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 .
Priority
The present application, filed October 13, 2023, is a national stage application of PCT/US2022/071736, filed April 15, 2022, and claims priority to PCT/CN2021/087731, filed April 16, 2021.
Status of the Application
Applicant’s preliminary amendment, received June 7, 2024, wherein claims 1, 6, 14, 15, 16, 18-20, 22-25, 27-31, 33, 34, 36, 37-44, and 46 are amended, claims 3-5 and 7-13 are canceled, and new claims 47 and 48 are added, is acknowledged.
Claims 1, 2, 6, and 14-48 are pending and examined on the merits herein.
Information Disclosure Statement
The information disclosure statement filed June 7, 2024 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. Non-patent literature document no. 670 is not published in English and does not include an explanation of relevance. The document has been placed in the application file, but the information referred to therein has not been considered.
Claim Objections
Claim 41 is objected to because of the following informalities: Claim 41 is missing a period from the end of the claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 38 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 38 depends from claim 2 and recites the limitation “forming the third reaction mixture” in line 3 of the claim. There is insufficient antecedent basis for this limitation in the claim. Claim 2 does not recite a “third reaction mixture,” and thus it is unclear what third reaction is further limited by claim 38.
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:
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.
Claims 1, 2, 6, 14-43, and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Xie (Publication no. WO 2021175296 A1; cited in IDS received June 7, 2024).
Xie is a published PCT publication that designates the U.S. in box 81 of the publication. The PCT publication is associated with application PCT/CN2021/079143, filed March 4, 2021, which is an earlier filing date than the earliest priority date of the present application. Therefore, Xie is eligible as prior art under 35 U.S.C. 102(a)(2).
Xie is cited in the IDS received June 7, 2024. However, because Xie was published in a language other than English, and multiple embodiments of Xie are cited in the rejection below, both the original document and an English language machine translation of Xie are included with this Office action and cited in the PTO-892. Citations in the rejection below refer to the original document or English translation, as indicated.
Xie teaches the synthesis of compound 5 presented in Example 17 (original document, p. 31 line 19; synthesis shown below). Compound 5 is the same compound as the compound of Formula (II-a) recited in claim 1.
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Xie teaches that step A of the synthesis of Example 17 requires adding 7-Iodopyrrolo[2,1-F][1,2,4]triazine-4-amine to anhydrous tetrahydrofuran, then adding trimethylchlorosilane at -10 °C. After stirring for 10 minutes, Xie teaches further adding 3M methyl magnesium bromide diethyl ether solution dropwise, stirring the reaction mixture for 20 minutes, adding 1.3M isopropyl magnesium chloride lithium chloride tetrahydrofuran solution, controlling the reaction temperature between -10 °C and 0 °C, and stirring the reaction mixture for about 1 hour. (English translation, document p. 159, [0360], lines 1-7).
Xie teaches that step B requires adding 2,3,5-Tribenzyloxy-D-ribonucleoside-1,4-lactone (compound 1 above) and N,O-dimethylhydroxylamine hydrochloride to anhydrous tetrahydrofuran. Xie teaches after cooling the reaction in an ice bath conditions, step B requires adding a 2M isopropyl magnesium chloride tetrahydrofuran solution, stirring for 3 h, and adding 2M isopropyl magnesium chloride. After 20 minutes, Xie teaches adding solution from Step A to the reaction mixture, and slowly raising the temperature of the reaction to room temperature and monitoring the reaction by TLC until the amount of product no longer increased (English translation, document pp. 156-157, [0361], lines 1-8).
Xie teaches adding the reaction solution to a saturated aqueous solution of ammonium chloride, stirring for 10 minutes, and then extracting with ethyl acetate. Xie teaches washing the organic layer with 1M dilute hydrochloric acid, saturated sodium bicarbonate and sodium chloride solutions, and concentrating the product to obtain an oily substance. Xie teaches that after purifying the product with silica gel column chromatography and slurrying the product with methyl ether, the overall yield of the reaction was 65% (English translation, document p. 160, second full paragraph, lines 1-9).
In this instance, the Step A from Xie describes the first input mixture, wherein the amine protecting agent is trimethylchlorosilane, the first base is methyl magnesium bromide, and the metalating agent is R2MgX2 with R2 as isopropyl and X2 as Cl (isopropyl magnesium chloride). Step B of Xie describes the second input mixture, wherein compound (V) recited in present claim is formed during step B and reacts with the output of Step A to form the compound of Formula (II-a). In this reaction, Ma is MgXa with Xa as Cl, Xb is I, and Ra is
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.
