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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09/19/2025 has been entered.
Claims 1-16 and 18-46 are pending in this application and were examined on their merits.
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 1-16 and 18-46 are rejected under 35 U.S.C. § 103 as being
unpatentable over Bulger et al. (US 8,236,519 B2), of record, in view of Keith et al.
(1992), cited in the IDS, Denny (US 5,151,370), of record, and Denny (US 4,224,034),
cited in the IDS.
Bulger discloses a kit for determining the concentration of acetaminophen (Column 4, Lines 64-48 and Column 5, Lines 39-42) in a sample, the kit comprising:
a first reagent (R1) comprising an aryl acylamidase for hydrolyzing acetaminophen to p-aminophenol;
a second reagent (R2) comprising a xylenol chromophore for oxidative coupling to the p-aminophenol;
and a suitable catalyst for catalyzing the oxidative coupling of the xylenol chromophore and the p-aminophenol, wherein the xylenol chromophore is 2,5- dimethylphenol and the catalyst is hydrated MnCl2 (Columns 19-20, Claims 1 and 6), reading on Claim 1.
With regard to the limitation of Claim 1, that the “oxidative coupling reaction takes place at a basic pH between about 9 and 12”, the Examiner notes that the claims are drawn to a kit and not to a method of using said kit. Thus, the limitation is directed to the manner in which the kit is intended to be used and does not structurally differentiate the claimed kit from that of the prior art.
The teachings of Bulger were discussed above.
Bulger does not teach a kit wherein the 2,5-dimethylphenol is pre-dissolved in DMSO, as required by Claims 1 and 6;
wherein the kit can detect 15.1 ug/mL acetaminophen in the presence of 1,000 mg/L of a sterile, non-pyrogenic fat emulsion comprising 20% soybean oil, 1.2% egg yolk phospholipids, 2.25% glycerin and water for injection, as required by Claim 1;
or wherein R2 comprises a concentration of 5.5 g/L of DMSO, as required by Claims 43-44.
Keith et al. teaches the solubility of 2,3-, 2,4-, 2,5- and 2,6-dimethylphenol in water and DMSO. In all cases, the solubility of these compounds is less than 1 mg/mL in the temperature range of 18 to 23 °C. However, the solubility of these compounds in DMSO is at greater than or equal to 100 mg/ml at temperatures between 18 to 23 °C (Pg. 169, Lines 1-23). From this disclosure, the ordinary artisan would reasonably conclude that the solubility of the claimed 2,5-dimethylphenol xylenol chromophore is very poor in water.
Denny (‘370) teaches an assay for the determination of serum iron. The reagent for the method is chromophore chromazurol B (CAB), chromazurol S (CAS) or an addition salt thereof, a surfactant that forms a ternary complex with iron and the chromophore, buffer and DMSO. The inclusion of DMSO provides multiple advantages by solubilizing the chromophore in its acid-form, eliminating interference of protein in serum and accelerating the reaction time (Column 3, Lines 50-68).
Denny (‘034) teaches that lipemia may interfere with direct serum methods for the measurement of iron because it causes turbidity of the sample at the time the color measurement is made. The turbidity has the effect of absorbing light. Hence the absorbance may be attributed to the absorbance by the chromophore which produces an error in the quantification of the iron in the sample (Column 4, Lines 6-22) and that the presence of DMSO in the assay reduces lipemia and/or protein interference in the assay (Column 4, Lines 55-61).
Denny (‘034) further states that the use of DMSO in an aqueous systems for the determination of iron or its binding capacity has the effect of increased iron liberation, minimization of the effects of turbidity and/or lipemia and providing increased protein solubilization (Column 11, Lines 29-34).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to pre-dissolve the 2,5-dimethylphenol xylenol chromophore of reagent R2 of the kit of Bulger in DMSO as taught by Keith et al. and both of Denny because of the art-recognized advantageous effects of doing so. The ordinary artisan would have been motivated to do so because Keith et al. teaches the use of DMSO improves the solubility of the 2,5-dimethylphenol xylenol chromophore over water. Furthermore, Denny teaches that DMSO minimizes the effects of turbidity caused by proteins and/or lipemia. Such a minimization of turbidity results in the quantification of the absorbance due to only the chromophore. Thus, the use of DMSO in aqueous assays to decrease the effects of turbidity due to lipemia and/or proteins and to improve the solubility of the same organic chromophore is the use of a known technique to improve a similar method in the same way (see MPEP 2148, I., C.). There would have been a reasonable expectation of success in making this modification because Bulger is directed to a kit comprising 2,5-dimethylphenol xylenol chromophore; Keith et al. is directed to methods of increasing solubility of xylenol chromophores, including 2,5-dimethylphenol, by combination with DMSO; and both of Denny teach that the use of DMSO in an aqueous systems minimizes the effects of turbidity and/or lipemia.
While the references listed above do not specifically teach the limitation of Claims 43-44, that the amount of DMSO in the R2 composition is 5.5 g/L, one of ordinary skill in the art would recognize that the percentage of DMSO in a composition is a result-effective optimizable variable.
