact, the results of Fig. 2A shows that cryopreservation in the exemplary cryopreservation medium does not increase binding to antibody binding to the haNK cells (also see [0021], [0056] of the specification filed 01/25/2022).
The written description must be established with reasonable clarity as of the filing date sought. See MPEP 2163.02. However, the specification as filed provides no disclosure on any “wherein the cryopreservation increases antibody binding to the haNK cells”. Thus, it does not provide support for the amended claim 1 or 32. Thus the limitation of amended claim 1 and its dependent claims is new matter because it is not supported by the as-filed disclosure.
Claims 3-8 and 33 are also rejected because these claims encompass new matter encompassed by the rejected claim above.
Conclusion
No claims are allowed.
All other objections and rejections set forth in the previous Office Action of 11/29/2025 are hereby withdrawn in view of the claim amendments and Applicant’s arguments.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHENG LU/ Examiner, Art Unit 1642
/PETER J REDDIG/ Primary Examiner, Art Unit 1646
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