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 .
Priority
Examiner acknowledges that, according to the Filing receipt received 10/03/2024, that the instant application 18/710,037 filed 05/14/2024 is a 371 of PCT/US2022/079848 filed 11/15/2022 which claims benefit of U.S. provisional application 63/279,236 filed 11/15/2021.
However, the limitations of the instant claims are not adequately supported or enabled in the manner provided by 35 U.S.C. 112(a) or pre-AIA U.S.C. 112, first paragraph by 63/279,236. More specifically, the limitations of treating a cancer associated with a Ras mutation are not taught or suggested in their entirety. The 63/279,236 application discloses a method of treating pancreatic ductal adenocarcinoma (PDAC) by administering a BET/EP300 inhibitor of formula I, while the broadest disclosure of treating a cancer associated with a Ras mutation is the disclosure of KRAS mutations in PDAC (p. 40). As such, claims 1-18 and 24 have been awarded the effective filing date of PCT/US2022/079848 filed 11/15/2022. Claim 27 has been awarded the effective filing date of 63/279,236 filed 11/15/2021.
Information Disclosure Statement
The Information Disclosure Statement filed on 05/14/2024 is in compliance with the provisions of 37 CFR 1.97 and has been considered in full. A signed copy of list of references cited from the IDS is included with this Office Action.
Specification
The disclosure is objected to because of the following informalities: on pages 2, 33, 57, 62, and 64 the following moiety is depicted.
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However, Rb, is not defined throughout the specification.
Appropriate correction is required.
The use of the terms such as "Sigma Aldrich" or "TNeasy Plus Mini Kit" on pages 65-78 of the specification, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1, 9, 11-12, 15, and 27 are objected to because of the following informalities:
Claims 1 and 27 use the presence or absence of dashes, as well as hyphens and em dashes, inconsistently; for example, “-CH2(CO)CH=CH2” is clearly preceded with a hyphen while “CH2(CO)CH2Cl” is not;
Claims 1 and 27: “R70, at each occurrence, are” should read “R70, at each occurrence, is”;
Claim 9 does not end in a period;
Claims 11 and 15: “CH(CH3)2” should read “CH(CH3)2”;
Claim 11: listed alternatives are inconsistently preceded by the article “a”;
Claims 11 and 12: “R36’ R37’” should read “R36’, and R37’”.
Appropriate correction is required.
Drawings
The drawings are objected to because they (all figures) are not of sufficient resolution to be legible in their axis labels and/or legends. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-18, 24, and 27 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 and 27 recite the following alternative for R11.
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However, the nitrogen circled above is substituted four times by C=O, Ra, Rb, and N. This violates the valence of nitrogen, which only forms three bonds. It is unclear how the above nitrogen is substituted four times. Claims 2-18 and 24 require and/or do not clarify the limitation at issue and are similarly rejected.
Claims 1 and 27 recite the above alternative for R11 which contains the variable “Rb,”. However, no definition for “Rb,” is set forth in the claims. The scope of the limitation at issue is therefore unclear. Claims 2-18 and 24 require and/or do not clarify the limitation at issue and are similarly rejected.
Claims 1 and 27 recite the following alternative for R11.
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However, it is impossible to form a ring with only one or two carbons (i.e., C1-C2 cycloalkylenyl). It is unclear what structure is intended by the above alternative. Claims 2-18 and 24 require and/or do not clarify the limitation at issue and are similarly rejected.
Claims 1 and 27 recite the following alternative for R70.
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It is unclear if “a” refers to a specific moiety, such as an amino acid, or if “a” is an article in the grammatical sense. Claims 2-18 and 24 require and/or do not clarify the limitation at issue and are similarly rejected.
Claims 1 and 27 recite the following alternatives for Ra and Rb.
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However, an alkenyl or alkynyl cannot be formed with a single carbon (i.e., C1 alkenyl or C1 alkynyl). It is unclear what structures would be intended by the aforementioned alternatives. Claims 2-18 and 24 require and/or do not clarify the limitation at issue and are similarly rejected.
Claims 1 and 27 recite “heterocycle” as an alternative for Rc and Rc’. However, the term “heterocycle” does not suggest a monovalent radical. It is unclear how the claimed compound of formula I would be substituted by a heterocycle. Claims 2-18 and 24 require and/or do not clarify the limitation at issue and are similarly rejected.
Claims 1 and 27 recite the following alternative for Re and Rf.
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However, it is impossible to form a ring with only one or two carbons (i.e., C1-C2 cycloalkyl). It is unclear what structure is intended by the above alternative. Claims 2-18 and 24 require and/or do not clarify the limitation at issue and are similarly rejected.
