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 .
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.
Priority
US National Stage of PCT
Acknowledgment is made that this application is the US national phase of international application PCT/US2022/036616 filed 07/11/2022.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 03/14/2024 & 05/06/2025 is/are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement(s) is/are being considered by the Examiner.
Claim Objections
Claim(s) 1-19 is/are objected to because of the following informalities:
As to independent claim 1,
“into into” is redundant, the Examiner suggesting “into
As to claim 8,
the Examiner objects to the unnecessary and confusing change in nomenclature to “nitrosamine analytes” without first introducing “analyte” (in independent claim 1, from which claim 8 depends, “analyte” is not part of the phrasing, whereas independent claim 13 utilizes said phrasing).
As to independent claim 13,
where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, see MPEP § 608.01(m) & 37 CFR 1.75(i); the Examiner objects to the formatting of the claim lacking the appropriate indentation for the first limitation. The Examiner further objects to skipping the first limitation when labeling with “a)” and “b)” (i.e., the first limitation should be “a)” and then “b)” and “c)” should follow).
As to claim 17,
“chromatorgraphy” comprises a typo, the Examiner suggesting “chromato[[r]]graphy”.
Dependent claim(s) of objected to claim(s) is/are likewise objected to.
Appropriate correction is required.
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.
Claim(s) 1, 7-8, and 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Applicant cited Wichitnithad et al (NPL Development of a Sensitive Headspace Gas Chromatography—Mass Spectrometry Method for the Simultaneous Determination of Nitrosamines in Losartan Active Pharmaceutical Ingredients; hereafter “Wichitnithad”) in view of newly cited Chen* et al (CN 112083088 A; hereafter “Chen”) with newly cited Cannon (US 4501608 A; hereafter “Cannon”).
*machine translation provided by Examiner with foreign document and utilized for English citations
Regarding independent claim 1,
Wichitnithad teaches a method for analyzing nitrosamines in a pharmaceutical sample (Title “Development of a Sensitive Headspace Gas Chromatography−Mass Spectrometry Method for the Simultaneous Determination of Nitrosamines in Losartan Active Pharmaceutical Ingredients”) comprising:
a) heating a pharmaceutical sample (drug products; e.g., sartans) suspected of containing one or more nitrosamines (Introduction “Angiotensin II receptor antagonists (sartans) such as valsartan, losartan, irbesartan, and olmesartan” and “contamination by the nitrosamine N-nitrosodimethylamine (NDMA). Subsequently, other nitrosamine impurities, including N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (DIPNA), and N-nitrosoethylisopropylamine (EIPNA), have been found”; page 11057 section 4 “method to analyze nitrosamine contamination in other sartan APIs and drug products”; page 11055 right column section 3.2 “temperature programing” and “oven sample was heated”);
b) displacing the nitrosamines from the pharmaceutical sample (drug products) into a gaseous phase (page 11055 section 3.2 “carrier gas”; page 11056 section 3.5 “nitrosamines were then vaporized into the vial headspace and directly injected into the column”); and
c) analyzing the nitrosamines in the gaseous phase (page 11049 left column first paragraph “headspace gas chromatography−mass spectrometry (HS-GC−MS) method for the quantitative analysis”; page 11049 right column first full paragraph “HSGC−MS method for the simultaneous determination of nitrosamines").
Wichitnithad does not teach wherein in situ nitrosamine formation is reduced or eliminated by heating the pharmaceutical sample in the presence of one or more nitrosating inhibitors.
However:
Chen teaches that a pharmaceutical sample can generate nitrosamines in a sample preparation process and therefore negatively affect the accuracy of a GC-MS detection (Title “GC-MS Coupling Detection Method Of N-nitrosodimethylamine In Metformin Hydrochloride Sustained-release Tablet”; Abstract “can effectively prevent the residual raw material dimethylamine in the sample from generating NDMA by chemical reaction of active oxide in the sample preparation process, improving the accuracy of the detection”; paragraph before middle of page 4 “effectively prevent the residual raw material dimethylamine in the sample from generating NDMA by chemical reaction of active oxide in the sample and test process, improving the accuracy of detection”).
The Examiner takes Official Notice that it is well-known that nitrosamine formation is accelerated by temperature increases (in particular, exponentially; see Arrhenius equation).
Furthermore, and as factually supporting evidence of the temperature dependence on nitrosamine formation, Cannon teaches wherein in situ nitrosamine formation is reduced or eliminated by the presence of one or more nitrosating inhibitors even when a sample is heated (Title “Nitrosamine Inhibition”; background col. 1, ll. 5-20 “Circumstances which favor nitrosamine formation, notably elevated temperatures, present a special problem”; col. 5, ll.32-33 “evaluated for the increase in nitrosamine content on heating”).
In view of the above, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include a nitrosating inhibitor to prevent further generation of a nitrosamine when performing analysis thereof—as supported by Chen—with Wichitnithad’s analysis of nitrosamines, thereby improving the accuracy of the detection by decreasing noise from unwanted further formations during the method. It further would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to introduce the nitrosating inhibitor such that said inhibitor was present during heating—as factually supported by Cannon’s teaching that elevated temperatures favor nitrosamine formation—with Wichitnithad’s analysis method involving heating thereby commonsensically avoiding the most detrimentally significant formations of nitrosamine during said heating (Examiner again noting the well-known Arrhenius equation).
