CTNF 18/416,271 CTNF 88651 DETAILED ACTION Claims 1-20 are pending. 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. Priority The instant application, filed 1/18/2024 is a Continuation of 17214309, filed 3/26/2021, now U.S. Patent # 11918586. 17214309 is a Continuation of 16301728 , filed 11/14/2018 ,now U.S. Patent # 10993947. 16301728, filed 11/14/2018, was a national stage entry of PCT/EP2017/025137, with an International Filing Date of 5/17/2017. PCT/EP2017/025137 claims Priority from Provisional Application 62/338,111, filed 5/18/2016 and claims foreign priority to 17151843.4, filed 1/17/2017. Information Disclosure Statement The Information Disclosure Statements (IDS) submitted on 8/5/2024 and 7/21/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the Information Disclosure Statements are being considered by the Examiner. Claim Rejections - 35 USC § 103 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 set forth in Graham v. John Deere Co. , 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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. 07-21-aia AIA Claim s 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Seykora US 20130178440 published July 11, 2013; Manara et al. “NVP-BEZ235 as a New Therapeutic Option for Sarcomas,” Clin Cancer Res; 16(2) January 15, 2010, 530-540; Cheng et al. CN 104557871 published April 29, 2015; Lu et al. CN 103483345 published January 1, 2014; and Cmiljanovic et al. WO 2010052569 published May 14, 2010 (all references provided in 16/301728) . Claim 1 is generally directed towards a method of preventing or treating a skin lesion in a subject in need thereof comprising administering an effective amount of a compound of formula (I) to said subject. Formula (I) is a PI3k/mTOR signaling inhibitor. Seykora generally teaches methods for treating a skin cancer related disease or disorder (e.g., a pre-cancerous skin lesion , a skin tumor, an actinic keratosis, a squamous cell carcinoma in situ like lesion and/or a cutaneous squamous cell carcinoma) in a subject, the methods include: topically administering to said subject a therapeutically effective amount of a PI3K /PDK1/AKT signaling pathway inhibitor. Seykora specifically teaches at [0138] [t]he efficacy of a 20 mM topical BEZ235 ointment , formulated as in the previous example, was evaluated in inducing regression of cSCCs in K14-Fyn Y528F mice. Topical BEZ235 ointment was applied daily (Monday-Friday) to a cohort of 15 mice with solitary cSCCs. A control cohort of 15 mice with solitary cSCCs was treated with ointment alone. The size range of tumors was similar in each cohort. Topical BEZ235 induced a marked regression of cSCCs in the treatment group compared to controls (FIG. 14). In the BEZ235 cohort, 80% of tumors completely regressed by five weeks, including many larger lesions >25mm2; in controls, tumor shrinkage was seen in small lesions <15mm2 and this cohort has more small lesions. This data show that targeting kinases activated downstream of Fyn induces cSCC regression (this is the same animal model used to enable the instant invention). Seykora in claim 23. A method for treating a skin cancer related disease or disorder in a subject, the method comprising: topically administering to said subject a therapeutically effective amount of a compound, wherein the compound inhibits both PI3K and mTOR . Manara is brought in to show that Dactolisib (BEZ235 or NVPBEZ235) is a synthetic small molecular mass compound belonging to the class of imidazoquinolines that potently and reversibly inhibits class 1 PI3K catalytic activity by competing at its ATP-binding site. NVP-BEZ235 also inhibits mammalian target of rapamycin (mTOR) catalytic activity, and this makes the compound particularly interesting for sarcomas. It was the first PI3K inhibitor to enter clinical trials, in 2006. These two references teach that using a compound inhibits both PI3K and mTOR would be reasonably expected to treat skin cancers/lesions, and BEZ235 specifically would reasonably be expected to treat skin cancers/lesions Cheng teaches an invention of compounds that inhibits both PI3K and mTOR . Cheng teaches the following compound: PNG media_image1.png 516 816 media_image1.png Greyscale About the reference from SciFinder: “The invention also discloses a method for preparing the compounds, a pharmaceutical compounds and the application thereof as PI3K/mTOR inhibitor. Thus, e.g., II was prepd. and showed 92% inhibition on PI3Kα and 19% inhibition on mTOR at 100 nM.” One of the SciFinder Therapeutic Use: “Skin neoplasm” A person of ordinary skill in the art would have a reasonable expectation of success in treating skin lesions with the PI3K/mTOR inhibitor of Cheng as Seykora teaches that a PI3K/mTOR inhibitor will generally treat skin cancers/lesions. As such the instant claims were prima facie obvious at the time of filing. Based on the same logic the following additional reference teaches more PI3K/mTOR inhibitors that would be reasonable expected to treat skin lesions/cancer. Lu teaches compounds and their use as PI3K kinase inhibitors for the treatment of cancer. Lu teaches the following compound: PNG media_image2.png 544 853 media_image2.png Greyscale A person of ordinary skill in the art would have a reasonable expectation of success in treating skin lesions with the PI3K/mTOR inhibitor of Lu as Seykora teaches that a PI3K/mTOR inhibitor will generally treat skin cancers/lesions. As such the instant claims were prima facie obvious at the time of filing. Based on the same logic the following additional reference teaches more PI3K/mTOR inhibitors that would be reasonable expected to treat skin lesions/cancer. Cmiljanovic teaches an invention of compounds that inhibits both PI3K and mTOR . Cmiljanovic teaches the following compound: PNG media_image3.png 710 774 media_image3.png Greyscale A person of ordinary skill in the art would have a reasonable