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 .
Election/Restrictions
Applicant’s election with traverse of Group II (claims 61-66) and the below-listed species in the reply filed on 04/15/2026 is acknowledged.
Elected Species:
An antagonist of PD-1, specifically nivolumab;
The PDE4-selective inhibitor roflumilast;
A solid tumor; and
Colon cancer, specifically metastatic colon cancer.
With regard to the traversal of the Restriction/Election requirement, Applicant argues on Page 2 of Remarks (04/15/2026) that M.P.E.P. §803 requires a showing of burden on the search and it is believed that the claims of the present application would be part of an overlapping search area. Furthermore, electronic searching allows for a search of many, or theoretically all, relevant subclasses without substantial additional effort. Thus, Applicant traverses the Restriction requirement on the grounds that a search and examination of the entire application would not place a serious burden on the Examiner, whereas it would be a serious burden on Applicant to prosecute and maintain separate applications.
Applicant’s arguments have been full considered, but are deemed not persuasive.
In response to Applicant’s arguments regarding M.P.E.P. §803 and search burden, it is specifically noted that the reference M.P.E.P. §803 pertains to Restriction/Election requirements under U.S. practice (i.e., applications filed under 35 U.S.C 111(a)) which require the independent and distinct analysis, whereas the instant application is filed under 35 U.S.C. 371, which falls under the unity of invention analysis as laid out in the Restriction/Election Requirement from 02/20/2026. Thus, the arguments regarding M.P.E.P. §803 and a search burden are moot.
In view of the above, the requirement is deemed proper and is therefore made FINAL.
Claim Status
Claims 67-91 have been cancelled and claims 3, 32, 34-35, 37, 39-54, 56-57, and 59-66 have been amended as requested in the preliminary amendment filed on 07/21/2023. Following the amendment, claims 1-66 are pending in the instant application.
Claims 1-60 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention in the Response filed 04/15/2026, there being no allowable generic or linking claim.
Claims 61-66 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, it is noted that no English translation of the foreign priority document has been provided. As such, the claim to foreign priority has not been perfected.
Claims 61-66 have an effective filing date of January 20, 2022 corresponding to PCT/CN2022/072887.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/21/2023 and 01/14/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosures statement are being considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code at Pages 23, 28, 44-45, and 71-72. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is further objected to for the use of the terms, for example, Xeloda, Opdivo, Keytruda, Tecentriq, and Imfinzi, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 103
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.
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 61-64 are rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Sasi et. al. (Leukemia, 2021, 35(7), 1990-2001; published online Dec. 2020; herein after referred to as "Sasi") in view of non-patent literature by Yaghoubi et. al. (Biomedicine & Pharmacotherapy, 2019, 110, 312-318; herein after referred to as "Yaghoubi ").
Sasi teaches that cyclic-AMP (cAMP) exerts suppressive effects in the innate and adaptive immune system and the PD-1/PD-L1 immune checkpoint down-regulates T-cell activity; using normal and malignant lymphocytes from humans, and the phosphodiesterase 4b (Pde4b) knockout mouse, the authors found that cAMP induces PD-L1 transcription and protein expression and mechanistically, the authors discovered that the cAMP effectors PKA and CREB induce the transcription/secretion of IL-10, IL-8 and IL-6, which initiate an autocrine loop that activates the JAK/STAT pathway and ultimately increase PD-L1 expression in the cell surface (Abstract). In vivo, the authors found that despite its immunosuppressive attributes, the PDE4 inhibitor roflumilast did not decrease the clinical activity of checkpoint inhibitors, an important clinical observation given the approved use of these agents in multiple diseases (Id.). The authors identified an elaborate autocrine loop as the mechanistic basis for the cAMP/PD-L1 interplay; in human and murine, normal and malignant, lymphocytes, cAMP induces the expression and secretion of the IL-10, IL-8, IL-6, which activated JAK/STAT signals, resulting in transcriptional activation of PD-L1. (Fig. 6), wherein he interplay between IL-10 and cAMP/PDE4 has been recognized before and linking them to PD-L1 expression expands the portfolio of immune-suppressive activities that are cAMP-driven and IL-10 executed (Pages 7-8, Discussion, Second Paragraph). The authors acknowledge that it is