DETAILED ACTION
This office action is in response to applicant’s filing dated November 5, 2025.
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
Claims 59 - 78 are pending in the instant application. Acknowledgment is made of Applicant’s amendments filed November 5, 2025.
Election/Restrictions
Applicant's election with traverse of:
(i) protein kinase PKMYT1 from the method of claim 59,
(ii) PKMYT1 inhibitor 5-((5-methoxy-2-((4-morpholinophenyl)amino)pyrimidin-4- yl)amino)-2-methylphenol from the inhibitors listed claim 67,
(iii) PPP2R2A from the PP2A subunits listed in claim 70, and
(iv) ovarian cancer tissue from the cancerous tissue listed in claim 75, as single species, in the reply filed on November 5, 2025 is acknowledged. The traversal is not addressed.
The requirement is still deemed proper and is therefore made FINAL.
Upon performing the search of prior art Examiner detected non-elected species. Hence, the election of species:
(ii) single disclosed PKMYT1 inhibitor;
(iii) single gene of nucleic acid encoding the PP2A subunit
and
(iv) single cancerous tissue, has been withdrawn and examination will proceed to the full scope of claims 59-67 and 70 - 78.
Claims 68 and 69 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on November 5, 2025.
Claims 59 - 67 and 70 – 78 are presently under consideration, as related to the elected species: protein kinase PKMYT1.
Priority
The present application is a CON of PCT/US2021/025230, filed March 31, 2021, which claims the benefit of priority of U.S. Provisional Application No. 63/003,736, filed April 1, 2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/19/2024, 06/06/2024, 04/18/2025 and 11/05/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
Acknowledgement is made of the drawings received on September 28, 2022. These drawings are accepted.
Claim Rejections - 35 USC § 112
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 59 - 67 and 70 – 78 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the method of treatment of liver, colon and ovarian cancer with small molecules PKMYT1 inhibitors dasatinib (as evidenced by applied art) and compounds recited in Table 5, does not reasonably provide enablement for the method of treatment of any cancer mediated by mutation in Protein Phosphatase 2 (PP2A) with any PKMYT1 inhibitors, encompassed by instant 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. This is a scope of enablement rejection.
To be enabling, the specification of the patent application 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 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in /n re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
Nature of the invention and the Breadth of the claims.
The invention is drawn to a method for treating different types of cancer recited by claims with any compounds acting as PKMYT1 inhibitors. The breadth of the claims is extensive.
Scope of the compound covered:
PKMYT1 inhibitors widely vary in structure and represent: natural compounds such as flavonoids (e.g. luteolin) or synthetic molecules, such as 2-amino-[1′-biphenyl]-3-carboxamides (e.g., RP-6306), diaminopyrimidines, aminoquinolines, quinazolines, pyrido[3-d]pyrimidines, pyrazolo[4-d]pyrimidines, and pyrrolo[3-b]quinoxalines, as well as PROTACs. These compounds encompass molecules that widely vary in the physical and chemical properties such as size, molecular weight, acidity, basicity, and properties that are known in the art to greatly influence pharmacokinetic and pharmacodynamics parameters, not to mention the ability to productively bind to claimed biological target molecules. The claims cover compounds easily in the hundreds. Each of these compounds is claimed to be useful in the method of treating all types of cancer, encompassed by instant claims.
Scope of the diseases covered:
The different types of cancer to be treated by the method of invention is any cancer type, mediated by mutation in Protein Phosphatase 2 (PP2A). The scope of disease is vast and vary considerably as detailed below:
Cancer is not a single disease, or cluster of closely related disorders, they have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level. Different cancers, driven by the same mutation can show different response to the same class of drugs or even to the same individual drug, targeting mutation.
2. The relative skill of those in the art.
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant’s invention would generally be a physician with a M.D. degree and several years of experience. However, given the state of the art as set forth above, the artisan is currently unaware of any one particular anticancer agent that is effective against all cancer cell types.
