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 .
DETAILED ACTION
Claims 2-7, 11-17, 19-23, 34-38, 40, 43-53, and 55-56 are canceled. Claims 57-65 are new. Claims 1, 8-10, 18, 33, 39, 41, 42, 54, and 57-65 are pending.
Information Disclosure Statement
The listing of references on pages 58-64 in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. For the browser-executable codes in the instant specification, see page 36 in line 28 and page 37 lines 1-4.
The use of the terms PowerLab (p. 47 lines11) and Toyobo (p. 48 p. 12) which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 54 and 61-63 are objected to because of the following informalities:
Claim 54 recites “a U/mL ratio from 10:5:1 to 49:8:1 U/mL” in line 13, which is redundant and can be replaced with “a ratio from 10:5:1 to 49:8:1 U/mL”
Claims 61-63 recite “8.05-8.95; or 8.15-8.95”, which should be replaced with “8.05-8.95, or 8.15-8.95” because the recitation ‘or 8.15-8.95’ is not a separate clause that needs to be separated by a semicolon.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 8-10, 18, and 61 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The amendment filed on 11/18/2024 has introduced new matter into the claims.
Claim 1, as filed on 11/18/2024 (after the filing date of the application), recites a sensor system for detecting creatinine in a sample, the system comprising: a) a composition comprising the enzymes creatininase, creatinase and sarcosine oxidase, respectively, at a ratio of between 10:5:1 and 49:8:1 U/ml, wherein the enzymes are in solution and the composition comprises a pH of 8.0-8.95; b) at least a first amperometric sensor, and c) a microfluidics circuit adapted for maintaining a steady flow of a sample and a steady flow of said composition into said steady flow of sample to provide a reaction mix; wherein the sensor system is arranged to allow said reaction mix to react for more than 60 seconds and less than 200 seconds before contact with said first amperometric sensor.
Applicant has not pointed out where the amended claims are supported, nor does there appear to be a written description of the claim limitation that requires the microfluidic circuit to be adapted for maintaining ‘a steady flow of said composition into said steady flow of sample to provide a reaction mix’ in the application as filed.
Claim 1 and dependent claims 8-10, 18, and 61 contain new matter because of the limitation that requires the microfluidic circuit to be adapted for maintaining a steady flow of said composition into said steady flow of sample to provide a reaction mixture.
The specification as filed and the original claims do not provide support commensurate in scope with the limitation underlined above. The instant specification states that “[f]or example, where the sensor system comprises microfluidics, in one embodiment the sensor reagent of the invention is flowed continuously into a stream of microdialysate from a subject” (see p. 32 lines 8-10). However, this disclosure is not commensurate in scope with instant claim 1, because the claims do not limit the sample to microdialysate from a subject. Furthermore, this disclosure does not clearly indicate whether the sensor reagent described on p. 32 in line 9 is equivalent to the instantly claimed composition comprising the enzymes creatininase, creatinase and sarcosine oxidase at a ratio of between 10:5:1 and 49:8:1 U/ml, wherein the enzymes are in solution and the composition comprises a pH of 8.0-8.95. Therefore, the specification does not provide support for a microfluidic circuit adapted for maintaining the required flow.
Such limitations recited in the instant claim 1 and dependent claims, which did not appear in the specification or original claims, as filed, introduce new concepts and violate the description requirement of the first paragraph of 35 U.S.C 112. Applicant is required to provide sufficient written support for the limitations recited in the instant claims. Applicant can remove the new matter limitations from the claims to obviate this rejection.
Claim Rejections - 35 USC § 112(b)
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.
Claim 1, 8-10, 18, 33, 39, 41-42, 54, and 57-65 are 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.
