CTNF 18/556,226 CTNF 98173 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. 12-151 AIA 26-51 12-51 Status of Claims The amendments to the claims filed October 19, 2023 are acknowledged and entered. Claims 1-19, 21 and 23-25 are pending. Priority This application is a 371 of PCT/US2022/025665, filed April 21, 2022, which claims the benefit of 63/180,221, filed April 27, 2021. Information Disclosure Statement Acknowledgement is made of the Information Disclosure Statements filed on December 14, 2023 and February 19, 2025. All references have been considered except where marked with a strikethrough. Specification 06-31 AIA The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any of the errors of which applicant may become aware of in the specification. Election/Restriction Applicant’s election of Group I, claims 1-10, 13-17, 21 and 23-25, drawn to a compound of Formula I and the species corresponding to compound 1-16, found on page 50 of the published application, US20240208986A1 (pictured below for convenience) in the reply filed on June 3, 2026 is acknowledged. Claims 11-12 and 18-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Therefore this restriction is considered proper and thus made FINAL . PNG media_image1.png 149 387 media_image1.png Greyscale PNG media_image2.png 190 304 media_image2.png Greyscale The elected species corresponds to Formula I wherein R 2 is taken with R 1 and forms a C 4 cycloalkyl; R 3 is haloC 1 alkyl; R 4 and R 6 form a -CH 2 bridge; U is O; and each of R 5 , R 7 , R 8 , R 9 , R 10 , R 14 , R 15 and R 16 is hydrogen. Applicant submits that claims 1-3, 5-7, 11-17, 21 and 23 encompass the elected species. The guidelines in MPEP § 803.02 provide that upon examination if prior art is found for the elected species, the examination will be limited to the elected species. The elected species was not found in the prior art and the search was expanded to include the following three subgenus of Formula I: Formula I wherein R 4 taken with R 5 or R 6 forms a -CH 2 - or -CH 2 CH 2 - bridge; Formula I wherein U is O; R 1 and R 2 are independently selected from the group consisting of methyl, t-butyl, fluoromethyl, difluoromethyl, fluorine, difluoroethyl, trifluoromethyl, ethyl, N(CH 3 ) 2 , CN and CH 2 CN; and R 3 is independently selected from the group consisting of methyl, difluoromethyl, fluorine, difluoroethyl, trifluoromethyl and ethyl; and Formula I wherein U is O and R 1 is taken with R 2 or R 2 and R 3 to form a C 3-10 cycloalkyl ring or heterocycloalkyl ring. And art was found. Claims 1, 3-4, 10, 13-16 and 21 (all in part, other than the above two indicated subgenus) are additionally withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species. The full scope of claims 2, 5-9, 17 and 23-25 are presently under examination. Claim Objections Claim 13 objected to because of the following typographical error: Claim 13 at line 2 recites “hydrogen chlorine”. Examiner believes the claim should instead recite “hydrogen, chlorine”. Appropriate correction is required. Claim Rejections - 35 USC § 112a 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. Claims 1-2, 4-10, 13-16, 21 and 23-25 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 a compound of Formula I wherein U is O or CR 12 R 13 and R 12 and R 13 are each hydrogen, does not reasonably provide enablement for Formula I wherein U is NR 11 , S or CR 12 R 13 wherein R 12 and R 13 are a group other than hydrogen. The specification is not adequately enabling for the scope of the compounds claimed. The only useful compounds are those embodiments disclosed at pages 58-65 and Tables 1-3 of specification and which are included in the subgenus of Formula I indicated above. This narrow scope of compounds does not give a reasonable assurance that all, or substantially all of the compounds within the scope of the claim are useful. The claims are not drawn in terms of a recognized genus but are directed to a more or less artificial selection of compounds. There is no reason why a claim drawn in this way should not be limited to those compounds which are shown to be useful. An Applicant is not entitled to a claim for a large group of compounds merely on the basis of a showing that a selected few are useful and a general suggestion of a similar utility in the others. There is no statement of utility beyond that for inhibition of RIPK1 (see page 2, Summary of the Invention, The compounds described herein are RIPK1 inhibitors). Ex