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 without traverse of the species of “A method of treating cancer in a cancer patient” in the reply filed on 26 May 2026 is acknowledged. This election reads on Claims 1, 5, 35, and 61.
Claims 2-4, 6-8, 36, 39, 42, and 62-64 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected s[ecoes, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 26 May 2026.
Claims 1, 5, 35, and 61, submitted on 26 May 2026, represent all claims currently under consideration.
Priority
This application is a 371 of PCT/US2022/024087, filed 8 February 2022, which claims priority to provisional US 63/297,960, filed 10 January 2022, provisional US 63/252,542, filed 5 October 2021, and provisional US 63/173,219, filed 9 April 2021. The effective filing date is 9 April 2021.
Information Disclosure Statement
Three Information Disclosure Statements (IDSs), submitted on 21 February 2024, 29 April 2025, and 28 May 2026, are acknowledged and have been considered.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details. The current abstract is fewer than 50 words.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it is fewer than 50 words long. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claim 61 is objected to because of the following informalities: There is a superfluous “or” after prostate cancer. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 5, 35, and 61 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of certain cancers which have aberrant or dysregulated KDM4 activity, it does not reasonably provide enablement for all forms of cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. Consideration of the relevant factors sufficient to establish a prima facie case for lack of enablement is set forth below:
The nature of the invention and breadth of the claims:
The claims are directed towards a method of treating cancer, comprising administering to a patient in need a therapeutically effective amount of
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. This compound is an inhibitor of the lysine demethylase (KDM) KDM4. Thus, the claims are directed to a method which can be used to treat all forms of cancer by inhibiting KDM4.
The state of the prior art and the predictability or unpredictability of the art:
Lee provides a review of KDM4A-D in cancers, as well as currently available inhibitors and their potential as therapeutic agents for cancer treatment (Abstract). Numerous studies have demonstrated that abnormal expression of KDMs can promote the progression of cancer, including reports that KDM4A, KDM4B, and KDM4C are amplified and overexpressed in breast, esophageal, lung, prostate, and lymphatic cancers among others (2- Altered Expression and Functions of KDM4s in Cancer). Table 1 (Page 3464) lists the number of research papers on cancer and KDM4, showing KDM4s known involvement in breast, prostate, lung, colorectal, pancreatic, gastric, liver, cervical, and endometrial cancers, as well as glioma, osteosarcoma, Hodgkin’s lymphoma, multiple myeloma, lymphoma, AML, head and neck squamous cell carcinoma, esophageal cell carcinoma, bladder cancer, Kaposi’s sarcoma, neuroblastoma, uveal melanoma, melanoma, and renal cancer.
However, not all cancers can be successfully treated in this manner, and there is currently no known treatment that can be used to treat all forms of cancer. Conquer Cancer (https://web.archive.org/web/20260507071106/https://www.conquer.org/news/why-havent-we-conquered-cancer-yet-understanding-complexities-curing-cancer) provides an overview of why there has not been a single treatment which can be used for all forms of cancer. Mutations which cause cancer are not the same in every body, and differ from person to person and even within the same tumor. This diversity makes developing a single, universal cure for cancer nearly impossible. Cancer cells are adaptable, allowing them to resist treatment, spread through the body and evolve. The biggest challenges to curing cancer include that it is not a single disease. It is hundreds of diseases. Each type of cancer behaves differently, responds to treatments differently, and requires unique approaches. Even within one cancer type, there can be multiple subtypes. Breast cancer includes HER-2 positive. HR-positive, and triple-negative subtypes, each requiring a tailored treatment strategy. Cancer is influenced by both genetics and the environment. Mutations can occur due to inherited genes, lifestyle choices, or exposure to carcinogens. Because there is no single cause, treatment requires multifaceted solutions. Cancer cells can adapt to survive even the most aggressive therapies, forcing researchers to continually explore innovative treatments. A significant barrier to curing cancer is metastasis. Once a cancer becomes metastatic, it is far more difficult to treat. Cancer’s diversity is the most formidable obstacle in finding a single cure. Even within an individual patient’s tumor, there can be immense differences in cells, called tumor heterogeneity.
The relative skill of those in the art:
The artisan would generally have an advanced degree related to the treatment or study of various cancers; however, their high level of training and knowledge would not be sufficient to overcome the lack of understanding of how to use the claimed compounds to treat all forms of cancer, as not all forms of cancer are sensitive to inhibition of KDM4 as not all forms of cancer overexpress KDM4, or have aberrant KDM4 activity.
