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 .
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 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.
Priority
The instant application, filed 02/03/2023, is a 371 filing of PCT/US2021/045277, filed 08/09/2021, and claims domestic benefit to US provisional application 63/063,014, filed 08/07/2020.
Status of Application, Amendments, and/or Claims
Applicant’s amendment of 12/12/2025 is acknowledged. Claims 116, 119-120, 127, 130-131, and 135 are amended and claims 1-115 are cancelled. Claims 116-135 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/17/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Withdrawn Objections and Rejections
In the office action of 09/12/2025,
Claim 120 was rejected under 35 USC 112(b). Applicant’s amendment to the claim to change dependency from claim 118 to claim 119 has overcome the rejection and the rejection is withdrawn.
Claim 135 was rejected under 35 USC 101. Applicant’s amendment to the claim to recite a method of treating and to limit the patient population to those who are identified as having or previously having pancreatitis has overcome the rejection and the rejection is withdrawn.
Claims 127-128 and 130-132 were rejected under 35 USC 102(a)(1) over Nesselhut. Applicant’s amendment to independent claim 127 to recite that the immunotherapy comprises an anti-PD-1 and an anti-CTLA-4 antibody has overcome the rejections and the rejections are withdrawn.
Claims 127-132 and 134 were rejected under 35 USC 102(a)(1) over Bassani-Sternberg. Applicant’s amendment to independent claim 127 to recite that the immunotherapy comprises an anti-PD-1 and an anti-CTLA-4 antibody has overcome the rejections and the rejections are withdrawn.
Claims 116-135 were rejected under 35 USC 103. Applicant’s amendment to the independent claims to recite that the immunotherapy comprises an anti-PD-1 and an anti-CTLA-4 antibody has overcome the rejections and the rejections are withdrawn.
The following grounds of rejections are new as necessitated by applicant’s amendment to the claims.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 116-122, 124, and 126 are rejected under 35 U.S.C. 103 as being unpatentable over Hiraoka, N., et al (2015) Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer British Journal of Cancer 112; 1782-1790 in view of US 2017/0106067 A1 (Jaffee, E. and L. Zheng) 20 APR 2017 and Victor, C.T., et al (2015) Radiation and dual checkpoint blockade activates non-redundant immune mechanisms in cancer Nature 520(7547); 373-377 as evidenced by John Hopkins (2019) Pancreatic Cancer Types, 5 pages, accessed from https://www.hopkins medicine.org/health/conditions-and-diseases/pancreatic-cancer/pancreatic-cancer-types.
Hiraoka teaches that pancreatic ductal carcinoma (PDC) is the fourth and fifth leading cause of cancer-related deaths in the US and Japan, respectively. As PDC shows aggressive growth and early metastatic dissemination, it is necessary to understand the pathobiological characteristics of PDC tissue more profoundly. In addition, the development of biomarkers to assist the selection of patient subsets is useful for studies aimed at reducing the mortality of PDC patients, especially in phase clinical studies evaluating various therapeutic approaches (page 1782, paragraph 1). It is noted that pancreatic ductal carcinoma is another name for pancreatic ductal adenocarcinoma as evidenced by John Hopkins, page 3.
Host immunity has critical roles in tumor surveillance. Tertiary lymphoid organs (TLOs) are induced in various inflamed tissue. Hiraoka investigated the clinicopathological and pathobiological characteristics of the tumor microenvironment in pancreatic ductal carcinoma (PDC) with TLOs (abstract, background). Hiraoka examined 534 PDCs to investigate the clinicopathological impact of TLOs and their association with tumor infiltrating immune cells, the cytokine milieu, and tissue characteristics (abstract, methods). Two different localizations of PDC-associated TLOs were identified including intratumoral and peritumoral. A better outcome was observed in patients with intratumoral TLOs and this was independent of other survival factors. The PDC tissues within TLOs showed significantly higher infiltration of T and B cells and lower infiltration of immunosuppressive cells, as well as significantly higher expression of Th1 and Th17 related genes. Tertiary lymphoid organs developed with an association with arterioles, venules, and nerves. These structures were reduced in association with cancer invasion in PDC tissues, except those with intratumoral TLOs (abstract, conclusions).
Hiraoka teaches that tumour-infiltrating CD4+ and CD8+ T cells in cancer tissues other than the area of TLOs in cases with intratumoral TLOs were also significantly higher compared with those without intratumoral TLOs. Higher tumour-infiltrating CD4+ and CD8+ T cells and B cells were shown to provide an antitumour immune microenvironment (page 1787, left column, paragraph 3). Hiraoka also studied the presence of CD11c+ DC and demonstrates presence of the DC in the tumor microenvironment of PDC (page 1786, Figure 2A).