parte Lanham, 108 USPQ at 135 states “It was never intended that a patent be granted upon a product, or a process producing a product, unless such product be useful.” The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the application coupled with information known in the art without undue experimentation. (United States v. Teletronics Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based on a single factor, but rather a conclusion reached by weighing many factors (See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). These factors include the following: 1) Amount of guidance provided by applicant. The Applicant has demonstrated the embodiments at pages 58-65 and Tables 1-3 of specification, and which are described by the above indicated subgenus of Formula I, are inhibitors of RIPK1 (see Table titled RIPK1-ADP-Glo Enzymatic Assay Data at pages 147-148). However, there is no evidence to show the full scope of Formula I which includes thousands of structurally diverse compounds have any use. 2) The nature of the invention and predictability in the art. The nature of the invention is compounds which are reportedly RIPK1 inhibitors. It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F. 2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved”. See In re Fisher , 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). 3) Number of working examples. A compound of Formula I wherein U is O or CR 12 R 13 where R 12 and R 13 are each H represents a narrow subgenus for which applicant has provided sufficient guidance regarding how to use (see Tables 1-3 and pages 147-148 of the specification). However, there are no working examples of Formula I wherein U is any group other than O or CH 2 . The art is highly unpredictable and this disclosure is not sufficient to allow extrapolation of the limited examples to enable the scope of the compounds instantly claimed. 4) Scope of the claims. The scope of the claims involves all of the thousands of structurally diverse compounds of the following formula: PNG media_image3.png 153 241 media_image3.png Greyscale Thus, the scope of the claims is very broad. 5) Level of skill in the art . The artisan using applicant' s invention would be a scientist with a Ph.D. degree and having several years of research experience. 6) Undue experimentation. MPEP §2164.01 (a) states, "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." The conclusion is clearly justified here that applicant is not enabled for the entire scope of a compound of Formula I that is claimed. Claim Rejections - 35 USC § 102 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. 07-15 AIA Claim (s) 1-3, 13-16 and 21 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Kabbe et al. (US 5,221,681)(hereinafter “Kabbe”) . Kabbe teaches Example 4 (col 6; pictured below for convenience) which corresponds to a compound of instant Formula I wherein R 2 is taken with R 1 and R 3 forms an unsubstituted aryl (phenyl); R 4 and R 6 form a -CH 2 bridge; U is O; R 16 is C 1 alkyl and each of R 5 , R 7 , R 8 , R 9 , R 10 , R 14 and R 15 is hydrogen. Kabbe further teaches a composition comprising Example 4 and a pharmaceutically acceptable carrier (claim 4). Kabbe teaches each and every limitation of the claims and therefore anticipates the claimed invention . PNG media_image4.png 233 550 media_image4.png Greyscale 07-15 AIA Claim s 1, 3-8, 10, 13-16, 21 and 23-24 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Fidalgo et al. (WO2018213632 A1)(hereinafter “Fidalgo”) Regarding claims 1, 3-4, 10 and 13-16, Fidalgo teaches Example 13 (page 131; pictured below for convenience) which corresponds to a compound of instant Formula I wherein R 1 and R 2 are independently methyl; and R 3 is difluoromethyl; U is O; R 7 is fluorine; and each R 4 , R 5 , R 6 , R 8 , R 9 , R 10 R 14 , R 15 , and R 16 is hydrogen. PNG media_image5.png 255 759 media_image5.png Greyscale Regarding claims 1, 3, 5-6, 8, 10, 13-16 and 24, Fidalgo teaches Example 9 (page 130; pictured below for convenience) which corresponds to a compound of instant Formula (I) wherein R 1 is taken with R 2 to form a heterocycloalkyl represented by PNG media_image6.png 73 99 media_image6.png Greyscale wherein the heterocycloalkyl is substituted with heteroaryl ( PNG media_image7.png 64 73 media_image7.png Greyscale ) substituted with halogen (F); R 3 is C 1 alkyl (methyl); U is O; and each R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 R 14 , R 15 , and R 16 is