The amount of direction or guidance presented and the presence or absence of working examples:
Example 1 (Paragraph 00119) demonstrates that Compound 1 is a potent pan KDM4 inhibitor, and induces cell cycle arrest in S-phase. Figure 4 demonstrates that the compound induces apoptosis in human cancer cell lines. Anti-proliferative activity was shown in eight solid and hematological cancer lines: Jurkat, MDA-MB-231, KYSE-150, MM.1s, HL-60, HT-29, MCF-7, and Loucy (Paragraph 00122). Table 3 (Paragraph 00129) shows the results of treatment with the compound in 301 cell lines, with 209 having an IC50 below 1 µM, and 89 lines insensitive to the compound. Thus not all forms of cancer are sensitive to the compound of the examined application.
The quantity of experimentation necessary:
Considering the state of the art as described above, in particular with regards to the lack of a panacea for the treatment of cancer due to the heterogenous nature of the disease, and the high unpredictability of the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate with the scope of the claims.
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.
Claims 1, 5, and 61 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Boloor (WO 2015/200709; Publication Date: 30 December 2015).
Boloor (See IDS, 21 February 2024) discloses compositions and methods for treating cancer and neoplastic disease. The compounds and compositions are useful for inhibition of histone demethylase. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer, and/or melanoma and the like (Abstract). One embodiment provides the compound of Formula (IIa), or pharmaceutically acceptable salt thereof, having the structure
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(Paragraph 0089). This compound is identical to the compound of the examined application. In one embodiment is the method for inhibiting the histone demethylase enzyme JMJD2C (KDM4C) comprising contacting the JMJD2C enzyme with a substituted pyridine derivative compound as disclosed herein (Paragraph 00155). In particular embodiments, provided herein is a method of treating a disease regulated by histone methylation and/or demethylation in a subject in need thereof by modulating the activity of a demethylase comprising a JmjC domain (e.g., a histone demethylase such as a JHDM protein) (Paragraph 00156). In one embodiment is provided a method of treating cancer in a patient in need thereof, comprising administering to the patient a composition comprising a compound of Formula I, II, IIa, III, IV, or IV, or a pharmaceutically acceptable salt thereof. In a further embodiment, is the method for treating cancer in a patient wherein the cancer is selected from prostate cancer, breast cancer, bladder cancer, lung cancer, or melanoma (Paragraph 00157). Example 187 (Paragraph 00848) has an IC50 against JMJD2C of between 100 and 1000 nM (Table 3, Page 327), indicating that this compound potently inhibits KDM4C.
Claims 1, 5, and 61 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schule (WO 2018/183370; Publication Date: 4 October 2018).
Schule (See IDS, 21 February 2024) discloses compounds and methods for inhibiting the enzymatic activity of lysine demethylase 4 (KDM4) and treating cancer. The subject compounds and compositions are useful for inhibiting lysine demethylase 4. Furthermore, the subject compounds and compositions are useful for the treatment of breast cancer and the like (Abstract). In one embodiment, KDM4(i) compounds abrogate expression of EGFR, a driver of therapy-resistant, triple negative breast tumor cells via inhibition of the KDM4A demethylase activity (Paragraph 0006). A compound of the invention exhibited striking selectivity in inhibiting breast cancer tumors, importantly, tumors of triple-negative breast cancer (Paragraph 0025). Dysregulation of KDM4 demethylases has been documented in a variety of cancers including breast cancer. It has been shown that KDM4 controls tumor cell proliferation, particularly in aggressive breast cancers (Paragraph 0030). At least one embodiment provides a KDM4(i) compound having the structure
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wherein X is O or CH2 and R6 is N(R1)(R2) or O(R2) wherein R1 is H or C1-C6 alkyl, and R2 is optionally substituted aryl, heteroaryl, cyclyl, or heterocycle (Paragraph 0047). In at least one embodiment, X is O and R6 is N(R1)(R2), in which R1 is methyl and R2 is substituted phenyl. For example, the phenyl is substituted with methyl, ethyl, propyl, or cyclopropyl. In a specific embodiment, the KDM4(i) is 3-([[(4R)-7-[methyl[4-propan-2-yl)phenyl]amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl]amino)pyridine-4-carboxylic acid (Paragraph 0062). This compound is identical to the compound of the examined application.
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 1, 5, 35, and 61 are rejected under 35 U.S.C. 103 as being unpatentable over Boloor (WO 2015/200709; Publication Date: 30 December 2015).
Determining the Scope and Contents of the Prior Art:
The teachings of Boloor are previously described and are fully incorporated into this rejection.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
Boloor does not teach a method wherein the cancer is relapsed after prior therapy, refractory to prior therapy, or acquired resistance to prior therapy.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would have extensive medical training, with further training in oncology and the treatment of cancers using chemotherapeutic agents.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
It would be obvious to one of ordinary skill in the art to utilize the compound of Formula IIa to treat cancers which have developed resistance to prior therapy, is refractory to prior therapy, or has relapsed as there is nothing which precludes the use of this compound in methods of treating these types of cancers. The artisan would be motivated to use this compound in methods to treat these forms of cancer as they have developed resistance to, or have shown less effectiveness against, the previous treatment regimen, and thus the artisan would be motivated to utilize a new therapy which is specific against cancers which have dysregulated KDM4 activity.