Xie further teaches in their general method, the magnesium-based deprotonating agent is selected from a group that includes both methyl magnesium bromide, the base used in Example 17, and phenyl magnesium chloride (PhMgCl) (English translation, document pp. 34-35, [0082]).
Moreover, Xie teaches that in some embodiments, variable group R8 is amino and PG is silyl (document p. 17, [0032]. Xie teaches as part of their method that the amino protecting group may be removed by deprotecting agents selected from the group consisting of fluorinated reagents, bases, acids, or combinations thereof (English translation, document p. 20, lines 1-2), and when the deprotecting group is an acid, the acid is selected from a group that includes both acetic acid and hydrochloric acid (English translation, document pp. 20-21, [0040]).
This reaction of Example 17 of Xie satisfies all limitations of present claim 1, except the requirement of claim 1 that the first base is PhMgCl.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to substitute the methyl magnesium bromide base used in step A of Example 17 with phenyl magnesium chloride. One of ordinary skill in the art would have been motivated to substitute the methyl magnesium bromide base used in step A of Example 17 with phenyl magnesium chloride because Xie teaches methyl magnesium bromide as the base used in Example 17, and because Xie additionally teaches the base used in their reactions may be selected from a group that includes both methyl magnesium bromide and phenyl magnesium chloride. Accordingly, one of ordinary skill in the art would have contemplated substituting methyl magnesium bromide for phenyl magnesium chloride, because each are suggested by Xie as acceptable magnesium-based deprotonating agents for use in their method.
Furthermore, the synthesis of Example 17, with phenyl magnesium chloride substituted in place of methyl magnesium bromide as the base in step A, would satisfy the limitations of claims 6, 14-17, 20-21, 25-26, and 39, wherein trimethylchlorosilane is interpreted as equivalent to trimethylsilyl chloride recited in claims 6 and 15, and wherein the treatment with dilute HCl is interpreted as satisfying the limitations of claim 25.
Furthermore, the reaction of compound 1 to form intermediate 2a, described in Step B of Example 17 of Xie satisfies the limitations of claim 31, wherein H-Ra is N,O-dimethylhydroxylamine, the third base R3MgX3 with R3 as isopropyl and X3 as Cl (isopropyl magnesium chloride), and the solvent is tetrahydrofuran. These conditions also satisfy the requirements of claims 32-35. Moreover, the ice bath conditions taught for this reaction satisfy the temperature requirements of claims 36 and 37.
Regarding the reactors required by claim 2, the instant specification defines “reactor” as referring to a vessel to which chemicals and reagents are added as an input mixture, and configured so that conversion of the chemicals, reagents, and other dependent variables are performed within the reactor (p. 5, [0009]). Therefore, any vessel in which a chemical reaction is performed is reasonably interpreted herein as a reactor. Accordingly, although Xie does not describe the vessels used when performing the steps of Example 17, one of ordinary skill in the art would have recognized that Xie must have performed these reactions in some reaction vessel, and accordingly, Example 17 would satisfy the requirements of claim 2, wherein the reaction vessels used in Step A and Step B satisfy the requirements of the first and second reactors of claim 2. Moreover, the temperature of -10 °C recited in Step A of Example 17 satisfies the limitations of claims 18 and 19, and the step of raising the temperature to room temperature as recited in Step B of Example 17 satisfies the limitations of claims 22-24, wherein room temperature is interpreted as about 20 °C.
Regarding the method of claim 38, the steps of Example 17, with reactors interpreted as described above, satisfy all limitations of claim 38, except for the first mixture comprising PhMgCl as required by (a). However, for the same reason as described above, one of ordinary skill would have contemplated substituting the methyl magnesium bromide base of Example 17 for PhMgCl.
Regarding the purity of the compound of Formula (II-a) or (II-b) recited in claim 40, Xie does not teach the purity of the product isolated in Example 17. However, as stated above, Xie teaches purification by silica gel column chromatography and a step of slurrying the product in diethyl ether. Xie further teaches the target compound prepared by their method can be prepared with a purity of at least about 90, 95, 96, 97, 98, or at least about 99% (English translation, document p. 86, second paragraph, lines 1-2). Accordingly, one of ordinary skill in the art, following the purification guidance provided by Xie, would have purified the product of Example 17 to a desired purity by known purification methods, including contemplating purities of about 90% to about 100%.
