DETAILED ACTION
Preliminary Amendment filed on 05/51/2023 is acknowledged. Claims 1-16 are pending in the application and are considered on merits.
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 .
Claim Rejections - 35 USC § 102
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 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.
Claim(s) 1 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ma et al. (Journal of Liquid Chromatography & Related Technologies, 2014) (Ma).
Regarding claim 1, Ma teaches a method for detecting contents and fingerprints of active ingredients in Compound Kushen Injection (abstract), the method comprising:
performing detection by using a high-performance liquid chromatography, wherein conditions for the high-performance liquid chromatography comprise a C18 column as a chromatographic column (page 209, par 3); and the active ingredients comprise matrine, oxymatrine, macrozamin, sophocarpine, oxysophocarpine and sophoridine, or/and 2,3-dihydroxy-2-[( 4-hydroxyphenyl)methyl]butanedioic acid (piscitic acid) (page 212, Fig. 1, page 213, Fig. 2).
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.
Claim(s) 2-3, 6-12 and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ma et al. (Journal of Liquid Chromatography & Related Technologies, 2014) (Ma).
Regarding claim 2, Waters XSelect CSH™ C18, TechMate C18-ST, Welch Ultimate AQ-C18, and Waters SunFire C18 are well-known commercial C18 column for HPLC. It would have been obvious to one of ordinary skill in the art to select the recited column with a dimension of 5 μm and 4.6mm x 250mm as the C18 column for HPLC, because the selection is based on its suitability for the intended use.
Regarding claim 3, Ma teaches that the method further comprises a mobile phase comprising an organic phase and a gradient elution in the aqueous phase (page 209, par 3). Methanol is commonly used in organic phase and phosphate is commonly used in aqueous phase for HPLC C18 column elution.
Regarding claim 6, it would have been obvious to one of ordinary skill in the art to optimize the column temperature (from 35 to 30 °C) by routine experimentation.
Regarding claim 7, it would have been obvious to one of ordinary skill in the art to optimize the flow rate (from 0.8 to 0.6 ml/min) routine experimentation.
Regarding claim 8, it would have been obvious to one of ordinary skill in the art to optimize the detection wavelength (from 225 to 211 nm) by routine experimentation.
Regarding claim 9, Ma teaches wherein conditions for the high performance liquid chromatography in the method comprise an injection amount of 3-20 μl, preferred 5-15 μl, more preferred 8-12 μl, and most preferably 10 μl (page 211, par 2).
Regarding claim 10, it is a common practice in the art to prepare blank solution similar to the elution condition.
Regarding claim 11, it is a common practice in the art to prepare reference substance solutions separately or semi separately. Ma also teaches similar way of preparing reference substance solutions separately or semi separately (page 210-211)
Regarding claim 12, it is a routine to prepare the test substance solution by accurately weighing the test substance solution, adding a blank solution to scale, shaking, filtering, and taking the subsequent filtrate as the test substance solution. Ma teaches similar way of preparing test substance solution (page 211).
Regarding claim 14, Ma teaches that wherein the method comprises constructing a fingerprint of the Compound Kushen Injection containing matrine, oxymatrine, macrozamin, sophocarpine, oxysophocarpine, and sophoridine (page 213, Fig. 2).
Claim(s) 4-5, 13 and 15-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ma et al. (Journal of Liquid Chromatography & Related Technologies, 2014) (Ma) in view of Agilent (Control pH During Method Development for Better Chromatography, 2015).
Regarding claim 4, 13 and 15, Ma does not explicitly teach that pH value of potassium dihydrogen phosphate is adjusted to 2.9-3.1, more preferably to 3.0, with phosphoric acid.
However, pH of the mobile phase affects the elution of the compounds in C18 HPLC. Agilent teaches that “In reversed-phase liquid chromatography, pH and ionic strength of the aqueous portion of mobile phases are important in developing rugged methods not sensitive to small variations in conditions. With ionic compounds, retention of typical species shows significant changes with pH. It is very important to control pH in reversed phase systems to stabilize retention and selectivity. A pH between 2 and 4 generally provides the most stable conditions for retention versus small changes in pH, and this pH range is recommended for starting method development with most samples, including basic compounds and typical weak acids” (Introduction). The active ingredients as recited in claim 1 are weak basic compounds and weak acids.
Thus, it would have been obvious to one of ordinary skill in the art to adjust the pH value of the mobile phase to 3.0, in order to provides the most stable conditions for retention versus small changes in pH.
Regarding claim 5, as has been discussed regarding claim 4, it would have been obvious to one of ordinary skill in the art to adjust the pH value of the mobile phase to 3.0, in order to provides the most stable conditions for retention versus small changes in pH.
it would also have been obvious to one of ordinary skill in the art to optimize the gradient of the elution by routine experimentation.
Regarding claim 13 and 15, as has been discussed regarding claims 2-12 above, it would have been obvious to one of ordinary skill in the art to adjust the pH value of the mobile phase to 3.0, in order to provides the most stable conditions for retention versus small changes in pH.
It would also have been obvious to one of ordinary skill in the art to optimize the HPLC conditions, such as column, mobile phase, flow rate, column temperature, gradient, reference substance solution, etc. by routine experimentation.
It is a common practice the art:
(4) Injecting samples in the order of the blank solution, reference substance solution, and the test substance solution, and
(5) Detection: injecting samples in the order of the blank solution, the reference substance solution, and the test substance solution to perform detection, and calculating the content using an external standard method.
Ma teaches construct a fingerprint of the Compound Kushen Injection containing matrine, oxymatrine, macrozamin, sophocarpine, oxysophocarpine, and sophoridine (page 213, Fig. 2).
Regarding claim 16, Ma shows that wherein the fingerprint in step (4) has 10 common characteristic peaks (page 213, Fig. 2). The relative intensity of each active ingredient is sample source related.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to XIAOYUN R XU, Ph. D. whose telephone number is (571)270-5560. The examiner can normally be reached M-F 8am-5pm.
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/XIAOYUN R XU, Ph.D./ Primary Examiner, Art Unit 1797