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 .
Response to Amendments
Applicant’s amendments to the claims of May 27, 2026, in response to the Office Action of February 27, 2026, are acknowledged.
Claim of Foreign Priority
The examiner acknowledges receipt of Applicant’s foreign priority documents and translation.
Response to Arguments
In view of the amendments to the claims, the examiner has withdrawn rejections under §112 rejection (Written Description), Scope of Enablement with respect to the compounds claimed, and the §101 rejection.
A Scope of Enablement Rejection is set forth for claims 23 and 25 because claim 23 includes prevention of any ATR-associated disease and therefore, claim 25 is also directed to prevention of numerous cancers. There is no indication that any of the claimed cancers can be prevented.
With respect to the traversal under § 103, the examiner responds.
Applicant argues that the prior art does not teach treating the cancers claimed that are specific to biomarkers.
The examiner notes that the claimed cancers are ATR kinase associated diseases. Mei teaches compounds that are ATR kinase inhibitors. The following article is cited to show that ATR kinase inhibition is particularly useful in ATM deficient tumors, including broadly against ovarian cancer, e.g.
However, the examiner notes that while the term prevention is included in claims 23 and 25 (rejected below under a Scope of Enablement rejection), the subject population needs to merely be susceptible or capable of having a claimed cancer.
Cui et al., “Depletion of ATR selectively sensitizes ATM-deficient human mammary epithelial cells to ionizing radiation and DNA-damaging agents,” Cell Cycle 2014 Oct 29;13(22):3541-3550, teaches that loss of ATM function is frequent is various types tumors and this places more reliance on ATR for checkpoint arrest and cell survival following DNA damage. Cui teaches ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy. Further, ATR overexpression in cancer cells can prolong G2/M arrest and contribute to resistance to radiation. This highlights the potential for ATR kinase inhibitors. Targeting ATR in ATM deficient cancer can improve therapeutic responses to radiation and chemotherapy.
Applicant has amended the claims to require the cyclic group with X and Y to be:
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and to further require the heteroaryl moiety with A1-A5 to be:
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. While these amendments are limiting, Compound 17 of Mei et al. is the following compound:
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in which both of these moieties are identical. The main distinction is the
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moiety in the claimed compound. However, that corresponds to “R3” in Mei et al., which can only be one of two substituents. Those two are shown below:
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As such, when a POSA reviews Mei et al. and looks at compound 17, they would immediately envisage the other alternative for R3. That is a compound of Formula (I) of claim 1. All of variables include NR7 for X, wherein R7 is Me; R1-R3 are hydrogen.
As such, no claim is allowed.
Status of the Claims
Claims 1, 21, 23, and 25 are pending and examined.
Claim Rejections - 35 USC § 112 (Scope of Enablement)
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 23 and 25 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for those compounds set forth in the instant Specification are not considered enabled for preventing all ATR-kinase “associated” diseases, including all hematological malignancies, CNS tumors, and other extensive types of cancer.
The Specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to arrive at the invention commensurate in scope with these claims. Prevention is not enabled for the ATR-kinase associated conditions.
The standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below
Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
In the instant case, the claimed invention pertains to compounds of Formula (I), which are alleged by the Specification to function ATR kinase inhibitors and can be used to treat a vast array of unrelated cancers, including, e.g., brain cancers and hematologic cancers.
The State of the Prior Art and the Relative Skill of those in the Art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.”
According to the CDC, https://www.cdc.gov/ovarian-cancer/prevention/index.html (date accessed June 23, 2026): “There is no known way to prevent ovarian cancer, but some things are associated with a lower chance of getting it.”
According to the University of Kansas, https://www.kucancercenter.org/outreach/prevention/preventable-cancers (date accessed June 23, 2026): “No cancer is 100% preventable. However, managing certain risk factors, following screening guidelines and being aware of your family history, can lower your chances of developing certain cancers.”
As discussed above, the instantly claimed invention pertains to compounds of Formula (I), which are alleged by the Specification to antagonize ATR kinase in an effort to prevent and treat cancers. At the time the instant application was filed, it would have been known by those of ordinary skill in the art that - compounds, in the vast majority of cases, demonstrate a remarkably high correlation between their structure, specificity and ability to produce a pharmacological effect. At the same time, it would have also been generally assumed that two compounds with similar chemical properties would exhibit similar biological effects. Thus, given a series of compounds that are shown to exert an activity of interest (or given a target of interest), the ordinarily skilled artisan would have expected that a limited genus of related compounds (e.g., compounds exhibiting near equal molecular shapes and volumes, approximately the same distribution of electrons, and similar physical properties such as hydrophobicity) would interact with the given target to elicit a related biological response.
