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 instant application, filed 07/07/2023, is a 371 filing of PCT/EP2022/050354, filed 01/10/2022, and claims foreign priority to DK PA202100027, filed 01/11/2021.
Information Disclosure Statement
The information disclosure statement(s) (IDS) were submitted on 07/07/2023 and 01/09/2026 before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
The claims under examination were submitted 07/07/2023. Claims 1-12 are under examination.
Claim Objection
Claim 3 is objected to because of the following informalities:
In claim 3, the examiner respectfully requests to correct the independent claim on which it is dependent. It is suggested that Applicant amend the claim to depend on claim 1.
Appropriate correction is required.
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.
Claims 1-6, 11, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over EP 525499 (published 02-03- 1993, filed with IDS dated 07/07/2023), in view of CN 109467592 (published 03-15-2019, filed with IDS dated 07/07/2023, Translation Provided) and CN 102093391 (published 06-15-2011, Translation Provided).
EP‘499 invention is directed to novel antibiotic A 40926, which are the amide derivatives of the compound, characterized by having a carboxy, (C1-C4)alkoxycarbonyl, aminocarbonyl, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl or hydroxymethyl substituent on the N-acylaminoglucuronyl moiety and a hydroxy or a polyamine substituent (Abstract, page 1). Regarding A 40926 (denoted Formula I in the current application), EP‘499 teaches about controlled esterification procedures useful for preparing A 40926 ester derivatives and demannosyl A 40926 ester derivatives which are starting materials of the compounds of this invention include esterification reactions wherein the A 40926 substrate is brought together with an excess of the selected alkanol in the presence of concentrated mineral acid at a temperature (line 11-14, page 5). EP‘499 discloses the process of precipitation of the reaction product with diethyl ether or a mixture methanol/diethyl ether (line 18-19, page 16). Also, EP‘499 demonstrates antibiotic A 40926 complex (150 mg; 0.0866 mmole), is dissolved in methanol (30 ml) and the pH adjusted to 2 with concentrated sulfuric acid. The mixture is stirred at room temperature for 26 hours. A precipitate appears when the pH is brought to 6 with 0.15 ml of triethylamine (TEA). After addition of diethyl ether the precipitate is collected, washed thoroughly with diethyl ether and dried (Example 1, line 21-25, page 29).
EP‘499 teaches the amidation reaction is carried out through the intermediate formation of an "activated ester" of the starting compound of formula (II), such "activated ester" is generally formed in situ or, alternatively, it may be isolated and then reacted with the amine of formula (III). The starting material of formula (II) is preferably protected on the N15- amino function to avoid any interference of the activating ester forming reagent with the N15- amino group (line 18-22, page 13). The obtained "activated ester" intermediate is then reacted with a molar excess of the amine derivative of formula (III) in the presence of an organic polar solvent (line 13-15, page 14). EP‘499 discloses that 3,3-dimethylamino-1-propylamine and 0.3 ml of diphenylphosphoroazidate (DPPA) are added. Also, the solid precipitated by adding 170 ml of diethyl ether is collected (Example 3A, line 8-9 and line 11-12, page 30). 3,3-dimethylamino-1-propylamine and 600 mg (about 1.2 mol) of phosphonium hexafluorophosphate are added at room temperature. After stirring at 20-25 ° c for 3 hours, 150 ml of diethyl ether are added. The precipitated solid is collected and then purified by reverse-phase column chromatography (Example 3B, line 22-24, page 30). EP‘499 also teaches the preferred hydrolysis conditions for the production of N-acylaminoglucuronyl aglycones comprise the usage of a mixture of dimethylsulfoxide/concentrated hydrochloric acid (line 45-46, page 4).
EP‘499 discloses that Dalbavancin was synthesized with the similar process with same intermediates as those described in the instant claims and specification of the application and that methyl ester derivatives of A 40926 were precipitated by addition of diethyl ether prior to amidation reaction.
EP‘499 do not teach about the use of tert-butyl methyl ether (TBME) or dimethoxyethane (DME) for the precipitation of the ester derivative as claimed.