Hiraoka further studied the clinicopathological characteristics of the patients and teaches that chronic pancreatitis was usually associated with PDC tissue (page 1784, left column, paragraph 1). Hiraoka further teaches that TLOs in the pancreatic tissue associated strongly with arterioles, venules, and peripheral nerve fibers. Tissue destruction and remodeling due to chronic inflammation often obstructed the venules, although the elastic fibres of the venules were retained, and the TLOs had developed in association with them. In contrast, no TLOs were found in most of PDC tissues in which these structures had been depleted or reduced, probably owing to cancer invasion followed by tissue remodeling, suggesting that such cancer invasion destroys some components that are necessary for the development of TLOs in the PDC tissue. The desmoplastic stromal response is capable of affecting the vascularity and vessel function in PDC tissue, although only the desmoplastic response that was also found in chronic pancreatitis did not usually deplete the structures necessary for TLO formation (page 1789, left column, paragraph 2). Hiraoka further teaches that Histological observation revealed that TLOs were strongly associated with peripheral nerves, arterioles, and venules and evaluated nerve fibers and vessels in PDC tissue with intratumoral TLOs compared with tissues of common pDC, most of which are without TLOs. The density of peripheral nerve fibers was apparently reduced within tissues of common PDC, in comparison with PDC tissues with intratumoral TLOs (page 1787, paragraph bridging columns; Figure 4A). Figure 4A also demonstrates a high area of nerve fibers in samples that had chronic pancreatitis (page 1788; Figure 4A). Hiraoka further teaches development of TLOs in murine models of chronic inflammation (page 1789, right column, paragraph 2). Hiraoka also teaches that inflammation related genes had significantly higher expression in PDC tissues with intratumoral TLOs (page 1787, left column, paragraph 4).
Hiraoka teaches that the presence of intratumoral TLOs in PDC is significantly correlated with an active immune reaction (page 1783, left column, paragraph 4). Hiraoka further teaches that the findings disclosed suggest that PDC cases with intratumoral TLOs might offer a higher chance of effector immune cells, drugs, or effector molecules coming into contact with cancer cells subjected to immunotherapy, chemotherapy, or molecular targeting therapy (page 1789, paragraph bridging columns).
Hiraoka concludes that the presence of intratumoral TLOs in PDC tissues appears to be an independent prognosticator and it is suggested that it also represents a microenvironment that is less vulnerable to cancer invasiveness, being associated with an active immune reaction, and relatively intact arterioles, venules, and nerves with vascular networks. It is also suggested that the presence of intratumoral TLOs is a useful hallmark to stratify PDCs by specific tumour microenvironment and to assist the selection of patient subsets for clinical studies evaluating various therapeutic approaches (page 1789, right column, paragraph 3). Hiraoka further teaches that Th1 associated genes including IFNg, TBX21, and IL12B showed significantly higher expression in PDC tissues with intratumoral TLOs compared to those without intratumoral TLOs (page 1787, left column, paragraph 3).
Hiraoka, however, does not disclose that the immunotherapy is an immune checkpoint therapy comprising an anti-PD-1 antibody and an anti-CTLA-4 antibody.
US’067 teaches that pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to late detection and resistance to conventional therapies. As such, there is a pressing need to identify additional treatment options (page 1, [0004]). Published results show that the PDA tumor microenvironment (TME) is predominantly infiltrated with immune suppressive cells and signals that, if altered, allow effective immunotherapy. However, single-agent checkpoint inhibitors including agents that alter immune suppressive signals in other human cancers including CTLA-4, PD-1, and its ligand PD-L1, have failed to demonstrate objective responses when given as single agents to PDA patients (page 10, [0101]).
US’067 teaches that PD-1, and one of its major ligands, PD-L1, constitute a major tolerance mechanism. PD-L1 is expressed by tumor cells, antigen presenting cells, B cells, and parenchymal cells and binds to PD-1 which is mainly expressed on activated T cells. The binding of PD-L1 to PD-1 results in T cell anergy or death, thereby blunting anti-tumor immune responses and promoting tumor growth. However, when anti-PD-L1 antibodies were tested in clinical trials for metastatic PDA patients, no objective responses were seen (page 11, [0110]). A possible explanation for the therapeutic failure of PD-1 or PD-L1 blockade therapy in PDA is the lack of a natural infiltration of effector immune cells in the majority of PDAs (page 11, [0111]).
US’067 teaches that a potential strategy to activate effector T cell trafficking into the TME is vaccine based immunotherapy. US’067 teaches the pancreatic cancer vaccine GVAX, which comprises allogeneic PDA tumor cell lines engineered to secrete GM-CSF. US’067 teaches that a recent clinical trial of GVAX as a neoadjuvant for resectable PDAs identified vaccine-induced tertiary lymphoid aggregates in PDAs surgically resected from the majority of patients who received the vaccine therapy 2 weeks before the surgery as well as infiltration of PD-L1+ cells within these lymphoid aggregates (page 11, [0111]). US’067 teaches that immune suppression in PDA was overcome by combining vaccine therapy with PD-1/PD-L1 blockade treatment resulting in prolonged survival and improved cure rates of pancreatic cancer bearing mice (page 1, [0005]).
Similarly to anti-PD-1 and anti-PD-L1, ipilimumab therapy, which is a checkpoint blockade against cytotoxic T lymphocyte antigen-4 (CTLA-4), approved by the FDA for the treatment of unresectable metastatic melanoma, failed to demonstrate durable and effective anti-tumor activity in metastatic PDA patients as a single agent. However, the combination of ipilimumab with PDA GVAX demonstrated objective clinical responses that were associated with prolonged survival compared to single agent ipilimumab (pages 11-12, [0112]). US’067 teaches that anti-CTLA-4 therapy leads to significantly more effector T cell immune responses (page 13, [0119]). US’067 teaches that, mechanistically, PD-L1/PD-1 and CTLA-4 function differently in T cell regulation (page 12, [0113]).
