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
Claims 1-11 of P. Manfredi et al., US 18/554,025 (Apr. 8, 2022) are pending and under examination on the merits. Claims 5 and 10 are rejected. Claims 1-4 and 6-9 are free of the art of record and in condition for allowance.
Rejections 35 U.S.C. 112(b)
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.
Pursuant to 35 U.S.C. 112(b), the claim must apprise one of ordinary skill in the art of its scope so as to provide clear warning to others as to what constitutes infringement. MPEP 2173.02(II); Solomon v. Kimberly-Clark Corp., 216 F.3d 1372, 1379, 55 USPQ2d 1279, 1283 (Fed. Cir. 2000). A claim is indefinite when it contains words or phrases whose meaning is unclear. MPEP § 2173.05(e) (citing In re Packard, 751 F.3d 1307, 1314, 110 USPQ2d 1785, 1789 (Fed. Cir. 2014)).
Claim 10 – No Recited Physical Method Steps
Attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness under 35 U.S.C. 112(b). MPEP § 2173.05(q).
Claim 10 is rejected under 35 U.S.C. 112(b) as indefinite because it not clear to one of ordinary skill what physical method steps are associated with or are required to effect the method of claim 10:
10. A method for the chromatography free and scalable preparation of a cyclic sulfamidate starting material selected from benzyl (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide, (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide, and (R,S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide.
because no method steps are recited. Claim 10 is a preamble only. For example, a claim which read: "[a] process for using monoclonal antibodies of claim 4 to isolate and purify human fibroblast interferon" was held to be indefinite because it merely recites a use without any active, positive steps delimiting how this use is actually practiced. MPEP § 2173.05(q) (citing Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986)). Here, Applicant cannot rely on the specification to impart method step limitations to the claim that are not recited in the claim itself. MPEP § 2173.05(q) (citing In re Prater, 415 F.2d 1393, 162 USPQ 541 (CCPA 1969)).
Claim Rejections - 35 USC § 102 (AIA )
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
§ 102(a)(1) Rejection over T Moss et al., 19 Chemistry a European Journal, 3071-3018 (2013) (“Moss”)
Claim 10 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by T Moss et al., 19 Chemistry a European Journal, 3071-3018 (2013) (“Moss”). Moss teaches chromatography free and scalable preparation of (R)-17f:
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Moss at page S33 (citing “General procedure for the synthesis of cyclic sulfamidates” at Moss page 31). Moss preparation of compound (R)-17f meets the claim 10 alternative of “(R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide”. Compound (R)-17f, having a tert-butyloxycarbonyl (Boc) is a “carboxylate” and is the same as compound 1 as depicted in specification Fig. 3, where the protecting group is tert-butyloxycarbonyl (Boc). See, specification at page 12, 2nd to last line (teaching tert-butyloxycarbonyl (Boc) is a suitable N-protecting group (PG). Here, Moss teaches that 3.46 g of (R)-17f was isolated by crystallization and no chromatography was used. The specification does not define the claim 10 term “scalable”. Moss’s reaction clearly reads on the plain meaning of “scalable”. MPEP § 2111.
§ 102(a)(1)/(2) Rejection over S. Scheinmann et al., US 6,143,933 (2000) (“Scheinmann”)
Claim 5 is rejected under 35 U.S.C. 102(a)(1)/(2) as being anticipated by S. Scheinmann et al., US 6,143,933 (2000) (“Scheinmann”).
Claim 5 is clearly claimed using ‘product by process language’:
Claim 5. An isolated compound, or a pharmaceutically acceptable salt thereof, prepared by the method of claim 1. . .
Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. MPEP § 2113(I). If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. MPEP § 2113(I) (citing In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)).
Scheinmann discloses R-(-)methadone, 9b in greater than 99% enantiomeric excess.
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Scheinmann at col. 5, line 55.
Scheinmann’s R-(-)methadone, 9b falls within the genus of claim 5. Although Scheinmann prepares R-(-)methadone, 9b by a process different than instant claim 1, Scheinmann R-(-)methadone in > 99% ee is the same product claimed. Claim 5 is therefore anticipated. MPEP § 2113(I).