Regarding claim 41, which requires the first reactor and the second are different reactors, because Example 17 states that the output of Step A is added to the reaction mixture of step B, Xie suggests that the reactions of Step A and Step B are performed, or may be performed, in different reaction vessels, which are interpreted herein as different reactors. Regarding these reactors as the same type of reactor or as different types of reactors as recited in claims 42-43, one of ordinary skill in the art would have routinely selected the appropriate reactors (i.e., reaction vessels) for each of Steps A and B of Example 17. In some instances, one of ordinary skill in the art may select the same type of reactor (i.e., the same type of reaction vessel), and in some instances, one of ordinary skill in the art may select different reactors (e.g., different sized reaction vessels), such as to accommodate an increased reaction volume required by step B of the Example 17. Accordingly, claims 41-43 are also obvious over Xie.
Regarding the choice of acid recited in claims 26-30 and 48, Xie teaches contacting the second output mixture with hydrochloric acid, as described above, which satisfies the requirements of claims 26-27. Regarding the organic acids of claims 28-30 and 48, because Xie teaches both hydrochloric acid and acetic acid for removing amine protecting groups, one of ordinary skill in the art would have contemplated substituting hydrochloric acid in Example 17 for acetic acid, because Xie teaches that each of hydrochloric acid and acetic acid may be used for removing the amine protecting groups. Accordingly, one of ordinary skill in the art would have recognized that contacting the output mixture of Step B of Example 17 with an acid would permit complete removal of the TMS protecting group for form the product of Example 17, and such deprotection may be reasonably performed by either hydrochloric acid or acetic acid.
Therefore the invention taken as a whole is prima facie obvious.
Claims 44-46 are rejected under 35 U.S.C. 103 as being unpatentable over Xie (Publication no. WO 2021175296 A1; cited in PTO-892) as applied to claims 1, 2, 6, 14-43, and 48 above, and further in view of von Keutz (von Keutz, T.; et al. Organic Process Research and Development 2020, vol. 24, pp. 2362-2368; cited in PTO-892).
Xie teaches as described in the above rejection under 35 U.S.C. § 103. In addition, Xie teaches their method as providing an intermediate for remdesivir (English translation, document p. 2, Abstract, line 1).
Xie does not teach wherein the first reactor and the second reactor are a single reactor, wherein the single reactor is a continuous flow reactor, a plug flow reactor, a continuous tubular reactor, or a mixed flow reactor, and wherein the first reactor is a first reaction zone in the single reactor and the second reactor is a second reaction zone in the single reactor, as recited in claims 44-46.
von Keutz teaches continuous flow processing has been demonstrated as a key technology in the manufacturing of high volume active pharmaceutical ingredients and is considered for use in production of remdesivir (p. 2362, Abstract, lines 1-3). von Keutz teaches that in particular, the challenging C-glycosylation of a pyrrolotriazinamine via metal−halogen exchange was identified as a transformation with significant potential benefit, as exemplified by calorimetric analysis of each reaction step, and that multiple simplifications of this process were attempted in batch but in general were found to be unfruitful (p. 2362, Abstract, lines 3-6). von Keutz teaches a five-feed process was then transferred to a flow setup, where specific conditions were found to circumvent solid formation and permit stable processing, and optimization of stoichiometries provided an improvement upon batch conditions with a total residence time of <1 min (p. 2362, Abstract, lines 6-8).
More specifically, von Keutz teaches the steps of activating compound 1, including protection of the amine to form compound 1a, deprotonation with PhMgCl to form compound 1b, and preparation of Grignard reagent 1c with iPrMgCl, before reaction with compound 2 to form compound 3, which has the same structure as the product formed in Example 17 of Xie (p. 2363, Scheme 1b)
Regarding the reaction of compounds 1 and 2, von Keutz teaches this C-glycosylation is expected to access substantial benefits by flow processing. von Keutz teaches the excellent
heat- and mass transfer characteristics instilled by continuous processing make this an ideal method of carrying out organometallic chemistry, and the long addition times required for exothermic reactions in batch can be circumvented, avoiding the need to hold unstable intermediates for prolonged time periods. von Keutz teaches as a result, reactions can often be performed at a higher temperature in flow compared with batch, and there can be
significant savings in the time and energy consumed in running these processes, alongside the potential for improved impurity profiles (p. 2362 right column, last paragraph to p. 2363, left column, lines 1-5). von Keutz teaches this synthesis is performed on a continuous flow reactor, using different positions in the reactor to perform different reactions in the synthesis of compound 3 taught by von Keutz, which is the same product of Example 17 of Xie and is the compound of Formula (II-a) recited in claim 1. (p. 2365, Scheme 4). These different positions are interpreted herein as different reaction zones, as required by claim 46.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to perform the synthesis of Example 17 taught by Xie using a continuous flow reactor. One of ordinary skill in the art would have been motivated to perform the synthesis of Example 17 taught by Xie using a continuous flow reactor because von Keutz adapts a synthesis of remdesivir to a flow reactor that includes the steps of activating compound 1 as a Grignard reagent, analogous to step A of Example 17 taught by Xie, before subsequent reaction to form compound 3, with a residence time of just 56 s for the overall three-step. In addition, because von Keutz teaches the general benefits of flow processing, including that the excellent heat- and mass transfer characteristics of continuous processing make it an ideal method of carrying out organometallic chemistry, and the long addition times required for exothermic reactions in batch can be circumvented, avoiding the need to hold unstable intermediates for prolonged time periods, one of ordinary skill in the art would have recognized the benefits of a continuous flow reactor for performing Example 17 of Xie.
