DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant's amendments to the claims and arguments filed on 06-13-2025 have been received and entered. Claims 1 has been amended. Claims 4, 6, 8-27 have been canceled. Claims 1-3, 5, and 7 are pending.
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-3, 5, 7, 9, and 11) in the reply filed on 12-23-2024 is acknowledged. The traversal is on the ground(s) that the groups of claims require the same technical feature and thus not patentably distinct inventions. Additionally, the traversal is on the grounds that restriction is not required unless one of one of the following reasons appear: separate classification; separate status in the art; or different field of search. This is not found persuasive because this application is a 371 of PCT/US2020/043743 filed on 07/27/2020. This application contains the inventions or groups of inventions which are not so linked as to form a single general inventive concept under PCT Rule 13.1: Group I is drawn to a method of treating cancer in a human subject, and Group II is drawn to a composition. Group I-II lack unity of invention because even though the inventions of these groups require the technical feature of “placental-derived natural killer cells comprising a CD38 chimeric antigen receptor (CAR)”, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of Zhang et al (WO2019087151A1, 09 May 2019) (see preceding restriction and below USC 103 rejection ). Additionally, the traversal is on the grounds that there in not a serious search burden on the Examiner to search invention of the groups I-II. Applicant’s argument of search burden is not found persuasive, because instant application is a national stage filing under 35 U.S.C. 371 and according to MPEP 1893.03(d), whether or not a serious burden is required is not a proper basis of traversal in a national stage application.
The requirement is still deemed proper and is therefore made FINAL.
Claims 16, 19-21, 23, 25, and 27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12-23-2024.
It is also noted that claims 16, 19-21, 23, 25, and 27 are canceled in the applicant's amendments to the claims filed on 06-13-2025
Claims 1-3, 5, and 7 are under consideration.
Priority
Instant application is a 371 of PCT/US2020/043743 filed on 07/27/2020 that claims priority from US provisional application no 62/943,709 filed on 12/04/2019 and 62/878,731 filed on 07/25/2019.
Withdrawn-Claim Rejections - 35 USC § 112
Claim 9 was 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. Applicant's cancelation of claim 9 obviates the basis of the rejection. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
Maintained in modified form - Claim Rejections - 35 USC § 112-Necessitated by amendments
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, 5, 7 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating lymphoma in a human subject comprising intravenous injection to the subject an effective amount of placental-derived natural killer cells comprising a CD38 chimeric antigen receptor (PNK-CAR38) to the subject so as thereby to provide an effective treatment of the cancer in the subject,
does not reasonably provide enablement for
a method of treating lymphoma in a human subject comprising administering via any administration routes to the subject an effective amount of any placental-derived natural killer cells comprising any CD38 chimeric antigen receptor (CAR) to the subject so as thereby to provide an effective treatment of the cancer in the subject,
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
In determining whether Applicant's claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform "undue experimentation" to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: "[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.0l(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection." These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform "undue experimentation" to make and/or use the invention and therefore, applicant's claims are not enabled.
Nature of the Invention:
The claims are directed to a method treating cancer in a human subject comprising administering to the subject an effective amount of placental-derived natural killer cells comprising a CD38 chimeric antigen receptor (CAR) to the subject so as thereby to provide an effective treatment of the cancer in the subject, wherein the placental-derived natural killer (NK) cells are CYNK cells that are placental CD34+ cell derived natural killer (NK) cells. The CYNK cells are characterized by expression of one or more cited markers which is lower or higher than expression of said markers in peripheral blood natural killer cells.
Breadth of the claims:
The claims are broadly directed to a method of treating any known or yet to be identified cancer in a human subject comprising administering via any administration routes to the subject an effective amount of autologous, allogeneic, xenogeneic placental-derived natural killer cells comprising a CD38 chimeric antigen receptor (CAR) to the subject so as thereby to provide an effective treatment of the cancer in the subject, wherein the placental-derived natural killer (NK) cells are CYNK cells that are placental CD34+ cell derived natural killer (NK) cells. The CYNK cells are characterized by expression of one or more cited markers which is lower or higher than expression of said markers in peripheral blood natural killer cells.
