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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 9, 2026 has been entered.
DETAILED ACTION
The amendment filed July 9, 2026 in response to the Office Action of April 10, 2026 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Claims 12-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.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In view of claim amendments, the 103 rejections set forth in the previous Office Action of 04/10/2026 are hereby withdrawn.
In view of claim amendments, the Double Patenting rejections set forth in the previous Office Action of 04/10/2026 are hereby withdrawn.
In view of claim amendments, the 112(b) rejections set forth in the previous Office Action of 04/10/2026 are hereby withdrawn.
In view of claim amendments, the 103 rejections set forth in the previous Office Action of 04/10/2026 are hereby withdrawn.
Information Disclosure Statement
The Information Disclosure Statements filed on 07/09/2026 and 08/25/2026 have been considered and entered by examiner.
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 and 32 contains the trademark/trade name “NK-92®”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe specific haNK cells and, accordingly, the identification/description is indefinite.
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 “in the form of a combined frozen preparation, …. wherein the therapeutic antibody is bound to the CD16 (158V) receptor of 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 “in the form of a combined frozen preparation, …. wherein the therapeutic antibody is bound to the CD16 (158V) receptor of the haNK cells” in claim 32 has no clear support in the specification as originally filed.
Applicants argue that support for the limitation can be found throughout the application as originally filed, e.g., paragraphs [0033], [0034] and [0040]. However, upon careful examination, no such support has been found through the specification or claims as originally filed. For example, paragraph [0033] teaches NK cells express Fc receptor which can bind to the Fc portion of immunoglobulins and elicit ADCC upon bound to tumor targets, as shown below:
[0033] NK cells express Fc receptor, which can bind to the Fc portion of immunoglobulins, eliciting cell signals within NK cells. Once activated through Fc receptors by antibodies bound to tumor targets, NK cells are able to induce target lysis. This antibody-dependent cell-mediated cytotoxicity (ADCC) of target cells is employed for cancer treatment. haNK cells are NK-92 cells that are engineered to express high affinity CD16 receptors (FcγRIIIA) to facilitate ADCC mediated lysis of tumor cells. High affinity CD16 receptors can dock soluble IgG. However, until now, the binding strength/ affinity as well as the ability of soluble antibodies to induce NK activation has not been tested. NK-92 cells are well known in the art (see e.g., Clin Cancer Res. 1998 November; 4(11):2859-68, and are also commercially available from NantKwest, San Diego, Calif.)
Paragraph [0033] does not support that a pharmaceutical composition comprising a broad genus of therapeutic antibodies (with or without an Fc portion) bound to the CD16 (158V) receptor of the haNK cells in a broad genus of cryopreservation media in a frozen combination, as instantly claimed, because CD16 only binds to IgG.
Paragraph [0034] teaches haNK cells may serve as a docking platform for soluble antibodies and can induce ADCC. In addition, paragraph [0034] also teaches a combination of haNK cells and a therapeutic antibody, as shown below:
[0034] The inventors have now unexpectedly found that high affinity CD16 receptor on cryopreserved haNK cell may serve as a docking platform for soluble therapeutic antibodies and can induce ADCC when co-incubated with tumor target cells. Thus, the inventive concept disclosed herein relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and therapeutically effective amounts of high affinity Natural Killer (haNK) cells and a therapeutic antibody in the form of a combined preparation.
Paragraph [0034] does not support that a pharmaceutical composition comprising a broad genus of therapeutic antibodies (with or without an Fc portion) bound to the CD16 (158V) receptor of the haNK cells in a broad genus of cryopreservation media in a frozen combination, as instantly claimed.