In this instance, the rationale “Use of known technique to improve similar methods in the same way” would apply. In view of von Keutz teaching use of a continuous flow reactor for synthesis of the same product of Xie and describing the benefits of flow processing for organometallic chemistry, one of ordinary skill in the art would have contemplated adapting the synthesis of Example 17 of Xie to be performed in a continuous flow reactor.
Therefore the invention taken as a whole is prima facie obvious.
Claims 6 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Xie (Publication no. WO 2021175296 A1; cited in PTO-892) as applied to claims 1, 2, 6, 14-43, and 48 above, and further in view of Basel (Basel, Y.; Hassner, A. Journal of Organic Chemistry 2000, vol. 65, pp. 6368-6380; cited in PTO-892).
Xie teaches as described in the above rejections under 35 U.S.C. § 103. In addition, Xie teaches that group R8, which corresponds to the amine of the presently claimed compound of Formula (IV), may be NHBoc (English translation, document p. 18, [0035]), and that the amino protecting group in the invention of Xie may be tertbutyloxycarbonyl (Boc) (English translation, document p. 78, [0189], second paragraph, lines 3-4).
Xie does not teach the method of claim 1, wherein the amine protecting agent is trifluoroacetic anhydride or di(tert-butyl) decarbonate, as recited in claim 47.
Basel teaches that di-tert-butyl dicarbonate (abbreviated as BOC2O by Basel) is a widely used reagents in organic chemistry to introduce the tert-butoxycarbonyl (BOC) protecting group (p. 6368, Introduction section, lines 1-7). Basel teaches that BOC2O may be used to install the BOC protecting group on amine groups (p. 6369, Scheme 1 and Table 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to substitute the trimethylchlorosilane amine protecting agent of Example 17 of Xie for the di(tert-butyl) decarbonate amine protecting agent. One of ordinary skill in the art would have been motivated to substitute the trimethylchlorosilane amine protecting agent of Example 17 of Xie for the di(tert-butyl) decarbonate amine protecting agent because Xie teaches the amine protecting agent in their invention may be the BOC protecting group, and because Basel teaches the use of di(tert-butyl) decarbonate for introducing a BOC protecting group for protecting an amine. Accordingly, by adhering to the suggested amine protecting agents taught by Xie, one of ordinary skill in the art would have contemplated substitution of trimethylchlorosilane for di(tert-butyl) decarbonate in Example 17 of Xie.
Therefore the invention taken as a whole is prima facie obvious.
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.
Claims 1, 2, 6, and 14-48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 and 13-22 of U.S. Patent No. 11,697,666 (reference patent, hereinafter ‘666; cited in PTO-892) in view of Xie (Publication no. WO 2021175296 A1; cited in PTO-892).
The present application and ‘666 are each assigned to Gilead Sciences, Inc.
Claim 1 of ‘666 claims a method of preparing a compound of Formula (II-a) or Formula (II-b) as shown in the claims, comprising (a) preparing a first input mixture, wherein the first input mixture comprises an amine protecting agent, a first base, a metalating agent, and a compound of Formula (IV) as shown to provide a first output mixture; and (b) preparing a second input mixture comprising the first output mixture and a compound of Formula (V) to provide a second output mixture comprising the compound of Formula (II-a) or Formula (II-b), wherein the compound of Formula (V) has the structure as shown, and wherein Ra is a group shown in the claims, Ma is Li or MgXa; Xa is Cl, Br, or I; Rb is hydrogen or -OH; and Xb is Cl, Br, or I.
The compound of Formula II-a and II-b of ‘666 has the same structure as the presently claimed compounds of Formula II-a and II-b, except the compounds of ‘666 have an additional CH2-OBn substitution at the 4’ position of the ribose group. The compound of Formula (V) of ‘666 has the same structure as the as the presently claimed compound of Formula (V), except the compound of ‘666 has the additional CH2-OBn substitution recited above.
