DETAILED ACTION
Preliminary Amendment filed on 04/22/2024 is acknowledged. Claims 21 is cancelled. Claims 1-20 are pending in the application and are considered on merits.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-3, 5-14 and 16-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Berry et al. (EP 0 470 652) (Berry) in view of Bauer (US 5,302,531, IDS) and Allen et al. (US 4,987,085) (Allen).
Regarding claim 1, Berry discloses an assay device for determining a concentration of sodium in a blood fluid sample (page 5, lines 53-55), wherein the assay device comprises:
a detection membrane (a carrier material, preferably filter paper, cellulose or synthetic fibre fleece) (page 6, line 1-2) and including (1) a complex comprising an ion (potassium ion) and a cryptand (Kryptofix® 221) having an affinity for the ion (page 5, line 53-55) and (2) an ion dependent agent (an enzyme) that is dependent on the ion from the complex (page 5, line 12-17),
Berry teaches a detection carrier including a complex comprising an ion and a cryptand having an affinity for the ion. Berry explains:
“An embodiment of the invention is a process, wherein the second binding agent is present and forms a complex with ‘indicator’ ions, from which complex the indicator ions are displaced stoichiometrically by the analyte ions, and wherein the influence of the displaced indicator ions on the activity of an enzyme is assayed, thereby giving an indirect measure of the concentration of analyte ions. For example, in such a process the enzyme is pyruvate kinase, the indicator ions are potassium, the binding agent is Kryptofix® 221 and the ion to be determined is sodium.” (page 5, lines 12-17).
Thus, Berry’s potassium ion is the claimed “ion,” and Kryptofix® 221 is the claimed cryptand having an affinity for the ion. Berry further confirms in Example C that:
“Potassium chloride is added to this reagent and displaced stoichiometrically from Kryptofix® 221 by sodium ions, thus allowing the sodium ion concentration of the specimen to be quantified.” (page 8, lines 44-45).
Accordingly, Berry discloses that, after sodium from the blood fluid sample is introduced to the detection carrier and binds to the cryptand, the indicator ion is released from the cryptand, and the amount of released indicator ion provides an indirect measurement of the sodium concentration. Berry states that “the released potassium ions stimulat[e] the activity of pyruvate kinase in proportion to the plasma sodium ion concentration” (page 5, lines 53-55).
Berry does not expressly disclose an ion-dependent dye that binds the released ion and elicits a quantifiable response. However, Bauer teaches this known alternative for detecting an ion released from a complexing agent. Bauer teaches that a polyvalent metal indicator ion is initially bound to a complexing agent and that sample cations displace the metal ion, after which the released metal ion binds an ion-dependent indicator to produce a measurable color response (col. 10, lines 34-38):
“[I]n the presence of a sufficient concentration of urinary cations, the polyvalent metal ion first is displaced from the complexing agent, then interacts with the indicator to form a polyvalent metal ion-indicator complex, and a color transition results.” (col. 10, line 34-38).
Bauer further teaches:
“After being displaced from the complexing agent, the polyvalent metal ions are available to interact with the indicator and form a polyvalent metal ion-indicator complex. The polyvalent metal ion-indicator complex is different in color from the reagent composition and test sample, and therefore provides a detectable and measurable color transition. The color transition can be correlated to the specific gravity of the test sample because the color transition is directly proportional to the amount of polyvalent metal ion released from the complexing agent, which in turn is directly proportional to the cation concentration of the test sample.” (col. 5, lines 46-59).
More specifically, Bauer demonstrates a reagent containing magnesium ions and the magnesium-dependent dye calmagite and reports that a sodium-containing solution produced a color response “showing that sodium ions displace magnesium ions from the complexing agent, and that a subsequent interaction between the magnesium ions and calmagite occurs” (col. 17, lines 9-22). Bauer also teaches incorporating the complexing agent, metal ion, and indicator into a porous carrier matrix to form a dry-phase test pad, including carrier matrices formed from filter paper, glass fiber, polymeric films, or microporous membranes (col. 6, lines 52-65; col. 18, lines 9-20).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify Berry’s blood-sodium assay device by using Bauer’s released-ion-dependent color indicator as the readout for the ion displaced from Berry’s binding agent and incorporating the reagents in the test-strip carrier. Berry and Bauer employ the same underlying competitive-displacement principle: sample cations bind a complexing agent, release a previously bound indicator ion, and the released ion is measured to determine the sample-cation concentration. Substituting Bauer’s dye-based indication for Berry’s enzyme-based indication would have been a predictable use of a known ion-detection technique to provide a directly observable and quantifiable response. One of ordinary skill in the art would have been motivated to use Bauer’s dye-based detection in the blood-sodium assay device because Bauer teaches that the resulting ion-indicator complex “provides a detectable and measurable color transition” and that the response can be detected “visually or instrumentally” in a dry-phase test pad (col. 5, lines 46-55; col. 6, lines 45-65).
