Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Mar. 2, 2026. Claims 84-87 and 89-104 are pending. Claims 93 and 98-103 are withdrawn. Claims 84-87, 89-92, 94-97 and 104 are currently examined.
Claim Rejections - 35 USC § 102/103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(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.
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 of this title, 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.
(Previous Rejection – Withdrawn) Claims 84-87, 89-92 and 94-97 were rejected under 35 U.S.C. 102/103 as being unpatentable over Suzuki et al. (US Patent 6015796, date of patent Jan. 18, 2000).
This rejection is withdrawn in view of the amendment filed on Mar. 2, 2026. Applicant’s arguments are moot.
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 of this title, 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.
(Previous Rejection – Withdrawn) Claims 84-87, 89-92, 94-97 and 104 were rejected under 35 U.S.C. 103 as being unpatentable over Oka et al. (Microbiol. Immunol., 46(5), 343―351, 2002).
This rejection is withdrawn in view of the amendment filed on Mar. 2, 2026. Applicant’s arguments are moot.
(New Rejection – Necessitated by Amendment) Claims 84-87, 89-92, 94-97 and 104 are rejected under 35 U.S.C. 103 as being unpatentable over Suzuki et al. (US Patent 6015796, date of patent Jan. 18, 2000; as applied in the withdrawn rejection above), Oka et al. (Microbiol. Immunol., 46(5), 343―351, 2002; as applied in the withdrawn rejection above; referred to hereinafter as Oka-MI-2002), and Oka et al. (Biol. Pharm. Bull. 26(9) 1336—1341 (2003), referred to hereinafter as Oka-BPB-2003) in view of Holland et al. (Clin Exp Immunol 1996; 105:429–435).
Base claim 84, as amended, is directed to a method for activating a regulatory T cell (Treg) having immunological memory of a non-target antigen component, which is suppressed in a subject, comprising:
(a) identifying the non-target antigen component based on a history of prior immune exposure of the subject an antigen responsiveness profile of the subject, wherein the antigen responsiveness profile comprises vaccination history and/or infection history,
(b) identifying whether the subject has immunological memory of the non-target antigen component, wherein step (b) comprises stimulating peripheral blood mononuclear cells (PBMC) isolated from the subject or infiltrating immune cells isolated from a tumor mass of the subject with the non-target antigen component, measuring cytokine production, and identifying the subject with an amount of cytokine production increased compared to the amount before stimulation as a subject having the immunological memory, and
(c) administering an effective amount of the non-target antigen component to the subject identified as having the immunological memory, thereby activating the Treg.
Relevance of Suzuki and Oka-MI-2002 is set forth in the withdrawn rejections above (see discussions in the previous Office action).
Briefly, Susuki teaches the treatment of a subject with AIDS by administering a hot-water extract from M. tuberculosis. The withdrawn 102 rejection establishes that a subject with AIDS is expected to be suppressed in regulatory T (Treg) cells. Oka-MI-2002 teaches a method comprising administering an effective amount of Z-100, a hot-water extract from M. tuberculosis, to mice in an animal model for melanoma metastasis. However, Susuki and Oka-MI-2002 are both silent on a subject identifying step comprising stimulating PBMCs tumor infiltrating immune cells from the subject with Z-100 (the non-target antigen component) and measuring cytokine production.
Oka-BPB-2003 teaches that Z-100, extracted from Mycobacterium tuberculosis strain Aoyama B, is an immunomodulator containing arabinomannan as the main component. It is clinically used in patients with leukopenia caused by radiation therapy in Japan. In preclinical experiments, Z-100 was shown to have various immunopotentiating activities including enhancement of protective activity against Pseudomonas aeruginosa infection, and antiviral activities against LP-BM5 murine leukemia virus, and herpes virus. Z-100 exhibited inhibition of tumor growth and metastasis, prolongation of survival time, and protection against opportunistic infection in syngeneic murine tumor models. In addition, Z-100 has been shown to exhibit these antimetastatic activities via suppression of Th2 cytokine production by tumor-associated Th2 cells. Furthermore, Z-100 improves the balance of Th1/Th2 cell responses in Meth-A tumor cell-bearing mice through both up-regulation of IL-12 production from macrophages and interferon (IFN)-g production from CD41 T cells. See page 1336.