Claim 11 depicts the following compound of Formula III.
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The following variables are additionally defined.
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No definition is set forth for R34’, R35’, R36’, or R37’. The scope of the structure of Formula III is therefore unclear. Claims 12-15 require and/or do not clarify the limitations at issue and are also rejected.
Claim 11 recites the following alternative for R32.
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However, an alkenyl cannot be formed with a single carbon (i.e., C1 alkenyl). It is unclear what structures would be intended by the aforementioned alternative. Claims 12-15 require and/or do not clarify the limitation at issue and are similarly rejected.
Claim 11 recites the following alternative for R33-R37’.
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However, a cycloalkyl cannot be formed with one or two carbons. It is unclear what structures would be intended by the aforementioned alternative. Claims 12-15 require and/or do not clarify the limitation at issue and are similarly rejected.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2-16 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 2, which depends from claim 1, recites the following structure of Formula II.
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R2 and R3 are further defined as below.
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However, the scope of claim 1 does not include compounds of Formula II wherein R3 is C1-C6 alkyl. While claim 1 recites that R11 is optionally substituted with 1, 2, or 3 substituents selected from –(C1-C6 alkylenyl)RcRc’, this alternative would not be interpreted to encompass wherein R3 is C1-C6 alkyl because the terminal location of RcRc’ suggests that RcRc’ would be substituted on the terminal carbon of the C1-C6 alkylenyl wherein “alkylenyl” is a divalent radical.
Additionally, the scope of claim 1 does not include the second or third alternatives listed for R2 as above. R11 is not defined such that it can be optionally substituted by C1 alkyl-(cycloalkyl or heterocyclyl). Claims 2-10 require the limitations at issue and are also rejected.
Claim 11, which depends from claim 1, recites the following compound of Formula III.
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Claim 11 additionally sets forth the following definitions.
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As above regarding claim 2 and the definition of R3, the definition of R32 is not supported by the limitations of claim 1. Moreover, the definition for R33-R37’ is not encompassed by claim 1. Namely, if R11 was –(C1-C6 alkylenyl)RcRc’ (see above discussion of claim 2), the substituents (Rd) for Rc do not include hydrogen, C1-C6 cycloalkyl, C1-C6 alkylamine, C1-C6 cycloalkylamine, C1-C6 alkylester, or C1-C6 alkylamide, wherein the alternatives for Rd as in claim 1 either do not recite the aforementioned alternatives (i.e., hydrogen, C1-C6 cycloalkyl) or recite a narrower alternative than the aforementioned alternatives (i.e., C1-C6 alkylamine, C1-C6 cycloalkylamine, C1-C6 alkylester, or C1-C6 alkylamide). Moreover, per claim 1, Rc’ is not further substituted. Claims 12-15 require the limitations at issue and are also rejected.
Claim 16, which depends from claim 1, recites the following compound of Formula IV.
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As above regarding claim 2 and the definition of R3, the substituent circled above is not supported by the limitations of claim 1.
Claims 2-16 therefore fail to include all the limitations of the claim from which they depend, as the limitations at issue either omit or replace the limitations set forth in claim 1. Therefore, claims 2-16 do not comply with the requirements of 35 U.S.C. 112(d).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
For purposes of moving examination forward, prior art which recites compounds within the scope of instant claims 2, 11, and 16 will be considered within the scope of claim 1.
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 1-18 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 ameliorating a cancer associated with a Ras mutation selected from lung cancer, gastrointestinal cancer, thoracic cancer, pancreatic cancer, colon cancer, haematologic cancer, small intestine adenocarcinoma, rectal adenocarcinoma, cholangiocarcinoma, gallbladder carcinoma, neuroblastoma, melanoma, head and neck squamous cell carcinoma, and pancreatic ductal adenocarcinoma, does not reasonably provide enablement for treating cancers associated with a Ras mutation generally, or preventing or curing cancers. 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.
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).
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Some experimentation is not fatal; the issue is whether the amount of experimentation is "undue"; see In re Vaeck, 20 USPQ2d 1438, 1444.
The treatment of cancer generally cannot possibly be considered enabled.
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."
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Some experimentation is not fatal; the issue is whether the amount of experimentation is "undue"; see In re Vaeck, 20 USPQ2d 1438, 1444.
The analysis is as follows:
1) Breadth of claims.
The instant claims are drawn to a method of treating cancer associated with a Ras mutation. The specification, paragraph [0091], additionally defines the term “treatment” to include prevention or cure of a disease or condition.
"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. 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.