Berry in view of Bauer does not expressly teach a separation membrane, wherein the detection membrane is located downstream from the separation membrane. Allen, however, teaches a blood-assay device having filtration membranes positioned upstream of a reagent-containing reactant pad. Allen teaches that the device uses a multilayer composite that removes interfering blood cells and feeds the resulting plasma to a measurement strip:
“The composite involves a multiplicity of fluid transferring layers which in the direction of movement through the composite device removes interfering red blood cells, feeding the resulting plasma to a metering layer combination.”
(col. 2, lines 35-43).
Allen further describes the physical arrangement:
“Final filtration membranes 42 and 44 are placed over the reactant pad 36 . . . . Two glass fiber membranes 46 and 48 complete the device and serve to remove substantially all of the red blood cells from blood drop 50, which passes through the membranes and filters until absorbed by reactant pad 36.” (col. 9, lines 22-33).
Thus, Allen’s filtration membranes constitute the claimed separation membrane, and Allen’s reagent-containing reactant pad, which receives the plasma after the blood passes through the filtration membranes, is downstream from the separation membrane in the direction of sample flow.
It would have been obvious to one of ordinary skill in the art before the effective filing date to position Allen’s blood-separation membrane upstream of the dye-containing detection membrane in the blood-sodium assay device. Berry expressly contemplates measuring sodium in blood, serum, or plasma, and Allen teaches a conventional structure for converting an applied whole-blood sample into plasma and delivering that plasma to a reagent pad. One of ordinary skill in the art would have been motivated to use Allen’s upstream filtration membranes so that the sodium-detection reagents receive plasma substantially free of interfering red blood cells, as Allen teaches that the membranes “remove substantially all of the red blood cells” before the blood fluid is absorbed by the reactant pad (Allen, col. 9, lines 28-33).
Regarding claim 12, Berry teaches a method of fabricating an assay device for determining a concentration of sodium in a blood fluid sample. Berry teaches determining sodium concentration in serum or plasma and producing the sodium assay as a dry test-strip device:
“The reagent according to the present invention can be present in dissolved or dry form. It can be present impregnated on an appropriate carrier. A diagnostic agent in the form of a test strip can be produced by impregnating a carrier material, preferably filter paper, cellulose or synthetic fibre fleece, with solutions of the necessary reagents.… This can take place in one or more impregnation steps.” (page 5, line 58 -page 6, line 5).
Berry teaches applying a complex comprising an ion and a cryptand having an affinity for the ion onto a detection membrane. Berry teaches a sodium-assay reagent containing potassium chloride and Kryptofix® 221 and explains:
“Potassium chloride is added to this reagent and displaced stoichiometrically from Kryptofix® 221 by sodium ions, thus allowing the sodium ion concentration of the specimen to be quantified.” (page 8, lines 43 - 46). Thus, potassium is initially complexed with the Kryptofix® 221 cryptand, and Berry’s impregnation of the necessary sodium-assay reagents onto a filter-paper or fibrous carrier applies the potassium–Kryptofix® 221 complex onto a detection membrane.
Berry does not teach applying an ion-dependent dye that is dependent on the ion from the complex onto the detection membrane. Bauer, however, teaches preparing a dry test pad from a reagent composition containing a complexing agent, a polyvalent metal ion, and an indicator dye:
“[T]he reagent composition including a complexing agent, a polyvalent metal ion, and an indicator and a carrier first is prepared. A bibulous matrix, such as filter paper … then is saturated with the reagent composition either by spreading, by immersing or by spraying the reagent composition onto precut strips of the filter paper.” (col. 18, line 49-57). Bauer therefore teaches applying the ion-dependent indicator onto the same detection membrane as the complexed ion.
