DETAILED ACTION
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 .
Applicant’s amendment and arguments filed on 04-23-2026 has been entered. Claim 1 has been amended. Claim 22 has been added. Claims 1-22 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-16, 21) in the reply filed on 08-05-2024 is acknowledged.
Claims 17-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08-05-2024.
Claims 1-16, 21-22 are under consideration.
Priority
This application is a CON of PCT/NL2020/050042 filed on 01/28/2020 , which claims priority from foreign applications No Netherlands 2022464 filed on 01/28/2019 and Netherlands 202416 filed on 12/19/2019.
Receipt is acknowledged of certified copies of applications No Netherlands 2022464 filed on 01/28/2019 required by 37 CFR 1.55.
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in Netherlands on 12/19/2019. It is noted, however, that applicant has not filed a certified copy of the Netherlands 202416 application as required by 37 CFR 1.55.
Maintained in modified form -Double Patenting-Necessitated by amendments
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 1, 7-13, 15-16, and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9-14, 16-17 and 21 of copending Application No. 17443656 (reference application) in view of Lievense (Lievense, S. (2017, March 31), Dissertation , Macrophages in Mesothelioma : Improving immunotherapy in pulmonary oncology. Retrieved from http://hdl.handle.net/1765/98474). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Pending claims 1 is directed to a method for the treatment of pancreatic cancer, comprising administering to a human patient in need thereof a CD40 agonist in combination with autologous to the human patient dendritic cells loaded with an allogeneic to the human patient mesothelioma lysate, wherein the mesothelioma lysate is obtained by a method comprising: (i) providing human mesothelioma tumour cells from at least two different mesothelioma tumour cell lines; (ii) inducing necrosis in the tumour cells; and (iii) lysing the necrotic tumour cells to obtain a lysate. wherein the administering of the CD40 agonist is intradermal or intravenous; and wherein the administering of the dendritic cells is intradermal or intravenous, wherein the treatment results in delayed tumour growth in the treated patient relative to an untreated control.
Co-pending claim 1 is directed to a method for the treatment of pancreatic cancer, comprising administering to a human patients- in need thereof of autologous to the human patient dendritic cells loaded with an allogeneic to the human patient mesothelioma lysate, wherein the mesothelioma lysate is obtained by a method comprising: (i) providing human mesothelioma cells from at least two different mesothelioma tumour cell lines; (ii) inducing necrosis in said tumour cells; and (iii) lysing the necrotic tumour cells to obtain a lysate wherein the administering is intradermal or intravenous, wherein the treatment results in delayed tumour growth in the treated patient relative to an untreated control.
Although the claims of the reference application do not recite CD40 agonist in combination with dendritic cells loaded with a lysate. However, Lievense (Lievense, S. (2017, March 31), Dissertation , Macrophages in Mesothelioma : Improving immunotherapy in pulmonary oncology. Retrieved from http://hdl.handle.net/1765/98474) teaches that combination therapy with a CD40-agonist and dendritic cell immunotherapy has additive effects in a murine mesothelioma model (Page 125, Title of chapter 6). Combination therapy of DC immunotherapy and a CD40-agonistic antibody induces additive immune activation in the peripheral blood of mesothelioma-bearing mice compared to the monotherapies. (Page 126, Abstract of Chapter 6). Lievense also teaches preparation of dendritic cells loaded with a tumor lysate (Page 128, 2nd para.). Thus, a person of ordinary skill in the art would be motivated to administer the CD40 agonist in combination with dendritic cells loaded with a lysate via intradermal route.
Pending claim 7 is directed to the method according to claim 1, wherein the induction of necrosis of the mesothelioma tumour cells is achieved by subjecting the cells to freeze-thawing cycles.
Co-Pending claims 9 is directed to the method according to claim 1, wherein induction of necrosis of the mesothelioma tumour cells is achieved by subjecting the cells to freeze-thawing cycles.
Pending claim 8 is directed to the method according to claim 1, further comprising (iv) subjecting the lysate obtained to at least 50 Gy irradiation.
Pending claim 9 is directed to the method according to claim 1, further comprising (iv) subjecting the lysate obtained to at least 100 Gy irradiation.
Co-Pending claim 10 is directed to The method according to claim 1, wherein after inducing necrosis and lysing of the tumour cells, the lysate obtained is subjected to at least 50 Gy irradiation.
