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 .
Status of the Claims
Claims 73-97 are pending in the instant application and subject to examination herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/30/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 91 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “cytokine-inducible SH2-containing protein” in claim 91 is used by the claim to mean “an intracellular immune checkpoint inhibitor,” while the accepted meaning is “an immune checkpoint.” The term is indefinite because the specification does not clearly redefine the term.
Claim 91 further limits claim 73, regarding a method of treating a cancer comprising the combination administration of Rigosertib1 and a checkpoint inhibitor, to a narrower genus of checkpoint inhibitor wherein the checkpoint inhibitor is cytokine-inducible SH2-containing protein (CISH). Thus, claim 91 claims CISH as a checkpoint inhibitor, when in fact, CISH is an immune checkpoint and not a checkpoint inhibitor.
The terms “checkpoint” and “checkpoint inhibitor” are used in the instant claims in a manner that is consistent with the commonly accepted definitions of these terms. The instant Specification does not provide an explicit definition of “checkpoint inhibitor”; however, the Specification does provide a description of checkpoint inhibitors (paragraph [0121]), from which a person of ordinary skill in the art would at once understand the meaning of the terms “checkpoint” and “checkpoint inhibitor” in the context of the disclosed invention:
In some embodiments, disclosed herein is a method of treating a cancer by administering an immunomodulatory agent. In some embodiments, disclosed herein is a method of treating a cancer by administering a compound of a disclosure and a cancer immunotherapy. In some embodiments, the cancer immunotherapy targets an immune checkpoint. In some embodiments, the cancer immunotherapy can block an inhibitory checkpoint and restore immune system function. In some embodiments, disclosed herein is a method of treating a cancer by administering a compound of the disclosure and an antibody. In some embodiments, disclosed herein is a method of treating a cancer by administering a compound of the disclosure and a biologic.
Thus, a person of ordinary skill in the art would recognize that a “checkpoint” is an endogenous mechanism that inhibits immune system function, and a “checkpoint inhibitor” is a biologic agent that, upon administration to the subject, blocks the checkpoint and restores immune system function. Applicant discloses a list of specific exemplary checkpoint inhibitors that is composed of monoclonal antibodies that are known in the art to bind to PD-1, PD-L1 or CTLA-4 (paragraph [0148]). Applicant also specifically discloses that in some embodiments of the invention, “the checkpoint inhibitor is cytokine-inducible SH2-containing protein (CISH)” (paragraphs [0125] and [0240]) without disclosing what immune checkpoint would be inhibited by CISH in a scenario where CISH would be a checkpoint inhibitor. In contrast, Applicant does specifically disclose known which checkpoint is inhibited by specific inhibitors, when the checkpoint is PD-1/PD-L1 (paragraphs [0130]-[0133]), and/or CTLA-4 (paragraph [0140]). CISH is not identified as an inhibitor of PD-1/PD-L1, or of CTLA-4, or of any other specific immune checkpoint.
A review of the field of art shows that CISH is, in fact, an immune checkpoint, rather than an immune checkpoint inhibitor – see, for example, the teaching of Chikuma (Chikuma, et al.; Cancer Science, v108, pp574-580; 2017). Chikuma teaches a review on the topic of cytokine signaling pathways as immune checkpoints for cancer immunotherapy, specifically including CISH, designated “CIS” by Chikuma (Abstract). Chikuma teaches that T-cell activation requires signals from cytokine receptors, and therefore negative regulators of cytokine signaling must be important immune checkpoint molecules that regulate anti-tumor immunity (page 574). Chikuma teaches that most cytokines, including interleukins, interferons and hematopoietic growth factors, activate the JAK/STAT pathway, and that Suppressors of Cytokine Signaling (SOCS) proteins and cytokine-inducible SH2-containing protein (“CIS”) compose a family of intracellular proteins that inhibit the JAK/STAT pathway via the binding of intracellular phosphorylated tyrosine residues of the activated cytokine receptors (pages 575-576, including Figure 2).