3. The predictability or unpredictability of the art and the state of the prior art.
The present claims relate to the mechanism underlying the treatment of the claimed diseases with the compounds of the instant invention. Although the discovery of such a mechanism may be an important piece of scientific knowledge, it still needs to be turned into a practical application in the form of a specified actual treatment of the pathological conditions. The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain). As illustrative of the state of the art, the examiner cites: Schmidt et al (Molecules 2017, 22, 2045, cited in IDS, filed 03/19/2024, hereinafter Schmidt), Remmerie et al (Frontiers in Oncology, June 2019, Volume 9, Article 462, hereinafter Remmerie) and da Costa et al (Nat Rev Drug Discov. 2023 January ; 22(1): 38–58, hereinafter da Costa).
With regards to unpredictability, Schmidt, cited for evidentiary purpose teaches: G2 checkpoint abrogation of the cell cycle of cancer cells is a promising concept to preferably damage cancerous cells over normal cells by a small molecule inhibitor. Therefore, WEE1 and PKMYT1 inhibitors proposed to be a promising option since WEE kinases bind Cdk1, altering equilibria and thus affecting G2/M transition (abstract). The G2 checkpoint abrogation can be induced by pharmacological manipulation, resulting in mitotic catastrophe and apoptosis. Confirmed or suggested targets for G2 checkpoint abrogation and mitotic catastrophe are WEE1, PKMYT1, Chk1, and Hsp90 (heat shock protein 90). For PKMYT1, only nine inhibitors were published as active, and included among them were drugs like the tyrosine kinase inhibitors Dasatinib, Bosutinib, PD0166285, PD1739525, PD1739552, and PD1809705. Furthermore Pelitinib, Saracatinib, and Tyrphostin AG14784 seem to be weak inhibitors. When comparing the number and strength of PKMYT1 inhibitors with other kinases, PKMYT1 appears to be restricted and difficult to inhibit. None of the potential PKMYT1 inhibitors reached clinical trials until now (page 10, 2nd paragraph). At the moment among ongoing clinical tryals of WEE1 inhibitor MK1775, two studies are still ongoing and five are terminated.
AstraZeneca-sponsored clinical trial NCT02087241 was also stopped earlier. A total of 14 subjects were enrolled in four cohorts with only one to seven patients. During the 13-month observation period, five subjects died and one cohort was extinguished completely. However, the particular reasons which led to the termination decision are unknown. NCT02087176, the third study with 32 participants that was also supported by AstraZeneca, was terminated before data collection and analysis were finished. Probably the weak response rate of 9.4% in the MK1775 + docetaxel group resulted in the decision to abort further investigations.
Furthermore, with regards to unpredictability, Remmerie, cited for evidentiary purposes, teaches therapeutic potential of direct and indirect PP2A targeting compounds, possibly in combination with other anti-cancer drugs, in EC (endometrial cancer), as well as potential of the PP2A status as a predictive and/or prognostic marker for type I and II ECs (abstract). Many human cancers have shown to be associated with PP2A dysfunction, such as via mutations in one of its subunits (page 3, right column, 2nd paragraph). Nevertheless, the distinct PP2A inactivating mechanisms between type I and type II ECs, as well as other gynecologic cancers, open up specific opportunities for direct or indirect, personalized therapeutic targeting of PP2A, in order to (re)-activate this phosphatase (page 5, right column). Besides the therapeutic potential of single agent targeting of PP2A, also combination therapies of PP2A activators with other drugs have gained attention. The combination of a PP2A activator with a kinase inhibitor seemed particularly beneficial in cases where oncogenic kinase activation simultaneously resulted in PP2A inhibition, and therapy resistance to a single agent kinase inhibitor occurred (page 7, left column, 2nd paragraph). Summarizing the review Remmerie concludes, that more studies should focus on these promising compounds in the specific context of type I and type II ECs (page 10, right column, 3rd paragraph).
