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 .
Information Disclosure Statement
An information disclosure statement has not been received. If the applicant is aware of any prior art or any other co-pending applications not already of record, he/she is reminded of his/her duty under 37 CFR 1.56 to disclose the same.
Claim Objection
Claim 1 recites the term “acetontile” which seems to be a misspelling of “acetonitrile”.
Claims 1 & 2 uses an acronym RRT. Acronyms should be introduced (e.g. Relative Retention Time (RRT)).
Claim 2 uses an acronym HPLC. Acronyms should be introduced (e.g. Relative Retention Time (high-performance liquid chromatographic).
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.
Claims 1 & 2 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 recites the limitation “dissolving in diluent selected from mixture of acetontile and water” where the term “selected” is unclear as to whether the mixture is required.
Claim 1 recites the limitation “preparing standard preparation from standard stock solution by mixing with said diluent” that is unclear as to what is additionally required by the terms “standard preparation from standard stock”. It seems the compound formula diluted in a mixture of acetonitrile and water is the preparation.
Claims 1 & 2 recite the limitation “preparing Related compound A” and “preparing Related compound B” which are unclear as to what are related compound A & B and how the preparation differs from the previous preparation steps. It seems an additional two samples are prepared for three analysis rounds in the HPLC.
Claim 2 recites the limitation “wherein the mobile phase is a mixture of acetic acid and water; acetonitrile” when the semicolon in front of the term “acetonitrile” is unclear as to whether it is in the mobile phase.
All dependent claims are rejected for their dependence on a rejected base claim.
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.
Claims 1 & 2 are rejected under 35 U.S.C. 103 as being unpatentable over Kwong; HPLC Analysis of Indomethacin and Its Impurities in Capsule and Suppository Formulations. Journal of Pharmaceutical Sciences. 1982;71(7):828-830. doi:10.1002/jps.2600710730: “Kwong”) in view of Swift (US 20230090994: “Swift”).
Claim 1. Kwong discloses a high-performance liquid chromatographic (HPLC) method to analyze pharmaceutical composition of a compound (I) or pharmaceutically acceptable salts [Abstract: Indomethacin and its impurities in suppository and capsule formulations were quantitatively determined by HPLC using a re- versed-phase, octadecyl column and a mobile phase of methanol- water-acetonitrile-acetic acid (55:35:101)] thereof, for administration to a body orifice (indomethacin)[Abstract: The latter two impurities were a result of the interaction of indomethacin and 4-chlorobenzoic acid with glycerin used in the suppository base], comprising:
a) preparing standard stock solution by weighing compound of formula (I) [page 829 second col. And 7¶: suppositories (100 mg of I/dose) were weighed and crushed. Five aliquots equivalent to 50 mg were placed in five 50-ml screw-capped culture tubes and treated as described previously] and dissolving in diluent selected from mixture of acetonitrile and water [Page 829 second col. 4th ¶: of nitrogen at 40 °C, and the residue was reconstituted by addition of 200 μL of acetonitrile-water (7:3, v:v). A 20-μL aliquot was injected onto the LC/MSn system];
b) preparing standard preparation from standard stock solution [page 829 second col. And 7¶: suppositories (100 mg of I/dose) were weighed and crushed. Five aliquots equivalent to 50 mg were placed in five 50-ml screw-capped culture tubes and treated as described previously] by mixing with said diluent [Page 829 second col. 4th ¶: of nitrogen at 40 °C, and the residue was reconstituted by addition of 200 μL of acetonitrile-water (7:3, v:v). A 20-μL aliquot was injected onto the LC/MSn system];
c) preparing Related compound A stock solution by weighing Related compound A and dissolving in said diluent [Page 829 second col. And 7¶: suppositories (100 mg of I/dose) were weighed and crushed. Five aliquots equivalent to 50 mg were placed in five 50-ml screw-capped culture tubes and treated as described previously];
d) preparing Related compound B stock solution by weighing Related compound B and dissolving in said diluent [Page 829 second col. And 7¶: suppositories (100 mg of I/dose) were weighed and crushed. Five aliquots equivalent to 50 mg were placed in five 50-ml screw-capped culture tubes and treated as described previously];
e) analyzing a sample of pharmaceutical composition of a compound (I) or the pharmaceutically acceptable salts thereof, for administration to a body orifice, wherein a column is provided and the mobile phase is acetic acid and acetonitrile [Page 1 second col. HPLC System-An isocratic HPLC'O equipped with a single piston pump", 204 loop injectorI2, fixed wavelength detectorI3 (254 nm), electronic data system printer/pl~tter*~, and a 5-j~ reversed-phase (C-18) column (4.6 mm X 25 cm)15 were used throughout. The mobile phase consisted of methanol-water-acetonitrile-acetic acid (55:35:10:1) and was pumped at 1 ml/min]; and
f) recording a chromatogram (Figure 1) and measuring response to calculate specified impurity and any individual unspecified impurities identified by RRT at about 0.71 and about 1.04 and purity of compound (I) [Table III list of impurities:
4-Chlorobenzoic Acid (II) 0.020 %
5-Methoxy-2-methyl-3-indole-acetic acid (III) 0.070 %
4-Chlorobenzoic acid- a-monoglyceride (IV) 0.390 %
Indomethacin-a-mono- glyceride (V) 0.919 %
Kwong does not explicitly disclose:
The column is a Gemini C6-phenyl, (150 mm x 4.6 mm; 3 μm)
Swift teaches a chromatographic method of assessing purity of a cytisine, Swift further teaches the diluent is acetonitrile [0042] and in the mobile phase [0049] assessing the purity of a cytisine using a column is a Gemini C6-phenyl, (150 mm x 4.6 mm; 3 μm) [Table 13 line 5 5 Phenyl; 150 × 4.6 mm, 3.0 μm].