Keith et al., Denny (‘370) and (‘034) teach the use of DMSO to increase the solubility of an insoluble chromophore or decrease lipemia and/or protein interference in an assay, minimization of the effects of turbidity and/or lipemia and providing increased protein solubilization. This is motivation for someone of ordinary skill in the art to practice or test the DMSO concentration parameter values widely to find those that are functional or optimal to sufficiently solubilize the 2,5-dimethylpheonol chromophore and provide reduced assay interference which would be inclusive or cover the instantly claimed values. Absent any teaching of criticality by the Applicant concerning the concentration of DMSO in the composition, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are an optimizable variable which can be met as a matter of routine optimization (see MPEP § 2144.05 (II)(B). Those of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to make this modification in order to obtain a dissolved soluble chromophore suitable for use in an aqueous assay. There would have been a reasonable expectation of success in making these modifications because Bulger is drawn to a kit containing the chromophore 2,5-dimethylphenol, Keith teaches that DMSO increases the solubility of 2,5-dimethylphenol and both of Denny teach that DMSO has other beneficial effects when in use in an aqueous assay.
With regard to the limitation of Claim 1, that the kit can detect 15.1 ug/ml acetaminophen in the presence of 1000 mg/L of a sterile, non-pyrogenic fat emulation comprising 20% soybean oil, 1.2% egg yolk phospholipids, 2.25% glycerin and water for injection, this would be a natural outcome of the use of the kit because the same reagents are being used in R1 and R2 of the prior art as claimed. Thus, the kit of the prior art would be expected to have the same characteristics as the claimed kit, when in use.
With regard to Claim 2, Bulger teaches the sample in an aqueous sample (Column 20, Claim 4).
With regard to Claim 3, Bulger teaches the sample is serum or plasma (Column 20, Claim 5).
With regard to Claim 4, Bulger teaches the sample is liquid-stable (Column 20, Claim 7).
With regard to Claim 5, Bulger teaches the kit further comprises instructions for carrying out an acetaminophen determination assay (Column 20, Claim 8).
With regard to Claim 6, Bulger teaches the instructions set forth the steps of: contacting the sample with R1 and a first suitable diluent to form a hydrolysis solution; incubating the hydrolysis solution to permit a hydrolysis reaction, wherein acetaminophen in the sample is converted to p-aminophenol; contacting the hydrolysis solution with R2 and a second suitable diluent to form an oxidative coupling solution; incubating the oxidative coupling solution to permit an oxidative coupling reaction, wherein the xylenol chromophore is coupled to the p-aminophenol in the presence of the catalyst to form a colored product; and determining the amount of the colored product formed, wherein the amount of the colored product is proportional to the amount of acetaminophen initially present in the sample (Column 20, Claim 9).
With regard to Claim 7, Bulger teaches the assay is reliable in the presence of i) biological molecules present in biological fluids, or ii) therapeutic levels of N- acetylcysteine (NAC) (Column 20, Claim 10).
With regard to Claim 8, Bulger teaches wherein the biological molecules are selected from the group consisting essentially of bilirubin and hemoglobin (Column 20, Claim 11).
With regard to Claim 9, Bulger teaches wherein the therapeutic levels of NAC are greater than 800 mg/L (Column 20, Claim 12).
With regard to Claim 10, Bulger teaches wherein R1 comprises aryl acylamidase at a concentration of about 10 U/L to about 5000 U/L (Column 20, Claim 13).
With regard to Claim 11, Bulger teaches wherein R2 comprises xylenol chromophore at a concentration of about 0.075 g/L to about 115 g/L (Column 20, Claim 14).
With regard to Claim 12, Bulger teaches wherein the catalyst is present in R1 in a concentration of about 0.0005 g/L to about 1.000 g/L (Column 20, Claim 15).
With regard to Claim 13, Bulger teaches wherein R2 comprises 2,5- dimethylphenol in a concentration of about 0.075 g/L to about 115 g/L and the catalyst is MnClz.4H2O and is present in R1 in a concentration of about 2.5 g/L to about 20 g/L (Column 20, Claim 16).
With regard to Claim 14, Bulger teaches wherein R2 further comprises reduced glutathione in a concentration of about 0.005 g/L to about 5.000 g/L (Column 20, Claim 17).
With regard to Claim 15, Bulger teaches wherein R1 further comprises a protein solubilizer, a protein stabilizer, an enzyme stabilizer, a metal chelator, a buffer, a surfactant, a pH adjuster, a preservative, an excipient, or a combination thereof (Column 20, Claim 18).
With regard to Claim 16, Bulger teaches wherein the enzyme stabilizer is selected from the group consisting essentially of polyvinylpyrrolidone 40,000 MW, BSA Fraction V, trehalose, sodium p-hydroxybenzoate, p-hydroxybenzoic acid, and combinations thereof (Column 20, Claim 19).
With regard to Claim 18, Bulger teaches wherein R1 comprises about 932.7 U/L aryl acylamidase and about 0.0525 g/L MnCl2.4H2O; and wherein R2 comprises about 7.5 g/L 2,5-dimethylphenol and about 0.500 g/L reduced glutathione (Columns 21-22, Claim 21).
