Inhibitors of Rho Associated Coiled-Coil Containing Protein Kinase

§102 §103 §112

DETAILED ACTION Claims 4, 5, and 20-37 are currently pending in the instant application. Claims 4, 5, and 20-21, 25-31, and 34-37 are rejected. Claims 32 and 33 are withdrawn as being for non-elected subject matter. Claims 22-24 are allowable. 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 . Continued Examination Under 37 CFR 1.114 A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 16 April 2026 has been entered. Election/Restrictions Applicant’s election without traverse of Group I and the species of example 211: PNG media_image1.png 219 201 media_image1.png Greyscale in the reply filed on 6 December 2023 has been previously acknowledged. According to MPEP 803.02, the examiner has previously determined whether the elected species is allowable. Applicants’ elected species appears allowable. Therefore, the search and examination has previously been extended to the compounds of claim 22 which also appear allowable and previously further to the compound: PNG media_image2.png 258 234 media_image2.png Greyscale which is not allowable and now to the compounds: PNG media_image3.png 228 552 media_image3.png Greyscale and PNG media_image4.png 124 126 media_image4.png Greyscale which are not allowable. Claims 4, 5, 20-31, and 34-37 have been examined to the extent that they are readable on the elected embodiment, the elected species and the above mentioned compounds. Claims 32 and 33 are withdrawn claims as these claims do not read on the elected species which has X1 as N and L1 as CH. Withdrawn claim 32 has X1 as O and withdrawn claim 33 has L1 as N. Response to Amendment and Arguments Applicant's amendment and arguments filed 16 April 2026 have been fully considered and entered into the instant application. In regards to the 35 USC 102 rejection as being anticipated by US Pre-Grant Publication 2003/0125344, Applicant has amended claim 4 to delete unsubstituted from the definition of R2 and R3 together forming a 4-7-membered fused ring. Additionally, new claim 29 does not allow for R6 to be substituted aryl. The 35 USC 102 rejection as being anticipated by US Pre-Grant Publication 2003/0125344 is therefore withdrawn. In regards to the 35 USC 103 rejection, Applicant’s argue that the ‘025 publication does not make the instant claims obvious that there is no finite number of predictable solutions and that the cited reference does not indicate why a methyl group should be attempted in this combinatorial synthesis as opposed to hydrogen for R6. Applicant argues that the reference fails to show why a person having skill in the art would be motivated to modify the cites structures, particularly example 100 as the ‘025 publication does not yield a teaching or suggestion of appending a substituent to pyrrolidine, particularly where X1 is CHR6, where R6 is substituted with a hydrocarbon or otherwise. This argument is not persuasive as any known compound may serve as a lead compound when there is some reason for starting with that lead compound and modifying it to obtain the claimed compound. See Eisai Co. Ltd. V. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353 (Fed. Cir. 2008). Therefore, while the ‘025 publication discloses a very large genus of formula (I), example 100 is exemplified. The compounds of the ‘025 publication are disclosed on Page 19 for the treatment of patients suffering from cardiovascular diseases, inhibition of tumor cell growth, weight loss, etc. Therefore, example 100 would qualify as a lead compound as the prior art reference provides direction to the compound of example 100 as the prior art reference exemplifies only 180 compounds out of the very large genus disclosed, discloses that Example 100 falls within formula (I) on page 3 wherein R2 can be -A-R10 wherein A can be heterocyclyl and R10 can be H or C1-10 alkyl, discloses that Example 100 is also within formula (II) on page 4 wherein R2 can be -A-R10 wherein A can be heterocyclyl and R10 can be H or C1-10 alkyl, and additionally because the compounds of the ‘025 publication are disclosed to have utility as treatment of patients suffering from cardiovascular diseases, inhibition of tumor cell growth, weight loss, etc. The reason to modify the prior art compound of example 100 is that it is well established that the substitution of methyl for hydrogen on a known compound is not a patentable modification absent unexpected or unobvious results. Additionally, the difference is the