DETAILED ACTION
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 .
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.
Claims 1, 16, 19, 23 – 24, 26, 29 – 30, 32, 40, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2009095163 A2 to Steinhagen et. al. (Steinhagen’163; cited on the ISR and IDS form).
Regarding claims 1, 16, 19, 23 – 24, 26, 29 – 30, 32, 40, and 44, Steinhagen’163 teach cyclic indole-3-carboxamides, their preparation and their use as pharmaceuticals. See page 1 line 1. In particular, Steinhagen’163 teach compounds of the formula I,
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where reference A, R, R10, R20, R30, R40, n, p, and q are defined. See page 1 lines 3 – 6. Additionally, Steinhagen’163 teach a compound where reference A, R, R10, R20, R30 , R40, n, p, and q can be selected from a list of alternatives. See pages 5 – 7. Specifically, Steinhagen’163 teach example 1 of the structure
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where instant Ring A = piperazine; instant R1 = H; instant n = 1; instant R2 = ORa where instant Ra = 5-fluoro-2-methyl phenyl; instant W = X = Y = Z = CH where instant RW = RX = RY = RZ = H; and instant R3 = R4 = R5 = R6 are H. See page 61 lines 4 – 8. See claim 1. See claim 19 limitation where R5 and R6 are H. See claim 23 limitation where RW = H. See claim 24 limitation where RX = H. See claim 29 limitation where RY = H. See claim 30 limitation where RY = H. See claim 32 limitation where RZ = H. See claim 40 limitation where n = 1.
Additionally, Steinhagen’163 teach that the compounds of the formula I, which includes example 1, and their physiologically acceptable salts and physiologically acceptable solvates thereof can therefore be as a pharmaceutical or medicament on their own, in mixtures with one another or in the form of pharmaceutical compositions. See page 53 lines 27 – 31 and see page 54 lines 1 – 6. See claim 44 limitation for a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
Regarding claim 16 limitation for a compound where R3 is C1-C6alkyl and R4 is C1-C6alkyl; as mentioned above, Steinhagen’163 teach a compound where reference R30, is selected from a list of alternatives. In particular, Steinhagen’163 teach that reference R30 can be phenyl substituted by one or more identical or different substituents chosen from halogen, (C1-C6)-alkyl, and OH. See page 5 lines 25 – 27 and page 6 lines 1 – 4. Now while Steinhagen’163 fails to exemplify a compound where R3 is C1-C6alkyl and R4 is C1-C6alkyl; Steinhagen’163 does teach (C1-C6)-alkyl as an option within a short list of alternatives. Thus given the relatively high skill level of one of ordinary skill in the organic synthetic arts it would be within the purview of such artisan given the above teachings to modify example 1 to include C1-C6alkyl groups phenyl positions that correlate with instant R3 and R4 positions.
Regarding claim 26 limitation for a compound where RX is C1-C6alkyl or cycloalkyl; as mentioned above, Steinhagen’163 teach a compound where reference R40, and v are selected from a list of alternatives. In particular, Steinhagen’163 teach that reference R40 can be (C1-C6)-alkyl or (C3-C7)-cycloalkyl-CvH2v where v = 0. See page 6 line 9 and page 7 line 10. Now while Steinhagen’163 fails to exemplify a compound where RX is C1-C6alkyl or cycloalkyl; Steinhagen’163 does teach both (C1-C6)-alkyl and (C3-C7)-cycloalkyl-CvH2v where v = 0 as an options within a short list of alternatives. Thus given the relatively high skill level of one of ordinary skill in the organic synthetic arts it would be within the purview of such artisan given the above teachings to modify example 1 to include either (C1-C6)-alkyl or (C3-C7)-cycloalkyl-CvH2v where v = 0 in position that correlates with instant R2.
Regarding claim 1 limitation for a compound where R1 is -C(=O)ORb where Rb is C1-C6alkyl or cycloalkyl; as mentioned above, Steinhagen’163 teach a compound where reference R10, is selected from a list of alternatives. In particular, Steinhagen’163 teach that reference R10 can be (C1-C6)-alkyl-O-CO- or (C3-C7)-cycloalkyl-CvH2v-O-CO- where v = 0. See page 5 lines 18 – 19. Now while Steinhagen’163 fails to exemplify a compound where R1 is -C(=O)ORb where Rb is C1-C6alkyl or cycloalkyl; Steinhagen’163 does teach both (C1-C6)-alkyl-O-CO- or (C3-C7)-cycloalkyl-CvH2v-O-CO- where v = 0 as options within a short list of alternatives. Thus given the relatively high skill level of one of ordinary skill in the organic synthetic arts it would be within the purview of such artisan given the above teachings to modify example 1 to include either (C1-C6)-alkyl-O-CO- or (C3-C7)-cycloalkyl-CvH2v-O-CO- where v = 0 in position that correlates with instant R1.