One skilled in the art knows that chemotherapy of brain tumors is especially difficult. This is because 1) the blood-brain barrier, which is often intact in parts or all of a brain tumor, will block out many drugs, as it is the purpose of the blood-brain barrier to protect the brain from alien chemicals, and 2) CNS tumors are characterized by marked heterogeneity, which greatly decreases vulnerability to chemotherapy. As a result, many categories of CNS tumors simply have no chemotherapy available. These include, generally, hemangioblastomas, meningiomas, craniopharyngiomas, acoustic neuromas, pituitary adenomas, optic nerve gliomas, glomus jugulare tumors and chordomas, to name just some. With regard to gliomas, GBM is considered untreatable; no effective agents have emerged for the treatment of GBM, despite 20 years of enrolling patients in clinical trials. It is radiation and surgery which are used for low grade gliomas (e.g. pilocytic astrocytoma and diffuse astrocytomas), as no drug has been found effective. There is no drug treatment established as effective for optic nerve gliomas or gangliogliomas. Indeed, very few gliomas of any type are treated with pharmaceuticals; it is one of the categories of cancer that is the least responsive to drugs.
Lymphomas of the stomach are not commonly treated with anti-cancer agents per se, but instead, surgery or radiation and antibiotic therapy (e.g. amoxicillin, metronidazole, bismuth, and omeprazole) are the primary treatments.
Neuroendocrine tumors of the cervix generally do not respond to chemotherapy.
A number of sarcomas, including alveolar soft part sarcoma (ASPS), retroperitoneal sarcoma, most liposarcomas, and the assorted chondrosarcomas, are generally considered not to respond to chemotherapy; no chemotherapeutic agent has been established as effective.
It is important to note that tumors can need to be treated quite differently even though they are tumors of the same organ. For example, the drugs used most often to treat Wilms tumor, the most common malignant tumor of the kidneys in children, are actinomycin D and vincristine. Such drugs are never used with clear cell renal carcinoma, which is treated, although without much success, with immunotherapy using the cytokines interleukin-2 and interferon-alpha. However, such immunotherapy has never been established as effective in non-clear cell RCC forms such as papillary renal cell carcinoma. Despite strenuous efforts over a period of decades, no chemotherapeutic agent has ever been found effective against this cancer. Cancers of the stomach can be lymphomas, GISTs, carcinoid tumors, carcinomas, or soft tissue sarcomas, and for a single agent to be effective against all or even most of these categories would be contrary to what is known in oncology.
The scope of treating inflammation generally is extraordinarily broad. Inflammation is a process which can take place in virtually any part of the body. There is a vast range of forms that it can take, causes for the problem, and biochemical pathways that mediate the inflammatory reaction. It is one of the most pervasive of all body processes. Inflammation is a very general term which encompasses a huge variety of specific processes.
2) The nature of the invention and predictability in the art.
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).
Regarding prevention, currently there is no known method to determine that a patient will develop cancer before the fact, nor have any medicaments been developed for the prevention of any cancer.
3) State of the Prior Art. The claimed compounds are of formula I. So far as the examiner is aware these compounds have not been successfully used as broad range anticancer agents, anticancer agents for the treatment of each and every cancer associated with a Ras mutation, or for curing or preventing cancer.
4) Working Examples. Applicants have provided no working examples which are successfully used as broad range anticancer agents. Applicants have, however, demonstrated the cytotoxicity of the compound XP-524 against pancreatic cancer cell xenografts. See specification, pages 65-78.
5) 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 tumor 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.
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. 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."
6) Scope of the claims. The scope of the claims involves the compounds of the following formula:
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and their use as potential treatment to cancers “associated” with a Ras mutation, thus, the scope of claims is very broad.
7) The quantity of experimentation needed. Given the fact that, historically, the development of new cancers drugs has been difficult and time consuming, and especially in view of factors 1 and 4 and 6, 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.
Claims 17-18 and 27 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 a PD-1 inhibitor, does not reasonably provide enablement for an immune checkpoint inhibitor generally, a PD-L1 inhibitor generally, or a CTLA-4 inhibitor generally. 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.
As stated in the MPEP 2164.01 (a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described as in the above rejection and are not re-stated here.
In the instant case, the Wands factors are relevant for the following reasons:
Nature of the invention
The instant claims are drawn to a method of treating cancers associated with a Ras mutation, comprising administering pyrrolopyridinone compounds of formula I to a subject in need thereof, as well as a composition comprising a compound of formula I. The claims are further directed toward combining the compound of formula I with an immune checkpoint inhibitor.
