CTNF 18/284,892 CTNF 101436 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Application and Claims Status Claims 5, 8, 11-13, 16, 17, 22, 23, 27, 28, 46-48, 51-54, 58, and 62 are currently pending. Election/Restrictions Applicant's election of species with traverse in the reply filed on 5/6/2024 is acknowledged. The traversal is on the ground(s) that the prior art used in the Restriction Requirement does not disclose any activity or method of use and does not teach each and every element of instant claim 5. Applicant is correct in that the provided reference was not sufficient to break unity of invention. However, Examiner has found new prior art that demonstrates lack of unity of invention. 18-07-02 AIA The claims lack unity of invention because even though the inventions of these groups require the technical feature of a method of treating cancer comprising a compound having the core structure of formula (I) in combination with radiation , this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of Nyati et al. (WO 2014/176475 A1, published 10/30/2014, cited on IDS filed on 12/10/2024)(hereinafter, ‘Nyati 2014’) . Nyati 2014 teaches a method for treating cancer comprising administering compound species that read on Formula (I) of instant claim 5 (Abstract; page 4-5, [0013]; claim 53) with the combined use of radiation (page 27-28, [0079]; claim 57). The election of species requirement is hereby maintained in view of the above reference. Therefore, claims 5, 8, 11-13, 16, 17, 22, 23, 27, 28, 46-48, 51-54, 58, and 62 are examined herein. Applicant elected the following species, with traverse , as described below: Election of a single compound species: Applicant elects Compound A, shown below: PNG media_image1.png 199 237 media_image1.png Greyscale Election of a single type of cancer: Applicant elects lung cancer. Election of a single oncogene and mutation: Applicant elects EGFR-mutated cancer with the del Exon 19 mutation. Applicant submits that claims 5, 8, 11-13, 16, 17, 22, 23, 27, 28, 46-48, 51-54, 58, and 62 read on these species. Applicant will be given the opportunity to traverse the election of species requirement and is therefore NOT FINAL . Priority The instant application is a 35 U.S.C. § 371 of International Application No. PCT/US2022/22990, filed April 1, 2022, which claims the benefit and priority to U.S. Provisional Application No. 63/170,038, filed April 2, 2021 . Information Disclosure Statement The information disclosure statements (IDS) filed on 1/5/2024, 12/10/2024, and 5/27/2026 are in compliance with the provisions of 37 CFR 1.97. All references have been considered except where marked with a strikethrough. A signed copy of Form 1449 is included with this Office Action. Specification Acknowledgement is made of the drawings received September 29, 2023. 06-22 AIA The drawings are objected to because : In FIG. 1A, 1B, and 1C, the y-axis labels, x-axis labels, and labels within the graphs (e.g. “Control”) are illegible. As recited in 37 CFR 1.84: (l) Character of lines, numbers, and letters. All drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined. The weight of all lines and letters must be heavy enough to permit adequate reproduction. This requirement applies to all lines however fine, to shading, and to lines representing cut surfaces in sectional views. Lines and strokes of different thicknesses may be used in the same drawing where different thicknesses have a different meaning . Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance. 06-15 AIA Applicant is reminded of the proper content of an abstract of the disclosure. In chemical patent abstracts for compounds or compositions, the general nature of the compound or composition should be given as well as its use , e.g., “The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics.” Exemplification of a species could be illustrative of members of the class . For processes, the type of reaction, reagents and process conditions should be stated, generally illustrated by a single example unless variations are necessary. The abstract of the disclosure is objected to because: the general nature of the compound or composition is not given. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b). Claim Objections Claim 11 is objected to because of the following informality: for the sake of consistency to claim 5, there should be parenthesis around the I in “Formula I” so as to read “…to the rest of the compound of Formula (I).” Claim 53 is objected to because of the following informality: there should also be a dash after the types of mutated cancer. Examiner suggests amending the claim to read, “…wherein the cancer is an EGFR-, KRAS-, or BRAF-mutated cancer”. Appropriate correction is required. Claim Rejections - 35 USC § 112(b) 07-30-02 AIA 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. 07-34-01 Claims 5, 51-52 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. 07-34-10 Regarding claim 5 , the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claims 51 recites the limitation "wherein R 3 is H". There is insufficient antecedent basis for this limitation in the claim. Claim 51 depends on claim 5, and claim 5 does not recite R 3 is H. Claim 52 recites the structure of Compound A, wherein R 3 is H. There is insufficient antecedent basis for this limitation in the claim. Claim 52 depends on claim 5, and claim 5 does not recite R 3 is H. Claim Rejections - 35 USC § 112(a) 07-30-01 AIA 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. Scope of Enablement - Prevention 07-31-03 Claims 5, 8, 11-13, 16, 17, 22, 23, 27, 28, 46-48, 51-54, 58, and 62 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AlA), first paragraph, because the specification, while being enabling for treatment , does not reasonably provide enablement for prevention . 