DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (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.
Priority
The present application filed on 06/12/2024, claims benefit of U.S. Provisional Application No. 63/472,579, filed on 06/12/2023. The content of this application is supported in the original disclosure provided in of U.S. Provisional Application No. 63/472,579, filed on 06/12/2023, thus instant claims 1-4, 6-9, 11, 17, 19, 21, 23-25, and 28-32 have an effective filing date of 06/12/2023.
Information Disclosure Statement
Three Information Disclosure Statement(s) (IDSs), filed on 09/24/2024, 02/19/2026, and 05/06/2026, are acknowledged and considered.
Claim Status
Claims 1-4, 6-9, 11, 17, 19, 21, 23-25, and 28-32 are pending. Claims 5, 10, 12-16, 18, 20, 22, and 26-27 are canceled. Claims 1-4, 6-9, 11, 17, 19, 21, 23-25, and 28-32 are examined herein below.
Claim Objections
Claim 23 has typographical errors that make the claim language read awkwardly and, therefore, should be corrected by both omitting the second “is” and correcting the spelling of “fasted” to “fasting” so that claim 23 reads “The method of claim 6, wherein the sample is obtained from a subject not required to be fasting.”
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.
Claim 32 is 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 32 recites “The method of claim 6, further comprising: start collecting the sample using a device comprising the biosensor; and in response to the detecting that a sufficient amount of fluid has been collected, stop collecting the sample”. The recitation of “the detecting” renders the claim indefinite because it is unclear whether it refers to the detecting of glycated albumin recited in claim 6 from which claim 32 depends, or whether “the detecting” refers solely to the determination of sufficient amount of fluid collection as recited in claim 32.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 17 and 31 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
Claim 17 recites “The method of claim 6, wherein: the sample comprises at least one of a tear, tear film, aqueous layer of the tear film, or aqueous humor sample of a subject; detecting the glycated albumin comprises detecting an amount glycated albumin in the sample , and the method further comprises diagnosing diabetes in the subject in response to determining that a concentration of glycated albumin in the sample is elevated as compared to a control sample or control standard”.
The claims are directed to judicial exceptions, mainly they are abstract ideas, specifically, mental processes that can be performed in the human mind, and/or are merely observing naturally occurring correlations (laws of nature/natural correlation). These judicial exceptions are not integrated into a practical application because there is no practical application recited in the claims such as performing a treatment in a way that is particular, and not merely instructions to "apply" the exception in a generic way. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional steps amount to mere data gathering that does not go beyond well-understood, routine, and conventional activity; as detailed below.
Step 1 – Whether a claim is to a statutory category - YES
The instantly claimed invention is directed to method of detecting the glycated albumin in a biological sample and diagnosing a subject with diabetes based on elevated glycated albumin levels compared to a control level. Therefore, the instantly claimed invention falls into one of the four statutory categories.
Step 2A Prong 1 – Whether the claim is directed to a judicial exception (i.e. Does the claim recite an abstract idea, law of nature, or natural phenomenon?) - YES
Claim 17 recites the following steps which fall under mental processes grouping of abstract ideas and/or laws of nature/natural correlation:
Claim 17 discloses a method of diagnosing a subject as having diabetes in response to determining that a concentration of glycated albumin in the sample is elevated as compared to a control sample or control standard.
These limitations recite a law of nature which is a judicial exception, because it is merely observing the correlation between naturally occurring biomarker (glycated albumin) and its relationship to a disease/disease state (diabetes), and using the levels of this biomarker to make a determination of a subjects’ disease state, which are abstract ideas, specifically, abstract mental processes. Additionally, claim 17 recites that the concentration of glycated albumin in the sample is compared to a control sample or control standard. These comparison steps also represent abstract ideas, specifically, abstract mental processes.
The “diagnosing/determining” steps can be regarded as a law of nature, namely, the naturally occurring correlation between biomarker (glycated albumin) presence/concentration and disease state (diabetes). Regarding the identification of a correlation between the presence of a biomarker in a bodily sample and disease state the courts have held similar claims to be laws of nature and/or natural phenomena, as in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017) which involved claims to simply instruct a user to apply a natural law, by correlating naturally occurring enzyme levels with disease risk. In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services V. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012). The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77).
Regarding the steps in claim 17 reciting a comparison of glycated albumin concentration in a sample to a control sample or control standard, the courts have held similar claims to be abstract mental processes, as in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014) which involved claims to "comparing BRCA sequences and determining the existence of alterations," where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind. The claims are also similar to that in Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011), which involved a claim to “collecting and comparing known information” (both of these court cases are discussed in MPEP 2106.04(a)(2) (II)(A)). The step of “diagnosing/determining” also constitutes an abstract mental process, involving assessing the concentration of the biomarkers in the sample, and then making an evaluation or judgment as to the severity/state of a test subjects’ particular disease (diabetes) based on that level. The comparison and “determining” steps could be performed in the human mind, or by a human using pen and paper, insofar as it reads on comparing levels and drawing conclusions from this about the health status of a subject.
Thus, claims 17 and 31 fall into a judicial exception.
Step 2A: Prong 2 - Does the claim recite additional elements that integrate the judicial exception into a practical application? The Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception.
Claim 17 does not recite any additional elements, including any that would integrate the exception into a practical application of the exception.