Regarding claim 7, which depends on claim 1,
Wichitnithad teaches wherein the temperature of the pharmaceutical sample (drug products) is heated to about 60°C to about 200°C (page 111055 section 3.2 “The oven sample was heated up to 150 °C”; page 11056 section 3.5 “sample was incubated in the headspace oven at 150 °C”. It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art, see MPEP § 2144.05 and In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 8, which depends on claim 1,
Wichitnithad teaches wherein the nitrosamine analytes being analyzed are semi-volatile (Title; Abstract “N-Nitrosodimethylamine (NDMA, m/z 74), N-nitrosodiethylamine (NDEA, m/z 102), N-nitrosoethylisopropylamine (EIPNA, m/z 116), and N-nitrosodiisopropylamine (DIPNA, m/z 130)”; page 11049 last paragraph “HS-GC−MS was developed and optimized for volatile nitrosamine impurity analysis”).
Regarding claim 10, which depends on claim 1,
Wichitnithad teaches wherein the nitrosamines in the gaseous phase are separated and analyzed using gas chromatography coupled with a GC detector selected from the group consisting of mass spectrometer, nitrogen-phosphorus detector, thermal energy analyzer, nitrogen chemiluminescence detector or flame ionization detector (Title “Development of a Sensitive Headspace Gas Chromatography−Mass Spectrometry Method for the Simultaneous Determination of Nitrosamines in Losartan Active Pharmaceutical Ingredients”).
Claim 2, 13, and 15-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Applicant cited Wichitnithad in view of newly cited Chen with newly cited Cannon and in further view of newly cited Rounbehler et al (US 4249904 A; hereafter “Rounbehler”).
Regarding claim 2, which depends on claim 1,
Wichitnithad as previously modified suggests a nitrosating inhibitor (see analysis of independent claim).
Wichitnithad does not teach wherein the nitrosating inhibitor is selected from pyrogallol, phloroglucinol, pyrrole, 2,5-dimethylpyrrole, catechol, ascorbic acid, hydrazine, propylgallate, gallic acid, diphenylamine, and/or N-methyl aniline.
However:
It has been held to be within the general skill of a worker in the art to select a known material on the basis of its suitability for the intended use as a matter of obvious design choice, see MPEP § 2144.07 and In re Leshin, 277 F.2d 197, 125 USPQ 416 (CCPA 1960). In the present case it is the Examiner’s position that only ordinary skill in the art is required to choose a particular nitrosating inhibitor, including based upon such factors as the type of sample being analyzed.
Furthermore, Rounbehler teaches utilizing ascorbic acid as a nitrosating inhibitor is selected (Title “Method And Apparatus For Extraction Of Airborne N-nitroso Compounds Without Artifact Formation”; Abstract “method and apparatus are disclosed for extracting N-nitroso compounds from air samples without artifact formation of nitrosamines from precursors in the sample”; col. 1, ll. 25-64 “detection of complex organic compounds, such as nitrosamines, in low concentrations”; col. 7, ll. 3-11 “complexing agents might be used, such as acids (particularly ascorbic acid)”).
In view of the above, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Rounbehler’s ascorbic acid for inhibiting nitrosamine formation with Wichitnithad’s nitrosamine analysis, thereby providing the expected aforementioned advantage of increasing accuracy by reducing (artifact) noise from unwanted formations during the analysis. The Examiner additionally notes that ascorbic acid is a common additive widely accepted in food & pharmaceutical products, already recognized to be generally safe/non-toxic, and is known to be a potent nitrite scavenger to rapidly reduce nitrosating species.
Regarding independent claim 13,
Wichitnithad teaches a method for analyzing nitrosamine analytes in pharmaceutical samples (drug products) (Title “Development of a Sensitive Headspace Gas Chromatography−Mass Spectrometry Method for the Simultaneous Determination of Nitrosamines in Losartan Active Pharmaceutical Ingredients”), comprising:
a) heating a pharmaceutical sample (drug products; e.g., sartans) suspected of containing one or more nitrosamine analytes (Introduction “Angiotensin II receptor antagonists (sartans) such as valsartan, losartan, irbesartan, and olmesartan” and “contamination by the nitrosamine N-nitrosodimethylamine (NDMA). Subsequently, other nitrosamine impurities, including N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (DIPNA), and N-nitrosoethylisopropylamine (EIPNA), have been found”; page 11057 section 4 “method to analyze nitrosamine contamination in other sartan APIs and drug products”; page 11055 right column section 3.2 “temperature programing” and “oven sample was heated”);
b) displacing the nitrosamine analytes into a gaseous phase (page 11055 section 3.2 “carrier gas”; page 11056 section 3.5 “nitrosamines were then vaporized into the vial headspace and directly injected into the column”); and
c) analyzing the nitrosamine analytes (page 11049 left column first paragraph “headspace gas chromatography−mass spectrometry (HS-GC−MS) method for the quantitative analysis”; page 11049 right column first full paragraph “HSGC−MS method for the simultaneous determination of nitrosamines").