Claims 1, 5, 35, and 61 are rejected under 35 U.S.C. 103 as being unpatentable over Schule (WO 2018/183370; Publication Date: 4 October 2018).
Determining the Scope and Contents of the Prior Art:
The teachings of Schule are previously described and are fully incorporated into this rejection.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
Schule does not teach a method wherein the cancer is relapsed after prior therapy, refractory to prior therapy, or acquired resistance to prior therapy.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would have extensive medical training, with further training in oncology and the treatment of cancers using chemotherapeutic agents.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
It would be obvious to one of ordinary skill in the art to utilize the compound of Schule to treat cancers which have developed resistance to prior therapy, is refractory to prior therapy, or has relapsed as there is nothing which precludes the use of this compound in methods of treating these types of cancers. The artisan would be motivated to use this compound in methods to treat these forms of cancer as they have developed resistance to, or have shown less effectiveness against, the previous treatment regimen, and thus the artisan would be motivated to utilize a new therapy which is specific against cancers which have dysregulated KDM4 activity.
Claims 1, 5, 35, and 61 are rejected under 35 U.S.C. 103 as being unpatentable over Boloor (WO 2015/200709; Publication Date: 30 December 2015) in view of Wang (US 2015/0267241; Publication Date: 24 September 2015), Daley (WO 2018/222831; Publication Date: 6 December 2018), Whetstine (WO 2018/102736; Publication Date: 7 June 2018), Whetstine (WO 2014/197835; Publication Date: 11 December 2014), Souto (Frontiers in Chemistry, 25 May 2020), and Lee (The FASEB Journal, 2020; 34:3461-3484).
Determining the Scope and Contents of the Prior Art:
The teachings of Boloor are previously described and are fully incorporated into this rejection.
Wang (See IDS, 21 February 2024) discloses a method for identifying a compound that inhibits the activity of a histone lysine demethylase (Abstract). The largest KDM4 gene family has been shown to be an eraser of a repressive mark H3K9me3/me2, while its subfamily KDM4A-KDM4C also demethylates H3K36me3/me2. KDM4A and KDM4B are overexpressed in a variety of cancers, including prostate, breast, colorectal, lung, gastric, esophageal, lymphoma, renal cancer, and medulloblastoma (Paragraph 0004). In one embodiment, the cancer is selected from prostate cancer, breast cancer, colorectal cancer, lung cancer, gastric cancer, esophageal cancer, lymphoma, renal cancer, or medulloblastoma. In a preferred embodiment, the cancer is a prostate cancer (Paragraph 0039).
Daley discloses methods for treating cancer comprising administering a compound that targets a KDM4 or KDM5 family member, wherein the subject has at least one mutation in an epigenetic modifier. Another aspect of the invention relates to a method of treating diffuse large B-cell lymphoma (Abstract). The method of treating cancer comprises administering a therapeutically effective amount of a compound that targets a KDM4 or KDM5 family member, wherein the patient may have overexpression of KDM4A and/or KDM4C (Paragraph 0008). Disclosed herein is a method of treating DLBCL. The method comprises diagnosing a subject as having DLBCL and administering a therapeutically effective amount of a compound targeting a KDM4/KDM5 family member to the subject (Paragraph 00010). The exemplary compound of the invention, JIB-04, targets KDM4A and KDM4C in cells which are sensitive to the compound. Thus, targeting KDM4/KDM5 family members in cells having overexpression of KDM4A and/or KDM4C can promote cancer cell apoptosis. Accordingly, provided herein are methods of treating cancer that relate to overexpression of KDM4A and/or KDM4C (Paragraph 00049).
Whetstine discloses methods for controlling DNA amplification in cancer cells (Abstract). Provided herein are methods for treating a subject who has a cancer with reduced levels or activity of KDM5A, or who is being treated with a KDM5A inhibitor, by administering to the subject a therapeutically effective amount of an inhibitor of KDM4A. Also provided are methods of treating a subject who has a cancer with reduced levels or activity of KDM5B, or who is being treated with a KDM5B inhibitor, by administering a therapeutically effective amount of an inhibitor of KDM4B. In some embodiments, the inhibitor of KDM4 inhibitors KDM4A, KDM4B, or both KDM4A and KDM4B (Page 3). In some embodiments, the subject has acute myeloid leukemia, acute lymphoblastic leukemia, or biphenotypic leukemia (Page 3). In some embodiments of the methods described herein, the cancer is a carcinoma, sarcoma, myeloma, metastatic disorder, or a hematopoietic neoplastic disorder (Page 4). Cancers that are associated with inhibitory KDM5A mutations include penile cancer, stomach cancer, melanoma, brain tumors, skin cancer, colorectal adenocarcinoma, ampullary carcinoma, cervical cancer, small cell lung cancer, bladder cancer, breast cancer, esaphogogastric cancer, and anal cancer (Page 17). In addition, an inhibitor of KDM4B (or KDM4B/C/D) can be used to treat a subject who has a cancer with reduced levels or activity of KDM5B. Cancers that are associated with inhibitory KDM5B mutations include breast, ovarian, oral, neuroblastoma, esophageal, hepatocellular carcinoma, glioma, cervical, and colorectal cancer (Page 21).