Guidance of the Specification and The Existence of Working Examples:
The specification provides a general description of a three-stage method of producing natural killer cells from hematopoietic stem or progenitor cells. CD34+ cells are cultured in the medium formulations for the indicated number of days, and aliquots of cells are taken for assessment of cell count, cell viability, characterization of natural killer cell differentiation and functional evaluation ([00355], page 102). The specification provides teaching for selection of stem cell mobilizing agents for the expansion of NK cells with compounds investigated for their ability to promote the expansion of NK cell populations in vitro ([00364], page 104). The specification also teaches characterization of three-stage NK cells by determining the phenotypic characteristics of three-stage NK cells with evaluating the compounds effects on NK cell expansion and differentiation ([00365-00369], page 110), magnetic-activated cell sorting, single cell rna sequencing, flow cytometry, qRT-PCR ([00371-00374], page 111). The specification also prophetically provides a general description of a treatment of cancers with NK CAR38 Cells. The anti-tumor activity of PNK-NT and PNK-CAR38 cells was assessed against Lymphoma lines - Daudi, Raji, HS Sultan and SUDHL6 and Multiple Myeloma cell lines Molp8, LPl and OPM2, at various effector to target (E:T) ratios using a 4-hour PKH26 flow cytometry-based method. Disseminated Daudi (lymphoma) xenograft model was established in NSG mice (a highly immunodeficient mouse strain). By i.v. inoculation of 3 x106 luciferase-expressing Daudi cells on Day 0, followed by IV injection of PBS, PNK-NT or PNK-CAR38 cells (l0x 106) on Days 1 and 3. Recombinant IL-15 was given to mice every other day for 15 days. Tumor burden was assessed weekly by Bioluminescence Imaging (BLI). Further in vivo evaluation of PNK-CAR38 is ongoing ([00381-00393], page 117-118).
State of the Art and Predictability of the Art:
The state of the art at the time of the invention and post-filing teaches that treating any cancer by using any placental-derived natural killer cells comprising any CD38 chimeric antigen receptor (CAR) was unpredictable before the filing date of the claimed invention:
Wang et al (International Immunopharmacology 74 (2019) 105695, Doi: 10.1016/j.intimp.2019.105695, 27 June 2019) teaches that the uncertainty about CAR-NK cell ability to migrate and penetrate tumor tissues is the main reason of initial reluctance to use NK cells in CAR engineered therapy. The limited time of NK cells in vivo is also a reason why not use CAR on NK cells initially. While this is an advantage for safety, it will limit the efficacy of therapy. At present, the application of CAR-NK cell therapy still faces some challenges (Page 3 left column).
Kang e al (Curr. Oncol. 2021, 28, 1077–1093. Doi:10.3390/curroncol28020105, 26 February 2021) teaches that despite the promising results of non-genetic- and genetic modified NK cells, NK cell-based cancer immunotherapy still has several challenges to overcome. Adoptive transfer of autologous-and allogeneic NK cells is hard to succeed in clinics due to the limitation of the number of infused cells. The optimization protocols may need to boost the number of the cell population for clinic usage. Although NK cell lines are unlimited cell expansions, which can provide benefit for cancer immunotherapy. The use of NK cell lines in the clinic has been demonstrated in low efficacy, and the lines needed to be irradiated in prior infusion to the patients. Even though NK cell-based monoclonal antibodies have been shown promising antitumor activity in patients with diverse tumor types, dose-limiting toxicities may need to manage and improve for the patient safety profile. Moreover, it remains some barriers for CAR-NK to accomplish in clinics, including the efficiency of CAR-transduction, limitation of cell expansion, lack of available targets, and weak elimination of the solid tumor. Therefore, some efforts should create to boost the efficiency of CAR-NK products. For TCR-NK-based therapy, many further studies must be continuing to investigate for the clinical application of TCR-NK in gene therapy, including engineering TCRs with primary NK cells or engineering NK cells with a variety range of TCR affinities for clinical benefit (Page 1086-1087, bridging para.).
