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 1-4 and 13-23 are pending in the instant application and subject to examination herein.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/KR2022/007722, filed on 05/31/2022.
Claim Rejections - 35 USC § 103 – Maintained
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.
The prior rejection of claims 1-4 and 13-23 under 35 U.S.C. 103 as being unpatentable over Aktas (US 2016/0318856 A1) in view of Brown (Brown, N.; Bioisosteres in Medicinal Chemistry, Wiley-VCH, Weinheim, 2012), is maintained. Applicant has traversed the rejection with the following arguments:
The replacement of urea for squaramide in the comparative molecular structures of compounds disclosed by Aktas and Applicant, respectively, does not meet the definition of a bioisosteric replacement because the urea/squaramide moieties are central to the structures and therefore is not a substituent change but rather a scaffold change and therefore is not “simple” but rather “fundamental” (pages 23-24, bridging paragraph);
Brown’s teaching “expresses a hope, not a predictable rule that a bioisosteric replacement(s) in bioactive compound(s) will preserve a given biological activity” (page 24);
Brown’s presentation of bioisosteric equivalence between urea and squaramide groups is irrelevant to the instant claims because Brown does not teach such replacement in the context of eIF2a phosphorylation (page 24);
A combination of Brown’s teaching on the bioisosteric equivalence between urea and squaramide with the Aktas’ disclosure of urea-based eIF2a inhibitor compounds must be a result of impermissible hindsight, because a person of ordinary skill in the art would not otherwise have any motivation to apply concepts of bioisosteric replacement to the disclosure of Aktas (page 25);
The instantly claimed compounds exhibit unexpected results that a person of ordinary skill in the art would never predict, even if applying the teaching of Brown to the disclosure of Aktas (pages 25-26).
Applicant’s arguments have been considered, but are not found persuasive, for the following reasons:
As discussed in the prior rejection, Brown teaches that “bioisosteric replacement of substituents, ring atoms, linkers, and other groups1 aims to generate chemical substitutes with related biological properties”, thus bioisosteric replacements are not limited to substituents; further, Brown teaches that “small, defined changes to an identified core structure (also chemotype or scaffold) by the addition or substitution of functional groups” is known as “scaffold hopping” and is “a subset of bioisosteric replacement” (page 9); finally, in the example of Brown presented in the prior rejection, of bioisosteric replacement of urea for squaramide, the respective groups are central to the structures shown, and are not substituents, thus Brown shows that replacement of urea for squaramide at the core of the structure meets the definition of bioisosteric replacement;
As stated in the prior rejection and the point above, Brown states that the core function of bioisosteric replacement is to “generate chemical substitutes with related biological properties”; thus, while improved chemical properties may be a hope, “related biological properties” is an expected result of bioisosteric replacement; further Brown provides a definitions of bioisosteres (i.e., the structures resulting from bioisosteric replacement) as follows: “Bioisosteres are groups or molecules which have chemical and physical similarities producing broadly similar biological properties”; thus, a person of ordinary skill in the art, following the teaching of Brown, would have a reasonable expectation that bioisosteric replacements will result in compounds with similar physicochemical and biological properties;
A person of ordinary skill in the art would at once recognize that Brown’s teaching of bioisosteric replacement is based on functional equivalence (or near-equivalence) between atoms and/or groups of atoms based on their size, shape and other chemical properties (e.g., electrostatic topography, hydrogen bonding, etc.) thus is not dependent on the biological application of the compounds themselves;
As discussed in the prior rejection, bioisosteric replacement is a common practice in the field of biomedicinal chemistry, and as discussed in the prior point above, the principle is not dependent on the biological application(s) of a compound or group of compounds; thus, a person of ordinary skill in the art would be reasonably expected to apply the principle of bioisosteric replacement to any disclosure on biologically active compounds, including the disclosure of Aktas, and does not require or involve hindsight leveraging the instant disclosure;
The bioisosteric equivalents to the compounds of Aktas presented in the prior rejection, namely Aktas’ compound I-18 and Aktas’ unnamed compound presented in the same table in the rejection, are matched by Applicant’s compounds 23 and 24, respectively, and actually outperform the instant compounds 23 and 24 in regards to enhancement of eIF2a phosphorylation, given that Applicant reports eIF2a phosphorylation activity as ~2X that of control, for both compounds, whereas Aktas’ compounds provide eIF2a phosphorylation activity of 25X and 5X for compound I-18 and the unnamed compound, respectively (Aktas’ Table 7, pages 120-121); thus, no unexpected improvement is observed.
Reiterated rejection:
Claims 1-4 and 13-23 are unpatentable over Aktas in view of Brown.
Claims 1-4 and 13-23 are rejected under 35 U.S.C. 103 as being unpatentable over Aktas (US 2016/0318856 A1) in view of Brown (Brown, N.; Bioisosteres in Medicinal Chemistry, Wiley-VCH, Weinheim, 2012).
Claim 1 is drawn to a genus of squaramide compounds, designated as “Chemical Formula 1”, bearing additional rings and particular substituents, as shown in the table below. Aktas discloses substituted urea compounds that are within bioisosterically equivalence to the instant “Chemical Formula 1” as activators of eIF2a kinase, for example Aktas’ compound I-182 and another, unnumbered compound3 shown in the table below (paragraph [0425] and paragraph [0484]/Table 7/page 120, respectively):
Claim Number(s) of Instant Application
Instant Application
Aktas
1
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170
320
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wherein:
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206
320
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(compound I-18)
1
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170
320
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wherein:
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86
350
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The compounds disclosed by Aktas differ from the scope of instant Chemical Formula 1 in that the central moiety is a urea rather than squaramide. However, one of ordinary skill in the art would have a reasonable expectation of success in selecting a squaramide group in place of the urea group because these groups are known to be bioisosteric equivalents of one another. For example, see the teachings of Brown and Tremblay.
