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 .
Claim Status
Claims 1, 23, 31, 34-38 and 40-51 are pending. Claims 31, 34-38 and 51 are withdrawn. Claims 1, 23, and 40-50 are rejected.
Election/Restrictions
Applicant’s election without traverse of Group I, directed to methods of administering a glucocorticoid, and the combined species elections of dexamethasone and solid tumor cancer in the reply filed on 10/23/2025 is acknowledged.
As per MPEP 803.02, the examiner will determine whether the entire scope of the claims is patentable. Applicant’s elected combination is not allowable under 35 USC 103. Therefore, examination has been limited to claims embracing the elected species which are claims 1, 23, and 40-50. Claims 1, 23, and 40-50 have been examined to the extent that they are readable on the elected embodiment. Subject matter not embraced by the elected embodiment is therefore withdrawn from further consideration. Any subject matter discussed beyond the scope of this has been presented in the interest of compact prosecution.
Claims 31, 34-38 and 51 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1, 43, 46-47, and 49-50 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018183927 A1 by Deisher cited in the IDS filed 10/23/2025.
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
The prior art teaches “replacement of cytotoxic preconditioning before cellular immunotherapy” (title) and discloses a method of “enhancing adoptive cellular therapy (ACT) in a patient, by administering to the patient a non-toxic lymphodepleting agent (NTLA) at a dose that is effective to cause substantial lymphodepletion and/or cause ablation of secondary lymphatic germinal centers” (paragraph [0013]).
Regarding instant claims 1, 43 and 46, the prior art discloses dexamethasone, prednisolone, methylprednisolone, dexamethasone sodium phosphate and betamethasone as suitable a NTLA (paragraph [0063]).
Regarding claims 1 and 47, Deisher teaches that dexamethasone may be administered at a dose of at least about 6 mg/kg to at least about 26 mg/kg (paragraph [0017]).
Regarding instant claim 49, the prior art states “[t] he desired in vivo effects of exemplary NTLAs would include reductions in germinal center and marginal zones in secondary lymphatics, direct tumor killing of some cancers particularly; multiple myeloma, renal cell carcinoma, leukemia and lymphoma, non-small cell lung cancer (NSCLC), prostate and breast cancer” (paragraph [0066]). Accordingly, a person of ordinary skill would have been motivated to administer the glucocorticoid to subjects with solid tumor cancers such as NSCLC, prostate or breast cancer.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
Deisher discloses a method of treating cancer comprising administering a glucocorticoid at a dose equivalent to at least 6 mg/kg (HED); however, the prior art does not teach that this method induces or mobilizes a population of natural killer T cells.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding the intended use of “producing a population of NKT cells” in claim 1 or the limitation from claim 43 which requires that the method produces/mobilizes a population of NKT cells in a subject wherein the NKT cells treat the subject’s disease, these statements do not distinguish the instant claims from the prior art method which teaches the active step of administering a glucocorticoid at a dose equivalent to at least 6 mg/kg (HED). The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
The same rationale applies to instant claim 50 which requires that the population of NKT cells: treat the cancer via tumor infiltration; promote infiltration of other immune cells into the tumor; directly kill cancer cells via CD1d-directed apoptosis; and/or treat the cancer by causing tumor necrosis.
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2018183927 A1 by Deisher as applied to claims 1, 43, 46-47, and 49-50 above, and further in view of Hu et al. (2011). Control of early stages in invariant natural killer T-cell development. Immunology, 134(1), 1–7.
Deisher discloses a method of treating cancer comprising administering a glucocorticoid at a dose equivalent to at least 6 mg/kg (HED); however, the prior art does not teach that this method induces or mobilizes a population of natural killer T cells with particular cell markers.
Hu et al. provide an introduction over NKT cells and state (page 1):
Although there are different types of NKT cells (see ref. 4 for a review), the most common, and better studied are type I NKT cells, also called invariant NKT cells (iNKT). These cells are characterized by the expression of an invariant T-cell receptor (TCR) a chain (Va14- Ja18 in mice or Va24-Ja18 in humans) in combination with certain TCR-b chains (using Vb8.2, Vb7 or Vb2 in mice, or Vb11 in humans). The iNKT cells in mice can be CD4+ or double-negative (DN; CD4) CD8) ), generally have a ‘memory’ or ‘activated’ phenotype (CD69+ CD62L) CD44hi IL-2Rbhi) and express markers characteristic of NK cells, including NK1.1, NKG2D and Ly49.
Deisher et al. tested the prior art treatment models in mice (paragraph [00269]). Hu et al. report that in mice, type I NKT cells can be CD4+ and express markers such as NK1.1. Accordingly, a person of ordinary skill performing the prior art method could expect to encounter a subject wherein administration of the glucocorticoid at a dose equivalent to about 6 - 45 mg/kg human equivalent dose (HED) of dexamethasone base induces a population of NKT cells as a natural consequence wherein the cells are characterized in that at least 60% express NK1.1 as required by instant claim 40.
