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 .
Receipt of claim amendments and arguments filed on December 19, 2025 is acknowledged. Claim 89 is newly added. Claims 76-89 are currently pending.
Terminal Disclaimer
The terminal disclaimer filed on 12/19/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of US Patent 11,939,296 and US Patent 11,472,774 has been reviewed and is accepted. The terminal disclaimer has been recorded. Accordingly, the nonstatutory double patenting rejections have been withdrawn.
Rejections and objections not reiterated herein have been withdrawn.
Claims 76-89 are the subject of this Final Office action.
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.
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.
Claim(s) 76-85 and 88 and 89 are rejected under 35 U.S.C. 103 as being unpatentable over Lin et al. (US 2019/0169127- priority document with EF of Dec. 6, 2017) in view of Cai et al. (Bioorganic & Medicinal Chemistry Letters 27 (2017) 4571-4575), Stowe et al. (Curr. Drug Deliv. 2015; 12(2): 223-230), Hampton et al. (Bioorganic & Medicinal Chemistry Letters 21 (2013) 5876-5885), Lee et al. (Bioorganic & Medicinal Chemistry Letters 20 (2010) 4317-4319), Boukraa et al. (Bioorganic & Medicinal Chemistry Letters 21 (2011) 6876-6879), and Subramanian et al. (ACS Med. Chem. Lett. 2014, 5, 989-992).
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Teachings of Lin et al.
Lin teaches compounds of formula:
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330
614
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214
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as representative examples of the genus of formula:
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42
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.
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. Note that R41 is all sorts of heteroalkyl groups, such as ORa and SRa, wherein Ra is not hydrogen, aryl or heteroaryl; S(O)Rb, NRcRd, S(O)2Rd, NRaS(O)2Rd, etc. in which at least one of the variables is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl or heterocycloalkyl.
The compounds and compositions are to be use as tubulin inhibitors for the treatment of certain cancers. Compounds 1 and 8 were particularly exemplified. See examples 1 and 2.
Teachings of evidentiary references
Exchanging the amide moiety for a retro-amide is a strategy successfully used in medicinal chemistry and drug design. Reversing an amide bond is a small change that may have significant impact on the compound’s activity. This list of references is not exhaustive but illustrates how common this approach is. In the field of antimicrobial research, the retro-amide modification has led to derivatives with increased activity against Candida albicans (Cai et al.) and A. baumannii (Stowe et al.).
Hampton disclosed reverse amides as follows:
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, for the treatment of malaria. Hampton stated: “These results are noteworthy as a small change, such as reversing an amide bond has had a significant impact on the observed activities and illustrates the importance of correct orientation of any functionality.”
Lee disclosed that the results “show that the retro-amide scaffold can be used as an excellent bioisostere of amide group for peptide inhibitors in the PDF inhibitor design.” See page 4319.
Boukraa disclosed: “In keeping with our work focusing on the amide function of AHLs, we were interested in testing new analogues having a ‘reverse-amide’ linkage. This approach is a common one for altering amide containing compounds, notably for the design of peptide analogues.”
Subramanian taught the design, synthesis and SAR studies of a series of reverse-amide compounds with anti-cancer properties:
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Ascertainment of the Difference Between the Prior Art and the Claims
(MPEP §2141.012)
The only difference between the compounds of Lin et al. cited above and claimed compounds of formula (I) is the replacement of the amide linker with a reverse-amide linker. That is, the amide (-CONH-) vs retro-amide (-NHCO-) linker between the Z and the alkylene group X.
Finding of prima facie obviousness--rational and motivation (MPEP §2142-2413)
The level of ordinary skill in the art is high. Someone preparing these compounds would be trained in organic chemistry and would recognize the very close structural similarity and would expect these compounds to have the same properties. One of ordinary skill would have been motivated to make reverse-amide (-NHCO-) linker derivatives of the compounds of Lin above because exchanging the amide moiety (-CONH-) for a retro-amide (-NHCO-) is a strategy commonly used in medicinal chemistry and drug design with the aim of obtaining derivatives with similar or increased activity. This replacement is a research technique routinely used before the filing date of the instant invention.
The claimed compounds have exactly the same formula and the same use as the compounds of Lin; they are analogs possessing chemical and pharmacological similarities. There would have been a high expectation of success due to that the prior at teaches how to prepare and use the compounds which share the same groups.
In addition, MPEP 2144.09 states: A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990) for an extensive review of the case law pertaining to obviousness based on close structural similarity of chemical compounds. See also MPEP § 2144.08, subsection II.A.4.(c) and (d).
Regarding instant claim 85, the ordinary artisan would have been motivated to select any of the R41 heteroalkyl groups disclosed by Lin to substitute the phenyl ring
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, and would have arrived at the claimed compounds wherein R1 is phenyl substituted with heteroalkyl. The motivation lies on that Lin taught that heteroalkyl substituents at that phenyl ring would also afford compounds expected to be tubulin inhibitors.
Under the Supreme Court rationales in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007), here at least exemplary rationales (A) through (D) apply:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results.