US’067 teaches a method of treating pancreatic ductal adenocarcinoma (PDA) in a subject comprising: administering a vaccine to the subject, and administering a PD-1 or PD-L1 inhibitor or a combination thereof. US’067 further teaches that the inhibitor is an antibody (page 20, claims 1, 3-4, and 7). US’067 teaches that the infiltration of CD8+ T lymphocytes, activated CD8+ T cells, and interferon gamma producing CD8+ T cells into the PDA tumor microenvironment is increased (page 20, claim 14). US’067 further teaches that the vaccine used in the combination can be selected from a group including a Listeria-based vaccine engineered to express cancer antigens, a vaccine that facilitates effector T cell infiltration into pancreatic tumors, a whole cell based vaccine, a dendritic cell vaccine, or a combination thereof (page 21, claim 32).
US’067 teaches that dendritic cell vaccines, i.e., dendritic cell therapies, are also useful in the methods described. The dendritic cell vaccines are administered prior to, concurrently with, or subsequent to administration of the PD-1 inhibitor and/or the PD-L1 inhibitor (page 2, [0013]).
US’067 further teaches that treatment with immunotherapeutic methods or compositions described can be a stand-alone treatment or may be one component or phase of a combination therapy regimen in which one or more additional agents are also administered to treat the patient (page 2, [0025]). The vaccine and PD-1/PD-L1 inhibitor may further be administered prior to, in combination with, or sequential to other immune modulators and/or targeted therapies, chemotherapy, and/or chemoradiation (page 2, [0015]). US’067 teaches that administration of Cy (the chemotherapeutic cyclophosphamide) induces the recruitment of high avidity CD8+ T cells, which is attributed with Treg depletion. In studies combining Cy with a vaccine, transient depletion of Tregs and expansion of tumor antigen specific T cells had been found (page 13, [0121]).
Victor studied the combination of radiation (RT), anti-CTLA-4, and anti-PD-1/PD-L1 in melanoma and in a pancreatic cancer model using PDA.4662 cells (page 7; In vivo mouse studies), which is an art recognized pancreatic ductal adenocarcinoma cell line. Victor teaches that RT is needed to achieve high CR rates as dual checkpoint blockade proved inferior to dual checkpoint blockade plus RT, a requirement additionally seen in a pancreatic cancer model (page 4, paragraph 2; Extended data Fig. 3j). Extended data Fig. 3j from Victor is provided below for convenience:
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Victor teaches that the superiority of triple therapy in multiple cancer types suggests non-redundant mechanisms for each treatment. To examine this notion, treatment related changes in TILs were assessed from unirradiated tumors. RF modeling of immune cell profiles confirmed that anti-CTLA-4 predominantly caused a decrease in Tregs, anti-PD-L1 strongly increased CD8 TIL frequency, and the blockade of both increased the CD8/Treg ratio. In contrast, RT caused only a modest increase in CD8 TILs; however, TCR sequencing revealed that this was accompanied by increased diversity of TCR clonotypes, which could be observed even in the presence of CTLA4 blockade. Thus, within the tumor microenvironment, CTLA4 blockade primarily decreases Tregs, PD-L1 blockade predominantly reinvigorates exhausted CD8 TILs, and RT diversifies the TCR repertoire of TILs from unirradiated tumors (page 4, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to treat subjects identified using the methods taught by Hiraoka with checkpoint blocking antibodies, including a combination of anti-PD-1 and/or anti-PD-L1 blocking antibodies and anti-CTLA-4 antibodies based on the teachings of US’067 which is further motivated by the teachings of Victor.
An ordinarily skilled artisan would have been motivated to treat the subject with a PD-1 and/or PD-L1 blocking antibody in order to block the checkpoint of PD-1 and its ligand PD-L1, which constitute a major tolerance mechanism resulting in T cell anergy or death and blunting anti-tumor immune responses and promoting tumor growth. An ordinarily skilled artisan would have been motivated to further include an anti-CTLA-4 antibody as US’067 teaches that antibodies to CTLA-4 result in enhanced effector T-cell immune responses. The combination of an anti-PD-1 antibody and an anti-CTLA-4 antibody is further supported by the teachings of Victor which demonstrates that, in PDA models, the combination of immune checkpoint blockade leads to longer survival than either checkpoint alone and, when used in combination with radiotherapy, leads to significantly higher response rates. Additionally, Victor teaches that within the TME, CTLA4 blockade decreases Tregs, PD-L1 blockade predominantly reinvigorates exhausted CD8 TILs, and RT diversifies the TCR repertoire of TILs demonstrating non-redundant mechanisms used to treat the cancer. An ordinarily skilled artisan would have had a reasonable expectation of success as US’067 teaches that a possible explanation for past therapeutic failure of checkpoint blockade in PDA is the lack of natural infiltration of effector immune cells in the majority of PDAs and teaches that a potential strategy is to activate effector T cell trafficking into the TME. US’067 uses vaccines to induce this trafficking and teaches that the vaccines result in tertiary lymphoid aggregates. As the method taught by Hiraoka identifies patients for treatment with immunotherapy by the presence of intratumoral TLOs, an ordinarily skilled artisan would reasonably expect that the checkpoint blocking antibodies of US’067 and Victor would be effective in these patient populations that already have TLOs, indicating an active immune response.