With regard to Claims 19, 25 and 40, Bulger teaches an aqueous assay for the quantitative determination of acetaminophen in a sample (Column 5, Lines 56-67 and Column 6, Lines 1-11);
comprising contacting the sample with a first reagent (R1) comprising an aryl
acylamidase wherein acetaminophen is enzymatically hydrolyzed to p-aminophenol in a
hydrolysis solution (Column 6, Lines 11-17);
contacting the hydrolysis solution with a second reagent (R2) containing a xylenol chromophore and oxidatively coupling the p-aminophenol with a xylenol chromophore in the presence of a catalyst to form a colored product (Column 5, Lines 17-23);
and determining the amount of colored product formed, the amount of the colored product formed being proportional to the amount acetaminophen initially present in the aqueous sample (Column 5, Lines 23-26),
wherein the method is reliable in the presence or absence of therapeutic levels of NAC in the aqueous sample (Column 5, Lines 26-28):
wherein the catalyst is hydrated MnCl2 (Column 7, Lines 58-60), and reading on Claims 19, 25 and 40.
With further regard to Claims 19, 25 and 40, Bulger teaches the coupling reaction is carried out at a basic pH between 9 and 12 (Column 12, Lines 29-30).
The teachings of Bulger were discussed above.
Bulger does not teach a method wherein R2 comprises 2,5-dimethylphenol pre-
dissolved in DMSO, as required by Claims 19, 25 and 40;
or wherein R2 comprises a concentration of DMSO of 5.5 g/L, as required by Claims 45 and 46.
Keith et al. teaches the solubility of 2,3-, 2,4-, 2,5- and 2,6-dimethylphenol in water and DMSO. In all cases, the solubility of these compounds is less than 1mg/mL in the temperature range of 18 to 23 °C. However, the solubility of these compounds in DMSO is at greater than or equal to 100 mg/ml at temperatures between 18 to 23 °C. From this disclosure, the ordinary artisan would reasonably conclude that the solubility of the claimed 2,5-dimethylphenol xylenol chromophore is very poor in water.
Denny (‘370) teaches an assay for the determination of serum iron. The reagent for the method is chromophore chromazurol B (CAB), chromazurol S (CAS) or an addition salt thereof, a surfactant that forms a ternary complex with iron and the chromophore, buffer and DMSO. The inclusion of DMSO provides multiple advantages by solubilizing the chromophore in its acid-form, eliminating interference for protein in serum and accelerating the reaction time (Column 3, Lines 50-68).
Denny (‘034) teaches that lipemia may interfere with direct serum methods for the measurement of iron because it causes turbidity of the sample at the time the color measurement is made. The turbidity has the effect of absorbing light. Hence the absorbance may be attributed to the absorbance by the chromophore which produces an error in the quantification of the iron in the sample (Column 4, Lines 6-22), and that the presence of DMSO in the assay reduces lipemia and/or protein interference in the assay (Column 4, Lines 55-62).
Denny (‘034) further states that the use of DMSO in an aqueous systems for the determination of iron or its binding capacity has the effect of increased iron liberation, minimization of the effects of turbidity and/or lipemia and providing increased protein solubilization (Column 11, Lines 29-34).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to pre-dissolve the 2,5-dimethylphenol xylenol chromophore of reagent R2 of the kit of Bulger in DMSO as taught by Keith et al. and both of Denny because of the art-recognized advantageous effects of doing so. The ordinary artisan would have been motivated to do so because Keith et al. teaches the use of DMSO improves the solubility of the 2,5-dimethylphenol xylenol chromophore over water. The ordinary artisan would have recognized and been motivated to make this modification because pre-dissolving the xylenol chromophore would increase its solubility and negate the need to for a method step of dissolving the chromophore in DMSO. Furthermore, Denny teaches that DMSO minimizes the effects of turbidity caused by proteins and/or lipemia. Such a minimization of turbidity results in the quantification of the absorbance due to only the chromophore. Thus, the use of DMSO in aqueous assays to decrease the effects of turbidity due to lipemia and/or proteins and to improve the solubility of the same organic chromophore is the use of a known technique to improve a similar method in the same way (see MPEP 2148, I. C.).
There would have been a reasonable expectation of success in making this
modification because Bulger is directed to a kit comprising 2,5-dimethylphenol xylenol
chromophore; Keith et al. is directed to methods of increasing solubility of xylenol
chromophores, including 2,5-dimethylphenol, by combination with DMSO; and both of
Denny teach that the use of DMSO in an aqueous systems minimizes the effects of
turbidity and/or lipemia.
