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 .
Status of the Claims
Claims 1, 3-20, 26, 32-34, 36-42 are pending in this application. Claims 2, 21-25, 27-31, and 35 have been cancelled by Applicant. Claims 26, 33-34, and 42 are withdrawn from consideration as being drawn to a non-elected species or invention. Claims 1, 3-20, 32, and 36-41 are under examination herein.
Claim Rejections - 35 USC § 103
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.
Claims 1, 3-9, 11, 14-20, and 36-41 are rejected under 35 U.S.C. 103 as being unpatentable over Diebold et al. (WO 2012/017251 A1 – previously cited) (“Diebold”); in view of in view of Zhai et al. (WO 2009/036035 A1 – previously cited) (“Zhai”).
Regarding claims 1, 3-9, 11, 14-20, and 36-41, Diebold discloses their compounds of Formula I as Bcl-2 and Bcl-XL inhibitors – which is the same intended use as the instant compounds (abstract). Diebold’s Formula D below (pages 24-26 and Diebold’s claim 1) renders the instant compounds obvious when: R1 (corresponding to instant R6) can be -OR1a, wherein R1a can be H or C1-4 alkyl (hydroxy or alkoxy); R2 (corresponding to instant -SO2CF3) can be -SO2CF3; R3 (corresponding to instant R3) can be H or C1-4 alkyl, wherein C1-4 alkyl can be optionally substituted with R40, wherein R40 can be -OH (hydroxyalkyl); and R4 (corresponding to instant R2) can be C1-4 alkyl, wherein C1-4 alkyl can be optionally substituted with R40, wherein R40 can be -OH (hydroxyalkyl); corresponding to instant R1, 4, 7-12 being H, R5 being -Cl, and r being 0.
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(Diebold’s Formula I)
Diebold specifically discloses their preferred embodiments 1, 4, and 25 below, which read on the instant compounds when instant R1 and R2 form a heterocycle, and wherein the heterocycle further comprises 1 to 3 heteroatoms.
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Ex. 4 [0877] page 163 Ex. 25 [0982] page 189 Ex. 1 [0859] page 159
While Diebold et al. does not specifically teach the compounds wherein their groups corresponding to instant R1 and R2, together with the carbon to which they are attached, form a heterocycle; the teachings of Zhai are relied upon for these disclosures.
Zhai discloses the compounds of Formula II below as Bcl-2 inhibitors – which is the same application as the instant compounds and as Diebold’s compounds – (abstract and page 6), reading on the instant compounds when R26 is aryl; W1 is CH; R27-27 can be H, oxo, alkyl, or aryl (corresponding to instant R6); W is CH; R23 is H; X2-4- are CH; X1 is CR25, wherein R25 can be sulfonyl; Z can be -S-; Ar can be phenyl; B1-2 can be absent or C1-6 alkyl; B3 can be a heterocycle (reading on instant aza-cycles and R1 and R2 joining to from heterocycles); B4 (corresponding to instant R3) can be absent or C1-6 alkyl; B5 can be absent or -O-; and B6 can be absent, with B4-6 corresponding to instant R3 being H or hydroxyalkyl.
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Therefore, regarding claims 1, 3-9, 11, 14-20, and 36-41, one having ordinary skill in the art would have found the claimed compounds prima facie obvious, since they are generically embraced by Diebold’s disclosed formula in view of Zhai’s related Bcl-2 inhibitors. The requisite motivation for arriving at the claimed compounds stems from the fact that they fall within the generic class of compounds disclosed by Diebold in view of Zhai’s related compounds, wherein the groups corresponding to instant R1 and R2 (Zhai’s B3) can merge to form heterocycles, reading on the instant pyrrolidines (when m = 2) and piperidines (when m = 3). Accordingly, further regarding claim 20, one having ordinary skill in the art would have been motivated to prepare, for example, any of the compounds below, which are embraced by the disclosed generic formulae:
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Applicant is advised that compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) 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).
Applicant is further reminded that a novel useful compound that is isomeric with the prior art compound is unpatentable unless it possesses some unobvious or unexpected beneficial property not possessed by the prior art compound. In re Norris, 179 F.2d. 970, 84 USPQ 458 (CCPA 1970). It has been held that a compound, which is structurally isomeric with a compound of the prior art, is prima facie obvious absent unexpected results. In re Finely, 81 USPQ 383 (CCPA 1949); 84 USPQ 458 (CCPA 1950).