Paragraph [0040] teaches haNK cells and the antibody are chemically conjugated and the methods of making the conjugate, as shown below:
[0040] In some cases, the haNK cells and the antibody are chemically conjugated. The chemical conjugation may be done by any method known to a skilled chemist. Once preferred method of chemical conjugation is the Huisgen 1,3-dipolar cycloaddition reaction (“click chemistry”), as disclosed in H. C. Kolb; M. G. Finn; K. B. Sharpless (2001). “Click Chemistry: Diverse Chemical Function from a Few Good Reactions”. Angewandte Chemie International Edition. 40 (11): 2004-2021. The term “click chemistry” as used herein thus refers to such cycloaddition reactions and in particular to the cycloaddition of an azide and an alkyne—a reaction that may be in some embodiments be carried out under the catalysis of Cu(I) or under exposure to microwaves. Click reactions occur in one pot, are not disturbed by water, generate minimal and inoffensive byproducts, and are spring-loaded—characterized by a high thermodynamic driving force that drives it quickly and irreversibly to high yield of a single reaction product, with high reaction specificity (in some cases, with both regio- and stereo-specificity). These qualities make click reactions particularly suitable to the problem of isolating and targeting molecules in complex biological environments.
Paragraph [0040] does not support that broadly claimed bound antibodies by different binding mechanisms. In addition, the chemical conjugation (such as the methods described in the paragraph) was not through CD16 (158V) of the hsNK cells, as instantly claimed.
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 (froze), thawed, washed, and tested without any post-thaw incubation time and substantially no ADCC based cell killing was observed”. Thus, the results do not support a pharmaceutical composition comprising a broad genus of therapeutic antibodies (with or without an Fc portion) bound to the CD16 (158V) receptor of the haNK cells in a broad genus of cryopreservation media in a frozen combination, as instantly claimed. In addition, the specification only tests a specific cryopreservation medium (comprising CryoStor10) and a process comprising cryopreservation, X-ray irradiation and post-thaw incubation (see Example 1) on a specific therapeutic antibody with an Fc domain (Rituxan).
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 therapeutic antibody is bound to the CD16 (158V) receptor of 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.
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) and Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016).
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 teaches 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 (haNK 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]).
Trastuzumab taught by Lee would bind CD16 in the NK-92 cells because trastuzumab is an IgG1 antibody. See Jochems below.
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 antibody bound to 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 “wherein the therapeutic antibody is bound to the CD16 (158V) receptor of the haNK cells”, Jochems teaches NK-92 cells have been engineered to express the CD16 high affinity FcγRIIIα (158V) receptor, designated haNK (page 86360, col. 1, para. 3).
Jochems teaches that prior clinical studies employing the IgG1 isotype MAbs cetuximab (Erbitux), trastuzumab (Herceptin), or rituximab (Rituxan) have shown that colorectal cancer, breast cancer, and lymphoma patients, respectively, whose NK cells express CD16 V allele only (V/V), have improved overall survival compared to patients with NK cells expressing the V/F or F/F alleles (page 86360, col. 1, para. 2).
Jochems teaches the engineered CD16 high affinity Fc receptor and IL-2 in haNK cells may enhance the potential clinical utility of these cells (page 86360, col. 1, para. 4).
Jochems teaches that CD16 expresses on the surface of NK-92 cells (Fig. 1 B, top row).
Jochems teaches that haNK cells expressing CD16 high affinity FcγRIIIα (158V) receptor have a higher affinity (3.4 times higher) to a therapeutic antibody: cetuximab (Fig. 7A).
Jochems teaches that since haNK cells are engineered to express the CD16 high affinity FcγRIIIα receptor, one potential clinical utility would be the combined use of haNK cells with humanized or chimeric IgG1 anti-tumor MAbs (page 86363, col. 2, para. 2). Ongoing preclinical studies and future clinical studies will undoubtedly use combinations of different cancer immunotherapy platforms, including anti-tumor MAbs, vaccines, checkpoint inhibitors, and immune modulators, to enhance effector functions or reduce or eliminate immunosuppressive entities (page 86369, col. 2, para. 2).
