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 .
Claims 1-16 and 18-46 are pending in this application and were examined on their merits.
Response to Amendment
The Declaration under 37 CFR 1.132 filed 05/11/2026 is insufficient to overcome the rejection of claims 1-16 and 18-46 based upon 35 U.S.C. § 103 as set forth in the last Office action because:
The Declarant argues that DMSO was selected for its ability to dissolve the 2,5-dimethylphenol chromophore with no expectation that the low concentration of DMSO in the composition would significantly reduce lipemia interference. Declarant cites portions of Specification indicating that lipemia was a known source of interference in absorbance assays and that addition of DMSO to the chromophore reagent disclosed in Bulger significantly reduced this interference and increased assay sensitivity (Declaration, Pgs. 4-6, #s 9-11).
This is not found to be persuasive for the following reasons, 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-dimethy|phenol xylenol chromophore is very poor in water. Thus, the ordinary artisan would have found obvious the use of DMSO to dissolve/pre-dissolve the 2,5-dimethylphenol based on its’ recognized poor water solubility and improved solubility in DMSO. 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). Thus, the ordinary artisan would not have been surprised that the inclusion of DMSO in an absorbance assay would have resulted in reduced lipemia interference and therefore increased assay sensitivity.
The Declarant cites the Examples in the Specification wherein inclusion of DMSO in the method and composition of Bulger resulted in reduced lipemia interference and increased assay sensitivity. Declarant concludes that DMSO is a critical solvent for the 2,5-dimethylpheol chromophore in a critical pre-dissolved reagent which results in unexpected improvement in assay sensitivity (Declaration, Pgs. 6-7, #s 12-19).
This is not found to be persuasive for the following reasons, as discussed above and in the prior action, the prior art makes obvious the inclusion of DMSO in the method and composition/kit of Bulger in order to pre-dissolve the 2,5-dimethy|phenol xylenol
chromophore of reagent R2 of the kit of Bulger as taught by Keith et al. because Keith teaches the use of DMSO improves the solubility of the 2,5-dimethylphenol xylenol chromophore over water. Furthermore, both of 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, thereby increasing assay sensitivity.
Thus, the use of DMSO in aqueous assays to decrease the effects of turbidity due to lipemia and/or proteins is not unexpected and the improvement of the solubility of the same organic chromophore in the prior art as claimed is the use of a known techniques to improve a similar method in the same way (see MPEP 2148, I., C.) and even if critical does not overcome the obviousness of doing so.
The Declarant opines that the assays for determining iron disclosed by both Denny Patents do not provide sufficient art-recognized advantages such that the ordinary artisan would have been motivated to use DMSO at the claimed amount to reduce assay lipemia in view of; Bulger not teaching the use of DMSO and the Denny references utilizing a much higher concentration of DMSO than that claimed of 5 ml/L/5.5g/L (Declaration, Pg. 8, #s 21-22).
This is not found to be persuasive for the following reasons, the Examiner has established that the amount of DMSO is an art-recognized, result-effective variable which would be subject to routine optimization and experimentation. Further, the Denny Patents enumerate the advantages of including DMSO in absorbance assays where lipemia interference can occur as well as increasing chromophore solubility. The Declarant has not provided any evidence of the criticality of the amount of DMSO, the comparison being merely its’ presence or absence from the method of Bulger and there is no comparison made to the DMSO concentrations disclosed by the Denny references.
The Declarant asserts that the Denny (‘370) Patent using a higher amount of DMSO, taught elimination of interference from serum protein but that interference from lipemia still remained. The Declarant thus concludes that the ordinary artisan would not have been motivated to use the lower claimed DMSO amount with the aim to reduce lipid interference in their assays (Declaration, Pg. 8, #23).
This is not found to be persuasive for the following reasons, Denny ('370) was
cited primarily 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, 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 and determining the optimal concentration of DMSO by routine experimentation and optimization.
The Declarant argues that as DMSO is absent from the composition of Bulger, the kit of the prior art would not be expected to have the same properties and characteristics when in use (Declaration, Pg. 9, #s 25-26).
In response to Declarant's arguments against the Bulger reference 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 finding of obviousness was not based on Bulger alone but a conclusion that the ordinary artisan would have found obvious the inclusion of DMSO (based on the teachings of Keith and the two Denny Patents) in an aqueous chromogenic absorbance assay using 2,5-dimethylphenol and subject to lipemia interference. The Examiner’s conclusion as to the properties of such a composition, when in use, are based on the combination not Bulger alone.
