DETAILED ACTION
Applicant's amendment and remarks, filed 5/1/26, are acknowledged.
Claims 27, 29, 32, 34-35, 45-46, 49 and 51 have been amended.
Claims 27-32, 34-42, 45-46, 49-51 are pending and are under examination.
In view of Applicant’s amendment and remarks, the 112b and 112a rejections are withdrawn.
The prior art rejections are withdrawn and updated to address Applicant’s claim amendments. Applicant’s relevant arguments will be addressed below.
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 27, 36-37, 39, 41-42, 45-46, 49-51 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2008/019366, in view of WO2018234516 (both of record).
WO2008/019366 teaches a method of treating cancer by eliciting an immune response to an antigen in subject in need thereof comprising contacting an APC in vitro with an antigenic preparation comprising a particle having an antigen attached to the surface, and then administering the APCs to the animal to stimulate the subjects T cells (i.e. a vaccine, see pages 9-10 and the claims, in particular). WO2008/019366 teaches that the APCs take up and phagocytose the particles (See page 3 and 12, in particular). WO2008/019366 teaches that the APC is a dendritic cell (see page 4, in particular). WO2008/019366 teaches the antigen is a cancer antigen, such as a mutant oncogenic form of p53 protein, and that the subject is one which is in need of an antigen specific immune response specific to the antigen, i.e. the p53 is expressed by the cancer cell in the subject, see abstract and pages 3-4 in particular. It is noted that p53 protein, which is hundreds of amino acids in length, would be comprised of numerous different peptide epitopes that are covalently linked to each other via peptide bonds, and would include a mutated epitope. WO2008/019366 teaches solid particles such as a polymer bead, latex bead, polystyrene bead, or iron oxide particles (i.e. paramagnetic), i.e. particles with a core (see pages 12-14, in particular). WO2008/019366 teaches that the antigen is attached via covalent methods ( see pages 12-14, in particular). Thus, WO2008/019366 teaches solid particles, wherein an antigen is covalently attached to the surface, which meets the limitations of a particle comprising a core and an antigenic covalently associated to the core. WO2008/019366 teaches that the APC are provided from the treated animal, i.e. from the subject as recited in claim 36 (see paragraph 37, in particular). WO2008/019366 teaches particular size of about 0.3uM to about 20 uM (see paragraph 13, in particular).
The reference differs from the claimed invention in that it does not explicitly teach using a personalized neoantigenic construct which is a tumor specific antigen (TSA) expressed by a cancer cell in the subject with particles that have a largest dimension of 1um.
WO2018234516 teaches methods of using APC such as dendritic cells, that have phagocytosed a phagocytosable particle having one or more personalized tumor neoantigenic constructs covalently associated thereto, for activating antigen specific T cells. WO2018234516 teaches including at least three different tumor neoantigens on the particles to maximize T cell expansion and that the tumor neoantigens are expressed in a cancer cell of the subject (see pages 5, 13, 15, and 20, in particular). WO2018234516 teaches a preferred phagocytosable particle size of 0.5- 2uM in a largest diameter, preferably about 1 uM (See pages 10-11, in particular). WO2018234516 teaches a preferred phagocytosable particle can be superparamagnetic with a polystyrene core (see page 11-13). WO2018234516 teaches that that particles should be treated with a sterilizing wash to remove contaminants like micro-organisms and endotoxin (See pages 11-13, in particular). WO2018234516 that the T cells and APCs are obtained from a blood sample of the subject (see page 21, in particular). W WO2018234516 teaches personalized neoantigen p53 mutations, wherein the mutations are identified by sequencing tumor cells from the cancer patient to provide a personalized neoantigen peptide that is known to be expressed in the tumor cells of the treated subject (i.e. the neoepitope is a tumor specific antigen, see, pages 4 and 46-47, 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 use a personalized neoantigen (i.e. somatically mutated) p53 mutant protein or peptide that is known to be expressed in cancer cells of the treated subject, as taught by WO2018234516, as the mutant p53 tumor antigen in the method of WO2008/019366. The ordinary artisan would be motivated to do so, since WO2018234516 teaches that one can sequence the tumor cells in subjects to be treated to provide a personalized form of the tumor antigen, providing individualized treatment for the patient known to express cancer cells having the mutation. Furthermore, it would be obvious to include at least three different tumor mutant neoantigens, since WO2018234516 teaches that it maximizes T cell expansion. Furthermore, optimizing the particles type and size, using the parameters of the cited references would be routine and well within the purview of the ordinary artisan. For example WO2008/019366 teaches a particle size range of 0.3-20 uM and WO2018234516 teaches that a preferred particle for loading dendritic cells to induce antigen specific T cells is paramagnetic with a polystyrene core of a size between 0.5 and 2 uM, preferably about 1 um. It would be obvious to use particle sizes from within the ranges taught in the references, such a 0.3uM or a 1 uM particle. Regarding claim 39, WO2008/019366 teaches experiments wherein dendritic cells are prepared for use in vitro to activate T cells, wherein they are washed before contact with the T cells (see paragraph 83, in particular). Furthermore, it would be obvious to perform a sterilizing wash, as taught by WO2018234516, in the method of treating cancer of WO2008/019366. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because WO2018234516 teaches that that particles should be treated with a sterilizing wash to remove contaminants like micro-organisms and endotoxin.. Furthermore, the use of a blood sample for providing T cells and dendritic cells, as taught by WO2018234516, would be routine and well within the purview of the ordinary artisan.