Breadth of the claims
The instant claims are directed toward a method of treating Ras mutation-associated cancers generally, comprising administering a compound of formula I (see previous rejection above) and an immune checkpoint inhibitor generally, or a composition comprising a compound of formula I and an immune checkpoint inhibitor generally. Thus, the scope of the claims is incredibly broad.
State of the art, skill, and predictability
Combinations of agents are generally considered in the art to be unpredictable despite a high level of skill. 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). 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".
Working examples and direction from inventor
The working examples are limited to combinations of formula I with a PD-1 inhibitor, which resulted in improved effects (specification, pages 65-78). Additional guidance regarding species of immune checkpoint inhibitors to be combined with formula I are limited to Nivolumab, Pembrolizumab, Cemiplimab, Atezolizumab, Avelumab, Durvalumab, and Ipilimumab (p. 36 of specification). Applicant provides no consideration or evidence as to why immune checkpoint inhibitors other than PD-1 inhibitors would be expected to be combinable with formula I.
Quantity of experimentation
Due to the known unpredictability in the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that Applicant is enabled for immune checkpoint inhibitors generally.
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 § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-18, 24, and 27 is/are rejected under 35 U.S.C. 102(a) as being anticipated by Principe et al. (PNAS; Jan. 2022).
Principe et al. discloses a method of treating pancreatic ductal adenocarcinoma in xenograft mouse models, comprising administering compound XP-524 (Abstract; p. 4-5). Principe discloses that XP-524 has the following structure (Fig. 2).
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Compound XP-524 is notably identical to the structure of Formula IV as instant claim 16. Principe et al. discloses combining XP-524 with anti-PD-1 which significantly improved survival in PDAC mice (p. 9).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-18, 24, and 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Thatcher et al. (WO 2019109057 A1; 2019) in view of Adeegbe et al. (Cancer Immunol Res.; 2018; IDS filed 05/14/2024) and Leal et al. (Cancers; 2020).
Thatcher et al. discloses bromodomain inhibitors, including Compound 70 (p. 76, p. 133).
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Thatcher et al. additionally discloses that Compound 70 has a strong binding selectivity toward BET family proteins (p. 146-147). Thatcher et al. teaches that Compound 70 inhibits the growth of fulvestrant-resistant breast cancer cell models (Fig. 7) and has superior potency over other clinical benchmark BET inhibitors, including JQ1 (Fig. 10). Thatcher et al. teaches that the disclosed compounds can be used to treat cancer, including pancreatic cancer and lung cancer (p. 22, 27-28). Thatcher et al. additionally suggests combining the compounds with additional active agents such as chemotherapeutics, anti-neoplastic agents, and immunomodulating agents (p. 95-96) in a pharmaceutical formulation.
Thatcher et al. does not teach a method of treating a cancer associated with a Ras mutation, or combining Compound 70 with an immune checkpoint inhibitor. These limitations are obvious over Adeegbe et al. and Leal et al.
Adeegbe et al. teaches a method of treating Kras-mutant non-small cell lung cancer (NSCLC) in mouse xenograft models comprising administering a combination of JQ1, a BET inhibitor, with an anti-PD-1 antibody which resulted in greater responses compared to either agent administered alone (Abstract; p. 8-9).
Leal et al. teaches a method of treating Kras-mutant pancreatic cancer in mouse xenograft models comprising administering BET inhibitor INCB057643 (Abstract; p. 2-3). Leal et al. additionally discloses that PD-1 and PD-L1 blockade has been historically unsuccessful in treating pancreatic cancer, but that epigenetic modulation has been considered as a strategy to reduce resistance to immunotherapy (p. 9) and that treatment with INCB057643 for 16 weeks resulted in reduced PD-L1 expression in the liver and pancreas of xenograft mice (p. 6).
It would have been prima facie obvious for one of ordinary skill in the art to administer Compound 70 of Thatcher et al. for the treatment of cancer associated with a Ras mutation, such as NSCLC or pancreatic cancer. One would have been motivated to do so, with reasonable expectation of success, as Compound 70 of Thatcher et al. exhibits superior potency over other known BET inhibitors. Thus, one of ordinary skill in the art would be apprised that substitution of Compound 70 for the compounds of Adeegbe et al. and Leal et al. would be expected to yield predictable, if not more potent effects, for the treatment of Kras-mutant NSCLC or pancreatic cancer.