Chikuma further teaches that CISH binds to phosphorylated cytokine receptors, such as the EPO receptor, IL-2 receptor, IL-3 receptor b chain, prolactin receptor, and the growth hormone (GH) receptor, which mostly activate STAT5 (pages 575-576, bridging paragraph). Thus, CISH is believed to suppress STAT5 by masking STAT5-binding phosphotyrosine motifs on the receptors, and also by inducing ubiquitin/proteasome-dependent degradation of the activated receptors, and further elaborates that genetic deletion of CISH in mice has been shown to lead to enhanced T-cell expression and function, resulting in pronounced and durable regression of cancer tumors (page 576). Chikuma’s Figure 2, shown below, shows CISH (“CIS1”) in its inhibitory interactions with the cytokine-activated JAK/STAT pathway. As an inhibitor of an immune activation cascade, CISH qualifies as an immune checkpoint, per the teaching of Chikuma and consistent with the implicit definition of immune checkpoint disclosed in the instant Specification. An inhibitor of CISH would therefore be an immune checkpoint inhibitor.
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Thus, Chikuma teaches that CISH is an intracellular immune checkpoint, not an intracellular checkpoint inhibitor. Claim 91 is indefinite for using the term “cytokine-inducible SH2-containing protein (CISH)” as a checkpoint inhibitor, when the commonly accepted meaning of the term is “an immune checkpoint”.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 73-74, 80-82, 84, 86, 88, 92 and 96-97 are anticipated by Veluswamy.
Claims 73-74, 80-82, 84, 86, 88, 92 and 96-97 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Veluswamy (Veluswamy, R.; Clinical Trial NCT04263090: “Rigosertib Plus Nivolumab for KRAS+ NSCLC Patients Who Progressed on First-Line Treatment,” Record date 02/07/2020, accessed from https://clinicaltrials.gov/study/NCT04263090?tab=history on 19Mar2026).
Claim 73 is drawn to a method of treating a cancer, comprising administering a combination of two agents, each in a therapeutically-effective amount, the two agents being (1) Rigosertib2 or a pharmaceutically acceptable salt or zwitterion thereof in a dosage of at least 100 mg, and (2) a checkpoint inhibitor.
Veluswamy teaches a clinical trial wherein patients with stage IV lung adenocarcinoma with KRAS mutation are treated with a combination of Rigosertib and Nivolumab (“Study Description” section, “Brief Summary” subsection). Veluswamy further teaches that the Rigosertib dosing is done at three levels: “(dose D1: 280mg twice daily; dose D2: 560mg in the morning (qAM), 280mg in the evening (qPM); dose D3: 560mg twice daily; taken by mouth for
21 consecutive days of the 28 day cycle)” (“Study Description” section, “Detailed Description”).
Thus, claim 73 is anticipated by the teaching of Veluswamy.
Claim 74 further limits claim 73 to wherein the cancer comprises a KRAS mutation, and is met by the teaching of Veluswamy as discussed above.
Claim 80 further limits claim 73 to wherein the cancer is non-small cell lung carcinoma. Veluswamy teaches that the lung adenocarcinoma to be treated in the study is non-small cell lung carcinoma (“Conditions” section).
Claim 81 further limits claim 73 to wherein the cancer is lung adenocarcinoma, and is met by the teaching of Veluswamy as discussed above.
Claim 82 further limits claim 73 to wherein the dose of Rigosertib Rigosertib (or the pharmaceutically acceptable salt or zwitterion thereof) is in the range of 100-3000 mg, and is met by the teaching of Veluswamy as discussed above.
Claim 84 further limits claim 73 to wherein Rigosertib (or the pharmaceutically acceptable salt or zwitterion thereof) is administered orally, and is met by the teaching of Veluswamy as discussed above.
Claim 86 further limits claim 73 to wherein the checkpoint inhibitor is a cell-surface checkpoint inhibitor. Claim 88 further limits claim 73 to wherein the checkpoint inhibitor is a PD-1 inhibitor. Claim 92 further limits claim 73 to wherein the checkpoint inhibitor is Nivolumab.