Brown teaches that “bioisosteric replacement of substituents, ring atoms, linkers, and other groups aims to generate chemical substitutes with related biological properties, in the hope that the new analogues may have somewhat better properties. Such replacements are the toolbox of medicinal chemists to optimize their lead structures with respect to lipophilicity, solubility, activity, selectivity, absorption, metabolism, and lack of toxic and other side effects” (Preface, page XV). Brown specifically teaches that squaramide is a known bioisosteric replacement for urea, with an example of a study on CXCR2 antagonists wherein a urea group was replaced with a squaramide group to provide a bioisosteric analogue with greater potency, as shown in Brown’s Figure 3.19 shown below (page 44):
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140
506
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Applicant’s invention is unpatentable over the disclosure of Aktas in view of the teaching of Brown, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of making and using bioisosterically equivalent analogues of Aktas’ compounds shown in the table above, as activators of eIF2a kinase, wherein the central urea group is replaced with a squaramide group, because urea and squaramide groups were known in the art as bioisosterically equivalent groups, per the teaching of Brown.
Thus, the invention was prima facie obvious at the time of filing.
Claims 2 and 3 further limit the genus of claim 1, each to a narrower genus that is met by the rejection above.
Claim 4 further limits claim 1 to a Markush group of specific compounds, including the two bioisosteric squaramide analogues of the urea compounds of Aktas discussed above, as shown in the table below:
Claim Number(s) of Instant Application
Instant Application
Aktas
4
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300
412
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3-(((trans)-4-(4-(trifluoromethyl)-phenoxy)cyclohexyl)amino)-4-((3-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione
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206
320
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(compound I-18)
4
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436
484
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4-(((trans)-4-((3,4-dioxo-2-((3-(trifluoromethyl)phenyl)amino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile
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86
350
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Thus, claim 4 is met by the rejection above.
Claim 13 is drawn to a method of preventing or treating cancer comprising administering a compound of instant “Chemical Formula 1”. Aktas discloses methods of treatment of disorders associated with a eukaryotic initiation factor-2a (eIF2a) kinase, eIF2a phosphorylation, uncontrolled translation initiation, or disorders that may be treated by inducing eIF2a phosphorylation, including cancer (paragraph [0384]).
Claims 14-15 further limit the genus of claim 13, each to a narrower genus that is met by the bioisosteric replacement of urea for squaramide groups in the compounds disclosed by Aktas as discussed in the rejection above.
Claim 16 further limits claim 13 to a Markush group of specific compounds that includes the two bioisosteric squaramide analogues of the urea compounds of Aktas discussed above.
Claim 17 further limits claim 13 to wherein the compound promotes phosphorylation of eIF2a. Aktas discloses that the invention disclosed therein includes the activation of HRI (heme regulated inhibitor) by the administered compound, which leads to phosphorylation of eIF2a (paragraph [0387]).
Claim 18 further limits claim 13 to wherein the cancer to be treated is selected from a Markush group of cancers that includes breast cancer. Aktas discloses specific cancers considered treatable by the administration of compounds disclosed therein, including breast cancer (paragraph [0385]).
Claim 19 is drawn to a method of inhibiting cancer cell metabolism, comprising administering a compound of instant “Chemical Formula 1”. As discussed above, Aktas discloses that the method of administering a compound of the invention disclosed therein to a subject includes the activation of HRI, which leads to phosphorylation of eIF2a (paragraph [0387]). Aktas also discloses that phosphorylation of eIF2a by kinases, including HRI, modulates protein translation initiation by reducing the available eIF2 for formation of an eIF2-GTP-Met-tRNAi complex needed for the translation initiation (paragraph [0004]) and that this ternary complex is coupled to cell physiology and plays many roles in normal and patho-physiology, and that proliferating cells synthesize proteins at a higher rate than quiescent cells of similar types, and that lower rates of protein translation is achieved by higher rates of eIF2a phosphorylation (paragraph [0005]). Aktas further discloses that induction of eIF2a phosphorylation pharmacologically can inhibit proliferation of cancer cells in vitro and tumor growth in vivo (paragraph [0007]). Thus, Aktas shows that administering compound(s) disclosed therein affects cell metabolism (protein translation initiation) that is particularly relevant to cancer cells.
Claims 20-21 further limit the genus of claim 19, each to a narrower genus that is met by the bioisosteric replacement of urea for squaramide groups in the compounds disclosed by Aktas as discussed in the rejection above.
Claim 22 further limits claim 19 to a Markush group of specific compounds that includes the two bioisosteric squaramide analogues of the urea compounds of Aktas discussed above.
Claim 23 further limits claim 19 to wherein the compound to be administered promotes phosphorylation of eIF2a to block metabolism of cancer cells, and is met by the disclosure of Aktas as discussed above.
Conclusion
THIS ACTION IS MADE FINAL. 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 W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Emphasis added by Examiner.
2 N-[trans-4-[4-(trifluoromethyl)phenoxy]cyclohexyl]-N′-[3-(trifluoromethyl)phenyl]urea
3 N-[trans-4-(4-cyanophenoxy)cyclohexyl]-N′-[3-(trifluoromethyl)phenyl]urea
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