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 following Wands factors have been considered if not explicitly discussed: (A) The breadth of the claims, (B) The nature of the invention, (C) The state of the prior art, (D) The level of one of ordinary skill, (E) The level of predictability in the art, (F) The amount of direction provided by the inventor, (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. The term “treatment” is defined on page 20, [0056] of the specification and said definition also embraces prevention. It is presumed “prevention” of the claimed condition would require a method of identifying those individuals who will develop the claimed condition before they exhibit symptoms. The current state of the art is that that full scope of diseases claimed within instant claims is not preventable or curable. There is no evidence in the prior art that the instant composition would be usable as a preventative method, particularly for preventing diseases such as cancer. “Preventing” connotes an absolute absence of a condition which cannot reasonably be achieved with regard to infections, with few exceptions (such as vaccines to prevent the development of pathogen-borne illnesses). In addition, there is no definitive method by which to determine whether a patient will develop a particular condition and, thus, be in need of preventive therapy. This is distinguished from preventing the relapse or recurrence of certain conditions, in which case an objective basis may exist to identify patients at risk of disease or infection, and could reasonably be construed as treatment. Prior to the initial onset or occurrence, however, even if a patient can be identified as having known risk factors for a condition, there is no certainty that the patient would in fact develop the condition. Further, the failure of a disease, infection, or condition to develop cannot reliably be attributed to the claimed active agent(s). The non-development of a condition such as diseases such as cancer may be due to other factors such as lifestyle. In this sense, in the context of preventing a disease, the level of unpredictability is extremely high. The factors to be considered in making an enablement rejection were summarized above. 1) Preventing diseases requires identifying those patients who will acquire the condition before the symptoms occur. This would require extensive and potentially open-ended clinical research on healthy subjects. 2) There is no working example of such a preventive procedure in man or animal in the specification. 4) The claims rejected are drawn to clinical pharmacology and are therefore physiological in nature. 5) The state of the art is that no general procedure is art-recognized for determining which patients generally will develop cancer before the fact. 6) The artisan using Applicants invention would be a Board Certified physician in oncological diseases with an MD degree. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prevention of cancer. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens , 163 USPQ 609. No such evidence has been presented in this case. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo Nordisk , 42 USPQ2nd 1001, 1006. This establishes that it is not reasonable for any agent to be able to prevent cancer. 7) 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). 8) The claims broadly read on all patients, not just those undergoing therapy for the claimed conditions. Claim Rejections - 35 USC § 102 07-06 AIA 15-10-15 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. 07-07-aia AIA 07-07 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 – 07-08-aia AIA (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. 07-12-aia AIA (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. 07-15 AIA Claim (s) 5, 8, 11-13, 16, 17, 22, 23, 27, 28, 46-48, 51-54, and 58 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Nyati 2014 . Regarding claims 5, 8, 11-13, 16, 17, 22, 23, 27, 28, 46-48, 51-52 : Nyati 2014 teaches a method of increasing degradation of EGFR or inhibiting EGFR dimerization comprising contacting EGFR with a compound of formula (II) in an amount sufficient to inhibit dimerization or induce degradation of EGFR (page 37-38, claims 1-4, 9-18, 20-24, 35-36). Nyati 2014 also teaches species of this genus (page 4-5, claim 57). The reference genus of Formula (II) and a representative specie are shown below: PNG media_image2.png 111 208 media_image2.png Greyscale PNG media_image3.png 114 244 media_image3.png Greyscale Thus, the compounds disclosed by Nyati 2014 read on Formula (I) of instant claim 5. Nyati 2014 further teaches administration of an EGFR degrader with radiation therapy for the treatment of cancer (page 27-28, [0079]; claim 53). Regarding claims 53-54 : Nyati 2014 teaches L858R-EGFR mutated cancers (page 28, [0081]), T790M-EGFR mutated cancers (page 9, [0026]; page 31, [0093]), and S768I-EGFR mutated cancers (page 8, [0021]-[0022]). Regarding claim 58 : Nyati 2014 teaches wherein the contacting comprises administering the compound to a subject in need thereof, wherein the subject is diagnosed with cancer including lung, pancreatic, head and neck, and colorectal cancer (page 40, claims 47-48 and 50) . Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 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. 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA 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. 