Regarding claim 122, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of Hiraoka, US’067, and Victor by further administering a dendritic cell vaccine as taught by US’067. An ordinarily skilled artisan would have been motivated to further administer a dendritic cell vaccine as US’067 teaches that checkpoint inhibitors combined with vaccines, including DC vaccines, augment effector T cell infiltration into the pancreatic tumors overcoming immune suppression and prolonging survival. An ordinarily skilled artisan would have had a reasonable expectation of success as Hiraoka, US’067, and Victor all studied treatment of pancreatic ductal adenocarcinoma and both Hiraoka and US’067 teach the importance of tertiary lymphoid structure presence for immunotherapy.
Regarding claim 124, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to try treating a subject who was previously treated but was resistant to prior therapies using the method taught by the combination of Hiraoka, US’067, and Victor based on the teachings of US’067. It would have been obvious to try treating this patient population as US’067 teaches that prior to the disclosed therapy, PDA had a poor prognosis due to late detection and resistance to conventional therapies (page 1, [0004]). An ordinarily skilled artisan would have had a reasonable expectation of success as Hiraoka is teaching methods of identifying patients who have active immune responses and US’067 is teaching methods of overcoming suppression in the PDA tumor microenvironment allowing for treatment. Additionally, Victor teaches combination therapies as a means to antagonize resistance in cancers, including PDA.
Regarding claim 126, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of Hiraoka, US’067, and Victor to further administer additional therapies including immune modulators and/or targeted therapies, chemotherapy, and/or chemoradiation based on the teachings of US’067 and Victor. It would have been obvious to administer an additional therapy as US’067 teaches the further administration of additional therapies including immune modulators and/or targeted therapies, chemotherapy, and/or chemoradiation. In particular, one of ordinary skill in the art would have been motivated to administer the chemotherapeutic cyclophosphamide as US’067 demonstrates that combining Cy with a vaccine results in transient depletion of Tregs and expansion of tumor antigen specific T cells. Alternatively, one of ordinary skill in the art would have been motivated to further administer radiation therapy as Victor demonstrates that RT combined with both PD-1 and CTLA-4 blockade results in significant increases in survival. An ordinarily skilled artisan would have had a reasonable expectation of success as Hiraoka, US’067, and Victor all teach methods of treating pancreatic cancers including pancreatic ductal adenocarcinoma.
Claim 123 is rejected under 35 U.S.C. 103 as being unpatentable over Hiraoka, N., et al (2015) Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer British Journal of Cancer 112; 1782-1790, US 2017/0106067 A1 (Jaffee, E. and L. Zheng) 20 APR 2017, and Victor, C.T., et al (2015) Radiation and dual checkpoint blockade activates non-redundant immune mechanisms in cancer Nature 520(7547); 373-377 as applied to claims 116 and 122 above, and in further view of Nesselhut, J., et al (2016) Systemic treatment with anti-PD-1 antibody nivolumab in combination with vaccine therapy in advanced pancreatic cancer Journal of clinical oncology 34(15 suppl); 1 page.
The combination of Hiraoka, US’067, and Victor teach the method of claim 122 as discussed in detail above.
The combination of Hiraoka, US’067, and Victor, however, do not explicitly teach that the dendritic cell vaccine is autologous or cDCs.
Nesselhut teaches that systemic treatment with antibodies against PD-1 has shown promising results in many solid tumors with pancreatic cancer being one of the few exceptions. This may be due to failure of activation and/or recruitment of effector T cells into the tumor. As an effective immune response against tumors requires the inhibition of inhibitory signals as well as the activation of antigen specific T-cell responses, therapy efficacy may be improved by combination of anti-PD-1 therapy and dendritic cell vaccines (background). Nesselhut teaches that seven patients with stage IV pancreatic cancer were included in a pilot study and received treatment with nivolumab and dendritic cells. Monocytes were isolated from the peripheral blood of the patients and antigen primed MoDC were generated using standard protocols. Nivolumab was given one day before DC vaccine at a reduced dose of 1-2 mg/kg body weight (methods). Using Recist criteria, 2 partial remissions were observed with overall survival after onset of therapy of 13 months and 5 months, respectively. Both patients are still alive with an ongoing therapy response. Most patients tolerated the therapy well with only mild side effects upon nivolumab therapy (results). Nesselhut teaches that it was previously shown that the efficacy of DC based therapy can be improved by blockade of PD-L1 on dendritic cells improving the T-cell specific response. Here it is shown that systemic anti-PD-1 therapy for patients with pancreatic cancer can be effective even at low doses when combined with DC vaccine therapy.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of Hiraoka, US’067, and Victor to prepare the dendritic cell vaccine by isolating monocytes from peripheral blood of the patient and forming antigen primed MoDCs using standard protocols as disclosed by Nesselhut, resulting in an autologous vaccine. It would have been obvious to use an autologous DC vaccine as Nesselhut demonstrates that such techniques were known and practiced in the art and had standard protocols already established. An ordinarily skilled artisan would have had a reasonable expectation of success as, like Hiraoka, US’067, and Victor, Nesselhut teaches combination therapy for the treatment of pancreatic cancer.