expectation of success in treating skin lesions with the PI3K/mTOR inhibitor of Cmiljanovic as Seykora teaches that a PI3K/mTOR inhibitor will generally treat skin cancers/lesions. As such the instant claims were prima facie obvious at the time of filing . Double Patenting 08-33 AIA The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg , 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman , 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi , 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum , 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel , 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington , 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA/25, or PTO/AIA/26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp. U.S. Patent No. 10,640,516 08-36 AIA Claim s 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1-21 of U.S. Patent No. 10,640,516 in view of Seykora US 20130178440 published July 11, 2013; and Manara et al. “NVP-BEZ235 as a New Therapeutic Option for Sarcomas,” Clin Cancer Res; 16(2) January 15, 2010, 530-540 . The compounds of ‘516 are taught as inhibitors of both PI3K and mTOR . The compounds also overlap with the instant claimed compounds. Seykora generally teaches methods for treating a skin cancer related disease or disorder (e.g., a pre-cancerous skin lesion , a skin tumor, an actinic keratosis, a squamous cell carcinoma in situ like lesion and/or a cutaneous squamous cell carcinoma) in a subject, the methods include: topically administering to said subject a therapeutically effective amount of a PI3K /PDK1/AKT signaling pathway inhibitor. Seykora specifically teaches at [0138] [t]he efficacy of a 20 mM topical BEZ235 ointment , formulated as in the previous example, was evaluated in inducing regression of cSCCs in K14-Fyn Y528F mice. Topical BEZ235 ointment was applied daily (Monday-Friday) to a cohort of 15 mice with solitary cSCCs. A control cohort of 15 mice with solitary cSCCs was treated with ointment alone. The size range of tumors was similar in each cohort. Topical BEZ235 induced a marked regression of cSCCs in the treatment group compared to controls (FIG. 14). In the BEZ235 cohort, 80% of tumors completely regressed by five weeks, including many larger lesions >25mm2; in controls, tumor shrinkage was seen in small lesions <15mm2 and this cohort has more small lesions. This data show that targeting kinases activated downstream of Fyn induces cSCC regression (this is the same animal model used to enable the instant invention). Seykora in claim 23. A method for treating a skin cancer related disease or disorder in a subject, the method comprising: topically administering to said subject a therapeutically effective amount of a compound, wherein the compound inhibits both PI3K and mTOR . Manara is brought in to show that Dactolisib (BEZ235 or NVPBEZ235) is a synthetic small molecular mass compound belonging to the class of imidazoquinolines that potently and reversibly inhibits class 1 PI3K catalytic activity by competing at its ATP-binding site. NVP-BEZ235 also inhibits mammalian target of rapamycin (mTOR) catalytic activity, and this makes the compound particularly interesting for sarcomas. It was the first PI3K inhibitor to enter clinical trials, in 2006. These two references teach that using a compound inhibits both PI3K and mTOR would be reasonably expected to treat skin cancers/lesions, and BEZ235 specifically would reasonably be expected to treat skin cancers/lesions. Therefore the instant claims are rejected for double patenting as the compounds overlap with ‘516 and they would reasonably be expected to treat skin lesions based on the supplied secondary references. U.S. Patent No. 10,993,947 Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10,993,947 as the ‘947 patent is directed o use the same compounds in the same method. U.S. Patent No. 11,186,591 08-36 AIA Claim s 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1-14 of U.S. Patent No. 11,186,591 in view of Seykora US 20130178440 published July 11, 2013; and Manara et al. “NVP-BEZ235 as a New Therapeutic Option for Sarcomas,” Clin Cancer Res; 16(2) January 15, 2010, 530-540 . The two references (Sevkora and Manara) teach that using a compound inhibits both PI3K and mTOR would be reasonably expected to treat skin cancers/lesions, and BEZ235 specifically would reasonably be expected to treat skin cancers/lesions. Therefore the instant claims are rejected for double patenting as the compounds overlap with ‘591 and they would reasonably be expected to treat skin lesions based on the supplied secondary references. U.S. Patent No. 11,918,586 Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,918,586 as the ‘586 patent is directed to use of the same compounds in the same method. Conclusion No claims allowed Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL J SCHMITT whose telephone number is (571)270-7047. The examiner can normally be reached on M-F 8-6 MidDay Flex. 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 Lundgren can be reached on 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see https://ppair-my.uspto.gov/pair/PrivatePair. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /MICHAEL J SCHMITT/Examiner, Art Unit 1629 /JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629 Application/Control Number: 18/416,271 Page 2 Art Unit: 1629 Application/Control Number: 18/416,271 Page 3 Art Unit: 1629 Application/Control Number: 18/416,271 Page 4 Art Unit: 1629 Application/Control Number: 18/416,271 Page 5 Art Unit: 1629 Application/Control Number: 18/416,271 Page 6 Art Unit: 1629 Application/Control Number: 18/416,271 Page 7 Art Unit: 1629 Application/Control Number: 18/416,271 Page 8 Art Unit: 1629 Application/Control Number: 18/416,271 Page 9 Art Unit: 1629 Application/Control Number: 18/416,271 Page 10 Art Unit: 1629
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