Bauer further teaches that the resulting indicator is configured as claimed:
“After being displaced from the complexing agent, the polyvalent metal ions are available to interact with the indicator and form a polyvalent metal ion-indicator complex. The polyvalent metal ion-indicator complex is different in color from the reagent composition and test sample, and therefore provides a detectable and measurable color transition. The color transition is directly proportional to the amount of polyvalent metal ion released from the complexing agent, which in turn is directly proportional to the cation concentration of the test sample.” (col. 5, lines 46–58). Bauer specifically demonstrates that sodium displaces magnesium from a complexing agent and that the released magnesium subsequently interacts with calmagite (col. 17, lines 18-22).
It would have been obvious to one of ordinary skill in the art to apply Bauer’s ion-dependent dye to the detection membrane containing Berry’s ion–cryptand complex. Berry and Bauer both use competitive displacement in which sample cations displace a previously complexed indicator ion. One of ordinary skill would have used Bauer’s dye-based detection of the released ion in Berry’s sodium assay to provide a directly detectable and measurable color response, as expressly taught by Bauer.
Berry in view of Bauer does not teach positioning a separation membrane upstream of the detection membrane. Allen teaches this fabrication step by positioning blood-filtration membranes over a reagent-containing reactant pad:
“Final filtration membranes 42 and 44 are placed over the reactant pad 36.… Two glass fiber membranes 46 and 48 complete the device and serve to remove substantially all of the red blood cells from blood drop 50, which passes through the membranes and filters until absorbed by reactant pad 36.” (col. 9, lines 22–33). Thus, Allen positions its separation membranes upstream of the reactant or detection pad in the direction of blood-sample flow.
It would have been obvious to one of ordinary skill in the art to position Allen’s blood-separation membrane upstream of the dye-containing detection membrane in the above sodium assay device. Berry analyzes sodium in serum or plasma, and Allen teaches positioning filtration membranes over a reactant pad to remove substantially all red blood cells before the resulting plasma reaches the pad. One of ordinary skill would have employed this arrangement to provide plasma substantially free of interfering red blood cells to the sodium-detection reagents.
The resulting fabricated assay device is configured such that sodium from the blood-fluid sample binds to Berry’s cryptand and releases the complexed ion, Bauer’s ion-dependent dye binds the released ion and produces a quantifiable response corresponding to the amount of released ion, and the amount of released ion corresponds to the sodium concentration, as taught by the stoichiometric displacement relationship of Berry and the proportional color-response relationship of Bauer.
Regarding claim 2 and 13, Berry in view of Bauer and Allen teaches the assay device of claim 1, as discussed above. Bauer further teaches wherein the ion is a divalent ion. Bauer teaches a reagent composition containing “a polyvalent metal ion having a valence of at least two” and explains that the metal ion is displaced from the complexing agent and thereafter interacts with an indicator to produce the color response (col. 5, lines 25-43).
Accordingly, the released indicator ion supplied by Bauer in the modified blood-sodium assay device is a divalent ion.
Regarding claim 3 and 14, Bauer teaches wherein the ion is Ca²⁺, Fe²⁺, Mg²⁺, or Mn²⁺. Bauer states:
“Accordingly, a polyvalent metal ion useful in the reagent composition is, for example, but not limited to, ferric ion, ferrous ion, calcium ion, magnesium ion, cobalt(II) ion, cobalt(III) ion, cupric ion, mercuric ion, stannic ion, nickel(II) ion, lead(II) ion, manganese(III) ion, cadmium(II) ion, zinc(II) ion, molybdenum(V) ion, chromium(IV) ion and vanadium(III) ion, or mixtures thereof.” (col. 13, lines 16-23).
Bauer thus expressly teaches at least Fe²⁺, Ca²⁺, and Mg²⁺, any one of which satisfies the alternative limitation of claim 3 (Bauer, col. 13, lines 16-23).
Bauer’s Example 1 more particularly teaches a reagent containing magnesium ion and calmagite and states:
“The resulting composition was lavender in color showing that sodium ions displace magnesium ions from the complexing agent, and that a subsequent interaction between the magnesium ions and calmagite occurs.” (col. 17, lines 18-22).
Thus, Bauer expressly demonstrates the claimed sodium-induced release and dye detection using Mg²⁺ (Bauer, col. 17, lines 18-22).
Regarding claim 5 ad 16, Berry in view of Bauer and Allen teaches wherein the ion is present on the detection membrane at a molar quantity ranging from about 0.1 micromoles/square centimeter to about 10 micromoles/square centimeter.