Moreover, with regards to unpredictability, da Costa, cited for evidentiary purposes, in the later dated reference teaches that, several ATR, CHK1, WEE1 and MYT1 inhibitors are undergoing clinical evaluation as monotherapies or in combination with other anti-cancer therapies to capitalize on high replication stress, overcome therapeutic resistance and promote effective antitumor immunity (abstract). Thus far, clinical evaluation of ATRi, CHK1i and WEE1i in early-phase clinical trials has demonstrated significant and durable monotherapy activity only in a subset of cancer patients. In addition, several new compounds are under preclinical development and/or undergoing first-in-human clinical trials, such as the ATRi M1774, RP-350 and ART0380, and the PKMYT1 inhibitor RP-6306. (page 19, 4th paragraph). Nonetheless, a major challenge for the clinical development of these agents remains toxicity, especially bone marrow toxicity. To address this, alternative dosing schedules and sequencing of administration of drug combinations are being explored and this is an active area of clinical investigation. Summarizing the review, da Costa concludes that, the development of biomarkers of response to ATR–CHK1–WEE1 inhibition is an evolving field with a rapidly growing body of preclinical data. Clinical data are immature as they include only small, early-phase trials with results that can only be considered hypothesis-generating at this juncture (page 20, 1st and 2nd paragraph).
These articles plainly demonstrate that the art of developing and testing therapies to treat all types of cancer with compounds of instant claims is 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 provided and the presence or absence of working examples.
The instant claims, directed to a method for treatment of any cancer mediated by mutated Protein Phosphatase 2 (PP2A) comprising administering to the subject in need of any PKMYT1 inhibitors and at least one additional active agent, are extremely broad in contrast with the specification that only provides data, showing therapeutic activity of few compounds (Table 5), PKMYT1 inhibitors on the liver (Hep3B, Huh1 cell lines), ovarian (OVCAR8 cell line) and colon (HCT116 cell line) cancer cells. While experimentation is presented for treatment of types of cancer listed above with the compounds recited in experimental examples, the specification does not provide working examples of treatment of any forms of cancer that are not liver, colon or ovarian cancer, with all the compounds encompassed by instant claims. Although specification provides general directions or guidance of administration regimen, route or dosage e.g.:
- For example, a small molecule may be administered at a concentration of about 0.5 nanomolar (nM) or about 10 μM;
- In some cases, the one or more therapeutic agents may be delivered to a subject in one or more delivery vesicles, such as a nanoparticle (page 26, [0099]);
- The one or more therapeutic agents may be formulated into an aerosol, pill, tablet etc. (page 27, [00104]), necessary to treat all of the various cancers encompassed by the claims, the directions are very broad and include vast variety of known formulations. There is no experimentation or mechanism of action presented or discussed in the specification regarding treatment of the cancers that are not liver, colon or ovarian cancer. Absence of working examples is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP 2164.
5. The quantity of experimentation necessary.
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that all the compounds encompassed by class PKMYT1 inhibitors are capable of treating all different cancers encompassed by claims. Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and ‘patent protection’ is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" (42 USPQ 2d 1001, Fed. Circuit 1997). As noted above, none of the experimentation provided is drawn to the treatment of a cancer that is not a liver, colon or ovarian cancer. A review of the state of the art fails to reveal that all possible compounds acting as PKMYT1 inhibitors are useful as a therapeutic for the treatment of all cancers recited by claims, except for a cancers listed above. Determining if any particular claimed compound would treat any particular cancerous disease state would require synthesis of the compound, formulation into a suitable dosage form, and subjecting it to clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment.
Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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.
Claims 59 - 67 and 70 – 78 are rejected under 35 U.S.C. 103 as being unpatentable over Narla (WO 2016/210134 A1, cited in IDS, filed 06/06/2024, hereinafter Narla) in view of Sangodkar et al (FEBS J, 283 (2016) 1004-1024, hereinafter Sangodkar).