Wichitnithad does not teach items: 1) wherein in situ nitrosamine formation is reduced or eliminated by heating the pharmaceutical sample in the presence of one or more nitrosating inhibitors; and 2) wherein the one or more nitrosating inhibitors are selected from the group consisting of pyrogallol, phloroglucinol, pyrrole, 2,5-dimethylpyrrole, catechol, ascorbic acid, hydrazine, propylgallate, and/or gallic acid.
Regarding item 1):
Chen teaches that a pharmaceutical sample can generate nitrosamines in a sample preparation process and therefore negatively affect the accuracy of a GC-MS detection (Title “GC-MS Coupling Detection Method Of N-nitrosodimethylamine In Metformin Hydrochloride Sustained-release Tablet”; Abstract “can effectively prevent the residual raw material dimethylamine in the sample from generating NDMA by chemical reaction of active oxide in the sample preparation process, improving the accuracy of the detection”; paragraph before middle of page 4 “effectively prevent the residual raw material dimethylamine in the sample from generating NDMA by chemical reaction of active oxide in the sample and test process, improving the accuracy of detection”).
The Examiner takes Official Notice that it is well-known that nitrosamine formation is accelerated by temperature increases (in particular, exponentially; see Arrhenius equation).
Furthermore, and as factually supporting evidence of the temperature dependence on nitrosamine formation, Cannon teaches wherein in situ nitrosamine formation is reduced or eliminated by the presence of one or more nitrosating inhibitors even when a sample is heated (Title “Nitrosamine Inhibition”; background col. 1, ll. 5-20 “Circumstances which favor nitrosamine formation, notably elevated temperatures, present a special problem”; col. 5, ll.32-33 “evaluated for the increase in nitrosamine content on heating”).
In view of the above, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include a nitrosating inhibitor to prevent further generation of a nitrosamine when performing analysis thereof—as supported by Chen—with Wichitnithad’s analysis of nitrosamines, thereby improving the accuracy of the detection by decreasing noise from unwanted further formations during the method. It further would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to introduce the nitrosating inhibitor such that said inhibitor was present during heating—as factually supported by Cannon’s teaching that elevated temperatures favor nitrosamine formation—with Wichitnithad’s analysis method involving heating thereby commonsensically avoiding the most detrimentally significant formations of nitrosamine during said heating (Examiner again noting the well-known Arrhenius equation).
Regarding item 2):
It has been held to be within the general skill of a worker in the art to select a known material on the basis of its suitability for the intended use as a matter of obvious design choice, see MPEP § 2144.07 and In re Leshin, 277 F.2d 197, 125 USPQ 416 (CCPA 1960). In the present case it is the Examiner’s position that only ordinary skill in the art is required to choose a particular nitrosating inhibitor, including based upon such factors as the type of sample being analyzed.
Furthermore, Rounbehler teaches selecting ascorbic acid as a nitrosating inhibitor (Title “Method And Apparatus For Extraction Of Airborne N-nitroso Compounds Without Artifact Formation”; Abstract “method and apparatus are disclosed for extracting N-nitroso compounds from air samples without artifact formation of nitrosamines from precursors in the sample”; col. 1, ll. 25-64 “detection of complex organic compounds, such as nitrosamines, in low concentrations”; col. 7, ll. 3-11 “complexing agents might be used, such as acids (particularly ascorbic acid)”).
In view of the above, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Rounbehler’s ascorbic acid for inhibiting nitrosamine formation with Wichitnithad’s nitrosamine analysis, thereby providing the expected aforementioned advantage of increasing accuracy by reducing (artifact) noise from unwanted formations during the analysis. The Examiner additionally notes that ascorbic acid is a common additive widely accepted in food & pharmaceutical products, already recognized to be generally safe/non-toxic, and is known to be a potent nitrite scavenger to rapidly reduce nitrosating species.
Regarding claim 15, which depends on claim 13,
Wichitnithad teaches wherein the temperature of the pharmaceutical sample (drug products) is heated to about 60°C to about 200°C (page 11055 section 3.2 “The oven sample was heated up to 150 °C”; page 11056 section 3.5 “sample was incubated in the headspace oven at 150 °C”. It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art, see MPEP § 2144.05 and In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 16, which depends on claim 13,
Wichitnithad teaches wherein the nitrosamine analytes being analyzed are semi-volatile (Title; Abstract “N-Nitrosodimethylamine (NDMA, m/z 74), N-nitrosodiethylamine (NDEA, m/z 102), N-nitrosoethylisopropylamine (EIPNA, m/z 116), and N-nitrosodiisopropylamine (DIPNA, m/z 130)”; page 11049 last paragraph “HS-GC−MS was developed and optimized for volatile nitrosamine impurity analysis”).