Claim 125 is rejected under 35 U.S.C. 103 as being unpatentable over Hiraoka, N., et al (2015) Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer British Journal of Cancer 112; 1782-1790, US 2017/0106067 A1 (Jaffee, E. and L. Zheng) 20 APR 2017, and Victor, C.T., et al (2015) Radiation and dual checkpoint blockade activates non-redundant immune mechanisms in cancer Nature 520(7547); 373-377 as applied to claim 116 above and in further view of Sparmann, G., et al (2001) Cytokine mRNA levels and lymphocyte infiltration in pancreatic tissue during experimental chronic pancreatitis induced by dibutyltin dichloride Digestive Diseases and Sciences 46(8); 1647-1656 and Kirkegard, J., et al (2020) Acute pancreatitis as an early marker of pancreatic cancer and cancer stage, treatment, and prognosis Cancer Epidemiology 64(101647); 1-31.
The combination of Hiraoka, US’067, and Victor teaches the method of claim 116 as discussed in detail above.
Hiraoka further teaches that tumor infiltrating CD3+ T cells and CD20+ B cells were all significantly higher in PDC tissues other than the area of TLOs in cases having intratumoral TLOs compared to cases not having intratumoral TLOs. Tumor-infiltrating CD4+ and CD8+ T cells in cancer tissues other than the area of TLOs in cases with intratumoral TLOs were also significantly higher compared with those without intratumoral TLOs. Higher tumor-infiltrating CD4+ and CD8+ T cells and B cells were shown to provide an antitumor immune microenvironment (page 1787, left column, paragraph 3). Hiraoka also studied the relationship of the cytokine milieu of cancer tissue and TLO grade and teaches that the results, combined with those observed in tumor-infiltrating immune cells, suggest that in immune reaction is more active in the tumour microenvironment in PDC tissues with intratumoral TLOs compared with those without intratumoral TLOs (page 1787, left column, paragraph 4). Hiraoka teaches that PDC cases with intratumoral TLOs might offer a higher chance of effector immune cells, drugs, or effector molecules coming into contact with cancer cells subjected to immunotherapy, chemotherapy, or molecular targeting therapy (page 1789, paragraph bridging columns).
The combination of Hiraoka, US’067, and Victor, however, does not disclose inducing pancreatitis in the subject with an infectious agent or pancreatic surgery prior to administration of the immunotherapy.
Sparmann analyzed the local cytokine profile and infiltrating lymphocytes in a rat model of chronic pancreatitis. Experimental pancreatitis was induced by a single intravenous application of dibultyltin dichloride (DBCT). During a time course of two months, the mRNA expression of cytokines using competitive PT-PCR was observed and lymphocytes were characterized by immunohistochemistry, FACS analysis, and the lymphocyte proliferation test. IL-1β, IL-6, IL-5, and IL-10 were immediately up-regulated in the acute phase of the disease, while lymphocyte restricted expression of IL-2, IL-2R, and IFN-γ was found in the chronic course. Among the infiltrating lymphocytes, CD4+ T cells dominated, but during the chronic process there was an increase of CD8+ T cells resulting in a reduced CD4/CD8 ratio. The results suggest that in experimental pancreatitis acute inflammatory reactions are followed by a T-lymphocyte mediated process (abstract). Sparmann shows a marked increase of T cells with a dominance of the CD4+ subset. The chronic phase of experimental pancreatitis was characterized by a continuous increase of the CD8+ cells resulting in a CD4+/CD8+ ratio of 1.78 on day 60 compared to 4.57 on day 14. A preferential accumulation of CD8+ T lymphocytes was also found in the tissue obtained by surgery from patients with chronic pancreatitis (2, 5). Sparmann teaches that leukocyte infiltration is a characteristic feature of human chronic pancreatitis. There is increasing evidence that immunocompetent cells may be involved in the pathogenesis of chronic pancreatitis (page 1647, left column, paragraph 1).
Kirkegard examined the association between acute pancreatitis, a potential early symptom of pancreatic cancer, and pancreatic cancer stage, treatment, and prognosis (abstract, background). Kirkegard conduced a cohort study that included 12,522 Danish and 37,552 US patients with pancreatic cancer and found that pancreatic cancer patients with acute pancreatitis diagnosed up to 90 days before cancer diagnosis had earlier stage at diagnosis and better survival than patients without acute pancreatitis (abstract, methods and results). Kirkegard teaches that patients with acute pancreatitis had 16-23% lower mortality within five years after surgery compared to patients without acute pancreatitis (page 3, right column, paragraph 4). Kirkegard also found a striking median survival difference of 17 months in patients undergoing surgery (page 4, left column, paragraph 1).
Kirkegard also teaches a US based study in which 2573 pancreatic cancer patients examining 100 patients with self-reported acute or chronic pancreatitis within 10 days before or after pancreatic cancer diagnosis. Kirkegard teaches that this study included patients diagnosed with pancreatitis after pancreatic cancer diagnosis which may have occurred due to resection (page 4, paragraph bridging columns).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of Hiraoka, US’067, and Victor by further inducing pancreatitis in the subject prior to immunotherapy administration based on the teachings of Sparmann and to induce pancreatitis through pancreatic surgery, such as resection, as taught by Kirkegard. An ordinarily skilled artisan would have been motivated to induce pancreatitis prior to administration of immunotherapy because Sparmann teaches that induced pancreatitis leads to upregulated proinflammatory cytokines and increased infiltrating lymphocytes and that immunocompetent cells are associated with pancreatitis. An ordinarily skilled artisan would have had a reasonable expectation of success as Hiraoka teaches that in PDC cases with intratumoral TLOs, cytokines and infiltrating lymphocytes are upregulated which offers a higher chance of effector immune cells, drugs, or effector molecules coming into contact with cancer cells subjected to immunotherapies. It would have been obvious to induce pancreatitis through pancreatic surgery as the teachings of Kirkegard demonstrate that, in pancreatic cancer, resection can result in pancreatitis after pancreatic cancer diagnosis. An ordinarily skilled artisan would have had a reasonable expectation of success as Kirkegard, like Hiraoka, US’067, and Victor, is concerned with immune responses in pancreatic cancer.