It would have prima facie been obvious to one of ordinarily skilled in the art before 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, high affinity CD16 is expressed on the surface of haNK cells and the therapeutic antibody bind to the haNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical composition as taught by Jochems. The motivation would be to use a well-tested and commercially available system to prepare the composition/kit, and to make the composition/kit with better enduring long term storage and thawing-cycles and easy application.
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 before 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 allow the therapeutic antibody bound to the hsNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical composition as taught by Jochems, 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 prepare the composition/kit, and to make the composition/kit with better enduring long time storage and thawing-cycles, and easy application.
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) and Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016), 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, Ramos and Jochems teach the pharmaceutical composition of claim 1 as set forth above. Lee also teaches NK cells are irradiated. However, Lee, Ramos and Jochems do 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 103 rejection, Applicant mainly argues:
Lee does not teach or suggest a composition in which the therapeutic antibody is bound
to the CD16 (158V) receptor of the haNK cells. Lee teaches a composition comprising modified
NK-92 cells and at least one antibody in the same formulation. See Lee, paragraph [0113]. Lee
also teaches that the NK-92 cells and antibody may be stored in one container in liquid form to
enhance shelf-life. See Lee, paragraph [0116]. However, in each of these disclosures, the cells
and the antibody are separate, independent components in the formulation. Lee never teaches or
suggests that the therapeutic antibody is bound to the CD16 receptor on the NK-92 cells.
Indeed, Lee itself acknowledges that NK-92 cells "do not express CD 16 on their cell
surfaces" and that "[d]ue to the absence of CD16 receptors, NK-92 cells are unable to lyse target
cells via the ADCC mechanism and, as such, cannot potentiate the anti-tumor effects of
endogenous or exogenous antibodies (i.e., Rituximab and Herceptin)." See Lee, paragraph
[0061]. While Lee teaches engineering NK-92 cells to express CD16, Lee does not teach a
composition in which the therapeutic antibody is actually bound to the CD 16 receptor on the
engineered cells. Lee's compositions have cells and antibody as separate, unbound components
- the antibody is not docked onto the CD 16 receptor
Applicant’s arguments have been considered, but have not been found persuasive. Contrary to Applicant’s arguments, Lee explicitly 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). Thus, Lee teaches NK-92 cells in the same formulation with IgG1 antibody such as trastuzumab.
In addition, as set forth above, Jochems teaches: 1) the engineered CD16 high affinity Fc receptor and IL-2 in haNK cells and CD16 expresses on the surface of NK-92 cells (Fig. 1 B, top row); 2) haNK cells expressing CD16 high affinity FcγRIIIα (158V) receptor have a higher affinity (3.4 times higher) to a therapeutic antibody (Fig. 7A). Based on the teachings of Jochems, one of ordinary skill in the art would have known that NK-92 cells would bound by an IgG1 antibody such as trastuzumab.
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), Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016) 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 antibody bound to the CD16 (158V) of the haNK cells, or irradiation step.
Lee, Ramos, Jochems 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. Jochems teaches that high affinity CD16 expressing on the surface of haNK cells and haNK cells bind to a therapeutic antibody with high affinity. 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.
It would have prima facie been obvious to one of ordinarily skilled in the art before the time the invention was filed to treat cancers with a combination therapy 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 CS10 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. Because high affinity CD16 is expressed on the surface of haNK cells as taught by Jochems, 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 and the antibody would bound to the haNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical 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 and easy application.
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), Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016) 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 antibody bound to the CD16 (158V) of the haNK cells, or irradiation step.
Lee, Ramos, Jochems 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. Jochems teaches that high affinity CD16 expressing on the surface of haNK cells and haNK cells bind to a therapeutic antibody with high affinity. 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.
It would have prima facie been obvious to one of ordinarily skilled in the art before the time the invention was filed to make a combination therapy (e.g. NK cells-CD16 v158-IL-2 + therapeutic antibody) 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, Jochems 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. Because high affinity CD16 is expressed on the surface of haNK cells as taught by Jochems, 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 and the antibody would bound to the haNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical 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 and easy application.