Whetstine discloses the role of KDM4A in cancer and the treatment of cancer (Abstract). Provided herein are methods of treatment relating to subjects having KDM4A mutations and/or altered activity levels as well as methods of treatment that copmrise modulating the activity levels of KDM4A (Paragraph 0007). In one aspect, described herein is a method of treating cancer, the method comprising administering an inhibitor of KDM4A (Paragraph 0012). In some embodiments, the cancer is selected from the group consisting of ovarian cancer, non-small cell lung cancer, multiple myeloma, breast cancer, pancreatic cancer, head and neck cancer, lung cancer, adenocarcinoma, lung adenocarcinoma, lung squamous cell carcinoma, renal cancer, stomach cancer, melanoma, colorectal cancer, AML, and uterine and endometrial cancer (Paragraph 0016).
Souto synthesized a set of analogs which displayed potent KDM4A inhibitory enzymatic activity in vitro in colon cancer cells, and strong antitumor action in several solid and hematological human cancer cell lines with no toxic effects in normal cells. The findings suggest that further development of this compound may lead to identification of new therapeutic antitumor agents that act through inhibition of KDM4A (Abstract). Cell death was observed in HCT-116 cells (colorectal carcinoma cell line), NB4 (acute promyeloctyic leukemia), U937 (histiocytic lymphoma), A549 (lung), MiaPaCa (Pancreatic), HT-29 (colon), HepG2 (hepatocellular carcinoma), and MCF7 (breast cancer) (Page 15, Figure 9).
Lee provides a review of KDM4A-D in cancers, as well as currently available inhibitors and their potential as therapeutic agents for cancer treatment (Abstract). Numerous studies have demonstrated that abnormal expression of KDMs can promote the progression of cancer, including reports that KDM4A, KDM4B, and KDM4C are amplified and overexpressed in breast, esophageal, lung, prostate, and lymphatic cancers among others (2- Altered Expression and Functions of KDM4s in Cancer). Table 1 (Page 3464) lists the number of research papers on cancer and KDM4, showing KDM4s known involvement in breast, prostate, lung, colorectal, pancreatic, gastric, liver, cervical, and endometrial cancers, as well as glioma, osteosarcoma, Hodgkin’s lymphoma, multiple myeloma, lymphoma, AML, head and neck squamous cell carcinoma, esophageal cell carcinoma, bladder cancer, Kaposi’s sarcoma, neuroblastoma, uveal melanoma, melanoma, and renal cancer. KDM4A amplification and overexpression is highly prevalent in ovarian cancer and squamous cell carcinoma. KDM4A has also been involved in prostate, breast, lung, colon, bladder, pancreatic, gastric, head and neck cancers, endometrial carcinoma, and glioblastoma. KDM4A is overexpressed in over 60% of breast cancers. KDM4A and KDM4D are predominantly overexpressed in basal breast cancer, while KDM4A expression is higher in infiltrating duct carcinoma than fibroadenoma, and KDM4B overexpression is predominant in both ER-positive and triple-negative breast cancer. Knockdown of KDM4A inhibits proliferation, migration and invasion of the breast cancer cell line MCF-7. A study of 188 patients with lung carcinoma implicated nuclear KDM4A and KDM4D in lymph node metastases. KDM4A is overexpressed in human and mouse lung cancer lines, while KDM4A knockdown inhibits tumor growth and promotes apoptosis of NSCLC cells. Data shows that KDM4A may play a dual role in lung tumorigenesis by upregulating tumor survival-related genes and by downregulating tumor suppressor genes. KDM4A, KDM4B, and KDM4C are each overexpressed in colon cancer cell lines. The depletion of KDM4A reduces CRC cell proliferation, blocks entry into the G2-M phase of the cell cycle, and increases apoptosis. In Ras-induced senescence, miR-137 targets and reduces KDM4A mRNA senescence, and this results in activation of p53 and retinoblastoma pathways. Restoration of KDM4A contributes to circumvention of miR-137-induced senescence, and inhibition of endogenous miR-137. miR-137 expression is substantially lower in pancreatic tumors, and the recovery of miR-137 inhibits proliferation and promotes the senescence of pancreatic cancer cells, suggesting that the KDM4A-miR-137 axis is a promising therapeutic target to treat pancreatic cancer. KDM4A is overexpressed in clinical gastric cancer tissues compared to normal gastric mucosa, and knockdown of KDM4A induces apoptosis by upregulating pro-apoptotic proteins and downregulating anti-apoptotic proteins, suggesting that KDM4A regulates gastric cancer growth and may be a potential target for gastric cancer treatment. KDM4A is also overexpressed in endometrial cancer, and downregulation of KDM4A reduces the proliferation, invasion, and metastasis of endometrial cancer lines. KDM4A expression is high in glioma cell lines U87 and T98G, while silencing KDM4A reduces cell viability, inhibits invasion, and promotes apoptosis of these