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 .
DETAILED ACTION
Claims 1, 4, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 48, 50, 52-53, 75 and 79 are pending are under consideration in the instant office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/03/2024, 12/20/2024 and 09/258/2025 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits. See attached copy of the PTO-1449.
Priority
This application is a U.S. national stage filing under 35 U.S.C. § 371 of PCT/US2022/032718, filed June 8, 2022, which claims the benefit of and priority to U.S. Provisional Application 63/208,882, filed June 9, 2021,
Claim Rejections - 35 USC § 112 (2nd Paragraph)
The following is a quotation of the second paragraph of 35 U.S.C. 112:
The specification shall conclude with one or more claims particularly pointing out and distinctlyclaiming the subject matter which the applicant regards as his invention.
Claim 1 and the dependent claims , 4, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 48, 50, 52-53, 75 as being indefinite for failing to particularly point out, and distinctly claiming the subject matter which the applicant regards as his invention. Claim 1 is vague and indefinite in that the metes and bounds of the “method of treating a subject in need thereof ” is unclear. It is unclear as to what the subject is need off, what condition or disease or symptom is the subject undergoing which is treated by the instantly claimed combination. While based on the second therpeautic agent one can maybe consider the treatment to be cancer, it encompasses other conditions such as autoimmune disorders and other inflammatory disorders.Applicant is required to clarify the specific condition which is to be treated in the patient.
Claims 17 and 52 are rejected under 35 U.S.C. 112, second paragraph, as being indefinite for failing to particularly point out, and distinctlyclaiming the subject matter which the applicant regards as his invention. Claims 17 and 52 recite the limitation "Table 1B" in claims 17 and 52 and Cpd. No. 15 in claim 52. There is insufficient antecedent basis for this limitation in the claims. It would be remedial to amend the claims to provide a clear antecedent basis for the term "Table 1B" a in claims 17 and 52 and Cpd. No. 15 in claim 52.
Additionally claims 17 and 52 are vague and indefinite in that the metes and bounds of the compounds described in "Table 1B" are unclear. Absence of any recitation of Table 1B with the compounds in the claims, it is impossible to ascertain which compounds were included in the Table.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 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, 4, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 48, 50, 52-53, 75 and 79 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for treating multiple myeloma, mantle cell lymphoma or diffuse large B-cell lymphoma with the combination of Compound No. 15 with Second Therapeutic Agent comprising the following : BTK inhibitors Ibrutinib and zanabrutinib, rituximab (anti- CD20 monoclonal antibodies), Mafosafamide an alkylating agents, topoisomerase II inhibitors doxorubicin or etoposide, vincrisitine, carboplatin or oxiliplatin, gemcitiabine, idelalisib a PI3K inhibitor, EZM2303 a CARM1 inhibitor, AZD0156, AZD6738, AZD7762, AZD1775, B02, Olaparib, Niraparib and MK2206 which are inhibitors of enzymes of DNA damage repair, tamatinib a SYK inhibitor and rametinib, a MEK inhibitors, does not reasonably provide enablement for treating any and every subject in need thereof or any and every other cancers in general with each and every compound encompassed by the compound of formula 1 with any known other anti-cancer agents encompassed by the broad categories claimed as the second therapeutic in the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The treatment of cancer generally cannot possibly be considered enabled.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc. 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
By way of background, four cases are of particular relevance to the question of enablement of a method of treating cancers broadly or even generally:
In In re Buting, 57 CCPA 777, 418 F.2d 540, 163 USPQ 689, the claim was drawn to “The method of treating a malignant condition selected from the group consisting of leukemias, sarcomas, adenocarcinomas, lymphosarcomas, melanomas, myelomas, and ascitic tumors” using a small genus of compounds. The Court decided that human testing “limited to one compound and two types of cancer” was not “commensurate with the broad scope of utility asserted and claimed”.
. In Ex parte Jovanovics, 211 USPQ 907 the claims were drawn to “the treatment of certain specified cancers in humans” by the use of a genus of exactly two compounds, the N-formyl or N-desmethyl derivative of leurosine. Applicants submitted “affidavits, publications and data” for one of the compounds, and a dependent claim drawn to the use of that species was allowed. For the other, no data was presented, applicants said only that the other derivative would be expected to be less effective; claims to the genus were refused.