Regarding claim 17, which depends on claim 13,
Wichitnithad teaches wherein the nitrosamine in the gaseous phase are separated and analyzed using gas chromatography coupled with a GC detector selected from the group consisting of mass spectrometer, nitrogen-phosphorus detector, thermal energy analyzer, nitrogen chemiluminescence detector or flame ionization detector (page 11049 left column first paragraph “headspace gas chromatography−mass spectrometry (HS-GC−MS) method for the quantitative analysis”; page 11049 right column first full paragraph “HSGC−MS method for the simultaneous determination of nitrosamines").
Claim 5-6 and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Applicant cited Wichitnithad in view of newly cited Chen with newly cited Cannon and in further view of newly cited Xiao et al (US 20210285920 A1; hereafter “Xiao”).
Regarding claim 5 and claim 6, where claim 5 depends on claim 1 and where claim 6 depends on claim 5,
Wichitnithad teaches a diluent & a solvent (page 111052 section 2.2.2. “method for nitrosamine determination focused on the diluents involved in sample preparation, e.g., DMSO and methanol”; page 11056 section 3.6.2. “diluents, e.g., DMSO and methanol”; page 11050 right column through top of page 11052 “Identifying the proper solvent for sample dilution before analysis”).
Wichitnithad does not teach: (claim 5) wherein the nitrosating inhibitor is in a diluent comprising an acid and solvent wherein the acid is non-volatile and selected from the group consisting of phosphoric acid, sulfuric acid, methanesulfonic acid, and (claim 6) wherein the solvent is selected from the group consisting of methanol, acetonitrile, acetone, ethanol, isopropanol, and 1-propanol or a mixture thereof.
However:
It has been held to be within the general skill of a worker in the art to select a known material on the basis of its suitability for the intended use as a matter of obvious design choice, see MPEP § 2144.07 and In re Leshin, 277 F.2d 197, 125 USPQ 416 (CCPA 1960). In the present case it is the Examiner’s position that only ordinary skill in the art is required to identify the proper solvent & diluent for a particular analysis and/or pharmaceutical.
Furthermore, Xiao teaches a method for analyzing nitrosamines in a pharmaceutical sample comprising (Title “DETECTION METHOD FOR N-NITROSODIMETHYLAMINE IMPURITIES”):
a) heating a pharmaceutical sample (sartan) suspected of containing one or more nitrosamines in the presence of a diluent & solvent ([0006] “trace N-nitrosodimethylamine (NDMA) will be produced in a sartan”; [0059], [0081], [0102], [0123], [0145], [0158], [0187], [0209], [0230], [0251], [0275], [0290], [0321], [0347] “heating procedure”);
b) displacing the nitrosamines from the pharmaceutical sample (sartan) into a gaseous phase ([0011] “prepared directly in a sample bottle or headspace bottle suitable for gas chromatography-mass spectrometry injection”); and
c) analyzing the nitrosamines in the gaseous phase ([0010] “detecting the test solution by gas chromatography-mass spectrometry (GC-MS) to determine the content of N-nitrosodimethylamine impurity in the sample”),
wherein the diluent comprises an acid wherein the acid is non-volatile and selected from the group consisting of phosphoric acid, sulfuric acid, methanesulfonic acid, and wherein the solvent is selected from the group consisting of methanol, acetonitrile, acetone, ethanol, isopropanol, and 1-propanol or a mixture thereof ([0026] “The solvent used in the process refer to the solvent used in the synthesis of the sartan API, including but not limited to ethyl acetate, toluene, xylene, methanol, N,N-dimethylformamide (DMF), methyl tert-butyl ether, dichloromethane and the like”; [0036] “solvent is one further selected from the group consisting of N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), methanol, ethanol, isopropanol, acetone, methyl tert-butyl ether, acetonitrile, ethylene glycol, propanediol, glycerol, formic acid, acetic acid, propionic acid, methanesulfonic acid, triethylamine, dimethylamine, dimethylpropylamine, pyridine, morpholine, piperazine, tetrahydropyrrole, and piperidine or any combination thereof”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute Xiao’s combination of solvent & diluent for Wichitnithad’s combination of solvent & diluent at least for the increased versatility and marketability for analysis of additional pharmaceuticals including of detecting NDMA for sartans/antihypertensive drugs (e.g., common well-known & used Losartan Potassium, Valsartan, Irbesartan, and Candersartan Celexetil Ester). The Examiner additionally notes that choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success is obvious to try, see MPEP § 2143(I)(E). The Examiner also notes that MPEP § 2145(III)(X)(B) states “An “obvious to try” rationale may support a conclusion that a claim would have been obvious where one skilled in the art is choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. “[A] person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.” KSR Int'l Co. v. Teleflex Inc., 550 U.S. 538, 421,82 USPQ2d 1385, 1397 (2007).” In the present case, it is the Examiner’s position that choosing from Xiaos’ taught combinations merely requires ordinary skill and can be reasonably expected to be successful.
Regarding claim 9, which depends on claim 5,
Wichitnithad is silent to wherein the ratio of diluent to the nitrosamine containing pharmaceutical sample (drug products) is from 1:5 to 10:1.