Accordingly, at the time the invention was made, the relative skill of those in the art tasked with identifying compounds exerting an activity of interest would have been high, as the ordinarily skilled artisan would have had, at minimum, a Ph.D. and experience with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods. Deciding which technique to use would have been determined by the skilled artisan’s knowledge regarding the compound and target of interest. Ligand based drug design relies on knowledge of a compound or compounds of interest (i.e., ligands) to derive new compounds that will, in theory, similarly interact with the target of interest to elicit the activity of interest. Conversely, structure based drug design relies on knowledge of the three dimensional structure of the target of interest (i.e., receptor, ion channel, or enzyme) to derive new compounds that will, in theory, interact with the target of interest to elicit the activity of interest. In either case, the compounds derived from these techniques (applied alone or in combination) are then subjected to in vitro testing for validation.
The Level of Predictability in the Art: Once a compound has been identified by ligand based and/or structure based drug design methods as potentially binding to the target molecule, it must be evaluated. However, as discussed by Anderson (Chem and Biol 10:787-797, 2003), “it is important to consider that the ranking assigned by the scoring function is not always indicative of a true binding constant, since the model of the target:ligand interaction is inherently an approximation. Usually, several molecules which scored well during the docking run are evaluated in further tests since even the top scoring molecule could fail in vitro assays… Finally, leads are brought into the wet lab for biochemical evaluation” (Page 794, Column 1). By that point, as noted by Thiel (Nature Biotechnol 2:513-519, 2004), “libraries are small and hit rates are on the order of one in ten” (Page 517, Column 2). This low level of predictability is not surprising considering that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Indeed, modifying even a single atom in a compound can dramatically change the compound’s overall structure and - even though complementarity in one portion of the compound might be improved by the chemical revision - the overall binding or activity might be severely compromised. This is certainly true in the case.
The Amount of Direction Provided by the Inventor / Existence of Working Examples: The amount of direction provided by the Applicant is considered to be determined by the Specification and the working examples. In the instant case, the Specification does not provide any examples of prevention in any respect.
Scope or Breadth of the Claims: As stated in MPEP 2164.01(c), “when a compound or composition claim is not limited by a recited use, any enabled use that would reasonably correlate with the entire scope of that claim is sufficient to preclude a rejection for nonenablement based on how to use” (emphasis added). Thus, as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). Indeed, 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 (Fed. Cir. 1993) (emphasis added).
At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Nor is it necessary that an Applicant test all the embodiments of his invention. In re Angstadt, 537 F.2d 498 (CCPA 1976) (emphasis added). In fact, as stated by the court in In re Buchner, 929 F.2d 660 (Fed. Cir. 1991), a patent need not teach, and preferably omits, what is well known in the art.
Accordingly, for purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. Thus, while “a patent application is entitled to claim his invention generically” it is necessary that “he provide a disclosure sufficient to enable one skilled in the art to carry out the invention commensurate with the scope of his claims". Amgen, Inc., v. Chugai Pharmaceutical Co., Ltd. (Fed. Cir. 1991). As noted by the court in In re Fisher, 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac, 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore, 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation”.
As to the first inquiry, as discussed above, the claims are drawn to compounds of Formula (I), which are alleged by the Specification to antagonize ATR kinase for use in treating many distinct forms of cancer. The only examples of metabolic stability are provided in Table 3, which shows some variability for compounds 1, 5, and 6. Thus, 3/36 compounds were administered to a mouse. Table 4 provides PK data for compounds 1, 3, and 5. There are no examples of prevention nor are the mechanism of action taught recognized as preventing any form of cancer.
Amount of Experimentation Necessary: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to compounds of Formula (I), which are alleged by the Specification to prevent all ATR kinase associated conditions, including many forms of cancer. Since identifying any compound which is capable of modulating the activity of a specific receptor, ion channel, or enzyme is extremely complex, the nature of the instant invention considered to be one of extreme complexity. Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan (armed with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods) could not reasonably predict which of the structural changes and embodiments of compounds encompassed by Formula (I) would exert the alleged activity based on the limited disclosure and substantial variability shown in the Specification. Although the skilled artisan would have known that certain chemical modifications to the disclosed compounds may predictably provide structurally related compounds having similarly activity, the skilled artisan would have also known that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme.
