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 .
Response to Amendment
The Amendment filed 11/26/2025 has been entered. Claims 16, 17, 20, 21, and 23-31 remain pending in the application. Claims 16, 17, 23, 26, 27, and 29-31 have been amended, and no new claims have been added. Claims 18, 19, and 22 are previously cancelled.
Status of Objections and Rejections
The objection to claims 16, 17, 20, 21, and 23-29, and 31 has been withdrawn in view of Applicant's amendment.
The rejection of claims 16, 17, 20, 21, and 23-31 under 35 U.S.C. 112(b) has been withdrawn in view of Applicant's amendments.
The rejection of claims 16, 17, 20, 21, and 23-31 under 35 U.S.C. 101 is maintained.
The rejection of claims 16, 17, 20, 21, and 23-29 under 35 U.S.C. 103 as being obvious over Kuenstner ‘310 and Kuenstner ‘674 in view of Beyette, and in further view of Gentinetta is withdrawn in view of Applicant’s arguments.
The rejection of claims 30-31 under 35 U.S.C. 103 as being obvious over Beyette is withdrawn in view of Applicant’s amendments.
New grounds of objection are necessitated by the amendments.
New grounds of rejection of claims 30 and 31 under 35 U.S.C. 103 are necessitated by the amendments.
Response to Arguments
Applicant’s arguments, see pp. 13-15, filed 11/26/2025, with respect to the rejection of claims 16, 17, 20, 21, and 23-31 under 35 U.S.C. 101 have been fully considered but they are not persuasive.
Applicant argues (p. 14), “The position of the Office Action is that that the invention, as currently described, is "directed to an abstract idea", in other words, a process that mainly involves mathematical operations or data analysis (the spectral calculations), rather than a technological process. To the contrary, the present invention is directed to a real-world biochemical process that:
Requires a biological sample,
Involves chemical dosing (for example, adding CO or sodium dithionite), and
Uses spectroscopic measurement to determine actual protein contents (e.g., oxyhemoglobin, hemopexin, bilirubin, etc.).
These are physical transformations in a laboratory setting, not theoretical computations.
The spectral analysis merely aids in interpreting those physical changes, and it is part of the technical method, not a standalone mathematical model”.
The Examiner respectfully disagrees.
Claims 16, 30-31 recite a method for determining contents of proteins or heme-derived pigment in a biological sample. As described in the claim, the method includes providing a spectrum, iteratively determining the contents using second derivative spectral analysis, deducing spectral components, removing those components from the spectrum, and outputting the determined contents.
The core of the claimed method therefore is drawn toward data analysis and mathematical relationships, which fall within the abstract idea category of mathematical concepts and mental processes (Step 2A/1 of Alice/Mayo framework). In regard to Applicant’s assertion of the claim limitations being physical transformations, the spectroscopic measurement itself (initial spectrum of a biological sample in step a) merely provides data used as input to the mathematical analysis and does not limit the claimed abstract idea. Providing a spectrum, as claimed, does not result in a change of state of the sample that results in a physical transformation (See MPEP 2106.05(c)). The Examiner, however, acknowledges that specific chemical dosing (e.g., adding CO or sodium dithionite) would constitute a physical transformation of the biological sample by affecting binding of target species. Such a physical transformation may qualify the claim as a whole to amount to significantly more than the judicial exception. However, the chemical dosing step is optional rather than required by the claims (see “or/and” language in step c1). Accordingly, the claim limitations do not amount to significantly more than the judicial exception, and the rejection of claims 16, 17, 20, 21, and 23-31 under 35 U.S.C. 101 is maintained.
Applicant argues (p.14), that “the method introduces specific improvements in quantification accuracy through:
Iterative spectral subtraction, and
Use of second-derivative normalization, a novel approach to reduce cross-interference
among protein spectra.
Indeed, the second-derivative normalization achieves a significant improvement, including a more accurate total plasma heme concentration”
The Examiner respectfully disagrees.
The claims fail to provide a specific improvement to a computer, technology, or a technical field resulting in a practical application of the judicial exception. There is no specific instrumentation (e.g. spectrophotometer) required in claim 16 to provide the initial spectrum, reference spectrum, or means for determining a protein content of the sample. Even though claims 30 and 31 recite a spectrophotometer for generating a spectrum and claim 30 recites a processor for carrying out the determination steps, the functioning of the spectrophotometer and the processor are unchanged. The processor is merely including instructions to apply the abstract idea and the spectrophotometer is performing as normal by generating a spectrum from a sample (See MPEP 2106.04(d) and 2106.05(f)). At most, the claims may offer an improvement in the use of mathematics which is an improvement to the abstract idea, but they fail to provide a practical application of the judicial exception.