As discussed above, Veluswamy teaches the administration of Nivolumab with Rigosertib. Veluswamy does not explicitly describe Nivolumab as a PD-1 inhibitor or as a cell-surface checkpoint inhibitor; however, a person of ordinary skill in the art would at once recognize Nivolumab as a PD-1 inhibitor and as a cell-surface checkpoint inhibitor, as these are inherent attributes of Nivolumab and were well known in the art as of the effective filing date of the instant application, as evidenced, for example, in Hamanishi (Hamanishi, et al.; International Journal of Clinical Oncology, v21, pp462-473; 2016). Hamanishi provides a review of clinical applications of PD-1 inhibitors and PD-L1 inhibitors, each of which are checkpoint inhibitors, in the treatment of cancer (Abstract), and Hamanishi includes a table showing known PD-1 and PD-L1 inhibitors, including Nivolumab, which Hamanishi teaches is a PD-1 inhibitor (Table 1, page 463). Hamanishi further shows that PD-1 is a surface receptor (Figure 1, page 463), thus a person of ordinary skill in the art would at once recognize that Nivolumab, as a PD-1 inhibitor, is a cell surface checkpoint inhibitor.
Claim 96 further limits claim 73 to wherein Rigosertib (or the pharmaceutically acceptable salt or zwitterion thereof) is administered on 21 consecutive days of a 28-day cycle. Veluswamy teaches that Rigosertib is administered for 21 consecutive days of the 28 day cycle of administration (“Study Description” section, “Detailed Description” subsection).
Claim 97 further limits claim 73 to wherein the checkpoint inhibitor is administered on day 1 and day 15 of a 28-day cycle. Veluswamy teaches that Nivolumab is administered every 2 weeks, and does not specific any staggering of the administration of Nivolumab from the administration of Rigosertib, by which a person of ordinary skill in the art would at once recognize that the specified combination therapy of Rigosertib and Nivolumab must begin together, on day 1, and therefore the second administration of Nivolumab must occur on day 15 of the 28 day cycle.
Thus, claims 74, 80-82, 84, 86, 88, 92 and 96-97 are anticipated by the disclosure of Veluswamy.
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 73-79, 80-82, 84, 86, 88, 92 and 96-97 are unpatentable over Veluswamy in view of Athuluri-Divakar.
Claims 73-79, 80-82, 84, 86, 88, 92 and 96-97 are rejected under 35 U.S.C. 103 as being unpatentable over Veluswamy (Veluswamy, R.; Clinical Trial NCT04263090: “Rigosertib Plus Nivolumab for KRAS+ NSCLC Patients Who Progressed on First-Line Treatment,” Record date 02/07/2020, accessed from https://clinicaltrials.gov/study/NCT04263090?tab=history on 19Mar2026) in view of Athuluri-Divakar (Athuluri-Divakar, et al.; Cell, v165, pp643-655; 2016).
The limitations of claims 73-74, 80-82, 84, 86, 88, 92 and 96-97 and the teaching of Veluswamy are discussed in the rejection above and hereby incorporated into the instant rejection.
Claims 75-78 further limit claim 74, each to a specific KRAS mutation, the mutations being G12V, G12D, G12C and I46T.
Claim 79 further limits claim 73 to wherein the cancer does not comprise a KRAS mutation.
As discussed above, Veluswamy teaches the treatment of lung adenocarcinoma patients with KRAS mutation. Veluswamy does not teach a specific KRAS mutant to be treated, or the treatment of lung adenocarcinoma without KRAS mutation; however, a person of ordinary skill in the art would have a reasonable expectation of success in using the treatment taught by Veluswamy for the treatment of lung adenocarcinoma patients having any of the specified mutations of claims 75-78 and/or lung adenocarcinoma lacking a KRAS mutation, because it was known in the art that the mechanism of KRAS inhibition by Rigosertib is independent of single-site KRAS mutations, or the lack thereof, because Rigosertib inhibits KRAS not by binding directly to KRAS, but rather by binding to KRAS effector proteins, per the teaching of Athuluri-Divakar.