07-21-aia AIA Claim 62 is rejected under 35 U.S.C. 103 as being unpatentable over Nyati 2014 . The same reasons provided in the 102 rejection above is equally applicable here. Regarding claim 62 : The instant claim recites that the radiation is administered in an amount of at least 2 Gy. In this instance, modifying concentrations or quantities (result effective variables) would be obvious based on routine optimization ( In re Aller), unless there is evidence to the contrary. Furthermore, the specification does not show that modification of said variables is critical to the claimed invention. The selection of reaction conditions is more optimization by more modification of routine experimentation and within one skilled in the art. Change in temperature, concentration, or both is not patentable modification in the absence of unexpected results which is different in kind and not degree. Therefore, the determination of dosage of radiation would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the criticality of the claimed minimum dosage of radiation, the determination of the optimum or workable minimum dosage of radiation given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. It is well-established that merely selecting proportions and ranges is not patentable absent a showing of criticality. In re Becket , 33 U.S.P.Q. 33 (C.C.P.A. 1937). In re Russell , 439 F.2d 1228; 169 U.S.P.Q. 426 (C.C.P.A. 1971). Please see MPEP 2144.05 [R-2](II)(A) and In re Aller , 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation."). Accordingly, claims 62 is rejected . 07-21-aia AIA Claim (s) 5, 8, 11-13, 16, 17, 22, 23, 27, 28, 46-48, 51-54, 58, and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Nyati 2014 and Nyati et al . (WO 2019/165358 A1, published August 29, 2019, cited on IDS filed on 05/27/2026)(hereinafter, ‘Nyati 2019’) . The same reasons provided in the 102 and 103 rejections above are equally applicable here. Nyati 2014 does not teach the elected species of the instant invention, Compound A, shown below: PNG media_image1.png 199 237 media_image1.png Greyscale Nyati 2019 does teach the instantly claimed species (Compound 8C, Table 1, page 10) for the same utility of the instant application as an EGFR degrader for the treatment of cancer (Abstract, [0001-0003], [0075]). Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, at the time before the effective filing date of the claimed the invention, to combine the EGFR degrader taught by Nyati 2019 (Compound 8C) with the EGFR degrader/radiation treatment taught by Nyati 2014 to arrive at the instantly claimed invention with reasonable expectation of success. At the time the invention was made, it was known that both EGFR degrader Compound 8C taught by Nyati 2019 and radiation treatment taught by Nyati 2014 could be used for treating cancer, specifically EGFR-mutated cancers. A skilled artisan would be motivated to combine because Nyati 2014 teaches the genus and related species of instantly claimed invention and Nyati 2019 teaches the exact species of the instant invention. A skilled artisan would expect the combined method of treating might provide an alternative synergistic combination therapy for treating cancer . 07-21-aia AIA Claim (s) 5, 8, 11-13, 16, 17, 22, 23, 27, 28, 46-48, 51-54, 58, and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Nyati 2014 and Joschko et al. (“Enhancement of Radiation-Induced Regrowth Delay by Gemcitabine in a Human Tumor Xenograft Model”, published December 7, 1998)(hereinafter, ‘Joschko’) and further in view of Feng et al. (“Role of epidermal growth factor receptor degradation in gemcitabine-mediated cytotoxicity”, published December 4, 2006, cited on IDS filed on 12/10/2024)(hereinafter, ‘Feng’) . Nyati 2019 teaches the instantly claimed species (Compound 8C, Table 1, page 10) for the same utility of the instant application as an EGFR degrader for the treatment of cancer (Abstract, [0001-0003], [0075]). Nyati 2019 teaches that the cancer is an EGFR-mutated cancer with L858, T790M, and C797S point mutations [0200]. Nyati 2019 teaches the use of Compound 8C in lung cancer cell lines (Example 49, [0193]; claim 57). Nyati 2019 does not teach the method of treating cancer comprising administering instant Compound A (an EGFR degrader) with radiation in an amount of at least 2 Gy. Joschko teaches that, in a human squamous carcinoma xenograft mouse model, gemcitabine significantly enhances radiation-induced regrowth delay and overall tumor control. Joschko teaches the administration of gemcitabine with 2 Gy fractions of radiation over 2 weeks for 5 days/week (Abstract, Fig. 1, Discussion page 68- XX). Joschko teaches, on page 68, “combining the two modalities was more effective in delaying tumor regrowth and reducing tumor volume than either the drug or radiation alone”, and indeed, Fig. 1, on page 66, demonstrates the dramatic synergistic effect of combined gemcitabine and radiation on tumor volume. Feng teaches that gemcitabine is an EGFR degrader in human head and neck cancer cells lines (Abstract, page 3433). Altogether, the combined references of Joschko and Feng teach a method of treating cancer using a combination of an EGFR degrader (gemcitabine) with radiation to dramatically reduce tumor volume than either treatment alone. Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, at the time before the effective filing date of the claimed the invention, to modify the invention of Joschko to substitute the EGFR degrader taught by Nyati 2019 (Compound 8C) to arrive at the instantly claimed invention with reasonable expectation of success. It is no more than the simple substitution of one known element for another with the predictable result of obtaining an enhanced reduction in tumor volume via combination of EGFR degrader and radiation. Conclusion No claims are allowed. All claims are rejected. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUKE ALAN BORALSKY whose telephone number is (571)272-9746. The examiner can normally be reached Monday - Friday 7:30 am - 5:00 am. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey H Murray can be reached at 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /L.A.B./ Examiner, Art Unit 1624 /SUSANNA MOORE/Primary Examiner, Art Unit 1624 Application/Control Number: 18/284,892 Page 2 Art Unit: 1624 Application/Control Number: 18/284,892 Page 3 Art Unit: 1624
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