Pending claim 10 is directed to the method according to claim 1, wherein the mesothelioma tumour cells provided comprise tumour cells from at least three mesothelioma tumour cell lines.
Co-Pending claim 11 is directed to the method according to claim 1, wherein the mesothelioma tumour cells provided comprise tumour cells from at least three mesothelioma tumour cell lines.
Pending claim 11 is directed to the method according to claim 1, wherein the mesothelioma tumour cells are chosen from two or more of the following cell lines: Thorr 01 (deposit No. DSM ACC3192), Thorr 02 (deposit No. DSM ACC3193), Thorr 03 (deposit No. DSM ACC3191), Thorr 05 (deposit No. DSM ACC3194), Thorr 06 (deposit No. DSM ACC3195).
Co-Pending claim 12 is directed to the method according to claim 1, wherein the mesothelioma tumour cells are chosen from two or more of the following cell lines: Thorr 01 (deposit No. DSM ACC3192), Thorr 02 (deposit No. DSM ACC3193), Thorr 03 (deposit No. DSM ACC3191), Thorr 05 (deposit No. DSM ACC3194), Thorr 06 (deposit No. DSM ACC3195).
Pending claim 12 is directed to the method according to claim 1, wherein the lysate comprises at least three mesothelioma cancer cell associated antigens.
Co-Pending claim 13 is directed to the method according to claim 1, wherein the lysate comprises at least three mesothelioma cancer cell associated antigens.
Pending claim 13 is directed to the method according to claim 12, wherein the mesothelioma cancer cell associated antigens are selected from the group consisting of RAGEl/MOK, Mesothelin, EphA2, Survivin, WTl, MUCl, RAB38/NY-MEL-l, BmG4, MAGE Al2, HER-2/Neu, Glypican, and LMP2.
Co-Pending claim 14 is directed to the method according to claim 13, wherein the mesothelioma cancer cell associated antigens are selected from the group consisting of: RAGEI/MOK, Mesothelin, EphA2, Survivin, WTI, MUCI, RAB38/NY-MEL-l, BING4, MAGE Al2, HER-2/Neu, Glypican, and LMP2.
Pending claim 15 is directed to the method according to claim 1, wherein the dendritic cells are loaded with between 1 tumour cell equivalents per 100 dendritic cells to 10 tumour cell equivalents per 1 dendritic cell.
Co-Pending claim 16 is directed to the method according to claim 1, wherein the dendritic cells are loaded with between 1 tumour cell equivalents per 100 dendritic cells to 10 tumour cell equivalents per 1 dendritic cell.
Pending claim 16 is directed to the method according to claim 1, wherein 1*106 to 1*109. loaded dendritic cells are administered per dose.
Co-Pending claim 17 is directed to the method according to claim 1, wherein the patient is administered 1*106 to 1*109 loaded dendritic cells per dose.
Pending claim 22 is directed to the method according to claim 1, wherein the delayed tumour growth is defined as a reduced tumour size (mm3) in the treated patient compared to the tumour size of an
untreated control at the same timepoint.
Co-Pending claim 21 is directed to the method according to claim 1, wherein the delayed tumour growth is defined as a reduced tumour size (mm3) in the treated patient compared to the tumour size of an untreated control at the same timepoint.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed on 04-23-2026 have been fully considered but they are not persuasive.
Applicant requests that the rejection be held in abeyance until indication by the Office of allowable claims in one of the co-pending applications (Remarks, page 8).
Response to Arguments: While Applicant has requested that the rejection be held in abeyance until allowable subject matter can be identified, a request of abeyance does not overcome or address an issue of obvious double patenting between claims in the instant case and US patent application. Thus, the rejection is maintained.
Maintained in modified form and New-Claim Rejections - 35 USC § 103- Necessitated by amendments
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 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 1-5, 7-11, 14-16 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Rong et al (Clin Exp Med (2012) 12:173–180, DOI 10.1007/s10238-011-0159-0) in view of Hegmans et al (Pub. No.: US 2015/0352200 A1, Pub. Date: Dec. 10, 2015) (Applicant’s own work) and Lievense (Lievense, S. (2017, March 31), Dissertation , Macrophages in Mesothelioma : Improving immunotherapy in pulmonary oncology. Retrieved from http://hdl.handle.net/1765/98474).
