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 .
Priority
This application is a 371 of PCT/EP2021/075830 (09/20/2021)
and claims foreign priority to PORTUGAL 117440 (09/03/2021).
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.
Claims 23-42 are rejected under 35 U.S.C. 103 as being unpatentable over Lourenco et al. (US20190263814) in view of Zhou et al. (CN110551079A, citations to English translation).
Lourenco teaches the synthesis of ethyl 1-(2-chloroethyl)-4-piperidine-4-carboxylate by reacting ethyl isonipecotate (aka ethyl piperidine-4-carboxylate) with 1-bromo-2-chloroethane in triethylamine and acetone at 25C for 24h (Example 1, [0076]). 1-(2-chloroethyl)-4-piperidine-4-carboxylate corresponds to claim 1’s formula (II) when X is C, R is C(O)OEt, m and n are 1; 1-bromo-2-chloroethane corresponds to bifunctional alkylating agent; and triethylamine corresponds to organic base. Lourenco teaches ethyl 1-(2-chloroethyl)piperidine-4-carboxylate is a “key intermediate” in the synthesis of the pharmaceutical umeclidinium bromide ([0004]-[0014]). Lourenco teaches the intermediate synthesis can have low yield ([0006]: 39%; [0076]: 65.6%)
Lourenco does not teach the reaction is solvent-free due to the presence of acetone.
Zhou teaches the solvent-free synthesis of 1-(3-chloropropyl)piperidine by reacting 1,3-bromochloropropane with piperidine (p. 3 Example 1, S1). Zhou’s synthesis has a yield of 78% (calculated from p. 3: 0.63 moles reactants with 0.49 moles product (97g/198) is a yield of 0.49/0.63 = 78%).
One of ordinary skill in the art would have been motivated to further improve the yield of the “key intermediate” identified by Lourenco through optimization of reaction condition including a solvent-free approach as Zhou demonstrated was successful in a structurally similar reaction. One of ordinary skill in the art would have had a reasonable expectation of success in the combination because those of ordinary skill in the art routinely look to the literature for related chemical transformations to identify improvements and in this case one of ordinary skill in the art would have considered Zhou’s teaching as applicable to Lourenco’s synthesis because of similarities in structure and mechanism. One of ordinary skill in the art would have also considered varying the ratios of reactants in order to optimize the yield of the key intermediate; performing the reaction in batch or continuous mode, including varying reaction time and temperature, as is routinely used in pharmaceutical synthesis scale-up. Regarding claim 32 specifying the organic base, Lourenco teaches the same base ([0052]) and one of ordinary skill in the art would consider routine substituting known bases particularly in view of Lourenco’s specific teaching. Regarding claim 40-42 specifying further use of the key intermediate product, one of ordinary skill in the art would have readily considered the intermediate’s use in synthesizing other compounds in the same manner as taught by Lourenco and Zhou.
With each of the claims, the level of skill in the art is very high such that one of ordinary skill in the art would consider routine the combination of elements from the teaching of the art. One of ordinary skill in the art would have recognized that the results of the combination would be predictable due to the well-known nature and optimizations routinely performed in the art. Thus, one of ordinary skill in the art would have arrived at the invention as claimed before the effective filing date with a reasonable expectation of success. “[W]here 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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) (“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.”); MPEP 2144.05. Thus, the claims are rejected as prima facie obvious.
Response to Remarks - 35 USC § 103
Applicant argues “a skilled person would understand that acetone is not an arbitrary component of the reaction … [because] … a polar aprotic solvent enhances the nucleophilicity of the amine, promotes reaction efficiency, facilitates departure of the leaving group, and provides a homogeneous reaction medium … [and also] … The solvent also assists with heat dissipation and process control. Removing the solvent would fundamentally alter the reaction environment of Lourenco.”
This argument is not persuasive because as Applicant points out, one of ordinary skill in the art is very high and would understand aspects of the nature of the reaction including tradeoffs for optimization. Lourenco teaches that the solvent can be selected from a range of solvents and specifically teaches: “As disclosed above, step a) may comprise exchanging the reaction solvent. The exchange solvent may comprise one or more alkanes, such as n-heptane or a mixture of heptanes.” ([0055]). In addition, Lourenco teaches that through optimization of the base, purity and yield was improved over a prior process ([0052]) and also teaches that the base was required to be removed by extraction ([0054]). Thus, one of ordinary skill in the art would have considered among the range of options suggested by Lourenco, the direct use of the two reactants where the ethyl isonipecotate would act as the base, particularly since they were both liquids (i.e. Example 1), thereby simplifying the reaction as the salt by-products would not need to be removed. Such an elimination of a step or element is obvious. MPEP 2144.04.
Applicant argues “A skilled person would expect that, in the absence of solvent, formation of such salts could rapidly increase viscosity or create a heterogeneous reaction mixture, giving rise to mixing difficulties, poorer process control, and an increased risk of side reactions.”
This argument is not persuasive because the evidence of record does not support Applicant’s argument and furthermore, one of ordinary skill in the art would have known how to adapt the reaction accordingly.
Applicant argues “Zhou concerns a different substrate system and a different alkylation reaction. The mere fact that Zhou reports a solvent-free reaction involving piperidine and a haloalkane does not establish that the specific process of Lourenco could likewise be rendered solvent-free with a reasonable expectation of success.”
This argument is not persuasive because it is a related alkylation that successfully utilized the reactants as a solvent that one of ordinary skill in the art would have considered, particularly due to the similarities in the reactants and product to the Lourenco process.
Applicant argues that “Complete removal of that reaction component is a qualitative redesign of the process environment, not selection of an optimum value within conditions taught by Lourenco.”
The argument is not persuasive because as per MPEP 2141: “A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.”KSR, 550 U.S. at 421, 82 USPQ2d at 1397. “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.”Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.”Id. at 418, 82 USPQ2d at 1396. In this case, one of ordinary skill in the art would have considered the possibility of simplifying the reaction by removing the solvent and through routine experimentation would have readily observed success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim23-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10759801 in view of Lourenco et al. (US20190263814 – same family/disclosure as US10759801) in view of Zhou et al. (CN110551079A, citations to English translation). The patent claims a reaction process that is the same as Lorenco’s Example 1 and for the same reasons provided in the 35 USC 103 rejection supra renders the instant claims obvious.
Response to Remarks - Double Patenting
Applicant argues nonobviousness by referencing the reasoning in the 103 rejection. This argument is not persuasive for the same reasons as detailed in the above response.
Conclusion
No claims 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 ROBERT H HAVLIN whose telephone number is (571)272-9066. The examiner can normally be reached 9am - 6pm.
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/ROBERT H HAVLIN/Primary Patent Examiner, Art Unit 1626