Subject Matter Free of the Art of Record
Claims 1-4, 6-9 and 11 are free of the art of record.
Claims 1-4, 6-9 and 11
Claims 1-4 and 6-9 are directed a method for preparing (S)-methadone, (R)-methadone or (R,S)-methadone from optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine. The structure of methadone hydrochloride is depicted below for reference.
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Specification at Fig. 3.
Claims 1-4 and 6-9 do not structurally depict the chemical species involved. Looking to the specification, it is taught that FIG. 4 “is a schematic representation of a procedure for preparation of N-protected cyclic sulfamidate starting material”. Specification at page 7, [0005] (emphasis added). In view of specification1 (particularly Fig. 4 and the working Examples), the claim 1 term optically pure ((S)- or (R)-) or racemic “N-protected 4-methyl-cyclic sulfamidate” is interpreted, consistently with the specification, as the following formulae, where PG is an amino protecting group2. MPEP § 2111.
Broadest Reasonable Interpretation of “optically pure ((S)- or (R)-) or racemic N-protected 4-methylcyclic sulfamidate”
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MPEP § 2111. The structural meaning of the claim term optically pure ((S)- or (R)-) or racemic “N-protected 2-methylaziridine” is clear, in view of the specification, as the following formulae, where the nitrogen is trivalent with a free lone electron pair (i.e., a neutral, non-salt):
Claimed “N-protected 2-methylaziridine”
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Specification at page 7 (referencing Fig. 5) stating “the preparation of N-protected 2-methylaziridine starting material”.
Claims 1-4 and 6-9 require the following steps (per independent claims 1 and 6).
Claims 1 and 6 . . . a ring opening reaction of optically pure ((S)- or (R)-) or racemic N-protected 4-methylcyclic sulfamidate or N-protected 2-methylaziridine with diphenylacetonitrile in the presence of a base to provide ((S)- or (R)-) or racemic N-protected-dinormethadone nitrile with retention of configuration;
a two-step/one-pot deprotection/reductive amination of the N-protected-dinormethadone nitrile to provide (R)-, (S)-, or (R,S)-methadone nitrile; and
a reaction of the (R)-, (S)-, or (R,S)-methadone nitrile with an organomagnesium halide reagent to form an ethyl-imine intermediate,
followed by imine hydrolysis to provide (R)-, (S)-, or (R,S)-methadone.
With reference to specification Fig. 3, and starting from either claimed alternative starting material (sulfamidate or aziridine), the above independent claim 1 and 6 steps are interpreted as requiring the following reactions and formulae. Specification at page 7, [0004] (referencing Fig. 3).
Interpretation of the claim 1 and 6 Reaction Steps and Formulae
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Specification at page 7, [0004] (referencing Fig. 3). Independent claim 11 is more narrowly directed to a method to prepare the intermediate (R)-, (S)-, or (R,S)-methadone nitrile according to the above Scheme.
The Closest Art of Record
The closest art of record is S. Scheinmann et al., US 6,143,933 (2000) (“Scheinmann”).3 Scheinmann teaches methadone synthesis involving the following SN2-nucleophilic attack of 2,2-diphenylacetonitrile anion (PH2C–CN) on the in situ formed intermediate 1,1,2-trimethylaziridin-1-ium 8 under basic conditions to give a mixture of desired 9 and regioisomeric byproduct 10.4
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Scheinmann at page 5, Scheme 2; Id. at col. 2, lines 39-47 (citing C. Barnett et al., 41 Journal of Organic Chemistry, 710-711 (1976) (“Barnett”)); see also Scheinmann working Examples for synthesis of 9a and 9b (R-(–)-methadone) at col. 5, line 21 – col. 6, line 11.
Scheinmann’s working Example for synthesis of 9a, teaches synthesis of R-(-)-2,2-diphenyl-4-dimethylaminopentanenitrile 9a (i.e., (R)-methadone nitrile), through intermediate 8, according to above Scheme 3. Scheinmann at col. 5, lines 21-53.