Athuluri-Divakar teaches a study in the binding behavior of Rigosertib and its role in the inhibition of KRAS (Abstract). Athuluri-Divakar teaches that RAS has a switch region that interacts with a large number of effector proteins containing a common RAS-binding domain (RBD), and that RBD-mediated interactions are essential for RAS signaling, and that Rigosertib acts as a RAS-mimetic and interacts with the RBDs of RAF kinases, resulting in their inability to bind to RAS, disruption of RAF activation, and inhibition of the RAS-RAF-MEK pathway, and that Rigosertib also binds to the RBDs of Ral-GDS and phosphoinositide 3-kinases (PI3Ks) (Abstract). Athuluri-Divakar shows that Rigosertib effectively inhibits cancer cells containing different KRAS mutations, in the inhibition of A549 lung cancer cells having KRASG12S mutation and HCT116 colorectal cancer cells having KRASG13D mutation, both as xenografts in nude mice, and shows that Rigosertib effectively decreased tumor growth compared to vehicle (water) treated mice (page 650, including Figures 4D-E). A person of ordinary skill in the art would recognize the comparability of results in the xenograft studies as resulting from the Rigosertib binding mode taught by Athuluri-Divakar – i.e., that the efficacy of Rigosertib is independent of the KRAS mutation state, because Rigosertib’s binding efficacy depends on its binding to the effector proteins of KRAS, not to the any subtle structural changes in the KRAS protein itself.
Applicant’s invention is unpatentable over the teaching of Veluswamy in view of the teaching of Athuluri-Divakar, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in using the method of cancer treatment taught by Veluswamy, comprising administering a combination of Rigosertib and Nivolumab, to treat lung adenocarcinoma having a site mutation at G12C, G12D, G12V, or I46T, or having no KRAS mutation, because it was known in the art that the mechanism of Rigosertib inhibition of KRAS does not depend on Rigosertib binding to KRAS itself but rather interacting with RAS-effector proteins, and so the specific site mutation (or lack thereof) on KRAS will not effect the binding efficacy of Rigosertib with its actual direct biological targets.
Thus, the invention was prima facie obvious at the time of filing.
Claims 73-74, 80-85, 86, 88, 92 and 96-97 are unpatentable over Veluswamy in view of Yaffe.
Claims 73-74, 80-85, 86, 88, 92 and 96-97 are rejected under 35 U.S.C. 103 as being unpatentable over Veluswamy in view of Yaffe (US 2015/0209359 A1).
The limitations of claims 73-74, 80-82, 84, 86, 88, 92 and 96-97 and the teaching of Veluswamy are discussed in the rejection above and hereby incorporated into the instant rejection.
Claim 83 further limits claim 73 to wherein the Rigosertib (or the pharmaceutically acceptable salt or zwitterion thereof) is administered intravenously.
Claim 85 further limits claim 73 to wherein Rigosertib is administered in the form of the sodium salt of Rigosertib.
Veluswamy teaches oral administration of Rigosertib; however, a person of ordinary skill in the art would have a reasonable expectation of success in using the method of cancer treatment of Veluswamy with intravenous administration of Rigosertib, because intravenous administration of Rigosertib was known in the art, per the disclosure of Yaffe.
Yaffe discloses pharmaceutical compositions and methods of cancer treatment, including combination treatment comprising an antiandrogen or androgen antagonist in combination with a Polo-like kinase (Plk) inhibitor, wherein the active agents can be administered separately or together (Abstract). Yaffe specifically discloses Rigosertib, in its sodium salt form, as a Plk1 inhibitor for use in the invention disclosed therein (paragraphs [0147]-[0148]), and discloses that the agents for use in the invention disclosed therein can be administered intravenously (paragraph [0181]) and specifically discloses intravenous administration of Rigosertib (paragraphs [0150] and [0152]).
Applicant’s invention is unpatentable over the teaching of Veluswamy over the disclosure of Yaffe, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in treating a lung adenocarcinoma patient with the treatment of Veluswamy, modified to administer Rigosertib intravenously and it its Rigosertib sodium salt form, because it was known in the art that the sodium salt form of Rigosertib can be made and used in the treatment of cancer and can be administered intravenously, per the disclosure of Yaffe.
Thus, the invention was prima facie obvious at the time of filing.
Claims 73-74, 80-82, 84, 86, 88, 92-93 and 96-97 are unpatentable over Veluswamy in view of Uras.
Claims 73-74, 80-82, 84, 86, 88, 92-93 and 96-97 are rejected under 35 U.S.C. 103 as being unpatentable over Veluswamy in view of Uras (Uras, et al.; International Journal of Molecular Sciences, v21, article 4325, pp1-31; 2020)3.