Claims 1, 33 and 54 recite “a ratio between 10:5:1 and 49:8:1 U/mL” (see lines 4-5 of claim 1, line 4 of claim 33 and line 13 of claim 54), which renders the claims indefinite because the upper and lower bounds of the range are unclear. The specification discloses the enzyme composition of the present invention may be any suitable ratio, for example 10:5:1 or 15:5:1, or 20:5:1, or 10:10:1, or 15:10:1, 50:20:1, 25:40:1, or 30:40:1, or 35:40:1, or 40:40:1, or 45:40:1. See p. 18 lines 26-36. The units “U/ml” is for enzyme concentration, which is placed after the range of ratio. Therefore, under one interpretation the “between 10:5:1 and 49:8:1” range encompasses (10 to 49 U/ml):(5 to 8 U/ml):(1 U/ml), such that the creatininase is 10 to 49 U/ml, the creatinase is 5 to 8 U/ml and the sarcosine oxidase is 1 U/ml regardless of their relative proportions. Under an alternative interpretation, the creatinase amount scales relative to the creatininase amount such that the creatinase is
1
2
to
1
6.125
the amount of creatininase because 10:5 creatininase to creatinase is equivalent to 2:1 and 49:8 is 6.125:1.
Claims 8-10, 18, 39, 41-42, and 57-65 depend from claim 1, 33 or 54 and are rejected for the reason set forth above.
Claim 1 is indefinite because the claim recites “c) a microfluidics circuit adapted for maintaining a steady flow of a sample and a steady flow of said composition into said steady flow of sample to provide a reaction mix” in lines 10-12. This recitation is indefinite because the specification does not describe structure(s) associated with the required microfluidic circuit adaption, and MPEP 2173.05(g) discloses that when claims merely recite a result achieved by the invention the boundaries of the claim scope may be unclear. Furthermore, the term “steady” recited in lines 10 and 11 is a relative term which renders the claim indefinite. The term “steady” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. As such, one of ordinary skill in the art cannot ascertain the metes and bounds of the required steady flow, as compared to any other flow.
Claims 8-10, 18, and 61 depend from claim 1 and are rejected for the reason set forth above.
Claim 9, recites the limitation “the buffer” in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 9 depends from claim 1, which does not require a buffer. Therefore, it is unclear which buffer is being referenced.
Claim 18 recites the limitation “the system further comprises means to take a sample from a patient or a sample from a closed-loop isolated perfused kidney organ” in lines 2-3, which invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function. The instant specification discloses that the system may comprise means to take a sample from a patient, for example from the blood, urine, plasma, tissue fluid or cerebrospinal fluid, though any sample is suitable. Furthermore, the specification discloses that the system may comprise means to take a sample from a closed-loop isolated perfused organ, for example a kidney. See p. 23 lines 17-20. However, such disclosure is insufficient because the disclosure is devoid of any structure associated with performing the required function of taking a sample from a patient or a sample from a closed-loop isolated perfused kidney. Therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
Claim 33 recites “the composition is dilutable in a dialysate sample to provide a final mixed solution comprising more than 100U/ml creatininase”, which renders the claim indefinite because it is unclear whether the presence of the final mixed solution comprising more than 100U/ml creatininase is required, or whether the intended use of the composition is merely to provide the final mixed solution.
Claims 39, 41-42 and 62 depend from claim 33 and are rejected for the reason set forth above.
Claim 41 recites “the composition or a buffer is at a pH 8.5”, which renders the claim indefinite because the claim does not set forth the structural relationship between the buffer and the composition of claim 33 from which claim 41 depends. Therefore, in one interpretation claim 41 requires the composition of claim 33 to further comprise a buffer that is at a pH of 8.5. In a second interpretation, claim 41 requires a buffer separate from the composition to be at a pH of 8.5. In a third interpretation claim 41 requires the composition of claim 33 to function as a buffer with a pH of 8.5.