Instant claims are drawn to a method for treating liver, ovarian or colon cancer, in a subject, comprising administering to said subject a therapeutically effective amount of a small molecule tyrosine/threonine 1 (PKMYT1) inhibitor, such as dasatinib, bosutinib or saracatinib, where the cancer has a decreased expression or activity of Protein Phosphatase 2 (PP2A) or a PP2A subunit (e.g. Aα, encoded by PPP2R1A or Bα, encoded by PPP2R2A), caused by mutation of or deletion of the nucleic acid encoding the PP2A subunit, and where the administration reduces proliferation or viability of the cancer. The method is further drawn to identifying the cancer cell as having the difference in expression or activity of PP2A or the PP2A subunit. The method further comprises administering to said subject a therapeutically effective amount of a second therapeutic agent comprising an anti-cancer agent.
Narla teaches methods and compositions for treating hepatocellular carcinoma, ovarian or colorectal (page 37, [00109]) cancer, characterized by cancer cells in which PP2A expression is reduced, by administering to the subject therapeutically effective amounts of a PP2A activator (SMAP) and a protein kinase inhibitor (page 1, [0005]), where protein kinase inhibitors are Src kinase inhibitors including saracatinib, dasatinib, bosutinib (page 33, [0099]). Narla further teaches that activity of Protein phosphatase 2A (PP2A) is frequently inhibited in a myriad of cancers via mutation, decreased expression of its subunits (page 45, [00133]). One of the crucial causes of PP2A inhibition is phosphorylation of the catalytic subunit at Tyrosine 307 (Y307), which is induced by action of oncogenic kinases, such as SRC. Thus, activation of PP2A can be achieved by maximally dephosphorylating this Y307 residue with novel pharmacological combination therapies with SRC inhibitor (page 46, [00134] and [00135]). Narla tested the effectiveness of treatment on MOLT4 T-ALL and A549 NSCLC cells, where Dasatinib combination with SMAPs significantly dephosphorylate amino acid residue Y307, leading to increased phosphatase (PP2A) activation (page 49, [00142]). The method, taught by Narla utilizes a therapeutically effective amount of compositions where the "therapeutically effective amount" is defined as an amount that is effective to reduce or arrest a disease or disorder such as abnormal cell growth or cell migration in a subject. The result can be a reduction and/or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological system. The effectiveness of treatment may be measured by evaluating a reduction in tumor load or tumor volume or decrease in tumor growth or tumor cell invasion and/or migration in a subject in response to the administration of a combination of a PP2A activator and a protein kinase inhibitor (page 6, [0031]).
The method, taught by Narla applies compositions where PP2A activators co-administered with protein kinase inhibitors, which administering said drugs in combination can enhance the anticancer effect of either class of compounds additively and/or synergistically (page 30, [0090]).
Narla does not explicitly teach where the PP2A has mutations in subunits encoded by PPP2R1A or PPP2R2A.
However, Sangodkar teaches that PP2A is genetically altered or functionally inactivated in many cancers highlighting a need for its therapeutic reactivation. Sangodcar further teaches that the gene PPP2R1A encoding the Aα subunit, has the highest mutation rate with the point mutation as the most common alteration. In gene PPP2R2A, encoding B55α subunit, the most commonly occurring alteration is deletion (page 1008, Table 1).
Thus, since prior art teaches the method for treatment of certain cancer types where PP2A expression is reduced due to mutations in certain genes encoding enzyme complex subunits, and where the pharmaceutical compositions applied for the treatment include small molecules, protein kinase inhibitors, which aim to reactivate PP2A through inhibition of certain oncogenic kinases related to PP2A inactivation, it would have been prima facie obvious to one of ordinary skill in the art before effective filing date of the claimed invention to apply teachings of prior art, to achieve the claimed invention. A person of ordinary skill in the art would have been motivated to do so in search of an improved method of treating cancer mediated by certain mutations to selectively target these mutations with a reasonable expectation of success.
Therefore, taking all together, taught by prior art, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
Claims 59 - 67 and 70 – 78 are rejected. No claim is allowed.
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/E.V.V./Examiner, Art Unit 1691
/SAVITHA M RAO/Primary Examiner, Art Unit 1691