Regarding dependent claim 31, it does not recite any additional elements that integrate the judicial exception into a practical application. The additional steps where the concentration of the glycated albumin in the sample is a ratio of an amount of glycated albumin in the sample compared to a total amount of albumin in the sample, are insufficient to integrate the exception into a practical application because the purpose is merely to obtain data to observe a naturally occurring correlation and/or perform a mental process.
As in In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989), such activity involving performing clinical tests on individuals constitutes mere data gathering, and does not go beyond insignificant extra-solution activity. See MPEP §§ MPEP 2106.04(d)(I) and 2106.05(g). There are no subsequent steps recited after the “determining” or comparison steps that would practically apply the method depending on the results of the measurements, e.g., specific treatment or other process steps that are performed after the test subject has been diagnosed with a disease.
In particular, of the claims indicated in the rejection heading, none of the additionally recited limitations amount to an additional element or combination of elements that apply, rely on, or use the judicial exceptions in a manner that impose meaningful limit on the judicial exceptions.
Step 2B; Whether the additional elements contribute an “inventive concept”. In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP 2106.05.
Briefly, claims 17 and 31 do not include additional elements that are sufficient to amount to significantly more than the judicial exception because of the following reasons. Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, has been found to be insufficient to add “significantly more” (MPEP 2106.05(I)(A)).
The additional steps recited above do not add a meaningful limitation to the instant method as they would have been routinely used by those of ordinary skill in the art as supported by Attar et al. (2019). “Electrochemical quantification of glycated and non-glycated human serum albumin in synthetic urine”. ACS applied materials & interfaces, 11(5), 4757-4765, (herein referred to as Attar), Tomlinson et al. (2010). “Comparison of human tear film osmolarity measured by electrical impedance and freezing point depression techniques”. Cornea, 29(9), 1036-1041, (herein referred to as Tomlinson), Shimizu et al. (2019). “A proposed glycemic control marker for the future: glycated albumin”. Journal of Laboratory and Precision Medicine, 4, (herein referred to as Shimizu), and Aihara et al. (03/22/2023). “Evaluation of glycated albumin levels in tears and saliva as a marker in patients with diabetes mellitus”. Diabetes Research and Clinical Practice, 199, 110637, (herein referred to as Aihara), Ramachandra et al. (WO2016077126A1), (herein referred to as Ramachandra), and Skafidas et al. (US 20210239586 A1, Date: 08/05/2021), (herein referred to as Skafidas).
Attar teaches a polymer-based electrode capable of specific detection of human serum albumin, and its glycated derivatives, where the sensor is constructed from a glass microscope slide coated with a synthesized, polythiophene film bearing a protected, iminodiacetic acid motif (abstract). Attar teaches that the electrode surface is then further elaborated to a functional biosensor through deprotection of the iminodiacetic acid, followed by metal-affinity immobilization of a specific and high-affinity, albumin ligand (abstract). Attar teaches that albumin was then quantified in buffer and synthetic urine via electrochemical impedance spectroscopy, and glycated albumin was next bound to a boronic acid-modified, single-cysteine dihydrofolate reductase variant to quantify glycation ratios by square-wave voltammetry (abstract). Attar teaches that the platform offers high sensitivity, specificity, and reproducibility in an inexpensive arrangement, and that the detection limits exceed the requirements for intermediate-term glycemic control monitoring in diabetes patients at 5 and 1 nM for albumin and its glycated forms, respectively (abstract).
Tomlinson teaches a comparison of human tear film osmolarity measured by electrical impedance and freezing point depression techniques (title). Tomlinson teaches that tear hyperosmolarity is diagnostic of dry eye disease (DED), yet difficulty in measurement has limited its utility; development of new instruments could facilitate its clinical application (abstract – Purpose). Tomlinson teaches that their study compares the new OcuSense TearLab osmometer (OTO) (OcuSense, Inc, San Diego, CA), based on electrical impedance ‘‘lab-on-a-chip’’ nanoliter technology, with the freezing point depression Clifton Osmometer (abstract – Purpose). Tomlinson teaches that samples were collected from the inferior tear meniscus for testing with both osmometers, and that tear film osmolarity measured with the OcuSense TearLab system correlates well with the Clifton Osmometer (abstract – Results). Tomlinson teaches that the OTO osmometer is based on electrical impedance and ‘‘lab-on-a-chip’’ technology, which allows the calculation of osmolarity, and that this technique allows osmolarity testing with a very small volume (less than 20 nL), is a quick and accurate measurement of osmolarity of the tear film in a clinical setting, and reduces the evaporation of the fluid (page 1037, column 1, 3rd paragraph).
Throughout the article, Shimizu teaches glycated albumin (GA) as a biomarker for hyperglycemia and using GA as a glycemic control indicator. Shimizu teaches that although HbA1c is the current standard for monitoring glycemic control, HbA1c does not provide a measure of plasma glucose fluctuation or hypoglycemia. Shimizu teaches that GA, on the other hand, reflects the glycemic control status for the previous 2-3 weeks and is, thus, more likely representative of plasma glucose fluctuation. Shimizu further teaches that for diabetic patients with end-stage renal disease (ESRD), HbA1c levels significantly underestimate glycemic control. Shimizu teaches that GA levels better estimated glycemic control for diabetic patients diagnosed with ESRD receiving hemodialysis. Shimizu further teaches reference ranges and cutoff/threshold values for GA levels used for diagnosing and screening diabetes (pg. 6, section "Screening and diagnosis of diabetes" and Table 1; and pg. 7, Table 2).