In Ex parte Busse, et al., 1 USPQ2d 1908, claims were drawn to “A therapeutic method for reducing metastasis and neoplastic growth in a mammal” using a single species. The decision notes that such utility “is no longer considered to be “incredible”, but that “the utility in question is sufficiently unusual to justify the examiner's requirement for substantiating evidence. Note also that there is also a dependent claim 5 which specified “wherein metastasis and neoplastic growth is adenocarcinoma, squamous cell carcinoma, melanoma, cell small lung or glioma.” The decision notes that “even within the specific group recited in claim 5 some of the individual terms used actually encompass a relatively broad class of specific types of cancer, which specific types are known to respond quite differently to various modes of therapy.”
In Ex parte Stevens, 16 USPQ2d 1379 a claim to “A method for therapeutic or prophylactic treatment of cancer in mammalian hosts” was refused because there was “no actual evidence of the effectiveness of the claimed composition and process in achieving that utility.”
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner's position that one skilled in the art could not practice the invention without undue experimentation.
(1) The nature of the invention and the Breadth of claims
The claims are drawn to methods of treating a subject in need thereof comprising administration compound of formula ! and a second therapeutic anticancer agents as listed in the claim.
Scope of the compounds covered: Instant claim covers compounds of formula 1 with several variables as follows, which include optionally substituted moieties, where in the substituents are not defined in the claim:
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The compounds covered by the instant claims are easily in millions with the various combinations of the variables. Each of these compounds in combination with each and every agent which comes under the broadly claimed second therapeutic is supposed to treat any and every disease in a subject in need thereof.
Scope of the second therapeutic agents covered: Applicants claim the combination of the vast number of compounds covered by formula I with the vast number of anti cancer agents covered by the broad categories as follows, one or more BTK inhibitors, one or more anti- CD20 monoclonal antibodies, one or more alkylating agents, one or more topoisomerase II inhibitors, one or more vinca alkaloids, one or more platinum-based drugs, one or more nucleoside anticancer agents, one or more PI3K inhibitors, one or more CDK4/6 inhibitors, one or more CARM1 inhibitors, one or more inhibitors of enzymes of DNA damage repair, one or more SYK inhibitors, or one or more MEK inhibitors, or a combination thereof. Millions of compounds and agents are covered under these categories as a whole. Again applicants are claiming treating any and every type of cancer with the combination of the compound of formula I with any and every agent or compounds which falls under each of these several categories of anti-cancer agents.
Scope of the diseases covered: First of all claim 1 does not specify the disease or condition the patient is suffering from, it recites a method of treating a subject in need thereof which could include subjects suffering from any and every type of disease known such as any autoimmune diseases or any other inflammatory diseases. Even if the diseases just encompassed cancer, the breadth of this claim is very broad. Taking cancers for example, Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. Here are a few of the assorted categories:
A. CNS cancers cover a very diverse range of cancers in many categories and subcategories. There are an immense range of neuroepithelial tumors. Gliomas, the most common subtype of primary brain tumors, most of which are aggressive, highly invasive, and neurologically destructive tumors are considered to be among the deadliest of human cancers. These are any cancers which show evidence (histological, immunohistochemical, ultrastructural) of glial differentiation. These fall mostly into five categories. There are the astrocytic tumors (astrocytomas): pilocytic astrocytoma (including juvenile pilocytic astrocytoma, JPA, and pediatric optic nerve glioma) diffuse astrocytomas (including fibrillary astrocytomas, protoplasmic astrocytomas and gemistocytic astrocytomas), anaplastic astrocytomas (including adult optic nerve glioma), Glioblastoma multiforme (GBM), gliosarcoma and giant cell glioblastoma.
B. Leukemia is any malignant neoplasm of the blood-forming tissues. Leukemia can arise from many different sources. These include viruses such as EBV, which causes Burkitt's lymphoma, and HTLV-1, linked to certain T cell leukemias. Others are linked to genetic disorders, such as Fanconi's anemia, which is a familial disorder, and Down's Syndrome. Other leukemias are caused by exposure to carcinogens such as benzene, and some are actually caused by treatment with other neoplastic agents. Still other leukemias arise from ionizing radiation, and many are idiopathic. Leukemias also differ greatly in the morphology, degree of differentiation, body location (e.g. bone marrow, lymphoid organs, etc.) There are dozens of leukemias. There are B-Cell Neoplasms such as B-cell prolymphocytic leukemia and Hairy cell leukemia (HCL, a chronic Lymphoid leukemia). There are T-Cell Neoplasms such as T-cell prolymphocytic leukemia, aggressive NK cell leukemia, adult T cell leukemia/lymphoma (ATLL), and T-cell granular Lymphocytic leukemia. There are different kinds of acute myeloid leukemias (undifferentiated AML, acute myeloblastic, acute myelomonocytic leukemia, acute monocytic leukemias, acute monoblastic, acute megakaryoblastic (AmegL), acute promyelocytic leukemia (APL), and erythroleukemia). There is also lymphoblastic leukemia, hypocellular acute myeloid leukemia, Ph-/BCR- myeloid leukemia, and acute basophilic leukemia.rphic xanthoastrocytoma.