Even so, the use of a ratio of second derivatives for normalization in spectral analysis is well-understood, routine and conventional in the art. A reference Myers (US 6473632 B1; 2002) measures the concentration of hemoglobin in blood samples by using a scaling factor created from a ratio of a second derivative value of a sample spectrum and a second derivative value at a reference wavelength (col. 4, ll. 66-67-col. 5, l. 1; Fig. 9). Myers also references Kuenstner (US 5377674 A; 1995, see 35 U.S.C. 103 rejection below) as teaching a similar methodology (col. 1, ll. 26-36; Myers)(column 7, lines 15-18; Kuenstner). These references establish that such mathematical derivative manipulation in regard to blood protein quantification was well-established. Likewise, iterative quantification of individual species in a mixture using reference spectrum subtraction with scaling coefficients was also well-known, routine and convention before the effective filing date of the instant application. A reference, Yaghoobi et al. (“Fast Sparse Raman Spectral Unmixing for Chemical Fingerprinting and Quantification”; 2016), teaches “The algorithm is based on iteratively subtracting the contribution of selected spectra and updating the contribution of each spectrum…The iteration terminates when the maximum number of expected chemicals has been found” (p. 99950E-1, para. 2). Reference Beyette applies a similar iteration to protein samples ([0013])(See 35 U.S.C. 103 rejection below). Finally, using chemical dosing of a sample (using CO, KCN, etc.) to quantify different blood protein species via spectroscopy is well-known, routine and conventional in the art (See claims 23-24 of reference Rieders et al., (US6194218B1; 2001) as well as Beyette and Kuenstner ‘674 in the 35 U.S.C. 103 rejection below. Accordingly, the claim limitations of iterative spectral subtraction, second-derivative ratio normalization, and chemical dosing of a sample do not amount to significantly more than the judicial exception, and the rejection of claims 16, 17, 20, 21, and 23-31 under 35 U.S.C. 101 is maintained.
Applicant argues (p. 15), “Furthermore, these specific improvements are important concerning the practical applications of the invention”. The Applicant refers to dependent claims 26-27 and 29 as providing a practical application of the judicial exception by predicting if a subject is at risk for a disorder, diagnosing a disorder, defining the stages of a disorder, qualifying or disqualifying a medical bag, and monitoring treatment of a disorder and requests that the rejections under 35 U.S.C. § 101 be withdrawn.
The Examiner respectfully disagrees.
The limitations of dependent claims 26-27 and 29 are also drawn to a judicial exception of an abstract idea through mental processing. Predicting if a subject is at risk for a disorder, diagnosing a disorder, defining the stages of a disorder, qualifying or disqualifying a medical bag, and monitoring treatment of a disorder can be performed in the mind by comparing the output of protein content in the sample to known values. The results of the judicial exception in independent claim 16 is being used as an input into even more judicial exceptions of claims 26-27 and 29. Once the comparisons are made, there is no further action. The results of the abstract ideas are not used in practical application, for example, treating the patient with a specific drug when bilirubin levels are above a threshold (See MPEP 2106.04(d)(2)). Accordingly, the judicial exceptions of claim 16, 30-31 and claims 26-27 and 29 are not integrated into practical application, and the rejection of claims 16, 17, 20, 21, and 23-31 under 35 U.S.C. 101 is maintained.
Applicant’s arguments, see pp. 17-24, filed 11/26/2025, with respect to the rejection of claims 16, 17, 20, 21, and 23-29 under 35 U.S.C. 103 have been fully considered and are persuasive. The rejection of claims 16, 17, 20, 21, and 23-29 has been withdrawn.
Claim Objections
Claims 16, 17, 20, 21, and 23-31 are objected to because of the following informalities:
Regarding claim 16, lines 32-33, recite "between a minima and a maxima of the second derivative of the second derivative". Applicant may amend the claim by omitting the second occurrence of “the second derivative” .
Claims 17, 20, 21, and 23-29 are rejected upon dependency of objected claim 16.
Regarding claim 16, ll. 21, 24, and 34, recite “said”. Applicant can amend the claim to read “the”.