Claim(s) 76-82, 85 and 88 and 89 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 12,247,010- priority document with EF of Dec. 6, 2017 in view of Cai et al. (Bioorganic & Medicinal Chemistry Letters 27 (2017) 4571-4575), Stowe et al. (Curr. Drug Deliv. 2015; 12(2): 223-230), Hampton et al. (Bioorganic & Medicinal Chemistry Letters 21 (2013) 5876-5885), Lee et al. (Bioorganic & Medicinal Chemistry Letters 20 (2010) 4317-4319), Boukraa et al. (Bioorganic & Medicinal Chemistry Letters 21 (2011) 6876-6879), and Subramanian et al. (ACS Med. Chem. Lett. 2014, 5, 989-992). The secondary references are the same as above.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Teachings of Lin et al.
Claim 20 of the patent describes compounds of formula:
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,
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and
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as representative examples of the genus of formula (VIIIa) of patented claim 1:
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. Note that in claim 1 variable E is similarly an amide (-CONH-) linker or a retro-amide (-NHCO-) linker. Note also that the pyridiny ring represented by B8 may be unsubstituted as in the first two compounds illustrated above.
The compounds and compositions are to be used as tubulin inhibitors for the treatment of certain cancers.
Teachings of evidentiary references
Exchanging the amide moiety for a retro-amide is a strategy successfully used in medicinal chemistry and drug design. Reversing an amide bond is a small change that may have significant impact on the compound’s activity. The list of secondary references and their pertinent teachings cited in the 103 rejection at numeral 4 above are incorporated in this rejection.
Ascertainment of the Difference Between the Prior Art and the Claims
(MPEP §2141.012)
The only difference between compounds of formula
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,
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of claim 20 of the patent and claimed compounds of formula (I) is the replacement of the amide linker with a reverse-amide linker. That is, the amide (-CONH-) vs retro-amide (-NHCO-) linker between the Z and the alkylene group X.
The only difference between compound of formula
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of claim 20 of the patent and claimed compounds of formula (I) is the methyl substituent at the pyridyl ring.
Finding of prima facie obviousness--rational and motivation (MPEP §2142-2413)
The level of ordinary skill in the art is high. Someone preparing these compounds would be trained in organic chemistry and would recognize the very close structural similarity and would expect these compounds to have the same properties. One of ordinary skill would have been motivated to make reverse-amide (-NHCO-) linker derivatives of the patented compounds above because exchanging the amide moiety (-CONH-) for a retro-amide (-NHCO-) is a strategy commonly used in medicinal chemistry and drug design with the aim of obtaining derivatives with similar or increased activity. This replacement is a research technique routinely used before the filing date of the instant invention. The disclosure in claim 1 of the patent, that E is similarly an amide (-CONH-) linker or a retro-amide (-NHCO-) linker, would have provided additional motivation and expectation of success.
The claimed compounds have exactly the same formula and the same use as the patented compounds; they are analogs possessing chemical and pharmacological similarities. There would have been a high expectation of success due to that the prior at teaches how to prepare and use the compounds which share the same groups.
In addition, MPEP 2144.09 states: A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990) for an extensive review of the case law pertaining to obviousness based on close structural similarity of chemical compounds. See also MPEP § 2144.08, subsection II.A.4.(c) and (d).
Regarding the patented compound of formula
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, the ordinary artisan would have been motivated to make and use an unsubstituted pyridyl analogue since the formula in the claims taught that the pyridyl ring could be unsubstituted and additionally, because one of ordinary skill would understand from the structures of patented claim 20 that an unsubstituted pyridyl ring was a preferred ring in the compounds of the invention.
Under the Supreme Court rationales in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007), here at least exemplary rationales (A) through (D) apply:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results.
Applicant’s arguments have been considered but were found unpersuasive. Applicant argues that the features wherein Y is -NR2-C(O)- and Z is heteroaryl unexpectedly and surprisingly contribute to the favorable anti-cancer activity and metabolic stability of compound WJA88. Applicant also discussed compound CMPD1. However, there is no comparative data to evaluate the alleged unexpected or surprising result. Further, Applicant has not compared their claimed compounds with the compounds of the prior art above.
Applicant further states that the compounds of the invention are tubulin inhibitors and are effective against certain cancers. In response, he compounds and compositions of the prior art are also used as tubulin inhibitors for the treatment of certain cancers. In addition, the compounds of the prior art are similar in size as the claimed compounds, with the only difference being the switching of the atom’s position of the amide group.
The unexpected results should be demonstrated with evidence that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). Moreover, evidence as to any unexpected benefits must be "clear and convincing" In re Lohr, 137 USPQ 548 (CCPA 1963), and be of a scope reasonably commensurate with the scope of the subject matter claimed, In re Linder, 173 USPQ 356 (CCPA 1972). Thus, applicant’s arguments are insufficient to overcome the rejection under 35 USC 103 for the reasons of record and the reasons stated above.
New grounds of rejection necessitated by amendments.
Claim Rejections - 35 USC § 112
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.
Claim 86 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Claim 86 now recites that R1 is substituted with heterocycloalkyl. This does not find support in the original specification or claims and it was never described therein. In the specification, one may find that R1 may be substituted by a halo group or a heteroalkyl group (e.g. O-alkyl, such as -OCH3 or OCH2CH3, or aminoalkyl, such as e.g. -CH2NH2 or -CH2CH2NH2). The original specification and the examples of substituents would not have reasonably lead those skilled in the art to the now claimed limitations. The new recitation would not have been obvious from the application description. See MPEP 2163 I. A and B.
Conclusion
Claims 76-86 and 88-89 are rejected. Claim 87 is objected to for depending of a rejected claim.
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.
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/VALERIE RODRIGUEZ-GARCIA/Primary Examiner, Art Unit 1621