Detailed Action
The present office action is in response to the RCE filed on 13 Mar 2026.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 13 Mar 2026 has been entered.
Status
Claims 44-45, 49-51, 54, 56, and 59 of the pending application have been examined on the merits. Claims 46-48,52-53,55,57-58 and 60-63 remain withdrawn. Acknowledgement is made of the cancelation of claims 1-43.
Priority
Applicants identify the instant application, Serial #: 17/766,945, filed 06 Apr 2022, as a National Stage Entry of International Patent Application #: PCT/US2020/054712, filed 08 Oct 2020, which claims priority from U.S. Provisional Application #: 62/912,108, filed 08 Oct 2019.
Response to Applicant Arguments
Regarding the rejection of claims 44-45, 49-51, 54, 56, and 59 under 35 U.S.C. § 103 over WO 2015/038778 (provided in the office action mailed 23 Jun 2025), hereinafter ‘778 further in view of Patani et al. (Chem Rev, 1996, 2017, 60:5391-5406; provided in the office action mailed 23 Jun 2025), hereinafter Patani, applicant's arguments filed 13 Mar 2026 have been fully considered but they are not persuasive.
Applicant argues on pg. 10 of the remarks that choosing the ninth-most active compound could have been included in the lead analysis the artisan was performing and ‘778 teaches preferred embodiments are not reasons for starting with the particular lead compound. Applicant argues these are mere facts that a lead compound exists which do not meet the standards of performing a lead compound analysis. Applicant further argues that the selection of structure 1 by the office appears to be founded on Applicant's disclosure rather than reasons for starting with that compound and is based on impermissible hindsight.
In response to applicant’s argument that the examiner’s conclusion of obviousness is based on improper hindsight reasoning, it must be recognized that any judgement on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill before the time of the claimed invention’s effective filing date, and does not include knowledge gleaned only from the applicant’s disclosure, such a reconstruction is proper. See MPEP § 2145(X). The lead compound may be selected based on reasoning which can be drawn from any number of sources and need not necessarily be explicitly found in the prior art of record. In this case, examiner has put forward several reasons why the reference compound would be chosen by the artisan to modify and so arrive at the instantly elected compound (see the Office Action mailed 29 Dec 2025, both the "Response to Applicant Arguments" and "Claim Rejections - 35 USC § 103" sections). See Example 11 of MPEP § 2143(I)(B).
Applicant submits on pg. 11 of the remarks that the previous arguments meet the standard for addressing both references and that office misapplied Keller and Merck in the rebuttal.
Examiner notes this argument in the record and thanks applicant for including an analysis of what '778 and Patani teach together in the current remarks.
Applicant argues on pg. 12 of the remarks that bioisosterism alone is insufficient to render a compound obvious because it fails to take into account any information specific to the enzyme, target or the properties of the drug itself and does not predict whether a particular structural change will improve potency, selectivity, or pharmacokinetics.
This is not persuasive. A prima facie case for obviousness may be made when two chemical structures are sufficiently close in similarity that there is an expectation that the compounds will have similar properties, including when structural differences include a known bioisosteric replacement. See MPEP § 2144.09(I) and MPEP § 2144.09(III). In this case, '778 teaches the core structure of the instantly claimed compound and the reasoning for choosing the compound to modify further. '778 also teaches compounds which have fluorine in the same position as the instantly elected compound and have similar activity to the main compound. Patani teaches the bioisosteric replacement of hydrogen with fluorine and the motivation to modify using fluorine. The artisan would therefore have modified the compound taught by '778 with a fluorine and arrive at the instantly claimed compound.
In light of the discussion above, the rejection of claims 44-45, 49-51, 54, 56, and 59 under 35 U.S.C. § 103 as obvious over ‘778 and Patani is maintained for the reasons of record and restated below.
Regarding the rejection of claims 44-45, 49-51, 54, and 56 under 35 U.S.C. § 103 over Yefidoff-Freedman et al. (J Med Chem, 2017, 60:5392-5406; provided in IDS 12/07/22), hereinafter Freedman, further in view of Patani, applicant arguments in the reply filed 13 Mar 2026 have been fully considered but they are not persuasive.
Applicant argues on pg. 14 of the remarks that the Office has not met the required lead compound standard under Eisai and argues that the selection of 3g by the Office for further modification appears to be founded on Applicant's disclosure rather than reasons for starting with the specific compound and is based on impermissible hindsight.
In response to applicant’s argument that the examiner’s conclusion of obviousness is based on improper hindsight reasoning, it must be recognized that any judgement on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill before the time of the claimed invention’s effective filing date, and does not include knowledge gleaned only from the applicant’s disclosure, such a reconstruction is proper. See MPEP § 2145(X). The lead compound may be selected based on reasoning which can be drawn from any number of sources and need not necessarily be explicitly found in the prior art of record. In this case, examiner has put forward several reasons why the reference compound would be chosen by the artisan to modify and so arrive at the instantly elected compound (see the Office Action mailed 29 Dec 2025, both the "Response to Applicant Arguments" and "Claim Rejections - 35 USC § 103" sections). See Example 11 of MPEP § 2143(I)(B).