The limitations of claims 73-74, 80-82, 84, 86, 88, 92 and 96-97 and the teaching of Veluswamy are discussed in the rejection above and hereby incorporated into the instant rejection.
Claim 93 further limits claim 73 to wherein the checkpoint inhibitor is Pembrolizumab (a known PD-1 inhibitor).
Veluswamy combines administration of Rigosertib with Nivolumab, a checkpoint inhibitor that is a PD-1 inhibitor. Veluswamy does not teach the replacement of Nivolumab with a different checkpoint inhibitor of the same type (PD-1 inhibitor), such as Pembrolizumab. However, a person of ordinary skill in the art would have a reasonable expectation of success in treating a lung adenocarcinoma using a modification of the method of Veluswamy, wherein Nivolumab is substituted for Pembrolizumab, another PD-1 inhibitor, because it was known in the art that pembrolizumab is a suitable checkpoint inhibitor for KRAS mutant NSCLC, including in combination with RAS/RAF/MEK kinase inhibitors, per the teaching of Uras.
Uras provides a review of therapeutic strategies tailored for KRAS mutant NSCLC (Abstract), including teaching that numerous therapeutic strategies have been developed including targeting KRAS membrane associations, synthetic lethality partners, blockage of downstream signaling cascades, targeting metabolic reprogramming, direct targeting of KRAS and immunotherapy (page 2, including Figure 3). Uras teaches that cancers escape immune surveillance by aberrantly expressing immune checkpoints (e.g., upregulation of the immunosuppressive protein PD-L1) that mask them from the host immune system. Immune checkpoint blockage using monoclonal antibodies against PD-1 and its main ligand PD-L1 has substantially improved the treatment landscape of advanced-stage NSCLC and made its most strong impact in the stage III and first-line stage IV settings (page 15). Uras advocates for “rational combinations (e.g., immunotherapy plus conventional therapies targeting RAS downstream cascade or cell cycle inhibitors) for a durable therapy response” in KRAS mutant NSCLC (page 16). As discussed above, Uras teaches a combination treatment with the MEK inhibitor trametinib along with the PD-1 inhibitor Pembrolizumab (page 16). Uras also teaches the same clinical trial as Veluswamy (NCT04263090), wherein combination administration of Rigosertib with Nivolumab is given to treat KRAS mutant NSCLC patients (page 13). Thus, Uras teaches that Pembrolizumab is a PD-1 inhibitor, like Nivolumab, and a viable immune checkpoint inhibitor for combination therapy with RAS/RAF/MEK target(s).
Applicant’s invention is unpatentable over the teaching of Veluswamy in view of the teaching of Uras, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in modifying the treatment of Veluswamy to substitute one PD-1 inhibitor for another to achieve a predictable result, namely to substitute Pembrolizumab for Nivolumab, because it was known in the art that both of these PD-1 inhibitors are useful in the treatment of KRAS mutant NSCLC wherein the treatment is combination therapy combining a PD-1 inhibitor with a target of the RAS/RAF/MEK pathway.
Thus, the invention was prima facie obvious at the time of filing.
Claims 73-74, 80-82, 84, 86-89, 92 and 94-97 are unpatentable over Veluswamy in view of Uras and Johnson.
Claims 73-74, 80-82, 84, 86-89, 92 and 94-97 are rejected under 35 U.S.C. 103 as being unpatentable over Veluswamy in view of Uras and Johnson (Johnson, et al.; Current Treatment Options in Oncology, v15, pp658-669; 2014).
The limitations of claims 73-74, 80-82, 84, 86, 88, 92 and 96-97 and the teachings of Veluswamy and Uras are discussed in the rejection above and hereby incorporated into the instant rejection.
Claim 87 further limits claim 73 to wherein the checkpoint inhibitor is a cytokine T-lymphocyte-associated protein 4 (CTLA-4) inhibitor. Claim 94 further limits claim 73 to wherein the checkpoint inhibitor is ipilimumab (a known CTLA-4 inhibitor).
Claim 89 further limits claim 73 to wherein the checkpoint inhibitor is a PD-L1 inhibitor. Claim 95 further limits claim 73 to wherein the checkpoint inhibitor is atezolizumab (a known PD-L1 inhibitor).