However:
It has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art, see MPEP § 2144.05 and In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). In the present case, it is the Examiner's position that only ordinary skill in the art is required to optimize the dilution including for reasons such as saving on cost of sample and/or diluent and/or for preventing exceeding an upper/lower detection limit.
Furthermore, Xiao reasonably suggests wherein the ratio of diluent to the nitrosamine containing pharmaceutical sample (drug products) is from 1:5 to 10:1 ([0036] “the diluent is selected from the group consisting of water, and a polar organic solvent or a mixture thereof. The polar organic solvent is one further selected from the group consisting of N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), methanol, ethanol, isopropanol, acetone, methyl tert-butyl ether, acetonitrile, ethylene glycol, propanediol, glycerol, formic acid, acetic acid, propionic acid, methanesulfonic acid, triethylamine, dimethylamine, dimethylpropylamine, pyridine, morpholine, piperazine, tetrahydropyrrole, and piperidine or any combination thereof”; [0032] “when the sample to be detected is the sartan API intermediate or sartan API, dissolving the sartan API intermediate or sartan API in the diluent, and preparing the test solution containing 1-5000 mg, preferably 1-1000 mg, more preferably 5-500 mg, and most preferably 5-200 mg of the sartan API intermediate or sartan API in 1 mL of the test solution”; [0033] “when the sample to be detected is the sartan API composition, disintegrating the sartan API composition in the diluent, and preparing the test solution containing 1-5000 mg, preferably 1-1000 mg, more preferably 5-500 mg, and most preferably 5-30 mg of the sartan API in 1 mL of the test solution”; Examiner notes that a rough estimate of mass-ratio exemplary for methanol is 1mL/5000mg ~ 1:6 1mL/500mg and that 1mL/50mg ~ 16:1). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists, see MPEP § 2144.05(I), In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976), and In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
In view of the above, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the ratio of dilution—including within the claimed range of 1:5 to 10:1—as factually supported by Xiao’s overlapping ranges and for the aforementioned reasons including saving on costs and/or for staying within the detection range.
Claim 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Applicant cited Wichitnithad in view of newly cited Chen with newly cited Cannon, newly cited Rounbehler, and in further view of newly cited Xiao.
Regarding claim 14, which depends on claim 13,
Wichitnithad teaches a diluent & a solvent (page 111052 section 2.2.2. “method for nitrosamine determination focused on the diluents involved in sample preparation, e.g., DMSO and methanol”; page 11056 section 3.6.2. “diluents, e.g., DMSO and methanol”; page 11050 right column through top of page 11052 “Identifying the proper solvent for sample dilution before analysis”).
Wichitnithad does not teach: wherein the nitrosating inhibitor is in a diluent comprising an acid and solvent wherein the acid is non-volatile and selected from the group consisting of phosphoric acid, sulfuric acid, methanesulfonic acid, and wherein the solvent is selected from the group consisting of methanol, acetonitrile, acetone, ethanol, isopropanol, and 1-propanol or a mixture thereof.
However:
It has been held to be within the general skill of a worker in the art to select a known material on the basis of its suitability for the intended use as a matter of obvious design choice, see MPEP § 2144.07 and In re Leshin, 277 F.2d 197, 125 USPQ 416 (CCPA 1960). In the present case it is the Examiner’s position that only ordinary skill in the art is required to identify the proper solvent & diluent for a particular analysis and/or pharmaceutical.
Furthermore, Xiao teaches a method for analyzing nitrosamines in a pharmaceutical sample comprising (Title “DETECTION METHOD FOR N-NITROSODIMETHYLAMINE IMPURITIES”):
a) heating a pharmaceutical sample (sartan) suspected of containing one or more nitrosamines in the presence of a diluent & solvent ([0006] “trace N-nitrosodimethylamine (NDMA) will be produced in a sartan”; [0059], [0081], [0102], [0123], [0145], [0158], [0187], [0209], [0230], [0251], [0275], [0290], [0321], [0347] “heating procedure”);
b) displacing the nitrosamines from the pharmaceutical sample (sartan) into a gaseous phase ([0011] “prepared directly in a sample bottle or headspace bottle suitable for gas chromatography-mass spectrometry injection”); and
c) analyzing the nitrosamines in the gaseous phase ([0010] “detecting the test solution by gas chromatography-mass spectrometry (GC-MS) to determine the content of N-nitrosodimethylamine impurity in the sample”),
wherein the diluent comprises an acid wherein the acid is non-volatile and selected from the group consisting of phosphoric acid, sulfuric acid, methanesulfonic acid, and wherein the solvent is selected from the group consisting of methanol, acetonitrile, acetone, ethanol, isopropanol, and 1-propanol or a mixture thereof ([0026] “The solvent used in the process refer to the solvent used in the synthesis of the sartan API, including but not limited to ethyl acetate, toluene, xylene, methanol, N,N-dimethylformamide (DMF), methyl tert-butyl ether, dichloromethane and the like”; [0036] “solvent is one further selected from the group consisting of N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), methanol, ethanol, isopropanol, acetone, methyl tert-butyl ether, acetonitrile, ethylene glycol, propanediol, glycerol, formic acid, acetic acid, propionic acid, methanesulfonic acid, triethylamine, dimethylamine, dimethylpropylamine, pyridine, morpholine, piperazine, tetrahydropyrrole, and piperidine or any combination thereof”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute Xiao’s combination of solvent & diluent for Wichitnithad’s combination of solvent & diluent at least for the increased versatility and marketability for analysis of additional pharmaceuticals including of detecting NDMA for sartans/antihypertensive drugs (e.g., common well-known & used Losartan Potassium, Valsartan, Irbesartan, and Candersartan Celexetil Ester). The Examiner additionally notes that choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success is obvious to try, see MPEP § 2143(I)(E). The Examiner also notes that MPEP § 2145(III)(X)(B) states “An “obvious to try” rationale may support a conclusion that a claim would have been obvious where one skilled in the art is choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. “[A] person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.” KSR Int'l Co. v. Teleflex Inc., 550 U.S. 538, 421,82 USPQ2d 1385, 1397 (2007).” In the present case, it is the Examiner’s position that choosing from Xiaos’ taught combinations merely requires ordinary skill and can be reasonably expected to be successful.