Moreover, it would have been prima facie obvious for one of ordinary skill in the art to combine Compound 70 with an immune checkpoint inhibitor, such as an anti-PD-1 antibody, either in the method of treatment or in a composition. One would have been motivated to do so in order to investigate greater effects in combining the two agents to treat cancer, and would have had a reasonable expectation of success as Adeegbe et al. demonstrates that the combination of BET inhibitor JQ1 with an anti-PD-1 antibody yields a more potent anti-cancer effect than either agent alone, while Compound 70 would be expected to be more potent than JQ1. Additionally, per Leal et al., BET inhibition could help improve the immunotherapeutic effects of PD-1/PD-L1 blockade.
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 1-18 and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11840533 B2 (“the ‘533 patent”) in view of Adeegbe et al. (Cancer Immunol Res.; 2018; IDS filed 05/14/2024) and Leal et al. (Cancers; 2020).
Claims 1-18 of the ‘533 patent are drawn to a method of treating cancer in a subject in need thereof, comprising administering the below compound of Formula XXVI.
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Claim 16 of the ‘533 patent particularly narrows the compound of Formula XXVI to the below compound.
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Claims 17-18 further claim administering an auxiliary active agent, including chemotherapeutic and immunomodulating agents.
While the claims do not teach a method of treating a cancer associated with a Ras mutation, or combining the claimed compounds with an immune checkpoint inhibitor, these limitations are obvious over Adeegbe et al. and Leal et al.
Adeegbe et al. and Leal et al. disclose as in the above rejection under 35 U.S.C. 103, which will not be restated here.
It would have been prima facie obvious for one of ordinary skill in the art to apply the method of the ‘533 patent for the treatment of cancer associated with a Ras mutation, such as NSCLC or pancreatic cancer. One would have been motivated to do so, with reasonable expectation of success, as the claimed compounds are BET inhibitors. Thus, one of ordinary skill in the art would be apprised that substitution for the compounds of Adeegbe et al. and Leal et al. would be expected to yield predictable effects for the treatment of Kras-mutant NSCLC or pancreatic cancer.
Moreover, it would have been prima facie obvious for one of ordinary skill in the art to combine the compounds of the method of the ‘533 patent with an immune checkpoint inhibitor, such as an anti-PD-1 antibody, in the method of treatment. One would have been motivated to do so in order to investigate greater effects in combining the two agents to treat cancer, and would have had a reasonable expectation of success as Adeegbe et al. demonstrates that the combination of BET inhibitor JQ1 with an anti-PD-1 antibody yields a more potent anti-cancer effect than either agent alone. Additionally, per Leal et al., BET inhibition could help improve the immunotherapeutic effects of PD-1/PD-L1 blockade.
Claims 1-18, 24, and 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11332466 B2 (“the ‘466 patent”) in view of Adeegbe et al. (Cancer Immunol Res.; 2018; IDS filed 05/14/2024) and Leal et al. (Cancers; 2020).
Claims 1-13 of the ‘466 patent are drawn to a compound of Formula XXVI.
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Claim 11 of the ‘466 patent particularly narrows the compound of Formula XXVI to the below subgenus.
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Claim 12 is directed toward a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
Claim 13 is directed toward a method of treating cancer, wherein the cancer is breast cancer, comprising administering a compound of claim 1 to a subject in need thereof.
While the claims do not teach a method of treating a cancer associated with a Ras mutation, or combining the claimed compounds with an immune checkpoint inhibitor, these limitations are obvious over Adeegbe et al. and Leal et al.
Adeegbe et al. and Leal et al. disclose as in the above rejection under 35 U.S.C. 103, which will not be restated here.
It would have been prima facie obvious for one of ordinary skill in the art to apply the method of the ‘533 patent for the treatment of cancer associated with a Ras mutation, such as NSCLC or pancreatic cancer. One would have been motivated to do so, with reasonable expectation of success, as the claimed compounds are BET inhibitors. Thus, one of ordinary skill in the art would be apprised that substitution for the compounds of Adeegbe et al. and Leal et al. would be expected to yield predictable effects for the treatment of Kras-mutant NSCLC or pancreatic cancer.
Moreover, it would have been prima facie obvious for one of ordinary skill in the art to combine the compounds of the method of the ‘533 patent with an immune checkpoint inhibitor, such as an anti-PD-1 antibody, either in the method of treatment or in a composition. One would have been motivated to do so in order to investigate greater effects in combining the two agents to treat cancer, and would have had a reasonable expectation of success as Adeegbe et al. demonstrates that the combination of BET inhibitor JQ1 with an anti-PD-1 antibody yields a more potent anti-cancer effect than either agent alone. Additionally, per Leal et al., BET inhibition could help improve the immunotherapeutic effects of PD-1/PD-L1 blockade.
Conclusion
No claims are allowed.
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/MADELINE E BRAUN/Examiner, Art Unit 1624 06/16/2026
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