DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 7, 10, 20-22 have been canceled. Claims 1, 8, 9, 16-19 and 23 have been amended. Claims 1-6, 8, 9, 11-19 and 23 are pending. Claims 5 and 6 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
It is noted that claim 23 was inadvertently listed as withdrawn from consideration, and rejected in the prior Office action. Claim 23 was rejected and is now under consideration.
Claims 1-4, 8, 9, 11-19 and 23 are under consideration.
The rejection of claims 8 and 18 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is withdrawn in light of applicant’s amendments.
The rejection of claims 1, 2, 7, 8, and 9 under pre-AIA 35 U.S.C. 102(a) as being anticipated by Krishnadas et al (Pediatrics, January 1, 2013, Vol. 131, No. 1, e336-e341, reference of the IDS filed 7/12/2021) is withdrawn in light of applicant’s amendment of claim 1 to specify that the cellular therapy is administration of a T-cell, stem cell, gene or pharmacologically modified immune cell or gene or pharmacologically modified cancer cells. The dendritic cells of Krishnadas et al are peptide-pulsed.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 2, 8, 10 and 23 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Andrieu et al (US 2005/0266012) in view of Dhodapkar et al (‘Dendritic Cell Vaccines’ In: Handbook of Cancer Vaccines, 2004, pp. 317-329, Morse, Clay and Lyerly, Eds, Humana Press, NJ) and Rees (WO2000/0407).
Andrieu et al teach a method for inducing and enhancing in vivo antigen-specific cytolysis by cytotoxic T lymphocytes comprising the administration or co-administration of a demethylating agent and an antigen to a subject (paragraph [0071]). Andrieu et al teach that the method allows for the treatment of tumors (paragraph [0075]) which meets the limitation of claim 23. Andrieu et al teach that the enhancement occurs when anti-CTL in an immunized subject are primed by a therapeutic vaccine, but not functionally activated (paragraph [0077]). Andrieu et al teach that the demethylating agent may be administered after, before or concomitant with the demethylating agent (paragraph 0078]) which meets the limitation of claim 10. Andrieu et al teach that demethylating agents can be demethylating agent can be either a cytidine analog or a non-competitive inhibitor of methyltransferase (paragraph [0023]). Andrieu et al teach that cytidine analogs with demethylating activity include, but are not limited to, 5-Azacytidine, 5,6-dihydro-5-azacytidine, 1-.beta.-D-arabinofuranosyl- -5-azacytidine, 5-Aza-2'-deoxycytidine (decitabine) or 1-(beta-D-ribofuranosyl)-1,2dihydropropyrimindin-2-one (zebularine), and that non-competitive inhibitors of methyltransferase include 4-aminobenzoic acid derivatives such as procanaimide and procaine (paragraphs [0024]-[0025]) which meets the limitations of DNA hypomethylating agent in claims 1 and 2. . Andrieu et al teach that the antigen includes polypeptides or peptides (paragraph [0026]) and can be a tumor antigen (paragraph [0030]). Andrieu et al define tumor antigen as a peptide associated with the cell surface of a specific cancer or tumor, and which is capable of inducing an immune response when expressed in the context of MHC (paragraph [0039]). Andrieu et al teach that tumor specific antigens include MAGE A, BAGE, GAGE and Her (paragraph [0040]). Andrieu et al teach that the azacytidine has been administered to treat hematopoietic and solid tumors as a single agent, but the results were disappointing (paragraph [006]). Andrieu et al do not teach that the tumor antigen peptide is administered to a patient with a tumor or cancer by means of a gene modified dendritic cell such that the dendritic cell presents the peptide encoded by the exogenous gene in the context of MHC.
Dhodapkar teaches that the fundamental premise behind clinical approaches for dendritic cell immunization in cancer is that the limiting defect in natural tumor anti-tumor immunity is in the level of antigen presentation and that evidence points to defects in activation or maturation in dendritic cells in the tumor bed of patients (page 318, lines 3-6 under the heading “Rationale for Targeting Dendritic Cells in Cancer Immunotherapy”). Dhodapkar teaches that dendritic cell maturation is critical for the initiation of effector T cell responses, and such defects in maturation impair activation of antitumor immunity in vivo (page 318, lines 6-8 under the heading “Rationale for Targeting Dendritic Cells….”). Dhodapkar teaches that targeting tumor antigens to dendritic cells ex vivo allows for an opportunity to bypass the defects in antigen presentation. And takes advantage of the specialized features of dendritic cells as potent antigen-presenting cells page 318, lines 9-12 under the heading “Rationale for Targeting Dendritic Cells….”). Dhodapkar teaches that mature dendritic cells induce functionally superior CD8T cells and polarize CD4 T cells toward IFNγ production (page 324, lines 7-9 under the heading “The Optimal DC Maturation State and Stimulus”).