Aihara teaches the evaluation of glycated albumin levels in tears and saliva as a marker in patients with diabetes mellitus (title). Aihara teaches that GA levels in both tear and saliva samples were significantly correlated with the GA levels in the blood (abstract). Aihara teaches that the GA level (%) is calculated as the ratio of the concentration of GA to total albumin and reflects the glycemic control status over the previous 2 weeks, similar to the blood fructosamine level, and is used in clinical practice in settings where determination of HbA1c is unreliable, such as in pregnant patients or patients with anemia and/or kidney disease (page 1, column 2, 1st paragraph). Aihara teaches that since GA reflects the average glycemic control over the previous about 2 weeks, GA measurement every 1 to 2 weeks could be used to grasp the glycemic control status and prescribe suitable lifestyle modifications for patients, and also that noninvasive GA measurement in tear and saliva specimens, as described in this study is expected to greatly reduce the burden on patients (page 3, column 2, 1st paragraph). Aihara teaches that strict glycemic control is important to minimize the risk of diabetic complications and frequent measurement of blood glucose levels by the invasive finger prick method is useful to achieve strict glycemic control, and measurement of HbA1c in hospital outpatients is also used to determine the glycemic control status (page 1, column 1, 1st paragraph).
Ramachandra teaches SGLT-2 inhibitors, such as ertugliflozin or a co-crystal or a pharmaceutically acceptable salt thereof, for treating and/or preventing metabolic disorders, such as type 1 or type 2 diabetes mellitus or pre-diabetes, in patients with renal impairment or chronic kidney disease (CKD) (abstract). Ramachandra teaches that the use of a number of anti-diabetes agents is restricted in patients with renal impairment, and therefore, there is a need for methods, medicaments and pharmaceutical compositions for the treatment of metabolic disorders, such as type 2 diabetes, in patients with renal impairment or chronic kidney disease (CDK) (page 1, lines 29-32). Ramachandra teaches a method of treating type 2 diabetes comprising: a) determining the eGFR of a patient in need of treatment for prediabetes, type 1 or type 2 diabetes mellitus; b) administering ertugliflozin or a co-crystal or a pharmaceutically acceptable salt thereof to the patient, if the eGFR of the patient is > 30 ml/min/1.73 m2 (page 5, lines 17-23). Ramachandra also teaches measuring % HbAlc of the free plasma glucose (FPG) in the patient (page 27, lines 30-31). Ramachandra teaches that selective inhibition of SGLT2 is expected to normalize plasma glucose by enhancing glucose excretion, and that SGLT2 inhibitors provide an attractive means for the improvement of diabetic conditions without increasing body weight or the risk of hypoglycemia (page 1, lines 17-19).
Throughout the disclosure, Skafidas teaches a device, system and method based on the continuous application of a periodic signal prior to and during sample collection by an electrode. Skafidas teaches the method provides continuous monitoring of the sample collection by a second electrode. Skafidas teaches in some embodiments the method provides assessment of signal fluctuation during sample collection. Skafidas teaches features that help ensure that (1) a sample has completed a circuit between two electrodes prior to measurement initiation and that the fluid is no longer being collected, and (2) the collected fluid is no longer moving within the sampling fluidics. Skafidas further teaches embodiments where a bodily fluid sample may be collected on a test strip. Skafidas teaches that it would be desirable to develop a device, system and method for assessing whether a bodily fluid sample is adequate for measurement and analysis, which can sometimes be a problem with some biological samples due to fluid viscosity ([0010]). Ideally, such devices, systems and methods would be sufficiently easy to use and cost effective to allow them to be used in a point-of-care setting, such as a home, office, gym, or the like, by an untrained user ([0012]).
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s). Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to a law of nature and abstract idea without significantly more. For additional guidance, applicant is directed generally to MPEP § 2106.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s)1-3, 6-8, 11, 24, 25, and 28-30 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Attar et al. (2019). “Electrochemical quantification of glycated and non-glycated human serum albumin in synthetic urine”. ACS applied materials & interfaces, 11(5), 4757-4765, (herein referred to as Attar).
Throughout the article, Attar teaches a biosensor for detecting human serum albumin (HAS) and glycated albumin (GA), referred to as glycated human serum albumin (gHSA), which comprises a modified poly-ethylenedioxythiophene (PEDOT) conductive electrode surface; a sensor electrode comprising copper (II), or Cu (II), with an iminodiacetic acid (IDA) motif immobilized; and a ligand with high affinity for human serum albumin (HSA) and for glycated human serum albumin (gHSA) called His6-tagged GFP peptide (αHSA). Attar teaches the His6-tagged GFP-αHSA ligand forms a ternary complex with the Cu (II) + IDA sensor electrode. Attar teaches detecting the binding of HSA and gHSA present in a sample comprises HSA and gHSA interacting with the αHSA ligand followed by measuring a change in electrical impedance caused by this binding event. Attar teaches determining total HSA + gHSA concentrations and determining the ratio of gHSA compared to total albumin in the sample. Attar also teaches that the platform offers high sensitivity, specificity, and reproducibility in an inexpensive arrangement, and that the detection limits exceed the requirements for intermediate-term glycemic control monitoring in diabetes patients (abstract).