hydrogen. PNG media_image8.png 142 380 media_image8.png Greyscale Alternatively, Example 9 corresponds to instant Formula I wherei n R 3 is taken with R 2 to form a heterocycloalkyl represented by PNG media_image6.png 73 99 media_image6.png Greyscale wherein the heterocycloalkyl is substituted with heteroaryl ( PNG media_image7.png 64 73 media_image7.png Greyscale ) substituted with halogen (F) and R 1 is C 1 alkyl (limitations of instant claim 6 and 24). Regarding claims 1, 3, 5-7, 13-16 and 23, Fidalgo teaches Example 1 (page 128; pictured below for convenience) which corresponds to a compound of instant Formula I wherein R 3 is taken with R 2 to form a C 4 cycloalkyl represented by PNG media_image9.png 72 61 media_image9.png Greyscale wherein the C 4 cycloalkyl is substituted two halogen (F); R 1 is hydrogen; U is O; and each R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 R 14 , R 15 , and R 16 is hydrogen. PNG media_image10.png 107 166 media_image10.png Greyscale Example 1 Regarding claim 21, Fidalgo further teaches a composition comprising Examples 1, 9 and 13 and a pharmaceutically acceptable carrier (claim 45). Fidalgo teaches each and every limitation of the claims and therefore anticipates the claimed invention . 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 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 and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kabbe et al. (US 5,221,681)(hereinafter “Kabbe”) Kabbe teaches a generic group of compounds which embraces applicants’ claimed compounds (see claim 1, Formula (I) ) for use as pharmaceuticals and compositions for treating a disease of the circulatory system (see claims 4-5). The claims differ from the reference by reciting specific species and a broader genus than the reference. However, it would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the invention to select any of the species of the genus taught by the reference, including those instantly claimed, because the skilled chemist would have the reasonable expectation that any of the species of the genus would have similar properties and, thus, the same use as taught for the genus as a whole. One of ordinary skill in the art would have been motivated to select the claimed compounds from the genus in the reference since such compounds would have been suggested by the reference as a whole. It has been held that a prior art disclosed genus of useful compounds is sufficient to render prima facie obvious a species falling within a genus. In re Susi , 440 F.2d 442, 169 USPQ 423, 425 (CCPA 1971), followed by the Federal Circuit in Merck & Co. v. Biocraft Laboratories , 847 F.2d 804, 10 USPQ 2d 1843, 1846 (Fed. Cir. 1989).” In particular Kabbe teaches Example 4 which was discussed in the above rejection and which is incorporated herein by reference. Example 4 is racemic and therefore teaches the required stereochemistry of the claims. The difference between Example 4 and the instant claims is that the instant claims require wherein R 1 , R 2 and R 3 are each methyl. Kabbe teaches an aryl group (phenyl, see rejection above) at this position; however, Kabbe further provides a genus of Formula (I) (claim 1; pictured below for convenience) which teaches that each of the groups corresponding to R 1 , R 2 and R 3 of the instant claim can each be a methyl group (see claim 1 R represents COR 4 wherein R 4 is a branched alkyl having up to 7 C atoms; see claim 2 R 4 represents alkyl having 4 C atoms). A compound of Kabbe wherein R is COR 4 and R 4 is branched alkyl having 4 C atoms corresponds to the claims wherein each of R 1 , R 2 and R 3 is methyl. Kabbe thus teaches the equivalence of phenyl and branched alkyl having 4 C atoms at the position corresponding to R 1 , R 2 and R 3 of the claims. PNG media_image11.png 221 737 media_image11.png Greyscale Kabbe does not teach a specific embodiment wherein R 1 , R 2 and R 3 are each methyl; however, it would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the instant application to modify Example 4 of Kabbe with the R 1 , R 2 and R 3 groups required by the claims because Kabbe taught the modification (i.e. Kabbe disclosed that the positions corresponding to R 1 , R 2 and R 3 of the instant claim can be branched alkyl having 4 C atoms which is the structure of the claims when R 1 , R 2 and R 3 are each methyl) One would have been motivated as a matter of practicing the invention of Kabbe and preparing additional compounds for treating a disease of the circulatory system. One would have had a reasonable expectation of success because Kabbe taught the groups corresponding to R 1 , R 2 and R 3 of the claims could either be a phenyl ring or a branched alkyl group having 4 C atoms. One therefore would have expected that such a modification would result in a compound that was also useful for treating disease . 