Claim 54 recites the term “steady” in lines 4 and 8, which is a relative term that renders the claim indefinite. The term “steady” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. As such, one of ordinary skill in the art cannot ascertain the metes and bounds of the required steady flow, as compared to any other flow. Furthermore, claim 54 recites “b) continuously challenging the sample in the microfluidics circuit with a steady flow of a solution comprising creatininase, creatinase and sarcosine oxidase to provide a reaction mix comprising: i) a pH of 8.0-8.95; and ii) creatininase, creatinase and sarcosine oxidase respectively in solution at a U/mL ratio from 10:5:1 to 49:8:1 U/mL”, which renders the claim indefinite because it is unclear whether the solution or the reaction mix is required to comprise the limitations of i) and ii).
Claims 57-60 and 63-65 depend from claim 54 and are rejected for the reason set forth above.
Claims 59-60 and 63 depend from claim 54 and recite “the composition”, which renders the claims indefinite because it is unclear which composition is being referenced. Claim 54 does not require a “composition”. Therefore, in one interpretation, “the composition” refers to the solution of claim 54 comprising creatininase, creatinase and sarcosine oxidase. Under an alternative interpretation “the composition” refers to the reaction mix of claim 54.
Claim Rejections - 35 USC § 112(d)
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.
Claim 58 is 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.
Claim 58 does not further limit claim 54 from which it depends. Claim 54 requires d) determining a creatinine clearance rate which is indicative of kidney function. Claim 58 recites “wherein a creatinine clearance rate below a reference is indicative of impaired kidney function”. This recitation does not limit the creatinine clearance rate required in claim 54. Rather, the recitation is merely a scientific fact inherent to any determined creatinine clearance rate. As such, claim 58 fails to further limit the subject matter of claim 54.
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, 8-10, 33, 39, 41-42, and 61-62 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (Analytical Chemistry, 2003, 75(3), 525-529) in view of Soya (JP2002303631A, original patent of record 06/22/2022 and translation provided herein), with evidence from Biofargo (2026, HEPPS(EPPS)).
Regarding claim 1, Wang teaches a system for the detection of creatinine. See the abstract. Wang teaches a running buffer containing: 15, 20, and 30 units mL-1 sarcosine oxidase (SOx), creatinase (CI) and creatininase (CA) respectively (i.e. 30:20:15 of creatininase, creatininase, sarcosine oxidase) and a phosphate buffer pH 9.5. See the caption of figure 2. Wang teaches a microchip apparatus that includes an amperometric detector. See p. 526 first paragraph of the ‘apparatus’ section. Wang discloses that in the single-channel chip layout (i.e. microfluidics circuit) the sample mixture and enzyme-reagent streams are mixed at the channel intersection using electrokinetic flow (i.e. a steady flow). See p. 527 the first sentence of the ‘results and discussion’ section and figure 1B for the layout of the microchip. Wang discloses that the enzymatic reaction proceeds further down in the separation channel producing a hydrogen peroxide species, which is separated and detected amperometrically at a migration time. See p. 527 second paragraph of the ‘electrophoresis procedure’ section. Wang teaches a peak around 110 seconds associated with the oxidation of hydrogen peroxide end product. Wang suggests that creatinine can be detected within less than 2 min (i.e. 120 seconds). See p. 527 last full paragraph. Therefore, Wang suggests that the microfluidic system is arranged to allow a reaction mix to react for under 110 seconds before contact with the amperometric sensor for detection, which overlaps with the instantly claimed more than 60 seconds and less than 200 seconds.
Wang does not teach creatininase, creatininase, and sarcosine oxidase respectively at a ratio between 10:5:1 and 49:8:1 U/mL. However, Wang does teach a 30:20:15 units mL-1 ratio.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to optimize Wang’s 30:20:15 U/mL ratio of creatininase, creatininase, and sarcosine oxidase. One of ordinary skill in the art would have been motivated to do so because Wang suggests that successful operation of the microchip requires proper attention to the levels of enzymes used, and that higher enzyme levels can result in increased background noise. See the paragraph spanning ps. 527-528. There would have been a reasonable expectation of success because Wang provides a starting ratio from which one could reasonably optimize. MPEP 2144.05(II)(A) states that “[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Wang does not teach a composition [of enzymes in solution] that comprises a pH of 8.0-8.95. However, Wang teaches enzymes in a phosphate buffer solution with a pH of 9.5.