While the references listed above do not specifically teach the limitation of Claim 45-46, that the amount of DMSO in the R2 composition is 5.5 g/L, one of ordinary skill in the art would recognize that the percentage of DMSO in a composition is a result-effective optimizable variable. Keith et al., Denny (‘370) and (‘034) teach the use of DMSO to increase solubility of an insoluble chromophore or decrease lipemia and/or protein interference in an assay, minimization of the effects of turbidity and/or lipemia and providing increased protein solubilization. This is motivation for someone of ordinary skill in the art to practice or test the DMSO concentration parameter values widely to find those that are functional or optimal to sufficiently solubilize the 2,5-dimethylpheonol chromophore and provide reduced assay interference which would be inclusive or cover the instantly claimed values. Absent any teaching of criticality by the Applicant concerning the concentration of DMSO in the composition, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are an optimizable variable which can be met as a matter of routine optimization (see MPEP § 2144.05 (II)(B). Those of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to make this modification in order to obtain a dissolved soluble chromophore suitable for use in an aqueous assay. There would have been a reasonable expectation of success in making these modifications because Bulger is drawn to an aqueous assay method which uses the chromophore 2,5-dimethylphenol, Keith teaches that DMSO increases the solubility of 2,5-dimethylphenol and both of Denny teach that DMSO has other beneficial effects when in use in an aqueous assay.
With regard to Claims 20 and 25, Bulger teaches the preferred enzyme for the hydrolysis reaction is an aryl acylamidase (Column 7, Lines 9-10).
With regard to Claim 26, Bulger teaches wherein R1 comprises the aryl acylamidase at a concentration of about 10 U/L to about 5000 U/L (Column 7, Lines 31 - 33).
With regard to Claims 21 and 27, Bulger teaches the xylenol chromophore is 2,5- dimethylphenol, 2,6-dimethylphenol or 2,3-dimethylphenol (Column 10, Lines 32-36).
With regard to Claims 22 and 28, Bulger teaches the catalyst is a weak oxidizer (Column 6, Lines 29-30) and is present in R1 in a concentration of about 0.0005 g/L to about 1.0 g/L (Column 7, Lines 61-62).
With regard to Claims 23 and 41, Bulger teaches the xylenol chromophore is 2,5- dimethylphenol (Column 10, Lines 36-37) and the catalyst is anhydrous or hydrated MnCl2 (Column 10, Lines 59-60).
With regard to Claims 24 and 39, Bulger teaches the aqueous sample is serum or plasma (Column 6, Lines 9-10).
With regard to Claims 29, Bulger teaches R2 comprises 2,5-dimethylphenol in a concentration of about 0.075 g/L to about 115 g/L (Column 10, Lines 46-48) and/or wherein the catalyst is hydrated MnCl2 and is present in R1 at a concentration of about 2.5 g/L to about 20 g/L (Column 7, Lines 65-67).
With regard to Claim 30, Bulger teaches wherein R2 further comprises reduced glutathione at a concentration of 0.5 g/L (within the claimed range of about 0.005 to about 5.9 g/L) (Column 12, Lines 11-13).
With regard to Claim 31, Bulger teaches wherein R1 further comprises one or more of a protein stabilizer, an enzyme stabilizer, a metal chelator, a buffer, a surfactant, a pH adjuster, a preservative, a diluent, a solvent, an excipient (Column 7, Lines 43-47).
With regard to Claim 32, Bulger teaches the enzyme stabilizer is selected from PVP-40, BSA Fraction V, trehalose, sodium p-hydroxybenzoate, p-hydroxybenzoic acid or a combination thereof (Column 8, Lines 21-24).
With regard to Claims 33 and 42, Bulger teaches wherein R2 further comprises a buffer, a surfactant, a pH adjuster, a preservative, an antioxidant, an excipient (Column 21, Claim 20).
With regard to Claim 34, Bulger teaches the optional dilution step involves a 1:1 dilution of R1 with a suitable diluent, such as deionized water (Column 6, Lines 41-43).
With regard to Claim 35, Bulger teaches R1 comprises about 932.7 U/L aryl acylamidase and about 0.0525 g/L MnCl2•4H2O; and wherein R2 comprises about 7.5 g/L 2,5-dimethylphenol and about 0.500 g/L reduced glutathione (Column 21, Claim 21).
With regard to Claim 42, Bulger teaches wherein R2 further comprises a buffer, a surfactant, a pH adjuster, a preservative, an antioxidant, an excipient, or a combination thereof (Column 21, Claim 20).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985);
In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-16 and 18-44 are rejected on the ground of nonstatutory double
patenting as being unpatentable over claims 1-21 of U.S. Patent No. 8,236,519 in view
of Keith et al. (1992), cited in the IDS, Denny (US 4,224,034) and Denny (US
5,151,370), all of record.
Claim 6 of ‘519 Patent includes all of the limitations of claim 1 of ‘519 and is
drawn to:
A kit for determining the concentration of acetaminophen in a sample, the kit
comprising:
a first reagent (R1) comprising an aryl acylamidase for hydrolyzing
acetaminophen to p-aminophenol;
a second reagent (R2) comprising a xylenol chromophore for oxidative coupling
to the p-aminophenol;
and a suitable catalyst for catalyzing the oxidative coupling of the xylenol
chromophore and the p-aminophenol, wherein the xylenol chromophore is 2,5-
dimethylphenol and the catalyst is hydrated MnCl2, reading on instant Claim 1.
With regard to instant Claim 1, that the “oxidative coupling reaction takes place at a basic pH between about 9 and 12”, the Examiner notes that the claims are drawn to a kit and not to a method of using said kit. Thus, the limitation is directed to the manner in which the kit is intended to be used and does not differentiate the claimed kit from that of the cited prior art.