Claims 23 and 41-42 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018183927 A1 by Deisher as applied to claims 1, 43, 46-47, and 49-50 above, and further in view of WO 2015112793 A2 by Pillai et al. and WO 2020028444 A1 by Chaudhary.
Deisher discloses a method of treating cancer comprising administering a glucocorticoid at a dose equivalent to at least 6 mg/kg (HED); however, the prior art does not teach that the method further comprises a step of isolating a population of NKT cells from the subject. In the prior art Deisher discloses an aspect of the invention which provides a method of performing adoptive cellular therapy (ACT) in a patient in need thereof, said method comprising performing a method of enhancing ACT by pretreating the patient with a nontoxic lymphodepleting agent such as dexamethasone and then performing the ACT by administering therapeutic cells to the patient (paragraph [0015]). Deisher provides a list of cell types that may be used for cellular immunotherapy including “T-cell Natural Killer cells” (paragraph [00217]).
Pillai et al. teach (title) “[m]ethods of expanding ex vivo natural killer t (NKT) cells and therapeutic uses thereof.” The prior art discloses that the NKT cells have therapeutic uses for treatment of cancers such as lymphomas, leukemias, lung cancer etc. which overlap with the cancers of Deisher (pages 1 and 23). Regarding instant claims 23 and 42, Pillai specify that the method for expanding NKT cells comprises steps of harvesting the cells from a subject, stimulating the harvested NKT cells, purifying the stimulated NKT cells and expanding the purified NKT cells (page 8). Additionally, Pillai states that the cells are introduced back into the same or different subject after expanding the cells.
Chaudhary teaches a method for “improving the efficacy and safety of adoptive cellular therapies” (title) and states that the method is for treatment of cancers including various leukemias and lymphomas (paragraph [0037]). The prior art teaches the following in paragraph [0007]:
The disclosure [is] related to improving the yield, expansion, activation, proliferation, expansion, diversity, tissue (e.g., tumor) penetrance, persistence and efficacy of immune cell therapies, such as engineered CAR-T, TCR-T, SIR-T, Ab-TCR-T cell therapies or NK cell therapies, by using mobilized immune cells for the manufacturing of cell therapy products. In various embodiments, the method involves mobilizing immune cells prior to collecton of immune cells (e.g. leukopheresis) from the donor. In various embodiments, the immune cells are mobilized by administrating to the donor from whom the immune cells are harvested a CXCR antagonist ( e.g ., Mozibil or Plerixafor), a cytokine (e.g., G-CSF, GM-CSF or sargramostim, Neulasta or Pegfilgastrim), a beta2 adrenergic agonist (e.g., epinephrine), a tyrosine kinase inhibitor (e.g., dasatinib), chemotherapy drug(s) (e.g., cyclophosphamide, doxorubicin) or a combination of the above agents prior to the collection of immune cells.
Chaudhary et al. teach that the immune cells may include natural killer T cells (paragraph [0058]). However, in the method of Deisher, dexamethasone rather than a chemotherapy is administered as a lymphodepleting agent to mobilize the immune cells.
Regarding instant claims 23 and 41, Chaudhary discloses an aspect of the invention wherein a mobilizing agent is administered and the immune cells, such as NKT cells, are collected from the subject about 96 hours after administration of the agent (paragraph [00201]). Chaudhary further teaches that the immune cells can be obtained from the blood collected from the subject, washed to remove the plasma, and subjected to subsequent processing steps, for example the prior art discloses isolating T cells from peripheral blood lymphocytes (paragraphs [00242] and [00243]).
Accordingly, a person of ordinary skill seeking to improve the method of adoptive cellular therapy disclosed by Deisher would have been motivated to expand and/or stimulate the NKT cells harvested from the subject as taught by Pillai et al. Furthermore, a person of ordinary skill would be motivated to modify the method of Deisher and Pillai et al. to include a step of isolating the NKT cells harvested from the subject after administering the lymphodepleting agent as taught by Chaudhary in order to improve the efficacy of the adoptive cellular therapy.
Claims 40, 44 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018183927 A1 by Deisher as applied to claims 1, 43, 46-47, and 49-50 above, and further in view of Krijgsman et al. (2018) The Role of Natural Killer T Cells in Cancer—A Phenotypical and Functional Approach. Front. Immunol. 9:367.
Deisher discloses a method of treating cancer comprising administering a glucocorticoid at a dose equivalent to at least 6 mg/kg (HED); however, the prior art does not teach that this method induces or mobilizes a population of natural killer T cells with particular cell markers.
Krijgsman et al. discuss the phenotype of type I NKT cell subsets and state (page 1):
Type I NKT cells constitutively express various T cell markers such as the TCR signaling complex CD3, and costimulatory receptors such as CD4, CD8, and CD28 (27–31). CD4 is expressed by 15–80% of the type I NKT cell population (27–29, 31) and is sometimes used to subdivide type I NKT cells into CD4− and CD4+ populations. Besides, type I NKT cells constitutively express various receptors that are usually observed on NK cells, such as the adhesion molecule CD56 and the activating NKR CD161 (27–30). 17–70% of the CD4− type I NKT cells express CD56, in contrast to only a small fraction of the CD4+ type I NKT cell population (3–11%) (29).