Soya teaches measuring creatinine in a sample using creatine amidinohydrolase (i.e. creatinase). See [0017]. Soya teaches that the pH during creatinine measurements is in the rage of 5-10, and preferably in the range of 6.5-8.5. Examples of buffer solutions used to achieve the aforementioned pH range include phosphate. See [0039].
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to optimize Wang’s 9.5 pH based on Soya’s suggestion. One of ordinary skill in the art would have been motivated to do so because Soya suggests that phosphate containing buffers should preferably be in a pH range of 6.5 to 8.5 for creatinine measurements. There would have been a reasonable expectation of success because Wang demonstrates using a phosphate containing buffer solution with a pH of 9.5; and Soya suggests that the pH can be between 5-10, but is preferably in the range of 6.5-8.5.
Regarding claim 8, Wang teaches a running buffer containing phosphate buffer. See the caption of figure 2.
Wang does not teach the composition comprising a buffer selected from the group consisting of EPPS, HEPBS, POPSO, HEPPSO and MOBS.
Soya teaches that the pH during creatinine measurements is in the rage of 5-10, and preferably in the range of 6.5-8.5. Examples of buffer solutions used to achieve the aforementioned pH range include phosphate, HEPPS and POPSO. See [0039].
Evidentiary reference Biofargo teaches that HEPPS and EPPS are synonyms. See the bottom of p. 1.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to substitute Soya’s buffer including EPPS or POPSO for Wang’s phosphate buffer. One of ordinary skill in the art would have been motivated to do so, because Soya suggests that certain ions can inhibit the activity of creatine amidinohydrolase (i.e. creatinase) (see [0190]). There would have been a reasonable expectation of success because Wang demonstrates using a phosphate buffer, and Soya suggests that phosphate buffers are interchangeable with HEPPS (i.e. EPPS) and POPSO for creatinine measurement.
Regarding claim 9, Soya teaches that the pH during creatinine measurements is preferably in the range of 6.5-8.5, which encompasses the instantly required pH of 8.5. See [0039].
Regarding claim 10, Soya teaches that the pH during creatinine measurements is preferably in the range of 6.5-8.5, which overlaps with the instantly required pH 8.0-8.5. Soya discloses that examples of buffer solutions used to achieve the aforementioned pH range include HEPPS. See [0039]. As evidenced by Biofargo, HEPPS is synonymous with EPPS. See the bottom of p. 1.
Regarding claim 33, Wang teaches a running buffer containing: 15, 20, and 30 units mL-1 sarcosine oxidase (SOx), creatinase (CI) and creatininase (CA) respectively (i.e. 30:20:15 of creatininase, creatininase, sarcosine oxidase) and a phosphate buffer pH 9.5. See the caption of figure 2. Wang discloses that the enzymatic reaction produces a hydrogen peroxide species, which is separated and detected amperometrically. See p. 527 second paragraph of the ‘electrophoresis procedure’ section.
Wang does not teach creatininase, creatininase, and sarcosine oxidase respectively at a ratio between 10:5:1 and 49:8:1 U/mL. However, Wang does teach a 30:20:15 units mL-1 ratio.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to optimize Wang’s 30:20:15 U/mL ratio of creatininase, creatininase, and sarcosine oxidase. One of ordinary skill in the art would have been motivated to do so because Wang suggests that successful operation of the microchip requires proper attention to the levels of enzymes used, and that higher enzyme levels can result in increased background noise. See the paragraph spanning ps. 527-528. There would have been a reasonable expectation of success because Wang provides a starting ratio from which one could reasonably optimize. MPEP 2144.05(II)(A) states that “[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Wang does not teach a pH of 8.0-8.95. However, Wang teaches enzymes in a phosphate buffer solution with a pH of 9.5.