cells. The selective inhibition of KDM4A efficiently suppresses glioblastoma cell survival by enhancing autophagy. The expression of KDM4A is higher in bladder cancer tissues than in corresponding non-neoplastic tissues, with KDM4A inhibition markedly suppressing bladder cancer cell growth. KDM4B overexpression is implicated in liver cancer, ovarian cancer, osteosarcoma, neuroblastoma, multiple myeloma, and Hodgkin’s lymphoma. KDM4B and KDM4C are overexpressed in osteosarcoma tissues compared to adjacent non-tumor tissues, and promotes osteosarcoma cell proliferation, migration, and invasion. KDM4B protein level is upregulated in human hepatocellular cancer, and expression is correlated with histological grade and TNM score. Interfering with KDM4B-mediated silencing of miRNA-615-5p and ensuing RAB24 upregulation is a strategy to inhibit hepatocarcinogenesis and metastasis. The depletion of KDM4B increases H3K9me3 at the promoters of metastatic genes such as LOXL2, LCN2, and PDGFB, reducing expression in ovarian cancer cells. KDM4B inhibition also suppresses ovarian cancer cell migration, invasion, and spheroid formation in vivo. KDM4B and MYCN expression levels are significantly correlated in neuroblastoma cells through mutual regulation by the MYC pathway. Ciclopirox, an approved small-molecule antifungal, inhibits KDM4B which reduces MYC function, inhibiting neuroblastoma cell viability and tumor growth associated with differentiation, suggesting that targeting KDM4B as an indirect MYC-targeting approach is a promising cancer therapy. Overexpression of KDM4B and KDM4D in reactive cellular infiltration and Reed-Sternberg cells is related to poor DFS in patients with HL, and is also associated with B-symptoms. Thus, KDM4B expression is associated with aggressive subtypes of classical HL and with radioresistance. Triptolide strongly suppresses the growth of human multiple myeloma cells through modulation of KDM4B and KDM1A/LSD1 activities, by including G0/G1 cell cycle arrest and apoptosis by downregulation of KDM4B. Amplification of KDM4C has been observed in B-cell lymphoma, Hodgkin’s lymphoma, esophageal squamous cell carcinoma, breast cancer, saromatoid carcinoma of the lung, and desmoplastic medulloblastoma. It is also deregulated in cancers such as prostate, lung, colon, osteosarcoma, ESCC, acute myeloid leukemia, and lymphoma.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
Boloor does not teach the treatment of all forms of cancer which are claimed.
Each of the cited references do not teach the use of the claimed KDM4 inhibitor for the treatment of these cancers which overexpress KDM4.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would have extensive medical training, with further training in oncology and the treatment of cancers using chemotherapeutic agents.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
Boloor and the cited references are considered analogous to the claimed invention as all are involved in the treatment of cancers which display aberrant KDM4 activity using modulators or inhibitors of KDM4. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to utilize the KDM4 inhibitor of Boloor to treat each of the cancers referenced in the cited references as the references demonstrate that these cancers are associated with aberrant KDM4 activity, and are responsive to inhibition of KDM4. The use of the inhibitor of Boloor for the treatment of the cancers referenced in the cited articles and patents is prima facie obvious substitution of one known element for another to obtain predictable results (See MPEP § 2143 I (B)). The compound of Boloor is known to be an inhibitor of KDM4 and is useful for treating certain cancers which have aberrant KDM4 activity, while the cited references demonstrate that these cancers each possess aberrant KDM4 activity and can be treated using inhibitors of KDM4. Thus, the artisan would recognize this, and would have a reasonable expectation of success in performing this substitution as Boloor demonstrates that this compound is a potent inhibitor of KDM4.
Regarding Claim 35, it would be obvious to one of ordinary skill in the art to utilize the compound of Formula IIa to treat cancers which have developed resistance to prior therapy, is refractory to prior therapy, or has relapsed as there is nothing which precludes the use of this compound in methods of treating these types of cancers. The artisan would be motivated to use this compound in methods to treat these forms of cancer as they have developed resistance to, or have shown less effectiveness against, the previous treatment regimen, and thus the artisan would be motivated to utilize a new therapy which is specific against cancers which have dysregulated KDM4 activity.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 35, and 61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,516,024 (Patent Date: 6 January 2026) (‘024).