Scheinmann’s working Example for synthesis of 9b, completes the synthesis of (R)-methadone by treatment of methadone nitrile 9a with ethyl magnesium bromide, followed by HCl. Scheinmann at col. 5, line 54 – col. 6, line 11. This meets the final claim 1 and 6 limitations of:
Claims 1 and 6 . . . a reaction of the (R)-, (S)-, or (R,S)-methadone nitrile with an organomagnesium halide reagent to form an ethyl-imine intermediate,
followed by imine hydrolysis to provide (R)-, (S)-, or (R,S)-methadone.
Differences between Scheinmann and Independent Claims 1, 6 and 11
Scheinmann does not teach the following limitations of claims 1, 6, and 11.
Claims 1, 6 and 11 . . . a ring opening reaction of optically pure ((S)- or (R)-) or racemic N-protected 4-methylcyclic sulfamidate or N-protected 2-methylaziridine with diphenylacetonitrile in the presence of a base to provide ((S)- or (R)-) or racemic N-protected-dinormethadone nitrile with retention of configuration;
a two-step/one-pot deprotection/reductive amination of the N-protected-dinormethadone nitrile to provide (R)-, (S)-, or (R,S)-methadone nitrile . . .
That is, Scheinmann teaches ring opening of the reactive in situ-formed intermediate 1,1,2-trimethylaziridin-1-ium 8, but does not teach ring opening of the claimed “N-protected 2-methylaziridine” or even mention ring opening of the claimed sulfamidate. Thus, Scheinmann’s aziridine cannot form the claimed N-protected-dinormethadone intermediate. And since Scheinmann is directed to a different aziridine intermediate, where the N-dimethylation is initially set, Scheinmann does not require the claimed “two-step/one-pot deprotection/reductive amination of the N-protected-dinormethadone nitrile” to provide the N-dimethylated (R)-, (S)-, or (R,S)-methadone nitrile”.
T Moss et al., 19 Chemistry a European Journal, 3071-3018 (2013) (“Moss”)
Moss teaches base catalyzed addition of pro-nucleophiles 1 to a suitably protected form of aziridine 2 according the following scheme.
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Moss at page 3072, Table 1. Moss further teaches diastereoselective ring opening of chiral cyclic sulfamidates under phase-transfer catalysis according the following scheme.
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Moss at page 3079, Table 5. Thus, Moss differs from the following claim 1, 6, and 11 limitation:
Claims 1, 6 and 11 . . . a ring opening reaction of optically pure ((S)- or (R)-) or racemic N-protected 4-methylcyclic sulfamidate or N-protected 2-methylaziridine with diphenylacetonitrile in the presence of a base to provide ((S)- or (R)-) or racemic N-protected-dinormethadone nitrile with retention of configuration;
in that Moss at least does not teach deprotonated diphenylacetonitrile as the ring opening nucleophile.
Castro et al., 34 Tetrahedron Letters, 4705-4708 (1993) (“Castro”)
Castro teaches the same type of deprotective, reduction amination as that claimed and taught in specification5:
Claims 1, 6 and 11 . . . a two-step/one-pot deprotection/reductive amination of the N-protected-dinormethadone nitrile to provide (R)-, (S)-, or (R,S)-methadone nitrile . . .
but with a different starting material to give a different product, summarized by CAS/CASREACT as follows:
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Castro at page 4706, Scheme 1; see also, CAS/CASREACT Abstract of J. Castro et al., 34 Tetrahedron Letters, 4705-4708 (1993). In sum, Castro teaches the claim 1, 6, and 11 limitation of:
Claims 1, 6 and 11 . . . a two-step/one-pot deprotection/reductive amination of the N-protected-dinormethadone nitrile to provide (R)-, (S)-, or (R,S)-methadone nitrile . . .
but with a different staring material to give a different product.