Claims 127-131 and 133-134 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0106067 A1 (Jaffee, E. and L. Zheng) 20 APR 2017 in view of Victor, C.T., et al (2015) Radiation and dual checkpoint blockade activates non-redundant immune mechanisms in cancer Nature 520(7547); 373-377.
The teachings of US’067 are as discussed above.
As discussed above, US’067 discloses methods of treating pancreatic ductal adenocarcinoma including an embodiment in which dendritic cell vaccines are administered prior to, concurrently with, or subsequent to administration of a PD-1 and/or PD-L1 inhibitor to treat pancreatic cancer (page 2, [0013]). US’067 also teaches that exemplary PD-1 inhibitors or PD-L1 inhibitors comprise anti-PD-1 antibodies, anti-PD-L1 antibodies, or combinations there of (page 2, [0014]). As discussed above, US’067 also teaches the use of anti-CTLA-4 antibodies in the treatment of pancreatic cancer (page 10, [0101]).
US’067, however, does not explicitly disclose the further administration of an anti-CTLA-4 antibody with the combination of dendritic cells and anti-PD-1 and/or anti-PD-L1 antibodies.
The teachings of Victor are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by US’067, in which dendritic cells are administered prior to, concurrently with, or subsequent to administration of a PD-1 and/or PD-L1 inhibitor to treat pancreatic cancer, to further administer an anti-CTLA-4 antibody based on the teachings of US’067 as a whole and as is further motivated by the teachings of Victor. An ordinarily skilled artisan would have been motivated to further include an anti-CTLA-4 antibody as US’067 teaches that antibodies to CTLA-4 result in enhanced effector T-cell immune responses. The combination of an anti-PD-1 antibody and an anti-CTLA-4 antibody is further supported by the teachings of Victor which demonstrates that, in PDA models, the combination of immune checkpoint blockade leads to longer survival than either checkpoint alone and, when used in combination with radiotherapy, leads to significantly higher response rates. Additionally, Victor teaches that within the TME, CTLA-4 blockade decreases Tregs, PD-L1 blockade predominantly reinvigorates exhausted CD8 TILs, and RT diversifies the TCR repertoire of TILs demonstrating non-redundant mechanisms used to treat the cancer. An ordinarily skilled artisan would have had a reasonable expectation of success as US’067 teaches that a possible explanation for past therapeutic failure of checkpoint blockade in PDA is the lack of natural infiltration of effector immune cells in the majority of PDAs and teaches that vaccines, including dendritic cell vaccines, are a potential strategy is to activate effector T cell trafficking into the TME. An ordinarily skilled artisan would have further had a reasonable expectation of success as US’067 teaches that both PD-1 and/or PD-L1 antibodies and CTLA-4 antibodies have separately been demonstrated to be effective when combined with vaccines in the treatment of PDA.
Regarding claim 133, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to try treating a subject who was previously treated but was resistant to prior therapies using the method taught by the combination of US’067, and Victor based on the teachings of US’067. It would have been obvious to try treating this patient population as US’067 teaches that prior to the disclosed therapy, PDA had a poor prognosis due to late detection and resistance to conventional therapies (page 1, [0004]). An ordinarily skilled artisan would have had a reasonable expectation of success as US’067 teaches methods of overcoming suppression in the PDA tumor microenvironment allowing for treatment. Additionally, Victor teaches combination therapies as a means to antagonize resistance in cancers, including PDA.
Regarding claim 126, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of US’067 and Victor to further administer additional therapies including immune modulators and/or targeted therapies, chemotherapy, and/or chemoradiation based on the teachings of US’067 and Victor. It would have been obvious to administer an additional therapy as US’067 teaches the further administration of additional therapies including immune modulators and/or targeted therapies, chemotherapy, and/or chemoradiation. In particular, one of ordinary skill in the art would have been motivated to administer the chemotherapeutic cyclophosphamide as US’067 demonstrates that combining Cy with a vaccine results in transient depletion of Tregs and expansion of tumor antigen specific T cells. Alternatively, one of ordinary skill in the art would have been motivated to further administer radiation therapy as Victor demonstrates that RT combined with both PD-1 and CTLA-4 blockade results in significant increases in survival. An ordinarily skilled artisan would have had a reasonable expectation of success as US’067 and Victor both teach methods of treating pancreatic cancers including pancreatic ductal adenocarcinoma.
Claim 132 is rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0106067 A1 (Jaffee, E. and L. Zheng) 20 APR 2017 in view of Victor, C.T., et al (2015) Radiation and dual checkpoint blockade activates non-redundant immune mechanisms in cancer Nature 520(7547); 373-377 as applied to claim 127 above, and in further view of Nesselhut, J., et al (2016) Systemic treatment with anti-PD-1 antibody nivolumab in combination with vaccine therapy in advanced pancreatic cancer Journal of clinical oncology 34(15 suppl); 1 page.