Berry teaches that its reagents may be provided in dry form by impregnating them onto a carrier material to form a test strip. Berry’s Example C employs 2.5 micromoles per assay of Kryptofix® 221 together with potassium chloride and teaches that the potassium is displaced stoichiometrically from the Kryptofix by sodium.
Bauer teaches saturating filter paper with the reagent composition and cutting the impregnated paper into pads having dimensions ranging from approximately 0.25 cm by 0.25 cm to 1.0 cm by 1.0 cm (col. 18, lines 47-65). Incorporating Berry’s stoichiometric potassium–Kryptofix assay quantity into Bauer’s disclosed 1 cm² test pad would provide approximately 2.5 micromoles/cm² of complexed indicator ion, which falls within the claimed range.
Moreover, Bauer expressly recognizes that the amount of indicator ion is selected based on the complexing agent, indicator, and desired maximum color transition, stating that “[t]he particular amount of polyvalent metal ion included in the reagent composition can be determined by a person skilled in the art of designing test kits” and generally disclosing metal-ion concentrations of about 0.02 mM to about 5 mM (col. 12, line 66-col. 13, line 9). It therefore would have been obvious to optimize the ion loading per unit area of the detection membrane within the claimed range to obtain the desired measurable response, because Bauer identifies ion quantity as a result-effective variable affecting the color transition.
Regarding claim 6 and 17, Berry in view of Bauer and Allen teaches the assay device according to claim 1. Berry further teaches wherein the cryptand is present on the detection membrane at a molar quantity ranging from about 0.2 micromoles/square centimeter to about 5 micromoles/square centimeter. Berry teaches incorporating the sodium-assay reagents into a carrier to form a dry test strip and teaches typical Kryptofix® 221 concentrations of about 1-10 mM for the competitive potassium-displacement assay. Berry’s Example C more specifically employs 2.5 micromoles per assay of Kryptofix® 221:
“The final incubation mixture contains for a 10 µl plasma sample: … 2.5 µmol/assay Kryptofix® 221. Potassium chloride is added to this reagent and displaced stoichiometrically from Kryptofix® 221 by sodium ions, thus allowing the sodium ion concentration of the specimen to be quantified.” (page 8, lines 28-45).
Berry does not expressly state the cryptand loading in micromoles per square centimeter. However, Bauer teaches saturating a porous carrier with a reagent composition, drying the carrier to form a test pad, and homogeneously maintaining the reagents throughout the carrier in a known concentration. It would have been obvious to one of ordinary skill in the art to select the amount of Berry’s cryptand deposited per unit area of the detection membrane within the claimed range through routine optimization of the reagent concentration, impregnating volume, and pad area to provide the desired competitive displacement and measurable response. Berry’s disclosed 2.5-micromole assay quantity falls within the claimed numerical quantity when incorporated over a one-square-centimeter detection region.
Regarding claim 7 and 18, Bauer teaches wherein the ion-dependent dye is an azoic dye. Bauer expressly identifies Eriochrome Black T and calmagite as useful indicators that bind a polyvalent metal ion and undergo a color change:
“Examples of indicators that bind to a polyvalent metal ion and undergo a color change include, but are not limited to, … eriochrome black T, rhodizonic acid, calmagite, gallocyanine ….” (col. 14, lines 19-27).
Eriochrome Black T and calmagite are azo dyes; their chemical structures respectively contain naphthylazo and phenylazo groups. (Google Patents) Bauer further demonstrates calmagite as the ion-dependent dye in a sodium-responsive displacement system, stating that sodium displaced magnesium from the complexing agent and that the released magnesium subsequently interacted with calmagite. Accordingly, it would have been obvious to select Bauer’s expressly disclosed azo indicator for the ion-dependent dye in the modified sodium-assay device.
Regarding claim 8 and 19, Berry in view of Bauer and Allen teaches wherein the ion-dependent dye is present on the detection membrane at a molar quantity ranging from about 0.2 micromoles/square centimeter to about 5 micromoles/square centimeter. Bauer teaches that the indicator concentration is selected to provide maximum visual color resolution and maximum sensitivity and discloses:
“The indicator generally is present in the reagent composition in a concentration of about 0.02 mM to about 4 mM, and preferably about 0.04 mM to about 3 mM. To achieve the full advantage of the present invention, the indicator is present in the reagent composition at a concentration of about 0.1 mM to about 2 mM.” (col. 14, lines 13-18).