possible that the cytokines involved as intermediaries in the cAMP-PD-L1 interplay will vary according to the tissue type, but the authors also found a significant correlation between PD-L1 and IL-10, IL-8, IL-6 expression in melanoma, lung and colon cancer (Page 8, First Paragraph). PDE4 inhibitors, which are FDA-approved for COPD and psoriatic arthritis, elevate cAMP levels in cells on the innate and adaptive immune system, and display broad immunosuppressive properties, which may at least part be due to PD-L1 expression; although increase in PD-L1 levels in tumor cells has been considered a desired biomarker for checkpoint inhibitors activity this concept needs to be contextualized and the authors’ postulate was that the output of PDE4 inhibition, with the potential to suppress cytotoxic secretion and the immune microenvironment, could in fact associate poor response to immune checkpoint blockade (Page 9, First Full Paragraph). Roflumilast did not decrease the anti-lymphoma activity of an anti-PD-L1 antibody, but this “neutral” outcome was achieved in unexpected ways: (i) the efficacy of anti-PD-L1 used as single agent was, predictably, associated with a substantial T-cell infiltrate in the tumor microenvironment and (ii) although the anti-lymphoma efficacy of the roflumilast/anti-PD-L1 combination was not significantly inferior to anti-PD-L1 alone, the T-cell infiltrate was quantitatively modest and instead displayed a subtle, and potentially consequential, qualitative changes, including an increase in CD8 cytotoxic T-cells and decrease in CD4 T-cells (Id.). The changes in the TIL profile mediated by PDE4 inhibition are not sufficient to promote anti-tumor immunity, as roflumilast was ineffective as a single agent, but they may explain how even in absence of a prominent T-cell infiltrate, the roflumilast/anti-PD-L1 combination still maintained anti-cancer activity (Id.). Thus, Sasi teaches that cAMP induces PD-L1 transcription (e.g., elevated cAMP with PDE4 inhibition via roflumilast) and protein expression and mechanistically, and the cAMP effectors PKA and CREB induce the transcription/secretion of IL-10, IL-8 and IL-6, which initiate an autocrine loop that activates the JAK/STAT pathway and ultimately increase PD-L1 expression in the cell surface, and suggests the administration of a combination of roflumilast and an anti-PD-L1 antibody maintains anti-cancer activity even in the absence of prominent T cell infiltrate. Sasi further teaches that while it is possible that the cytokines involved as intermediaries in the cAMP-PD-L1 interplay will vary according to the tissue type, he authors also found a significant correlation between PD-L1 and IL-10, IL-8, IL-6 expression in melanoma, lung and colon cancer, suggesting that the relationships established in the present study are likely to apply to other similar tumor types (including colon cancer).
However, it is noted that Sasi does not explicitly disclose/suggest the combination of roflumilast with an anti-PD-1 antibody, such as nivolumab. This deficiency is remedied by Yaghoubi.
Yaghoubi teaches that colorectal cancer (CRC), as a prominent cause of cancer-related deaths, has historically been notable worldwide and many attempts have been made to raise the overall survival of CRC patients and immune response has long been a question of great interest in a wide range of fields such as cancer therapies and anti-tumor immunity through checkpoint inhibitors, specifically anti PD-1/ PD-L1 interaction, is a new line of research for treatment of CRC patients; following the successful development of anti-PD-1 for melanoma, renal cell carcinoma, and non-small cell lung cancer, several clinical trials have been conducted on monoclonal antibodies (MAbs) against PD-1 in CRC, and there is a growing body of literature that recognizes the importance of anti-PD-1 therapy for MSI (Microsatellite instability) tumors among CRC subtypes (Abstract). A large and longitudinal study on paired adenocarcinoma and normal colon mucosa from 142 patients, revealed a significant increase of the CD4/CD8 ratio and accumulation of regulatory T cells (Tregs) within the adenocarcinoma of colon wherein the high frequency of Tregs correlated with the local infiltration and extension of the tumor (Page 313, Column 2, Last Full Paragraph). NK cells can identify cancer cell surface ligands such as natural cytotoxicity receptors, and their activation and subsequent cytotoxic activity are provided by down regulation or lack of major histocompatibility complex (MHC) class I molecule on colon cancer cells, but high expression of PD-1 on NK cells from patients of colorectal cancer, results in NK cell dysfunction and poor prognosis (Last Line of Page 313 through Page 314). Following the successful development of anti-PD-1 for melanoma, renal cell carcinoma, and non-small cell lung cancer, several trials have been performed on solid tumors, in particular, mCRC; nivolumab (BMS-936558; MDX-1106) is