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 .
DETAILED ACTION
2. This Office Action is responsive to Applicant’s Amendment and Remarks, filed January 29, 2026. The amendment, filed January 29, 2026, is entered, wherein claim 98 is amended, claims 1 – 72 are canceled, and claims 73 – 97 and 104 – 107 are withdrawn.
Claims 73 – 107 are pending in this application and claims 98 – 103 are currently examined.
Priority
3. The application is a national stage application of PCT/CN2021/104973, filed July 7, 2021, which claims benefit of foreign priority document CN202010650788.6, filed July 8, 2020.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
“Failure to provide a certified translation may result in no benefit being accorded for the non-English application” is only pertinent when interference arises.
Withdrawn Rejections
4. The rejection of claims 98 – 103 in the previous Office Action, mailed October 29, 2025, under 35 U.S.C. 103 as being unpatentable over Gu et al. in view of Bowles et al., Peltzer et al., Clark, and Brown has been considered and is withdrawn in view of the amended claim 98.
The following are modified / new grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed January 29, 2026, wherein claim 98 is amended. Previously and newly cited references have been used to establish the modified / new grounds of rejection.
Modified / New 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 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:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. 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.
Claims 98 – 103 are rejected under 35 U.S.C. 103 as being unpatentable over Gu et al. (WO2016/173425A1, cited in the previous Office Action mailed June 27, 2025) in view of Bowles et al. (Organic Process Research & Development, 2013, Vol. 18, Issue 1, page 66 – 81, cited in the previous Office Action mailed June 27, 2025), Peltzer et al. (Journal of the American Chemical Society, January 2020, Vol. 142, Issue 6, page 2984 – 2994, cited in the previous Office Action mailed June 27, 2025), Greene (John Wiley & Sons, 2007, Reference included with PTO-892), and Craig (Organic Syntheses, 1962, Vol. 42, Reference included with PTO-892).
a. Regarding claims 98 – 103, Gu et al. teach a compound having Formula (I) (page 3, line 23):
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and a method of synthesizing the compound (Abstract).
However, Gu et al. do not teach the claimed method for preparing compound (I) and step 4 of the claimed method B.
Bowles et al. teach a preparation of compound 1:
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wherein the preparation involves
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wherein 100 g of compound 22 reacts with 62.29 g 2,2-dimethoxypropane, 35.92 g methanesulfonic acid, and 14.81 g oxalic acid in 600 mL MtBE (page 75, Right Col., para. 6; page 76, Left Col., para. 1), THF is used in the reaction to obtain compound 35 and hydrogenation is carried out in the presence of Pd/C under an acidic condition, wherein the acid is hydrochloric acid (page 74, Scheme 15). When obtaining compounds 30a/b and 35, the reaction temperature are 20 – 25 ⁰C and 20 ⁰C, respectively (page 75, Right Col., para. 6; page 78, Left Col., para. 3). The reaction uses 8.06 g of compound 35 (page 78, Left Col., para. 4), 2.8 g of Pd/C (page 78, Right Col., para. 2), 6.49 g of compound 34e (page 78, Left Col., para. 2), and 10.09 g of compound 30a/b (page 77, Right Col., para. 6). Bowles et al. teach another synthetic pathway of compound 4 (page 67, Scheme 1):
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wherein compound 3 is an aryl organometallic reagent that reacts with compound 2 at the amide carbonyl functional group for the coupling of compounds 2 and 3 to yield compound 4. Bowles et al., therefore, teach that the coupling may be performed through the aryl bromide of compound 34e or through the aryl organometallic reagent of compound 3. Bowles et al. further teach (page 70, Scheme 10)
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wherein toluene is used.
Peltzer et al. teach the Grignard reagent, an organomagnesium species RMgX, where R is an organic residue and X is a halogen (usually Cl or Br), that promotes the addition of its organic residue to an electrophilic substrate (page 2984, Left Col., para. 1).
Greene teaches that benzyl is a common protecting group for amine (page 814, N-Benzylamine (R2N-Bn)). Greene teaches different ways to protect amine with benzyl moiety. One of the formations is shown (page 814):
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wherein BnCl is used.
Finally, Craig teaches that piperazine bearing NH functional group reacts with benzyl chloride to form the N-benzylpiperazine (page 2):
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.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the known compound (I) as taught by Gu et al. using the closely related synthetic methodology in view of Bowles et al. to obtain the compound of Formula (I) by Gu et al. because Bowles et al. teach a route for synthesizing Compound 1, which is an analogous product that is different from Formula (I) by a methyl group:
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.