Moreover, in regards to claim 1 limitation where the compound contains a OH on the meta position of the phenyl ring boxed here:
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; as mentioned above, Steinhagen’163 teach a compound where reference R30, is selected from a list of alternatives. In particular, Steinhagen’163 teach that reference R30 can be phenyl substituted by one or more identical or different substituents chosen from OH. See page 5 lines 25 – 27 and page 6 lines 1 – 4. Now while Steinhagen’163 fails to exemplify a compound where there is a OH on the meta position; Steinhagen’163 does teach OH as an option within a short list of alternatives. Thus given the relatively high skill level of one of ordinary skill in the organic synthetic arts it would be within the purview of such artisan given the above teachings to modify example 1 to include a meta OH group on the phenyl position.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the formula (I) of Steinhagen’163 for a compound that meets the structural limitations for claim 1. One of ordinary skill in the art would have been motivated to make the modification and have a reasonable expectation of success because Steinhagen’163 taught a compound formula where reference A, R10, R30 , R40, n, p, and q can be selected from a list of alternatives that meet the structural limitations of claim 1.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over under 35 U.S.C. 103 as being unpatentable over WO 2009095163 A2 to Steinhagen et. al. (Steinhagen’163; cited on the ISR and IDS form) in view of Patani et. al. ((1996) Bioisosterism A rational approach in drug design, Chem. Rev., 96, 3147-3176).
The teachings of Steinhagen’163 as they relate to claim 1, from which claim 10 depend, are given previously in this office action and are fully incorporated here.
However, Steinhagen’163 fail to teach a compound where the compound is of Formula (Ia), (lb), (le), (Id), or (le). See claim 10.
Nevertheless, Patani et. al. teach that the concept of bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents. See page 3147 column 1 paragraph 1 and column 2 paragraph 1. Furthermore, Patani et. al. teach the ability of a group of bioisosteres to elicit similar biological activity has been attributed to common physicochemical properties. See page 3148 column 1 paragraph 2. Moreover, Patani et. al. teach that bioisosteres have been classified as either classical or nonclassical with classical bioisosteres have been traditionally divided into several distinct categories: (A) monovalent atoms or groups; (B) divalent atoms or groups; (C) trivalent atoms or groups; (D) tetrasubstituted atoms; and (E) ring equivalents. See page 3148 column 2 paragraph 4 and page 3149 column 1 paragraph 1. Specifically, Patani et. al. teach the trivalent substitution of -CH= with -N= is commonly used in modern drug design. See page 3159 column 2 paragraph 4. Moreover, Patani et. al. teach an example where a trivalent ring substitution of -CH= with -N= in the antibacterial agent norfloxacin (56a) resulted in enoxacin (56b, Figure 38) which is also in clinical use for its antibacterial activity. See page 3159 column 2 paragraph 4.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify example 1 of Steinhagen’163 of structure
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in view of Patani et. al. that is to have a trivalent ring substitution of instant V from -CH= to -N=. One of ordinary skill in the art would have been motivated to make this modification to rationally modify example 1 to be safer and/or more clinically effective agent. One of ordinary skill in the art would have had a reasonable expectation of success because the trivalent substitution of -CH= with -N= is commonly used in modern drug design. Moreover, in the prior art example where a trivalent ring substitution of -CH= with -N= in the antibacterial agent the bioisostere was also exhibited favorable biological affect.
Claim 39 is rejected under 35 U.S.C. 103 as being unpatentable over under 35 U.S.C. 103 as being unpatentable over WO 2009095163 A2 to Steinhagen et. al. (Steinhagen’163; cited on the ISR and IDS form) in view of Meanwell ((2011), Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design, J. Med. Chem., 54, 2529 – 2591).
The teachings of Steinhagen’163 as they relate to claim 1, from which claim 39 depend, are given previously in this office action and are fully incorporated here.
However, Steinhagen’163 fail to teach a compound where R1 is halogen, C1-C6alkyl or C1-C6haloalkyl. See claim 39.
