DETAILED ACTION
This office action is in response to applicant’s filing dated June 29, 2026.
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, 63 – 69, 71 – 73 and 76 – 78 are pending in the instant application. Receipt and consideration of Applicants' amended claim set and remarks/arguments filed on June 29, 2026 are acknowledged. Claims 68 and 69 remain withdrawn, as being drawn to an unelected invention or species. Acknowledgement is made of Applicant's amendment of 59, 71 and 72 and cancelation of claims 60 – 62, 70, 74 and 75.
Claims 59, 63 – 67, 71 – 73 and 76 – 78 are under consideration in the instant office action.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on June 29, 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Objections and/or Rejections and Response to Arguments
Applicants' arguments, filed on June 29, 2026, have been fully considered.
Acknowledgement is made of the Applicant’s amendment of claim 59, wherein the scope of claim was narrowed to the method for treating enumerated types of cancer.
Acknowledgement is made of the Applicant’s cancelation of claims 60 – 62, 70, 74 and 75.
Accordingly, the rejection of claims 59 - 67 and 70 – 78 under 35 U.S.C. 112(a) for lacking enablement is partially withdrawn.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
Modified Objections and/or Rejections
Modifications Necessitated by Claim Amendment
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 76 and 77 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 76 and 77 are unclear because they depend directly or indirectly from canceled claim 74. It is therefore unclear, what is encompassed by the method of claims 76 and 77. It is noted, that claims must be given their broadest reasonable interpretation in light of the specification (See MPEP §2111) and therefore, for purposes of compact prosecution, the abovementioned claims are being interpreted as dependent from claim 59. It is suggested to amend “The method of claim 74…” in claims 76 and 77 to “The method of claim 59…” in order to obviate this rejection."
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, 63 – 67, 71 – 73 and 76 – 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 cancers recited in claim 59 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 said cancers mediated by mutation in Protein Phosphatase 2 (PP2A) with any therapeutic agent, whose administration results in a difference in expression or activity of PKMYT1 or PKMYT1 inhibitors of all varieties of chemical structure, 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. 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 types of cancer recited by claims with any therapeutic agent, whose administration results in a difference in expression or activity of PKMYT1, where said therapeutic agent is a small molecule, a protein or a nucleic acid; or where the therapeutic agent is a PKMYT1 inhibitor of all varieties of chemical structure, encompassed by instant claims. The breadth of the claims is extensive.
Scope of the compound covered:
The term “therapeutic agent, wherein the administration results in a difference in expression or activity of PKMYT1” is extremally broad and encompasses any drug or molecule that changes how much PKMYT1 protein is made or how the existing PKMYT1 protein functions compared to untreated state. The term would include direct inhibitors, allosteric modulators, activators, as well as agents targeting the production of PKMYT1 (e.g. upstream inhibitors, protein degraders, nucleic acids etc.).
Even the term “PKMYT1 inhibitors” is broad, as it covers agents widely varying 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 or even thousands. Each of these compounds or molecule is claimed to be useful in the method of treating the types of cancer, encompassed by instant claims.
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 an M.D. degree and several years of experience. However, given the state of the art as set forth above, the artisan would not accept, without undue experimentation, that all the agents encompassed by instant claims possess equivalent or similar therapeutic efficacy or comparable safety profiles.
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 certain cancers with all therapeutic agents encompassed by 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 certain types of cancer mediated by mutated Protein Phosphatase 2 (PP2A) comprising administering to the subject in need any therapeutic agent, whose “administration results in a difference in expression or activity of PKMYT1” 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), small molecules PKMYT1 inhibitors on cancer cell lines. While experimentation is presented for treatment of certain types of cancer with the small molecules PKMYT1 inhibitors recited in experimental examples, the specification does not provide working examples of treatment of those cancers with all the compounds or molecules 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 with therapeutic agents that are not the small molecules PKMYT1 inhibitors. 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 agents whose “administration results in a difference in expression or activity of PKMYT1”, where said therapeutic agent is e.g. a small molecule, a protein or a nucleic acid are capable of treating 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 with therapeutic agents that are not the small molecules PKMYT1 inhibitors. A review of state of the art fails to reveal that all possible compounds or molecule, whose administration results in a difference in expression or activity of PKMYT1, are useful as a therapeutic agents for the treatment of cancers recited by claims, except for the small molecules PKMYT1 inhibitors. Determining if any particular claimed compound or molecule 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.
Response to Arguments
Applicant argues:
- The claims are not directed to treating cancer indiscriminately but to treating a specific, biomarker-defined cancer population. Specifically, claim 59 recites, "wherein said cancer comprises a cell comprising a difference in expression or activity of Protein Phosphatase 2 (PP2A) or a PP2A subunit, or comprising a mutation or deletion of a nucleic acid encoding the PP2A subunit, as compared to a non-cancer control."
- The specification teaches the underlying relationship between PP2A dysfunction and sensitivity to PKMYT1 targeting. Working examples in the specification clearly demonstrate that when PPP2R2A is knocked out in a cell line, the PKMYT1 inhibitors show increased potency (see for example Table 5 and Figure 12). This demonstrates that PPP2R2A and PKMYT1 or PPP2R1A and PKMYT1 may be a synthetic lethal pair that can be used as a viable cancer treatment. Thus, the specification clearly indicates that the invention as now defined in claim 59 may be effective in the treatment of cancers and practiced without undue experimentation.
Examiner’s response:
Applicant's arguments have been fully considered but they are not persuasive because: as set forth above, although amended claim 59 recites enumerated types of cancer to be treated with claimed agents, claims are still extremely broad regarding variety of said agents. Claims are broader than enabled as they recite any drug or molecule, whose administration changes how much PKMYT1 protein is made or how the existing PKMYT1 protein functions compared to untreated state, and include any direct inhibitors, allosteric modulators, activators, as well as agents targeting the production of PKMYT1 (e.g. upstream inhibitors, protein degraders, nucleic acids etc.).