It would have been obvious to modify the starting reactants to one with an extra methyl group to achieve the claimed compound (I) using the same synthetic pathway because Gu et al. teach the target compound (I) containing the additional methyl substituent and Bowles teach a closely related synthetic route for preparing the same core structure differing only by the absence of the methyl group. Thus, one of ordinary skill in the art would have been motivated to select the corresponding starting material with the extra methyl group in order to prepare the known compound (I) of Gu et al. using the closely related synthetic pathway disclosed by Bowles et al. It would have been obvious to employ the synthetic methodology disclosed by Bowles et al., with said modifications, to prepare the known compound (I) as taught by Gu et al. because Bowles et al. teach the same general type of protected intermediate formation, coupling step, and deprotection sequence, thereby yielding predictable results. The additional methyl group would have been expected to be carried through the same sequence of reaction without altering the overall reaction pathway. For the reaction parameters, such as pH and the amount of reagents, it would have been obvious to adjust these parameters and one would have performed routine experimentation to discover the best parameters for optimal reaction characteristics. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to modify the synthesis as taught by Gu et al. into the preparation of Compound 1 in view of Bowles et al. because Gu et al. teach the claimed compound (I) and Bowles et al. teach a synthesis of Compound 1, which is only differed by a methyl group, thereby, the modification of the synthesis based on Bowles et al. will yield predictable results.
It would have been prima face obvious to substitute compound 34e with compound 3 as taught by Bowles et al. because Bowles et al. teach compound 3 as an alternative reagent for performing the same carbon-carbon bond forming reaction at the amide carbonyl functional group. One would have been motivated to substitute compound 34e with compound 3 as taught by Bowles et al. because use of compound 3 avoids the need for a later deprotection step. One of ordinary skill in the art would have had a reasonable expectation of success to substitute compound 34e with compound 3 as taught by Bowles et al. because Bowles et al. explicitly teach that compound 3 reacts at the amide carbonyl to form the corresponding coupled product, thereby demonstrating that compound 3 is suitable for introducing the same aryl residue by the same type of carbon-carbon bond forming reaction. It would have been prima facie obvious to substitute the Li in compound 3 as taught by Bowles et al. with Grignard reagent, RMgX, in view of Peltzer et al. because Bowles et al. teach compound 3 as an aryl organometallic reagent that reacts at the amide carbonyl to form the corresponding coupled product and Peltzer et al. teach that Grignard reagent is an organomagnesium species that adds an organic residue to an electrophilic substrate. One would have been motivated to substitute the Li in compound 3 as taught by Bowles et al. with Grignard reagent, RMgX, in view of Peltzer et al. because Peltzer et al. teach that Grignard reagent will promote the addition of the organic residue to an electrophilic substrate. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success obvious to substitute the Li in compound 3 as taught by Bowles et al. with Grignard reagent, RMgX, in view of Peltzer et al. because Peltzer et al. clearly teach the benefit of Grignard reagent, thereby, the substitution will yield a more efficient reaction.
It would have been prima facie obvious to substitute the methyl group in compound 30a/b:
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as taught by Bowles et al. with a benzyl group in view of Greene because Greene teaches that benzyl group is a common protecting group for amine. One would have been motivated to substitute the methyl group in compound 30a/b:
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as taught by Bowles et al. with a benzyl group in view of Greene because it is known in the art that benzyl is a conventional amine protecting group that protect the amine functional group during the coupling step, thereby reducing interference of the nitrogen during the Grignard reaction and allowing the desired reaction to proceed. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to substitute the methyl group in compound 30a/b as taught by Bowles et al. with a benzyl group in view of Greene because benzyl group is known in the art as a amine protecting group that would reduce interference by the nitrogen during Grignard reaction and allowing the desired addition to proceed.