C. Carcinomas of the Liver include hepatocellular carcinoma, combined hepatocellular cholangiocarcinoma, cholangiocarcinoma (intrahepatic), bile duct cystadenocarcinoma and undifferentiated carcinoma of the liver.
D. The main types of lung and pleural cancer are small cell (i.e. oat cell, including combined oat cell), adenocarcinomas, bronchioloalveolar carcinomas (nonmucinous, mucinous, and mixed mucinous and nonmucinous or indeterminate cell type), acinar, papillary carcinoma, solid adenocarcinoma with mucin, adenocarcinoma with mixed subtypes, well-differentiated fetal adenocarcinoma, mucinous (colloid) adenocarcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma, and clear cell adenocarcinoma), squamous cell (papillary, clear cell, small cell and basaloid), mesothelioma (including epithelioid, sarcomatoid, desmoplastic and biphasic) and large cell carcinoma (which include large-cell neuroendocrine carcinoma, combined large-cell neuroendocrine carcinoma, basaloid carcinoma, clear cell carcinoma lymphoepithelioma-like carcinoma, and large-cell carcinoma with rhabdoid phenotype).
E. Thyroid cancer comes in four forms: papillary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, and medullary thyroid cancer.
F. Cancer of the skin cells is melanoma. Malignant melanomas come in four fundamental forms: superficial spreading melanoma, nodular melanoma (including its variant, Polypoid melanoma), lentigo maligna melanoma and acral melanoma. Mucosal melanomas are sometimes malignant. These sometime occur in amelanotic form, such as in desmoplastic melanoma.
H. There are many types of colorectal cancers. The carcinomas include
adenocarcinoma; mucinous adenocarcinoma; signet-ring cell carcinoma;small cell carcinoma; adenosquamous carcinoma; medullary carcinoma; choriocarcinoma; and undifferentiated carcinoma. The malignant lymphomas include marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type; mantle cell lymphoma; Diffuse large B-cell lymphoma; Burkitt lymphoma; and Burkitt-like/atypical Burkitt lymphoma.
Similarly there exists various types of Renal Cancers, Prostate cancer, Carcinomas of the bile ducts, Breast cancers, Ovarian cancers, Testicular cancers, Paratesticular cancers, Cancer of the vulva, Vaginal cancers, Endometrial carcinomas, Stomach cancers, esophagus cancers, cancers of spleen, Salivary gland carcinomas, heart cancers, cancers of the oral cavity, cervical cancers, throat cancers, gall bladder cancers, non-hodgkin lymphomas etc.
(2) The relative skill of those in the art
Many, many mechanisms have been proposed over the decades as methods of treating the assorted cancers generally. Cytotoxic agents could be applied directly to the tumors cells, directly killing them. Immunotherapy involves stimulating the patient's immune system to attack cancer cells generally, either by immunization of the patient, in which case the patient's own immune system is trained to recognize tumor cells as targets, or by the administration of therapeutic antibodies as drugs, so the patient's immune system is recruited to destroy tumor cells by the therapeutic antibodies. Another approach would be to increase the amount or activity of the body’s tumor suppressor genes, e.g. p53, PTEN, APC and CD95, which can for example activate DNA repair proteins, suppress the Akt/PKB signaling pathway, or initiate apoptosis of cancer cells. The angiogenesis inhibitor strategy was based on cutting off the blood supply that growing tumors need by shutting off the growth of new blood vessels by, for example, suppressing proliferation of endothelial cells or inducing apoptosis of endothelial cells. There is also the cancer stem cell paradigm, which hypothesizes that cancer could be treated generally, either by targeting the cancer stem cells themselves, or by targeting the epithelial-to-mesenchymal transition which supposedly generates the cancer stem cells. Yet another approach is to inhibit one or more of the assorted HSP90 proteins, which will supposedly disrupt the proper folding of signaling proteins that all cancers rely on. Inhibiting telomerase was said to be able to be able to simply stop cancer cells generally from being able to proliferate. Many of these approaches --- and there have been others as well --- have produced anti-cancer drugs. However, despite high hopes for success, and a plausible theory why these should work for cancers generally, none of these approaches have ever produced a drug which come remotely near such a goal.