Khorasani et al (International Immunopharmacology 110 (2022) 109041, Doi: 10.1016/j.intimp.2022.109041, 12 July 2022) teaches that there are also restrictions for CAR NK cell treatment in solid tumors, leading to less acceptable outcomes as compared to hematologic malignancies. The paucity and heterogeneity of target antigens, anatomical impediments, inadequate trafficking to the tumor site, and tumor microenvironment (TME) limitations are the key restrictions within this context (Page 12, left column, 4th para). The presence of immunosuppressive soluble factors like TGF-β, adenosine, IL-10, arginase-1, indoleamine 2,3-dioxygenas, and prostaglandin E2 (PGE2) in TME is also limiting the efficacy of CAR NK cell therapy (Page 12, right column, 5th para.). The field of CAR-NK therapy is still in its infancy and several questions such as the determination of the best source of NK cells, the optimal vector system, the most biologically relevant signaling domain for CAR activation as well as strategies to surmount the barriers in solid tumors like persistence and trafficking of CAR NK cells, improving their cytotoxicity while preserving their safety, and augmenting their resistance to the immunosuppressive TME remain to be addressed (Page 15, left column, last para).
Konen et al (Cells 2020, 9, 52; doi:10.3390/cells9010052, 24 December 2019) teaches that while the role of CD38 in hematological malignancies has been extensively studied, the impact of CD38 expression within solid tumors is largely unknown, though most current data indicate an immunosuppressive role for CD38. However, CD38 is far from a simple enzyme, and there are several remaining questions that require further study. To effectively treat solid tumors, we must learn as much about this multifaceted protein as possible—i.e., which infiltrating immune cell types express CD38 for functional activities, the most effective CD38 inhibitor(s) to employ, and the influence of other similarly functioning enzymes that may also contribute towards an immunosuppressive microenvironment (Abstract). The understanding of the role CD38 plays in the progression and immune evasion of solid tumors is only just beginning. Though limited, there have been studies in melanoma, glioma, esophageal, cervical, and lung cancers. In these diseases, CD38 appears to function as a tumor-promoting factor, though conflicting data does exist for the influence of CD38 in the progression of prostate cancer. While CD38 expression on cells within the TME, such as T cells, myeloid cells or macrophages, still exists as the prime focus of these research efforts, more data is beginning to accumulate regarding the influence of CD38 expression on the tumor cells (Page 6, 2nd para.). In addition to the complexity of CD38 expression on immune subpopulations, there are insufficient data to definitively indicate which function of CD38 would need to be targeted in order for effective tumor cell killing, or whether inhibition of both enzymatic and receptor functions would be necessary. Evidence from T cells demonstrate that these two functions of CD38 are, in fact, independent of each other, and thus CD38 functioning within solid tumors may vary based on the circumstances or on which population(s) of cells are expressing the molecule. Data generated from our laboratory suggested that the enzymatic function of CD38 on the tumor cells is integral to the immunosuppressive microenvironment, namely through the accumulation of adenosine and adenosine receptor activation on tumor infiltrating T cells. However, the receptor function of CD38 was not fully explored in this model, nor was the expression of CD38 on immune subpopulations within the tumor (Page 12, 2nd para). While CD38 and other metabolic regulators within the TME, such as CD73, have gained traction as novel immunomodulating molecules and, thus, as potential targets for treatment, it remains unclear how inhibition of CD38 in solid tumors may impact anti-tumor immune functionality within these same tumors. More extensive research is imperative, focusing on exactly which tumor-infiltrating immune populations express and utilize CD38, what occurs downstream of CD38 upregulation in these immune cells as well as in the tumor cells, and how best to target this complicated molecule in terms of class of inhibitor and potential combinations to improve efficacy. Without addressing at least some of these remaining unknowns, the outcome of CD38 targeting within solid tumors may fall short in a clinical setting, and thus an important opportunity would be missed (Page 13, last para).