a monoclonal antibody against the PD-1 receptor, which has been tested in patients with CRC (Page 314, Column 1, Second Full Paragraph). A phase I clinical trial (NCT00441337) with 39 patients with various types of advanced solid tumor was conducted; fourteen patients had mCRC and these patients received nivolumab with four escalating dose cohorts of 0.3, 1, 3 and 10 mg/kg (Id.). One durable complete response off-treatment was achieved in one patient with CRC (3 mg/kg); the tumor cell surface PD-L1 (B7-H1) expression was indicated as the possible predictor marker of response to treatment (Id.). A complete response was reported in one dMMR CRC (deficiency in mismatch repair of DNA) patient with PD-L1 expression (B7-H1) on tumor cells, so PD-L1 expression and also dMMR genotype, were considered as probable markers of response to PD-1 inhibitors (Id.). Further investigation into the expression of PD-L1 in 19 CRC patients, revealed that PD-L1 expressing tumors may predict activity of nivolumab in advanced cancers (Id.). Continuous assessment of nivolumab in patients with metastatic dMMR or MSI-H CRC, from 31 sites (academic centers and hospitals) in eight countries, through an open label, phase II study, revealed that nivolumab provided durable responses and disease control in pre-treated patients with dMMR/MSI-H metastatic CRC; of the 74 patients who were enrolled, 51 patients had disease control for 12 weeks or longer and eight had responses lasting 12 months or longer (Kaplan-Meier 12-month estimate 86%, 95% CI 62–95) (Page 314, Column 1, Last Paragraph). Dramatic differences have been reported in response to PD-1 inhibitors between responders and non-responders; immunohistochemistry (IHC) for PD-L1 protein expression showed that rate of immune response is identical to 48% in PD-L1+ tumors in comparison to 15% in PD-L1− tumors and evaluation of PD-L1 expression in some subtypes of CRC revealed that about 37% of MMR proficient and 29% of MMR deficient CRCs were PD-L1+ wherein this finding correlated well with better response to PD-1 inhibitors and improved survival (Page 316, Column 1, Last Paragraph). Thus, Yaghoubi teaches that anti-PD-1 antibody nivolumab is indicated for the treatment of colorectal cancers (including cancers originating in the colon specifically) and further suggests that PD-L1 expression and also dMMR genotype, were considered as probable markers of response to PD-1 inhibitors an improved survival.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute the anti-PD-L1 agent of Stasi, used in combination with the PDE4 specific inhibitor roflumilast, with the anti-PD-1 antibody nivolumab for the treatment of a solid cancer (e.g., colon cancer, including metastatic cancer). One would have been motivated to substitute the anti-PD-L1 agent of Stasi with nivolumab because Stasi teaches that roflumilast has been implicated in elevated cAMP levels and subsequently the innate and adaptive immune system, wherein cAMP initiates an autocrine loop that is suggested to increase PD-L1 expression at the cell surface in various solid tumors (e.g., in lymphoma, colon cancer, lung cancer, melanoma) and Yaghoubi teaches that nivolumab is established in the treatment of solid tumors (including metastatic colorectal cancers) wherein PD-L1 expression is indicated to be predictive of response and increased survival with nivolumab treatment. One of ordinary skill in the art would have a reasonable expectation of success because the combination of roflumilast with an anti-PD-L1 agent has been shown to have anti-cancer activity, as indicated by Sasi, and nivolumab is specifically indicated as a therapeutic agent in the treatment of colorectal cancers expressing PD-L1, as indicated by Yaghoubi.
Further, it is known in the art that anti-PD-1 and anti-PD-L1 agents work through inhibiting the PD-1/PD-L1 axis by blocking the interaction of PD-1 and PD-L1. One of skill in the art could have substituted one known PD-1/PD-L1 axis inhibitor for another, the anti-PD-L1 agent of Stasi for the anti-PD-1 agent nivolumab of Yaghoubi, and the results of the combination therapy would have been predictable in that it would reasonably be expected to have anti-cancer effects.
Claims 65-66 are rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Sasi et. al. (Leukemia, 2021, 35(7), 1990-2001; published online Dec. 2020; herein after referred to as "Sasi") and non-patent literature by Yaghoubi et. al. (Biomedicine & Pharmacotherapy, 2019, 110, 312-318; herein after referred to as "Yaghoubi "), as applied to claims 61-64 above, and in further view of non-patent literature by McEwan (Doctoral Thesis, University of Glasgow, 2008; herein after referred to as “McEwan”).
Claims 61-64 are rendered obvious by the combination of Sasi and Yaghoubi. However, neither reference teaches or suggests the treatment of a metastatic tumor, specifically metastatic colon cancer, with liver metastasis. This deficiency is remedied by McEwan.