Specifically, the prior art knows that there never has been a compound capable of treating cancers generally. “The cancer therapy art remains highly unpredictable, and no example exists for efficacy of a single product against tumors generally.” (<http://www.uspto.gov/web/offices/pac/dapp/1pecba.htm#7> ENABLEMENT DECISION TREE, Example F, situation 1). A similar statement appears at In re Application of Hozumi et al., 226 USPQ 353: “In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way”. There are compounds that treat a modest range of cancers, but no one has ever been able to figure out how to get a compound to be effective against cancer generally, or even a majority of cancers.
The attempts to find compounds to treat the various cancers arguably constitute the single most massive enterprise in all of pharmacology. This has not resulted in finding any treatment for tumors generally. Indeed, the existence of such a "silver bullet" is contrary to our present understanding in oncology. This is because it is now understood that there is no “master switch” for cancers generally; cancers arise from a bewildering variety of differing mechanisms. Even the most broadly effective antitumor agents are only effective against a small fraction of the vast number of different cancers known. This is true in part because cancers arise from a wide variety of sources, primarily a wide variety of failures of the body's cell growth regulatory mechanisms, but also such external factors such as viruses (an estimated at least 20% are of viral origin e.g. Human papillomavirus, EBV, Hepatitis B and C, HHV-8, HTLV-1 and other retroviruses, and quite possibly Merkel cell polyomavirus, and there is some evidence that CMV is a causative agent in glioblastoma), exposure to chemicals such as tobacco tars, excess alcohol consumption (which causes hepatic cirrhosis, an important cause of HCC), ionizing radiation, and unknown environment factors.
Accordingly, there is substantive “reason for one skilled in the art to question the objective truth of the statement of utility or its scope” (In re Langer, 183 USPQ 288, 297), specifically, the scope of covering cancer generally.
Similarly, In re Novak, 134 USPQ 335, 337-338, says “unless one with ordinary skill in the art would accept those allegations as obviously valid and correct, it is proper for the examiner to ask for evidence which substantiates them.” There is no such evidence in this case. Likewise, In re Cortright, 49 USPQ2d 1464, states: “Moreover, we have not been shown that one of ordinary skill would necessarily conclude from the information expressly disclosed by the written description that the active ingredient” does what the specification surmises that it does. That is exactly the case here. Moreover, even if applicants’ assertion that cancer in general could be treated with these compounds were plausible --- which it is not ---, that “plausible” would not suffice, as was stated in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297, 1301: “If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success.”
Different types of cancers affect different organs and have different methods of growth and harm to the body, and different vulnerabilities. The skill thus depends on the particular cancer involved. There are some cancers where the chemotherapy skill level is high and there are multiple successful chemotherapeutic treatments. The mechanism in these situations, however, is not necessarily the same as is alleged for these compounds.
(3) The predictability or unpredictability of the art and the state of the prior art.
The unpredictability of the pharmaceutical cancer art is high. Additionally, the lack of significant guidance from the present specification or prior art with regard to the actual treatment of cancer cell types in a mammal, including a human, with the claimed compounds as the active ingredients makes practicing the claimed method unpredictable. With specific reference to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the “general unpredictability of the field [of] …anti-cancer treatment.” In re Application of Hozumi et al., 226 USPQ 353 notes the “fact that the art of cancer chemotherapy is highly unpredictable”. More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). (4) The amount of direction or guidance presented and presence or absence of working examples
Applicant's specification appears to only be enabled for the treatment of a limited number of cancer such multiple myeloma, mantle cell lymphoma, or diffuse large B-cell lymphoma. (Examples 2-3 of the instant disclosure). The in-vitro studies here were conducted with just one compound of formula I which is Compound 15 and also very specific agents from the broad categories claimed as the second therapeutic agent as listed in Tables A-G. As is evident in the tables A-G, the activity of these secondary agents with the compound 15, is varied, for example he BTK inhibitor Acalbrutinib, had no effect on all three of the cell lines in Table C and D and four of the five call line tested for Diffuse Large B-cell lymphoma in Table 5, Rituximab had no effect on one of the cell lines, and showed synergy with only one cell line. Also noted AZD0156, AZD6738, AZD7762, AZD1775, B02, Olaparib, Niraparib and MK2206 which are inhibitors of enzymes of DNA damage repair were not tested against Mantle call lymphoma cell lines. It is also noted that the data presented is prophetic in the sense that there is no quantitative data shown which compares the combination result with individual agents to show the actual synergy or additive action. Clearly applicants have not set forth a representative number of examples of the compound of Formula I , secondary therapeutic agents or the different types of cancer claimed which would be treated by the claimed combination of compounds.