Nevertheless, Meanwell teach that in the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates. See page 2529 column 1 paragraph 1. Additionally, Meanwell teach that bioisosteres are typically less than exact structural mimetics and are often more alike in biological rather than physical properties. See page 2529 column 1 paragraph 1. Moreover, Meanwell teach that H, F, OH, NH2, and CH3 are classical monovalent bioisosteres. See page 2530 column 1 Table 1. Thus, Meanwell suggest the ability to substitute H for either F or CH3 with a reasonable expectation that compounds with either H, F, or CH3 would have similar biological properties.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filling date of the instant application to modify example 1 of Steinhagen’163 of structure
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in view of Meanwell, that is to substitute the H in the instant R1 position for either F or CH3. One of ordinary skill in the art would be motivated to make this modification and have a reasonable expectation of success because H, F, and CH3 are classical monovalent bioisosteres and would be reasonable expected to at least have the same biological properties.
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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, 10, 16, 19, 21, 23 – 24, 26, 29 – 30, 32, 34 – 37, 39, 40, 43 – 44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 7, 9 – 10, 12, 14 – 15, 17, 19, 21, 23, and 27, of copending Application No. 18/846613 to Wang et.al. (reference application; Wang’613).
Although the claims at issue are not identical, they are not patentably distinct from each other because both copending applications direct to heteroaromatic compounds with overlapping species between the copending applications. In particular, Wang’613 recite a compound of Formula A
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where (reference) R1-7, Y, and Z are defined. See reference claim 1. See examined claim 1. Moreover, Wang’613 recite compound species which overlap with the species of the examined application. See reference claims 2 – 7, 9 – 10, 12, 14 – 15, 17, 19, 21, and 23. See examined claims 10, 16, 19, 21, 23 – 24, 26, 29 – 30, 32, 34 – 37, 39, 40, and 43. Furthermore, Wang’613 recites a pharmaceutical composition for treating a PKMYT1-associated disease or condition, which comprises the compound or a pharmaceutically acceptable salt, so acceptable carrier or excipient. See reference claim 27. See examined claim 44.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, and 45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, and 30 of copending Application No. 18846613 to Wang et.al. (Wang’613) in view of Zhang et. al. ((2019), Overexpressed PKMYT1 promotes tumor progression and associates with poor survival in esophageal squamous cell carcinoma, Cancer Management and Research, 11, 7813 – 7824).
Wang’613 recite a compound of Formula A
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where (reference) R1-7, Y, and Z are defined. See reference claim 1. See examined claim 1. Additionally, Wang’613 recite a method of treating a PKMYT1-associated disease or condition in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof of (reference) claim 1. See reference claim 30.
However, Wang’613 fails to recite whether a PKMYT1-assosaicted disease or condition includes cancer. See examined claim 45.
Nevertheless, Zhang et. al. teach that esophageal carcinoma (EC) is the ninth common carcinoma and the sixth leading cause of cancer-related death all over the world. See page 7813 paragraph 1. Furthermore, Zhang et. al. teach that even with the evolution of the multidisciplinary treatment, including novel surgical approaches, chemotherapy, radiotherapy, and molecular-targeted therapy, the 5-year overall survival rate remains poor. See page 7813 paragraph 1. Furthermore, Zhang et. al. teach that PKMYT1 was highly expressed in ESCC cell lines and ESCC patients, and high PKMYT1 expression induced poorer prognosis in patients with ESCC. See page 7814 column 1 paragraph 1. Thus, Zhang et. al. teach that PKMYT1 might be a potential target in the treatment of ESCC. See page 7814 column 1 paragraph 1. Moreover, Zhang et.al. teach that down-regulated of PKMYT1 expression in ESCC cells could inhibit cell proliferation, promote cell apoptosis, and restrict the EMT phenotype in vitro. See page 7822 column 2 paragraph 3. Furthermore, Zhang et. al. teach that PKMYT1 downregulation also suppressed the Akt/mTOR/S6 signaling pathway in ESCC cells. See page 7822 column 2 paragraph 3.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of copending Wang’613 for the treatment of PKMYT1-associated disease or condition in view of Zhang et. al. that is to treat esophageal carcinoma. One of ordinary skill in the art would have been motivated to make this modification and because PKMYT1 was highly expressed in ESCC cell lines and ESCC patients, and high PKMYT1 expression induced poorer prognosis in patients with ESCC. One of ordinary skill in the art would have had a reasonable expectation of success because down-regulated of PKMYT1 expression in ESCC cells could inhibit cell proliferation, promote cell apoptosis, and restrict the EMT phenotype in vitro.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1, 10, 16, 19, 21, 23 – 24, 26, 29 – 30, 32, 34 – 37, 39 – 40, and 43-45 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAWANNA S WHITE whose telephone number is (703)756-4687. The examiner can normally be reached 7:00 am - 5:00 pm [EST] M - Th.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
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