Regarding the argument about genes synthetic lethal pair is not persuasive because features upon which applicant relies (i.e., genes synthetic lethal pair) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Thus, according to In re Wands factors (see above): the claims are broad in scope; the nature of the invention is sophisticated; the state of the prior art does not establish that all the claimed agents would effectively treat claimed cancers; the level of skill is high; the level of unpredictability is high; the direction provided by the inventor is limited to specification; the existence of working examples is limited to the small molecules PKMYT1 inhibitors; and the quantity of experimentation includes testing all the claimed compositions against every cancer cell line. Thus, based on the In re Wands factors, the claims lack enablement.
Therefore, Applicant arguments are not found persuasive and rejection of claims 59, 63 – 67, 71 – 73 and 76 – 78 under 35 U.S.C. 112(a) as lacking enablement for treating cancers with all the claimed agents is maintained.
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, 63 – 67, 71 – 73 and 76 – 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, where 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. Sangodkar 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.
Response to Arguments
Applicant argues:
- Narla does not teach treating PPP2R1A- or PPP2R2A-deficient cancers by targeting PKMYT1. Even if Narla teaches treating PP2A-reduced cancers by targeting PP2A itself with a PP2A activator, Narla does not teach using PPP2R1A or PPP2RA2 reduction as a biomarker showing sensitivity to target PKMYT1. Narla does not identify PKMYT1 as a relevant kinase target, nor that reduced PPP2R1A or PPP2R2A predict sensitivity to PKMYT1-targeted treatment. Although Sangodkar discloses that PPP2R1A and PPP2R2A have high mutation rates in many cancers, neither Sangodkar nor Narla teaches that cancers with PPP2R1A or PPP2R2A mutations would be susceptible to PKMYT1 inhibition.
- Even if a POSA combined the references, there still would be no reasonable expectation of success, as a POSA would have been lead to further investigate the PP2A reactivation strategy of Narla, rather than the PKMYT1 targeting of the present claims.
Examiner’s response:
Applicant's arguments have been fully considered but they are not persuasive because: as set forth above, instant claims are drawn to a method to treat cancers comprising administering to the subject a small molecule 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. Narla teaches a method to treat the same types of cancer, where the cancer is characterized by reduced activity of Protein phosphatase 2A (PP2A) or reduced PP2A expression, caused by mutations. The method taught by Narla comprises administering to the subject therapeutically effective amounts of a protein kinase inhibitor such as saracatinib, dasatinib or bosutinib. Thus, Narla teaches the same method, to be practiced with the same drugs. The only information that is missing in Narla are genes where the specific mutations occur. However, Sangodkar teaches that the genes PPP2R1A and PPP2R2A are commonly occurring PP2A mutations. Although Narla does not specify saracatinib, dasatinib, bosutinib as PKMYT1 inhibitors, "PKMYT1 inhibition" will naturally flow from the teachings of (or method made obvious by) the prior art (see above rejection), since the same compound (saracatinib, dasatinib, bosutinib) is being administered to the same subjects (subjects suffering from the cancer, characterized by reduced activity of Protein phosphatase 2A (PP2A) or reduced PP2A expression). In other words, products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances. In other words, even though the prior art is silent regarding "PKMYT1 inhibition", by practicing the method made obvious by the prior art: "the administration of an effective amount of saracatinib, dasatinib or bosutinib to a subject suffering from cancer, characterized by reduced activity of Protein phosphatase 2A (PP2A) or reduced PP2A expression", one will also be "inhibiting PKMYT1", even though the prior art was not aware of it.
MPEP 2145 II states: "The fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious". Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f)).
Regarding the argument about lack of reasonable expectation of success, it is not persuasive because as set forth above, Narla teaches the method of treatment of cancers, characterized by reduced activity of Protein phosphatase 2A (PP2A) or reduced PP2A expression with saracatinib, dasatinib, bosutinib, where saracatinib, dasatinib or bosutinib can be administered in absence of PP2A activator (page 2, [0008]). Thus, teachings of Narla suggest practicing the method without PP2A activator.
Therefore, considering all said above, since Narla teaches the same method of treatment without identifying specific mutations, and Sangodkar teaches specific mutations as common within the same genes, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to modify the method of Narla to incorporate the known genetic mutations with the reasonable expectation of success, as doing so merely applies known genetic data to a known method. As stated in MPEP 2142: if the examiner does produce a prima facie case, the burden of coming forward with evidence or arguments shifts to the applicant who may submit additional evidence of nonobviousness, such as comparative test data showing that the claimed invention possesses properties not expected by the prior art, or rebuttal arguments. The decision of whether to submit evidence after a rejection should be influenced by the goals of compact prosecution, which encourages the early submission of such evidence. It is also noted that evidence submitted after final rejection may be denied entry into the record.
The argument that reduced PPP2R1A or PPP2R2A predict sensitivity to PKMYT1-targeted treatment is not persuasive because features upon which applicant relies (i.e., reduced PPP2R1A or PPP2R2A predict sensitivity to PKMYT1-targeted treatment) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Therefore, Applicant’s arguments are not persuasive and the rejection of claims 59, 63 – 67, 71 – 73 and 76 – 78 as obvious over teachings of Narla and Sangodkar is maintained.
Conclusion
Claims 59, 63 – 67, 71 – 73 and 76 – 78 are rejected.
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/E.V.V./ Examiner, Art Unit 1691
/SAVITHA M RAO/ Primary Examiner, Art Unit 1691
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