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
This Office action is responsive to Applicant's preliminary amendment filed 18 May, 2024. As filed, claims 1-18 are pending.
Priority
This application, filed 03/18/2024 is a National Stage entry of PCT/IL2022/051083 , International Filing Date: 10/12/2022 18692847 Claims Priority from Provisional Application 63255539 , filed 10/14/2021.
Information Disclosure StatementApplicants' information disclosure statements (IDS) have been considered except where lined through. Please refer to Applicants' copy of the 1449 submitted herewith.
Claim Objections
Claims 2-4 are objected to because of the following informalities: said claims lack end period.
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.
Claims 1-18 are 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.
1.Claim 1 is drawn to a method of preparation of 1-( 4-(benzyloxy)-3-
(hydroxymethyl)phenyl)-2-(tert-butylamino)ethanol by reaction substrate A with a catalyst represented by the structure of formula Ia or Ia' under hydrogen
pressure, wherein in formula Ia and Ia’, variable M is defined a transition metal Ru(I) or Mn(II); however, claim 1 also recites “if M is Mn(I)” and “if M is Ru(II)” rendering said claim and its dependents indefinite because in not clear if variable M is M is Ru(II) or Ru(I) or Mn(II) instead of Mn(I).
2.Claim 2 recites the catalyst is represented by the
structure of formula lb or lb' without provide a definition for variables of said formula, rendering said claim and its depended claims 15, 17 indefinite.
Similarly, claim 3 recites the catalyst is represented by the
structure of formula lc or lc' without provide a definition for variables of said formula, rendering said claim and its depended claims 16, 18 indefinite.
Claim 4 recites the catalyst is represented by the structure of formula ld, Id’, Ie, or le' without provide a definition for variables of said formula, rendering said claim indefinite.
Claim 5 recites the catalyst is represented by the
structure of formula If, If’, Ig, Ig’ without provide a definition for variables of said formula, rendering said claim indefinite.
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 of this title, 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 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:
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 1-4, 6-16 are rejected under 35 U.S.C. 103 as being unpatentable over Vanoost et al. Tetrahedron Letters (2020), 61(28) (cited by Applicants in IDS) and further in view of Das et al, J. Am. Chem. Soc. 2019, 141, 12962−12966 (cited in PTO-892 attached herewith).
Instant claims are drawn to a process for the preparation of 1-( 4-(benzyloxy)-3-
(hydroxymethyl)phenyl)-2-(tert-butylamino)ethanol
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by reacting (E)-methyl 2-(benzyloxy)-5-(2-(tertbutylimino) acetyl)benzoate
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with a catalyst represented by the structure of formula Ia or Ia' under hydrogen pressure (claims 1-13, 15-18); and a process for the preparation of Salbutamol, wherein the process comprises reduction of Salbutamol intermediate 1-(4-(benzyloxy)-3- (hydroxymethyl)phenyl)-2-(tert-butylamino)ethanol (claim 14).
The article by Vanoost teaches method for manufacturing racemic salbutamol hemisulfate (which corresponds to product of insta claim 14) by reduction of ketone 16 into the corresponding benzyl 16 using sodium borohydride followed by cleavage of the N-benzyl group under Red/Al catalyzed conditions (claim 1). Next, O-benzylsalbutamol 18 was smoothly hydrogenated using 5 wt% of 10% Pd / C in ethanol under 2 bar of hydrogen ( which corresponds to the process of claim 14). Shown below is the reaction disclosed by Vanoost as shown on Scheme 5 page 4:
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The two-step strategy of reduction of imino ketone 16 (first NaBH4 / MeOH then Red-Al toluene) was applied to our substrate and amino alcohol 17 crystallized
spontaneously upon formation in methanol Addition of 4 equivalents of Red-Al to a suspension of compound 17 in toluene at 60 C resulted in an efficient reduction
to O-benzyl salbutamol 18 (complete conversion; 98.8% selectivity
by HPLC). Excess Red-Al was quenched by the careful addition of acetone followed by an aqueous solution of Rochelle salt. The phase split proceeded uneventfully and provided compound 18 in 90% yield after toluene concentration and reslurry from ethyl
acetate. Finally, O-benzylsalbutamol 18 was smoothly hydrogenated using 5 wt% of 10% Pd / C in ethanol under 2 bar of hydrogen. In process control by HPLC showed complete conversion and 85% area of salbutamol after 2 h under these conditions. Catalyst filtration yielded a ready to use ethanol solution of salbutamol
freebase. Addition of concentrated sulfuric acid gave the corresponding hemi sulfate which crystallized smoothly. Salbutamol hemi sulfate 1 was isolated in 77% yield and 98.7% purity by HPLC.