CN‘592 teaches the amidation reaction organic solvent is dichloromethane, trichloromethane, acetonitrile, methyl tert-butyl ether, dimethyl sulfoxide, N, N-dimethylformamide, tetrahydrofuran of at least one (CN‘592, Claim 8). Methyl tert-butyl ether and tert-butyl methyl ether (TMBE) are the same chemical compound (CH3)3COCH3 where TMBE is used in the instant claims of the application.
At the time before the effective filing date of the claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to substitute diethyl ether taught by EP‘499 for TMBE taught by CN‘592 to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in synthesizing Dalbavancin with an improved process. It is prima facie obvious to substitute equivalents known in the art for the same purpose. MPEP §2144.06.
CN‘391 teaches a method for preparing antibiotic ceftiofur. CN‘391 teaches the use of dimethoxyethane (DME) as a precipitating agent in one of the steps of synthesis of antibiotic ceftiofur. CN‘391 discloses that much crystallization solvent is added for separating the ceftiofur sodium out in the reaction on the ceftiofur free acid and sodium switching reagent, where the crystallization solvent comprises tetrahydrofuran, dioxane, dimethoxyethane (CN‘391, Claim 8). As recited in claim 1 of CN’391, much crystallization solvent is added for separating the ceftiofur sodium out or concentrating by other method for removing the solvent, filtering and drying to obtain the ceftiofur sodium.
At the time before the effective filling date of the claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to substitute diethyl ether taught by EP‘499 for DME taught by CN‘391 to arrive at the presently claimed invention. DME is widely used as a solvent in the synthesis of pharmaceuticals due to its ability to dissolve wide range of organic compounds. It is especially used as a reagent for creating drug intermediates. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in synthesizing Dalbavancin with an alternative and improved process. It is prima facie obvious to substitute equivalents known in the art for the same purpose. MPEP §2144.06.
Regarding claim 1, EP‘499 teaches that it is possible to transform antibiotic A 40926 complex, its single factors or a mixture of factors in any proportion into the corresponding N-acylaminoglucuronyl aglycone complex AB, N-acylaminoglucuronyl aglycone factor A, N-acylaminoglucuronyl aglycone factor B, and the mannosyl aglycone of A 40926 by controlled acid hydrolysis of one of the sugar moieties of the starting material (line 40-44, page 4). Preferred hydrolysis conditions for the production of N-acylaminoglucuronyl aglycones comprise the usage of a mixture of dimethylsulfoxide/concentrated hydrochloric acid (line 45-46, page 4). EP‘499 teaches that the ester derivatives are prepared by reacting the N15 -protected (in this description the term "N15 " refers to the nitrogen atom of the amino function attached to the carbon atom of A 40926 molecule conventionally designated with the number 15) or N15- free amino A 40926 substrate or its demannosyl derivative (i.e. N-acylaminoglucuronyl aglycone) with an alkanol in an acid medium, or a N15- protected A 40926 derivative or its demannosyl analogue with an alkyl halide (preferably bromide, chloride or iodide), optionally, in the presence of an hydrohalic acid acceptor, in particular, with an excess of the selected alkanol in the presence of concentrated mineral acid (line 2-8, page 5). Controlled esterification procedures useful for preparing A 40926 ester derivatives and demannosyl A 40926 ester derivatives which are starting materials of the compounds of this invention include esterification reactions wherein the A 40926 substrate is brought together with an excess of the selected alkanol in the presence of concentrated mineral acid (line 11-14, page 5). 3,3-dimethylamino-1-propylamine and 0.3 ml of diphenylphosphoroazidate are added (Example 3, line 8-9, page 30).
Regarding claim 2, CN’592 taught adding 170ml methyl tertiary butyl ether to deposit, filtering, below 35 degrees centigrade, drying in vacuum to obtain the intermediate II (Example 1).