Claims 4-21 of ‘519 correspond to instant claims 2-16 and 18-42 respectively.
Claims 19-42, 45 and 46 newly rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 8,236,519 in view of Bulger et al. (US 8,236,519 B2), of record, Keith et al. (1992), cited in the IDS, Denny (US 4,224,034) and Denny (US 5,151,370), all of record.
Regarding the instant method steps, the instructions of Claim 9 of ‘519 make the claimed methods obvious, wherein the instructions comprise:
contacting the sample with R1 and a first suitable diluent to form a hydrolysis solution; incubating the hydrolysis solution to permit a hydrolysis reaction, wherein acetaminophen in the sample is converted to p-aminophenol;
contacting the hydrolysis solution with R2 and a second suitable diluent to form an oxidative coupling solution;
incubating the oxidative coupling solution to permit an oxidative coupling reaction, wherein the xylenol chromophore is coupled to the p-aminophenol in the presence of the catalyst to form a colored product;
and determining the amount of the colored product formed, wherein the amount of the colored product is proportional to the amount of acetaminophen initially present in the sample, as in instant Claims 19, 25 and 41.
The kit components of Claims 2-5 and 7-20 of ‘591 make obvious the limitations of instant claims 20-24, 26-35, 39 and 41 because claims 2-5 and 7-20 of ‘591 define appropriate concentrations of the reagents R1 and R2 and further components necessary to carry out the methods of instant method claims.
The claims of ‘519 do not teach that the oxidative coupling takes place at a basic pH between about 9 and 12, as required by instant Claims 19, 25 and 41;
wherein the dimethylphenol, such as the 2,5- dimethylphenol of R2 is dissolved in DMSO in the kit or pre-dissolved in DMSO for the method, as required by instant Claims 1, 19, 25 and 41;
wherein the kit can detect 15.1 g/mL acetaminophen in the presence of 1,000 mg/L of a sterile, non-pyrogenic fat emulsion comprising 20% soybean oil, 1.2% egg yolk phospholipids, 2.25% glycerin and water for injection, as required by instant Claim 1;
or wherein R2 comprises DMSO in a concentration of 5.5 g/L, as required by instant Claims 43-46.
With regard to Claims 19, 25 and 40, Bulger et al. teaches the coupling reaction is carried out at a basic pH between 9 and 12 (Column 12, Lines 29-30).
Keith et al. teaches the solubility of 2,3-, 2,4-, 2,5 and 2,6-dimethylphenol in water and DMSO. In all cases, the solubility of these compounds is less than 1mg/mL in the temperature range of 18 to 23 °C. However, the solubility of these compounds in DMSO is at greater than or equal to 100 mg/ml at temperatures between 18 to 23 °C. From this disclosure, the ordinary artisan would reasonably conclude that the solubility of the claimed 2,5-dimethylphenol xylenol chromophore is very poor in water.
Denny (‘370) teaches an assay for the determination of serum iron. The reagent for the method is chromophore chromazurol B (CAB), chromazurol S (CAS) or an addition salt thereof, a surfactant that forms a ternary complex with iron and the chromophore, buffer and DMSO. The inclusion of DMSO provides multiple advantages by solubilizing the chromophore in its acid-form, eliminating interference for protein in serum and accelerating the reaction time (Column 3, Lines 50-68).
Denny (‘034) teaches that lipemia may interfere with direct serum methods for the measurement of iron because it causes turbidity of the sample at the time the color measurement is made.
The turbidity has the effect of absorbing light. Hence the absorbance may be attributed to the absorbance by the chromophore which produces an error in the quantification of the iron in the sample (Column 4, Lines 6-22) and that the presence of DMSO in the assay reduces lipemia and/or protein interference in the assay (Column 4, Lines 60-65).
Denny (‘034) further states that the use of DMSO in an aqueous systems for the determination of iron or its binding capacity has the effect of increased iron liberation, minimization of the effects of turbidity and/or lipemia and providing increased protein solubilization (Column 11, Lines 29-34).
It would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the instructions of the ‘519 Patent to include the performance of the oxidative coupling at a pH of around 9-12 as taught by Bulger because the ‘519 Patent does not indicate under what conditions the coupling takes place. Those of ordinary skill in the art would have been motivated to make this modification in order to provide suitable conditions for the coupling reaction to take place. There would have been a reasonable expectation of success because both Bulger and the ‘519 Patent are drawn to the same field of endeavor, that is, methods and kits for determining the concentration of acetaminophen.
It would have been further obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to pre-dissolve the 2,5-dimethylphenol (xylenol chromophore) of reagent R2 of the kit of the ‘519 Patent in DMSO as taught by Keith et al. and both of Denny because of the art-recognized advantageous effects of doing so. The ordinary artisan would have been motivated to do so because Keith et al. teaches the use of DMSO improves the solubility of the 2,5-dimethylphenol chromophore in water. Furthermore, Denny teaches that DMSO minimizes the effects of turbidity caused by proteins and/or lipemia. Such a minimization of turbidity results in the quantification of the absorbance due to only the chromophore. Thus, the use of DMSO in aqueous assays to decrease the effects of turbidity due to lipemia and/or proteins and to improve the solubility of the same organic chromophore is the use of a known technique to improve a similar method in the same way (see MPEP 2148, I., C.). There would have been a reasonable expectation of success in making this modification because the ‘519 Patent is directed to a kit comprising 2,5-dimethylphenol xylenol chromophore; Keith et al. is directed to methods of increasing solubility of xylenol chromophores, including 2,5- dimethylphenol, by combination with DMSO; and Denny teaches that the use of DMSO in an aqueous systems minimizes the effects of turbidity and/or lipemia.
