DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/18/2024 has been entered.
Applicant’s amendments to the claims and arguments filed on November 18, 2024 have been received and entered. Claim 1 has been amended, while claims 3-5 have been canceled. Claims 1-2, 6-10 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claims 1-6 (group 1) in the reply filed on December 12, 2023 was acknowledged.
Claims 7-10 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 12, 2023.
Priority
This application is a continuation of PCT/CN2019/093028 filed on 06/26/2019, which claims priority from a foreign application 201810706038.9 filed in China on 06/28/2018. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claims 1-2, 6 are under consideration.
Withdrawn--Claim Rejections - 35 USC § 103
Claims 1-2 were rejected under 35 U.S.C. 103 as being unpatentable over Samudio et al (Blood. 2016;127(21):2575-2586) as evidenced by Raftery (Journal of Exp. Medicine, 1999, 1103-1113), Sato et al (PNAS, 2006, 103(46) 17343-17348)/Lund (J. Exp. Med., 2003, 198 (3), 513-520), Zhao (PLoS ONE, 2014, e93103, 9(3), 1-11) Brinkmann et al ( J Exp Med, 1993, 1655-1663). In view of Applicants’ amendment of base claim 1, introducing the limitation “ he activated immunocytes are capable of killing breast cancer cell or colon cancer cell in vivo", the previous rejections of claims are hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are however subject to new rejections over the prior art of record, as set forth below.
Claims 1 and 6 were rejected under 35 U.S.C. 103 as being unpatentable over Samudio et al (Blood. 2016;127(21):2575-2586) as evidenced by Raftery (Journal of Exp. Medicine, 1999, 1103-1113), Sato et al (PNAS, 2006, 103(46) 17343-17348)/Lund (J. Exp. Med., 2003, 198 (3), 513-520), Zhao (PLoS ONE, 2014, e93103, 9(3), 1-11) Brinkmann et al ( J Exp Med, 1993, 1655-1663) and Liu (CN102146418, 8/10/2011, 1-23). The rejection is withdrawn for the reasons discussed above.
New-Claim Rejections - 35 USC § 103- Necessitated by amendments
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 1-2 are rejected under 35 U.S.C. 103 as being unpatentable over Samudio et al (Blood. 2016;127(21):2575-2586), Yin et al (Therapeutics and Clinical Risk Management 2017:13 117–130), Sato et al (PNAS, 2006, 103(46) 17343-17348)/ /Lund (J. Exp. Med., 2003, 198 (3), 513-520), Zhao (PLoS ONE, 2014, e93103, 9(3), 1-11) as evidenced by Brinkmann et al ( J Exp Med, 1993, 1655-1663).
Claims are directed to a method for activating immunocyte, said method comprising (i) isolating immunocytes from peripheral blood or malignant pleural effusion samples of a patient; (ii) Co-incubating inactivated herpes simplex viruses type II with the immunocytes, to activate the immunocytes; and (iii) Removing the inactivated herpes simplex viruses to obtain the activated CD4+ and NK cells.
Claim interpretation: Claims are interpreted to isolate immunocytes from peripheral blood of any patient (receiving treatment of any disorder). It is noted that claim are not limited to any patient. Further, recitation of capable is interpreted as
With respect to claims 1, Samudio teaches a method for activating immunocyte, said method comprising (i) isolating immunocyte from peripheral blood of a human subject or from a patient with AML (see page 2576, col. 1, last para, page 2577, col. 2, para. 4.), (ii) co-incubating UV-inactivated herpes simplex viruses-1 with the PBMC for 16 hours (see fig. 1 E) and (iii) harvesting the cells after washing twice in medium [to remove the virus from the cells) (see page 2574, col. 2, para. 3) . Samudio further teaches that UV-treated HSV-1, at a UV dose that made HSV-1 incapable of infection or replication, was as potent as live HSV-1 in activating human allogenic PBMCs to kill acute myelogenous leukemia (AML) cells, while sparing normal leukocytes partly via Toll-like receptor-2/protein kinase C/nuclear factor-kB signaling (abstract). It is further disclosed that UV-HSV-1 is a bona fide activator of NK-cell function (see page 2582, col. 2, para. 1) and activates isolated NK cells in part via TLR-2/NF-kB signaling (see page 2581, col. 2, para.1). Samudio differs from claimed invention by not explicitly teaching (i) co-incubating with HSV-II and (ii) activating CD4+ and NK cells., wherein activated immunocytes are capable of killing breast or colon cancer.
