Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
The amendments to the claims filed March 17, 2025 are acknowledged and entered. Claims 1-13 and 19-25 are pending.
Priority
This application is a 371 of PCT/US2022/080199, filed November 19, 2022, which claims the benefit of 63/281,508, filed November 19, 2021, and priority of PCT/US2022/080165, filed November 18, 2022.
Information Disclosure Statement
No IDS has been filed with the instant application.
As a reminder, Applicant and other individuals substantially involved with the preparation and/or prosecution of the application have a duty to disclose to the office all information known to that individual to be material to patentability as defined in 37 CFR §1.56.
Specification
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any of the errors of which applicant may become aware of in the specification.
Claim Rejections - 35 USC § 112a
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 19 and 25 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 method of treating uterine cancer, endometrial cancer, breast cancer, ovarian cancer, stomach cancer, gastric cancer, colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma, sarcoma, esophageal cancer, bladder cancer, lung cancer, cholangiocarcinoma, adrenocortical carcinoma, or mesothelioma does not reasonably provide enablement for
A method of treating a solid tumor cancer 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.
Applicant teaches that a compound of Formula (I-1) is an inhibitor of CDK2 (see paragraph [0026] These compounds are selective inhibitors of CDK2). However, inhibition of CDK2 is not known to be correlated with the treatment of the entire scope of solid tumor cancers claimed. Applicant’s disclosure is only enabling for the treatment of conditions which Applicant has demonstrated may be treated by the instant compound, and of conditions which the prior art is already aware may be treated by a compound with the disclosed activity (i.e. CDK2 inhibitors) and for which Applicant has written support. Case law is clear on this point. In an unpredictable art, such as drug therapy to treat disease, models may be used for enablement only if there is a reasonable correlation between the activity in question and the asserted utility. Given the guidance provided by Applicant, one skilled in the art would not be able to practice the full scope of the invention without undue experimentation.
In evaluating the enablement question, several factors are to be considered. Note In re Wands, 8 USPQ2d 1400 and Ex parte Forman, 230 USPQ 546. The factors include: 1) The nature of the invention, 2) the state of the prior art, 3) the predictability or lack thereof in the art, 4) the amount of direction or guidance present, 5) the presence or absence of working examples, 6) the breadth of the claims, and 7) the quantity of experimentation needed. The determination that “undue experimentation” would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations.
The nature of the invention & breadth of claims:
Claim 1 is drawn to a compound of Formula (I-1). The specification teaches Formula (I-1) is an inhibitor of CDK2 (see paragraph [0026] These compounds are selective inhibitors of CDK2).
Claim 19 depends from claim 1 and recites a method of treating a subject suffering from a solid tumor cancer, comprising administering to the subject a therapeutically effective amount of a compound of claim 1.
Claim 25 depends from claim 19 and includes the limitation “solid tumor cancer”.
The specification does not provide a complete definition of solid tumor cancers embraced by the claims. The specification does not provide a definition of “subject”.
The nature of the invention is a method of treating a solid tumor cancer in a subject, the scope of which could include humans, comprising administration of an inhibitor of CDK2 (Formula (I-1). Because no complete definition of solid tumor cancers is provided, the scope of the claims is very broad including at least a general method of treating all solid cancers known in the art.
The state of the prior art
The state of the prior art is aware that uterine cancer, endometrial cancer, breast cancer, ovarian cancer, stomach cancer, gastric cancer, colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma, sarcoma, esophageal cancer, bladder cancer, lung cancer, cholangiocarcinoma, adrenocortical carcinoma, or mesothelioma may potentially be treated by inhibition of CDK2. For instance, Lukasik et al. (Int J Mol Sci 2021, 22, 2395) teaches CDK2 is associated with some cancers including breast, colon, ovary, lung, hepatocellular and prostate cancers (page 11-12, 6.2 CDK2).
As per the broad treatment of cancer, no compound has ever been found to treat cancers of all types generally. Since this assertion is contrary to what is known in medicine, proof must be provided that this revolutionary assertion has merits. The existence of such a “silver bullet” is contrary to our present understanding of oncology. The state of the art is not indicative any pharmaceutical agents that are useful in the treatment of cancer generally. Cecil Textbook of Medicine states that “each specific type has unique biologic and clinical features that must be appreciated for proper diagnosis, treatment and study” (see the enclosed article, page 1004). Different types of cancers affect different organs and have different methods of growth and harm to the body. Also see In re Buting, 163 USPQ 689 (CCPA 1969), wherein 'evidence involving a single compound and two types of cancer, was held insufficient to establish the utility of the claims directed to disparate types of cancers'. Thus, it is beyond the skill of oncologists today to get an agent to be effective against cancers generally.
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.
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 for a compound that treats all types of cancer. 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.”