compound of example 100 of the prior art has the position equivalent to applicant’s R6 as hydrogen, whereas the instant claims can have R6 as lower alkyl. Example 100 falls within formula (I) on page 3 of US Pre-Grant Publication 2015/0252025 wherein R2 can be -A-R10 wherein A can be heterocyclyl and R10 can be H or C1-10 alkyl. Example 100 is also within formula (II) on page 4 wherein R2 can be -A-R10 wherein A can be heterocyclyl and R10 can be H or C1-10 alkyl . The difference is one of hydrogen versus a methyl. In re Wood, 199 U.S.P.Q. 137 (C.C.P.A. 1978) and In re Lohr, 137 U.S.P.Q. 548, 549 (C.C.P.A. 1963). The motivation to make the claimed compounds derives from the expectation that structurally similar compounds would possess similar activity (ie., treatment of patients suffering from cardiovascular diseases, inhibition of tumor cell growth, weight loss, etc). Additionally, according to MPEP 2144.08, compounds which are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. It is not necessary for the reasoning to be explicitly found in the prior art of record nor is it necessary for the prior art to point to only a single lead compound. See Altana Pharma AG v. Teva Pharms. USA, Inc., 566 F.3d 999 (Fed. Cir. 2009). Therefore, the 35 USC 103 rejection is maintained. Claim Rejections - 35 USC § 112 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 4, 5, 20-21, 25-31, and 34-37 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. Specifically, claims 4 and 29 define R6: PNG media_image5.png 126 812 media_image5.png Greyscale . The term “including” renders the claim indefinite as it is unclear whether the ring has 4 to 7 ring atoms and also can include an additional 0 to 3 ring heteroatoms, or if the 0 to 3 ring heteroatoms are included within the 4 to 7 ring atoms. It is suggested that the definition be amended to “has from 4 to 7 ring atoms wherein 0 to 3 of the ring atoms can be heteroatoms.” Claim Rejections - 35 USC § 102 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 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 – (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. Claim(s) 4, 5, 20, 21, 29, 31, and 34-37 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2015/054317 (IDS filed 2/1/2023). WO 2015/054317 discloses the compound of example 2 on page 49: PNG media_image6.png 202 458 media_image6.png Greyscale . Page 27 provides pharmaceutical compositions in solid dosage forms for oral administration. The compound of example 2 corresponds to the formula PNG media_image7.png 214 300 media_image7.png Greyscale wherein L2 is N; L1 is CH; R5 is H; R2 is H; R3 is H; R4 is PNG media_image8.png 80 104 media_image8.png Greyscale ; X1 is CHR6; n is 1; a is 1; and two R6 substituents attached to different ring carbons are taken together to form a ring which has 6 ring atoms. Claim(s) 4, 5, 20, 25-30, and 34-36 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Registry No. 1346419-35-9. Registry No. 1346419-35-9 is: PNG media_image9.png 232 562 media_image9.png Greyscale . Registry No. 1346419-35-9 corresponds to the instant formula II: PNG media_image7.png 214 300 media_image7.png Greyscale wherein L2 is N; L1 is CH; R5 is variably substituted on the indazole and is NRR’; R is H and R’ is substituted aralkyl; R2 is halo; R3 is H; R4 is PNG media_image8.png 80 104 media_image8.png Greyscale ; X1 is NH; n is 2; a is 1; and R6 is lower alkyl. (R6)a is variably substituted on applicant’s R4 of instant formula II. The compound of the prior art corresponds to the instant claims wherein a is 1 and R6 substitutes on the position X1 of the R4 ring PNG media_image8.png 80 104 media_image8.png Greyscale , thereby replacing the hydrogen of NH at position X1. Registry number 1346419-35-9 is available as prior art as of 28 November 2011, the date it was indexed into the CAplus database. See MPEP 2128: ELECTRONIC PUBLICATIONS AS PRIOR ART Status as a "Printed Publication" An electronic publication, including an on-line database or Internet publication, is considered to be a “printed publication” within the meaning of 35 U.S.C. 102(a) and (b) provided the publication was accessible to persons concerned with the art to which the document relates. See In re Wyer, 655 F.2d 221, 227, 210 USPQ 790, 795 (CCPA 1981) Since this date represents the date that each compound entered the CAPlus database on STN, this represents the date that each compound was made accessible to the public. The aforementioned compound anticipates the instantly