Benzodiazepine Pyrazolo Carboxamides as N-protein Inhibitors

§103 §112 §DOUBLEPATENT

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 . DETAILED ACTION Claims 1-20 are pending and examined on the merits herein. Priority This application claims the following priority: PNG media_image1.png 79 670 media_image1.png Greyscale Abstract The abstract of the disclosure is objected to because: -a space should be inserted between “carboxamides” and “and” in line 2; and -the abstract contains numerous grammatic errors, such as “The invention relates to benzodiazepine pyrazolo carboxamides. . .to their use in medicine,” “The compounds of invention,” and “inhibit the activity RSV N-proteins,” and others, that render the abstract unclear. 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 Rejections - 35 USC § 112(b) 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 1-5, 10-11, and 18-20 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. -In claims 1 and 5, the compound of Formula (I) and the species of claim 5 recite the term “abs.” It is not clear what property or structure the term “abs” imparts to the compound. While pg. 39 if the instant Specification references the “absolute stereochemistry” of Enantiomer 1 and 2 in reference to the two compounds recited in instant claim 5, pg. 39 merely recites “The absolute stereochemistry of Enantiomer 1 and Enantiomer 2 were not assigned.” As such, it is not clear from this teaching of “absolute stereochemistry” that “absolute stereochemistry” is “abs.” The acronym or abbreviation “abs” is not further defined in the specification and “abs” is not an art recognized acronym. As such, the term “abs” renders the claims indefinite. All other claims not specifically recited are rejected for depending from an indefinite claim and failing to cure the deficiency. 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 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. Claims 1-13 and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over WO2022/008911 to Barrett (published 2022, IDS of 6/12/2025). Barrett teaches: PNG media_image2.png 138 173 media_image2.png Greyscale (pgs. 139 and 143, #41), which meets the limitations of instant Formula (I) when R1 and R2 are -CH3. Barrett teaches this compound as having an RSV A2 Plaque EC50 (nM) of 29 and a cell cytotoxicity CC50 (nM) of >25,000. Regarding claims 1-3 and 6-9, PNG media_image2.png 138 173 media_image2.png Greyscale differs from that of instant Formula (I) in that it does not teach –S(O)2CH2CH3, PNG media_image3.png 194 171 media_image3.png Greyscale . Barrett additionally teaches that the phenyl ring can be substituted with -SOmR, wherein m can be 2 and R can be a C2 alkyl (pgs. 213, claim 1, the definition of R1 and R2), and exemplifies the following compound: PNG media_image4.png 127 171 media_image4.png Greyscale (pgs. 197-198, # 197). Barrett teaches this compound as having an RSV A2 Plaque EC50 (nM) of 97 and a cell cytotoxicity CC50 (nM) of >25,000. It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the H at PNG media_image5.png 182 173 media_image5.png Greyscale , with -S(O)2CH2CH3 to arrive at a compound of instant Formula (I). One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because: -Barrett teaches that PNG media_image6.png 141 173 media_image6.png Greyscale can be substituted with -SOmR, wherein m can be 2 and R can be a C2 alkyl, and -Barrett exemplifies a structurally and functionally similar compound with -S(O)2CH2CH3 at this position, PNG media_image7.png 127 171 media_image7.png Greyscale . As such, an ordinary skilled artisan would have been motivated to make such a substitution to predictably arrive at a structurally and functionally similar compound. Regarding claims 4-5, Barrett differs in that it does not teach the instant R2 position as -CH2OH. It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the CH2 group of PNG media_image8.png 194 162 media_image8.png Greyscale with -CH2OH, to arrive at instant claims 4-5. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because: -Barrett teaches that its R4 and R5 of (I-1) can be a C1 alkyl or CH2OH (pgs. 213-214, claim 1), and -Barrett exemplifies compounds substituted with -CH2OH at its R4/R5 position (pgs. 171, 175-176, #’s 110, 128, 130, 134) and teaches these compounds as having RSV A2 Plaque EC50 (nM) values of 51, 41, 350, 83, respectively, and cell cytotoxicity CC50 values (nM) of >25,000. As such, an ordinary skilled artisan would have been motivated to make such a substitution to predictably arrive at a structurally and functionally similar compound. Regarding the (S) configuration of claims 7-9 and the disastereomers of instant claim 5, Barrett teaches that “The compounds of the invention may contain asymmetric or chiral centres, and therefore exist in different stereoisomeric forms. . .not limited to, diastereomers. . .as well as racemic mixtures. . .The present invention embraces all geometric and positional isomers of compounds of the invention” (pgs. 38, line 14-pg. 39, line 6), and compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.), MPEP 2144.09. Regarding claims 9 and 11, Barrett teaches pharmaceutically acceptable salts of its compound (pgs. 213-214, claim 1; pg. 39, line 29-pg. 40, line 10). Regarding claims 10-11, Barrett teaches pharmaceutical compositions comprising its compounds and carriers or diluents (pg. 237, claim 9). Regarding claim 12 and 17, Barrett teaches a method of treating RSV infection comprising administering to a subject an effective amount of its compounds (pg. 237, claims 11-13). Regarding claim 13, Barrett teaches combining its compounds with an additional RSV therapeutic agent (pgs. 237-238, claims 14-15). Regarding claims 18-20, the “for use” recitations are interpreted as intended uses. Since the compounds of Barrett are capable of performing the recited intended uses, the compounds of Barrett meet the limitations of “for use as a medicament,” “for use in the treatment of a RSV infection,” “for the manufacture of a medicament for the treatment of a RSV infection,” as recited in claims 18-20. See MPEP 2111.02. Moreover, as discussed above, Barrett teaches its compounds in the form of pharmaceutical compounds or compositions thereof for the treatment of RSV, and teaches preparing its compounds for such use. Claims 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over WO2022/008911 to Barrett (published 2022, IDS) as applied to claims 1-13 and 17-20 above, and further in view of Cockerill (Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion, published 2021, PTO-892). Barrett is applied as discussed above and incorporated herein. Regarding claims 14-16, Barrett differs in that it does not teach sisunatovir as the additional therapeutic agent. Cockerill teaches sisunatovir as a potent antiviral in patients with RSV (abstract). Sisunatovir is taught as an inhibitor of RSV fusion that has high oral bioavailability and efficient penetration into lung tissue (pg. 3670, Conclusion.). It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select sisunatovir as the additional therapeutic agent of Barrett, to arrive at instant claims 14-16. