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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/01/2026 has been entered.
No amendments were made to the claims rejected in the Final Rection of 03/06/2026. Claims 76-89 are currently pending.
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 remain 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:
PNG
media_image1.png
508
622
media_image1.png
Greyscale
PNG
media_image2.png
330
614
media_image2.png
Greyscale
PNG
media_image3.png
214
616
media_image3.png
Greyscale
as representative examples of the genus of formula:
PNG
media_image4.png
120
398
media_image4.png
Greyscale
PNG
media_image5.png
42
194
media_image5.png
Greyscale
.
PNG
media_image6.png
178
658
media_image6.png
Greyscale
. 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:
PNG
media_image7.png
164
270
media_image7.png
Greyscale
, 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:
PNG
media_image8.png
148
364
media_image8.png
Greyscale
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
PNG
media_image9.png
72
80
media_image9.png
Greyscale
, 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 remain 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:
PNG
media_image10.png
117
352
media_image10.png
Greyscale
,
PNG
media_image11.png
116
348
media_image11.png
Greyscale
and
PNG
media_image12.png
114
328
media_image12.png
Greyscale
as representative examples of the genus of formula (VIIIa) of patented claim 1:
PNG
media_image13.png
171
354
media_image13.png
Greyscale
. 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
PNG
media_image10.png
117
352
media_image10.png
Greyscale
,
PNG
media_image11.png
116
348
media_image11.png
Greyscale
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
PNG
media_image12.png
114
328
media_image12.png
Greyscale
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
PNG
media_image12.png
114
328
media_image12.png
Greyscale
, 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 filed on 06/01/2026 have been considered but were found unpersuasive.
Applicant first argues that the invention surprisingly demonstrates an increased tolerance of heteroaryl moieties at Z, as well as tolerance of reversing the amide bond at Y. This is unpersuasive because there is no measure or comparison of tolerance in the specification or provided with the arguments. Applicant argues that the compounds demonstrate significant anti-cancer activity as shown in the Examples and Figures and that the compounds also demonstrate desirable microsomal stability. This is unpersuasive because Applicant has not offered more than general allegations of “significant anti-cancer activity” allegedly demonstrated in the specification. MPEP 716.05(b) states that the burden is on applicant to establish that any results are unexpected and significant. Applicants have the burden of explaining the data as evidence of non-obviousness.
Applicant states that there is comparative data demonstrating whether the features contribute to the favorable anti-cancer activity and metabolic activity of WJA88. Applicant then directs the examiner’s attention to page 34 and Figures 3 and 5 of the specification, which they say it demonstrate and improved biological activity and metabolic stability compared to compound CMPD1. The examiner is not persuaded. The examiner previously informed applicant that compound CMPD1 is not a compound of the prior art above. Applicant is not comparing their compounds with the compounds of the primary reference above, which are closer in structure to the claimed compounds, and only differ on the reverse-amide linker. Applicant insists in comparing the compounds of the instant claims with compound CMPD1, that not only differs in the reverse-amide linker, but also differs in the Z group. That is not an appropriate comparison because the primary references above disclosed compounds with the Z group as claimed (being a heteroaryl), thus, the primary references compounds have only one difference from the claimed compounds. Applicant must compare the claimed subject matter with the closes prior art to be effective to rebut a prima facie case of obviousness. See MPEP 716.02(e).
Applicant further argues against the secondary references individually, with the notion that the secondary references do not teach the claimed combination of features. Regarding Cai, applicant reproduced a comparison between compounds 7b and 2a in which the only difference was a reverse-amide. The result was that the compounds have the same use and same activity. This provides a motivation to make the same adjustment to the compounds of the primary references. As stated above, all other secondary references are evidence that exchanging the amide moiety for a retro-amide is a strategy successfully used in medicinal chemistry and drug design.
In addition, 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).
Regarding the following applicant’s arguments at page 9:
PNG
media_image14.png
138
640
media_image14.png
Greyscale
It is not correct that there are 2 structural changes between the prior art compounds and the claimed compounds. The compounds of the prior art have a heteroaryl substitution at Z, and therefore, only differ in the direction of the amide.
Applicant further states that the compounds of the invention are tubulin inhibitors and are effective against certain cancers. However, the compounds and compositions of the prior art are also used as tubulin inhibitors for the treatment of certain cancers. See the primary references. Applicant also states that the compounds of the invention are able to penetrate the BBB. However, the compounds of the prior art are of the same exact size and have the same exact groups as the claimed compounds. The compounds of the prior art would be expected to have this same property since the molecular size and weight are the same.
MPEP 716.02(b):
III. DIRECT AND INDIRECT COMPARATIVE TESTS ARE PROBATIVE OF NONOBVIOUSNESS
Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e).
Thus, applicant’s arguments are insufficient to overcome the rejection under 35 USC 103 for the reasons of record and the reasons stated above.
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.
Applicant argues that the definition of R1 as substituent with a heterocycloalkyl group represents a reasonable extrapolation form the compounds exemplified in the specification. Applicant argues that the synthesis of WJA88 together with the selection of appropriate starting materials provides support for R1 as claimed. The examiner is not persuaded because not a single compound exemplified in the specification contains R1 substituted with heterocycloalkyl, and the synthesis of WJA88 also does not contain R1 substituted with heterocycloalkyl. The selection of appropriate starting materials involves choosing from those defined or suggested by the specification, and the specification does not have, and does not suggest, R1 substituted with heterocycloalkyl.
Conclusion
Claims 76-86 and 88-89 are rejected. Claim 87 is objected to for depending of a rejected claim.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 VALERIE RODRIGUEZ-GARCIA whose telephone number is (571)270-5865. The examiner can normally be reached Monday-Friday 9:30am-5:30pm.
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, Clinton Brooks can be reached at 571-270-7682. 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.
/VALERIE RODRIGUEZ-GARCIA/Primary Examiner, Art Unit 1621
Prosecution Insights