While the references listed above do not specifically teach the limitation of Claim 43-46, that the amount of DMSO in the R2 composition is 5.5 g/L, one of ordinary skill in the art would recognize that the percentage of DMSO in a composition is a result-effective optimizable variable.
Keith et al., Denny (‘370) and (‘034) teach the use of DMSO to increase solubility of an insoluble chromophore or decrease lipemia and/or protein interference in an assay, minimization of the effects of turbidity and/or lipemia and providing increased protein solubilization. This is motivation for someone of ordinary skill in the art to practice or test the DMSO concentration parameter values widely to find those that are functional or optimal to sufficiently solubilize the 2,5-dimethylpheonol chromophore and provide reduced assay interference which would be inclusive or cover the instantly claimed values. Absent any teaching of criticality by the Applicant concerning the concentration of DMSO in the composition, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are an optimizable variable which can be met as a matter of routine optimization (see MPEP § 2144.05 (II)(B). Those of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to make this modification in order to obtain a dissolved soluble chromophore suitable for use in an aqueous assay. There would have been a reasonable expectation of success in making these modifications because Bulger is drawn to a kit containing the chromophore 2,5-dimethylphenol, Keith teaches that DMSO increases the solubility of 2,5-dimethylphenol and both of Denny teach that DMSO has other beneficial effects when in use in an aqueous assay.
With regard to the limitation of Claim 1, that the kit can detect 15.1 ug/ml acetaminophen in the presence of 1000 mg/L of a sterile, non-pyrogenic fat emulation comprising 20% soybean oil, 1.2% egg yolk phospholipids, 2.25% glycerin and water for injection, this would be a natural outcome of the use of the kit because the same reagents are being used in R1 and R2 of the prior art as claimed. Thus, the kit of the prior art would be expected to have the same characteristics as the claimed kit, when in use.
With regard to the limitation of Claim 1, that the “oxidative coupling reaction takes place at a basic pH between about 9 and 12”, the Examiner notes that the claims are drawn to a kit and not to a method of using said kit. Thus, the limitation is directed to the manner in which the kit is intended to be used and does not structurally differentiate the claimed kit from that of the prior art.
The Examiner notes that the same rationale as applied above, is also applied to a finding of obviousness in the instant method Claims 19, 25 and 41.
Claims 1-16, 43 and 44 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. 8,715,952 in view of Keith et al. (1992), cited in the IDS, Denny (US 5,151,370) and Denny (US 4,224,034), both of record, for the same reasoning as provided above.
Claims 18-42, 45 and 46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. 8,715,952 in view of in view of Bulger et al. (US 8,236,519 B2), of record, Keith et al. (1992), cited in the IDS, Denny (US 5,151,370) and Denny (US 4,224,034), both of record, for the same reasoning as
provided above.
Regarding the instant claims 1-16 and 18-42, these claims correspond to instant
claims 1-23 of ‘952, respectively.
Response to Arguments
Applicant's arguments filed 09/19/2025 have been fully considered but they are not persuasive.
The Applicant argues that the instant Claim 1 contains three limitations not found in the ‘519 application and that the Examiner has no addressed the limitations or explained why they are rendered obvious (Remarks, Pg. 10, Lines 29-33 and Pgs. 11-22, Lines 1-23).
This is not found to be persuasive for the reasoning provided in the above rejections which address each claimed limitation as well las providing obviousness-type rationale and motivation for modifying the co-pending application in view of the cited prior art.
The Applicant argues that the Denny patents do not teach or suggest pre-dissolving the chromophore in DMSO (Pg. 23, Lines 1-9 and Pg. 61, Lines 1-3).
This is not found to be persuasive for the following reasons, as discussed above,
it would have been obvious to one of ordinary skill in the art before the effective filing
date of the claimed invention to pre-dissolve the 2,5-dimethylphenol (xylenol
chromophore) of reagent R2 of the kit of the ‘519 Patent in DMSO as taught by Keith and both of Denny because of the art-recognized advantageous effects of doing so.
The ordinary artisan would have been motivated to do so because Keith et al. teaches
the use of DMSO improves the solubility of the 2,5-dimethylphenol chromophore in
water. Furthermore, Denny teaches that DMSO minimizes the effects of turbidity
caused by proteins and/or lipemia. Such a minimization of turbidity results in the
quantification of the absorbance due to only the chromophore. Thus, the use of DUSO
in aqueous assays to decrease the effects of turbidity due to lipemia and/or proteins and
to improve the solubility of the same organic chromophore is the use of a known technique to improve a similar method in the same way (see MPEP 2148, I., C.). The
Examiner notes that the Applicant has provided no evidence of the record of the alleged
“criticality” of using DMSO to pre-dissolve the chromophore.