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Applicant cited Wichitnithad in view of newly cited Chen with newly cited Cannon and in further view of newly cited Basheer et al (US 20170261482 A1; hereafter “Basheer”).
Regarding claim 11, which depends on claim 1,
Wichitnithad teaches wherein the method for analyzing nitrosamines is selected as headspace gas-chromatography (Title “Development of a Sensitive Headspace Gas Chromatography−Mass Spectrometry Method for the Simultaneous Determination of Nitrosamines in Losartan Active Pharmaceutical Ingredients”; page 11049 left column first paragraph “headspace gas chromatography−mass spectrometry (HS-GC−MS) method for the quantitative analysis”; page 11049 right column first full paragraph “HSGC−MS method for the simultaneous determination of nitrosamines").
Wichitnithad does not teach: liquid injection GC-NPD, headspace GC- NPD or full evaporation headspace GC with NPD.
Wichitnithad teaches a nitrogen phosphorus detector is a common analytical method for analyzing nitrosamines ([0002] “method of detecting and quantifying one or more N-nitrosamines”. Omission for brevity: [0007] “The most common analytical methods used for determination of NAs are…(iv) gas chromatography (GC) with a different detector such as a flame ionization detector (FID) (Jurado-Sanchez, B., Ballesteros, E., Gallego, M., J. Chromatogr A, 2007, 1154, 66-73—incorporated herein by reference in its entirety), a nitrogen phosphorous detector (NFD) (Andrade, R., Reyes, F. G. R., Rath, S., Food Chem. 2005, 91, 173-179—incorporated herein by reference in its entirety), a thermal energy detector (TED) (Incavo, J. A., Schafer, M. A., Anal. Chim. Acta, 2006, 557, 256-261—incorporated herein by reference in its entirety), a nitrogen chemiluminescence detector (NCD) (Ozel, M. Z., Gogus, F., Yagci, S., Hamilton, J. F., Lewis, A. C., Food Chem. Toxicol. 2010, 48, 3268-3273—incorporated herein by reference in its entirety), and with mass spectrometry detectors (MSDs) (Anna, V., Rimma, S., Lev, O., Jenny, G., Anal. Chim. Acta. 2011, 685, 162-169—incorporated herein by reference in its entirety)”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to alternatively/additionally utilize a common N-nitrosamine detector such as a nitrogen-phosphorus detector—as factually supported by Basheer—for the expected advantages of selective sensitivity, low cost, ease of use, and simple maintenance. The Examiner further emphasizes that an ordinary artisan would trivially recognize that a known alternative method could have been combined with predictable results, see MPEP § 2143(a).
Therefore, Wichitnithad as modified suggests headspace GC- NPD.
Claim(s) 11-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Applicant cited Wichitnithad in view of newly cited Chen with newly cited Cannon and in further view of newly cited Basheer with newly cited Markelov (US 5441700 A; hereafter “Markelov”).
Regarding claim 12 and further regarding claim 11, where claim 11 depends on claim 1 and where claim 12 depends on claim 1,
Wichitnithad teaches wherein the method for analyzing nitrosamines is selected as headspace gas-chromatography (Title “Development of a Sensitive Headspace Gas Chromatography−Mass Spectrometry Method for the Simultaneous Determination of Nitrosamines in Losartan Active Pharmaceutical Ingredients”; page 11049 left column first paragraph “headspace gas chromatography−mass spectrometry (HS-GC−MS) method for the quantitative analysis”; page 11049 right column first full paragraph “HSGC−MS method for the simultaneous determination of nitrosamines").
Wichitnithad does not teach items: 1) NPD; and 2) full evaporation.