(5) The quantity of experimentation necessary
Given the fact that, historically, the development of new cancers drugs has been difficult and time consuming, and especially in view of the factors listed above, the quantity of experimentation needed is expected to be great.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 4, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 48, 50, 52-53, 75 and 79 are rejected under 35 U.S.C. 103(a) as being unpatentable over by Lampe et al. (WO 2020/037079) in view of Klaus et al. (US 2017/0232030), referenced in the instant IDS 04/03/2024)
Instant claims are drawn to a method of treating multiple myeloma, mantle cell lymphoma or diffuse large B-cell lymphoma with the combination of Compound No. 15 (N-(1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methy1-1-indole- 15 2-carboxamide)
with Second Therapeutic Agent selected from the following : BTK inhibitors Ibrutinib and zanabrutinib, rituximab (anti- CD20 monoclonal antibody), Mafosfamide an alkylating agents, topoisomerase II inhibitors doxorubicin or etoposide, vincrisitine, carboplatin or oxiliplatin, gemcitiabine, idelalisib a PI3K inhibitor, EZM2303 a CARM1 inhibitor, AZD0156, AZD6738, AZD7762, AZD1775, B02, Olaparib, Niraparib and MK2206 which are inhibitors of enzymes of DNA damage repair, tamatinib a SYK inhibitor and rametinib, a MEK inhibitors
Lampe et al. discloses treatment of Multiple Myeloma (claim 83) or Mantle cell lymphoma and Diffuse large B-cell lymphoma (Table 3) with Compound no.15 (N-(1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methy1-1-indole- 15 2-carboxamide) (page 53 having the following structure
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a pharmaceutically acceptable salt or solvate thereof(para [0361]) and (b) a Second Therapeutic Agent, useful in the treatment of cancer (para [0377], [0398], claim 78)
Lampe et al. while teaching the combination with an additional therapeutic agent fails to disclose the instantly claimed combination of compound 15 with the said second therapeutic agents.
However, Klaus et al. teaches a method of treating lymphomas cancer in a subject in need thereof (para [0494]) comprising administering an effective amount of a histone methyltransferase inhibitor (para [0016]-[0020], DOT1L inhibitor) in combination with a second therapeutic agent (para [0034], a compound of Formula (I) (e.g., EPZ-5676 or EPZ-4777) or a pharmaceutically acceptable salt, polymorph, solvate, or stereoisomer thereof and the one or more therapeutic agents), wherein the Second Therapeutic Agent comprises one or more BTK inhibitors (para [0225]), one or more anti-CD20 monocional antibodies, one or more alkylating agents (para [0234]), one or more topoisomerase Il inhibitors (para [0097], Fig 5, Daunorubicin), one or more vinca alkaloids (para [0225], Vincristine), one or more platinum-based drugs (para [0024], cisplatin), one or more nucleoside anticancer agents, one or more PI3K inhibitors (para [0225]), one or more CDK4/6 inhibitors (para [0225]), one or more CARM1 inhibitors, one or more inhibitors of enzymes of DNA damage repair, one or more SYK inhibitors, or one or more MEK inhibitors (para [0225]), or a combination thereof, wherein the combination therapy results in a synergistic effect (para [0302]-[0303]). They specifically teach doxorubicin [0236], or Carboplatin [0235] or Rituximab [0240] or vincristine [0245], or Ibrutinib or Mafosfamide [0225], Etoposide [0245], Gemcitabine [0237], Olaparib [0221] as the second therapeutic agents. It would have been obvious to one of ordinary skill in the art to combine the teachings of Lampe et al. and Klaus et al., as both are directed to anti-cancer combination therapy comprising a histone methyltransferase inhibitor and a second therapeutic agent, and include one or more of the second therapeutic agents disclosed in Klaus et al. in the method of Lampe et al as a secondary agent with compound 15., in order to take advantage of potential synergistic effects brought about by the combined administration (Klaus et al., para [0302]-[0303]), and thereby enhance the efficacy of said method toward treating cancer in a subject (Epizyme-079, para [0377], [0382]).