Veluswamy combines administration of Rigosertib with Nivolumab, a checkpoint inhibitor that is a PD-1 inhibitor. Veluswamy does not teach the replacement of Nivolumab with a different checkpoint inhibitor a different type, such as a CTLA-4 inhibitor, or a PD-L1 inhibitor. However, a person of ordinary skill in the art would have a reasonable expectation of success in treating a lung adenocarcinoma using a modification of the method of Veluswamy, wherein Nivolumab is substituted for another checkpoint inhibitor of another type such as a PD-L1 inhibitor or a CTLA-4 inhibitor, including for the specific checkpoint inhibitors Atezolizumab (PD-L1) or Ipilimumab (CTLA-4 inhibitor), because it was known in the art that PD-L1 and CTLA-4 modes of checkpoint inhibition are synergistic with RAS/RAF/MEK inhibition in NSCLC bearing mutant KRAS, per the teaching of Uras, and it was known in the art that Atezolizumab and Ipilimumab are effective exemplary PD-L1 and CTLA-4 inhibitors, respectively, in the treatment of NSCLC, per the teaching of Johnson.
As discussed above, Uras teaches that immune checkpoint blockage using monoclonal antibodies against PD-1 and its main ligand PD-L1 has substantially improved the treatment landscape of advanced-stage NSCLC and made its most strong impact in the stage III and first-line stage IV settings, as well as that mutant KRAS has been associated with increase in PD-L1 expression (page 15). Uras advocates for “rational combinations (e.g., immunotherapy plus conventional therapies targeting RAS downstream cascade or cell cycle inhibitors) for a durable therapy response” in KRAS mutant NSCLC (page 16). As discussed above, Uras teaches a combination treatment with the MEK inhibitor trametinib along with the PD-1 inhibitor Pembrolizumab (page 16). Alongside MEK/PD-1 combination therapy, Uras also teaches the study of the RAF/MEK inhibitor RO5126766 for patients who have previously received treatment with a PD-1 or PD-L1 inhibitor (NCT03681483) (page 13). Uras teaches a combination treatment of pulsatile MEK inhibition combined with CTLA4-blockage, that gave improved anti-tumor activity compared to the MEK inhibition alone (page 16). Uras teaches a combination pulsatile regimen of the MEK inhibitor selumetinib with antibodies targeting both PD-L1 and CTLA-4 (page 16). Thus, Uras shows that PD-L1 inhibition and CTLA-4 inhibition are comparable modes of checkpoint inhibition alongside PD-1 inhibition.
Johnson teaches a review of immune checkpoint inhibition in the treatment of NSCLC, not limited to KRAS mutant NSCLC. Johnson teaches that “Immune checkpoint inhibitors have shown promising results in phase I trials and are being evaluated in ongoing clinical trials in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) patients. These include agents targeting the programmed cell death-1 receptor and its ligand (PD-1/PD-L1; notably nivolumab, pembrolizumab, MPDL3280A, and MEDI-4736) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; ipilimumab and tremelimumab); these agents induce antitumor responses by inhibiting critical negative T cell regulators” (Abstract). While Johnson does not further identify the agent “MPDL3280A” as Atezolizumab, a person of ordinary skill in the art would at once recognize that the identifier “MPDL3280A” represents Atezolizumab, as this is an inherent aspect of Atezolizumab that was well-known in the art at the effective time of filing, as evidenced, for example, in Hamanishi (see above), who identifies Atezolizumab as a PD-L1 inhibitor named “MPDL3280A” (Table 1, page 463). Johnson teaches that MPDL3280A showed an overall response rate (ORR) of 23% among 53 patients in a clinical trial for NSCLC, and that there was no difference in response between KRAS wild type and mutant NSCLC patients (page 665). Johnson teaches that CTLA-4 is expressed on the surface of T-cells, and that Ipilimumab was the first checkpoint inhibitor (of any kind) to be evaluated in NSCLC patients (pages 659-660, bridging paragraph). Johnson teaches a clinical trial wherein patients received either a combination of Ipilimumab, concurrent with or phased after cytotoxic chemotherapy (carboplatin plus paclitaxel), and that in the phased combination arm, immune relate progression free survival (irPFS) was improved compared to treatment with chemotherapy alone (page 660). Johnson also teaches the combination of Nivolumab with Ipilimumab in NSCLC (page 666). Thus, Johnson shows that Atezolizumab and Ipilimumab are exemplary checkpoint inhibitors for the PD-L1 and CTLA-4 modes of checkpoint inhibition, respectively.