Claim 13 of ‘666 claims the amine protecting agent is trimethylsilyl chloride (TMSCl);
the first base is PhMgCl; the metalating agent is iPrMgCl; and Ma is MgCl.
Neither claim 1 or 13 of ‘666 claim a method to prepare the same compound as present claim 1.
Xie teaches as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to modify the method claimed by ‘666 and substitute the compound (V) recited in claim 1 of ‘666 with a derivative of compound (V) lacking the CH2-OBn substitution, because ‘666 claims a method of preparing the compound of Formula (II-a) or Formula (II-b) with the same steps as the method of present claim 1, and because Xie teaches a method of synthesizing the presently claimed compound of Formula (II-a) or Formula (II-b) by the same method as ‘666, proceeding through the presently claimed compound of Formula (V). Accordingly, in view of the claims of ‘666 and Xie, one of ordinary skill in the art would have recognized that the method claimed by ‘666 may be used for the synthesis of the compound of Formula (II-a) or Formula (II-b) by selecting the appropriate compound of Formula (V), such as the compound of Formula (V) lacking the CH2-OBn substitution taught by Xie.
Therefore, claims 1 and 13 of ‘666, in view of Xie, renders obvious claims 1, 14, and 15.
Claim 2 of ‘666 requires preparing the first input mixture in a first reactor and adding the first output mixture and the compound of Formula (V) to form the second input mixture in a second reactor, and wherein second reactor provides the second output mixture comprising the compound of Formula (II-a) or Formula (II-b). Claim 2 of ‘666, together with Xie, renders obvious present claim 2.
Claim 3 of ’666 claims the steps shown therein, which together with Xie, render obvious present claim 38.
Claim 10 of ‘666 claims the amine protecting agent is selected from a group that includes trifluoroacetic anhydride, di(tert-butyl) dicarbonate, and trimethylsilyl chloride. Claim 10 of ‘666, together with Xie, renders obvious present claims 6 and 47.
Claim 14 of ‘666 claims the first input mixture further comprises a first solvent that is selected from a group that includes tetrahydrofuran (THF). Claim 14 of ‘666, together with Xie, renders obvious present claims 16 and 17.
Claim 15 of ‘666 claims the second input mixture further comprises a second solvent that is selected from a group that includes tetrahydrofuran (THF). Claim 15 of ‘666, together with Xie, renders obvious present claims 20 and 21.
Claim 16 of ‘666 claims a step of further comprising combining the second output mixture and an acid, and claim 17 claims the acid comprises formic acid, acetic acid, citric acid, propanoic acid, butyric acid, or benzoic acid. Claims 16 and 17 of ‘666, together with Xie, render obvious present claims 25-30 and 48.
Claim 21 of ‘666 claims the yield of the compound of Formula (II-a) or Formula (II-b) is from about 60% to about 90%, and claim 22 claims the purity of the compound of Formula (II-a) or Formula (II-b) is from about 90% to about 100%. Claims 21 and 22 of ‘666, together with Xie, render obvious present claims 39-40.
Claim 4 of ‘666 depends from claim 2 and requires the first reactor and the second are different reactors, claim 5 requires the first reactor and the second reactor are the same type of reactor, claim 6 requires the first reactor and the second reactor are different types of reactors, claim 7 requires the first reactor and the second reactor are a single reactor, claim 8 requires the single reactor is a continuous flow reactor, a plug flow reactor, a continuous tubular reactor, or a mixed flow reactor, and claim 9 requires the first reactor is a first reaction zone in the single reactor and the second reactor is a second reaction zone in the single reactor. These claims, together with Xie, render obvious present claims 41-46.
Claim 18 of ‘666 claims the method of claim 1, further comprising preparing the compound of Formula (V), the method comprising forming a third reaction mixture comprising a compound of Formula (III) a shown, an amine of formula H-Ra; and a third base that is R3MgX3 or R3Li; wherein R3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or phenyl; and X3 is Cl, Br, or I; thereby providing the compound of Formula (V). Claim 19 requires the amine has the formula as shown and that the third base is iPrMgCl. Claim 20 requires the third reaction mixture further comprises a third solvent is chosen from a group that includes THF. Claims 18-20 of ‘666, together with Xie, 31-35 and 38.
Regarding the temperatures required by present claims 18-19, 22-24, and 36-37, because Xie discloses each of these steps with temperatures that fall within the claimed range, the choice of these specific temperatures also would have been obvious over the claims of ‘666 and Xie.
Conclusion
No claims are allowed.
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/B.M.B./Examiner, Art Unit 1693
/ANDREA OLSON/Primary Examiner, Art Unit 1693
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