Regarding claim 8, Diebold discloses their compounds of Formula I wherein R3 and R4 can form a 5-member ring, corresponding to instant m being 2.
Regarding claim 9, Diebold discloses their compounds 1, 4, and 25 above, wherein the group corresponding to instant R5 is Cl.
Regarding claims 11 and 37, Diebold discloses their compounds of Formula I wherein the group corresponding to instant R3 (Diebold’s R3) can be H or C1-4 alkyl, wherein C1-4 alkyl can be optionally substituted with R40, wherein R40 can be -OH (hydroxyalkyl). Diebold also discloses preferred embodiment 4, shown above, wherein the group corresponding to instant R3 is hydroxyalkyl.
Regarding claim 15, Diebold discloses their compounds of Formula I wherein the group corresponding to instant R4 is H.
Regarding claim 16, Diebold discloses their compounds of Formula I wherein the group corresponding to instant R6 (Diebold’s R1) can be -OR1a, wherein R1a can be H or C1-4 alkyl (hydroxy or alkoxy).
Regarding claim 17, Diebold discloses their compounds of Formula I wherein the group corresponding to instant R7-9 are H.
Regarding claim 18, Diebold discloses their compounds of Formula I wherein the group corresponding to instant R10-11 are H.
Regarding claim 19, Diebold discloses their compounds of Formula I wherein the group corresponding to instant r is 0.
Regarding claim 32, Diebold speaks to a pharmaceutical composition comprising their compounds of Formula I, further comprising at least one acceptable carrier, diluent, or excipient (Diebold’s claim 15).
Regarding claims 38 and 40, Diebold discloses their preferred embodiment 1 below, wherein the position α-to the nitrogen indicated (corresponding to instant R4) is H; and the position β-to the nitrogen (corresponding to instant R10-11) are also H.
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Regarding claim 39, Diebold discloses their preferred embodiment 1 below, wherein the position corresponding to instant R6 is -OH.
Further regarding claim 41, Applicant is reminded that compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.
Claims 10 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Diebold et al. (WO 2012/017251 A1 – previously cited) (“Diebold”); in view of in view of Zhai et al. (WO 2009/036035 A1 – previously cited) (“Zhai”); as applied to claims 1, 3-9, 11, 14-20, and 36-41; further in view of Wong et al. (Life Sciences, 57, 1995, 411-441 – previously cited) (“Wong”); and Deutsch et al. (PhD Dissertation, 2016, LMU München <URL: https://edoc.ub.uni-muenchen.de/20416/> - previously cited) (“Deutsch”).
The teachings of Diebold and Zhai are disclosed above and incorporated herein.
While Diebold in view of Zhai doesn’t specifically teach their compounds with a -CF3 in the position corresponding to instant R5; the teachings of Wong and Deutsch are relied upon for these disclosures.
Wong discloses a study of different R-substituents on the leftmost phenyl of their compound below (Table 3, page 417) and reports that replacing the 4-Cl with a 4-CF3 group resulted in a significant increase in potency for their compounds.
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Deutsch confirms Wong’s disclosure, revealing that -Cl and -CF3 groups are examples of monovalent bioisosteres (Table 1, page 15).
Therefore, regarding instant claims 10 and 12-13, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application prepare Diebold’s and Zhai’s Bcl-2 inhibitor compounds with a -CF3 group in place of the chlorine. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in light of Diebold’s in view of Zhai’s disclosure of their Bcl-2 compounds of Formula I; further in view of Wong’s disclosure that -CF3 substitution improved the activity of their compound significantly; and Deutsch teachings that -Cl and -CF3 groups are known monovalent bioisosteres.
Response to Arguments
Claims
Claim amendments are acknowledged. Now new matter has been introduced.
Specification
Amendments to the specification are acknowledged and have been entered. No new matter has been introduced.
Claim Rejections - 35 USC § 112(b)
Applicant’s arguments, see page 14, filed 11/19/2025, with respect to 35 USC § 112(b) rejection of the claims have been fully considered and are persuasive. The 35 USC § 112(b) rejection of the claims has been withdrawn.
Claim Rejections - 35 USC § 103
Applicant's arguments filed 11/19/2025 have been fully considered but they are not persuasive.