Applicant’s invention is unpatentable over the teaching of Veluswamy in view of the teachings of Uras and Johnson, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in using the method of cancer treatment of Veluswamy while substituting the PD-1 inhibitor Nivolumab with either Atezolizumab (a PD-L1 inhibitor) or Ipilimumab (a CTLA-4 inhibitor), because it was known in the art that checkpoint inhibition, including in combination with RAS/RAF/MEK inhibition, can be accomplished using any of the PD-1, PD-L1 or CTLA-4 checkpoint inhibition modes in the treatment of NSCLC, per the teaching of Uras, and it was known in the art that Atezolizumab and Ipilimumab are exemplary PD-L1 and CTLA-4 checkpoing inhibitors, respectively, that have shown positive results in the treatment of NSCLC, per the teaching of Johnson.
Thus, the invention was prima facie obvious at the time of filing.
Claims 73-74, 80-82, 84, 86, 88, 91-93 and 96-97 are unpatentable over Veluswamy in view of Uras.
Claims 73-74, 80-82, 84, 86, 88, 91-93 and 96-97 are rejected under 35 U.S.C. 103 as being unpatentable over Veluswamy in view of Uras and further in view of Aktoudianakis (US pG Pub 2019/0345131 Al) and Bailly (Bailly, et al.; Cancers, v13, article 3034, pp-24; 2021).
The limitations of claims 73-74, 80-82, 84, 86, 88, 92-93 and 96-97 and the teachings of Veluswamy, Uras and Johnson are discussed in the rejection above and hereby incorporated into the instant rejection.
Claim 91 further limits claim 73 to wherein the checkpoint inhibitor is an intracellular checkpoint inhibitor.
Veluswamy combines administration of Rigosertib with Nivolumab, a checkpoint inhibitor that is a PD-1 inhibitor. Nivolumab is a monoclonal antibody that a person of ordinary skill in the art would not recognize as an intracellular inhibitor, since only small molecule inhibitors would be expected to cross the cell membrane into the intracellular environment. Similarly, while Uras advocates for “rational combinations (e.g., immunotherapy plus conventional therapies targeting RAS downstream cascade or cell cycle inhibitors) for a durable therapy response” in KRAS mutant NSCLC, Uras provides for PD-1, PD-L1 and CTLA-4 inhibitors that are all monoclonal antibodies. However, a person of ordinary skill in the art would have a reasonable expectation of success in treating a lung adenocarcinoma using a modification of the method of Veluswamy, wherein Nivolumab is substituted for another checkpoint inhibitor of another type such as a PD-L1 inhibitor, as advocated by Uras, including a small molecule inhibitor of PD-L1 that would inhibit PD-L1 both in the extracellular domain of membrane-bound PD-L1 and in the soluble PD-L1 found in the intracellular domain, because small molecule inhibitors that inhibit PD-L1 were known in the art, per the disclosure of Aktoudianakis, and it was known in the art that soluble PD-L1 (sPD-L1) is found in the intracellular domain and is also a worthwhile target for immune checkpoint blockade, per the teaching of Bailly.
Aktoudianakis discloses small molecule inhibitors and methods of their use as inhibitors of PD-1/PD-L1 interaction in treating patients having cancer (paragraph [0006]), including for example Aktoudianakis’ compound 1, shown below (paragraph [1200], Table 1, page 100):
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Aktoudianakis discloses that the compounds disclosed therein inhibit the PD-1/PD-L1 interaction by dimerizing PD-L1 – i.e., inducing or stabilizing PD-L1 dimer formation (paragraph [0327]), and further elaborates that the dimerization occurs at the extracellular domain of PD-L1 (paragraph [1206]). Aktoudianakis discloses biological assays demonstrating potency for the compounds disclosed therein, including compound 1, to inhibit PD-1/PD-L1 interaction (paragraph [1202], including Table 3) and to dimerize PD-L1 (paragraph [1207], including Table 4).