Claim interpretation: The specification of the claimed invention teaches that with "unresected" in this context is meant that the tumor has not been either partly or completely removed by surgery. Such tumor can either be the primary or a metastatic secondary pancreatic tumor (Page 10, 2nd para, lines 4-6). Thus, unresected pancreatic cancer is interpreted as intact tumor without surgery.
Claim interpretation:
According to claim 22, the delayed tumor growth is defined as a reduced tumor size. Thus, the delayed tumor growth is interpreted as reduced tumor size or tumor regression.
Regarding to claim 1, Rong et al teach “A phase I pilot trial of MUC1-peptide-pulsed dendritic cells in the treatment of advanced pancreatic cancer” (title) and assess the toxicity and immunological response induced by the intradermal (i.d.) administration of MUC1-peptide-pulsed dendritic cells (DCs) in advanced pancreatic cancer patients. Patients with recurrent lesions or metastasis after surgery, and immunohistochemistry positive for MUC1 were treated in cohorts that received 3–6 x 106 DCs i.d. for three or four vaccines. Each vaccine was composed of autologous DCs pulsed with MUC1-peptide (Abstract). Immature DCs are able to take up antigens, and they can activate T cells after maturation and migration into lymphoid organs . DCs pulsed with immunogenic peptides; tumor cell lysates and gene-transfected DCs can induce primary T-cell responses (Page 174, left column, 1st para.).
Rong et al do not teach the lysate is obtained by using at least two different mesothelioma tumor cell lines. However, Hegmans et al cures the deficiency.
Hegmans et al teach “a method for the preparation of an immunogenic lysate from mesothelioma tumor cells, …… to dendritic cells loaded with the lysate” (Abstract), and “method for the preparation of an immunogenic lysate comprising the steps of: i) providing allogeneic mesothelioma tumor cells from at least two different cell lines; ii) inducing necrosis or apoptosis in the tumor cells; iii) lysing the necrotic or apoptotic tumor cells, such that a lysate is obtained” ([0012], page 2). Hegmans et al stated that “Preferably, the dendritic cells cultured are autologous dendritic cells. The advantage of using autologous dendritic cells is that immune reactions of the patients against these dendritic cells is avoided and that the immunological reaction is triggered against the antigens from the mesothelioma tumor cells, which were present in the lysate” ([0061], Page 5).
It is noted that Rong et al teach treating pancreatic cancer with DCs pulsed with tumor cell lysates can induce primary T-cell responses (Page 174, left column, 1st para) and stated that “the advantage of tumor lysate-pulsed DCs is that may present more epitopes and may elicit a stronger immune response” (Page 177, right column, 2nd para.), and Hegmans et al teach a method for the preparation of an immunogenic lysate from mesothelioma tumor cells to prepare dendritic cells loaded with the lysate (Abstract); therefore, a person of ordinary skill in the art would be motivated to combine the teachings of prior art to prepare dendritic cells loaded with the mesothelioma lysate to treat pancreatic cancer.
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of treating pancreatic cancer as taught by Rong et al to prepare autologous dendritic cells loaded with a lysate by using an immunogenic lysate with allogeneic mesothelioma tumor cells from at least two different cell lines, inducing necrosis or apoptosis in the tumor cells and lysing the necrotic or apoptotic tumor cells as taught by Hegmans et al with a reasonable expectation of success. 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 do so because Hegmans et al stated that “Allogeneic DC-based immunotherapy showed an increased survival rate of the treated mice compared to untreated mice, as is shown in Figure I. Besides an increase in the amount of CD8 positive cytotoxic T cells, the percentage of IFN-gamma and granzyme B production per cell was higher in allogeneic DC treated mice compared to non-treated mice. The killing capacity of splenocytes from allogeneic treated mice were highly increased when cells were co-cultured with chromium labelled AC29 tumor cells” ([0103], page 8). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Hegmans et al were successful in using allogeneic tumor lysate to increase survival rate of the treated mice compared to untreated mice, provide detailed instructions for using pulsed dendritic cells in immunotherapy for treating cancers with the use of immunogenic peptide or lysate.
The above references do not specifically teach a CD40 agonist in combination with dendritic cells loaded with a lysate. However, Lievense cures the deficiency.
