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
Response to Amendments
Acknowledgement is made of Applicant's amendment filed 09/29/2025, wherein claims 72-75 are cancelled, new claim 91 is added. It’s noted claim 71 is amended to recite specific base (Et3N) with reaction temperature.
Claim status
Claims 71, 76-83 and 87-91 are pending.
Claims 78-82, 87 and 88 remain withdrawn.
Claims 71, 76-77, 83 and 89-91 are under examination in this office action.
Response to Arguments
Applicant's arguments filed 09/29/2025 have been fully considered, but they are NOT persuasive to overcome the rejection over Xu ’887 (US 8,268,887) in view of Wang under 35 U.S.C.§103.
Applicant argues “Xu and Wang do not teach stereoselectivity, which is a claimed element. Xu and Wang lack any teaching to prevent epimerization of the chiral center to the carbonyl of naproxen. The chiral center of Naproxen is prone to racemization because the chiral center of Naproxen is α to a carbonyl … Xu and Wang lack any teaching of stereoselectivity of the chiral center a to both carbonate oxygens. Yet the reaction conditions of the present claims provide the compound of Formula 1 in both high enantio- and diastereo- selectivity”.
Response: Please note the test for obviousness is not that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. Although ‘887 does not specifically teach the stereoselectivity of the chiral center α to both carbonate oxygens, Xu ‘887 teaches chiral purification to achieve desired diastereomers. It’s noted product compound 5 from step C
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disclosed by instant specification (See [0244]) is the same as taught by Xu ‘887 , while instantly claimed compound of Formula I is obtained from further recrystallization .
The examiner does not dispute possible epimerization/racemization associated with different reaction conditions in Step B and Step C. The examiner agrees optimizing reaction conditions to ensure α carbon is not deprotonated for the retention of enantiopurity. Wang teaches preparation of chiral pregabalin-conjugate F2 ( [0323]-[0334], Examples 3) wherein pregabalin reacts with activated 2-fluorophenyl carbonate as the intermediate, and a variety of methods/process A-K and conditions (See [0293]- [0322]) for preparation of pregabalin-conjugate wherein triethylamine is used as base, added at different temperature range, with acetonitrile /tert-butyl methyl ether as solvent that read on the amended claim 71. Instant claim 71 does not recite any purity limitation of enantio- and diastereo- selectivity, or reaction conditions that are different from prior art. As such, the combined teachings of Xu ‘887 and Wang render instantly claimed process recited in claim 71 prima facie obvious to a skilled artisan.
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As explained in last office action, instantly alleged high purity is the result of combination of specific experiment conditions for specific steps. It’s noted claim 71 is amended to recite specific base (Et3N) in step C with reaction temperature. However, claim 71 does not recite any specific solvent and the amount/ratio of compound 4 to pregabalin, reaction time, etc. that are critical factors for yield and stereoselectivity. Instant specification (See[0244]-[0247]) disclosed the process of preparation of compound of Formula I, wherein Step C is done in acetonitrile and methyl tert-butyl ether( MTBE/MeCN) (See [0247]). Instant specification does not disclose the carbamate final product could be prepared from other solvent, for example, DMF, DCM, water, alcohol, etc. Instant specification does not disclose the amount/ratio of compound 4 to pregabalin in Step C, wherein excessive compound 4 or pregabalin would interfere with the purification/ recrystallization process for the desired final product.
Claims 83 and new claim 91 are directed to preparing of compound 4 in the presence of Cu2O. However, claims 83 and 91 do not recite any solvent, temperature, amount/ratio that are critical factors for yield and stereoselectivity. Wang teaches activated 2-fluorophenyl carbonate ( intermediate formula III ) is prepared from activating a carboxylic acid with 1-chloroethyl (2-fluorophenyl) carbonate D2-1 in presence of Cu2O at elevated temperature (e. g. 115- 120°C) in a solvent ( e.g. heptane, toluene, etc.) that read on limitation recited in instant claims.