The Applicant argues that the Denny patents teach the use of a high concentration of DMSO (at least ≥ 70ml/L) while the claimed invention is drawn to 5ml/L and it would not have been obvious to modify the references to use a lower concentration and still achieve the same effect (Remarks, Pg. 23, Lines 12-25 and Pg. 27, Lines 26-29 and Pg. 1-2 and Pg. 30, Lines 7-18 and Pg. 38, Lines 13-17).
This is not found to be persuasive for the following reasons, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which Applicant relies (i.e., a DMSO concentration of 5ml/L) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The Examiner notes that DMSO concentration is found only in dependent claims (in a concentration of 5 g/L) and the independent claims do not require any particular amount of DMSO. Applicant has provided no evidence on the record to show that modification of the co-pending application in view of the Denny patents use of DMSO and routine optimization and experimentation to determine the optimal amount of DMSO would not result in the advantages taught by the Denny patents.
The Applicant argues that the Denny patents do not teach or suggest the multi-step process of generating a chromophore, Applicant also notes the reaction in Denny occurring at acid pH while the claimed reaction occurs at basic pH (Remarks, Pg. 23, Lines 1-10 and Pg. 28, Lines 3-11 and Pg. 38, Lines 12-13).
In response to Applicant's arguments against the Denny references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this instance, the co-pending application teaches the multi-step process of generating a chromophore, The Denny patents were cited only for their teaching relating to the use of DMSO in aqueous chromogenic assays. The Bulger reference was cited for its teaching that the coupling reaction is carried out at a basic pH between 9 and 12.
The Applicant argues that the Denny references are not analogous art as they
are drawn to metal chelation at low pH with high concentrations of DMSO (Pg. 27, Lines
12-17).
In response to Applicant's argument that Denny (‘034 and ‘370) are non-
analogous art, it has been held that a prior art reference must either be in the field of the
inventor's endeavor or, if not, then be reasonably pertinent to the particular problem with
which the inventor was concerned, in order to be relied upon as a basis for rejection of
the claimed invention. See In re Oetiker, 977 F.2d 1448, 24 USPQ2d 1443 (Fed. Cir.
1992). In this case, Denny ('034) and (‘370) are reasonably pertinent to the particular
problem which the inventor was concerned, that is the use of DMSO in the reduction of
interfering influences in an assay for the chromogenic detection of a compound in blood
serum.
The Applicant argues that the Denny references do not teach or suggest a
separate pre-dissolution step of premixing the chromophore with DMSO. Applicant alleges that the DMSO is a critical solvent for preparing the reagent and notes that Denny describes DMSO as an “additive” and the reference uses a higher concentration of DMSO and lower pH than the claimed invention (Remarks, Pg. 27, Lines 18-25 and Pg. 33, Lines 15-21 and Pg. 64, Lines 5-17).
This is not found to be persuasive for the following reasons, as discussed above, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to pre-dissolve the 2,5-dimethylphenol (xylenol chromophore) of reagent R2 of the kit of the ‘519 Patent in DMSO as taught by Keith and both of Denny because of the art-recognized advantageous effects of doing so. The ordinary artisan would have been motivated to do so because Keith teaches the use of DMSO improves the solubility of the 2,5-dimethylphenol chromophore in water. Furthermore, Denny teaches that DMSO minimizes the effects of turbidity caused by proteins and/or lipemia. Such a minimization of turbidity results in the quantification of the absorbance due to only the chromophore. Thus, the use of DUSO in aqueous assays to decrease the effects of turbidity due to lipemia and/or proteins and to improve the solubility of the same organic chromophore is the use of a known technique to improve a similar method in the same way (see MPEP 2148, I., C.). The Examiner notes that the Applicant has provided no evidence of the record of the alleged “criticality” of using DMSO to pre-dissolve the chromophore.
The Applicant asserts that the instant invention is not drawn to the assay of iron,
noting that Denny ‘034 teaches the use of DMSO to accelerate its iron assay and
reduce lipemia/protein turbidity. Applicant argues that ‘034 and ‘370 are not analogous
to the claimed method as neither ‘034 or ‘370 use a xylene chromophore to detect end
product but uses a sulfonated chelator to measure aqueous iron (Remarks, Pg. 29,
Lines 28-35 and Pg. 30, Lines 1-2 and Pg. 37, Lines 3-12 and Pg. 43, Lines 7-10).
In response to Applicant's argument that Denny (‘034 and ‘370) are non-
analogous art, it has been held that a prior art reference must either be in the field of the
inventor's endeavor or, if not, then be reasonably pertinent to the particular problem with
which the inventor was concerned, in order to be relied upon as a basis for rejection of
the claimed invention. See In re Oetiker, 977 F.2d 1448, 24 USPQ2d 1443 (Fed. Cir.
1992). In this case, Denny ('034) and (‘370) are reasonably pertinent to the particular
problem which the inventor was concerned, that is the use of DMSO in the reduction of
interfering influences in an assay for the chromogenic detection of a compound in blood
serum.
