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
1. This application is a 371 of PCT/US2021/030456 05/03/2021; PCT/US2021/030456 has PRO 63/019,865 05/04/2020; PCT/US2021/030456 has PRO 63/019,874 05/04/2020.
Claims 1-37 are pending.
Response to Amendments
2. The rejection of claim 15 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn based upon the amendments.
The rejection of claim(s) 1, 9-10, 17 under 35 U.S.C. 103 as being unpatentable over Chessari US 9,783,538 in view of Anderson is maintained. The rejection of claim(s) 18 under 35 U.S.C. 103 as being unpatentable over Chessari in view of Anderson as applied to claim 1, 9-10, 17 above, and further in view of Aslund US 9,149,539 is also maintained. Applicants’ representative’s arguments submitted on March 6, 2026 have been fully considered but are not persuasive. According to the arguments, the references while teaching all the claimed elements “do not provide any motivation to replace the free base intermediate of Chessari
with an oxalate salt, specifically, with a reasonable expectation of success. None of Chessari or Anderson provides any disclosure that suggests that the replacing free base intermediate of Chessari with an oxalate salt would predictably result in a crystalline and isolable product.” As explained in the rejection, amines, as free bases, present a number of issues on scale-up including difficult on column purification due to high polarity and the tendency to resist crystallization due to oiling out. One solution to the problem of purifying amine intermediates is to make a salt form, the oxalate being an exemplary one as discussed in Anderson. Anderson describes the oxalic acid as “Acids, for crystallizing amines”. The artisan would be motivated to prepare these compounds on the expectation that doing so would result in a purer crystalline form or a precipitated high melting solid that is easier to handle.
Applicant argues that there is no reasonable expectation of success in making a salt of the amine free base with oxalic acid pointing to the fact that crystallization may not always occur. All that is required in a reasonable expectation of success. Aslund prepared oxalates of some amine drugs, US 9,149, 539 “[I]t is believed that an oxalate salt will increase the likelihood of success for manufacturing purposes.” Finally applicant points out that oxalic acid is not suitable for API, however Chessari envisions the use of additional salt forms of intermediates that are not suitable for API on column 23 lines 20 ff.:
[S]alts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms , which may be useful , for example, in the purification or separation of the compounds of the invention, also form part of the invention.
A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989). Nonpreferred embodiments constitute prior art. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). See M.P.E.P. §2123.
The objection to claims 2-8, 11-14, 16, 26-27 is maintained.
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.
3. Claim(s) 1, 9-10, 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chessari US 9,783,538 in view of Anderson, N. G. Practical Process Research and Development, Academic Press, New York, 2000 pages 230-254. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determination of the scope and content of the prior art
(MPEP 2141.01)
Chessari teaches the process of claim 1 steps (i), (ii) and (iii) as the processes of column 89 lines 12-40 (amination), the HCl-dioxane treatment of column 104 lines 27-39 (deprotection), Preparation 19 column 121-23 Examples 43/44 (lactate salt formation), respectively. The process of claim 9-10, is taught as preparation 8 on column 82-83 where benzyl group is removed by hydrogenation.
Anderson explains: “Salt formation may be key for the efficient purification of ionizable compounds. Various salts can display different solubilities and tendencies to crystallize and might possess physicochemical differences that can be exploited for convenient processing on scale.” [Page 238] Table 11.4 lists the oxalate as a good selection for crystallizing amines.
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Ascertainment of the difference between the prior art and the claims
The prior art differs only by the use of the oxalate salt. Chessari uses the free base compounds XX and XVI.
Finding of prima facie obviousness
Rationale and Motivation
(MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to use an oxalate salt in the process of the prior art to produce the instant invention. Amines, as free bases, present a number of issues on scale-up including difficult on column purification due to high polarity and the tendency to resist crystallization due to oiling out. One solution to the problem of purifying amine intermediates is to make a salt form, the oxalate being an exemplary one as discussed in Anderson. This type of experimentation is used throughout Chessari where amine salts of various intermediates are prepared, including the hydrochlorides and lactates. Chessari envisions the use of additional salt forms of intermediates on column 23 lines 20 ff.:
[S]alts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms , which may be useful , for example, in the purification or separation of the compounds of the invention, also form part of the invention.
The experienced organic chemist, who would make Applicants' compounds, would be motivated to prepare these compounds on the expectation that doing so would result in a purer crystalline form or a precipitated high melting solid that is easier to handle.
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 forgoing 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.
4. Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chessari US 9,783,538 in view of Anderson as applied to claim 1, 9-10, 17 above, and further in view of Aslund US 9,149,539. Claim 18 is drawn to using MTBE as a solvent for making an oxalate. Aslund prepared oxalates of some amine drugs, US 9,149, 539 “[I]t is believed that an oxalate salt will increase the likelihood of success for manufacturing purposes.” Aslund explains on column 9 lines 30ff. “In certain embodiments, the methods comprises the steps of dissolving mPEG7-O-naloxol free base in a first solvent comprising ethanol and methyl t-butyl ether (MTBE), adding oxalic acid in methyl t-butyl ether to the dissolved mPEG7-O-naloxol, optionally seeding the mixture, to produce a slurry, and filtering the slurry to yield the naloxol-polyethylene glycol conjugate oxalate salt in Solid form.… In some embodiments, the oxalic acid, dissolved in 5-15 relative volumes of MTBE, preferably 10 relative volumes, is added to the dissolved mPEG7-O-naloxol solution over a period of at least 2 hours to produce a slurry. In some embodiments, the oxalic acid is added over a period of at least 5 hours. In some embodiments, the oxalic acid is added at a temperature of between about 0°C. to about 50° C., between about 15° C. to about 30°C., between about 15° C. to about 25° C”. MTBE is a known good solvent of oxalate amine salt formation.
Objections
5. Claims 2-8, 11-14, 16, 26-27 is objected to for depending from a rejected base claim, but would be allowable in independent format with all the limitations of the base claim and any intervening claim.
Allowable Subject Matter
6. Claim 37 is allowed The following is a statement of reasons for the indication of allowable subject matter: Claim 37 has a novel preparation of compound X by carbonylating the intermediate with CO. This step is not taught or suggested in the prior art. The step in the prior art on column 47-48 is a formylation with DMF, “reacting the compound of formula ( XIII ) with MeLi in THF followed by addition of tBuLi in hexane followed by addition of dimethylformamide.” Col 48 Lines 50ff.
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This is followed by a reduction.
Conclusion
7. 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 DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
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