Regarding item 1), Wichitnithad teaches a nitrogen phosphorus detector is a common analytical method for analyzing nitrosamines ([0002] “method of detecting and quantifying one or more N-nitrosamines”. Omission for brevity: [0007] “The most common analytical methods used for determination of NAs are…(iv) gas chromatography (GC) with a different detector such as a flame ionization detector (FID) (Jurado-Sanchez, B., Ballesteros, E., Gallego, M., J. Chromatogr A, 2007, 1154, 66-73—incorporated herein by reference in its entirety), a nitrogen phosphorous detector (NFD) (Andrade, R., Reyes, F. G. R., Rath, S., Food Chem. 2005, 91, 173-179—incorporated herein by reference in its entirety), a thermal energy detector (TED) (Incavo, J. A., Schafer, M. A., Anal. Chim. Acta, 2006, 557, 256-261—incorporated herein by reference in its entirety), a nitrogen chemiluminescence detector (NCD) (Ozel, M. Z., Gogus, F., Yagci, S., Hamilton, J. F., Lewis, A. C., Food Chem. Toxicol. 2010, 48, 3268-3273—incorporated herein by reference in its entirety), and with mass spectrometry detectors (MSDs) (Anna, V., Rimma, S., Lev, O., Jenny, G., Anal. Chim. Acta. 2011, 685, 162-169—incorporated herein by reference in its entirety)”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to alternatively/additionally utilize a common N-nitrosamine detector such as a nitrogen-phosphorus detector—as factually supported by Basheer—for the expected advantages of selective sensitivity, low cost, ease of use, and simple maintenance. The Examiner further emphasizes that an ordinary artisan would trivially recognize that a known alternative method could have been combined with predictable results, see MPEP § 2143(a).
Regarding item 2), Markelov teaches a headspace full evaporation technique for a gas chromatograph (Title “Headspace Autosampler Apparatus”; Abstract “A headspace autosampling apparatus (92) for generating and delivering gaseous samples to a gas chromatograph” and “using the full evaporation technique (FET)” and “gas chromatograph wherein analytes in the headspace volume are analyzed to determine the composition thereof”; col. 4, ll. 5-8 “headspace autosampling apparatus that is adapted for use with full evaporation technique (FET) headspace analysis”; col. 4 line 64 through col. 5 line 6 “full evaporization technique (FET) which enables minimization of matrix effects”; col. 10, ll. 34-48 “analytical method known as the full evaporation technique (FET). Using FET headspace analysis matrix effects in samples are reduced. FET involves reducing the sample size and correspondingly increasing temperatures so that analytes are transferred nearly completely from a condensed matrix to a confined vapor phase. This effectively eliminates the effect of the partition coefficient for the matrix. The technique is described in detail in the recent paper entitled "Matrix Independent Headspace Gas Chromatographic Analysis-The Full Evaporation Technique". Analytica Chimica Alta, 276 (1993) 235-245, Elsevier Science Publishers B.V., Amsterdam, authored by Dr. Michael Markelov and John P. Guzowski, Jr.”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Markelov’s explicitly full evaporation technique for headspace gas chromatography with Wichitnithad’s headspace gas chromatography for the aforementioned advantages including reducing sample size, completely transferring analytes, and/or minimizing matrix effects.
Claim 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Applicant cited Wichitnithad in view of newly cited Chen with newly cited Cannon, newly cited Rounbehler, and in further view of newly cited Basheer.
Regarding claim 18, which depends on claim 13,
Wichitnithad teaches wherein the method for analyzing nitrosamines is selected as headspace gas-chromatography (Title “Development of a Sensitive Headspace Gas Chromatography−Mass Spectrometry Method for the Simultaneous Determination of Nitrosamines in Losartan Active Pharmaceutical Ingredients”; page 11049 left column first paragraph “headspace gas chromatography−mass spectrometry (HS-GC−MS) method for the quantitative analysis”; page 11049 right column first full paragraph “HSGC−MS method for the simultaneous determination of nitrosamines").
Wichitnithad does not teach: liquid injection GC-NPD, headspace GC- NPD or full evaporation headspace GC with NPD.
Wichitnithad teaches a nitrogen phosphorus detector is a common analytical method for analyzing nitrosamines ([0002] “method of detecting and quantifying one or more N-nitrosamines”. Omission for brevity: [0007] “The most common analytical methods used for determination of NAs are…(iv) gas chromatography (GC) with a different detector such as a flame ionization detector (FID) (Jurado-Sanchez, B., Ballesteros, E., Gallego, M., J. Chromatogr A, 2007, 1154, 66-73—incorporated herein by reference in its entirety), a nitrogen phosphorous detector (NFD) (Andrade, R., Reyes, F. G. R., Rath, S., Food Chem. 2005, 91, 173-179—incorporated herein by reference in its entirety), a thermal energy detector (TED) (Incavo, J. A., Schafer, M. A., Anal. Chim. Acta, 2006, 557, 256-261—incorporated herein by reference in its entirety), a nitrogen chemiluminescence detector (NCD) (Ozel, M. Z., Gogus, F., Yagci, S., Hamilton, J. F., Lewis, A. C., Food Chem. Toxicol. 2010, 48, 3268-3273—incorporated herein by reference in its entirety), and with mass spectrometry detectors (MSDs) (Anna, V., Rimma, S., Lev, O., Jenny, G., Anal. Chim. Acta. 2011, 685, 162-169—incorporated herein by reference in its entirety)”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to alternatively/additionally utilize a common N-nitrosamine detector such as a nitrogen-phosphorus detector—as factually supported by Basheer—for the expected advantages of selective sensitivity, low cost, ease of use, and simple maintenance. The Examiner further emphasizes that an ordinary artisan would trivially recognize that a known alternative method could have been combined with predictable results, see MPEP § 2143(a).