Lievense teaches that combination therapy with a CD40-agonist and dendritic cell immunotherapy has additive effects in a murine mesothelioma model (Page 125, Title of chapter 6). Combination therapy of DC immunotherapy and a CD40-agonistic antibody induces additive immune activation in the peripheral blood of mesothelioma-bearing mice compared to the monotherapies. (Page 126, Abstract of Chapter 6). Lievense also teaches preparation of dendritic cells loaded with a tumor lysate (Page 128, 2nd para.). Since Lievense teaches CD40-agonistic antibody injected similar to the DCs (Page 129, 1st para.) and the Rong et al teach the intradermal (i.d.) administration of MUC1-peptide-pulsed dendritic cells (DCs) in advanced pancreatic cancer patients (Abstract), a person of ordinary skill in the art would be motivated to administer the CD40 agonist via intradermal route.
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Rong et al and Hegmans et al by using CD40 agonistic antibody to improve potential of immunotherapy in mesothelioma as taught by Lievense, as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Lievense teaches that ombination therapy of DC immunotherapy and a CD40-agonistic antibody induces additive immune activation in the peripheral blood of mesothelioma-bearing mice compared to the monotherapies. (Page 126, Abstract of Chapter 6). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Lievense provides instruction for using CD40 agonistic antibody with dendritic cell loaded with AB1 tumor cell lysate immunotherapy.
Regarding to claim 22 and claim 1- the claimed: wherein the treatment results in delayed tumor growth in the treated patient relative to an untreated control: Rong et al stated that “none of the patients experienced local tumor growth at the site of the vaccine injection.” (Page 176, right column, 2nd para.). Rong et al stated that “we were able to observe IFN-γ and granzyme B production by PBMCs in response to MUC1-peptide in some patients following vaccination” (page 179, right column, 2nd para) and “T-cell response to tumor antigen by way of IFN-γ release appears to be associated with conditions that favor tumor regression” (page 178, right column, 2nd para).
Additionally, Lievense teaches that “……in pancreatic cancer, a tumor type with a microenvironment dominated by macrophages as mesothelioma, tumor regression after treatment with a CD40 agonist required macrophages….” (Pages 222, last para). Lievense teaches that combination therapy with a CD40-agonist and dendritic cell immunotherapy has additive effects in a murine mesothelioma model (Page 125, Title of chapter 6). Combination therapy of DC immunotherapy and a CD40-agonistic antibody induces additive immune activation in the peripheral blood of mesothelioma-bearing mice compared to the monotherapies. (Page 126, Abstract of Chapter 6). Since Lievense teaches that “in pancreatic cancer, a tumor type with a microenvironment dominated by macrophages as mesothelioma (Pages 222, last para.), and Hegmans et al teach that dendritic cell-based immunotherapy had a beneficial effect on survival and reducing tumor growth in a mouse model for malignant mesothelioma ([0004], page 1), a person of ordinary skill in the art would be motivated to use combination therapy with a CD40-agonist and dendritic cell immunotherapy for treating pancreatic cancer as mesothelioma. A person of ordinary skill in the art would expect tumor regression and/or reducing tumor growth as suggested by the cited references as described above
According to the specification of the claimed invention, delayed tumor growth was observed in mice treated with CD40 and DC vaccination (see instant disclosure page 8, example 8). Since the method steps and structural limitations of CD40 agonist in combination with patient dendritic cells have been rendered obvious, a person of ordinary skill in the art would expect the same results as the claimed invention.
Regarding to claim 2, Hegmans et al teach that the mice used in the study were injected with autologous AB1 mesothelioma cell lines, such that mesothelioma would develop from these cells ([0097], page 8). Administration of loaded dendritic cells to mice suffering from mesothelioma: Dendritic cells loaded with AC29 cell lysate were injected intraperitoneally in either BALB/c or CBA/J mice 14 and 7 days prior to a lethal tumor injection (protective setting) or 1 and 8 days after tumor injection (therapeutic setting). At least 4 mice per group/condition were used. The occurrence of tumor growth, body weight, physical well-being, and survival was measured for two months ([0102], page 8). Thus, it would have been prima facie obvious for a person of ordinary skill in the art to administer the loaded dendritic cells to intact tumor without surgery for treatment of the cancer, with reasonable expectation of success.