Oka-BPB-2003 teaches a study wherein the role of interleukin (IL)-12 on the antimetastatic effect of Z-100 was investigated using wildtype C57BL/6 mice or IL-12p40 knockout (IL-12p40 KO) mice inoculated with highly metastatic B16F10 melanoma. When C57BL/6 mice were inoculated with B16F10 melanoma (2x105 cells/mouse i.v.), Z-100 (10 mg/kg i.p.) significantly suppressed the pulmonary metastasis of B16F10 melanoma 14 d after tumor inoculation. On the other hand, the antimetastatic effect of Z-100 was not observed in IL-12p40 KO mice inoculated with B16F10 melanoma. These results indicate that IL-12 is essentially required for the appearance of the antimetastatic effect of Z-100. Since helper T (Th) 2 cell responses have been reported to have a role in tumor metastasis, the regulatory effect of Z-100 on the immune balance of Th1/Th2 cell responses was investigated. In both C57BL/6 mice and IL-12p40 KO mice bearing B16F10 melanoma, Th1 cytokine production (IL-2, interferon-g) was significantly suppressed as compared with those in normal mice. On the other hand, Th2 cytokine production (IL-4, IL-10) in these mice was increased. The administration of Z-100 (10 mg/kg i.p.) in C57BL/6 mice bearing B16F10 melanoma improved the balance of Th1/Th2 cell responses from the Th2-dominant state to the normal state. However, the improvement of Th1/Th2 cell responses by Z-100 was not observed in IL-12p40 KO mice bearing the same tumors. In addition, Z-100 significantly increased IL-12 production by macrophages in a concentration-dependent manner, while Z-100 significantly decreased IL-10 production by these cells in vitro. These results suggested that up-regulation of IL-12 production and down-regulation of IL-10 production by Z-100 are related to the improvement of Th1/Th2 cell responses from the Th2-dominant state to the normal state, which resulted in suppression of tumor metastasis. See Abstract.
Oka-BPB-2003 further teaches that to determine the role of IL-12 in the antimetastatic activity of Z-100, C57BL/6 mice and IL-12p40 KO mice were inoculated with B16F10 melanoma (23105 cells/mouse) and then those mice were administered Z-100 (10 mg/kg i.p.). The number of pulmonary metastases was counted 14 d after tumor inoculation. As shown in Fig. 1a, administration of Z-100 (10 mg/kg) significantly suppressed the pulmonary metastasis of tumors in C57BL/6 mice inoculated with B16F10 melanoma, as compared with that in tumor control mice (suppression rate: 80.6%, p,0.01). In IL-12p40 KO mice inoculated with the same tumors, Z-100 did not suppress pulmonary metastasis (suppression rate: 19.1%) (Fig. 1b). These results indicate that Z-100 exhibits its antimetastatic activity through the function of IL-12. On the other hand, Z-100 (200m g/ml) did not suppress the growth of B16F10 melanoma cells in vitro. The results indicate that Z-100 does not have a direct tumoricidal effect but acts through a host-mediated mechanism against tumor cells. See page 1337, right column, para 4.
Oka-BPB-2003 compares the regulatory effects of Z-100 on cell responses in C57BL/6 mice and IL-12p40 KO mice inoculated with B16F10 melanoma. It teaches that C57BL/6 mice bearing B16F10 melanoma were administered Z-100 (10 mg/kg i.p.), and then the production of Th1 cytokines (IL-2, IFN-g) and Th2 cytokines (IL-4, IL-10) by CD4+ T cells prepared from the splenocytes of those mice were measured 14 d after tumor inoculation. The results indicate that Z-100 improved the balance of Th1/Th2 cell responses from the Th2-dominant immune responses to the normal state in C57BL/6 mice bearing B16F10 melanoma. See page 1338, left column, para 1.
Oka-BPB-2003 teaches that to determine the role of IL-12 in the regulatory effect of Z-100 on the balance of Th1/Th2 cell responses, IL-12p40 KO mice bearing B16F10 melanoma were administered Z-100 (10 mg/kg i.p.), and IL-2, IFN-g, IL-4, and IL-10 from the CD4+ T cells prepared from splenocytes of those mice were measured 14 d after tumor inoculation. IL-2 and IFN-g production was significantly decreased in IL-12p40 KO mice bearing B16F10 melanoma, as compared with that in normal IL-12p40 KO mice (IL-2, p,0.01; IFN-g, p,0.05, Figs. 3a, b). IL-4 and IL-10 production was significantly increased in IL-12p40 KO mice bearing B16F10 melanoma, as compared with that in normal IL-12p40 KO mice (p,0.01, Figs. 3c, d). The results suggest that Z-100 improved the balance of Th1/Th2 cell responses from Th2-dominant immune responses to the normal state through the activities of IL-12 as observed in C57BL/6 mice bearing B16F10 melanoma. See page 1338, right column, para 1.