Determining the Scope and Contents of the Prior Art:
Claim 1 of ‘024 (See IDS, 26 May 2026) is directed to a method of treating cancer associated with KDM4 activity in a patient in need thereof the compound
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, wherein the KDM4-associated cancer is Burkitt’s lymphoma. This compound is identical to the compound claimed in the examined application. The claims at issue are not identical but are not patentably distinct because the examined claims are directed to a method of treating cancer using this compound, and in particular, treating Burkitt’s lymphoma using this compound.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
The prior art does not teach the treatment of cancers which have developed resistance to prior therapy, is refractory to prior therapy, or has relapsed.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would have extensive medical training, with further training in oncology and the treatment of cancers using chemotherapeutic agents.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
It would be obvious to one of ordinary skill in the art to utilize the compound of ‘024 to treat cancers which have developed resistance to prior therapy, is refractory to prior therapy, or has relapsed as there is nothing which precludes the use of this compound in methods of treating these types of cancers. The artisan would be motivated to use this compound in methods to treat these forms of cancer as they have developed resistance to, or have shown less effectiveness against, the previous treatment regimen, and thus the artisan would be motivated to utilize a new therapy which is specific against cancers which have dysregulated KDM4 activity.
Claims 1, 5, and 35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2 and 24 of U.S. Patent No. 10,385,047 (Patent Date: 20 August 2019) (‘047).
Determining the Scope and Contents of the Prior Art:
Claim 2 of ‘047 (See IDS, 21 February 2024) is directed to a method of treating esophageal cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a composition comprising a compound of Formula IIa or a pharmaceutically acceptable salt thereof
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. Claim 24 claims the method of Claim 2 wherein the compound is
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, which is identical to the compound claimed in the examined application. The claims at issue are not identical but are not patentably distinct because the examined claims are directed to a method of treating cancer using this compound, and in particular, treating esophageal cancer using this compound.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
The prior art does not teach the treatment of cancers which have developed resistance to prior therapy, is refractory to prior therapy, or has relapsed.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would have extensive medical training, with further training in oncology and the treatment of cancers using chemotherapeutic agents.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
It would be obvious to one of ordinary skill in the art to utilize the compound of ‘047 to treat cancers which have developed resistance to prior therapy, is refractory to prior therapy, or has relapsed as there is nothing which precludes the use of this compound in methods of treating these types of cancers. The artisan would be motivated to use this compound in methods to treat these forms of cancer as they have developed resistance to, or have shown less effectiveness against, the previous treatment regimen, and thus the artisan would be motivated to utilize a new therapy which is specific against cancers which have dysregulated KDM4 activity.
Claims 1 ,5, 35, and 61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 9,994,561 (Patent Date: 12 June 2018) (‘561) in view of Wang (US 2015/0267241; Publication Date: 24 September 2015), Daley (WO 2018/222831; Publication Date: 6 December 2018), Whetstine (WO 2018/102736; Publication Date: 7 June 2018), Whetstine (WO 2014/197835; Publication Date: 11 December 2014), Souto (Frontiers in Chemistry, 25 May 2020), and Lee (The FASEB Journal, 2020; 34:3461-3484).
Determining the Scope and Contents of the Prior Art:
Claim 1 of ‘561 (See IDS, 21 February 2024) is directed to a method of treating cancer in a subject comprising administering a therapeutically effective dose of a compound of Formula I
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wherein
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. THe compound of the examined application meets the limitations set forth in ‘561.
‘561 does not specify that it is treating the cancers which are claimed in the examined application.
The teachings of the cited references are previously described and are fully incorporated into this rejection.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
‘561 does not teach the treatment of all forms of cancer which are claimed.
Each of the cited references do not teach the use of the claimed KDM4 inhibitor for the treatment of these cancers which overexpress KDM4.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would have extensive medical training, with further training in oncology and the treatment of cancers using chemotherapeutic agents.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
‘561 and the cited references are considered analogous to the claimed invention as all are involved in the treatment of cancers which display aberrant KDM4 activity using modulators or inhibitors of KDM4. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to utilize the KDM4 inhibitor of ‘561 to treat each of the cancers referenced in the cited references as the references demonstrate that these cancers are associated with aberrant KDM4 activity, and are responsive to inhibition of KDM4. The use of the inhibitor of ‘561 for the treatment of the cancers referenced in the cited articles and patents is prima facie obvious substitution of one known element for another to obtain predictable results (See MPEP § 2143 I (B)). The compound of ‘561is known to be an inhibitor of KDM4 and is useful for treating certain cancers which have aberrant KDM4 activity, while the cited references demonstrate that these cancers each possess aberrant KDM4 activity and can be treated using inhibitors of KDM4. Thus, the artisan would recognize this, and would have a reasonable expectation of success in performing this substitution as ‘561 demonstrates that this compound is a potent inhibitor of KDM4.