Rees teaches that dendritic cells transfected with a viral vector comprising a gene encoding peptides or proteins of a tumor antigen allows for the delivery of the gene into the dendritic cells and results in the expression of the peptides or proteins and the presentation of appropriate peptide sequences to T-lymphocytes (page 9, lines . Rees teaches that this is an alternate approach to dendrtic cells which are mixed or pulsed with proteins or peptides from the tumour antigen
It would have been prima facie obvious at the time the invention was made to provide a recombinant dendritic cell vaccine comprising a gene encoding tumor antigens in place of the tumor peptide vaccine in the method of Andrieu et al which fulfills the limitations for gene-modified immune cells as immunomodulatory agent. One of skill in the art would have been motivated to do this based on the teachings of Dhodapkar on the improvements in using a dendritic cell vaccine rather than a peptide vaccine to insure that the peptides are presented in a mature dendritic cell which administered to the patient. One of skill in the art would expect that the administered demethylating agent would enhance the effectiveness of the CTL generated from the administered dendritic cell made ex vivo because that is what is taught by Andrieu et al. It would also have been obvious to treat solid tumors because Andrieu et al teach that the demethylating agents were administered as single agents to treat these cancers, and because Andrieu et al teach that the tumor antigens can be MAGE, BAGE, GAGE and Her which are well known tumor antigens of solid cancers, thus fulfilling the limitations of claim 8. IT would also be obvious to provide the recombinant dendritic cell comprising the gene expressing the tumor antigens as a renewable source of cells wherein the expression of the tumor antigens in the context of MHC would not be subject to batch-to-batch variation and useful therefore for multiple doses of tumor antigen to a patient in need thereof.
Claims 1-4, 8, 18, and 23 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Andrieu et a, Dhodapkar et al and Rees as applied to claims 1, 2, 7, 8, 10 and 23 above, and further in view of Met et al (Cancer Letters, 2006, Vol. 231, pp. 247-256).
Claim 3 embodies the method of claim 2 further comprising the administration of an immunomodulating antibody. Claim 4 specifies that the immunomodulatory antibody is selected from a group including anti-CTLA-4.
Claim 18 embodies the method of claim 3 wherein the cancer is caused by a solid or hematopoietic tumor.
The combined teachings of Andrieu et al, Dhodapkar et al and Rees render obvious the limitations of claims 1, 2, 8, and 23 for the reasons set forth above, wherein the immunomodulatory agent is a dendritic cell. Neither of Andrieu et al, Dhodapkar et al nor Rees teach or specifically suggest the inclusion of an immunomodulatory antibody with the recombinant dendritic cell comprising the gene expressing the tumor antigens.
Met et al teach the combination of a dendritic cell pulsed with a target peptide in combination with an anti-CTLA-4 antibody led to tumor rejection or retarded tumor growth in 60% of mice transplanted with E.G7-OVA lymphoma cells (abstract). Met et al teach that the antibody mediated blocking of CTLA-4 combined with a dendritic cell based minimal peptide vaccination provides an effective tool for the treatment of growing tumors by enhancing level of T cell activation and memory (page 155, first column, lines 1-5).
It would have been prima facie obvious at the time the invention was made to include an anti-CTLA-4 antibody with the administered recombinant dendritic cell vaccine. One of skill in the art would have been motivated to do so by the teachings of Met et al on the improvement in tumor rejection and tumor growth when anti-CTLA-4 antibody was administered with a dendritic cell vaccine.
Claims 1-4, 8, 9, 18, 19 and 23 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Andrieu et al, Dhodapkar et al, Rees and Met et al as applied to claims 1-4, 7, 8, 10, 18, 20 and 23 above, and further in view of Graziani et al (Pharmacological Research, 2012, Vol. 65, pp. 9-22).
Claims 9 and 19 require that the tumor of claims 8 and 18, respectively, is resistant or refractory.