claimed compounds: It is further noted that for the purposes of determining if a reference is a “printed publication” for the purposes of 102(b), MPEP 2128 states the following: PNG media_image10.png 99 480 media_image10.png Greyscale where “prior art disclosures…on an on-line database are considered to be publicly available as of the date the item was publicly posted.” Since each of the database entries above lists the date that each compound was entered into the on-line database, the compounds were made publicly available as of that date in each citation, and the claims are anticipated. Regarding the compositions of claim 20 and 36 comprising the anticipatory compounds and an excipient, the Registry entry for Registry no. 1346419-35-9 discloses a mass solubility in unbuffered water. This teaching in of water anticipates the claimed composition, wherein the compounds are present with an excipient (i.e., water). 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. Claim(s) 4, 5, 20, 21, 29, 31, and 34-37 is/are rejected under 35 U.S.C. 103 as being unpatentable over US Pre-Grant Publication 2015/0252025. Determination of the scope and content of the prior art (MPEP §2141.01) US Pre-Grant Publication 2015/0252025 discloses the compound of example 100, page 51: PNG media_image11.png 212 265 media_image11.png Greyscale . Example 100 falls within formula (I) on page 3 of US Pre-Grant Publication 2015/0252025 wherein R2 can be -A-R10 wherein A can be heterocyclyl and R10 can be H or C1-10 alkyl. Example 100 is also within formula (II) on page 4 wherein R2 can be -A-R10 wherein A can be heterocyclyl and R10 can be H or C1-10 alkyl . Page 21 provides pharmaceutical compositions, including solid dosages for oral administration which include pharmaceutically acceptable carriers. Page 19 provides utility for the prior art compounds, such as the treatment of patients suffering from cardiovascular diseases, inhibition of tumor cell growth, weight loss, etc. Ascertainment of the difference between the prior art and the claims (MPEP §2141.02) This prior art compound corresponds to the instant claims, for example, as follows: The prior art compound corresponds to the formula (II) PNG media_image12.png 185 254 media_image12.png Greyscale of claim 4 and 29, for example, wherein R5 is H; L1 is CH; L2 is N; R2 is H; R3 is halo; R4 is PNG media_image13.png 82 135 media_image13.png Greyscale wherein a is 0; n is 1; and X1 is CHR6. The difference is the compound of example 100 of the prior art has the position equivalent to applicant’s R6 as hydrogen, whereas the instant claims can have R6 as lower alkyl. The difference is one of hydrogen versus a methyl. The prior art compound corresponds to the formula (IIa) PNG media_image14.png 187 269 media_image14.png Greyscale of claim 5, for example, wherein R5 is H; R2 is H; R3 is halo; R4 is PNG media_image13.png 82 135 media_image13.png Greyscale wherein a is 0; n is 1; and X1 is CHR6. The difference is the compound of example 100 of the prior art has the position equivalent to applicant’s R6 as hydrogen, whereas the instant claims can have R6 as lower alkyl. The difference is one of hydrogen versus a methyl. Finding of prima facie obviousness--rational and motivation (MPEP §2142-2413) However, it would have been obvious of one of ordinary skill in the art to replace hydrogen with methyl at the position of example 100 that is equivalent to applicants X1 as CHR6 wherein R6 is hydrogen to be X1 as CHR6 wherein R6 is methyl as the prior art provides direction in formula (I) and (II) wherein R10 can be H or C1-10 alkyl. Additionally, it is well established that the substitution of methyl for hydrogen on a known compound is not a patentable modification absent unexpected or unobvious results. In re Wood, 199 U.S.P.Q. 137 (C.C.P.A. 1978) and In re Lohr, 137 U.S.P.Q. 548, 549 (C.C.P.A. 1963). The motivation to make the claimed compounds derives from the expectation that structurally similar compounds would possess similar activity. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA L ANDERSON whose telephone number is (571)272-0696. The examiner can normally be reached Monday-Friday from 6am-2pm. 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, Andrew Kosar can be reached at 571-272-0913. 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. /REBECCA L ANDERSON/Primary Examiner, Art Unit 1626 ____________________ 13 October 2026 Rebecca Anderson Primary Examiner Art Unit 1626, Group 1620 Technology Center 1600