Before the effective filing date of instant application Yin teaches anti-tumor effects of oncolytic herpes simplex virus type 2 on colorectal cancer in vivo, and specifically discloses the us of an oncolytic herpes simplex virus type 2 (oHSV2) that is a conditionally replicating HSV-2 resulting from deletion of ICP34.5 and ICP47 genes and insertion of granulocyte-macrophage colony stimulating factor (GMCSF) (see page 118, col. 1, last para.). It is disclosed that method produces multiple immunostimulatory effects, and is involved in recruiting and activating dendritic cells (DC), and induces tumor-specific cytotoxic T lymphocytes. In the construction of OV. Yin teaches that he results show that the proportion of DCs is significantly increased due to direct injection of oHSV2 into established mice, resulting in local GM-CSF accumulation, which may attract and mature DCs (see page 118, col. 2, para. 1). The GM-CSF has been shown to play an important role in recruiting and maturing DCs that act as powerful stimulators, presenting tumor antigens to CD4 + T cells via MHC class II or CD8 + T cells via MHC class I (see page 128, col. 1, para. 2). The activated T cells display specific cytotoxic activity against target cells and mediate tumor destruction (see page 128, col. 1, para. 2). The studies shows that oHSV2injection in a murine CRC model produces a tumor-specific T lymphocyte response that effectively responds (page 128, col. 1, last para. Figure 2, Figure 6). Yin differs from that claimed invention by not disclosing the use of inactivated herpes simplex virus with immunocyte an in vitro system. .
However, before effective filing date of instant invention, Sato teaches co-incubating UV-inactivated HSV type with an immunocyte (see page 17348, col. 2, para. 4) and washing in PBS. It is further disclosed that systemic inoculation of UV irradiated HSV-2 results in IFN a production in a TLR9-dependent manner (see page 17343, col. 1, para. 2, Fig. 6). Likewise, Lund teaches co incubating UV-HSV-2 in presence of bone marrow cells containing immunocyte secrete considerably higher levels of IFN-α (see Fig. 2 and 3, page 515 col. 2, para. 2). The combination of references differs from claimed invention by not disclosing activating CD4+ cells.
However, before the effective filing date of instant application, Zhao reported increase in NK cell number following use of oncolytic HSV2 (see abstract, fig. 5), while Brinkmann reported IFN-alpha factors increases the frequency of interferon gamma producing human CD4+ T cells in PBMC (see abstract, table 1, fig. 2).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the method of Samudio by substituting UV- HSV-1 with UV- oHSV-2 as disclosed in Yin and Lund/Sato to activate immunocytes in vitro, in the method of activating immunocytes, as instantly claimed, with a reasonable expectation of success, before the effective filing date of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to use HSV2 because prior art suggested use of HSV2 (i) recruit adaptive immune responses for an enhanced therapeutic impact as in Yin (abstract) and (ii) may be better for oncolysis as compared to HSV 1 (see Zhao page 1, col. 2, para. 2). Absent evidence of any unexpected results, one of skill in the art would have been expected to have a reasonable expectation of success in using UV-inactivated HSV2 because the art teaches the successful activation of immunocytes following co culture of immunocyte with UV-HSV2 as evident from the teaching of Yin/Lund in view of Zhao and Brinkmann. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claims 1 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Samudio et al (Blood. 2016;127(21):2575-2586), Yin et al (Therapeutics and Clinical Risk Management 2017:13 117–130), Sato et al (PNAS, 2006, 103(46) 17343-17348)/ /Lund (J. Exp. Med., 2003, 198 (3), 513-520), Zhao (PLoS ONE, 2014, e93103, 9(3), 1-11) as evidenced by Brinkmann et al ( J Exp Med, 1993, 1655-1663) and Liu (CN102146418, 8/10/2011, 1-23)
The teaching of Samudio,, Yin, Sato, Zhao and Brinkmann have been discussed above and relied in same manner here. The combination of references differs from claimed invention by not disclosing the use of oHSV-2 having preservation number CGMCC No. 3600 for activation of immunocyte.
Liu teaches a method of making and using oncolytic HSV-2 with preservation number he CGMCC No. 3600 (see para. 74).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the method of Samudio by substituting UV- HSV-1 with UV- oHSV-2 as disclosed in Yin and Lund in view of Liu to activate immunocytes in vitro, in the method of activating immunocytes, as instantly claimed, with a reasonable expectation of success, before the effective filing date of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to use HSV2 because prior art suggested use of HSV2 (i) recruit adaptive immune responses for an enhanced therapeutic impact as in Yin (abstract) and (ii) may be better for oncolysis as compared to HSV 1 (see Zhao page 1, col. 2, para. 2). Other limitation of using HSV-2 with preservation number he CGMCC No. 3600 would be obvious use of oHSV2 as per the teaching of Liu who reported how to make and use said HSV2. Absent evidence of any unexpected results, one of skill in the art would have been expected to have a reasonable expectation of success in using UV-inactivated HSV2 because the art teaches the successful activation of immunocytes following co culture of immunocyte with UV-HSV2 as evident from the teaching of Yin, Sato in view of Zhao and Brinkmann. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at www.uspto.gov/ web/offices/dcom/bpai/prec/ fd071925.pdf).