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 4, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 48, 50, 52-53, 75 and 79 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14, 16, 32-33, 37-39, 44-46, 51-53, 58-60 and 65-67 of U.S. Patent 12,116,358 (‘358) in view of Klaus et al. (US 2017/0232030), referenced in the instant IDS.
Instant claims are drawn to method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of:(a) compound of Formula I
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or a pharmaceutically acceptable salt or solvate thereof; and(b) a Second Therapeutic Agent, wherein: the Second Therapeutic Agent comprises one or more BTK inhibitors, one or more anti- CD20 monoclonal antibodies, one or more alkylating agents, one or more topoisomerase II inhibitors, one or more vinca alkaloids, one or more platinum-based drugs, one or more nucleoside anticancer agents, one or more PI3K inhibitors, one or more CDK4/6 inhibitors, one or more CARM1 inhibitors, one or more inhibitors of enzymes of DNA damage repair, one or more SYK inhibitors, or one or more MEK inhibitors, or a combination thereof.
Claims 14, 16, 32-33, 37-39, 44-46, 51-53, 58-60 and 65-67 or ‘358 are drawn to a method of treating a subject in need thereof, the method comprising administering to the subject the compound of formula IV shown below, wherein the subject has multiple myeloma., diffuse large B-cell lymphoma or renal cell carcinoma.
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“358 does not claim the combianation of the compound of formula IV with a secondary therapeutic agent instantly claimed.
However, Klaus et al. teaches a method of treating lymphomas cancer in a subject in need thereof (para [0494]) comprising administering an effective amount of a histone methyltransferase inhibitor (para [0016]-[0020], DOT1L inhibitor) in combination with a second therapeutic agent (para [0034], a compound of Formula (I) (e.g., EPZ-5676 or EPZ-4777) or a pharmaceutically acceptable salt, polymorph, solvate, or stereoisomer thereof and the one or more therapeutic agents), wherein the Second Therapeutic Agent comprises one or more BTK inhibitors (para [0225]), one or more anti-CD20 monoclonal antibodies, one or more alkylating agents (para [0234]), one or more topoisomerase Il inhibitors (para [0097], Fig 5, Daunorubicin), one or more vinca alkaloids (para [0225], Vincristine), one or more platinum-based drugs (para [0024], cisplatin), one or more nucleoside anticancer agents, one or more PI3K inhibitors (para [0225]), one or more CDK4/6 inhibitors (para [0225]), one or more CARM1 inhibitors, one or more inhibitors of enzymes of DNA damage repair, one or more SYK inhibitors, or one or more MEK inhibitors (para [0225]), or a combination thereof, wherein the combination therapy results in a synergistic effect (para [0302]-[0303]). They specifically teach doxorubicin [0236], or Carboplatin [0235] or Rituximab [0240] or vincristine [0245], or Ibrutinib or Mafosfamide [0225], Etoposide [0245], Gemcitabine [0237], Olaparib [0221] as the second therapeutic agents. It would have been obvious to one of ordinary skill in the art to combine the teachings of ‘358 and Klaus et al., as both are directed to anti-cancer combination therapy comprising a histone methyltransferase inhibitor and a second therapeutic agent, and include one or more of the second therapeutic agents disclosed in Klaus et al. in the method of ‘358 as a secondary agent with compound 15., in order to take advantage of potential synergistic effects brought about by the combined administration (Klaus et al., para [0302]-[0303]), and thereby enhance the efficacy of said method toward treating cancer in a subject (Epizyme-079, para [0377], [0382])., thus rendering them obvious over the instantly claimed claims.
Although the conflicting claims in the instant application and claims of ‘358 are not identical as stated above, they are not patentably distinct from each other in view of Klaus et al.