Soya teaches measuring creatinine in a sample using creatine amidinohydrolase (i.e. creatinase). See [0017]. Soya teaches that the pH during creatinine measurements is in the rage of 5-10, and preferably in the range of 6.5-8.5. Examples of buffer solutions used to achieve the aforementioned pH range include phosphate. See [0039].
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to optimize Wang’s 9.5 pH based on Soy’s suggestion. One of ordinary skill in the art would have been motivated to do so because Soya suggests that phosphate containing buffers should preferably be in a pH range of 6.5-8.5 for creatinine measurements. There would have been a reasonable expectation of success because Wang demonstrates using a phosphate containing buffer solution with a pH of 9.5; and Soya suggests that the pH can be between 5-10, but is preferably in the range of 6.5-8.5.
Wang and Soya do not teach the composition is dilutable in a dialysate sample to provide a final mixed solution comprising more than 100U/ml creatininase.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention that Wang and Soya’s composition comprising creatininase, creatinase and sarcosine oxidase is necessarily dilutable in a dialysate sample to provide a final mixed composition comprising more than 100U/ml creatininase. There would have been a reasonable expectation of success because Wang demonstrates diluting stock solutions (see p. 526 right column first passage).
Regarding claim 39, Wang teaches a running buffer containing phosphate buffer. See the caption of figure 2.
Wang does not teach the composition comprising a buffer selected from the group consisting of EPPS, HEPBS, POPSO, HEPPSO and MOBS.
Soya teaches that the pH during creatinine measurements is in the rage of 5-10, and preferably in the range of 6.5-8.5. Examples of buffer solutions used to achieve the aforementioned pH range include phosphate, HEPPS and POPSO. See [0039]. HEPPS and EPPS are synonyms, as evidenced by Biofargo (bottom of p. 1).
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to substitute Soya’s buffer including EPPS or POPSO for Wang’s phosphate buffer. One of ordinary skill in the art would have been motivated to do so, because Soya suggests that certain ions can inhibit the activity of creatine amidinohydrolase (i.e. creatinase) (see [0190]). There would have been a reasonable expectation of success because Wang demonstrates using a phosphate buffer, and Soya suggests that phosphate buffers are interchangeable with HEPPS (i.e. EPPS) and POPSO for creatinine measurement.
Regarding claim 41, Soya teaches that the pH during creatinine measurements is preferably in the range of 6.5-8.5, which encompasses the instantly required pH of 8.5. See [0039].
Regarding claim 42, Soya teaches that the pH during creatinine measurements is preferably in the range of 6.5-8.5, which overlaps with the instantly required pH 8.0-8.5. Soya discloses that examples of buffer solutions used to achieve the aforementioned pH range include HEPPS. See [0039]. As evidenced by Biofargo, HEPPS is synonymous with EPPS. See the bottom of p. 1.
Regarding claim 61, Soya teaches that the pH during creatinine measurements is preferably in the range of 6.5-8.5, which encompasses the instantly required pH of 8.05-8.95. See [0039].
Regarding claim 62, Soya teaches that the pH during creatinine measurements is preferably in the range of 6.5-8.5, which encompasses the instantly required pH of 8.05-8.95. See [0039].
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Wang (Analytical Chemistry, 2003, 75(3), 525-529) and Soya (JP2002303631A, 06/22/2022 and translation provided herein), as applied to claims 1, 8-10, 33, 39, 41-42, and 61-62 above and further in view of Stjernström (Intensive care medicine, 1992, 19(7), 423-428).
Regarding claim 18, Wang teaches collecting urine samples from healthy volunteers over a 24-h period and filtering the samples. See p. 526 right column first passage. Wang teaches a glass microchip that consists of a four-way injection cross. See p. 526 the first sentence of the ‘apparatus’ section. Wang discloses that the microchip includes a sample reservoir that is filled with mixtures containing creatinine. See p. 527 the first paragraph of the ‘electrophoresis procedure’ section, and see “S” in figure 1(B) for the sample reservoir. Wang suggests that additional sample manipulations, e.g. filtration, may be added to the chip platform, as needed to address the complexity of biological fluids. See p. 529 right column first full paragraph.