Regarding instant claims 7-13, the article by Vanoost teach the synthesis of compound 18 which corresponds to claimed formula (B) by reaction of compound 16 which corresponds to claimed formula (B) (40.0 g, 0.113 mol, 1.0 equiv.) was suspended in 200 mL of MeOH in a 500 mL round bottom flask under nitrogen. Sodium borohydride (4.28 g, 0.113 mol, 1.0 equiv.) was introduced portion wise over 20 min keeping the internal temperature below 35 °C. The reaction was exothermic and gas release was observed (caution, H2). The resulting orange solution turned to a yellow suspension upon stirring for 2 hours at room temperature. The suspension was further cooled to 5 °C and stirred for 1 hour. The suspension was filtered and washed twice with 40 mL of MeOH. Next, the mixture of 17 was heated to 60 °C and Red-Al (65% in toluene) (90.8 g, 0.292 mol, 4 equiv.) was added dropwise over 1 h 30 at this temperature. The reaction was slightly exothermic, effervescence was observed, and the initial suspension became a yellow solution (supplemental experimental).
It is noted that generally, differences in temperature, pressure, concentration parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such parameter is critical. The skilled artisan would have been motivated to modify the reaction conditions as part of routine optimization in attempting to obtain the highest product yield. In other words, it is inherent that a person of ordinary skill in art would be motivated to optimize a reaction by varying experimental parameters in search of optimal conditions. See MPEP 2144.05 II.A:
“[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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”)
The method of the present application differs from the method described in the article by Vanoost in that prior art teach reduction reaction of ketone 16 mediated by sodium borohydride and Red-Al for the formation of the same compound instead of catalyst represented by the structure of formula Ia or Ia' in the presence of a base.
It is noted that Mn- bases catalyst for reduction reaction in the presence of base as alternative catalyst for the reduction is known in the prior art as discussed in the article by Das.
The article by Das teaches catalytic hydrogenation of polar bonds, such carbonyl groups, offers a green route for the synthesis of useful organic building blocks such as alcohols and amines. Regarding instant claims 1-4, 6, 15, 16 Das teaches studies of reaction conditions for reduction of various substrates under 40 bar of H2 at 110 °C for 24 h to show that the stable and efficient catalytic system comprising a base such as BuOK and Mn complexes 1-4 (Scheme 2 and Tables 1 and 2 on page 12963
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has higher catalytic activity and selectivity under mild conditions in excellent yields. The Mn complex 1 corresponds to claimed formula Ia, Ib in which M is Mn, L1 is PRaRb, Ra and Rb are each butyl; L2, L3 are each CO, Z is zero, R is CH2L4, L4 is PRaRb, Ra and Rb are each butyl ( see entire document).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to combine the teachings of Vanoost concerning preparation of 1-( 4-(benzyloxy)-3-(hydroxymethyl)phenyl)-2-(tert-butylamino)ethanol by hydrogenation with the teachings of Das regarding utilizing Mn complexes 1-4 as catalyst because the prior art teach specifically teach that catalyst system comprising Mn complexes 1-4 and base is stable and efficient for the reduction of a broad scope of substrate under milder and more efficient conditions.
The rationale to support a conclusion that the claim would have been obvious is that teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. KSR, 550 U.S. at_, 82 USPQ2d at 1395.
Therefore, the claimed invention as a whole is prima facie obvious over the combined teachings of the prior art.
Conclusion
Claims 1-18 are rejected.
Telephone Inquiry
Any inquiry concerning this communication or earlier communications from the
examiner should be directed to:
Ana Muresan
(571) 270-7587 (phone)
(571)270-8587 (fax)
Ana.Muresan@uspto.gov
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/ANA Z MURESAN/Primary Examiner, Art Unit 1692
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