Applicant’s arguments filed 5/1/26 have been fully considered, but they are not persuasive.
Applicant argues that the experimental examples in WO2008/019366 involve CMV antigens and not a personalized tumor neoantigenic construct. Applicant argues that although WO2008/019366 mentions mutant oncogenic form of p53, that this is not the same as a neoepitope that is not expressed in somatic cells.
The claims do not require a neoepitope “not expressed in somatic cells” as argued by Applicant. A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v.Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). WO2008/019366 teaches the antigen is a cancer antigen, such as a mutant oncogenic form of p53 protein, and that the subject is one which is in need of an antigen specific immune response specific to the antigen. Thus, the ordinary artisan would understand that in the method of WO2008/019366, the subject in need thereof would be one which has a cancer expressing the mutant oncogenic form of p53, i.e. a somatic cell with a mutation that causes cancer. Furthermore, as noted above, WO2018234516 specifically teaches neoepitope p53 and that the patients cancer cells can be sequenced to provide a personalize neoepitope (i.e. a somatic mutant) p53 that is known to be expressed by the cancer cells. Therefore, it would be obvious to use a personalized neoantigen p53 protein or peptide as taught by WO2018234516, as the mutant form of p53, in order to provide a personalize neoantigen, tumor specific antigen in the method of WO2008/019366.
Applicant argues the WO2018234516 does not disclose using the DC in vivo, but rather uses them as APCs in vitro to produce anti-tumor T cells which are then administered to a patient.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
WO2008/019366 teaches that dendritic cells which have phagocytosed a tumor antigen particle can be used in vivo or in vitro.
Applicant further argues that WO2008/019366 only teaches a broad generic rage of about 0.3 to about 20, and there would be no reason to select a 1um particle.
It is noted that the claims do not require a 1um particle, but rather recite a particle comprising a core “having a largest dimension of 1 um”. In other words, the claimed core can be no larger than 1um. For example, the specification discloses that in a preferred embodiment the core is a sphere and the dimension refers to a diameter. Thus, based on the specification the “dimension” recited in the instant claims encompasses a diameter. A core having a largest diameter (i.e. dimension) of 1 uM would clearly encompass diameters of 1uM or less.
Selecting from within the range specifically disclosed by the cited reference would be obvious. For example, one could select a 0.3 uM particle size.
Applicant further argues that WO2008/019366 teaches away from use of a chemical (i.e. covalent) attachment, showing in Fig. 9-10 that the antigen should be presented on the surface using a Agag1p-Agaa2p binding arrangement, and that chemical crosslinking to attach was ineffective at cross-presentation.
In Fig. 9-10, both conjugates are covalent, one being covalently bound using a site specific tag (such as Agagg1p-Agga2p) which covalently binds the antigen to the particle (See paragraph and 51 and examples), and the second being directly bound via reductive amination. The first covalent attachment induces both CD8 and CD4 T cells, while the second induces CD4 T cells.
However, the present claims are not limited to a particular type of chemical conjugation. For example, the claims would encompass direct or indirect covalent attachment of the antigen to the particle core. The site specific tag used for covalent attachment to the particle in the cited reference would be within the scope of the instant claims. Furthermore, WO2008/019366 teaches numerous methodologies by which the antigen can be covalently attached to the particle to facilitate suitable release (see paragraphs 51-59,in particular). Additionally, it is noted that WO2018234516 teaches covalent linkage to the disclosed particles, such as by using carboxylic groups and that the phagocytosable particles linked to the neoantigens can be cross-presented and induce both CD4 and CD8 T cells.