Applicant argues that Diebold doesn’t disclose their groups corresponding to instant R1 and R2 forming a ring, that Diebold’s compounds form a heterocycle with the groups corresponding to instant R2 and R3, and that therefore, the instant structures “differ significantly”. Applicant further states that neither Wong nor Zhai teach or suggest a ring form by the groups corresponding to instant R1 and R2. Applicant states it is known that med. Chem. is an experimental science, and it is unpredictable to determine where and how to modify a chemical molecule to achieve a desired effect, and the result is always unpredictable, thus there is no expectation of success.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, Diebold discloses their compounds of Formula I as Bcl-2 and Bcl-XL inhibitors – which is the same intended use as the instant compounds (abstract).
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(Diebold’s Formula I)
Diebold specifically discloses their preferred embodiments 1, 4, and 25 below, which read on the instant compounds when instant R1 and R2 form a heterocycle, and wherein the heterocycle further comprises 1 to 3 heteroatoms.
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Ex. 4 [0877] page 163 Ex. 25 [0982] page 189 Ex. 1 [0859] page 159
Applicant is reminded that compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.
Applicant is further reminded that a novel useful compound that is isomeric with the prior art compound is unpatentable unless it possesses some unobvious or unexpected beneficial property not possessed by the prior art compound. In the present case, Diebold discloses their compounds as Bcl-2 and Bcl-XL inhibitors (abstract) with IC50 values of 0.8 nM and 0.5 nM for Ex. 4 (shown above) for Bcl-XL and Bcl-2 inhibition, respectively (Table 1, entry 4, page 49). Instant compound 11 (page 68, bottom) is disclosed to have Ki values of 0.1 nM and 0.04 nM for Bcl-XL and Bcl-2, respectively (Tables 1 and 2, pages 78-79, entries 2-11). Therefore, it would have been obvious to one of ordinary skill to expect similar properties of structurally similar compounds since they are suggestive of one another. It has been held that a compound, which is structurally isomeric with a compound of the prior art, is prima facie obvious absent unexpected results.
Furthermore, Zhai discloses their related compounds of Formula II below as Bcl-2 inhibitors – which is the same application as the instant compounds and as Diebold’s compounds – (abstract and page 6), wherein B1-2 can be absent or C1-6 alkyl; B3 can be a heterocycle (reading on instant aza-cycles and R1 and R2 joining to from heterocycles); B4 (corresponding to instant R3) can be absent or C1-6 alkyl; B5 can be absent or -O-; and B6 can be absent, with B4-6 corresponding to instant R3 being H or hydroxyalkyl.
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Thus, one having ordinary skill in the art would have found the claimed compounds prima facie obvious, since they are generically embraced by Diebold’s disclosed formula in view of Zhai’s related Bcl-2 inhibitors. The requisite motivation for arriving at the claimed compounds stems from the fact that they fall within the generic class of compounds disclosed by Diebold in view of Zhai’s related compounds, wherein the groups corresponding to instant R1 and R2 (Zhai’s B3) can merge to form heterocycles, reading on the instant pyrrolidines (when m = 2) and piperidines (when m = 3). Accordingly, one having ordinary skill in the art would have been motivated to prepare any of the compounds encompassed by the claims.
In response to examiners argument that med chem is unpredictable and that there is no expectation of success, Applicant is advised that similar properties may normally be presumed when compounds are very close in structure. Dillon, 919 F.2d at 693, 696, 16 USPQ2d at 1901, 1904. See also In re Grabiak, 769 F.2d 729, 731, 226 USPQ 870, 871 (Fed. Cir. 1985) (“When chemical compounds have very close structural similarities and similar utilities, without more a prima facie case may be made.”). Thus, evidence of similar properties or evidence of any useful properties disclosed in the prior art that would be expected to be shared by the claimed invention weighs in favor of a conclusion that the claimed invention would have been obvious. Dillon, 919 F.2d at 697-98, 16 USPQ2d at 1905; In re Wilder, 563 F.2d 457, 461, 195 USPQ 426, 430 (CCPA 1977); In re Linter, 458 F.2d 1013, 1016, 173 USPQ 560, 562 (CCPA 1972) (see MPEP 2144.08(d)).
In the present case, Diebold and Zhai disclose their related compounds as Bcl-2 inhibitors, thus a compound resulting from the combination of specific features from these disclosures would be expected to also be a Bcl-2 inhibitor with a reasonable expectation of success.
Request for Rejoinder
No claim was found to be allowable in this final action, therefore, previously withdrawn claims stand withdrawn.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JACKSON J HERNANDEZ whose telephone number is (571)272-5382. The examiner can normally be reached Mon - Thurs 7:30 to 5.
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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