The Declarant argues that the Denny patents are drawn to assaying the level of iron, comprises metal chelation, low pH and high DMSO concentration while the claimed invention is drawn to assay of acetaminophen, enzymatic synthesis, high pH and low concentration of DMSO, and thus the ordinary artisan would not have been motivated to modify Bulger in view of the Denny patents to arrive at the claimed invention (Declaration, Pg. 9, #s 27-30).
This is not found to be persuasive for the following reasons, Bulger teaches a kit and method for assay of acetaminophen and an appropriate basic pH for the coupling reaction.
Further, Denny (‘034) and ('370) were not cited for any 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. As discussed both above, and in the prior action the determination of an optimal concentration of an art-recognized, result-effective variable (DMSO concentration to reduce lipemia interference and dissolve the chromophore) is not inventive. The
ordinary artisan would have been motivated to make the proposed modification because Keith 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 ordinary artisan would have been motivated to 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 as claimed.
The Declarant cites prior art NPL teaching that DMSO has three concentration dependent modes of action and thus selection of a particular concentration for a given application is critical. Declarant notes that at lower concentrations, DMSO induces cell membrane thinning and increases fluidity while at higher concentrations in induces transient pores and desorption of lipid molecules from cell membranes prior to lipid bilayer disintegration.
Declarant notes that DMSO also intercalates into lipid structures and causes destabilization and the ordinary artisan would not have expected that the claimed low concentration of DMSO would have the same turbidity reducing effect seen in the Denny Patents (Declaration, Pgs. 10-11, #s 31-34).
This is not found to be persuasive for the following reasons, the Declarant’s cited references are drawn to the effects of DMSO on cell lipid membranes. None of the cited references (or the instant claims) for that matter are drawn to cells or the lipid membranes thereof. Thus, the Examiner fails to see the relevance of the cited references particularly as the Denny prior art is specifically drawn to the reduction of lipemia in biological samples prior to assay. Further, none of the cited NPL contain any teaching related to the claimed DMSO concentration or the DMSO concentrations of the cited prior art such that it can be determined where those concentrations fall in the Declarant’s alleged “low” and “elevated” parameters.
Claim Interpretation
Claim 1 contains an optional limitation. “wherein the kit optionally contains DMSO”. The broadest, reasonable interpretation of the claim is that the optional limitation is not required and the claim has been construed thusly.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-16, 18 and 42-44 are newly rejected under 35 U.S.C. § 112(b) or 35 U.S.C. §112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, as necessitated by Applicant’s amendments to the claims filed 05/11/2026. Claim 1 now recites, “where the kit optionally comprises DMSO” and “wherein R2 comprises 2,5-dimethylphenol pre-dissolved in DMSO”. It is unclear how the presence of DMSO in the kit can be optional as the claim requires its presence to pre-dissolve the phenol chromophore. Claims 1-16, 18 and 42-44 are rejected for being dependent upon rejected Claim 1 and failing to remedy the indefiniteness of Claim 1.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 43 and 44 are newly rejected under 35 U.S.C. § 112(d) or pre-AIA 35 U.S.C. § 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends, as necessitated by Applicant’s amendment to the claims filed 05/11/2026. Claim 1 recites. “wherein the DMSO is at a concentration of 5 ml/L” and Claims 43 and 44 recite, “wherein R2 comprises a concentration of 5.5 g/L of DMSO”. To convert: 5ml/L x DMSO density 1.10 g/ml = 5.5 g/L. Thus, Claims 43 and 44 are drawn to the same amount of DMSO as Claim 1 and do not further limit Claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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,
or wherein the DMSO is at a concentration of 5 ml/L, as now required by Claim 1;
wherein the kit can detect 15.1 µg/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-dimethy|phenol 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-dimethy|phenol 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 1 and 43-44 respectively, that the amount of DMSO in the R2 composition is 5 ml/L or 5.5 g/L, one of ordinary skill in the art would recognize that the percentage of DMSO in the 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 µg/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”, 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.