Recently, Wu (Journal of Hematology & Oncology 2022 (15) 143) discloses that between 1991 and 2021 there have been 228 new cancer drugs approved by the U.S. Food and Drug Administration of which 120 of these are drawn to the treatment of solid tumors alone (Abstract). Wu teaches that there are 21 different approved drugs for treating lung cancers, some of which have different cellular targets (Table 1, page 5). Similarly, breast cancer (see Table 2, page 10) has 22 different drugs that have varied cellular targets and are indicated for different types of breast cancer. More still, Table 4 (page 17) indicates that there are 17 different drugs available to treat different forms of gastrointestinal cancers. See also Table 6 (page 25), drugs approved for urologic cancers, Table 7 (page 28), drugs approved for skin cancers, and Table 8 (page 33), drugs approved for thyroid cancer. Wu further provides an illustration summarizing the protein structure of some cellular targets and the binding site of their respective drugs (Fig 12, page 38). Taken as a whole, Wu teaches that no single therapeutic has ever been identified as a treatment for all forms of cancer; and closer examination of Fig 12 provides a logical explanation: As highlighted in Fig 12, molecular protein targets implicated in different cancers (e.g. EGFR for lung cancer (see Table 1), VEGFR2 for gastric cancer (see Table 4)) have different three-dimensional protein structures, different active sites, and therefore require different drugs with the right shape and chemical groups in order to bind the target active site and have an effect in treating the cancer. In other words, there is no one size fits all approach to treating cancer simply for the reason that no single molecule will have the shape and chemical functional groups necessary to bind and modulate all molecular targets of cancer, all of which all have varied shapes. It is commonly known in the pharmaceutical arts that shape dictates function wherein drugs which have a shape complimentary to the protein target will bind and have an effect (this is often referred to simplistically as a “Lock and Key” model). Given the varied shape of protein targets in cancer (e.g. EGFR and VEGFR2), it is pure fantasy to speculate that a single drug with a single three dimensional shape will bind all protein targets implicated in cancer therapy and have an effect in treating all forms of the disease.
In view of the above, the state of the prior art and current state of the art are not aware of any “silver bullet” drug therapy to treat all forms of solid tumor cancers as is claimed presently, at least for the reason that persons skilled in the art recognize that different forms of cancer have different treatment requirements and therefore require different drug therapies.
The Level of One of Ordinary Skill
The level of skill in the art is high. The artisan using the claimed invention would be a person with medical training such as a medical doctor or physician with an MD degree or the equivalent.
Predictability in the art
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F. 2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved”. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is a reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F.2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Amount of guidance/working examples
Applicant provides in vitro data to show that a compound of Formula (I-1) is an inhibitor CDK2 (see paragraphs [00353]-[00358 ]) therefore suggesting that the claimed compounds may be of use in the treatment of cancers associated with CDK2.
However, no experimental or other data is provided to show the instant compounds may have use in the treatment of the full scope of cancers claimed, and least of all those cancers for which there is no known association with CDK2. The specification does not provide any guidance to one of ordinary skill in the art to extrapolate the in vitro data provided by Applicant to the treatment of the many different forms of cancer included in the scope of the method.
The quantity of experimentation needed:
MPEP 2164.01(a) states, "A conclusion of lack of enablement means that, based on theevidence 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 and one skilled in the art could not practice the full scope of the claimed invention without undue experimentation.
This rejection could be overcome by amending the claims to incorporate the cancers recited in claims 20-24 for which applicant is enabled.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(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) 1-5, 12-13, 19-21, 23-25 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Taylor et al. (WO2022/174031 A1, effectively filed February 12, 2021) (hereinafter “Taylor”).
Taylor teaches (1R,3S)-3-(3-(pyrimidin-2-ylamino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (see page 504 and 507, Example 37, product of step 5; pictured below for convenience) which corresponds to instant Formula (I) or Formula (I-1) wherein R1 is C3 alkyl; R2 is H; X1, X2 and X3 are each CR3 wherein each R3 is H; and X4 is N.
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254
840
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Taylor teaches compound 563 (page 157, pictured below for convenience) which corresponds to instant Formula (I) or Formula (I-1) wherein R1 is C3 alkyl; R2 is H; X1, X2 and X4 are each CR3 wherein two R3 are H and one R3 is C2 alkoxy substituted with one OR3a wherein R3a is H ; and X3 is N.
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170
364
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Taylor further teaches a pharmaceutical composition comprising the compound (see claim 20) and a method of using the compound to treat a CDK-mediated disorder wherein the CDK2-mediated disorder is breast cancer, endometrial cancer, ovarian cancer (claims 22-23) and wherein ovarian cancer has amplification in CCNE1 (Example 51 at paragraph [00756], OVCAR3 cells are ovarian cancer cells).
Claim(s) 1-8, 12-13 and 19-25 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Grandner et al. (WO 2023/060057 A1, effectively filed October 5, 2021) (hereinafter “Grandner”).
Grandner teaches many compounds which corresponds to instant Formula (I) or Formula (I-1) (see Table 1 at page 57; compounds 2C, 3F-3G, 2E, 2F, 2G, 2H, 2I, 4G, 4I, 4J, 2L, 2M, 2N, 2O, 5, 5A, 5B, 2P, 2Q, 2R, 2T, 2V, 2JJ, 3, 3A, 3B, 3C, 3E, 3D; see Table 2 compounds 8B, 10E).