Therefore, Wichitnithad as modified suggests headspace GC-NPD.
Claim 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Applicant cited Wichitnithad in view of newly cited Chen with newly cited Cannon, newly cited Rounbehler, and in further view of newly cited Basheer with newly cited Markelov.
Regarding claim 19 and further regarding claim 18, where claim 18 depends on claim 13 and where claim 19 depends on claim 13,
Wichitnithad teaches wherein the method for analyzing nitrosamines is selected as headspace gas-chromatography (Title “Development of a Sensitive Headspace Gas Chromatography−Mass Spectrometry Method for the Simultaneous Determination of Nitrosamines in Losartan Active Pharmaceutical Ingredients”; page 11049 left column first paragraph “headspace gas chromatography−mass spectrometry (HS-GC−MS) method for the quantitative analysis”; page 11049 right column first full paragraph “HSGC−MS method for the simultaneous determination of nitrosamines").
Wichitnithad does not teach items: 1) NPD; and 2) full evaporation.
Regarding item 1), Wichitnithad teaches a nitrogen phosphorus detector is a common analytical method for analyzing nitrosamines ([0002] “method of detecting and quantifying one or more N-nitrosamines”. Omission for brevity: [0007] “The most common analytical methods used for determination of NAs are…(iv) gas chromatography (GC) with a different detector such as a flame ionization detector (FID) (Jurado-Sanchez, B., Ballesteros, E., Gallego, M., J. Chromatogr A, 2007, 1154, 66-73—incorporated herein by reference in its entirety), a nitrogen phosphorous detector (NFD) (Andrade, R., Reyes, F. G. R., Rath, S., Food Chem. 2005, 91, 173-179—incorporated herein by reference in its entirety), a thermal energy detector (TED) (Incavo, J. A., Schafer, M. A., Anal. Chim. Acta, 2006, 557, 256-261—incorporated herein by reference in its entirety), a nitrogen chemiluminescence detector (NCD) (Ozel, M. Z., Gogus, F., Yagci, S., Hamilton, J. F., Lewis, A. C., Food Chem. Toxicol. 2010, 48, 3268-3273—incorporated herein by reference in its entirety), and with mass spectrometry detectors (MSDs) (Anna, V., Rimma, S., Lev, O., Jenny, G., Anal. Chim. Acta. 2011, 685, 162-169—incorporated herein by reference in its entirety)”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to alternatively/additionally utilize a common N-nitrosamine detector such as a nitrogen-phosphorus detector—as factually supported by Basheer—for the expected advantages of selective sensitivity, low cost, ease of use, and simple maintenance. The Examiner further emphasizes that an ordinary artisan would trivially recognize that a known alternative method could have been combined with predictable results, see MPEP § 2143(a).
Regarding item 2), Markelov teaches a headspace full evaporation technique for a gas chromatograph (Title “Headspace Autosampler Apparatus”; Abstract “A headspace autosampling apparatus (92) for generating and delivering gaseous samples to a gas chromatograph” and “using the full evaporation technique (FET)” and “gas chromatograph wherein analytes in the headspace volume are analyzed to determine the composition thereof”; col. 4, ll. 5-8 “headspace autosampling apparatus that is adapted for use with full evaporation technique (FET) headspace analysis”; col. 4 line 64 through col. 5 line 6 “full evaporization technique (FET) which enables minimization of matrix effects”; col. 10, ll. 34-48 “analytical method known as the full evaporation technique (FET). Using FET headspace analysis matrix effects in samples are reduced. FET involves reducing the sample size and correspondingly increasing temperatures so that analytes are transferred nearly completely from a condensed matrix to a confined vapor phase. This effectively eliminates the effect of the partition coefficient for the matrix. The technique is described in detail in the recent paper entitled "Matrix Independent Headspace Gas Chromatographic Analysis-The Full Evaporation Technique". Analytica Chimica Alta, 276 (1993) 235-245, Elsevier Science Publishers B.V., Amsterdam, authored by Dr. Michael Markelov and John P. Guzowski, Jr.”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Markelov’s explicitly full evaporation technique for headspace gas chromatography with Wichitnithad’s headspace gas chromatography for the aforementioned advantages including reducing sample size, completely transferring analytes, and/or minimizing matrix effects.
Allowable Subject Matter
Claim(s) 3-4 is/are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
When this application is finally acted upon and allowed (i.e., the Notice of Allowance), the Examiner will determine, at the same time, whether the reasons why the application is being allowed are sufficiently evident from the record; see MPEP § 1302.14(I).
Conclusion
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure. Applicant is invited to review PTO form 892 accompanying this Office Action listing Prior Art relevant to the instant invention cited by the Examiner.
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/DAVID L SINGER/Primary Examiner, Art Unit 2855 14MAR2026