The Applicant argues that Denny (‘370) and ('034) teach an iron assay in an
acidic environment while the claimed assay requires the hydrolysis reaction take place
at a pH of about 8.6 and the oxidative coupling take place at a pH of about 10.8
(Remarks, Pg. 30, Line 19 and Pg. 31, Lines 1-3 and Pg. 58, Lines 11-23).
This is not found to be persuasive for the following reasons, Bulger teaches an appropriate basic pH for the coupling reaction. Further, Denny (034) and (‘370) were not cited for the teaching directed to performing a chromogenic iron assay at any particular pH but solely for their teachings related to the advantageous use of DMSO in chromogenic assays of components in serum.
The Applicant argues that interference from lipemia remains in the method of
determining serum iron taught by Denny ‘370 even though the method removes
interference from protein. Applicant concludes that the ordinary artisan could not have
predicted reduced interference from serum lipemia based on pre-dissolving the claimed
chromophore in DMSO as claimed in view of Denny ‘370 (Remarks, Pg. 31, Lines 11-17
and Pg. 32, Lines 1-5).
This is not found to be persuasive for the following reasons, Denny ('370) was cited for its teaching that DMSO inclusion advantageously solubilizes the chromophore in its acid-form, eliminating interference from serum protein and accelerating reaction time. However, while (‘370) teaches that some interference from lipemia associated turbidity can still cause error, (‘034) teaches that the presence of DMSO in the assay reduces/minimizes lipemia and/or protein interference (Column 4, Lines 60-65 and Column 11, Lines 29-34). Therefore, the ordinary artisan could have reasonably predicted reduced interference from serum lipemia based on pre-dissolving the claimed chromophore in DMSO.
The Applicant argues that because serum lipemia interference still remains in the iron assay of Denny (‘370) and (‘034), it would not have been predictable to the ordinary artisan that pre-dissolving the claimed chromophore in DMSO would have reduced serum lipemia associated interference based on the cited prior art with a reasonable expectation of success and therefore no motivation exists to modify the teachings of the ‘519 patent to include DMSO pre-dissolved chromophore (Remarks, Pg. 32, Lines 6- 20 and Pg. 47, Lines 13-18 and Pg. 49, Lines 1-16).
This is not found to be persuasive for the following reasons, as discussed above, Denny (‘034) teaches that the presence of DMSO in the assay reduces/minimizes lipemia and/or protein interference (Column 4, Lines 60-65 and Column 11, Lines 29- 34). Therefore, the ordinary artisan could have reasonably predicted reduced
interference from serum lipemia based on pre-dissolving the claimed chromophore in
DMSO with a reasonable expectation of success. Motivation to make this modification
would come from the potential to increase the solubility of the chromophore as
well as minimizing interference from turbidity associated with serum lipemia and/or
proteins.
The Applicant argues that the claimed invention allegedly provides “surprising
and significant” tolerance of lipemia noting that Denny (‘370) use of DMSO did not
resolve serum lipemia interference and therefore does not provide motivation to modify
the chromophore of ‘519 by pre-dissolving in DMSO (Remarks, Pg. 32, Lines 21-26 and
Pg. 33, Lines 1-4 and Pg. 47, Lines 29-33 and Pg. 48, Lines 1-9 and Pg. 55, Lines 20-21 and Pg. 56 and Pg. 57, Lines 1-16 and Pg. 59, Lines 7-15 and Pg. 60 and Pg. 64, Lines 1-4).
This is not found to be persuasive for the following reasons, Denny (‘034)
teaches that the presence of DMSO in the assay reduces/minimizes lipemia and/or
protein interference (Column 4, Lines 60-65 and Column 11, Lines 29-34). Therefore,
the ordinary artisan could have reasonably predicted reduced interference from serum
lipemia based on pre-dissolving the claimed chromophore in DMSO with a reasonable expectation of success. Thus, the alleged “surprising” results of tolerance of lipemia are no more than an expected beneficial result indicative of obviousness. See MPEP 716.02(c). The Examiner further notes that the Applicant has not provided any evidence with regard to an explanation of the “significance” of the alleged unexpected result.
Applicant asserts that DMSO was selected for its ability to dissolve the chromophore with no expectation that the claimed concentration would affect lipemia interference.
Applicant notes Denny uses concentrations of DMSO which are allegedly higher than the claimed 5 ml/L, therefore it would not have been obvious that a lower concentration would also have beneficial effects (Remarks, Pg. 33, Lines 22-28 and Pg. 34, Lines 1-7 and Pg. 38, Lines 17-18 and Pg. 39, Lines 5-18 and Pg. 40, Lines 6-8 and Pg. 44, Lines 9-19 and Pg. 57, Lines 17-25 and Pg. 58, Lines 1-10 and Pg. 62, Lines 1-19).
This is not found to be persuasive for the following reasons, as discussed above, Keith teaches that the chromophore is poorly soluble and that solubility can be increased with DMSO while the Denny patents teach that DMSO also is known to reduce lipemia in aqueous assays.
In response to Applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which Applicant relies (i.e., a DMSO concentration of 5ml/L) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read i