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 .
Applicant's amendment and remarks, filed 3/12/26, are acknowledged.
Claims 1, 8, 12-13, 15 have been amended.
Claims 16-17 have been added.
Claims 1, 3, 5, 8-17 are pending.
In view of Applicant’s amendment to claims 13-15 to be depend from claim 1, they are being included in the examination. Claims 9 is withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claims 1, 3, 5, 8, 10-17 are being acted upon.
The previous grounds of rejection are withdrawn in view of Applicant’s claim amendments.
The following are new grounds of rejection necessitated by Applicants’ claim amendments. Applicant’s arguments relevant to the new grounds of rejection will be addressed below.
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, 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, 3, 8, 10-12, 16-17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2016/146035, as evidenced by Xie, 2010, or, in the alternative, under 35 U.S.C. 103 as obvious over WO2016/146035 and Xie, 2010 (all of record).
WO2016/146035 teaches a method of treating cancer comprising administering to an individual an effective amount of tumor antigen peptide activated T cells and further comprising administering an inhibitor of PD-1 or PD-L1 (see claims 1, 15, 53-54). WO2016/146035 teaches that the T cells are autologous, i.e. from the subject (See claim 15). WO2016/146035 teaches that the inhibitor of PD-1 or PD-L1 is an antibody such as nivolumab and simultaneous administration of the inhibitor and the T cells (see page 64-70 and 75, in particular). WO2016/146035 teaches administering about 1x109 to 1x1010 cells/individual to treat cancer and also teaches that the administered T cells comprises 16-22% CD4+ T cells (see page 10-11, 13). Thus, a dose of a dose of 1 x1010 having 20% T cells, would have 2 x109 CD4+ T cells.
As evidenced by Xie, CD62L is a marker expressed by naïve CD4 T cells, and antigen activated CD4 T cells are CD62Llow (See page 652, in particular). See also page 97 of the instant specification which discloses that naïve T cells lose expression of CD62L upon recognition of antigen, and become primed effector T cells and that effector T cells that have been primed by an antigen recognition are CD62Llow. Therefore, the antigen, primed activated CD4 T cells administered in the method of WO2016/146035 would inherently comprise 2 x 109 CD62Llow CD4 T cells (i.e. a therapeutically effective amount). Alternatively, it would be obvious that the T cells would contain the recited amounts of CD62LowCD4 T cells based on the teachings of the cited references. Sustaining the effect of the checkpoint inhibitor and make the checkpoint inhibitor more effective would be a latent property of the prior art method.
Regarding claim 17, the claim is directed to a administering a composition “comprising” purified CD62LlowCD4+ T cells. The term comprising is an open term that does not exclude unrecited steps or elements. For example, the “purified” CD62Llow CD4+ T cells in the claimed method can be co-administered in the same composition with CD8 T cells or other types of CD4 T cells. Furthermore, the claims do not recite any particular level of purity. For example, the T cells of the prior art above have been “purified” as compared to the starting population in peripheral blood which comprises red blood cells, B lymphocytes, monocytes, etc. Therefore, the recitation of that the cells are purified (which is also a product by process limitation) does not distinguish from the method of WO2016/146035.
Claim(s) 1, 3, 5, 8, 10-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2015069770, in view of Wang, 2007 (both of record) and US 2003/0170238.
WO2015069770 teaches a method of treating cancer comprising administering a to a subject a combination therapy comprising a checkpoint inhibitor and adoptive T cell therapy (See page 6, in particular). WO2015069770 teaches that the combination enhances anti-tumor responses, that the method enhances efficacy of the checkpoint inhibitor and is more effective at treating cancer (i.e. it sustains a cancer immunotherapy and makes cancer immunotherapy more effective in the treated subjects, see pages 3 and 6-7, in particular). WO2015069770 teaches that the checkpoint inhibitor can be a PD-1 inhibitor such as an anti-PD-1 antibody (see page 5-6 and 18, in particular). WO2015069770 teaches that the T cells are autologous (i.e. from the subject to whom they are administered) and are targeted against tumor antigens (see page 6, in particular). WO2015069770 teaches that the method enables a subject to respond to a checkpoint inhibitor (i.e. sustains checkpoint therapy in a subject to whom the therapy is predicted to be ineffective, see page 7, in particular). WO2015069770 teaches administration of the T cells one hour or one day prior to the checkpoint inhibitor, or chronologically at the same time as the checkpoint inhibitor (i.e. concomitantly, see page 36, in particular). WO2015069770 teaches nivolumab (See page 25, in particular). WO2015069770 teaches administration of combination of checkpoint inhibitors including inhibitors of PD-1, PD-L1, and CTLA-4 (see page 5 and 7, in particular).