Claim 28-32, 34-35, 38-40 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2008/019366 and WO2018234516, as applied to claim 27, and further in view of 5,662,907 and WO2019185041. The teachings of WO2008/019366 and WO2018234516 are described above. WO2008/019366 also teaches an embodiment for treating cancer wherein APC that have been treated in vitro for delivery of the antigenic particles can be used to directly stimulate a patients T cells with the APCs outside the body so as to expand antigen specific T cells, and then the T cells are transplanted back into the body (See paragraph 41, in particular).
The references differ from the claimed invention in that they do not explicitly teach preparing the T cells from a subject whom has previously been administered a DC cancer vaccine or administration of both the APC and the T cells. The reference also does not explicitly teach using blood dendritic cells, a PDL1 inhibitor, multiple different tumor antigens, or treating skin cancer.
The ‘907 patent teaches peptides incorporated into dendritic cells for use as vaccines and also teaches adoptive transfer of antigen specific T cells (see columns 12-13, in particular). The ‘907 patent teaches that a combination of both vaccine administration and adoptive T cell transfer can be used to induce a strong immune response (See column 2, in particular). The ‘907 patent also teaches T cell transfer together with IL-2 to prolong survival of the T cell in vivo (i.e. simultaneously, see columns 12-13, in particular).
WO2019185041 teaches a method of treating cancer comprising administering to a subject antigen loaded dendritic cells in combination with antigen specific T cells (see pages 1-4, in particular). WO2019185041 teaches that the T cells are prepared by culturing T cells in vitro with tumor antigen loaded dendritic cells, and that both the dendritic cells and the T cells are provided from the subject to be treated (see pages 1-4). WO2019185041 also teaches that that the dendritic cells loaded with the tumor antigens can be administered prior to the T cells (See paragraph 155, in particular). WO2019185041 also teaches that repeating entire treatment method, including the T cell preparation method, after administration of the dendritic cells and T cells (See paragraph 156, in particular). WO2019185041 teaches using multiple different tumor antigens, wherein the antigens are neoantigens, including using at least three different tumor antigens, in order to improve T cell activation (i.e. different antigenic constructs comprising different peptide epitopes, see paragraph 39). WO2019185041 teaches including a checkpoint inhibitor, such as anti-PD-1 or anti-PD-L1 in the T cell dendritic cell co-cultures to enhance T cell responses, or further administering said checkpoint inhibitor (See paragraph 9-13, 98, page 54, and Fig. 5, in particular). WO2019185041 teaches treating various types of cancer including melanoma (i.e. a skin cancer, see paragraph 118, in particular). WO2019185041 teaches that dendritic cells can be provided from PMBC, i.e. from the blood (see paragraph 15, 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 administer both the dendritic cells having phagocytosed the antigen particles, and the antigen specific T cells produced by culture with said dendritic cells, in the method of treating cancer of WO2008/019366 and WO2018234516, as taught by the ‘907 patent and WO2019185041. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because the ‘907 patent teaches that doing so can induce a strong immune response. Therefore, one would combine both treatment regiments (dendritic cell and T cells taught) to provide for an increased and strong immune response to better treat cancer in the subject. Regarding the timeframes recited in claim 28, it is noted that the cited references render obvious providing T cells and dendritic cells from the patient, and it would be obvious to do so to create each respective cell type to provide a treatment, which would meet the limitation of performing steps a)-c) before administering dendritic cells. However, it would also be obvious to repeat the entire treatment regimen to enhance treatment, since WO2019185041 specifically teaches that the entire treatment method, including the T cell preparation method, can be repeated after dendritic cell vaccination, thus also meeting the limitations of performing steps a)-c) after dendritic cell vaccination. Repeating the treatment, as made obvious by the cited references, would also meet the limitations of claim 30, wherein the subject has been previously administered a dose of anti-cancer T cells, and the limitations of claim 34, wherein the subject has previously been administered a DC cancer vaccine.
Furthermore, the ordinary artisan would also be motivated to culture the cells with a PD-L1 inhibitor and to administer the cells with the checkpoint inhibitor, and to use multiple different tumor antigens, as taught by WO2019185041 to enhance T cell responses and to improve T cell activation The ordinary artisan would also be motivated to further administer IL-2, as taught by the ‘907 patent to prolong survival of the T cell in vivo. Furthermore, selecting from sources of dendritic cells, such as blood dendritic cells, optimizing the particle sizes, or types of cancer that could be treated, as taught by the cited references, 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).
Applicant argues that the claims are not obvious for the same reasons set forth above.