As elaborated in previous office actions, activating carboxylic acid for carbamate/conjugate formation are well-known common reactions in organic synthesis and pharmaceutical industry as taught by Xu ’887 and Wang, and evidenced by Ghosh (2015) on the record. Exploration of different activating agent/intermediate and preparation thereof (e.g. temperature, base, ratio of reagents, catalyst, etc.) are routine experimentation and optimization in the process of synthesizing organic compounds.
Purification /crystallization for pure product is also common practice within the general knowledge of skilled artisan in the art. As stated in MPEP 2144.05, " It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.".
As stated in MPEP 716.02(d): “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of non-obviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”. Applicant’s alleged unexpected high enantio- and diastereoselectivity does not commensurate with the scope of instant claimed process in absence of limitations of specific combination of experimental conditions(e.g. solvent, amount/ratio of reactants, etc.). Thus, 35 USC § 103 rejection over Xu ’887 in view of Wang is maintained and made Final.
Priority
This instant application 17/055,513 filed on 11/13/2020 is a U.S. National Stage application of PCT/CN2019/086809 filed on 05/14/2019, which claims foreign priority to PCT/CN2018/086755 filed on 05/14/2018.
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 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:
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 non-obviousness.
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 71, 76-77, 83 and 89-91 are rejected under 35 U.S.C. 103 as unpatentable over Xu et al. (US 8,268,887, Xu ’887) in view of Wang et al (US 2014/0243544, Applicant’s IDS dated 05/05/2023 under “US Patent Document”, Cite No. 001) (maintained).
Claim interpretation: Claims 71, 76-77 are directed to carbamate/conjugate formation between activated carboxylic acid intermediate and pregabalin. Claims 83 and 91 are directed to preparation of activated carboxylic acid intermediate( i. e., substituted phenyl carbonate ).
Regarding the process recited in claim 71, Xu ’887 teaches method for synthesis of GABA-drug conjugate through different route utilizing different activated carboxylic acid intermediate and various coupling conditions ( Schemes 1- 4, Examples 1-3).
Xu ’887 explicitly teaches preparation of pregabalin-naproxen conjugates 5b having structure of instant Formula I and its stereoisomers through reacting pregabalin with N-hydroxy succinimide ester intermediate compound 4 followed by chiral purification to achieve desired diastereomers (Example 1, Col. 44- Col. 46; claims 11-13).
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Xu ’887 also teaches that drugs containing carboxylic acid ( e.g. naproxen) can be activated by chloroethyl p-nitrophenyl carbonate in presence of a base to form activated p-nitrophenyl carbonate intermediate compound 7 which further reacts with amino group of GABA analogs in presence of a base to form GABA-drug conjugate of formula (8) ( Scheme 3, Col. 18; Example 2, Col. 46).
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Xu ’887 further teaches synthesis of GABA analog-drug conjugate ( e. g. gabapentin- GHB conjugate) using activated p-nitrophenyl carbonate intermediate which is prepared from activating carboxylic acid with chloroethyl p-nitrophenyl carbonate, in presence of base following Scheme 3 that read on amended claim 71( Example 2, Col. 46).
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Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05. It would have been obvious to one of the ordinary skill in the art to further explore different reaction conditions, such as different activated carboxylic acid intermediate, base , temperature range etc. based on the teachings of Xu ’887 and general knowledge of carbamate/conjugate formation through routine experimentation and optimization and arrive the desired limitation recited in instant claims 71.
Regarding recrystallization limitation recited in claims 76 and 77, Xu ’887 teaches recrystallization of compound 4 (line 66, Col. 43). It is routine practice that most active pharmaceutical compounds and salts thereof are purified and isolated by crystallization from appropriate solvent/conditions. It would have been obvious to one of the ordinary skill in the art to further explore different recrystallization conditions, such as different solvent or combination of solvent, temperature etc. based on the teachings of Xu ’887 and general knowledge of crystallization through routine experimentation and optimization and arrive the desired limitation recited in instant claims 76-77.