The reference differs from the claimed invention in that it does not explicitly teach at least 2 x 108 CD62LlowCD4+.
Wang teaches that administration of T cells comprising CD62LlowCD4+T cells synergically mediates tumor regression (see pages 4866-4867, in particular). Wang teaches that including the CD4+ T cells in an adoptive T cell therapy has advantages such as enhanced and persistent of anti-tumor responses (see page 4871, in particular). Wang teaches obtaining the CD62LlowCD4+T cells by a purification process comprising depleting CD62Lhigh cells using a MACS bead kit (See page 4866, in particular).
The ’238 publication teaches adoptive immunotherapy with T cells for treating cancer, and teaches that the T cells can be CD4+ and/or CD8+ (see paragraphs 15-18, 45, in particular). The ‘238 publication teaches that it is preferred that the T cells should be CD62Llow, since they have ability to traffic to the tumor after infusion (See paragraph 44 and 148, in particular). The ‘238 publication teaches that the number of T cells for adoptive immunotherapy can be at least 109 (see paragraph 50, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to include purified CD62LlowCD4+, as taught by Wang and the ‘238 publication, as the adoptive T cell therapy compositions, in the method of WO2015069770. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because Wang teaches that administration of T cells comprising CD62LlowCD4+T cells synergistically mediates tumor regression and the ‘238 publication teaches that T cells CD62Llow T cells are preferred since they traffic to the tumor. Furthermore, including at least 2x108 of said CD4 T cells would be well within the purview of the ordinary artisan, since the ‘238 publication teaches T cells for immunotherapy should be administered in a dose of at least 109 T cells.
Applicant argues that the anti-tumor effect in WO2015069770 is contingent upon the presence of CD8 T cells. Applicant cites paragraph 166 of WO2015069770 that teaches that depletion of CD8 T cells in mice abolished therapeutic effect, demonstrating that CD8+ T cells are indispensable for treatment. Applicant argues Wang only teaches that CD4 T cells perform a helper function to assist CD8 positive T cells, and that administration of CD4 T cells alone does not induce complete tumor regression. Applicant argues that the present claims rely upon the novel finding that CD62LlowCD4+ T cells themselves exert an anti-tumor effect and the prior art teaches away from the claimed invention.
The present claims are directed to a method of administering a composition “comprising” CD62LlowCD4+T cells, which does not exclude unrecited elements, such as also administering CD8 T cells. For example, the cited references would make obvious administering purified CD4+CD62Llow T cells and CD8 T cells, which would be within the scope of the instant claims. Furthermore, the cited references make above combined treatment with PD-L1 inhibitor for the reasons set forth above. For example, WO2015 teaches that PD-1 is expressed by dendritic cells and tumor cells, and that it limits T cell responses, including CD4 and CD8 T cells (see paragraph 78-80, in particular). WO teaches that administration of a checkpoint inhibitor with T cell adoptive therapy prolongs anti-tumor response in the subject (See page 3 and 6, in particular).
Furthermore, the prior art does not “teach away” from administration of CD4 T cells, as argued by Applicant. In fact, Wang teaches that administration of CD4CD62LLow T cells alone is effective in treating cancer, resulting a reduction in metastases. The references do teach away from depleting T cells in the treated subjects. For example, as noted by Applicant, WO2015069770 teaches that depleting mice of CD8+ T cells abrogates therapeutic benefit. Wang also teaches that if either CD4+ or CD8+ T cells are depleted in hosts, treatment of tumors is inhibited. However, the claimed method does not require depletion of T cells in treated subjects, which is what is what the prior art teaches away from.
Furthermore, the instant specification teaches that the role of CD4 T cells is the same as that of the prior art, i.e. as providing a helper function for CD8 T cells. For example, the instant specification discloses the importance of the CD8 subpopulation as correlating with anti-tumor response. See page 35 where it is taught that CD4 T cells stimulate dendritic cells, which in turn stimulate CD8 T cells, i.e. the role of CD4 T cells is as a “helper” cell in activating CD8 T cells, which is the same mechanisms taught in the prior art. In other words, the administered CD4 T cells in the present claims also provide a “helper” benefit by producing cytokines and increased CD8 anti-tumor cytolytic effects, and the specification suggests that the presence of CD8 T cells in the treated mice would also be “necessary”. The specification does not demonstrate that administering CD4 T cells with PD-1 blockade is effective in mice in which CD8 T cells have been depleted, for example.