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 MnCl2.4H2O 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); and
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 is pre-dissolved in DMSO, as required by Claims 19, 25 and 40,
or wherein the DMSO is at a concentration of 5 ml/L, as now required by Claim 19;
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 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. 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-dimethy|phenol xylenol chromophore of reagent R2 of the method/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 method/kit comprising 2,5-dimethy|phenol 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 19 and 45-46 respectively, that the amount of DMSO in the R2 composition is 5 ml/L or 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 Denny ('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- dimethylphenol 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 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 Patent 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 the '591 Patent 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 ml/L, as now required by Claims 1 and 19;
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 instant Claims 1 & 19 and 43-46 respectively, that the amount of DMSO in the R2 composition is 5 ml/L or 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”, 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. 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 directly 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 05/11/2026 have been fully considered but they are not persuasive.
The Applicant argues that the cited prior art does not teach or suggest a benefit for modifying the kit/method of Bulger for determining acetaminophen concentration by pre-dissolving the 2,5-dimethylphenol chromophore in DMSO before its addition to the R2 reagent (Remarks, Pg. 15, Lines 11-29 and Pg. 16, Lines 1-2).
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 to pre-dissolve the 2,5-dimethy|phenol xylenol chromophore of reagent R2 of the kit/method 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 Applicant argues that DMSO was selected as the pre-mix solvent for the chromophore solely for its’ ability to dissolve the chromophore with no expectation or intention that the DMSO would reduce lipemia interference, especially given the low concentration used (Remarks, Pg. 16, Lines 3-8).
This is not found to be persuasive for the following reasons, as discussed above, 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-dimethy|phenol xylenol chromophore is very poor in water. Thus, the ordinary artisan would have found obvious the use of DMSO to dissolve/pre-dissolve the 2,5-dimethylphenol based on its’ recognized poor water solubility and improved solubility in DMSO. 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). Thus, the ordinary artisan would not have been surprised that the inclusion of DMSO in an absorbance assay would have resulted in reduced lipemia interference and therefore increased assay sensitivity.
The Applicant argues that the DMSO concentrations used by Denny are higher than that claimed, and the ordinary artisan would not have been motivated to modify the kit/method of Bulger by pre-dissolving the chromophore in DMSO at the claimed lower DMSO concentration with a reasonable expectation of success (Remarks, Pg. 16, Lines 9-27 and Pg. 17, Lines 1-13).
This is not found to be persuasive for the following reasons, as discussed above, the Examiner has established that the amount of DMSO used in the composition is an art-recognized, result-effective variable which would be subject to routine optimization and experimentation. Further, the Denny Patents enumerate the advantages of including DMSO in absorbance assays where lipemia interference can occur as well as increasing chromophore solubility. The Applicant has not provided any evidence of the criticality of the amount of DMSO, and there is no comparison made to the DMSO concentrations disclosed by the Denny references.
Denny ('370) was cited primarily 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, 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 and determining the optimal concentration of DMSO by routine experimentation and optimization. Those of ordinary skill in the art would have been motivated to make the Examiner proposed modifications to Bulger in order to obtain a dissolved soluble chromophore suitable for use in an aqueous assay with reduced lipemia interference. There would have been a reasonable expectation of success in making these modifications because Bulger is drawn to a method/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.
The Applicant notes the Declaration cited prior art NPL teachings that DMSO has three concentration dependent modes of action and thus selection of a particular concentration for a given application is critical. Applicant notes that at lower concentrations, DMSO induces cell membrane thinning and increases fluidity while at higher concentrations in induces transient pores and desorption of lipid molecules from cell membranes prior to lipid bilayer disintegration.
Applicant notes that DMSO also intercalates into lipid structures and causes destabilization and the ordinary artisan would not have expected that the claimed low concentration of DMSO would have the same turbidity reducing effect seen in the Denny Patents (Remarks, Pg. 18, Lines 9-28 and Pg. 19, Lines 1-2 and Pg. 26, Lines 13-23 and Pg. 27, Lines 1-16).
This is not found to be persuasive for the following reasons, the Declaration cited references are drawn to the effects of DMSO on cell lipid membranes. None of the cited references (or the instant claims) for that matter are drawn to cells or the lipid membranes thereof. Thus, the Examiner fails to see the relevance of the cited references particularly as the Denny prior art is specifically drawn to the reduction of lipemia in biological samples prior to assay. Further, none of the cited NPL contain any teaching related to the claimed DMSO concentration or the DMSO concentrations of the cited prior art such that it can be determined where those concentrations fall in the Declarations alleged “low” and “elevated” parameters.