Regarding claim 1, the instant Specification clarifies that the sensor electrode can have one or more ligands that can be layered or immobilized and the ligand layer does not necessarily need to be continuous (instant Specification pg. 11). Using the broadest reasonable interpretation, in light of the Specification, Attar teaches a biosensor for detecting glycated albumin in a biological sample, the biosensor comprising: a conductive layer (PEDOT), a layer of at least one ligand (His6-GFP-αHSA) that can specifically bind glycated albumin (gHSA) interacting with the conductive layer; and at least one sensor electrode (Cu (II) + IDA) [pgs. 4757-4758, Abstract, section "Introduction," and Fig. 1).
Regarding claim 2, Attar teaches the biosensor of claim 1, wherein the at least one sensor electrode is between the conductive layer and the layer of the at least one ligand (pgs. 4757-4758, Abstract, section "Introduction," and Fig. 1).
Regarding claims 3 and 29, Attar teaches the biosensor of claim 1 and the method of claim 6, wherein the at least one ligand comprises one or more antibodies, nucleic acids, proteins, peptides, peptidomimetics, polymers, ions, small molecules, enzymes, or aptamers configured to specifically bind glycated albumin (pgs. 4757-4758, Abstract, section "Introduction," and Fig. 1).
Regarding claim 6, Attar teaches a method for detecting glycated albumin in a sample the method comprising: causing an interaction between the sample and a conductive layer of a biosensor; binding glycated albumin interacting with the conductive layer with at least one ligand of the biosensor; and detecting the glycated albumin with at least one sensor electrode of the biosensor (pg. 4757-4758, Abstract, section "Introduction," and Fig. 1, conductive layer = PEDOT; ligand layer = His6 -GFP-αHSA; sensor electrode = Cu (II) + IDA; and pg. 4760, Fig. 4).
Regarding claim 7, Attar teaches the method of claim 6, wherein binding or interaction of the glycated albumin and the at least one ligand is detected based on a change in electrical impedance caused by the binding or interaction of the glycated albumin in the sample with the at least one ligand (pg. 4757-4758, Abstract, section "Introduction," and Fig. 1; and pg. 4759).
Regarding claim 8, Attar teaches the method of claim 6, wherein the sample comprises one or more of tears, a tear film, an aqueous layer of the tear film, an aqueous humor, sweat, blood, serum, plasma, urine, or saliva (pg. 4757, Abstract and full para 1).
Regarding claim 11, Attar teaches the method of claim 6, wherein detecting the glycated albumin further comprises measuring a change in electrical impedance of the sample, and displaying the change in impedance, thereby detecting one or more analytes in the sample (pg. 4757-4758, Abstract, section "Introduction," and Fig. 1; and pgs. 4759 and 4763).
Regarding claim 24, the instant Specification clarifies that a “data acquisition system can be, e.g., a computer, a hand-held device, a cell phone, and/or a tablet. (Spec pg. 13, full para 2).” Thus, using the broadest reasonable interpretation, and in light of the Specification, Attar teaches a handheld device comprising a biosensor comprising conductive layer; a layer of at least one ligand specific for glycated albumin interacting with the conductive layer; and at least one sensor electrode; and a detector connected to a data acquisition system (pg. 4757-4758, Abstract, section "Introduction," and Fig. 1; pgs. 4762-4763, Fig. 6 and section "Biosensor Fabrication and Characterization"; pg. 4763, Fig. 7 and section "Electrochemical Impedance Spectroscopy").
Regarding claim 25, the instant Specification clarifies that "a digital or analog multimeter that can measure voltage, current, impedance and/or resistance. A detector can also be a spectrophotometer, fluorometer, or a spectrometer like a Raman spectrometer or a Fourier transform infrared spectrometer (Spec, pg. 13, full para 1)." Thus, using the broadest reasonable interpretation, in light of the Specification, Attar teaches a wherein the detector is a multimeter (pgs. 4762-4763, Fig. 6 and section "Biosensor Fabrication and Characterization"; pg. 4763, Fig. 7 and section Electrochemical Impedance Spectroscopy").
Regarding claim 28, Attar teaches the biosensor of claim 1, wherein the layer of the at least one ligand is configured to form at least one of covalent bonds, non-covalent bonds, electrostatic interactions with the conductive layer (pg. 4757-4758, Abstract, section "Introduction," and Fig. 1; pgs. 4762-4763, Fig. 6 and section "Biosensor Fabrication and Characterization"; pg. 4763, Fig. 7 and section "Electrochemical Impedance Spectroscopy").
Regarding claim 30, Attar teaches the method of claim 6, wherein the at least one ligand comprises one or more antibodies, nucleic acids, proteins, peptides, peptidomimetics, polymers, ions, small molecules, enzymes, or aptamers configured to specifically bind glycated albumin (pg. 4757-4758, Abstract, section "Introduction," and Fig. 1).
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.
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) 4 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Attar as applied to claims 1 and 6 above, in view of Tomlinson et al. (2010). “Comparison of human tear film osmolarity measured by electrical impedance and freezing point depression techniques”. Cornea, 29(9), 1036-1041, (herein referred to as Tomlinson), and as evidenced by Justis et al. (2020). “Development of a quantitative immunoassay for tear lacritin proteoforms”. Translational Vision Science & Technology, 9(9), 13-13, (herein referred to as Justis).