The combined teachings of Andrieu et al, Dhodapkar et al, Rees and Met et al render obvious claims 1-4, 8, 18, and 23 for the reasons set forth above. None of Andrieu et al, Dhodapkar et al, Rees or Met et al teach that the tumor of the patient being treated with demethylating agent, the dendritic cell vaccine and the anti-CTLA-4 antibody is resistant or refractory.
Graziani et al teach ipilimumab which is an anti-CTLA-4 antibody. Graziani et al suggest the use of ipilimumab in the treatment of melanoma or other refractory or advanced solid tumors alone or in combination with additional immunostimulating agents or molecularly targeted therapies (abstract, last sentence).
It would have been prima facie obvious at the time that the invention was made to treat the solid tumors which are resistant or refractory to prior therapy with the demethylating agent, dendritic cell vaccine and ipilimumab. One of skill in the art would have been motivated to do so by the teachings of Graziani et al that ipilimumab can be combined with immuostimulating agents or molecularly targeted agents for the treatment of melanoma or other refractory or advanced solid tumors.
Claims 1-4, 8, 9, 11-14 and 23 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Andrieu et al, Dhodapkar et al and Rees as applied to claims 1, 2, 7, 8, 10 and 23 above, and further in view of Mao et al (Clinical Cancer Research, e-pub December 8, 2012, Vol. 19, pp. 657-667).
Claim 9 requires that the tumor treated in claim 8 is resistant or refractory to at least one anti-tumor therapy.
Claim 11 specifies that the method of claim 1 further embodies the administration of an effective amount of at least one targeted therapy agent to the patient.
Claim 12 requires that the targeted therapy agent is, in part, a MAP kinase pathway inhibitor
Claim 13 specifies that the MAP kinase inhibitor is a BRAF inhibitor.
Claim 14 requires that the BRAF inhibitor is PLX4720.
Mao et al teach that the demethylating agents sensitize BRAF-mutant colon cancer cells to BRAF inhibition (title), and that the BRAF inhibitor, PLX4720, synergizes with the DNA methyltransferase inhibitor, 5-azacytidine, to produce tumor growth inhibition both in vitro and in vivo (page 662, first column, lines 3-13). Mao et al teach that BRAF-resistant colon cancer is a poor-prognosis subtype of colorectal cancer (page 658, last sentence in the boxed paragraph headed “Translational Relevance”)
It would have been prima facie obvious at the time the inventio was made to add the BRAF inhibitor, PLX4720, to 5-azacytidine, to the recombinant dendritic cell vaccine for the treatment of BRAF-resistant colon cancer. One of skill in the art would have been motivated to dos o by the teachings of Mao et al on the synergy between PLX4720, and 5-azacytidine to inhibit colon cancer growth. One of skill in the art would understand that BRAF-resistant colon cancer, having a poor prognosis, would require synergistic agents which inhibit the colon cancer growth, and multiple types of therapy, including the immunotherapy with dendritic cell vaccines.
Claims 1, 2, 8, 10, 11-13 and 23 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Andrieu et al, Dhodapkar et al and Rees as applied to claims 1, 2, 7, 8, 10 and 23 above, and further in view of Jackson et al (International Journal of Cancer, 2008, Vol. 123, pp. 623-632).
Claim 13 requires, in part, a MEK inhibitor.
The combine teachings of Andrieu et al, Dhodapkar et al and Rees render obvious the limitations of claims 1, 2, 8, 10 and 23, above. Neither Andrieu et al, Dhodapkar et al nor Rees each the administration of demethylation agent, a recombinant dendritic cell vaccine and a MEK inhibitor.
Jackson et al teach that dysfunctional dendritic cells are common in cancer patients (line 1, abstract). Jackson et al teach a melanoma-lysate loaded dendritic cell as a model of adoptive immunotherapy and also necrotic cells common in many tumors (abstract, lines 6-8, page 623, second column, lines 3-5 of the bottom paragraph). Jackson et al teach that in contrast to dendritic cells loaded with HUVEC lysate, the dendritic cells loaded with melanoma lysate were less able to generate Th1 response from naïve T cels and that the p44/42 MAPK signaling pathway was hyperactive by melanoma cell lysate (abstract, lines 18-21). Jackson et al teach that blockade of MEK1/2 the upstream kinase for p44/42, prevented p44/42 activation, restored Il12p70 and permitted effective generation of Th1 responses (abstract, lines 22-24).