Wo et al (Cells 2020, 9, 26; doi:10.3390/cells9010026, 20 December 2019) teaches that CD38 has long been considered an immune molecule due to its ubiquitous expression across the immune system, and previous studies have shown that CD38 serves a complex, multifactorial role in the promotion of tumor growth and resistance to cancer immunotherapy. CD38 is known to be expressed on immune infiltrates in the TME of multiple types of solid tumor, where it exerts an immunosuppressive effect through multiple mechanisms. CD38 also mediates resistance to certain forms of cancer immunotherapy. Wo et al concluded that the role of CD38 can be both pro-tumoral and anti-tumoral. This is highly dependent on the cancer type, cell type, and interplay among various cell types that are present in the microenvironment. Further studies are required to explore and uncover the complexities and interplay of these factors (Page 13, 2nd para.).
The claims are broadly directed to administering any placental-derived natural killer cells into human subject. Thus, the claims are interpreted to read on xenotransplantation of placental-derived natural killer cells. One of ordinary skill in the art could not rely on the state of the xenotransplantation art for guidance because the state of the xenotransplantation art is unpredictable with respect to rejection of foreign grafted cells to treat lymphoma before the effective filing date of the claimed invention:
Liu et al, 2021 (Stem Cell Research & Therapy (2021) 12:376; Doi: 10.1186/s13287-021-02427-l) disclose that most xenograft and allograft experiments used high doses of immunosuppressants throughout the lifespan of the animals or use immunodeficiency animals. However, overdosed immunosuppression or immunodeficiency results in the susceptibility to infections and thus short lifespan of animals, which contrasts to the prolonged time windows required by human neural cells to fully mature and integrate into host brain networks (Page 2-Background). The major route of graft rejection occurs via the recognition of foreign protein molecules (e.g., MHC molecules) by the host immune system. The rate at which heterogenous grafts are rejected depends on both MHC disparities and transplantation site ....... there is still quite a lack of knowledge on the immunological graft-host interactions in the central nervous system (CNS). A more precise knowledge about the survival of human neural stem cells in animal brain without immunosuppression, and the mechanisms underlying the rejection in the CNS, may prevent unnecessarily excessive suppression of the immune system in preclinical animal studies, even in patients, warranting the present study (Page 2-Background).
Tomov (Neural Regen Res 15(7):1173-1178. doi:10.4103/1673-5374.270296, January 9, 2020) teaches that despite the concept of replacing a certain degenerated cell population with the intent of reversing the deficit provoked by their degeneration is very straightforward, the practical results are often not so consistent. What is known both from animal studies as well as from the limited clinical experience is that intracerebral transplantation does not always work as intended (Page 1173, right column, 2nd para.). In one of the clinical studies with intracerebral dopaminergic transplantation, patients with seemingly functional grafts deteriorated quickly after withdrawal of immunosuppression, with a postmortem finding of extensive microglial infiltration of the grafts. Moreover, the expression level of general markers of immune response has been correlated with the degree of deterioration of grafts with poorer functional outcome. Therefore, it is certain that successful engraftment of dopaminergic grafts without systemic immunosuppression is extremely difficult to obtain (Page 1176, bridging last para in left column to right column). Given the lack of guidance provided by the specification with respect to donor-host compatibility of xenografts it would have required undue experimentation to make and use the invention as claimed for treating disease without a reasonable expectation of success.