The combination of US’067 and Victor teaches the method of claim 127 as discussed in detail above.
The combination of US’067 and Victor, however, does not explicitly teach that the dendritic cell vaccine is autologous or cDCs.
The teachings of Nesselhut are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of US’067 and Victor to prepare the dendritic cell vaccine by isolating monocytes from peripheral blood of the patient and forming antigen primed MoDCs using standard protocols as disclosed by Nesselhut, resulting in an autologous vaccine. It would have been obvious to use an autologous DC vaccine as Nesselhut demonstrates that such techniques were known and practiced in the art and had standard protocols already established. An ordinarily skilled artisan would have had a reasonable expectation of success as, like US’067, Nesselhut teaches a combination therapy for the treatment of pancreatic cancer comprising a DC vaccine and an anti-PD-1 antibody.
Claim 135 is rejected under 35 U.S.C. 103 as being unpatentable over Hiraoka, N., et al (2015) Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer British Journal of Cancer 112; 1782-1790, Sparmann, G., et al (2001) Cytokine mRNA levels and lymphocyte infiltration in pancreatic tissue during experimental chronic pancreatitis induced by dibutyltin dichloride Digestive Diseases and Sciences 46(8); 1647-1656, US 2017/0106067 A1 (Jaffee, E. and L. Zheng) 20 APR 2017, and Victor, C.T., et al (2015) Radiation and dual checkpoint blockade activates non-redundant immune mechanisms in cancer Nature 520(7547); 373-377.
The teachings of Hiraoka are as discussed in detail above.
As discussed in detail above, Hiraoka teaches that the presence of intratumoral TLOs in PDC is a useful hallmark to stratify PDCs by specific tumor microenvironment and to assist the selection of patient subsets for clinical studies evaluating various therapeutic approaches (page 1789, right column, paragraph 3). Hiraoka also teaches that therapeutic approaches including immunotherapy, chemotherapy, or molecular targeting therapy (page 1789, paragraph bridging columns).
Hiaroka, however, does not explicitly disclose that the biomarker used to select patient subsets is pancreatitis or that the immunotherapy is immune checkpoint blockade comprising an anti-PD-1 antibody and an anti-CTLA-4 antibody.
The teachings of Sparmann, US’067, and Victor are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention modify the method of Hiraoka to use pancreatitis as the marker for the stratification of PDCs in place of TLOs based on the teachings of Hiraoka and Sparmann and to use the method to select patients for treatment with immune checkpoint inhibitors including an anti-PD-1 antibody and an anti-CTLA-4 antibody based on the teachings of Hiaroka, US’067, and Victor.
It would have been obvious to use pancreatitis as the biomarker as Hiraoka teaches that tissues affected by chronic pancreatitis have a large area of nerve fibers, which are taught to be associated with intratumoral TLOs, that TLO formation is associated with chronic inflammation, and that chronic pancreatitis does not deplete structures necessary for TLO formation during tissue destruction and remodeling, suggesting a correlation between pancreatitis and active immune response in pancreatic cancer. Additionally, Sparmann teaches that immunocompetent cells may be involved in the pathogenesis of chronic pancreatitis, further supporting pancreatitis as a marker for active immune response during pancreatic cancer. An ordinarily skilled artisan would have had a reasonable expectation of success as both Hiraoka and Sparmann teach immune responses in patients and associations with pancreatitis.
An ordinarily skilled artisan would have been motivated use the method of selecting patients for treatment with immune checkpoint inhibitors as Hiraoka teaches that the presence of intratumoral TLOs might offer a higher chance of effector immune cells, drugs, or effector molecules coming into contact with cancer cells subjected to immunotherapy, chemotherapy or molecular targeted therapy and suggests the presence of TLOs in PDC tissues as a means to stratify PDCs by specific tumor microenvironment to assist the selection of patient subsets for therapeutic approaches. An ordinarily skilled artisan would have been motivated to treat the subject with a PD-1 and/or PD-L1 blocking antibody in order to block the checkpoint of PD-1 and its ligand PD-L1, which constitute a major tolerance mechanism resulting in T cell anergy or death and blunting anti-tumor immune responses and promoting tumor growth. An ordinarily skilled artisan would have been motivated to further include an anti-CTLA-4 antibody as US’067 teaches that antibodies to CTLA-4 result in enhanced effector T-cell immune responses. The combination of an anti-PD-1 antibody and an anti-CTLA-4 antibody is further supported by the teachings of Victor which demonstrates that, in PDA models, the combination of immune checkpoint blockade leads to longer survival than either checkpoint alone and, when used in combination with radiotherapy, leads to significantly higher response rates. Additionally, Victor teaches that within the TME, CTLA-4 blockade decreases Tregs, PD-L1 blockade predominantly reinvigorates exhausted CD8 TILs, and RT diversifies the TCR repertoire of TILs demonstrating non-redundant mechanisms used to treat the cancer. An ordinarily skilled artisan would have had a reasonable expectation of success as US’067 teaches that a possible explanation for past therapeutic failure of checkpoint blockade in PDA is the lack of natural infiltration of effector immune cells in the majority of PDAs and teaches that a potential strategy is to activate effector T cell trafficking into the TME. US’067 uses vaccines to induce this trafficking and teaches that the vaccines result in tertiary lymphoid aggregates. As the method taught by Hiraoka and Sparmann identifies patients for treatment with immunotherapy by the presence of an active immune response, an ordinarily skilled artisan would reasonably expect that the methods taught by Hiraoka and Sparmann could be used to identify subsets of patients in which the checkpoint blocking antibodies of US’067 and Victor would be effective as the patients would be identified as having an active immune response.