The teachings of Attar are incorporated herein.
Regarding claim 4, Attar teaches all of the limitations of claim 1 of the instant application, and also teaches that the modularity of their biosensor device design lends itself to rapid development of alternative sensors with different specificities (page 4761, column 1, 4th paragraph).
However, Attar does not teach that the biosensor is further configured to detect osmolarity of the biological sample.
Tomlinson teaches a comparison of human tear film osmolarity measured by electrical impedance and freezing point depression techniques (title). Tomlinson teaches that tear hyperosmolarity is diagnostic of dry eye disease (DED), yet difficulty in measurement has limited its utility; development of new instruments could facilitate its clinical application (abstract – Purpose). Tomlinson teaches that their study compares the new OcuSense TearLab osmometer (OTO) (OcuSense, Inc, San Diego, CA), based on electrical impedance ‘‘lab-on-a-chip’’ nanoliter technology, with the freezing point depression Clifton Osmometer (abstract – Purpose). Tomlinson teaches that samples were collected from the inferior tear meniscus for testing with both osmometers, and that tear film osmolarity measured with the OcuSense TearLab system correlates well with the Clifton Osmometer (abstract – Results). Tomlinson teaches that the OTO osmometer is based on electrical impedance and ‘‘lab-on-a-chip’’ technology, which allows the calculation of osmolarity, and that this technique allows osmolarity testing with a very small volume (less than 20 nL), is a quick and accurate measurement of osmolarity of the tear film in a clinical setting, and reduces the evaporation of the fluid (page 1037, column 1, 3rd paragraph). Tomlinson also teaches that the OTO osmometer employs a proprietary impedance spectroscopy technique (page 1038, column 1, 3rd paragraph). Tomlinson also teaches that the use of electrical impedance to measure the electrical conductivity of a fluid has been well documented, and that a previous study had used thin film microelectronic technology to produce a flexible sensor that measures osmolarity (page 1038, column 1, 3rd paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the biosensor for detecting human serum albumin (HAS) and glycated albumin (GA) recited by Attar, to be configured to detect osmolarity of the sample, as taught by Tomlinson, as a matter of applying a known technique to a known device ready for improvement to yield predictable results. The biosensor comprising a conductive layer and a sensor electrode that can detect glycated albumin recited by Attar represents a base device upon which the instant invention can be seen as an improvement due to its additionally capacity to detect osmolarity. The osmolarity detection capability taught by Tomlinson would be applicable to the base device of Attar because: both devices/methods use electrochemical impedance spectroscopy for measurement purposes, and Attar teaches that their biosensor design lends itself to modification to create sensors with different specificities.
A person of ordinary skill would have been motivated to make this modification because it would allow for the clinical application of osmolarity as a diagnostic, as taught by Tomlinson, which could improve patient outcomes, and allow for multiplex measurement of glycated albumin and osmolarity to save time and improve diagnostic capabilities. Furthermore, a person of ordinary skill would have had a reasonable expectation of success in making this modification because Tomlinson teaches that the use of electrical impedance to measure the electrical conductivity of a fluid has been well documented, and that a previous study had used thin film microelectronic technology to produce a sensor that measures osmolarity, and Attar uses such a thin film in its sensor.
Regarding claim 9, Attar teaches all of the limitations of claim 6 of the instant application, but does not teach a sample volume is 0.05- 5 µL.
Tomlinson teaches that tear samples were collected from the inferior tear meniscus using Schirmer test strips. Tomlinson teaches holding strips in place for 5 minutes and measuring the length of tear wetting on the strip (pg. 1037, section "Schirmer I Test"). The length of wetting, normally in units of mm, on the Schirmer test strips is called the Schirmer value. To calculate the volume of tear sample collected from a subject, the following line equation is can be used: y = 1.34x - 0.07, where x = uL volume of tears and y = the Schirmer value (see Justis et al., 2020, Trans Vis Sci Tech, 9, 9, 13, pg. 4, Fig. 1D, line equation y=1.34x-0.07; and pg. 5, "Results"). Tomlinson further teaches the following range in Schirmer values for tear samples collected: 0- 8 mm, which when using the line equation to substitute y with 0 mm and 8 mm and solving for x, corresponds to a sample volume range of 0.052- 6.02 uL (see Justis et al., 2020, Trans Vis Sci Tech, 9, 9, 13, pg. pg. 4, Fig. 1D, line equation y=1.34x-0.07; and pg. 5, "Results"). Thus, using the broadest reasonable interpretation, Tomlinson teaches the limitation(s) of claim 9 reciting wherein a volume of the sample is between 0.05 uL and 5 uL, which is within the range taught by Tomlinson (pg. 1037, section "Schirmer I Test"). Tomlinson also teaches that the device and method used is a quick and accurate measurement of osmolarity of the tear film in a clinical setting, and reduces the evaporation of the fluid (page 1037, column 1, 3rd paragraph). Additionally, Tomlinson teaches that obtaining large tear sample volumes necessitates the collection of reflex tears, which in turn could lower the osmolarity values obtained (page 1037, column 1, 2nd paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for detecting human serum albumin (HAS) and glycated albumin (GA) recited by Attar, to use a sample volume of 0.05- 5 µL, as taught by Tomlinson, as it would be “obvious to try”. Attar is silent with regards to the sample volume used, however, a person of ordinary skill would have been motivated to make this modification and use a sample volume of 0.05- 5 µL because Tomlinson teaches that their osmolarity measurement using this volume was accurate and correlated well with other methods. Additionally, Tomlinson teaches that with some sample types, the need to collect relatively large sample volumes can skew the results and not represent true basal levels of osmolarity. The osmolarity detection capability taught by Tomlinson would be applicable to the base device of Attar because: both devices/methods use electrochemical impedance spectroscopy for measurement purposes, and Attar teaches that their biosensor design lends itself to modification to create sensors with different specificities.