Regarding Claim 35, it would be obvious to one of ordinary skill in the art to utilize the compound of ‘561 to treat cancers which have developed resistance to prior therapy, is refractory to prior therapy, or has relapsed as there is nothing which precludes the use of this compound in methods of treating these types of cancers. The artisan would be motivated to use this compound in methods to treat these forms of cancer as they have developed resistance to, or have shown less effectiveness against, the previous treatment regimen, and thus the artisan would be motivated to utilize a new therapy which is specific against cancers which have dysregulated KDM4 activity.
Claims 1, 5, 35, and 61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, and 25-27 of copending Application No. 19/112,898 (Amended Claims of 18 March 2025) (‘898) in view of Wang (US 2015/0267241; Publication Date: 24 September 2015), Daley (WO 2018/222831; Publication Date: 6 December 2018), Whetstine (WO 2018/102736; Publication Date: 7 June 2018), Whetstine (WO 2014/197835; Publication Date: 11 December 2014), Souto (Frontiers in Chemistry, 25 May 2020), and Lee (The FASEB Journal, 2020; 34:3461-3484).
Determining the Scope and Contents of the Prior Art:
Claim 1 of ‘898 is directed to a crystalline form of the compound of the examined application, wherein the crystalline form is Form 1. Claim 25 of ‘898 is directed to a solid pharmaceutical composition comprising the crystalline form of Claim 1 and a pharmaceutically acceptable excipient. Claim 26 is directed to a method of treating cancer in a subject in need thereof comprising administering the composition of Claim 25 to the subject. Claim 27 is directed to the method of Claim 26 wherein the cancer is selected from colorectal cancer, esophageal cancer, gastric cancer, breast cancer, and lymphoma.
‘898 does not claim the treatment of all cancers which are claimed in the examined application.
The teachings of the cited references are previously described and are fully incorporated into this rejection.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
‘898 does not teach the treatment of all forms of cancer which are claimed.
Each of the cited references do not teach the use of the claimed KDM4 inhibitor for the treatment of these cancers which overexpress KDM4.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would have extensive medical training, with further training in oncology and the treatment of cancers using chemotherapeutic agents.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
‘898 and the cited references are considered analogous to the claimed invention as all are involved in the treatment of cancers which display aberrant KDM4 activity using modulators or inhibitors of KDM4. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to utilize the KDM4 inhibitor of ‘898 to treat each of the cancers referenced in the cited references as the references demonstrate that these cancers are associated with aberrant KDM4 activity, and are responsive to inhibition of KDM4. The use of the inhibitor of ‘898 for the treatment of the cancers referenced in the cited articles and patents is prima facie obvious substitution of one known element for another to obtain predictable results (See MPEP § 2143 I (B)). The compound of ‘898 is known to be an inhibitor of KDM4 and is useful for treating certain cancers which have aberrant KDM4 activity, while the cited references demonstrate that these cancers each possess aberrant KDM4 activity and can be treated using inhibitors of KDM4. Thus, the artisan would recognize this, and would have a reasonable expectation of success in performing this substitution as ‘898 demonstrates that this compound is a potent inhibitor of KDM4.
Regarding Claim 35, it would be obvious to one of ordinary skill in the art to utilize the compound of ‘898 to treat cancers which have developed resistance to prior therapy, is refractory to prior therapy, or has relapsed as there is nothing which precludes the use of this compound in methods of treating these types of cancers. The artisan would be motivated to use this compound in methods to treat these forms of cancer as they have developed resistance to, or have shown less effectiveness against, the previous treatment regimen, and thus the artisan would be motivated to utilize a new therapy which is specific against cancers which have dysregulated KDM4 activity.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 5, 35, and 61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 66, 78, 80, and 82 of copending Application No. 18/722,083 (Amended Claims of 21 May 2025) (‘083) (reference application).
Determining the Scope and Contents of the Prior Art:
Claim 66 of ‘083 is directed to a pharmaceutical composition comprising the same compound as claimed in the examined application and at least one pharmaceutialyl acceptable excipient wherein the compound has been subjected to milling. Claim 78 is directed to the composition of Claim 66 wherein the composition is a tablet dosage form or a capsule dosage form. Claim 80 is directed to the composition of Claim 78 for use in treating a cancer in a patient in need thereof. Claim 82 is directed to the composition of claim 80, wherein the cancer is selected from the same cancers as claimed in Claims 5 and 61 of the examined application.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
‘083 claims he use of a pharmaceutical composition of the compound of the invention for the treatment of cancer, while the examined claims claim the use of the compound for treatment.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would have extensive medical training, with further training in oncology and the treatment of cancers using chemotherapeutic agents.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
Claim 66 of ‘083 is directed to a pharmaceutical composition comprising the same compound as claimed in the examined application and at least one pharmaceutically acceptable excipient wherein the compound has been subjected to milling. Claim 78 is directed to the composition of Claim 66 wherein the composition is a tablet dosage form or a capsule dosage form. Claim 80 is directed to the composition of Claim 78 for use in treating a cancer in a patient in need thereof. Claim 82 is directed to the composition of claim 80, wherein the cancer is selected from the same cancers as claimed in Claims 5 and 61 of the examined application.