Bauer further teaches saturating filter paper with the reagent composition and drying the impregnated carrier to form a test pad in which the reagent is held homogeneously at a known concentration. Although Bauer expresses the indicator amount as a solution concentration rather than an areal loading, the amount deposited per square centimeter is determined by the disclosed indicator concentration, the carrier’s uptake per unit area, and the pad dimensions. It would have been obvious to optimize these recognized test-pad parameters to place the dye within the claimed range because Bauer expressly identifies the indicator amount as affecting color resolution and sensitivity.
Regarding claim 9 and 20, Berry teaches wherein the concentration of sodium ranges from about 135 millimolar to about 145 millimolar. Berry teaches that its sodium assay is intended for biological fluids having sodium concentrations greater than 100 mM and operates over:
“the usual analytical range (110–170 mmol/l).” (page 5, lines 48-49).
Berry explains that the sodium-binding agent reduces the free sodium concentration so that the enzyme is most sensitive to small changes within that analytical range. The claimed range of about 135–145 mM is entirely encompassed by Berry’s expressly disclosed range of 110–170 mM.
Regarding claim 10 and 20, Berry in view of Bauer and Allen teaches wherein the separation membrane and the detection membrane contain less than 100 parts per million of residual sodium. Bauer teaches that the carrier used for the assay must be substantially inert and must not contaminate or appreciably alter the sample in a manner that makes the assay inaccurate:
“the carrier matrix is substantially inert with respect to the chemical reagents and does not contaminate the urine or other test samples either by test sample extraction of components comprising the carrier matrix or by appreciably altering the urine or test sample in a way to make the subsequent assays inconclusive, inaccurate or doubtful.” (col. 18, lines 1-7).
In the modified assay device, sodium is the analyte being quantified. Any sodium contributed by the separation or detection membrane would be indistinguishable from sample sodium and would increase the background response and reduce measurement accuracy. It therefore would have been obvious to select and manufacture the separation and detection membranes with sufficiently low residual sodium, including less than 100 ppm, to prevent the membranes from contaminating the sample and producing an inaccurate sodium result, as expressly cautioned against by Bauer. The residual-sodium content would have been a result-effective variable routinely minimized until it no longer materially affected assay accuracy.
Regarding claim 11, Berry in view of Bauer and Allen teaches In-vitro use of the assay device claims 1 for determining the concentration of sodium present in the blood fluid sample (Berry, page 5, lines 53-55).
Claim 4 and 15 is rejected under 35 U.S.C. § 103 as being unpatentable over Berry in view of Bauer and Allen as applied to claim 1 and 12 above, and further in view of He et al. (US 2007/0259443) (He).
Regarding claim 4, Berry teaches the assay device substantially as recited in claim 1 and further teaches wherein the ion is K⁺. Berry teaches:
“In another method of determining plasma sodium ion concentration, the sodium ions are allowed to displace potassium ions from Kryptofix® 221, the released potassium ions stimulating the activity of pyruvate kinase in proportion to the plasma sodium ion concentration.” (page 5, lines 53-55)
Berry’s Example C similarly states:
“Potassium chloride is added to this reagent and displaced stoichiometrically from Kryptofix® 221 by sodium ions, thus allowing the sodium ion concentration of the specimen to be quantified.” (page 8, lines 44-45).
Thus, Berry expressly teaches K⁺ as the ion initially complexed with the cryptand and subsequently released by sodium.
Berry does not teach an ion-dependent dye that binds the released K⁺. He, however, teaches a potassium-dependent colorimetric dye. He teaches:
“The invention relates to a chromoionophore comprising [a] chromophore and an ionophore capable of selectively binding potassium ions,” (par [001])
where contacting the chromoionophore with potassium changes an absorption maximum in the visible region and permits calculation of the potassium concentration (par [0001]). He further teaches that the chromoionophore contains chelating moieties capable of selectively binding potassium and produces a visible response whose magnitude is proportional to the potassium concentration (par [0010]-[0011]).
One of ordinary skill in the art would have selected He’s potassium-selective chromoionophore as the ion-dependent dye in Berry’s potassium-release sodium assay so that released K⁺ would bind the chromoionophore and produce a directly measurable visible response proportional to the amount of released K⁺. He expressly teaches that potassium binding changes the chromophore’s visible absorption properties and that the magnitude of the change is proportional to potassium concentration. Allen supplies the upstream blood-separation membrane and downstream reagent pad for the reasons discussed regarding claim 1.
Conclusion
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/XIAOYUN R XU, Ph.D./ Primary Examiner, Art Unit 1797
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