Claim(s) 17 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Attar in view of Tomlinson as applied to claims 4 and 9 above, in further view of Shimizu et al. (2019). “A proposed glycemic control marker for the future: glycated albumin”. Journal of Laboratory and Precision Medicine, 4, (herein referred to as Shimizu), and Aihara et al. (03/22/2023). “Evaluation of glycated albumin levels in tears and saliva as a marker in patients with diabetes mellitus”. Diabetes Research and Clinical Practice, 199, 110637, (herein referred to as Aihara), as evidenced by Rescalli et al. (2022). “Analytical challenges in diabetes management: towards glycated albumin point-of-care detection”. Biosensors, 12(9), 687, (herein referred to as Rescalli).
The teachings of Attar and Tomlinson are incorporated herein.
Regarding claim 17, Attar teaches all of the limitations of claim 6 of the instant application and further teaches detecting an amount glycated albumin in the sample (pg. 4757-4758, Abstract, section "Introduction," and Fig.1; and pg. 4760, Fig. 4). Additionally, Attar in view of Tomlinson teaches wherein the sample comprises at least one of a tear, tear film, aqueous layer of the tear film, or aqueous humor sample of a subject.
However, Attar in view of Tomlinson does not teach the method further comprises diagnosing diabetes in the subject in response to determining that a concentration of glycated albumin in the sample is elevated as compared to a control sample or control standard.
Throughout the article, Shimizu teaches glycated albumin (GA) as a biomarker for hyperglycemia and using GA as a glycemic control indicator. Shimizu teaches that although HbA1c is the current standard for monitoring glycemic control, HbA1c does not provide a measure of plasma glucose fluctuation or hypoglycemia. Shimizu teaches that GA, on the other hand, reflects the glycemic control status for the previous 2-3 weeks and is, thus, more likely representative of plasma glucose fluctuation. Shimizu further teaches that for diabetic patients with end-stage renal disease (ESRD), HbA1c levels significantly underestimate glycemic control. Shimizu teaches that GA levels better estimated glycemic control for diabetic patients diagnosed with ESRD receiving hemodialysis. Shimizu further teaches reference ranges and cutoff/threshold values for GA levels used for diagnosing and screening diabetes (pg. 6, section "Screening and diagnosis of diabetes" and Table 1; and pg. 7, Table 2).
Aihara teaches the evaluation of glycated albumin levels in tears and saliva as a marker in patients with diabetes mellitus (title). Aihara teaches that GA levels in both tear and saliva samples were significantly correlated with the GA levels in the blood (abstract). Aihara teaches that the GA level (%) is calculated as the ratio of the concentration of GA to total albumin and reflects the glycemic control status over the previous 2 weeks, similar to the blood fructosamine level, and is used in clinical practice in settings where determination of HbA1c is unreliable, such as in pregnant patients or patients with anemia and/or kidney disease (page 1, column 2, 1st paragraph). Aihara teaches that since GA reflects the average glycemic control over the previous about 2 weeks, GA measurement every 1 to 2 weeks could be used to grasp the glycemic control status and prescribe suitable lifestyle modifications for patients, and also that noninvasive GA measurement in tear and saliva specimens, as described in this study is expected to greatly reduce the burden on patients (page 3, column 2, 1st paragraph). Aihara teaches that strict glycemic control is important to minimize the risk of diabetic complications and frequent measurement of blood glucose levels by the invasive finger prick method is useful to achieve strict glycemic control, and measurement of HbA1c in hospital outpatients is also used to determine the glycemic control status (page 1, column 1, 1st paragraph). Aihara teaches that while all of the aforementioned methods are useful, they are invasive and burdensome (page 1, column 1, 1st paragraph).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for detecting GA in a tear sample as recited by Attar in view of Tomlinson, to use elevated GA levels to diagnose diabetes, as taught by Shimizu, using tear samples, as taught by Aihara, in order to create a rapid method and non-invasive method of diagnosing/monitoring diabetes in a patient. Shimizu teaches that blood glycated albumin levels can be used to diagnose diabetes, and Aihara teaches that tear glycated albumin levels are correlated with blood levels and can be used as a diabetes marker.