Regarding to claim 3-4, Rong et al teach “A phase I pilot trial of MUC1-peptide-pulsed dendritic cells in the treatment of advanced pancreatic cancer” (title) and assessing the toxicity and immunological response induced by the intradermal (i.d.) administration of MUC1-peptide-pulsed dendritic cells (DCs) in advanced pancreatic cancer patients (Abstract).
Regarding to claim 5, Lievense teaches that following injection, DCs were allowed to migrate to the lymph nodes and 48 hours later, the CD40-agonistic antibody (FGK4.5) was administered i.p. (5 mg/kg) or an isotype antibody for the control group (Page 130, 2nd Para.).
Regarding to claim 7, Hegmans et al teach necrosis of the allogeneic mesothelioma tumor cells, can be achieved by methods commonly known in the prior art. However, subjecting the cells to freeze thawing cycles is particularly preferred. Preferably, the cells are made necrotic and lysed by freezing at temperatures below-70 degrees Celsius and thawing at temperatures of more than 30 degrees Celsius ([0046], page 4).
Regarding to claim 8-9, Hegmans et al teach preferably the tumor cells are treated with at least 50 Gy irradiation, preferably at least 100 Gy irradiation. This way it is avoided that any of the tumor cells remains viable ([0047], page 4).
Regarding to claim 10, Hegmans et al teach in order to obtain a good immunogenic response it is preferred to use a mixture of allogeneic mesothelioma tumor cells, ……, preferably at least three mesothelioma tumor cell-lines…. ([0030], page 3).
Regarding to claim 11, Hegmans et al teach presently six human mesothelioma cell lines have been developed that provide particularly good results. These cell lines have been deposited at “Deutsche Sammlung von Mikro-organismen and Zellkulturen' in Germany, hereinafter DSMZ. The cell lines were given the following codes and accession numbers: Thorr 01 (deposit No. DSMACC3191), Thorr O2 (deposit No. DSMACC3192), Thorr 03 (deposit No. DSM ACC3193), Thorr 04 (deposit No. DSM ACC3194), Thorr (05 (deposit No. DSMACC3195), Thorr 06 (deposit No. DSMACC3196) ([0043], page 4).
Regarding to claim 14, Hegmans et al teach that preferably, the dendritic cells cultured are autologous dendritic cells. The advantage of using autologous dendritic cells is that immune reactions of the patients against these dendritic cells is avoided and that the immunological reaction is triggered against the antigens from the mesothelioma tumor cells, which were present in the lysate ([0061], page 5).
Regarding to claim 15, Hegmans et al teach that preferably, the dendritic cells are loaded with at least 0.1 tumor cell equivalents per dendritic cell (1 tumor cell per 10 dendritic cell), ……most preferably at least one tumor cell equivalent per dendritic cell ([0064], page 5).
Regarding to claim 16, Hegmans et al teach that preferably, a dosage of the composition administered to a patient comprises 1*103 to 1*1010 loaded dendritic cells …… ([0068], page 5).
Claims 6, 21 are rejected under 35 U.S.C. 103 as being unpatentable over Rong et al (Clin Exp Med (2012) 12:173–180, DOI 10.1007/s10238-011-0159-0) in view of Hegmans et al (Pub. No.: US 2015/0352200 A1, Pub. Date: Dec. 10, 2015) and Lievense (Lievense, S. (2017, March 31), Dissertation , Macrophages in Mesothelioma : Improving immunotherapy in pulmonary oncology. Retrieved from http://hdl.handle.net/1765/98474) as applied to claims 1-5, 7-11, 14-16, 22 above, and further in view of Das et al (Curr. Treat. Options in Oncol. (2018) 19: 48, DOI 10.1007/s11864-018-0566-5, Published online: 20 August 2018).
The teachings of Rong et al, Hegmans et al, Lievense are as described above and are incorporated herein in their entirety.
The above references do not specifically teach CD40 agonist is chosen from the group consisting of CP-870, CP-893, CDX-1140, APX005M, RG7876/selicrelumab, ADC-1013/JNJ-64457107, ABBV-428, SEA-CD40 and MEDI5083. However, Das et al cures the deficiency.