The Applicant argues that Denny uses DMSO as a direct reagent in the serum itself while the claimed invention pre-dissolves an insoluble chromophore in the DMSO (Remarks, Pg. 19, Lines 3-10 and 25-30 and Pg. 20, Lines 1-2).
This is not found to be persuasive for the following reasons, 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 Denny references were cited only for their use of DMSO to reduce lipemia in absorbance assays while Keith taught the use of DMSO to increase the solubility of the chromophore. Thus, the ordinary artisan would have found obvious the pre-dissolution of the known water insoluble chromophore in DMSO prior to use in an aqueous absorbance assay.
The Applicant argues that the Denny patents are drawn to assaying the level of iron, comprises metal chelation, low pH and high DMSO concentration while the claimed invention is drawn to assay of acetaminophen, enzymatic synthesis, high pH and low concentration of DMSO, and thus the ordinary artisan would not have been motivated to modify Bulger in view of the Denny patents to arrive at the claimed invention (Remarks, Pg. 20, Lines 10-26 and Pg. 21 and Pg. 26, Lines 3-12).
This is not found to be persuasive for the following reasons, Bulger teaches a kit and method for assay of acetaminophen and an appropriate basic pH for the coupling reaction.
Further, Denny (‘034) and ('370) were not cited for any 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. As discussed both above, and in the prior action the determination of an optimal concentration of an art-recognized, result-effective variable (DMSO concentration to reduce lipemia interference and dissolve the chromophore) is not inventive. The
ordinary artisan would have been motivated to make the proposed modification to Bulger because Keith 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 ordinary artisan would have been motivated to 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 as claimed.
The Applicant argues that the Denny references are not analogous prior art (Remarks, Pg. 22-25 and Pg. 26, Lines 1-2 and Pg. 27, Lines 18-26 and Pg. 28-32 and Pg. 33, Lines 1-2)
In response to Applicant's argument that the Denny references are nonanalogous 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 1443, 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 assays for the chromogenic detection of a compound in blood
serum.
The Applicant argues, citing the Declaration, that there is evidence of criticality (Remarks, Pg. 33, Lines 16-25 and Pg. 34 and Pg. 35, Lines 1-2).
This is not found to be persuasive for the following reasons, as discussed above and in the prior action, the prior art makes obvious the inclusion of DMSO in the method and composition/kit of Bulger in order to pre-dissolve the 2,5-dimethy|phenol xylenol
chromophore of reagent R2 of the kit of Bulger as taught by Keith et al. because Keith teaches the use of DMSO improves the solubility of the 2,5-dimethylphenol xylenol chromophore over water. Furthermore, both of 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, thereby increasing assay sensitivity.
Thus, the use of DMSO in aqueous assays to decrease the effects of turbidity due to lipemia and/or proteins is not unexpected and the improvement of the solubility of the same organic chromophore in the prior art as claimed is the use of a known techniques to improve a similar method in the same way (see MPEP 2148, I., C.) and even if critical does not overcome the obviousness of doing so.
The Applicant argues that it is not predictable that the higher concentrations of DMSO used by the Denny references would reduce NAC interference in the claimed method (Remarks, Pg. 35, Lines 5-27 and Pg. 36-, Lines 1-9).
This is not found to be persuasive for the following reasons, as discussed above and in the prior action, the prior art makes obvious the inclusion of DMSO in the method and composition/kit of Bulger in order to pre-dissolve the 2,5-dimethy|phenol xylenol
chromophore of reagent R2 of the kit of Bulger as taught by Keith et al. because Keith teaches the use of DMSO improves the solubility of the 2,5-dimethylphenol xylenol chromophore over water. Furthermore, both of 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, thereby increasing assay sensitivity.
Thus, the use of DMSO in aqueous assays to decrease the effects of turbidity due to lipemia and/or proteins is not unexpected, is predictable, and the improvement of the solubility of the same organic chromophore in the prior art as claimed is the use of a known technique to improve a similar method in the same way (see MPEP 2148, I., C.) and even if critical does not overcome the obviousness of doing so.
The Applicant argues that with regard to the non-statutory obviousness type double patenting rejections, the Denny references are not analogous art (Remarks, Pg. 38, Lines 5-25 and Pg. 39, Lines 1-20).
In response to Applicant's argument that the Denny references are nonanalogous 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 1443, 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 assays for the chromogenic detection of a compound in blood
serum.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Sharmila G Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL C MARTIN/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/ Supervisory Patent Examiner, Art Unit 1653
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