Regarding instant claims 40, 44 and 48, Krijgsman et al. report that type I NKT cells express CD3, CD8 and that up to 80% express CD4. Accordingly, a person of ordinary skill performing the prior art method could expect to encounter a subject wherein administration of the glucocorticoid at a dose equivalent to about 6 - 45 mg/kg human equivalent dose (HED) of dexamethasone base induces a population of NKT cells as a natural consequence wherein the cells are characterized in that at least 60% express CD3 and CD4 (claims 40 and 44) and that the NKT cells express CD4 and CD8 (claim 45).
Claim(s) 48 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2018183927 A1 by Deisher as applied to claims 1, 43, 46-47, and 49-50 above, and further in view of Fujii et al. NKT cells as an ideal anti-tumor immunotherapeutic. Front Immunol. 2013 Dec 2;4:409.
Deisher discloses a method of treating cancer comprising administering a glucocorticoid at a dose equivalent to at least 6 mg/kg (HED); however, the prior art does not suggest administering an NKT cell activator.
Fujii et al. discuss (title) “NKT cells as an ideal anti-tumor immunotherapeutic.” Regarding treatment of non-small cell lung cancer, the prior art reports the following results of a clinical trial of NKT cell-targeted immunotherapy in patients with advanced or recurrent non-small cell lung cancer refractory to standard treatments, including surgery, chemotherapy, and radiation therapy (pages 3-4):
The patient’s peripheral blood mononuclear cells (PBMCs) obtained by apheresis were cultured with GMP grade GM-CSF and IL-2 for 7 days and then pulsed with α-GalCer (29). The α-GalCer-pulsed PBMCs were then intravenously administered (1 × 109 cells/m2/injection) back into autologous patients twice with a 1-week interval followed by two courses with a 1-month interval between the second and third administration.
In the 17 patients who completed the protocol of a phase IIa clinical trial, the treatment was well-tolerated, and no severe adverse events related to the cell therapy were observed (28, 30). To monitor IFN-γ production by NKT cells from the patients, an enzyme-linked immunospot (ELISPOT) assay was performed (31). The results demonstrated that a significant increase in the number of IFN-γ-producing PBMCs was detected in 10 out of 17 patients, which was correlated with a significantly prolonged median survival time (MST; 29.3 months) in comparison with the group with no increase compared to the pretreatment status in IFN-γ-producing cells (MST of 9.7 months) (Figure 1B) (32). The α-GalCer-reactive IFN-γ spot forming cells appeared to include both NKT cells and NK cells (31, 33), consistent with the notion that α-GalCer-activated NKT cells subsequently stimulate NK cells to produce IFN-γ (34, 35). We also investigated NKT cell infiltration in the surgically resected tumor samples and found a significant increase (25- to 60-fold) in the number of NKT cells in the tumor in situ (36). Because of the clinical correlation between increased IFN-γ production and prolonged overall survival, we conclude that IFN-γ may be a good biological marker for predicting clinical efficacy of this treatment. Although this prediction cannot be made prior to α-GalCer/DCs administration, the monitoring of IFN-γ production would still be valuable for patients receiving this immunotherapy. Although none of the cases showed significant tumor regression, the overall MST of all 17 patients (18.6 months) was superior to that of patients with best supportive care (4.6 months) or those treated with other types of therapies (average 10 months) in Figure 1B (37–40).
Accordingly, a person of ordinary skill seeking to treat subjects with cancers such as non-small cell lung cancer would have been motivated to modify the method of Deisher to administer α-GalCer loaded dendritic cells as an NKT cell activator as taught by Fujii et al. to improve therapeutic outcomes in subjects that are unresponsive to standard treatments.
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.
Claims 1, 23 and 40-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11219628 in view of WO 2018183927 A1 by Deisher, Krijgsman et al. (2018) The Role of Natural Killer T Cells in Cancer—A Phenotypical and Functional Approach. Front. Immunol. 9:367., Hu et al. (2011). Control of early stages in invariant natural killer T-cell development. Immunology, 134(1), 1–7., Fujii et al. NKT cells as an ideal anti-tumor immunotherapeutic. Front Immunol. 2013 Dec 2;4:409., WO 2015112793 A2 by Pillai et al. and WO 2020028444 A1 by Chaudhary.
Claims 1 and 8 of the patent disclose a method of enhancing adoptive cellular therapy in a human patient suffering from cancer comprising administering a dose of dexamethasone between 5-26 mg/kg which serves as the basis of a rejection under 35 USC 103. The teachings and rationale of
Deisher, Krijgsman et al., Hu et al., Fujii et al., Pillai et al. and Chaudhary relative to instant claims 1, 23, and 40-50 are incorporated here by reference. The instant claims are deemed to be variants of the subject matter of the patent for the same reasons as under 35 USC 103.
Conclusion
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/A.A.C./Examiner, Art Unit 1626
/MATTHEW P COUGHLIN/Primary Examiner, Art Unit 1626