The claims embrace cell transfer or cell therapy of placental-derived natural killer cells in vivo. The state of the art of cell therapy for administering placental-derived natural killer cells into human via various administration routes was unpredictable before the effective filing date of the claimed invention:
Caplan et al (Front. Immunol. 10:1645, doi: 10.3389/fimmu.2019.01645, published 31 July 2019) discussed that the Intra-arterial (IA) delivery of MSCs for stroke entails the potential risk of cerebral infarcts, caused by emboli of cells in the cerebralmicrovasculature. Factors such as vascular access, cell size, cell dosage and delivery speed must be considered, especially when delivering cells into coronary or cerebral arteries. Intra-venous Infusion (IV) infusion certainly may result in limited numbers of cells reaching target tissues, a more transient persistence of cells, and a dilution of paracrine factors reaching target tissues. While it may be part of MSCs MoA in modulating immune responses, IV delivery likely facilitates the rapid removal of clinical MSCs by innate host immune cells (Page 4). Lin et al., 2021 (Mater. Adv., 2021, 2, 2561-2583, DOI: 10.1039/d0ma00732c) discuss injectable hydrogels in stroke and spinal cord injury treatment (e.g., title): cell transplantation commonly faces major cell death, low cell migration and integration, as well as limited directional guidance of axonal growth (Page 2562). Depending on the types of tissues and application, the rate of degradation, gelation time and mechanical properties of hydrogels need to be carefully considered (Page 2563). Also, significant axonal regrowth does not always equate to functional recovery. For example, HA-based hydrogels were observed to promote axonal regrowth in the previous sections. However, not all studies showed the expected functional recovery .... only a portion of transplanted cells would differentiate into mature and functional oligodendrocytes and myelinated axons......... late-differentiated cells were less effective in promoting functional recovery ..... In addition, the type of transplanted cell also plays a role in either supporting the growth of endogenous tissues or integrating with the host tissues (Page 2575). Cell transplantation faces minimal success at clinical stage mainly to due poor survivability and poor tissue integration of transplanted cells (Page 2576). Many studies only focused on the potential and differentiation outcomes of cell encapsulation within injectable hydrogels in vitro, but did not proceed with cell transplantation in vivo and only focused on the effects of acellular hydrogels and encapsulated molecules on tissue regeneration. It is difficult to determine the best scaffold material with the most effective therapeutic outcomes. For example, certain materials are more effective in promoting cell survival (e.g., natural materials) and certain materials promote cell differentiation (e.g., SAPs) (Page 2576). Thus, it was unpredictable before the effective filing date of the claimed invention whether sufficient cell can be delivered to the target site in a subject via various administration routes locally or systemically so as to provide therapeutic effect of to treat ischemic injury. Absent specific guidance, one skilled in the art before the effective filing date of the claimed invention would not know how to practice the full scope of the invention claimed.
The amount of experimentation necessary:
One skilled in the art before the effective filing date of the claimed invention would require to fully characterize and identify the composition of placental-derived natural killer cells, trial and error experimentation to show the production of placental-derived natural killer cells are reproducible with reliable number of cell types, trial and error experimentation to show improving recovery of human/mouse suffering from any cancer by administering via any administration routes a therapeutically effective amount of placental-derived natural killer cells into human/mouse subject (with or without being immunodeficient). There specification fails to enable administering via nay administration route placental-derived natural killer cells for treatment of any cancer. Accordingly, unpredictable nature of the state of the art of cell grafts for treatment of cancer has not been overcome given the limited guidance provided by the specification. For the reasons set forth above, one skilled in the art before the effective filing date of the claimed invention would have to engage in undue experimentation to practice over the full scope of the invention claimed. This is particularly true based upon the nature of the claimed invention, the state of the art, the unpredictability found in the art, the teaching and working examples provided, the level of skill which is high, the amount of experimentation required, and the breadth of the claims.
Response to Arguments
Applicant's arguments filed on 06-13-2025 have been fully considered but they are not persuasive.
Applicant argues that in the instant Amendment, Claim 11 has been canceled, without prejudice, and Claim 1 has been amended to be directed towards, inter alia, a method of treating lymphoma. As explained above, the Examiner has admitted the instant Specification is enabled for a method of treating lymphoma
Response to Arguments:
As described previously in the preceding office action mailed on 03-13-2025 and repeated above with modifications (Necessitated by amendments): Claims 1-3, 5, 7 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating lymphoma in a human subject comprising intravenous injection to the subject an effective amount of placental-derived natural killer cells comprising a CD38 chimeric antigen receptor (PNK-CAR38) to the subject so as thereby to provide an effective treatment of the cancer in the subject,
does not reasonably provide enablement for
a method of treating lymphoma in a human subject comprising administering via any administration routes to the subject an effective amount of any placental-derived natural killer cells comprising any CD38 chimeric antigen receptor (CAR) to the subject so as thereby to provide an effective treatment of the cancer in the subject,
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Maintained in modified form - Claim Rejections - 35 USC § 102-Necessitated by amendments
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.