It would have been prima facie obvious at the time that the claimed invention was made to add U0126 to the demethylating agent and the recombinant dendritic cell vaccine for the treatment of solid tumors. One of skill in the art would be motivated to do so because although the dendritic vaccine rendered obvious by Andrieu et al, Dhodapkar et al is pulsed with tumor antigens rather than tumor cell lysate, the “melanoma lysate” would be represented by the necrotic tumor cells within the tumor microenvironment, as taught by Jackson et al. One of skill in the would be motivated to neutralize or modulate the negative effect of the necrotic cells in the tumor interior by administration of the U0126 MEK1/2 inhibitor to inhibit the p44/42 signaling axis responsible for dendritic cell disfunction.
Claims 1, 2, 8, 11, 13, 15 and 23 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Andrieu et al, Dhodapkar et al, Rees and Jackson et al as applied to claims 1, 2, 7, 8, 10, 13 and 23 above, and further in view of Holt et al (British Journal of Cancer, 2012, Vol. 106, pp. 858-866).
The combined teachings of Andrieu et al, Dhodapkar et al, Rees and Jackson et al render obvious claims 1, 2, 8, 13 and 23 for the reasons set forth above with regard to the addition of the MEK1/2 inhibitor of U0126. The combination does not specifically address the use of selmetinib as a MEK1/2 inhibitor
Holt et al teach the combination of the MEK1/2 inhibitor, selumetinib with temozolomide, docetaxel or barasetinib was more beneficial than either of the agents as monotherapy in mice carrying human tumor xenografts (abstract and page 859 under the heading of “In vivo studies”).
It would have been prima facie obvious to substitute selumetinib for U0126 as the MEK1/2 inhibitor in the method rendered obvious by the combined teachings of Andrieu et al, Dhodapkar et al, Rees and Jackson et al. One of skill in the art would have been motivated to do so because Holt et al teach selumetinib to be active in vivo for the inhibition of MEK1/2 and to provide enhancement of anti-tumor efficacy in combination with various anti-tumor agents.
Claims 1, 2, 8, 11, 12, 16, 17, and 23 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Andrieu et al, Dhodapkar et al and Rees as applied to claims 1, 2, 7, 8, 10 and 23 above, and further in view of Emami et al (PNAS, 2004, Vol. 101, pp. 12682-12687).
Claim 16 requires, in part, that the WNT pathway inhibitor is a beta catenin inhibitor. Claim 17 specifies that the β-catenin inhibitor is ICG-001.
Emami et al teach that ICG-001 is a small molecule that downregulates β-catenin/T cell factor signaling by specifically binding to cyclic AMP response element binding protein (abstract, lines 6-9). Emami et al teach that ICG-001 selectively induces apoptosis in transformed colon cancer cells but not in normal colon cells, reduces in vitro and in vivo growth of colon cancer (abstract, lines 9-12).
It would have been prima facie obvious at the time the invention was made to combine the method of treating cancer in a patient in need thereof rendered obvious by the combined teachings of Andrieu et al, Dhodapkar et al and Rees with the β-catenin inhibitor ICG-001.
The instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose in order to produce a third composition that is to be used for the very same purpose since the idea of combining them flows logically from both compounds having been taught individually in the prior art. Applying the same logic to the instant method claim, given the teaching of the prior art of combining demethylating agents and dendritic cell vaccine for the treatment of cancer and the teachings of the prior art of usingICG-001 for the treatment of colon cancer, it would have been obvious to use demethylating agents, dendritic cell peptide vaccine and ICG-001 for the treatment of cancer because the idea of doing so would have logically followed from their having been individually taught in the prior art to be useful as agents for the treatment of cancer.
Applicant argues that the claims are now limited to the administration of specific cells which exclude dendritic cells. This has been considered but not found persuasive because gene-modified immune cells include gene-modified dendritic cells.
Claims 1-4, 8, 9, 11-19 and 23 are rejected.
All other rejections as set forth in the prior Office action are withdrawn in light of applicant’s amendments.
Conclusion
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 KAREN A CANELLA whose telephone number is (571)272-0828. The examiner can normally be reached M-F 10-6:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/ Primary Examiner, Art Unit 1643