Wang and Soya do not teach a system further comprising means to take a sample from a patient or a sample from a closed-loop isolated perfused kidney organ, wherein the sample from a patient is a microdialysate, from blood, urine, plasma, or tissue fluid.
Stjernström teaches using microdialysis to monitor creatinine in patients. See p. 423 right column first passage. Stjernström teaches a microdialysis probe (i.e. means to take a sample from a patient) that is inserted into veins by percutaneous technique. Microdialysate samples are collected in 60 min fractions during 24 hours. Dialysates and blood plasma are analyzed for creatinine. See p. 423 last full paragraph. Stjernström suggests that conventional blood samples often require time consuming handing to avoid contamination from blood cells or enzymatic degradation. Since cells and enzymes do not pass the microdialysis membrane, such handling is not required for dialysate. Furthermore, microorganisms do not pass the membrane so the risk of transmission of blood viral diseases to the hospital staff is reduced. See the paragraph spanning ps. 426-427.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to combine Stjernström’s microdialysis probe for taking microdialysate samples from a patient with Wang’s microchip. One of ordinary skill in the art would have been motivated to do so because Wang suggests adding filtration to the chip platform to address the complexity of biological fluids (p. 529 right column first full paragraph); and Stjernström suggests that the microdialysis probe includes a membrane that filters contaminants from biological fluid and reduces the risk of disease transmission (the paragraph spanning p. 426-427). There would have been a reasonable expectation of success because Wang and Stjernström both take samples over a 24-h period for creatinine monitoring.
Claims 54, 58-60 and 63-64 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (Analytical Chemistry, 2003, 75(3), 525-529) in view of Soya (JP2002303631A, original patent of record 06/22/2022 and translation provided herein), and Hsu (Primer on kidney diseases, 2009 (5th ed.)) with evidence from Biofargo (2026, HEPPS(EPPS)).
Regarding claim 54, Wang discloses that urine levels of creatinine indicate the glomerular filter rate of the kidney (i.e. kidney function). See p. 525 right column first full paragraph. Wang teaches urine samples collected from volunteers (i.e. isolated sample) over 24-h. See p. 526 right column first passage. Wang teaches measuring the renal marker creatinine in clinical samples using a capillary electrophoresis (CE) microchip (i.e. microfluidic circuit). See p. 528 last passage and figure 6. In the chip layout, the sample mixture and enzyme-reagent streams are mixed (i.e. challenged) at the channel intersection using electrokinetic flow (i.e. a steady flow). See p. 527, the first sentence of Results and Discussion. Wang teaches an enzyme-reagent, also referred to as a running buffer, containing: 15, 20, and 30 units mL-1 sarcosine oxidase (SOx), creatinase (CI) and creatininase (CA) respectively (i.e. 30:20:15 of creatininase, creatininase, sarcosine oxidase) and a phosphate buffer pH 9.5. See the caption of figure 2. Wang discloses that the enzymatic reaction produces a hydrogen peroxide species, which is separated and detected amperometrically at a migration time. See p. 527 second paragraph of the ‘electrophoresis procedure’ section. As shown in figure 6, the urine samples show a peak around 110 seconds. Wang suggests that the peak around 110 seconds is the hydrogen peroxide end product. See p. 527 last full paragraph. Therefore, Wang suggests that the microfluidic system is arranged to allow a reaction mix to react for under 110 seconds before contact with the amperometric sensor, which overlaps with the instantly claimed more than 60 seconds and less than 200 seconds. Furthermore, Wang discloses that CA, CI and SOx convert creatinine into H2O2. See p. 526 left column.
Wang does not teach i) a pH of 8.0-8.95. However, Wang teaches enzymes in a phosphate buffer solution with a pH of 9.5.