Response to Arguments
Applicant’s arguments in the response filed 12/12/2025 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
With regards to the rejections under 35 USC 103, applicant argues that one of ordinary skill in the art would not have been motivated to administer both an anti-PD-1 antibody and an anti-CTLA-4 antibody based on the teachings of Hiraoka and US’067 (referred to by applicant as “Jaffee” in the response). Applicant argues that US’067 teaches that PD-1/PD-L1 and CTLA-4 function differently in T cell regulation and that, because of this, combining anti-PD-1 and anti-CTLA-4 antibodies without a clear rationale risks unpredictable immune modulation. Applicant further argues that US’067 teaches that immune related adverse effects are common and severe with ipilimumab therapy in contrast to those seen with PD-1/PD-L1 blockade. Applicant argues that, accordingly, one of ordinary skill in the art would recognize that a combination of an anti-PD-1 antibody and an anti-CTLA-4 antibody could lead to overlapping or excessive immune activation leading to adverse effects without the benefit of synergy, especially in pancreatic cancer.
In the rejections of the instant office action, the reference Victor has been applied to demonstrate that combination of an anti-PD-1 antibody and an anti-CTLA-4 antibody had been previously studied in pancreatic tumor models and demonstrated synergistic results. Specifically, as shown in Victor Extended data Fig. 3j, the combination of anti-PD-1 and anti-CTLA-4 antibodies leads to longer survival compared to monotherapies and, when used in combination with radiation, significant increases in survival are observed. As discussed by applicant in the response, US’064 teaches that PD-1/PD-L1 and CTLA-4 function differently in cell regulation, Victor further elaborates on these non-redundant mechanisms as contributing to the superiority observed in the combinations tested. For instance, Victor teaches that anti-CTLA-4 predominantly causes a decrease in Tregs, anti-PD-L1 strongly increased CD8 TIL frequency, and the blockade of both increased the CD8/Treg ratio (page 4, paragraph 2). The teachings of Victor demonstrate that targeting the non-redundant pathways can lead to synergistic results, including in models of pancreatic cancer. With regards to immune related adverse effects, while US’067 does disclose that such events are more common and severe with anti-CTLA-4 compared to anti-PD-1 antibodies, US’067 does not suggest that these events are limiting nor does US’067 teach against the use of anti-CTLA-4 antibodies. Rather, the teachings of US’067 demonstrates that anti-CTLA-4 antibodies were routinely studied in the art as a treatment modality. For instance, US’067 teaches that the anti-CTLA-4 antibody ipilimumab had been approved by the FDA for the treatment of unresectable melanoma (pages 11-12, [0112]) and also teaches that inhibition of the CTLA-4 pathway, when given in combination with T cell inducing vaccines, gives objective responses in metastatic PDA patients (page 10, [0101]). Victor also teaches the use of anti-CTLA-4 antibodies and concludes that the addition of anti-PD-L1/PD-1 blockade to RT + anti-CTLA-4 may show significant efficacy in clinical trials (page 6, paragraph 2) suggesting that the art did not view immune related adverse effects caused by the antibodies as limiting their use.
Applicant further argues that the instant disclosure shows that administration of an anti-PD-1 antibody and an anti-CTLA-4 antibody can successfully treat pancreatic cancer citing the instant specification, paragraphs [00133]-[00135]. Applicant argues that, collectively, the inventor’s results indicate that PDAC tumors are resistant to checkpoint immunotherapy due to characteristics of the tumor microenvironment and that chronic pancreatitis renders PDACs amendable to combination immunotherapy.
While applicant’s results do demonstrate that chronic pancreatitis renders PDACs susceptible to combination immunotherapy, such results would have been expected based on the combined teaching of the prior art. For instance, as discussed in detail in the rejections of the instant office action, Hiraoka teaches that the presence of intratumoral tertiary lymphoid organs in PDC tissue can be used as a biomarker to assist in the selection of patient subsets for treatment with immunotherapy. Additionally, Hiraoka teaches that the intratumoral tertiary lymphoid organs in PDC is significantly correlated with an active immune reaction. Hiraoka also teaches that tissues affected by chronic pancreatitis have a large area of nerve fibers which are associated with intratumoral TLOs, that TLO formation is associated with chronic inflammation, and that chronic pancreatitis does not deplete structures necessary for TLO formation during tissue destruction and remodeling, suggesting a correlation between chronic pancreatitis and intratumoral TLO formation. This is further supported by the teachings of Sparmann, which is applied in the rejection of claim 135, and demonstrates that immunocompetent cells are involved in the pathogenesis of chronic pancreatitis and that, in models of induced pancreatitis, continuous increases in the number of CD8+ T cells were observed demonstrating an active immune response.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 mailing date of this final action.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693