Regarding present claims 3-6, EP’499 do not specify the use of anhydrous acid, however, EP’499 teaches the generation of in situ anhydrous acid by the reaction of mineral acid and alkanol stated above and additional examples like antibiotic A 40926 complex (150 mg; 0.0866 mmole), obtained according to EP-A-1 77882, is dissolved in methanol (30 ml) and the pH adjusted to 2 with concentrated sulfuric acid (EP’499, Example 1, line 21-22, page 29). This is in direct correlation with the instant specification of the claims which defines the acid may be added to the alcohol solution in the form of an anhydrous acid. However, not all acids are available as anhydrous acids. In one embodiment, the acid may be generated in situ in the alcohol solution by addition of an acyl halide to the alcohol solution.
Regarding Claims 11 and 12, EP‘499 teaches the excess of the alkali metal borohydride is eliminated by adding a suitable amount of an acid, for example, a (C1-C4)alkylorganic acid, a (C1 -C6 )alkyl sulfonic acid, an aryl sulfonic acid and the like, dissolved in a polar protic solvent such as, for example a (C1 -C4 )alkyl alcohol (line 20-22, page 15). EP’499 further teaches that the preferred lower alkanols are linear and branched (C1-C4)alkyl alcohols, which the most preferred among are n-butanol, ethanol and methanol (line 53-54, page 14). EP’499 discloses the term "alkyl", either alone or in combination with other substituents, includes both straight and branched hydrocarbon groups (line 2-3, page 6). For example more particularly, the term "(C1 -C4)alkyl" represents a straight or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 1 ,1-dimethylethyl, and 2- methylpropyl (line 3-6, page 6).
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over EP 525499 (published 02-03- 1993, filed with IDS dated 07/07/2023), in view of CN 109467592 (published 03-15-2019, filed with IDS dated 07/07/2023, Translation Provided) and CN 102093391 (published 06-15-2011, Translation Provided) as applied to claim 1 above, and in further view of Alkyl Halides”, Michigan State University (MSU), Chemistry, Chapter 12 (online publish date 04-29-2015).
The teachings of EP’499, CN’592, and CN’391 are discussed above. EP’499 teach alkyl halide (preferably bromide, chloride or iodide) (line 6, page 5), and preferably carried out by reaction with benzyl bromide in the presence of an hydrogen halide acceptor (line 27-28, page 5). However, EP’499, CN’592, and CN’391 do not teach about the specific acyl halide substitution reactions as claimed.
Literature from MSU Chemistry on “Alkyl Halides” teach the functional group of alkyl halides is a carbon-halogen bond, the common halogens being fluorine, chlorine, bromine and iodine. With the exception of iodine, these halogens have electronegativities significantly greater than carbon. Consequently, this functional group is polarized so that the carbon is electrophilic and the halogen is nucleophilic. Two characteristics other than electronegativity also have an important influence on the chemical behavior of these compounds - first of these is covalent bond strength and the second factor to be considered is the relative stability of the corresponding halide anions, which is likely the form in which these electronegative atoms will be replaced. This stability may be estimated from the relative acidities of the H-X acids, assuming that the strongest acid releases the most stable conjugate base (halide anion). With the exception of HF (pKa = 3.2), all the hydrohalic acids are very strong, small differences being in the direction HCl < HBr < HI. With use of a common alkyl halide, such as methyl bromide, and a common solvent, ethanol, the rate at which various nucleophiles substitute the methyl carbon can be estimated. Nucleophilicity is thereby related to the relative rate of substitution reactions at the halogen-bearing carbon atom of the reference alkyl halide ( MSU Chemistry, Chapter 12, Alkyl Halides) .
At the time before the effective filling date of the claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to substitute benzyl halide taught by EP’499 for acyl halide or acetyl halide to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to apply the teachings related to alkyl halide chemistry to the method of EP’499 yielding predictable results with a reasonable expectation of success in synthesizing Dalbavancin with an improved reaction speed and efficient process. It is prima facie obvious to substitute equivalents known in the art for the same purpose. MPEP §2144.06.
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Conclusion
No claim is allowed.
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/KOYELI BANERJEE/Examiner, Art Unit 1658
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654