Furthermore, it would have been prima facie obvious for a person of ordinary skill in the art to replace the N-methyl substituent of compound 22a/b as taught by Bowles et al. with a hydrogen atom to provide a piperazine nitrogen having a NH functional group in view of Greene because Greene teaches that benzyl is a conventional protecting group for amines. Greene further teaches that amine with the NH functional group may be benzylated using benzyl halides, such as benzyl chloride, to form the corresponding N-benzylamine. In addition, Craig teaches that piperazine having NH functional groups reacts with benzyl chloride to form N-benzylpiperazine. Thus, the disclosure of Craig demonstrates a well-known chemical transformation in the art. Therefore, one of ordinary skill in the art would have had a reasonable expectation of success to replace the N-methyl substituent of compound 22a/b as taught by Bowles et al. with a hydrogen atom to provide a piperazine nitrogen having a NH functional group in view of Greene and Craig because Greene teaches that benzyl is a conventional protecting group for amines and Craig teaches the reaction of NH containing piperazine compound with benzyl chloride to form the N-benzylpiperazine, thereby the modification will yield compound 22a/b with the NH functional groups for the protection reaction using benzyl protecting group to obtain compound (III).
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed January 29, 2026, have been fully considered and are found to be not persuasive.
Regarding Gu et al., Applicant argues that the reaction pathway of Gu et al. could not be modified to arrive at the claimed method because Gu et al. disclose a reaction pathway that is completely different from that of the instant claims. However, this argument is not persuasive because the rejection is not based on modifying the exact synthetic route disclosed by Gu et al. Instead, Gu et al. is relied upon for teaching the claimed compound (I) and Bowles et al. is relied upon for teaching a closely related process for preparing Compound 1 that is an analogous product of the claimed compound (I). Therefore, the fact that Gu et al. disclose a different reaction pathway does not overcome the rejection.
Regarding Bowles et al., Applicant argues that the claimed compound (III) differs from compound 30a/b not only by the substitution of H for a methyl group, but also by the presence of a different substituent on the piperazine nitrogen. Applicant further argues that Bowles et al. do not disclose or suggest such modifications and that differences in substrate structure would significantly affect the course and outcome of the reaction. Applicant concludes that the Office Action proposes a new reaction pathway from Bowles et al. that changes the principle of operation of Bowles et al. and does not support an obviousness rejection. However, these arguments are not persuasive. Bowles et al. is relied upon for the teaching of closely related intermediate compound 30a/b containing the same core structure and Greene is relied upon for teaching that benzyl is a conventional protecting group for amines and the NH functional group of the amine may be benzylated using benzyl chloride, such as benzyl chloride. Craig further teaches that piperazine containing a NH functional group reacts with benzyl chloride to form N-benzylpiperazine. Thus, the cited references in combination demonstrate that the modification of the piperazine nitrogen and the subsequent benzyl protection reaction are well known in the art and the combination of Bowles, Greene, and Craig would have suggested modifying the piperazine substituent and performing the benzyl protection reaction to obtain the claimed compound (III). Furthermore, Greene and Craig demonstrate that amines with a NH functional group will undergo benzylation reactions using benzyl halides. Such protection reaction is routine and predictable chemical transformation in the art.
Regarding Peltzer et al., Clark, and Brown, Applicant argues that these references do not provide sufficient motivation to modify the reaction pathway of Bowles et al. to arrive at the claimed method. Applicant further argues that Peltzer et al. is merely a literature review of Grignard reactions and does not provide protocols for developing a new reaction pathway, Clark is an introductory teaching reference that would not be relied upon by a person of ordinary skill in the art, and Brown discloses numerous bioisosteres without identifying a finite number of predictable solutions. Applicant concludes that the combination of Peltzer et al., Clark, and Brown does not provide sufficient guidance or motivation to modify Bowles et al. and that the proposed modification would improperly alter the principle of operation of Bowles et al. However, the argument is not persuasive and moot because the rejection is no longer based on Clark and Brown. Regarding the argument against Peltzer et al., Peltzer et al explicitly teach Grignard reaction and Grignard reagents, which is RMgX that promote addition of organic residue to an electrophilic substrate. Bowles et al. teach the closely related intermediate compound 30a/b containing the same core structure and the synthetic pathway, Greene teaches that benzyl is a conventional protecting group for amines, and Craig teaches that piperazine containing NH functional groups reacts with benzyl chloride to form the N-benzylpiperazine. The rejection is based on the combination of these teachings which render the claimed invention obvious. The cited references teach known and routine chemical reactions, including Grignard addition, amine protection, and benzylation of NH containing piperazine, which provide sufficient guidance and predictability for one of ordinary skill in the art.
Conclusion
No claim is found to be allowable.
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 HOI YAN LEE whose telephone number is 571-270-0265. The examiner can normally be reached Monday - Thursday 7:30 - 17:30.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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