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Bailly teaches a review of the expression, form, and biological activity of soluble PD-L1 (sPD-L1) as compared to other known biological forms of PD-L1, including membrane-bound PD-L1 (mPD-L1) as well as exosomal PD-L1 (ePD-L1) and nuclear PD-L1 (nPD-L1) (Abstract). Bailly teaches that soluble PD-L1 is not anchored into a plasma membrane or vesicle, but is free in solution and plays an important immune-regulatory role (pages 3-4, bridging paragraph). Bailly teaches that PD-L1 has a structure that includes immunoglobulin-like extracellular domains (IgV and IgC), a short stalk region that connects the IgC domain to a transmembrane domain, and an intracellular tail region ((pages 3-4, bridging paragraph). Bailly teaches that sPD-L1 is formed by proteolytic cleavage at the short stalk region (Page 5, including Figure 3, below). Thus, sPD-L1 comprises the PD-L1 extracellular domains, including the IgV domain, which Bailly teaches is the target site for monoclonal antibodies, peptides and small molecule inhibitors of PD-L1 (page 5).
Bailly teaches that sPD-L1 can also be generated from a non-proteolytic process, via expression of the protein from certain alternative gene spliced variants (pages 7-8, including Figure 5). Bailly teaches that circulating soluble PD-L1 has been largely exploited as a diagnostic, therapeutic, or
prognostic biomarker for cancers (page 8). Bailly further teaches that sPD-L1 does bind to PD-1 and is understood to present a negative regulatory signal. Bailly teaches that native human sPD-L1 has been found to induce suppressive effects on activated T-cells, thus mimicking the effect of membrane-bound PD-L1 (mPD-L1), and that a study on sPD-L1 isolated from serum of breast cancer patients showed that sPD-L1 can inhibit T lymphocyte function, and similar results have been obtained using sPD-L1 released from lung cancer cells (page 9). Finally, Bailly teaches that sPD-L1 can play the role of a decoy or a sink for PD-L1 inhibitors, for example anti-PD-L1 antibodies, and that “a therapeutic anti-PD-L1 entity can be useful to target simultaneously the different active species that are mPD-L1, exPD-L1 and sPD-L1.” A person of ordinary skill in the art would at once recognize that a small molecule anti-PD-L1 entity, capable of acting on both membrane PD-L1 (mPD-L1) and soluble PD-L1 (sPD-L1) would be both a cell-surface checkpoint inhibitor when acting on mPD-L1 and an intracellular checkpoint inhibitor when acting on sPD-L1 in the intracellular environment.
Applicant’s invention is unpatentable over the teaching of Veluswamy in view of the teaching of Uras, and further in view of the disclosure of Aktoudianakis and the teaching of Bailly, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in using the method of combination Rigosertib/Nivolumab cancer treatment of Veluswamy while substituting the PD-1 inhibitor Nivolumab with a PD-L1 inhibitor disclosed by Aktoudianakis, because it was known in the art that checkpoint inhibition, including in combination with RAS/RAF/MEK inhibition, can be accomplished using any of the PD-1, PD-L1 or CTLA-4 checkpoint inhibition modes in the treatment of NSCLC, per the teaching of Uras, and it was known in the art that PD-L1 can be inhibited with small molecule inhibitors that inhibit PD-L1 by dimerizing the checkpoint protein into an inactive form via binding of the extracellular domain, per the disclosure of Aktoudianakis, and it was known in the art that PD-L1 is present not only on the cell surface (membrane) but also in the intracellular environment in the form of soluble PD-L1 (sPD-L1) that comprises the extracellular domain, and that sPD-L1 is an immune checkpoint protein capable of suppressing T-cells, per the teaching of Bailly.
Thus, the invention was prima facie obvious at the time of filing.
Conclusion
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 ((E)-2-(5-((2,4,6-trimethoxystyryl sulfonyl)methyl)-2-methoxyphenylamino)acetic acid
2 ((E)-2-(5-((2,4,6-trimethoxystyryl sulfonyl)methyl)-2-methoxyphenylamino)acetic acid
3 Cited in Applicant’s Information Disclosure Statement dated 09/30/2024.