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to use Swift’s selection of acetonitrile without methanol in the diluent and mobile phase and column selection of a Gemini C6-phenyl, (150 mm x 4.6 mm; 3 μm) as Kwong’s column analysis because using a consistent organic solvent reduces erroneous peak shifts and selection of the best stationary phase provides good resolution of all impurities and comparable peak shape [Swift 0049 & 0090].
Claim 2. Kwong discloses a method to analyze purity of pharmaceutical composition of compound (I) or pharmaceutically acceptable salts [Abstract: Indomethacin and its impurities in suppository and capsule formulations were quantitatively determined by HPLC using a re- versed-phase, octadecyl column and a mobile phase of methanol- water-acetonitrile-acetic acid (55:35:101)] thereof, for administration to a body orifice comprising: analyzing compound (I) using the HPLC conditions (indomethacin)[Abstract: The latter two impurities were a result of the interaction of indomethacin and 4-chlorobenzoic acid with glycerin used in the suppository base], wherein the mobile phase is a mixture of acetic acid and water; acetonitrile [Page 828: second col. First ¶: Methanol, water, and acetonitrile were HPLC quality6, and acetic acid7 and ethers were reagent grade. TLC plates were precoated with silica gel G-25 UV (254) (20 X 20 cm, 0.25 mm). Solvents used for TLC were reagent grade8]; the diluent is a mixture of acetonitrile and water [Page 829 second col. 4th ¶: of nitrogen at 40 °C, and the residue was reconstituted by addition of 200 μL of acetonitrile-water (7:3, v:v). A 20-μL aliquot was injected onto the LC/MS system]; and the column to determine presence of Related compound A and Related compound B [Page 828 second Col. Second ¶: HPLC System-An isocratic HPLC'O equipped with a single piston pump", 204 loop injectorI2, fixed wavelength detectorI3 (254 nm), electronic data system printer/plotter*~, and a 5-j~ reversed-phase (C-18) column (4.6 mm X 25 cm)15 were used throughout. The mobile phase consisted of methanol-water-acetonitrile-acetic acid (55:35:10:1) and was pumped at 1 ml/min], any individual unspecified impurities identified by RRT at about 0.71 and about 1.04 and purity of compound (I), and quantifying Related compound A and Related compound B.
Table III list of impurities by % of compound with impurities between .71 % and 1.04 %:
4-Chlorobenzoic Acid (II) 0.020 %
5-Methoxy-2-methyl-3-indole-acetic acid (III) 0.070 %
4-Chlorobenzoic acid- a-monoglyceride (IV) 0.390 %
Indomethacin-a-mono- glyceride (V) 0.919 %
Kwong does not explicitly disclose:
The dilution medium is acetonitrile.
The column is a Gemini C6-phenyl, (150 mm x 4.6 mm; 3 μm).
Swift teaches a chromatographic method of assessing purity of a cytisine, Swift further teaches the diluent is acetonitrile [0042] and in the mobile phase [0049] assessing the purity of a cytisine using a column is a Gemini C6-phenyl, (150 mm x 4.6 mm; 3 μm) [Table 13 line 5 5 Phenyl; 150 × 4.6 mm, 3.0 μm].
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to use Swift’s selection of acetonitrile without methanol in the diluent and mobile phase and column selection of a Gemini C6-phenyl, (150 mm x 4.6 mm; 3 μm) as Kwong’s column analysis because using a consistent organic solvent reduces erroneous peak shifts and selection of the best stationary phase provides good resolution of all impurities and comparable peak shape [Swift 0049 & 0090].
Conclusion
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/MONICA S YOUNG/Examiner, Art Unit 2855
/PETER J MACCHIAROLO/Supervisory Patent Examiner, Art Unit 2855