A skilled artisan would have been motivated to modify the method of Attar in view of Tomlinson because it would enable a less invasive and less burdensome test (using tears vs. blood) requiring less frequent monitoring using GA as the biomarker (compared to HbA1c), and GA further provides an advantages over the commonly measured HbA1c by being more reliable in pregnant patients or patients with anemia and/or kidney disease, as taught by Aihara. A skilled artisan would have been motivated to measure tear GA using the method of Attar in view of Tomlinson because Attar teaches that the platform offers high sensitivity, specificity, and reproducibility in an inexpensive arrangement, and that the detection limits exceed the requirements for intermediate-term glycemic control monitoring in diabetes patients. Additionally, the need for a point-of-care glycated albumin test for diabetes management was established in the art, as evidenced by Rescalli, which also teaches a potential processing pipeline and highlights how the setup might be employed outside a laboratory environment to reduce the time from measurement to clinical decision (abstract). A person of ordinary skill would have had a reasonable expectation of success in making this modification because Attar in view of Tomlinson teaches the method of measuring GA in a tear sample, using those levels to diagnose diabetes would merely require evaluating GA levels in tear samples versus known levels for diabetes/control patients, which is provided by Aihara.
Regarding claim 31, Attar, Tomlinson, and Shimizu teach all the limitations of claims 6 and 17. Attar further teaches wherein the concentration of the glycated albumin in the sample is a ratio of an amount of glycated albumin in the sample compared to a total amount of albumin in the sample (pg. 4758).
Claim(s) 19 is rejected under 35 U.S.C. 103 as being unpatentable over Attar in view of Tomlinson, Shimizu, and Aihara, as applied to claim 17 above, and further in view of Ramachandra et al. (WO2016077126A1), (herein referred to as Ramachandra).
The teachings of Attar in view of Tomlinson, Shimizu, and Aihara are incorporated herein.
Regarding claim 19, Attar in view of Tomlinson, Shimizu, and Aihara teaches all the limitations of claim 17 of the instant application, but does not teach treating the subject in response to diagnosing diabetes in the subject.
Ramachandra teaches SGLT-2 inhibitors, such as ertugliflozin or a co-crystal or a pharmaceutically acceptable salt thereof, for treating and/or preventing metabolic disorders, such as type 1 or type 2 diabetes mellitus or pre-diabetes, in patients with renal impairment or chronic kidney disease (CKD) (abstract). Ramachandra teaches that the use of a number of anti-diabetes agents is restricted in patients with renal impairment, and therefore, there is a need for methods, medicaments and pharmaceutical compositions for the treatment of metabolic disorders, such as type 2 diabetes, in patients with renal impairment or chronic kidney disease (CDK) (page 1, lines 29-32). Ramachandra teaches a method of treating type 2 diabetes comprising: a) determining the eGFR of a patient in need of treatment for prediabetes, type 1 or type 2 diabetes mellitus; b) administering ertugliflozin or a co-crystal or a pharmaceutically acceptable salt thereof to the patient, if the eGFR of the patient is > 30 ml/min/1.73 m2 (page 5, lines 17-23). Ramachandra also teaches measuring % HbAlc of the free plasma glucose (FPG) in the patient (page 27, lines 30-31). Ramachandra teaches that sodium-glucose co-transport (SGLT) inhibitors have been found to be effective in treating prediabetes, type 1 or type 2 diabetes mellitus, and particularly SGLT2 inhibitors have been shown to block the reabsorption of glucose from the renal filtrate in the glomerulus thereby inducing glucose excretion in the urine (page 1, lines 11-14). Ramachandra teaches that selective inhibition of SGLT2 is expected to normalize plasma glucose by enhancing glucose excretion, and that SGLT2 inhibitors provide an attractive means for the improvement of diabetic conditions without increasing body weight or the risk of hypoglycemia (page 1, lines 17-19).
It would have been prima facie obvious, at the time of filing, to combine the method for detecting GA and using those levels to diagnose diabetes as taught by Attar in view of Tomlinson, Shimizu, and Aihara, to treat the patients with SGLT-2 inhibitors, as taught by Ramachandra, as it would be “obvious to try”. At the time of filing, it was known in the art that subjects diagnosed with diabetes require medical intervention to enable absorption of sugar or provide a supply of replacement insulin hormone to attain healthy blood sugar levels (see Ramachandra). Furthermore, Ramachandra teaches that SGLT2 inhibitors had already been known as an effective diabetes treatment. A skilled artisan would have been motivated to modify the method of Attar in view of Tomlinson, Shimizu, and Aihara to treat the subject diagnosed with diabetes to improve patient outcomes. A person having ordinary skill in the art would have a reasonable expectation of success in making this modification because administering treatments to treat diabetes is a well understood, routine, and conventional activity in the art, Ramachandra teaches that the use of SGLT2 inhibitor treatment of is not restricted in patients with renal impairment.
Claim(s) 21 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Attar as applied to claim 6 above, in view of Shimizu.
The teachings of Attar and Shimizu are incorporated herein.
Regarding claim 21, Attar teaches all of the limitations of claim 6 of the instant application, but does not teach wherein the sample is obtained from a subject having at least one of end-stage renal disease, liver cirrhosis, iron deficiency, or anemia.
Shimizu further teaches obtaining the sample from a subject with end-stage renal disease (pgs. 2-3, section "End stage of renal disease (ESRD)").