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because: -Barrett teaches administering its compounds with additional therapeutic agents, such as RSV antivirals, and -Cockerill teaches sisunatovir as an RSV antiviral. Thus, an ordinary skilled artisan would have been motivated to make such a selection, to predictably arrive at a more therapeutically effective method of treating RSV by further inhibiting RSV fusion. Double Patenting 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 § 2146 et seq. 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/apply/applying-online/eterminal-disclaimer. Claims 1-13 and 17-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. US 12,678,446 (PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other. Note: US 12,678,446 is in the same patent family as WO2022/008911 to Barrett, the primary reference relied upon in the above prior art rejections. ‘446 claims PNG media_image2.png 138 173 media_image2.png Greyscale (claim 5), which meets the limitations of instant Formula (I) when R1 and R2 are -CH3. Regarding claims 1-3 and 6-9, PNG media_image2.png 138 173 media_image2.png Greyscale differs from that of instant Formula (I) in that it does not claim –S(O)2CH2CH3, PNG media_image3.png 194 171 media_image3.png Greyscale . ‘448 additionally claims that the phenyl ring at its “W” position can be substituted with -SOmR, wherein m can be 2 and R can be a C2 alkyl (claim 1), and exemplifies the following compound: PNG media_image4.png 127 171 media_image4.png Greyscale (claim 5). It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the H at PNG media_image5.png 182 173 media_image5.png Greyscale , with -S(O)2CH2CH3 to arrive at a compound of instant Formula (I). One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because: -‘446 claims that PNG media_image6.png 141 173 media_image6.png Greyscale can be substituted with -SOmR, wherein m can be 2 and R can be a C2 alkyl, and -‘446 exemplifies a structurally and functionally similar compound with -S(O)2CH2CH3 at this position, PNG media_image7.png 127 171 media_image7.png Greyscale . As such, an ordinary skilled artisan would have been motivated to make such a substitution to predictably arrive at a structurally and functionally similar compound. Regarding claims 4-5, ‘446 differs in that it does not claim the instant R2 position as -CH2OH. It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the CH2 group of PNG media_image8.png 194 162 media_image8.png Greyscale with -CH2OH, to arrive at instant claims 4-5. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because: -‘446 claims that its R4 and R5 can be a C1 alkyl or a CH2OH (claim 1), and -‘446 claims compounds substituted with -CH2OH at its R4/R5 position (claim 5). As such, an ordinary skilled artisan would have been motivated to make such a substitution to predictably arrive at a structurally and functionally similar compound. Regarding the (S) configuration of claims 7-9 and the disastereomers of instant claim 5, compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.), MPEP 2144.09. Regarding claims 9 and 11, ‘446 claims pharmaceutically acceptable salts of its compounds (claim 1). Regarding claims 10-11, ‘446 claims pharmaceutical compositions comprising its compounds and carriers or diluents (claims 6-7). Regarding claim 12 and 17, ‘446 claims a method of treating RSV infection by administering to a subject an effective amount of its compounds (claims 8-9). Regarding claim 13, ‘446 claims combining its compounds with an additional RSV therapeutic agent (pgs. 237-238, claim 9). Regarding claims 18-20, the “for use” recitations are interpreted as intended uses. Since the compounds of ‘446 are capable of performing the recited intended uses, the compounds of Barrett meet the limitations of “for use as a medicament,” “for use in the treatment of a RSV infection,” “for the manufacture of a medicament for the treatment of a RSV infection,” in claims 18-20. See MPEP 2111.02. Moreover, as discussed above, ‘446 claims its compounds in the form of pharmaceutical compounds or compositions thereof for the treatment of RSV. Claims 14-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 12,678,446 (PTO-892), as applied to claims 1-13 and 17-20 in view of Cockerill (Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion, published 2021, PTO-892). ‘446 is applied as discussed above and incorporated herein. Regarding claims 14-16, ‘446 differs in that it does not claim sisunatovir as the additional therapeutic agent. Cockerill teaches sisunatovir as a potent antiviral in patients with RSV (abstract). Sisunatovir is taught as an inhibitor of RSV fusion that has high oral bioavailability and efficient penetration into lung tissue (pg. 3670, Conclusion.). It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select sisunatovir as the additional therapeutic agent of ‘446, to arrive at instant claims 14-16. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because: -‘446 claims administering its compounds with additional therapeutic agents, such as RSV antivirals, and -Cockerill teaches sisunatovir as an RSV antiviral. Thus, an ordinary skilled artisan would have been motivated to make such a selection, to predictably arrive at a more therapeutically effective method of treating RSV by inhibiting RSV fusion. Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN WELLS whose telephone number is (571)272-7316. The examiner can normally be reached M-F 7:00-4:30. 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, James (Jim) Alstrum-Acevedo can be reached on 571-272-5548. 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. /LAUREN WELLS/Primary Examiner, Art Unit 1622