Soya teaches measuring creatinine in a sample using creatine amidinohydrolase (i.e. creatinase). See [0017]. Soya teaches that the pH during creatinine measurements is in the rage of 5-10, and preferably in the range of 6.5-8.5. Examples of buffer solutions used to achieve the aforementioned pH range include phosphate. See [0039].
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to optimize Wang’s 9.5 pH based on Soya’s suggestion. One of ordinary skill in the art would have been motivated to do so because Soya suggests that phosphate containing buffers should preferably be in a pH range of 6.5-8.5 for creatinine measurements. There would have been a reasonable expectation of success because Wang demonstrates using a phosphate containing buffer solution with a pH of 9.5; and Soya suggests that the pH can be between 5-10, but is preferably in the range of 6.5-8.5.
Wang and Soya do not teach ii) creatininase, creatininase, and sarcosine oxidase respectively at a ratio between 10:5:1 and 49:8:1 U/mL. However, Wang does teach a 30:20:15 units mL-1 ratio.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to optimize Wang’s 30:20:15 U/mL ratio of creatininase, creatininase, and sarcosine oxidase. One of ordinary skill in the art would have been motivated to do so because Wang suggests that successful operation of the microchip requires proper attention to the levels of enzymes used, and that higher enzyme levels can result in increased background noise. See the paragraph spanning ps. 527-528. There would have been a reasonable expectation of success because Wang provides a starting ratio from which one could reasonably optimize. MPEP 2144.05(II)(A) states that “[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Wang does not teach a composition [of enzymes in solution] that comprises a pH of 8.0-8.95. However, Wang teaches enzymes in a phosphate buffer solution with a pH of 9.5.
Soya teaches measuring creatinine in a sample using creatine amidinohydrolase (i.e. creatinase). See [0017]. Soya teaches that the pH during creatinine measurements is in the rage of 5-10, and preferably in the range of 6.5-8.5. Examples of buffer solutions used to achieve the aforementioned pH range include phosphate. See [0039].
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to optimize Wang’s 9.5 pH based on Soya’s suggestion. One of ordinary skill in the art would have been motivated to do so because Soya suggests that phosphate containing buffers should preferably be in a pH range of 6.5-8.5 for creatinine measurements. There would have been a reasonable expectation of success because Wang demonstrates using a phosphate containing buffer solution with a pH of 9.5; and Soya suggests that the pH can be between 5-10, but is preferably in the range of 6.5-8.5.
Wang and Soya do not teach d) determining a creatinine clearance rate which is indicative of kidney function.
Hsu disclose that creatinine clearance (CrCl) reflects kidney function. See p. 20 first passage. Hsu teaches the Cockcroft-Gault equation, which estimates CrCl in milliliters per minute using serum creatinine concentration. See p. 20 left column second paragraph. Hsu discloses that timed 24-hour urine collections have long been used clinically to measure CrCl and hence glomerular filtration rate. See p. 20 right column first paragraph under ‘the role of 24-hour urine collections’ section.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to apply Hsu’s creatinine clearance rate determination to Wang’s urine samples collected over 24-hours. One would have been motivated to do so because Wang suggests that creatinine clearance is a good indicator in the diagnosis of renal disease (see p. 525 right column). There would have been a reasonable expectation of success because Wang demonstrates a urine collection over 24-h, and Hsu teaches using 24-hour urine collections to determine creatinine clearance rates.
Regarding claim 58, Hsu discloses that a glomerular filtration rate <15 mL/min/1.73m2 indicates kidney failure. See table 2-1. Furthermore, Hsu teaches estimating the glomerular filtration rate from the 24-hour urine creatinine clearance and the Cockcroft-Gault equation. See p. 20 right column third paragraph.
Regarding claim 59, Wang teaches a running buffer containing phosphate buffer. See the caption of figure 2.
Wang does not teach the composition comprising a buffer selected from the group consisting of EPPS, HEPBS, POPSO, HEPPSO and MOBS.