Regarding to claim 6 and 21, Das et al teach harnessing the immune system in pancreatic cancer (Title), and in preclinical models, CD40 agonists such as APX005M bind to the CD40 receptor (part of TNF receptor family) on antigen-presenting cells and B cells as well as activated CD4 and CD8 T-cells. These compounds cause tumor regression in both T-cell-independent, largely through macrophage reprogramming to a TH1 phenotype, and T-cell dependent manners. Prior work with CD-40 agonists such as CP-870, 893. In a two-center study, mPDA patients were treated with standard dose gem or standard dose gem plus CP-870, 893 2 days after the first dose of gemcitabine with each cycle. Four of 21 patients achieved PR, and 11 achieved stable disease as their best response for a DCR of 71.4%. Median progression-free survival (PFS) was 5.2 months, and median overall survival (OS) was 8.4 months. A collaborative effort between the Parker Institute and Cancer Research Institute has led to a phase I/II randomized trial of gem, nab, and nivolumab with or without the CD40 agonist monoclonal antibody APX005M in previously treated mPDA patients (Page 3, last para. left column to right column).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of the above references by using CD40 agonist monoclonal antibody such as APX005M, CP-870, 893 as taught by Das et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Das et al teach “Immunotherapy’s general tolerability and potential to generate durable responses make it particularly appealing for mPDA patients” and “combinatorial strategies targeting unique aspects of PDA including the tumor microenvironment and desmoplastic stroma have shown preclinical or early-phase success.” (Abstract). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Das et al provide instructions for using APX005M, CP-870, 893 to yield predictable results.
Claims 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Rong et al (Clin Exp Med (2012) 12:173–180, DOI 10.1007/s10238-011-0159-0) in view of Hegmans et al (Pub. No.: US 2015/0352200 A1, Pub. Date: Dec. 10, 2015) and Lievense (Lievense, S. (2017, March 31), Dissertation , Macrophages in Mesothelioma : Improving immunotherapy in pulmonary oncology. Retrieved from http://hdl.handle.net/1765/98474) as applied to claims 1-5, 7-11, 14-16, 22 above, and further in view of Deicher et al (Cancer Cell Int (2018) 18:85, DOI: 10.1186/s12935-018-0585-0, Published on line: 18 June 2018).
The teachings of Rong et al, Hegmans et al, Lievense are as described above and are incorporated herein in their entirety.
The above references do not specifically teach three mesothelioma cancer cell associated antigens and wherein the mesothelioma cancer cell associated antigens are selected from the group consisting of RAGEl/MOK, Mesothelin, EphA2, Survivin, WT1, MUCl, RAB38/NY-MEL-l, BING4, MAGE Al2, HER-2/Neu, Glypican, and LMP2. However, Deicher et al cures the deficiency.
Regarding to claim 12 and 13, Deicher et al teach targeting dendritic cells in pancreatic ductal adenocarcinoma (Title). There is also growing evidence for the effectiveness of vaccination with DCs pulsed with tumor antigens to initiate adaptive cytolytic immune responses via T cells. Most experience with DC-based vaccination has been gathered for MUC1 and WT1 antigens, where clinical studies in advanced pancreatic cancer have provided encouraging results (Abstract). Deicher et al also teaches MUC1, WT1 and Mesothelin antigens in Table 1: Published series on dendritic cell-based immunotherapy in pancreatic cancer (Page 4).
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Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of the above references by using mesothelioma cancer cell associated antigens such as MUC1, WT1 and Mesothelin antigens as taught by Deicher et al, as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Deicher et al stated that” DC-based vaccination with MUC1 and WT1 antigens have provided encouraging results” (Abstract) and “Tumor lysates allow for a broad selection of tumor associated antigens (TAAs) and thereby a more comprehensive tumor attack.” (Page 3, left column, last para) . One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Deicher et al provided examples and instructions of using MUC1, WT1 and Mesothelin antigens for dendritic cell-based immunotherapy in pancreatic cancer.
Response to Arguments
Applicant's arguments filed on 04-23- 025 have been fully considered but they are not persuasive.
Applicant argue that neither Rong et al., Hegmans nor Lievense, alone or in combination, would teach, suggest or render obvious each and every element of amended claim 1. In particular, neither Rong et al., Hegmans nor Lievense teaches "wherein the treatment delays tumour growth in the treated patient relative to an untreated control" as recited by claim I as amended, specifically in the context of treating pancreatic cancer with dendritic cells loaded with a lysate obtained from mesothelioma cells (Remarks, page 6-8).