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), Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016) 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, or kit as instantly claimed, e.g. the antibody bound to the CD16 (158V) of the haNK cells, or irradiation step.
Lee, Ramos, Jochems 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. Jochems teaches that high affinity CD16 expressing on the surface of haNK cells and haNK cells bind to a therapeutic antibody with high affinity. 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.
It would have prima facie been obvious to one of ordinarily skilled in the art before 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 of the composition. Because high affinity CD16 is expressed on the surface of haNK cells as taught by Jochems, 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 and the antibody would bound to the haNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical 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 and easy application.
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), Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016) 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 antibody bound to the CD16 (158V) of the haNK cells, or irradiation step.
Lee, Ramos, Jochems 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. Jochems teaches that high affinity CD16 expressing on the surface of haNK cells and haNK cells bind to a therapeutic antibody with high affinity. 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.
It would have prima facie been obvious to one of ordinarily skilled in the art before 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. Because high affinity CD16 is expressed on the surface of haNK cells as taught by Jochems, 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 and the antibody would bound to the haNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical composition. The motivation would be to use a well-tested and commercially available system to prepare the composition/kit, and to make the composition/kit with better enduring long term storage and thawing-cycles and easy application.
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), Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016) 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 antibody bound to the CD16 (158V) of the haNK cells, or irradiation step.
Lee, Ramos, Jochems 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. Jochems teaches that high affinity CD16 expressing on the surface of haNK cells and haNK cells bind to a therapeutic antibody with high affinity. 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.
It would have prima facie been obvious to one of ordinarily skilled in the art before 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. Because high affinity CD16 is expressed on the surface of haNK cells as taught by Jochems, 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 and the antibody would bound to the haNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical 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 and easy application.
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), Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016) 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 antibody bound to the CD16 (158V) of the haNK cells, or irradiation step.
Lee, Ramos, Jochems 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. Jochems teaches that high affinity CD16 expressing on the surface of haNK cells and haNK cells bind to a therapeutic antibody with high affinity. 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.
It would have prima facie been obvious to one of ordinarily skilled in the art before 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. Because high affinity CD16 is expressed on the surface of haNK cells as taught by Jochems, 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 and the antibody would bound to the haNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical 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 and easy application.
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), Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016) 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 antibody bound to the CD16 (158V) of the haNK cells, or irradiation step.
Lee, Ramos, Jochems 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. Jochems teaches that high affinity CD16 expressing on the surface of haNK cells and haNK cells bind to a therapeutic antibody with high affinity. 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.
It would have prima facie been obvious to one of ordinarily skilled in the art before 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. Because high affinity CD16 is expressed on the surface of haNK cells as taught by Jochems, 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 and the antibody would bound to the haNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical 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 and easy application.
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), Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016) 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 antibody bound to the CD16 (158V) of the haNK cells, or irradiation step.
Lee, Ramos, Jochems 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. Jochems teaches that high affinity CD16 expressing on the surface of haNK cells and haNK cells bind to a therapeutic antibody with high affinity. 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.
It would have prima facie been obvious to one of ordinarily skilled in the art before 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. Because high affinity CD16 is expressed on the surface of haNK cells as taught by Jochems, 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 and the antibody would bound to the haNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical 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 and easy application.
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), Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016) 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 antibody bound to the CD16 (158V) of the haNK cells, or irradiation step.
Lee, Ramos, Jochems 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. Jochems teaches that high affinity CD16 expressing on the surface of haNK cells and haNK cells bind to a therapeutic antibody with high affinity. 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.
It would have prima facie been obvious to one of ordinarily skilled in the art before 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. Because high affinity CD16 is expressed on the surface of haNK cells as taught by Jochems, 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 and the antibody would bound to the haNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical 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 and easy application.
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), Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016) 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 antibody bound to the CD16 (158V) of the haNK cells, or irradiation step.