Soya teaches that the pH during creatinine measurements is in the rage of 5-10, and preferably in the range of 6.5-8.5. Examples of buffer solutions used to achieve the aforementioned pH range include phosphate, HEPPS and POPSO. See [0039]. HEPPS and EPPS are synonyms, as evidenced by Biofargo (bottom of p. 1).
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to substitute Soya’s buffer including EPPS or POPSO for Wang’s phosphate buffer. One of ordinary skill in the art would have been motivated to do so, because Soya suggests that certain ions can inhibit the activity of creatine amidinohydrolase (i.e. creatinase) (see [0190]). There would have been a reasonable expectation of success because Wang demonstrates using a phosphate buffer, and Soya suggests that phosphate buffers are interchangeable with HEPPS (i.e. EPPS) and POPSO for creatinine measurement.
Regarding claim 60, Soya teaches that the pH during creatinine measurements is preferably in the range of 6.5-8.5, which overlaps with the instantly required pH 8.0-8.5. Soya discloses that examples of buffer solutions used to achieve the aforementioned pH range include HEPPS. See [0039]. As evidenced by Biofargo, HEPPS is synonymous with EPPS. See the bottom of p. 1.
Regarding claim 63, Soya teaches that the pH during creatinine measurements is preferably in the range of 6.5-8.5, which encompasses the instantly required pH of 8.05-8.95. See [0039].
Regarding claim 64, Wang teaches urine samples collected from volunteers (i.e. subjects) over 24-h. See p. 526 right column first passage.
Claims 57 and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (Analytical Chemistry, 2003, 75(3), 525-529) in view of Soya (JP2002303631A, original patent of record 06/22/2022 and translation provided herein), and Hsu (Primer on kidney diseases, 2009 (5th ed.)), as applied to claims 54, 58-60 and 63-64 above, and further in view of Curtis (US 2008/0288399)
Claim interpretation: The instant specification discloses that microdialysis a method for obtaining continuous samples from a tissue or solution of interest. See p. 4 lines 26-27. Therefore, the claimed microdialysate encompasses any sample obtained by microdialysis.
Regarding claim 57, Wang teaches urine samples. See p. 526 right column first passage.
Wang, Soya, and Hsu do not teach a sample that is microdialysate.
Curtis teaches collecting data derived from the perfused organ or tissue. See claim 15 of Curtis. Curtis teaches data collected by microdialysis. See claim 18 of Curtis. Curtis teaches assaying an effluent from a perfused organ including creatinine from the kidney. See [0018]. Curtis teaches measuring creatinine in urine, perfusate and kidneys. See [0120].
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to substitute Curtis’s microdialysate (i.e. the perfusate collected by microdialysis) for Wang’s urine sample. One of ordinary skill in the art would have been motivated to do so because Curtis suggests measuring creatinine perfusate collected by microdialysis. There would have been a reasonable expectation of success because Wang demonstrates using urine samples and Curtis suggests that perfusate collected by microdialysis is interchangeable with urine for creatinine measurements.
Regarding claim 65, Wang teaches urine samples. See p. 526 right column first passage.
Wang, Soya, and Hsu do not teach a sample that is taken from an isolated perfused kidney.
Curtis teaches isolated perfused human kidneys. See [0111]. Curtis teaches assaying an effluent from a perfused organ including creatinine from the kidney. See [0018]. Curtis teaches measuring creatinine in urine, perfusate and kidneys. See [0120].
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to substitute Curtis’s isolated perfused kidney for Curtis’s urine. One of ordinary skill in the art would have been motivated to do so because Curtis suggests measuring creatinine from kidney perfusate. There would have been a reasonable expectation of success because Wang demonstrates using urine samples and Curtis suggests that perfusate is interchangeable with urine for creatinine measurements.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY C BREEN whose telephone number is (571)272-0980. The examiner can normally be reached M-Th 7:30-4:30, F 8:30-1:30 (EDT/EST).
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/K.C.B./ Examiner, Art Unit 1657
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