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 is rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by Zhang et al (WO 2019/087151 A1, 09 May 2019, EFD: 3 Nov 2017).
Regarding to claim 1, Zhang et al teach CD38-directed chimeric antigen receptor constructs (title), and provides methods for treating a cancer or inhibiting tumor growth in a subject in need thereof, the method comprising administering to the subject an isolated host cell comprising an anti-CD38 CAR, or a population of transduced host cells ([00211], page 41). Zhang et al further teaches that the host cell or the population of host cells are selected from a group consisting of placental derived natural killer host cells ([0053], page 11). Zhang et al also provides a method for treating a cancer, wherein the cancer comprises a hematologic cancer which is selected from a group consisting of non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL), …. ([00137], page 27).
Thus, Claim 1 is anticipated by Zhang et al.
Response to Arguments
Applicant's arguments filed on 06-13-2025 have been fully considered but they are not persuasive.
Applicant argues that Claims 1, 7, 17-19, 21 and 24 have been rejected under 35 USC 102(a)(l) as being anticipated by the teachings of Canadian application (CA3082880Al (the CA'880 application), and the population of Exosomes disclosed in the CA'880 application is positive for the "elective species" CD11c. Indeed, it appears that the disclosure of the "elective species" CD l lc the CA'880 application is the basis of the instant rejection. However, it is respectfully submitted that there was no required election of a species in the Restriction Requirement mailed 30 October 2024 (Remarks page 7)
Response to Arguments:
It is noted that the preceding office action mailed on 03-13-2025 did not cite the Canadian application (CA3082880Al) with the inventor of Qian Ye for the 35 U.S.C. 102 (a)(1) and (a)(2) rejection. As repeated above the claim is rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by Zhang et al (WO 2019/087151 A1, 09 May 2019, EFD: 3 Nov 2017). There is no citation for Canadian application (CA3082880Al) with the inventor of Qian Ye which has no relationship with the reference of Zhang et al (WO 2019/087151 A1), and there is no limitation of “CD11c” in the claims or in the preceding rejection. It is unclear what the arguments are intended to mean for the CA3082880A1, “CD l lc” or “elective species”.
Maintained in modified form - Claim Rejections - 35 USC § 103 - Necessitated by amendments
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.
Claims 2-3, 5, 7 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (WO 2019/087151 A1, 09 May 2019) in view of Kang et al (WO 2016109668, 7 July 2016) as evidenced by Carlino et al (Blood, 15 March 2008, Volume 111, Number 6, DOI 10.1182/blood-2007-08-105965.) and Sun et al (PLOS ONE | DOI:10.1371/journal.pone.0147186 January 20, 2016).
Claim interpretation:
The specification of the claimed invention teaches that the CYNK cells are placental CD34+ cell-derived natural killer (NK) cells ([0021], page 6 and claim 3). The term CYNK are CD34+ cell-derived NK cells produced by the methods described herein. In specific embodiments, CYNK cells are placental-derived NK cells. In other specific embodiments, CYNK-001 is a specific formulation of CYNK cells ([0038], page 9). Thus, placental CD34+ cell-derived natural killer (NK) cells are interpreted as CYNK cells.
The teachings of Zhang et al are as described above and are incorporated herein in their entirety. Zhang et al do not specifically teach placental cell derived natural killer cells are placental CD34+ cell derived natural killer (NK) cells. However, Kang et al cure the deficiency.