Claims 1, 4, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 48, 50, 52-53, 75 and 79 are provisionally rejected under the judicially created doctrine of obviousness-type double patenting over claims 19, 21, 23, 25-26 of copending Application No. 18/706, 071 ('071) and claims 5, 17, 19, 21, 25, 26, 29, 31, 33, 65-74 copending Application no 17/904,570 (’570) in view of Klaus et al. (US 2017/0232030
An obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but an examined application claim not is patentably distinct from the reference claim(s) because the examined 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).
Instant claims are as recited above
Claims of ‘071 are drawn to a method of treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of the crystalline form of N-((1R,3S)-3-(4-acetylpiperazin-1-yl)cyclohexyl)-4-fluoro-7-methyl-1H-indole- 2-carboxamide (specie of the instantly claimed compound of Formula 1 and specific compound 15 instantly claimed)
Claims of ‘570 are drawn to a method of treating multiple myeloma or mantle cell lymphoma in a subject in need thereof, the method comprising administering to the subject :(a) a compound of Formula IV-A:
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b) a Second Therapeutic Agent, wherein: the Second Therapeutic Agent is dexamethasone, pomalidomide, lenalidomide, venetoclax, CC-122, selinexor, panobinostat, or tazmetostat comprises one or more glucocorticoid receptor agonists, one or more immunomodulatory drugs, one or more proteasome inhibitors, one or more Bcl-2 inhibitors, one or more pleiotropic pathway modulators, one or more XPO1Reply to Office Action of August 25, 2025 inhibitors, one or more histone deacetylase inhibitors, or one or more EZH2 inhibitors, or a combination thereof.
‘071 and ‘570 claims the method of treatment of the specie of the instantly claimed condition with the species of the instantly claimed compound. ‘071 does not disclose the combination with a second therapeutic agent while the ‘570 application claims the inclusion of the second therapeutic agent, the agents claimed are different from that instantly claimed.
However, Klaus et al. teaches a method of treating lymphomas cancer in a subject in need thereof (para [0494]) comprising administering an effective amount of a histone methyltransferase inhibitor (para [0016]-[0020], DOT1L inhibitor) in combination with a second therapeutic agent (para [0034], a compound of Formula (I) (e.g., EPZ-5676 or EPZ-4777) or a pharmaceutically acceptable salt, polymorph, solvate, or stereoisomer thereof and the one or more therapeutic agents), wherein the Second Therapeutic Agent comprises one or more BTK inhibitors (para [0225]), one or more anti-CD20 monoclonal antibodies, one or more alkylating agents (para [0234]), one or more topoisomerase Il inhibitors (para [0097], Fig 5, Daunorubicin), one or more vinca alkaloids (para [0225], Vincristine), one or more platinum-based drugs (para [0024], cisplatin), one or more nucleoside anticancer agents, one or more PI3K inhibitors (para [0225]), one or more CDK4/6 inhibitors (para [0225]), one or more CARM1 inhibitors, one or more inhibitors of enzymes of DNA damage repair, one or more SYK inhibitors, or one or more MEK inhibitors (para [0225]), or a combination thereof, wherein the combination therapy results in a synergistic effect (para [0302]-[0303]). They specifically teach doxorubicin [0236], or Carboplatin [0235] or Rituximab [0240] or vincristine [0245], or Ibrutinib or Mafosfamide [0225], Etoposide [0245], Gemcitabine [0237], Olaparib [0221] as the second therapeutic agents. It would have been obvious to one of ordinary skill in the art to combine the teachings of ‘071 and ‘570 with that of Klaus et al., as they all are directed to anti-cancer combination therapy comprising a histone methyltransferase inhibitor and a second therapeutic agent, and include one or more of the second therapeutic agents disclosed in Klaus et al. in the method of ‘070 and ‘570 as a secondary agent with compound 15., in order to take advantage of potential synergistic effects brought about by the combined administration (Klaus et al., para [0302]-[0303]), and thereby enhance the efficacy of said method toward treating cancer in a subject (Epizyme-079, para [0377], [0382])., thus rendering them obvious over the instantly claimed claims.
Although the conflicting claims in the instant application and claims of ‘070 and 570 not identical as stated above, they are not patentably distinct from each other in view of Klaus et al.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Conclusion
Claims 1, 4, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 48, 50, 52-53, 75 and 79 are rejected. No claims are allowed
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/SAVITHA M RAO/Primary Examiner, Art Unit 1691