McEwan teaches using modulators of cAMP pathways, including inhibitors of phosphodiesterase 4 (PDE4) enzymes, which are under clinical development for other disease states, to inhibit the breakdown of cAMP and to assess the effects of raising intracellular cAMP on colon cancer proliferation and survival; McEwan (i) found that some chemoresistant cancer cells are addicted to keeping low cAMP in PDE4 regulated compartments, and modulation of this pool causes G1/S-phase arrest and apoptosis, (ii) shows that PDE4 controlled cAMP negatively regulates the PI3-Kinase/Akt pathway, which some cells are addicted to for survival, and (iii) investigated the expression and role of PDE4 enzymes in metastatic colon cancer cells and assessed the effects of modulating their expression on survival (Abstract). McEwan established that PDE4 expression and activity is altered in metastatic cells (see Chapter 5). Treatment of KM12C cells with the adenylyl cyclase activator, Fsk (50 μM; Fsk elevates cAMP), completely inhibits their proliferation whilst treatment with 1 μM Fsk results in approximate 50 % inhibition of their proliferation (Figures 14 C and 30 A), and a number of variants of this cell line have been described that differ in their abilities to metastasize to the liver of nude mice following intrasplenic injection; McEwan evaluated the KM12L4A and KM12SM metastatic variants of the KM12C cells for their abilities to proliferate in the presence of Fsk (Page 164, Section 5.2). KM12L4A cells exhibited increased tolerance to Fsk-mediated growth inhibition (Figure 30 B) compared to the non-metastatic KM12C parental cell line (Figure 30 A); KM12L4A cells were resistant to growth inhibition up to a concentration of 25 μM Fsk, which gave an approximate 50% inhibition of proliferation at day 5 of the assay and was statistically significant (P < 0.01; Figure 30 D) and KM12SM cells, also a metastatic variant of KM12Cs, exhibited increased tolerance to Fsk mediated inhibition of proliferation (Figure 30 C) with 10 μM Fsk giving an approximate 50% inhibition (Figure 30 D), which was also statistically significant (P < 0.05) compared to 10 μM Fsk treated KM12C cells at day 5 (Id.). Furthermore, KM12C cells had relatively low PDE4 activity (13 ± 3 pmol/min/mg protein; Figure 15 E and Figure 31 A) whereas KM12L4A metastatic cells had a 4 to 5 fold increase in PDE4 specific activity (70 ± 3 pmol/min/mg protein; Figure 31 A) and KM12SM cells had a similar increase in PDE4 specific activity (60 ± 7 pmol/min/mg protein; Figure 31 A) (Page 168, Section 5.3). McEwan found that the metastatic derivatives of KM12C cells, namely the experimentally derived KM12L4A and spontaneous metastatic cell line KM12SM, have increased resistance to cAMP induced inhibition of proliferation; it appears that a hierarchal correlation exists between increasing metastatic potential and decreased sensitivity to Fsk, where Fsk resistance is ordered as such KM12C < KM12SM < KM12L4A; with KM12C cells being least metastatic (and most sensitive to Fsk) and KM12L4A cells being producing the greatest frequency of liver metastases (and being least sensitive to Fsk) when injected into the spleens of nude mice (Page 182, Section 5.7). The studies of McEwan raise the possibility that PDE4 expression may be generally associated with late stage metastatic tumours, and that this may be a result of increased cAMP signaling occurring during tumour progression (Page 184). In summary, McEwan found that PDE4 activity is 4 to 5-fold higher in two highly-metastatic variant cell lines, namely KM12L4A and KM12SM, compared to their poorly-metastatic parental cell line KM12C and the important role of PDE4s in the Fidler model of colorectal cancer cell line in regulating proliferation raises the exciting prospect that a Fsk/rolipram-type of treatment (rolipram is a PDE4-specific inhibitor) may be exploited as a therapeutic strategy for epithelial cancers (Page 186, Section 5.10). Thus, McEwan teaches that cAMP, and more specifically PDE4, is implicated in colon cancer cell lines, and PDE4 is significantly upregulated in metastatic cancer cell lines (i.e., cancer cell lines that produce liver metastases) and suggests that treatments that elevate cAMP and/or inhibit PDE4 activity can be exploited as a therapeutic strategy.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to use the anti-cancer combination of roflumilast and nivolumab, rendered obvious by Sasi and Yaghoubi, to treat subjects who have metastatic colon cancer, wherein said metastatic colon cancer has liver metastases as suggested by McEwan. One would have been motivated to treat said subjects with metastatic colon cancer with liver metastasis because McEwan specifically suggests that colon cancer with liver metastasis has increased PDE4 activity and inhibition of PDE4 activity can be exploited as a therapeutic strategy. One of ordinary skill in the art would have a reasonable expectation of success treating subjects who have metastatic colon cancer, wherein said metastatic colon cancer has liver metastases as suggested by McEwan because McEwan suggests PDE4 inhibition as a therapeutic strategy, and the combination of Sasi and Yaghoubi renders obvious treating metastatic colon cancer with the anti-cancer combination of roflumilast (a PDE4 specific inhibitor) and nivolumab.
Conclusion
Claims 1-66 are pending. Claims 1-60 are withdrawn. Claims 61-66 are rejected. No claims are allowed.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
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