Thus, in order to identify usable compounds of Formula (I), the skilled artisan (at minimum) would have to carry out ligand based drug design methods using the 36 disclosed compounds as a starting point and, assuming the structure of the target receptor was known, combine the findings with data derived from structure based drug design methods to arrive at a small library of “lead” compounds believed to possess the activity of interest. The skilled artisan would then synthesize lead compounds that are within Formula (I) for in vitro testing. At this point, however, even "the top scoring molecule could fail in vitro assays” (Page 794, Column 1) and “hit rates are on the order of one in ten” (Page 517, Column 2). Given the unpredictability of the claimed compounds, as evidenced by the IC50 value variability for almost identical compounds in the instant Specification, it is highly unpredictable whether any compound within the subgenus of compounds of Formula (I) identified by rational drug design based on the instant disclosure would, in fact, be usable to prevent cancer. Whether the other compounds of Formula (I) (i.e., those not identified by rational drug design based on the instant disclosure) would be usable is even less predictable. As such, the only way to ascertain which of the conditions among the many that can be treated with specific claimed compounds would require undue experimentation. That is, the only way one skilled in the art is enabled to use the entire scope of the claim based on the instant disclosure entails undue experimentation.
To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
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.
Claims 1, 21, 23, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Mei et al., (WO2022/028598A1) (priority dates of August 7, 2020, and August 19, 2020) (cited in IDS), in view of Cui et al., “Depletion of ATR selectively sensitizes ATM-deficient human mammary epithelial cells to ionizing radiation and DNA-damaging agents,” Cell Cycle 2014 Oct 29;13(22):3541-3550.
Mei teaches ATR kinases to treat many forms of cancer. See par. 1. The compounds has the following generic core.
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R3 is
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. See p2. Variable “B” is a 5 or 6 membered heterocycle with examples being the following:
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. Further, variable “A” can be a 5 or 6 membered heterocyclyl. See p2.
These substituents described for use for a same purpose of inhibiting ATR kinase render obvious the claimed compound.
Z1 through Z4 variables are shown below in examples.
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. See page 8, e.g.
With regard to claim 6, R1 can be hydroxyl on Ring A. Compounds 86 and 91 provide examples wherein this is the case. See pp. 319 and 327. Even further, the embodiment set forth below shows a compound that is similar to the claimed compound.
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Further, compound 105 provides an example in which A is
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. Similarly, compounds 83 and 84 provide a 6 membered ring with a single oxygen. Compound 17 provides an example in which variable A is
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. See compound 17. The A variable can be substituted with R1, wherein R1 can include cyano, hydrogen, methyl, C1-C6 alkyl. See par. 174. It can also be hydrogen, halogen, hydroxyl, cyano, alkyl, haloalkyl, hydroxylalkyl, -C (O) N (R a) 2, -C (O) OR a, -S (O) 2(R b) , –S (O) (NH) (R b) and –P (O) (R b) 2. See par. 18.
The forms of cancer taught to be treated are extensive including lung cancer, hematologic malignancies, brain cancers, breast cancers, and others. A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).
Cui teaches that loss of ATM function is frequent is various types tumors and this places more reliance on ATR for checkpoint arrest and cell survival following DNA damage. Cui teaches ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy. Further, ATR overexpression in cancer cells can prolong G2/M arrest and contribute to resistance to radiation. This highlights the potential for ATR kinase inhibitors. Targeting ATR in ATM deficient cancer can improve therapeutic responses to radiation and chemotherapy.
It would have been prima facie obvious to a person having ordinary skill in the art prior to the filing of the instant application to arrive at the claimed compounds in view of the cited prior art. One would be motivated to do so because the prior art teaches that compounds that are substantially similar and inclusive of claimed compounds function as ATR kinase inhibitors that are capable of treating various forms of cancer. The breadth of the core formula taught by the prior art encompasses the instantly claimed compounds wherein singular distinction is that Applicant has claimed a 6 ring heterocyclyl group having one nitrogen and one oxygen atom and the prior art provides for the same, while providing examples in which 6 membered heterocyclyl rings have a single oxygen atom or two nitrogen atoms. Each of the claims including claim 20 include examples in which two nitrogen atoms or one oxygen atom are included for Y and X. The main distinction over the prior art is based on the definition of Y and X. However, the prior art provides specific embodiments in which Y and X are both N, as shown above. Further, the claimed compounds are ATR kinase inhibitors which are known to be able to treat ATM deficient cancers. As such, a POSA would understand from the cited prior art that compounds including those claimed fall within the scope of the teachings of the prior art and could therefore have ATR kinase inhibitory activity in treating forms of cancers taught to be treated.
Conclusion
THIS ACTION IS MADE FINAL. 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 extension fee 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D. BARSKY whose telephone number is (571)-272-2795. The examiner can normally be reached on Monday through Friday from 8:30 to 5:30. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Amy L. Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628
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