Lee, Ramos, Jochems 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. Jochems teaches that high affinity CD16 expressing on the surface of haNK cells and haNK cells bind to a therapeutic antibody with high affinity. 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.
It would have prima facie been obvious to one of ordinarily skilled in the art before 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. Because high affinity CD16 is expressed on the surface of haNK cells as taught by Jochems, 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 and the antibody would bound to the haNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical 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 and easy application.
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), Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016) 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 antibody bound to the CD16 (158V) of the haNK cells, or irradiation step.
Lee, Ramos, Jochems 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. Jochems teaches that high affinity CD16 expressing on the surface of haNK cells and haNK cells bind to a therapeutic antibody with high affinity. 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.
It would have prima facie been obvious to one of ordinarily skilled in the art before 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. Because high affinity CD16 is expressed on the surface of haNK cells as taught by Jochems, 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 and the antibody would bound to the haNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical 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 and easy application.
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), Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016) 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 antibody bound to the CD16 (158V) of the haNK cells, or irradiation step.
Lee, Ramos, Jochems 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. Jochems teaches that high affinity CD16 expressing on the surface of haNK cells and haNK cells bind to a therapeutic antibody with high affinity. 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.
It would have prima facie been obvious to one of ordinarily skilled in the art before 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. Because high affinity CD16 is expressed on the surface of haNK cells as taught by Jochems, 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 and the antibody would bound to the haNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical composition. The motivation would be to use a well-tested and commercially available system to prepare the composition/kit, and to make the composition/kit with better enduring long term storage and thawing-cycles and easy application.
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), Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016) 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 has at least 95% sequence identity to SEQ ID NO: 41, 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 antibody bound to the CD16 (158V) of the haNK cells, or irradiation step.
Lee, Ramos, Jochems 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. Jochems teaches that high affinity CD16 expressing on the surface of haNK cells and haNK cells bind to a therapeutic antibody with high affinity. 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.
It would have prima facie been obvious to one of ordinarily skilled in the art before 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. Because high affinity CD16 is expressed on the surface of haNK cells as taught by Jochems, 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 and the antibody would bound to the haNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical 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 and easy application.
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), Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016) 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 antibody bound to the CD16 (158V) of the haNK cells, or irradiation step.
Lee, Ramos, Jochems 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. Jochems teaches that high affinity CD16 expressing on the surface of haNK cells and haNK cells bind to a therapeutic antibody with high affinity. 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.
It would have prima facie been obvious to one of ordinarily skilled in the art before 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. Because high affinity CD16 is expressed on the surface of haNK cells as taught by Jochems, 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 and the antibody would bound to the haNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical composition. The motivation would be to use a well-tested and commercially available system to prepare the composition/kit, and to make the composition/kit better enduring long term storage and thawing-cycles and easy application.
This is a provisional nonstatutory double patenting rejection.
Application No. 19/272,876
Claims 1, 3-8, 32 and 33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of copending Application No. 19/272,876 (hereinafter Appl. 876, US20250340664A1) 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), Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016) and Klingemann (Klingemann et al., Frontiers in Immunology, Vol. 7, Article 91, Publication Date: 03/14/2016, of record).
Claim 1 of Appl. 876 teach an NK-92 cell line comprising NK-92 cells genetically modified to comprise a bicistronic expression construct, wherein the bicistronic expression construct comprises, in the 5′ to 3′ direction, a polynucleotide encoding a CD16 polypeptide having a valine at position 158 of the mature form of the CD16 polypeptide, and a polynucleotide encoding an interleukin-2 (IL-2) polypeptide targeted to the endoplasmic reticulum (ER). Thus, the NK-92 cells of Appl. 876 encompass haNK cells of the instant application.
However, the claims of Pat. 876 do not teach a pharmaceutical composition in combination or kit as instantly claimed, e.g. the antibody bound to the CD16 (158V) of the haNK cells, or irradiation step, or in combination with an antibody.
Lee, Ramos, Jochems 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. Jochems teaches that high affinity CD16 expressing on the surface of haNK cells and haNK cells bind to a therapeutic antibody with high affinity. 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.