Regarding to claim 2-3, Kang et al teaches methods of treating a cancer in a subject in need thereof ([0008]), and the NK cells comprising the CAR and/or the homing receptor are derived from CD34+ hematopoietic stem cells (HSCs) that are engineered to express the CAR and/or the homing receptor ([0027], page 4). The hematopoietic cells are placental hematopoietic cells…. Placental hematopoietic cells are CD34+ ([00211], page 51).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Zhang et al by using placental CD34+ cell-derived natural killer as taught by Kang et al, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Kang et al teach CD34+ hematopoietic stem cells can be engineered to express the CAR and/or the homing receptor ([0027], page 4), and the NK progenitor cells possess a greater ability to engraft bone marrow (e.g., in vivo) than non-progenitor NK cells with longer telomeres than peripheral blood (PB) derived NK cells ([00127], page 27). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Kang et al was successful in isolation of placental CD34+ cell from placental perfusate to generate placental CD34+ cell-derived natural killer ([00211], page 51) with detailed instructions and working examples
Regarding to claim 5 and 7, as described above, Kang et al teaches placental CD34+ cell-derived natural killer. As evidenced by Carlino et al who teach that in regard to the chemokine receptor profile, decidual NK (dNK-placental natural killer cell) cells differently from the peripheral blood NK (pbNK) cell counterpart exhibit lower levels of CXCR4 (page 3109, left column, 1st para.). Additionally, as evidenced by Sun et al who teach that Tim-3 (also known as HAVCR2) was mainly expressed by decidual NK cells (dNK) and Tim-3 (HAVCR2) level in dNK was higher than peripheral NK cells (pNK) (Abstract). Thus, placental natural killer cells such as decidual NKs have lower expression of CXCR4 and higher expression of HAVCR2 (Tim-3) as compared to peripheral NK cells.
Response to Arguments
Applicant's arguments filed on 06-13-2025 have been fully considered but they are not persuasive.
Applicant argues that
The cells disclosed in the WO' 151 publication are genetically modified to express a CAR. Moreover, the treatment of cancer, e.g., lymphoma disclosed in the WO'668 publication comprises administering isolated NK cells or a pharmaceutical composition thereof and administering a second agent or a pharmaceutical composition thereof that can be used to treat cancer. Quite to the contrary, the instant invention does not require the administration of any second agent to a subject to treat lymphoma and is not genetically modified. Hence, there is no teaching or suggestion to combine the teachings of these publications (Remarks, page 9).
Examiner utilized impermissible hindsight combining the teachings of these two references in an unsuccessful attempt to construct the claimed Invention. MPEP § 2142 makes clear that impermissible hindsight"... must be avoided and the legal conclusion must be reached on the basis of the facts gleaned from the prior art (emphasis added)." (Remarks, page 9).
Response to Arguments:
It is noted that the claimed invention teaches genetically modified placental-derived natural killer cells comprising a CD38 chimeric antigen receptor (CAR) with the presence of an additional pharmaceutical agent: the specification of the claimed invention teach “Gene Modification and PNK Culture: PNK-CAR38 cells were generated through transduction of human placental CD34+ cells using retroviral vector carrying antiCD38 CAR (CAR2-anti-CD38 A2; CD38scFv-CD28CD3~) followed by expansion and differentiation to NK cells in presence of cytokines including thrombopoietin, SCF, Flt3 ligand, IL-7, IL-15 and IL-2.” (see [00382], page 117). NK cell and/or ILC3 cell populations produced using the three-stage method described herein, can be formulated into pharmaceutical compositions for use in vivo. Such pharmaceutical compositions comprise a population of NK cells and/or ILC3 cells in a pharmaceutically-acceptable carrier, e.g., a saline solution or other accepted physiologically acceptable solution for in vivo administration ([00341], page 96). Thus, the cited prior arts are similar to the claimed invention.
Additionally, the claims recite the term “comprising”, and there is no limitation in the claim to prevent the claimed method not to add second agent. According to MPEP 2111.03, The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004) ("[L]ike the term ‘comprising,’ the terms ‘containing’ and ‘mixture’ are open-ended."). Invitrogen Corp. v. Biocrest Manufacturing, L.P., 327 F.3d 1364, 1368, 66 USPQ2d 1631, 1634 (Fed. Cir. 2003) ("The transition ‘comprising’ in a method claim indicates that the claim is open-ended and allows for additional steps."); Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, an ordinary skill before the effective filing date of the rejected claims would easily select hematopoietic cells that are placental hematopoietic cells and are CD34+ without using any knowledge gleaned only from the applicant's disclosure (see Kang et al [00211], page 51).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHOA NHAT TRAN whose telephone number is (571)270-0201. The examiner can normally be reached M-F (9-5).
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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