Claim(s) 1, 10, 12-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2003/0170238, in view of Wang, 2007 (of record) and Ding, 2014.
The ‘238 publication teaches a method of T cell immunotherapy comprising administering to a patient a T cell population, (see page 1, in particular). The ‘238 publication teaches administration of at least 1010 T cells or higher (see page 2 and 4-5, in particular). The ‘238 publication teaches that the immunotherapy is for treating cancer, and that the cells can be isolated from a human subject with cancer and administered to the subject from which they were isolated (see page 2, 10, in particular). The ’238 publication teaches that the T cells are purified CD4+ T cells that are CD62Llow (see pages 10-12 and paragraph 148, in particular). The ‘238 publication teaches that the T cell population should be highly purified (See paragraph 44). See also Wang, which teaches that administration of T cells comprising CD62LlowCD4+T cells mediates tumor regression (see pages 4866-4867, in particular). Wang teaches that including the CD4+ T cells in an adoptive T cell therapy has advantages such as enhanced and persistence of anti-tumor responses (see page 4871, in particular). Wang teaches obtaining the CD62LlowCD4+T cells by a purification process comprising depleting CD62Lhigh cells using a MACS bead kit (See page 4866, in particular).
The references differ from the claimed invention in that they do not explicitly teach administering a checkpoint inhibitor.
Ding teaches that PD-1-PD-L1 blockade can lead to persistence of CD4+ effector T cells after CD4+ T cell adoptive immunotherapy and durable anti-tumor effects. Ding teaches using anti-PD-1 monoclonal antibody (see Fig. 5, in particular). Ding teaches that including said PD-1-PD-L1 blockade increases the tumor free survival, as compared to T cell immunotherapy alone, (i.e. it is effective in a subject to whom cancer T cell immunotherapy is predicted to be ineffective see Fig. 5).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to further administer checkpoint inhibitors, as taught by Ding, as part of the adoptive T cell therapy in the method of the ‘238 publication and Wang. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because Ding teaches that doing so leads to durable anti-tumor effects.
Claims 3, 5, 8, 10-11 are rejected under 35 U.S.C. 103(a) as being unpatentable over US 2003/0170238, in view of Wang, 2007 and Ding, 2014, as applied to claim 1 above, and further in view of WO2015069770.
The combined teachings of the ‘238 publication, Wang and Ding are discussed above.
They do not explicitly teach nivolumab, combination with CTLA-4 or that the method sustains the effect of the checkpoint inhibitor.
WO2015069770 teaches a method of treating cancer comprising administering a to a subject a combination therapy comprising a checkpoint inhibitor and adoptive T cell therapy (See page 6, in particular). WO2015069770 teaches that the combination enhances anti-tumor responses, that the method enhances efficacy of the checkpoint inhibitor and is more effective at treating cancer (i.e. it sustains a cancer immunotherapy and makes cancer immunotherapy more effective in the treated subjects, see pages 3 and 6-7, in particular). WO2015069770 teaches that the checkpoint inhibitor can be a PD-1 inhibitor such as an anti-PD-1 antibody (see page 5-6 and 18, in particular). WO2015069770 teaches that the method enables a subject to respond to a checkpoint inhibitor (i.e. sustains checkpoint therapy in a subject to whom the therapy is predicted to be ineffective, see page 7, in particular). WO2015069770 teaches administration of the T cells chronologically at the same time as the checkpoint inhibitor (i.e. concomitantly, see page 36, in particular). WO2015069770 teaches nivolumab (See page 25, in particular). WO2015069770 teaches administration of combination of checkpoint inhibitors including inhibitors of PD-1, PD-L1, and CTLA-4 (see page 5 and 7, in particular).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the invention was made to apply the teachings of WO2015069770, to the method made obvious by US 2003/0170238, Wang, 2007 and Ding, 2014. One of ordinary skill in the art at the time the invention was made would have been motivated further administer a CTLA-4 checkpoint inhibitor to enhance treatment, and would have recognized that combination therapy would sustain the effect of the checkpoint inhibitor, including in a subject to whom cancer immunotherapy alone was predicted be ineffective, as specifically taught by WO2015/069770. Furthermore, optimizing the timing of administration, or using nivolumab as the PD-1 antibody, as taught by WO 2015/069770 would be well within the purview of the ordinary artisan and would involve choosing among a finite number of predictable options which could be pursued with a reasonable expectation of success. A person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (see KSR International Co. V. Telefex Inc 82 USPQ2d 1385).
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 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY E JUEDES whose telephone number is (571)272-4471. The examiner can normally be reached on M-F from 7am to 3pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644
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