The claims stand rejected for the same reasons set forth above. It is additionally noted that claims 34-35 encompass expanding T cells using any phargocytosable particle and cancer protein or peptide antigen. As noted above, WO2008/019366 teaches an embodiment for treating cancer wherein APC that have been treated in vitro for delivery of the antigenic particles can be used to directly stimulate a patients T cells with the APCs outside the body so as to expand antigen specific T cells, and then the T cells are transplanted back into the body (See paragraph 41, in particular). This would be within the scope of steps ba) and bb). The only difference in the method of claim 34 is that it requires that the T cell used for culture are from a subject that has previously been treated with DC having phagocytes a particle having a core covalently attached to a neoantigen. The method of claim 34 does not require actually treating with said DC. In other words, the claims recite product by process limitations for how the T cells are provided, however, the T cells made obvious above would be from a subject treated with a DC vaccine, and would be structurally identical to the claimed T cells.
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 27-32, 34-42, 45-46, 49-51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 51-81 of copending Application No. 18/999,139 or claims 1-21 of 19/317,328 in view of WO2008/019366, 5,662,907 and WO2019185041.
The copending applications claim a method of treating cancer in a subject comprising administering to the subject anti-tumor T cells producing by contacting a phagocytosable particle with an APC, wherein the phagocytosable particle has tumor neoantigen covalently associated thereto, and contacting T cells samples from the subject with the APC in vitro to expand the T cells. The copending applications claim three or more tumor neoantigen construct comprising peptides that induce T cells, i.e. epitopes, that the antigens are expressed in cancer cells of the subject, performing a sterilizing wash, and that the particles have paramagnetic properties and a size of less than 5.6 uM, and that the particles is a polymer particle, i.e. particles with a core. Although not specifically claimed, it would be obvious to further administer a dendritic cell that has phagocytosed the particles prior to the T cells to improve the immune response in the treated subject, based on the teachings of WO2008/019366, 5,662,907 and WO2019185041, for the same reasons set forth above. Furthermore, it would be obvious to repeat the treatment based on WO2019185041 for the same reasons set forth above. Furthermore, it would be obvious to wash the APCs after contact, to use dendritic cells as the APC, and to contact with a PDL1 inhibitor, and to administer IL-2, based on the teachings of WO2008/019366, 5,662,907, WO2018234516, and WO2019185041 for the same reasons set forth above.
This is a provisional nonstatutory double patenting rejection.
Applicant argues that the claims are nonobvious for the reasons set forth above.
The claims stand rejected for the reasons set forth above.
Claims 27-32, 34-42, 45-46, 49-51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14, 18-19, 21-36 of copending Application No. 17/417,601, in view of WO2008/019366, 5,662,907, WO2018234516, and WO2019185041.
The ‘601 application claims a method of treating cancer in a subject comprising administering to the subject a phagocytosable particle comprising a core and a neoantigen construct tightly associated to the core, wherein the core has a largest dimension of 0.5uM to 2 uM, wherein the neoantigen construct comprises a peptide or protein expressed by the cancer cell in the subject, and further comprising producing anti-tumor T cells by contacting a phagocytosable particle with an APC from the subject, wherein the phagocytosable particle has tumor neoantigen construct tightly associated thereto, contacting T cells samples from the subject with the APC in vitro and administering the T cells to the subject. The copending application claims using two or more tumor neoantigen construct comprising peptides that induce T cells, that the particles have paramagnetic properties that the core comprises polystyrene. The ‘601 application claims treating breast cancer or colon cancer. The ‘601 application does not explicitly claim that the first step comprises administering a dendritic cell loaded with said particle. However, it would be obvious to do so based on the teachings of WO2008/019366, which teaches the use of particles administered directly to the subject as a vaccine, or alternatively, that they can be administered in the form of a dendritic cell that has been loaded with the particles in vitro prior to administration. Selecting from the methods of administering phagocytosable particles for inducing T cell responses 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). . Furthermore, it would be obvious to repeat the administration regimen, as taught by WO2019185041 and the ‘907 patent, to increase the immune responses, and doing so would result in administration of the dendritic cells and anti-cancer T cells to a subject who has previously been administered a dose of anti-cancer T cells and dendritic cells. Furthermore, it would be obvious to wash the APCs after contact, to perform a sterilizing wash, to use dendritic cells as the APC, and to contact with a PDL1 inhibitor, and to further administer IL-2, based on the teachings of WO2008/019366, 5,662,907, WO2018234516, and WO2019185041 for the same reasons set forth above.
This is a provisional nonstatutory double patenting rejection.
Applicant argues that the instant claims require a core having a largest dimension of 1 uM, which is different than the claims of the ‘601 application.
The ‘601 application a particle size range of 0.5-2, and selecting from within the specifically disclosed range, such as 0.5um or 1 uM, would be obvious and well within the purview of the ordinary artisan.
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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