Response to arguments
To the extent that Applicants’ arguments are pertinent to the new rejections, they are addressed as follows:
Applicant disagree with the rejection arguing that the cited in the Office Action and the prior art used activated immunocytes to kill the cells of the blood system cancers rather than solid tumors. Applicant assert that the applicant limits the use of the activated immunocytes, thereby distinguishing claim 1 from prior art. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it is noted that breadth of the claims encompasses isolating immunocytes from peripheral blood samples of any patient. The patient recited in the claim is not limited to a cancer patient. Therefore, recitation of the activated immunocytes is capable of killing breast cancer cell or colon cancer in vivo in the claim provides an intended use limitation and to the extent one of ordinary skill the art based on the teachings of the prior art would conclude that activated immunocyte disclosed in Samudio in view of Yin will serve to treat any cancer including breast or colon, it is applicable to the rejection. The co-culturing of PBMC derived from a patient with inactivated HSV-II meets the structural limitations of the active method step of claimed method and thereby it must necessarily be capable of treating any cancer cell. It is emphasized that claimed method neither require isolating immunocyte from peripheral blood of any specific patient nor does claim require any specific oncolytic HSV type II virus.
Applicant should note that none of the claim require activation of active method step of using autologous or allogeneic immunocyte derived from breast or colon cancer patient that is co-incubated with an o-HSV2 in which ICP34.5 I, and ICP47 gene is knocked out and an expression cassette in which human granulocyte-macrophage colony-stimulating factor (hGM-CSF) is inserted that is specifically exemplified in the instant application (see para. 55 of the instant application). Further, none of the method step require activated CD4+ and NK to cells to have any in vivo killing effect on breast or colon cancer cell.
In the instant case, it appears that Applicant is arguing that the cited references do not expressly suggest the claimed invention as it is limited to cancer of blood and not to solid tumor. However, it is well established in case law that a reference must be considered not only for what it expressly teaches, but also for what it fairly suggests. In re Burkel, 201 USPQ 67 (CCPA 1979). Furthermore, in the determination of obviousness, the state of the art as well as the level of skill of those in the art are important factors to be considered. The teaching of the cited references must be viewed in light of these factors. It also appears that applicant is attempting to attack each reference individually. However, in a 103 rejection the references must be considered as a whole. Applicants have further engaged in selective reading of the teachings of Samudio et al. to formulate the grounds for teaching away.
It should be noted that the ultimate goal of co incubating HSV2 with immunocyte is to provide activated immunocytes. As previously indicated, Samudio et al. in describing a method activating immunocyte teaches (i) isolating immunocyte from peripheral blood of a human subject or from a patient with a cancer (AML) (see page 2576, col. 1, last para, page 2577, col. 2, para. 4.), (ii) co-incubating UV-inactivated herpes simplex viruses-1 with the PBMC for 16 hours (see fig. 1 E) and (iii) harvesting the cells after washing twice in medium [to remove the virus from the cells) (see page 2574, col. 2, para. 3) . It is further disclosed that UV-HSV-1 is a bona fide activator of NK-cell function (see page 2582, col. 2, para. 1) and activates isolated NK cells in part via TLR-2/NF-kB signaling (see page 2581, col. 2, para.1), The prior art also teaches HSV1 and HSV2 are highly similar virus and HSV-2 Is suggested to be better for oncolysis than HSV-1. A domain of HSV-2 can activate the RAS/MEK/MAPK pathway and improve the efficiency of virus reproduction. Further, HSV-2 can selectively infect tumor cells and form syncytia, resulting in a better antitumor immune response than HSV-1 [ (see Zhao, see page 1, col. 2, para. 2). The newly cited art of Yin provides guidance with respect to use of oHSV2 that express GM-CSF that has been shown to play an important role in recruiting and maturing DCs that act as powerful stimulators, presenting tumor antigens to CD4 + T cells via MHC class II or CD8 + T cells via MHC class I (see page 128, col. 1, para. 2) (emphasis added). The activated T cells display specific cytotoxic activity against target cells and mediate colon tumor destruction (see page 128, col. 1, para. 2). This is supported by Zho who reported oHSV2 increases NK cell number thereby affecting breast cancer cells. In view of foregoing, it is apparent that co-incubating UV-inactivated o-HSV2 with an immunocyte would also increase mature DC cells and effector T cells as evident from Yin that are capable of killing colon cancer cells. It should be noted that obviousness does not require absolute predictability of success; for obviousness under 35 U.S.C. § 103, all that is required is a reasonable expectation of success. See In re O’Farrell, 7 USPQ2d 1673 (CAFC 1988). Absent evidence of any unexpected result, a person of skill in the art would be motivated modify the method of Samudio by substituting UV- HSV-1 with UV- HSV-2 as disclosed in Yin/Lund to activate immunocytes in vitro, in the method of activating immunocytes intended to kill colon cancer cells, as instantly claimed, with a reasonable expectation of success, with a reasonable expectation of success.
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants’ arguments are not compelling and do not overcome the
rejection of record.
Examiners note: Should applicant provide evidence of unexpected superior effect with co-incubating immunocyte with a specific o-HSV-2 showing superior killing of breast or colon cancer as compared to other o-HSV2, instant obviousness rejection may be overcome pending further consideration.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Ciaramella et al (20200054737, or WO2017070623, dated 4/27/2017) teaches priming of immune effector cells, for example, to activate peripheral blood mononuclear cells (PBMCs) ex vivo, which are then infused (re-infused) into a subject (see para. 295).
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632