The claims are not identical but are not patentably distinct because ‘083 is directed to a method of treating cancer using a pharmaceutical composition comprising the same compound of the examined application. Formulation is common in the pharmaceutical arts, and the artisan would be motivated to formulate a compound to improve bioavailability and enhance delivery of the compound to the patient in need thereof.
Regarding Claim 35, it would be obvious to one of ordinary skill in the art to utilize the compound of ‘083 to treat cancers which have developed resistance to prior therapy, is refractory to prior therapy, or has relapsed as there is nothing which precludes the use of this compound in methods of treating these types of cancers. The artisan would be motivated to use this compound in methods to treat these forms of cancer as they have developed resistance to, or have shown less effectiveness against, the previous treatment regimen, and thus the artisan would be motivated to utilize a new therapy which is specific against cancers which have dysregulated KDM4 activity.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5, 35, and 61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 23, 25, 27, and 29 of copending Application No. 19/407,674 (Amended Claims of 3 December 2025) (‘674) in view of Wang (US 2015/0267241; Publication Date: 24 September 2015), Daley (WO 2018/222831; Publication Date: 6 December 2018), Whetstine (WO 2018/102736; Publication Date: 7 June 2018), Whetstine (WO 2014/197835; Publication Date: 11 December 2014), Souto (Frontiers in Chemistry, 25 May 2020), and Lee (The FASEB Journal, 2020; 34:3461-3484).
Determining the Scope and Contents of the Prior Art:
Claim 1 of ‘674 is directed to a compound of the structure
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. Claim 23 of ‘674 claims specific compounds, including
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which is the same compound of the examined application. Claim 25 claims a compoistion comprising a compound of Claim 23 and a pharmaceutically acceptable excipient. Claim 27 is drawn to a method of inhibiting a cancer associated with KDM4 activity comprising adminsteirng to a patient in need thereof a pharmacuetiucal composition of Claim 25. Claim 29 is drawn to the method of Claim 29 wherein the KDM4-associated cancer is triple negative breast cancer.
‘674 does not claim the treatment of all forms of cancer claimed in the examined application.
The cited references are previously described and are fully incorporated into this rejection.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
‘674 does not claim the treatment of all forms of cancer claimed in the examined application using the claimed KDM4 inhibitor.
The cited references do not teach the specific use of the claimed compound for the treatment of cancers which are known to have KDM4 involved in their pathogenesis.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would have extensive medical training, with further training in oncology and the treatment of cancers using chemotherapeutic agents.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
‘674 and the cited references are considered analogous to the claimed invention as all are involved in the treatment of cancers which display aberrant KDM4 activity using modulators or inhibitors of KDM4. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to utilize the KDM4 inhibitor of ‘674 to treat each of the cancers referenced in the cited references as the references demonstrate that these cancers are associated with aberrant KDM4 activity, and are responsive to inhibition of KDM4. The use of the inhibitor of ‘674 for the treatment of the cancers referenced in the cited articles and patents is prima facie obvious substitution of one known element for another to obtain predictable results (See MPEP § 2143 I (B)). The compound of ‘674 is known to be an inhibitor of KDM4 and is useful for treating certain cancers which have aberrant KDM4 activity, while the cited references demonstrate that these cancers each possess aberrant KDM4 activity and can be treated using inhibitors of KDM4. Thus, the artisan would recognize this, and would have a reasonable expectation of success in performing this substitution as ‘674 demonstrates that this compound is a potent inhibitor of KDM4.
Regarding Claim 35, it would be obvious to one of ordinary skill in the art to utilize the compound of ‘674 to treat cancers which have developed resistance to prior therapy, is refractory to prior therapy, or has relapsed as there is nothing which precludes the use of this compound in methods of treating these types of cancers. The artisan would be motivated to use this compound in methods to treat these forms of cancer as they have developed resistance to, or have shown less effectiveness against, the previous treatment regimen, and thus the artisan would be motivated to utilize a new therapy which is specific against cancers which have dysregulated KDM4 activity.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1, 5, 35, and 61 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHILLIP MATTHEW RZECZYCKI whose telephone number is (703)756-5326. The examiner can normally be reached Monday Thru Friday 730AM-5PM EST.
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/P.M.R./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
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