It would have been prima facie obvious, at the time of filing, to modify the method for detecting GA as taught by Attar, to measure a sample from a subject with end-stage renal disease, as taught by Shimizu, as it would be “obvious to try”. Shimizu teaches that diabetes is the leading cause of chronic kidney disease (CKD), and that for diabetic patients with end-stage renal disease (ESRD), HbA1c levels significantly underestimate glycemic control. Shimizu teaches that GA levels better estimated glycemic control for diabetic patients diagnosed with ESRD receiving hemodialysis. A skilled artisan would have been motivated to modify the method of detecting GA in a sample as taught by Attar to measure a sample from a subject with end-stage renal disease, because measuring GA in a diabetic subject diagnosed with end-stage renal disease (ESRD) enables more accurate estimate of glycemic control for kidney disease patients (vs. HbA1c), and the GA detection method of Attar provides high sensitivity, specificity, and reproducibility in an inexpensive arrangement, and good detection limits for intermediate-term glycemic control monitoring in diabetes patients. A person having ordinary skill in the art would have a reasonable expectation of success in making this modification to the method of Attar because it merely requires choosing to use a sample from a different patient population that has end-stage renal disease, as the GA detection method would not require a different configuration due to disease type.
Regarding claim 23, Shimizu further teaches wherein the sample is obtained from a subject not required to be fasting (pg. 6, full para 7; and pg. 7, Table 2, indicating fasting for fasting plasma glucose (FPG) measured in conjunction with HbA1c levels but not for GA measurements).
It would have been prima facie obvious, at the time of filing, to modify the method for detecting GA as taught by Attar, to use a sample from a subject that is not required to be fasted, as taught by Shimizu, as it would be “obvious to try”. Shimizu teaches that GA levels reflect a 2-week average of blood glucose levels in a subject, and therefore, a skilled artisan would have recognized that the 2-week average measurement of GA would not be affected by food consumption at the time or close to the time of sample collection. Thus, a skilled artisan would have been motivated to modify the method of Attar because it would avoid inconveniencing the patient by unnecessarily requiring fasting prior to sample collection, and would remove a potential impedance of extra protocols that may skew the results if the patient does not follow it properly. A person having ordinary skill in the art would have a reasonable expectation of success in making this modification to the method of Attar because it would merely require informing the patients that they do not have to be fasted prior to sampling, and because whether the patient is fasted or not will not require alteration to the method of glycated albumin detection.
Claim(s) 32 are rejected under 35 U.S.C. 103 as being unpatentable over Attar as applied to claim 6 above, in view of Skafidas et al. (US 20210239586 A1, Date: 08/05/2021).
The teachings of Attar are incorporated herein.
Regarding claim 32, Attar teaches all of the limitations of claim 6 of the instant application, and also teaches that further development of their method/sensor could establish sensors for point-of-care, at-home, or lab-based gHSA monitoring (page 4761, column 1, 4th paragraph).
However, Attar does not teach that the method further comprises: start collecting the sample using a device comprising the biosensor; and in response to the detecting that a sufficient amount of fluid has been collected, stop collecting the sample .
Throughout the disclosure, Skafidas teaches a device, system and method based on the continuous application of a periodic signal prior to and during sample collection by an electrode. Skafidas teaches the method provides continuous monitoring of the sample collection by a second electrode. Skafidas teaches in some embodiments the method provides assessment of signal fluctuation during sample collection. Skafidas teaches features that help ensure that (1) a sample has completed a circuit between two electrodes prior to measurement initiation and that the fluid is no longer being collected, and (2) the collected fluid is no longer moving within the sampling fluidics. Skafidas further teaches embodiments where a bodily fluid sample may be collected on a test strip. Skafidas teaches that it would be desirable to develop a device, system and method for assessing whether a bodily fluid sample is adequate for measurement and analysis, which can sometimes be a problem with some biological samples due to fluid viscosity ([0010]). Ideally, such devices, systems and methods would be sufficiently easy to use and cost effective to allow them to be used in a point-of-care setting, such as a home, office, gym, or the like, by an untrained user ([0012]).
Skafidas teaches the limitation(s) of claim 32 reciting start collecting the sample using a device and in response to the detecting that a sufficient amount of fluid has been collected, stop collecting the sample (Abstract; Fig. 5; and paras 0013 and 0027).
It would have been prima facie obvious, at the time of filing, to modify the method for detecting glycated albumin in a sample, as taught by Attar, to monitor for sample collection and stop the sample collection when sufficient sample is detected, as taught by Skafidas, as a matter of applying a known technique to a known method ready for improvement to yield predictable results. The GA detection method taught by Attar represents the base device upon which the claimed invention can be seen as an improvement. Skafidas teaches the method of fluid sample detection/monitoring as discussed above, which would be applicable to the base device, as it merely requires a simple electrode configuration, and Attar already uses electrodes in their device/method. Additionally, the method would be applicable because both references teach that their device/methods can be used in the context of point-of-care devices, and Attar specifically points out the modularity of their design. A skilled artisan would have been motivated to make this modification in order to ensure adequate amount of sample is present which can sometimes otherwise be an issue with viscous samples, thereby improving standardization of the sample without processing in order to enable accurate analyte detection. A person of ordinary skill in the art would have a reasonable expectation of success in making this modification to the method of Attar because Attar already has a system that uses electrodes and teaches the modularity of their design, and additionally Skafidas teaches that there is several potential electrode configurations in their design ([0016]) giving a level of adaptability.
Conclusion
For all the reasons discussed above, claims 1-4, 6-9, 11, 17, 19, 21, 23-25, and 28-32 are rejected and therefore no claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER JOSEPH HOFFMAN whose telephone number is (571)272-9080. The examiner can normally be reached 10:00-6:30 M-F.
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/ALEXANDER J. HOFFMAN/ Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 September 18, 2026
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