Applicant argues on pg. 15 of the remarks that bioisosterism alone is insufficient to render a compound obvious because it fails to take into account any information specific to the enzyme, target, or the properties of the drug itself and so does not predict whether a particular structural change will improve potency, selectivity, or pharmacokinetics. Yefidoff-Freedman and Patani do not provide concrete guidance to replace the meta-H with a fluoro.
This is not persuasive. A prima facie case for obviousness may be made when two chemical structures are sufficiently close in similarity that there is an expectation that the compounds will have similar properties, including when structural differences include a known bioisosteric replacement. See MPEP § 2144.09(I) and MPEP § 2144.09(III). In this case, Yefidoff-Freedman teaches the core structure of the instantly claimed compound and the reasoning for choosing the compound to modify further. Patani teaches the bioisosteric replacement of hydrogen with fluorine and the motivation to modify using fluorine. The artisan would therefore have modified the compound taught by Yefidoff-Freedman with a fluorine and so arrive at the instantly claimed compound.
In light of the discussion above, the rejection of claims 44-45, 49-51, 54, and 56 under 35 U.S.C. § 103 as obvious over Freedman and Patani is maintained for the reasons of record and restated below.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claim(s) 44-45, 49-51, 54, 56, and 59 is/are rejected under 35 U.S.C. 103 as being unpatentable by WO 2015/038778, hereinafter ‘778, further in view of Patani et al. (Chem Rev, 1996, 96:3147-3176), hereinafter Patani.
Applicant has elected Compound 5-VI (below) as the species in the instant application.
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The instant claims further recite a pharmaceutical composition of the elected species and a pharmaceutically acceptable excipient (instant claim 59).
‘778 teaches compound which are eIF2α kinase activators (Abstract and pg. 1, lines 10-11). ‘778 teaches the following generic formula (V) (pg. 63, line 4 and claim 5):
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This genus includes the elected species when Z1 and Z2 are NH; Z is O; R1 is O-trifluoromethylphenyl; R2 is independently CN and F in the proper positions; m is 2; and n is 0. ‘778 also teaches that for the purpose of oral therapeutic administration, the active compounds of the reference can be incorporated with excipients and used in the form of tablets, troches, or capsules (pg. 128, lines 5-7). ‘778 further teaches a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of the reference specification (reference claim 36). However, ‘778 does not teach the instantly elected compound.
‘778 teaches the following preferred embodiments, structure 1:
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(pg. 114, lines 13-14; pg. 163; and claim 29),
and structure 2:
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(pg. 114, lines 7-9; pg. 163; and claim 29). ‘778 teaches structure 1 to have a 10-fold improved activity in a surrogate eIF2α phosphorylation assay over the DMSO vehicle (pg. 163). These embodiments teach that the core structure of the instantly elected species is in reference formula (V) when Z1 and Z2 are NH; Z is O; and R1 is O-trifluoromethylphenyl. The reference structures also teach the correct positions of the -CN and -F substituents on the phenyl ring of the instantly elected species.
Patani teaches that the substitution of hydrogen by fluorine is one of the more commonly employed monovalent isosteric replacements (pg. 3149, column 1). Patani also teaches that the ability of fluorine to replace hydrogen is an effective method of exploring the affinity of an agent to the target site by virtue of its greater electronegativity while other parameters such as steric size and lipophilicity are maintained (pg. 3150, column 1).
It would be obvious to a person having ordinary skill in the art to replace hydrogen with fluorine, as taught by Patani, on the reference species:
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taught by ‘778, to arrive at the instantly elected compound. It would be obvious to the artisan that ‘778 teaches embodiments of reference formula (V) which include fluorine at the correct position of the instantly elected invention. A person having ordinary skill in the art would be motivated to replace hydrogen with fluorine to explore the affinity of an agent to the target site while maintaining parameters such as steric size and lipophilicity.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 44-45, 49-51, 54, and 56 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yefidoff-Freedman et al. (J Med Chem, 2017, 60:5392-5406; provided in IDS 12/07/22), hereinafter Freedman, further in view of Patani.
Freedman teaches the development of selective eIF2α activators including compound 3g (pg. 5395, Table 1):
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Where R1 is H; R2 is H; R3 is CF3; R4 is H; R5 is CN; R6 is H; and X is C. Freedman teaches that compound 3g has favorable physicochemical properties and has an IC50 against cancer cells of 0.49 µM (pg. 5396, column 1 and Table 1). However, Freedman does not teach the instantly elected compound.
Patani teaches that the substitution of hydrogen by fluorine is one of the more commonly employed monovalent isosteric replacements (pg. 3149, column 1). Patani also teaches that the ability of fluorine to replace hydrogen is an effective method of exploring the affinity of an agent to the target site by virtue of its greater electronegativity while other parameters such as steric size and lipophilicity are maintained (pg. 3150, column 1).
It would be obvious to a person having ordinary skill in the art to replace hydrogen with fluorine, as taught by Patani, on Compound 3g, taught by Freedman, to arrive at the instantly elected compound. A person having ordinary skill in the art would be motivated to replace hydrogen with fluorine to explore the affinity of an agent to the target site while maintaining parameters such as steric size and lipophilicity.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed. 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jonathan D. Mahlum whose telephone number is (703)756-4691. The examiner can normally be reached 8:30 AM - 5:00 PM ET, M-F.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at (571) 272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.D.M./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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