For instance, compound 3F (pictured below) corresponds to the claimed compounds wherein R1 is 4 membered heterocyclyl (azetidinyl) substituted with one C1 alkyl (methyl); and R2 is H; X2, X3 and X4 are each CR3 wherein each R3 is H; and X1 is N.
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133
212
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Compound 2E (pictured below) corresponds to the claimed compounds wherein R1 is C3 alkyl; R2 is H; X1, X2 and X4 are each CR3 wherein each R3 is H; and X3 is N.
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123
226
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Compound 3A (pictured below) corresponds to the claimed compounds wherein R1 is C3 cycloalkyl substituted with one C1 alkyl (methyl); and R2 is H; X2, X3 and X4 are each CR3 wherein each R3 is H; and X1 is N.
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140
213
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Compound 2Q (pictured below) corresponds to the claimed compounds wherein R1 is C3 alkyl; R2 is H; X1 and X3 are each CR3 wherein one R3 is H and the other R3 is NRaRb wherein Ra and Rb are each C1 alkyl ; and X2 and X4 are each N.
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145
237
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Grandner further teaches a pharmaceutical composition comprising the compounds (see claim 70) and a method of using the compound to treat a CDK-mediated disorder wherein the CDK2-mediated disorder is breast cancer, endometrial cancer, ovarian cancer (claim 73) and wherein the breast cancer is hormone receptor positive, human epidermal growth factor 2 negative (see [0214] breast cancer, e.g. hormone receptor positive breast cancer, triple negative breast cancer). Grander teaches wherein cancers having amplification in CCNE1 include ovarian and breast cancer (see [0216]).
Claim(s) 1-6, 8, 12-13 19-21 and 24 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Yunfei et al. (WO 2023/083201 A1, effectively filed November 9, 2021) (hereinafter “Yunfei”).
Yunfei teaches many compounds which corresponds to instant Formula (I) or Formula (I-1) (see compounds disclosed throughout pages 6-38 of the attached English translation).
For instance, the following two compounds at the top of page 6 (pictured below) correspond to the claimed compounds wherein R1 is C3 alkyl; R2 is H; X1, X2, X3 and X4 are each CR3 wherein three R3 are H and one R3 is CN.
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51
356
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The compound pictured below (see page 10, col 1 of row 4) corresponds to the compound of the claims wherein R1 is C3 cycloalkyl substituted with one C1 alkyl (methyl); and R2 is H; X1, X2, X3 and X4 are each CR3 wherein three R3 are H and one R3 is CN.
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59
148
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See also example compounds pictured below (page 11, rows 6-8)
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73
448
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The example compound pictured below (see page 12, row 6) corresponds to the claimed compounds wherein R1 is C3 alkyl; R2 is H; X1, X2, X3 and X4 are each CR3 wherein three R3 are H and one R3 is SOwRc wherein w is 2 and Rc is C1 alkyl.
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59
187
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See also example compound pictured below (see page 34, row 4) which corresponds to the claimed compound wherein R1 is C4 alkyl; R2 is H; X2, X3 and X4 are each CR3 wherein two R3 are H and one R3 is CN.
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61
207
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Yunfei also teaches a pharmaceutical composition comprising the claimed compounds (page 38) and a method of treating a subject suffering from breast cancer or ovarian cancer (page 38).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1 and 9-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yunfei et al. (WO 2023/083201 A1, effectively filed November 9, 2021) (hereinafter “Yunfei”).
As noted in the above rejection, Yunfei teaches many compounds of instant formulae (I) or (I-1) which have use in treating cancer, the teachings of which are incorporated herein by reference. Yunfei further teaches a genus of formula I (page 1 of translation; pictured below for convenience) which provides that the variables corresponding to instant R1 and R2 of the claims can form a 3-7 membered heterocyclyl ring optionally substituted by alkyl including methyl (page 1; R1 and R2 form a 3 to 7 membered heterocycloalkyl group…optionally substituted with R1B; R1B is alkyl; “alkyl” includes methyl, see definition of “alkyl” at page 39). Yunfei thus teaches the groups corresponding to R1 and R2 of the claims can independently be H, alkyl, cycloalkyl or, alternatively, may come together to form a heterocyclyl ring substituted by alkyl.
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78
219
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The difference between the instant claims and Yunfei is that the claims require wherein R1 and R2, taken together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl ring that is optionally substituted with methyl. Yunfei does not teach an embodiment wherein the groups corresponding to R1 and R2 form a heterocyclyl ring optionally substituted with methyl; however, it would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the instant application to modify Yunfei into the claimed invention because Yunfei had disclosed that the groups corresponding to R1 and R2 can alternatively form a heterocyclyl ring optionally substituted with alkyl including methyl.
One would have been motivated as a matter of practicing the invention of Yunfei and making additional compounds that may be useful for treating breast cancer.
One would have had a reasonable expectation of success because Yunfei disclosed that groups corresponding to R1 and R2 of the claims could alternatively be H, alkyl, cycloalkyl or may come together to form a heterocyclyl ring optionally substituted by alkyl, including methyl, as required by the claims.
Conclusion
No claim is allowed.
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June 26, 2026
/KEVIN S MARTIN/Examiner, Art Unit 1624
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