Oka-BPB-2003 teaches that Macrophages have been shown to produce IL-12 and to be the primary target cells for immunological activity of Z-100. Therefore, the effects of Z-100 on IL-12 production by macrophages were determined. The macrophages prepared from BCG-treated mice were cultured in the presence of saline or Z-100 (200m g/ml) for 24, 48, and 72 h at 37 °C in 5% CO2. The amounts of IL-12 (p40 and p70) in the culture fluid harvested were measured using an ELISA kit (Fig. 4a). The results indicate that Z-100 significantly increases IL-12 production by macrophages (p,0.01). See page 1338, right column, para 2.
Oka-BPB-2003 further teaches IL-10 production by macrophages stimulated with Z-100. It teaches that the effects of Z-100 on IL-10 production by macrophages prepared from BCG-treated mice were determined. The macrophages were cultured in the presence of saline, as the control group, or Z-100 (200m g/ml) for 24, 48, and 72 h, and the amounts of IL-10 in the culture fluids were measured using an ELISA kit (Fig. 5a). The results indicated that Z-100 significantly decreases IL-10 production by macrophages at concentrations of 25mg/ml or more (p,0.01). See page 1339, left column.
Oka-BPB-2003 teaches that, in conclusion, the authors demonstrated that Z-100 increases IL-12 production, decreases IL-10 production, and improves Th1/Th2 cell responses from the Th2-dominant state to the normal state. In addition, the findings indicate that the antimetastatic activity of Z-100 is exerted through host mediated immune systems. Since these studies were carried out in mice, the clinical relevance of the results is unknown, but they suggest that Z-100 treatment of patients with cancer could prevent metastasis via above the host immune system.
Accordingly, Oka-BPB-2003 teaches a method of treating metastasis associated with melanoma by administration of Z-100, a non-target immunomodulator extracted from Mycobacterium tuberculosis strain Aoyama B to a subject in need thereof. Its teachings indicate that the treatment effect is related to the host’s immune system, e.g., the balance helper T cells (Th1/Th2 balance) and the cytokines IL-12 and IL-10 production. Teachings of Oka-BPB-2003 suggest that the subject’ genetic background is important for the effect of the Z-100 therapy by showing that mice with a genetic background of abnormal IL-12 (IL-12p40 KO mice) is not responsive to the Z-100 treatment of B16F10 melanoma metastasis compared to wildtype mice (C57BL/6).
Oka-BPB-2003 is silent on testing PBMCs from the subjects to be treated with Z-100 by stimulating them with Z-100 and measuring cytokine production. Instead, Oka-BPB-2003 teaches testing immune cells, such as splenocytes from mice administered with Z-100 (stimulated in vivo) and macrophages prepared from BCG-treated mice stimulated with Z-100 in vitro, for various cytokines.
Holland teaches a study on in vitro proliferative and cytokine responses of PBMC to chlamydial antigens in 30 subjects with conjunctival scarring due to trachoma, and 30 age-, sex- and location-matched controls. The cytokines studied include those known to be important in immunity to chlamydial infection (IFN-g) and are representative of the Th1 (IFN-g) and Th2 (IL-4, IL-10) subsets. Cytokine production in response to chlamydial antigens was assessed by assay of IFN-g in culture supernatant, by the enumeration of PBMC secreting IFN-g and IL-4, and by the detection of mRNA for IFN-g, IL-4 and IL-10 using reverse transcriptase polymerase chain reaction (RT-PCR). Within a subset of subjects they have examined associations between polymorphism of HLA class II genes (DRB1 and DQB1) and these immune responses. See page 430, left column, para 2.
The authors found that stimulation with the chlamydial heat shock protein (hsp)60 resulted in increased numbers of IL-4- producing cells in PBMC isolated from patients with scarring disease. In addition, IL-4 mRNA was detected exclusively in PBMC of patients with scarring disease after in vitro stimulation with chlamydial antigens. Stimulation of PBMC from the control group with hsp60 increased secretion of IFN-g, whilst stimulation with chlamydial major outer membrane protein (MOMP) resulted in increased levels of IFN-g-producing cells. These data suggest a role for Th2 cells and cytokines in the pathogenesis of trachomatous scarring. See page 430, left column, para 3.