07-21-aia AIA Claim (s) 1, 5-6, 8-9 and 24-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fidalgo et al. (WO2018213632 A1)(hereinafter “Fidalgo”) . Fidalgo teaches a generic group of compounds which embraces applicants’ claimed compounds (see claim 1, Formula (I) ) for use as pharmaceuticals and compositions for treating ulcerative colitis (see claims 45 and 49-50). The claims differ from the reference by reciting specific species and a broader genus than the reference. However, it would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the invention to select any of the species of the genus taught by the reference, including those instantly claimed, because the skilled chemist would have the reasonable expectation that any of the species of the genus would have similar properties and, thus, the same use as taught for the genus as a whole. One of ordinary skill in the art would have been motivated to select the claimed compounds from the genus in the reference since such compounds would have been suggested by the reference as a whole. In particular Kabbe teaches Example 9 which was discussed in the above rejection and which is incorporated herein by reference. PNG media_image12.png 235 795 media_image12.png Greyscale The difference between Example 9 and the instant claims is that the instant claims require that the heteroaryl corresponding to PNG media_image13.png 69 82 media_image13.png Greyscale is substituted with CN. As noted in the above rejection, Example 9 of Fidalgo teaches wherein PNG media_image13.png 69 82 media_image13.png Greyscale is substituted with fluorine. However, Fidalgo also provides a genus of Formula (Ia) (claim 4; pictured above for convenience) which provides that PNG media_image13.png 69 82 media_image13.png Greyscale can be substituted with either fluorine or CN (see claim 4 and claim 1, R 5 is heteroaryl substituted with R 5c and R 5c is halogen, cyano). Fidalgo thus teaches fluorine and CN are equivalent substituents on heteroaryl ring PNG media_image13.png 69 82 media_image13.png Greyscale of the instant claims. Fidalgo does not teach a specific embodiment wherein PNG media_image13.png 69 82 media_image13.png Greyscale is substituted with CN; however, it would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the instant application to modify Example 9 of Fidalgo into the claimed invention by exchanging fluorine for CN because Fidalgo had disclosed that fluorine and CN where equivalent groups at this position. One would have been motivated as a matter of practicing the invention of Fidalgo and preparing additional compounds for treating ulcerative colitis. One would have had a reasonable expectation of success because Fidalgo taught fluorine and CN were equivalent groups. One therefore would have expected such a modification to result in a compound that would also be useful for treating ulcerative colitis. Conclusion No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEVIN MARTIN whose telephone number is (571)270-0917. The examiner can normally be reached Monday - Friday 8 am - 5 pm. 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 Murray can be reached on (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. June 12, 2026 /KEVIN S MARTIN/Examiner, Art Unit 1624 Application/Control Number: 18/556,226 Page 2 Art Unit: 1624 Application/Control Number: 18/556,226 Page 3 Art Unit: 1624 Application/Control Number: 18/556,226 Page 4 Art Unit: 1624 Application/Control Number: 18/556,226 Page 5 Art Unit: 1624 Application/Control Number: 18/556,226 Page 6 Art Unit: 1624 Application/Control Number: 18/556,226 Page 7 Art Unit: 1624 Application/Control Number: 18/556,226 Page 8 Art Unit: 1624 Application/Control Number: 18/556,226 Page 9 Art Unit: 1624 Application/Control Number: 18/556,226 Page 10 Art Unit: 1624 Application/Control Number: 18/556,226 Page 11 Art Unit: 1624 Application/Control Number: 18/556,226 Page 12 Art Unit: 1624 Application/Control Number: 18/556,226 Page 13 Art Unit: 1624 Application/Control Number: 18/556,226 Page 14 Art Unit: 1624
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