Claims 1-4 and 6-9 Are not Obvious over the above Cited Art
Claims 1-4 and 6-9 are not obvious over the above cited art because one of ordinary skill is not motivated to combine Scheinmann with both Moss and Castro so as to arrive at the claimed invention with a reasonable expectation of producing (S)-methadone, (R)-methadone or (R,S)-methadone. MPEP § 2143.01; MPEP § 2143.02(I). The mere fact that references can be combined or modified does not render the resultant combination obvious unless the results would have been predictable to one of ordinary skill in the art. MPEP § 2143.01(III). Here, one of ordinary skill must envision and predict: (1) that a ring opening reaction of optically pure ((S)- or (R)-) or racemic N-protected 4-methylcyclic sulfamidate or N-protected 2-methylaziridine with diphenylacetonitrile will provide N-protected-dinormethadone nitrile (where Scheinmann teaches neither the claimed aziridine nor the claimed sulfamidate and Moss does not teach diphenylacetonitrile), and still further envision and predict ; (2) that the so formed N-protected-dinormethadone can thereafter be converted methadone by deprotection/reductive amination, where Castro’s process involves a different staring material to give a different product.
Conclusion
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ALEXANDER R. PAGANO
Examiner
Art Unit 1692
/ALEXANDER R PAGANO/Primary Examiner, Art Unit 1692
1 Fig. 4, compound 1 (and its enantiomer and racemic form) are also the only formulae/species of “N-protected 4-methyl-cyclic sulfamidate” disclosed in the specification. See e.g. specification working Examples. Specification at pages 15-23.
2 In the chemical arts, protecting groups are frequently used when a chemical reaction is to be carried out selectively at one reactive site in a multifunctional compound and other reactive sites must be temporarily blocked, where the protecting group is subsequently selectively removed in high yield. T. Greene, Greene’s Protective Groups in Organic Synthesis, 1-15, 696-771 (4th ed., 2007) (“Greene”) (see, Greene at page 1). Greene teaches that that protection of amino groups is well known and a many protecting groups have been developed and are available for this purpose. Greene at page 696 et seq.
3 G. Mkrtchyan et al., US 2017/0057909 (2017) (“Mkrtchyan”), as cited in the specification, provides teachings similar to Scheinmann and could equally be applied as the closest prior art of record. Specification at page 3, [0009]. Mkrtchyan’s corresponding PCT case (G. Mkrtchyan WO 2017/035224 (2017)) was cited against the instant claims in the associated Written Opinion of the International Searching Authority
4 With respect to Scheinmann’s obtained regiosiomeric mixture of 9 and byproduct 10, the specification teaches
All the synthetic procedures disclosed in the literature (for example WO2013/168000, WO2017/35224, WO2013/77720, and US2015/152081) are based on one key step shown at step "iv" in FIG. 1, namely the attack of 2,2-diphenylacetonitrile anion on the 1,1,2-trimethylaziridin-1-ium generated by an intramolecular SN2-reaction of (generally) 1-dimethylamino-2- chloropropane under basic conditions. The diphenylacetonitrile anion can then attack from two sides of the aziridinium salt resulting in competitive ring-opening reactions with low levels of regiochemical discrimination. In case of an attack at the least substituted C-atom of the aziridinium salt, the desired methadone-nitrile is formed. However, if the attack occurs at the higher order C-atom, the by-product isomethadone-nitrile is formed (See FIG. 2). Under the optimal mixture of base, solvent, and reaction conditions, the outcome of this reaction is at best a 1:3 (isomethadone-nitrile:methadone-nitrile) mixture of the two regioisomeric products.
Specification at page 4 (emphasis added).
5 The specification working Examples teach that the claimed two-step/one-pot deprotection/reductive aminations of benzyl (S)- or (R)-(4-cyano-4,4-diphenylbutan-2-yl)carbamate ((S)-4') to form (S)- or (R)-methadone nitrile ((S)-5 or (R)-5) can be accomplished using either formaldehyde/Pd(OH)2 or formaldehyde/NaBH3CN. Specification at page 20, [0075]; Id. at page 21 (formaldehyde/Pd(OH)2), [0081] (formaldehyde/NaBH3CN).