Xu ’887 does not explicitly teaches activated 2-fluorophenyl carbonate intermediate compound 4 recited in instant claims 71, 83 and 91. However, it is common practice for the skilled artisan in the pharmaceutical industry to explore different activating agent of carboxylic acid group and other coupling reaction conditions such as temperature, base, etc. for carbamate/conjugate formation. As illustrated from structure/scheme, p-nitrophenyl carbonate intermediate is structurally and functionally equivalent to 2-fluorophenyl carbonate intermediate with regard to formation of carbamate/conjugate. Furthermore, all activated intermediate including N-hydroxy succinimide ester compound 4 and p-nitrophenyl carbonate compound 7 taught by Xu ’887, and 2-fluorophenyl carbonate compound 4 of instant application are activated carboxylic acid intermediate that react with amino group of GABA analog to form GABA-drug conjugate, therefore construed as equivalent in the preparation of GABA-conjugate.
With respect to conjugate preparation process using activated 2-fluorophenyl carbonate intermediate, Wang et al. teaches preparation of carbamate/conjugate formula I by reacting amine-containing drugs with substituted phenyl carbonate intermediate ( formula III) in presence of base, wherein formula III is prepared from activating carboxylic acid with chloroethyl phenyl carbonate formula II in presence of metal oxide ([0058]-[0069], [0147], [0222], [0253]-0254], [0323]-[0334], Examples 2 and 3, claims 1-15 and 19-20).
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Wang et al. explicitly teaches preparation of pregabalin-conjugate F1 and F2 ( [0323]-[0334], Examples 2 and 3) wherein pregabalin reacts with activated 2-fluorophenyl carbonate as the intermediate formula III that read on limitation recited in claim 71 except that acid is not naproxen as recited in instant claim 71.
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Wang et al. teaches different methods/process and conditions for preparation of pregabalin-conjugate wherein triethylamine is used as base, added at different temperature range that read on the amended claim 71 ( See [0323]-[0334], Examples 2 and 3, claims 13-15). Wang et al. teaches compounds may be isolated and purified by known standard procedures such as recrystallization, column chromatography or HPLC( [0211]) and teaches isopropanol as solvent ([0096]).
Wang et al. also teaches activated 2-fluorophenyl carbonate ( intermediate formula III ) is prepared from activating a carboxylic acid with 1-chloroethyl (2-fluorophenyl) carbonate D2-1 in presence of Cu2O at elevated temperature (e. g. 115- 120 °C) in a solvent ( e.g. heptane, toluene, etc.) that read on limitation recited in instant claims 83 and 91([0079]-[0081],[0084], [0222], [0253]-0255], claims 4-7, 11-12).
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It would have been obvious to one of ordinary skill in the art before the time of the invention to combine the preparation of pregabalin-naproxen conjugates taught by Xu ’887 with the preparation of pregabalin-drug conjugates using activated intermediate 2-fluorophenyl carbonate taught by Wang et al., together with general knowledge of carbamate/conjugate formation to arrive at the instant invention with reasonable expectation of success, because at the time the invention was made, it was taught by Xu ’887 that pregabalin-naproxen conjugates can be made through different activating intermediate such as N-hydroxy succinimide ester and 4-nitrophenyl carbonate intermediate. It was also known that pregabalin-drug conjugates can be prepared using activated 2-fluorophenyl carbonate intermediate in presence of base (i .e. triethylamine), as taught by Wang et al. The skilled artisan would be motivated to combine the teaching of Xu ’887 and Wang et al. because both teachings are directed to preparation of pregabalin-drug conjugates through reaction of pregabalin with activated carboxylic acid intermediate.
As stated in MPEP 2144.05, " It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.". In instant case, activated intermediate N-hydroxy succinimide ester, 4-nitrophenyl carbonate taught by Xu et al and 2-fluorophenyl carbonate taught by Wang et al. are construed as equivalents with regard to activating carboxylic acid and reacting with amino group of pregabalin in the process of pregabalin conjugate formation.
The combined teachings of Xu ’887 and Wang et al., together with further experimentation/ optimization based on the general knowledge of carbamate/conjugate formation would provide an alternative process of preparing pregabalin-naproxen conjugates. One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole is 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 claims are allowed.
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 LIYUAN MOU whose telephone number is (571)270-1791. The examiner can normally be reached Mon-Fri 9:00-5:30.
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/L.M./Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628