It would have prima facie been obvious to one of ordinarily skilled in the art before the time the invention was filed to make a haNK cell line as taught by the claims of Appl. 876, and to make a pharmaceutical composition and kits for treating cancers comprising haNK cells of Appl. 876 + 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. Because high affinity CD16 is expressed on the surface of haNK cells as taught by Jochems, 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 and the antibody would bound to the haNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical 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 and easy application.
This is a provisional nonstatutory double patenting rejection.
Application No. 19/707,692
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. 19/707,692 (hereinafter Appl. 692, US20250340664A1) 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), Jochems (Jochems et al., Oncotarget, 2016, Vol. 7, No. 52, pp: 86359-86373, Publication Date: 11/16/2016) and Klingemann (Klingemann et al., Frontiers in Immunology, Vol. 7, Article 91, Publication Date: 03/14/2016, of record).
Claim 1 of Appl. 692 teaches a method of producing an isolated recombinant natural killer (NK) cell with persistent homozygous expression of CD16 158V, comprising: providing a plurality of NK cells that are natively heterozygous for CD16, wherein the native CD16 gene has a CD16 158V allele and a CD16 158F allele; introducing into the NK cells (1) a recombinant constitutive promotor sequence upstream of the native CD16 gene that is functionally in place of a native promotor sequence of the native CD16 gene, thereby leading to detectable expression of the CD16 158V allele, but not the 158F allele; (2) a recombinant nucleic acid encoding interleukin-2 (IL-2) in a secreted or non-secreted (ERIL2) form; and isolating an NK cell expressing CD16 and IL-2 to so obtain the isolated recombinant natural killer (NK) cell with persistent homozygous expression of CD16 158V.
Claim 3 of Appl. 692 teaches the method of claim 1, wherein the recombinant nucleic acid encoding the IL-2 is introduced by viral transduction.
Claim 10 of Appl. 692 teaches the method of claim 1, wherein the NK cell is an NK-92 cell.
Claim 13 of Appl. 692 teaches the method of claim 1, wherein the isolated recombinant NK cell, compared to a non-recombinant NK cell, has a reduced signal-to-noise ratio for ADCC.
Claim 19 of Appl. 692 teaches a plurality of isolated recombinant NK cells produced by the method of claim 1. The isolated recombinant NK cells of Appl. 692 encompass haNK cells of the instant application.
Claim 20 of Appl. 692 teaches the plurality of isolated recombinant NK cells of claim 19, wherein the NK cells are frozen. Thus, claims of Appl. 692 teach recombinant NK-cells in a frozen preparation.
However, the claims of Pat. 692 do not teach a pharmaceutical composition in combination or kit as instantly claimed, e.g. the antibody bound to the CD16 (158V) of the haNK cells, or irradiation step, or in combination with antibody.
Lee, Ramos, Jochems 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. Jochems teaches that high affinity CD16 expressing on the surface of haNK cells and haNK cells bind to a therapeutic antibody with high affinity. 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.
It would have prima facie been obvious to one of ordinarily skilled in the art before the time the invention was filed to make a haNK cell line as taught by the claims of Appl. 692, and to make a pharmaceutical composition and kits for treating cancers comprising haNK cells of Appl. 692 + rituximab, for treating CD20-expressing cancer and streamlining the treatment and improved efficacy, as taught by Lee and Klingemann and Jochems, 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. Because high affinity CD16 is expressed on the surface of haNK cells as taught by Jochems, 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 and the antibody would bound to the haNK cells through the interaction between Fc domain and CD16 (158V) in the pharmaceutical composition. The motivation would be to use a well-tested and commercially available system to prepare the composition/kit, and to make the composition/kit better enduring long term storage and thawing-cycles and easy application.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/CHENG LU/ Examiner, Art Unit 1642
/PETER J REDDIG/Primary Examiner, Art Unit 1646
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