Accordingly, teachings of Holland indicate that PBMCs can be used to study host immune cell responses to antigens or immunomodulators by testing expression of various cytokines produced by immune cells included in the PBMCs after in vitro stimulation.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to introduce the practice of PBMC testing of Holland into the treatment of AIDS and melanoma metastasis by Z-100 taught or suggested by Suzuki, Oka-MI-2002 and Oka-BPB-2003. One would have been motivated to do so to evaluate in advance if the subject to be administered Z-100 is responsive to Z-100 by an in vitro test using PBMCs from the subject for cytokine expressions after Z-100 stimulation. There is a reasonable expectation of success that PBMCs from an AIDS or melanoma metastasis patient can be obtained, stimulated by Z-100 and cytokine expressions measured, based on teachings of Oka-BPB-2003 and Holland, and that the assay results may help a clinician to predict if the subject is likely to be responsive to Z-100 treatment.
Regarding claim 91, which specifies that the subject has a history of an infection involving the antigen component, it is known in the art that a portion of the general population may have been infected with M. tuberculosis, including subjects with AIDS. There is no reason to exclude those subjects if they need the treatment disclosed in Suzuki.
Regarding claim 94, which specifies that the subject receiving treatment has melanoma (see the 112(b) rejection above), teachings of Olsen et al. (PLoS ONE, 2014, 9(4): e95096) indicate that patients with HIV/AIDS may also have risk of melanoma. See Abstract. There is no reason to exclude patients with melanoma if they need the treatment disclosed in Suzuki.
Regarding claim 95, specifying that the antigen component comprises a protein, it is noted that these claims do not require a protein as the main part of function. In other words, the claim does not exclude a protein as contaminant. Suzuki teaches that the process of preparing the M. tuberculosis hot water extract comprises a process to remove proteins – “in order to remove proteins, one (w/v) % sulfosalicylic acid was added to the concentrate. The mixture was allowed to stand for 15-20 minutes at a temperature of not higher than 10°C. Precipitates were removed by centrifugal separation (10° C. or lower temperature, 1,150xG, 10 minutes), to thereby recover the supernatant.” This process appears to remove proteins in the M. tuberculosis hot water extract by precipitation in a sulfosalicylic acid solution and a mild centrifugal separation (1,150xG, 10 minutes). It is reasonable to expect that there is still protein left in the supernatant which is further processed into the final antigen product.
Double Patenting Rejection
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this 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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/forms/. The 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
(Previous Rejection – Withdrawn) Claims 84-87, 89-92, 94-97 and 104 were rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-19 of US Patent 6,015,796 (issued to Suzuki et al. cited in the art rejection above).
This rejection is withdrawn in view of the amendment filed on Mar. 2, 2026. Applicant’s arguments are moot.
(New Rejection – Necessitated by Amendment) Claims 84-87, 89-92, 94-97 and 104 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-19 of US Patent 6,015,796 (issued to Suzuki et al. cited in the art rejection above) in view of Suzuki, Oka-MI-2002, Pka-BPB-2003 and Holland cited in the art rejection above.
Although the conflicting claims are not identical, they are not patentably distinct from each other. Both sets of claims may involve a composition encompassing a M. tuberculosis hot water extract. The differences include (1) that the reference claims are limited to the M. tuberculosis hot water extract and specific for treating AIDS, while the instant claims are generic in both the composition and the conditions to be treated, only specifying the function of activating a regulatory T cell having immunological memory of a non-target antigen component, and (2) the reference claims are silent on the subject identifying step recited in the instant claims.
As indicated in the art rejection above, the method of the reference claims is expected to have the function of activating a regulatory T cell because of the presence of the M. tuberculosis hot water extract, and one of skill in the art would have found it obvious to go through a subject identifying step specified in the instant claims to evaluate a subject’s potential response to the Z-100 treatment before beginning the actual treatment.
Reference claims 14-19 are included in this rejection based on the decision of the Court of Appeals for the Federal Circuit in Pfizer Inc. v Teva pharmaceuticals USA Inc., 86 USPQ2d 1001, at page 1008 (March 2008), which indicates that there is no patentable distinction between claims to a product and a method of using that product disclosed in the specification of the application and that the preclusion of such a double patenting rejection under 35 USC 121 does not apply where the present application is other than a divisional application of the patent application containing such patentably indistinct claims.
Conclusion
No claims are 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 extension fee 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 NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/
Primary Examiner, Art Unit 1671