Response to Arguments:
It appears that Applicant is arguing that the cited references do not expressly suggest the claimed invention. 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. In the instant case: It should be noted that the ultimate goal of co incubating dendritic cells with a patient mesothelioma lysate is to provide an cancer immunotherapy:
Rong et al stated that “none of the patients experienced local tumor growth at the site of the vaccine injection” (Page 176, right column, 2nd para.). Rong et al stated that “we were able to observe IFN-γ and granzyme B production by PBMCs in response to MUC1-peptide in some patients following vaccination” (page 179, right column, 2nd para) and “T-cell response to tumor antigen by way of IFN-γ release appears to be associated with conditions that favor tumor regression” (page 178, right column, 2nd para).
Additionally, Lievense teaches that “……in pancreatic cancer, a tumor type with a microenvironment dominated by macrophages as mesothelioma, tumor regression after treatment with a CD40 agonist required macrophages….” (Pages 222, last para). Lievense teaches that combination therapy with a CD40-agonist and dendritic cell immunotherapy has additive effects in a murine mesothelioma model (Page 125, Title of chapter 6). Combination therapy of DC immunotherapy and a CD40-agonistic antibody induces additive immune activation in the peripheral blood of mesothelioma-bearing mice compared to the monotherapies. (Page 126, Abstract of Chapter 6). Since Lievense teaches that “in pancreatic cancer, a tumor type with a microenvironment dominated by macrophages as mesothelioma (Pages 222, last para.), and Hegmans et al teach that dendritic cell-based immunotherapy had a beneficial effect on survival and reducing tumor growth in a mouse model for malignant mesothelioma ([0004], page 1), a person of ordinary skill in the art would be motivated to use combination therapy with a CD40-agonist and dendritic cell immunotherapy for treating pancreatic cancer as mesothelioma. A person of ordinary skill in the art would expect tumor regression and/or reducing tumor growth as suggested by the cited references as described above
According to the specification of the claimed invention, delayed tumor growth was observed in mice treated with CD40 and DC vaccination (see instant disclosure page 8, example 8). Since the method steps and structural limitations of CD40 agonist in combination with patient dendritic cells have been rendered obvious, a person of ordinary skill in the art would expect the same results as the claimed invention.
2. Applicant argue that as disclosed on page 177 of Rong et al (left column, last paragraph) and summarized in Table 3, every patient in their study showed measurable tumor lesions that increased in size or number within three months after the start of vaccination (Remarks, page 6).
Response to Arguments:
It is noted that the claims do not require the delayed tumor growth to last indefinitely and the claims do not specify local tumor growth at the site of the vaccine injection or tumor growth in other locations: Although Rong et al teach measurable tumor lesions increased in number or size within 3 months of beginning vaccination, Rong et al also stated that “none of the patients experienced local tumor growth at the site of the vaccine injection” (Page 176, right column, 2nd para.). Thus, at least, local tumor growth at the site of the vaccine injection has been delayed. Also, Rong et al teach “IFN-γ and granzyme B production by PBMCs in response to MUC1-peptide in some patients following vaccination” (page 179, right column, 2nd para) and “T-cell response to tumor antigen by way of IFN-γ release appears to be associated with conditions that favor tumor regression” (page 178, right column, 2nd para). Furthermore, Rong et al teach the benefits of using cancer vaccination with peptide-pulsed dendritic cells: “All these patients in the study were in late stage of the pancreatic cancer …... However, patient 2, who had recurrence 1 year after surgery, was able to finish 4 vaccinations. He was then treated with gemcitabine chemotherapy 4 weeks after the last vaccine. This patient lived 14 months; however, the median survival time of pancreatic cancer patients with metastasis is only 3–6 months” (see page 179, left column, last para.). Additionally, Hegmans et al (Applicant’s own work) teach that dendritic cell-based immunotherapy had a beneficial effect on survival and reducing tumor growth in a mouse model for malignant mesothelioma ([0004], page 1). Thus, taken together, a person of ordinary skill in the art would expect to have the effects of reducing tumor growth as suggested by the cited references.
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. Applicant is reminded the Court commented that "[r]esponding to concerns about uncertainty in the prior art influencing the purported success of the claimed combination, this Court [in O'Farrell] stated: “[o]bviousness does not require absolute predictability of success ... all that is required is a reasonable expectation of success."' Kubin, 561 F.3d at 1360 (citing In re O'Farrell, 853 F.2d at 903-904).
Conclusion
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 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.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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