Claims 17, 20, 21, and 23-29 are rejected upon dependency of objected claim 16.
Regarding claim 30, step c1), line 1, recites “first a protein”. Applicant can amend the claim to read “a first protein”.
Regarding claim 30, step d), line 1, recites “in first protein”. Applicant can amend the claim to read “in the first protein”.
Regarding claim 31, step d) l. 1, recites “in first protein”. Applicant can amend the claim to read “in the first protein”.
Regarding claim 31, line 6, recites “in protein”. Applicant can amend the claim to read “of proteins”.
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 16, 17, 20, 21, and 23-31 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (Step 2A/1)(i.e., a law of nature, a natural phenomenon, or an abstract idea) without practical application (Step 2A/2) or significantly more (Step 2B) (See MPEP 2106). Although the instant claims encompass a process (claim 16), a manufacture (claim 30), and a machine (claim 31)(Step 1), they are directed to the following judicial exceptions including abstract ideas through mental processes, mathematical calculations and law of nature through natural correlation (Step 2, Prong 1):
Claim 16 recites:
- b) setting a current spectrum as the initial spectrum.
- c) iterating the following steps:
- c1) determining the content of a first protein in the sample independently of a content of a second protein… the determination being carried out by using a spectral analysis of the current spectrum… wherein said spectral analysis comprises:
providing a reference spectrum associated with the first protein, and
calculating a normalization coefficient between the reference spectrum and the current spectrum, said normalization coefficient is the ratio between the value of second derivative of the first protein and the value of second derivative of the reference spectrum, the value of second derivative of the reference spectrum being defined as the maximum amplitude over the wavelength range of interest of the second derivative with wavelength of the reference spectrum or the maximum value over the wavelength range of interest of an absolute value of the difference between a minima and a maxima of the second derivative of the second derivative with wavelength of the reference spectrum”,
- c2) deducing an overall spectral component on the wavelength range of interest associated to the first protein based on the determined content for the first protein,
- c3) removing the deduced spectral component from the current spectrum,
- d) outputting the determined contents in said protein, wherein each of steps c1), c2), and c3) is performed for the first protein, and step c) is iterated successively until the content of the first protein is determined for at least oxyhemoglobin, methemoglobin, carboxyhemoglobin, heme bound to serum albumin and hemopexin and bilirubin.
Claims 26-27, and 29 recite predicting if a subject is at risk for a disorder, diagnosing a disorder, defining the stages of a disorder, qualifying or disqualifying a medical bag, and monitoring treatment of a disorder.
Claims 30 and 31 recite the same abstract ideas (1)-(6) except for the definition of chemical dosing.
The claims are directed to the concept of analyzing a biological sample to determine protein content by measuring and processing spectral data.
Recitation b) is directed to the abstract idea of a mental process in naming a spectrum which can be performed in the mind. Recitation c1) is directed to the abstract idea of mathematical calculations of spectral data. Providing a reference spectrum is retrieval of data by remembering what a known protein’s spectrum looks like. A human with training could mentally compare the shape of two graphs (the current spectrum and the reference spectrum). Calculating the normalization coefficient is a simple ratio (value of the second derivative from the sample divided by the value of the second derivative of a protein peak from the reference). Ratios are basic arithmetic operations that can be carried out mentally, on paper, or with pencil and paper, without requiring a computer or specialized machine. A derivative is a simple rate of change, and a second derivative is the rate of change of the first derivative. Labeling different points on the curve and calculating these rates and maximums can be performed in the mind and by hand. Conceptually, a person could look at curves of different spectra, estimate which spectrum has the sharpest slope change, and proceed in order by mentally ranking the graphs from largest to smallest change. Recitation c2) is a mathematical operation that applies the normalization coefficient of c1) to the reference spectrum in order to produce another dataset. Such mathematical manipulation of data is an abstract idea. Because the step can be performed in the human mind or with pen and paper (by scaling and subtracting known spectral curves), it falls within the judicial exception of a mental process. Recitation c3) can be performed by overlaying the deduced overall spectrum of c2) with the current spectrum and tracing the residual curve that is created. Since it can be carried out mentally or with simple arithmetic tools, it falls into the mental process abstract idea category along with recitation d). Outputting is conceptually no different from mentally reporting results, and a human can easily write the numbers down after calculating them from the previous step. Although claims 30 and 31 are within the statutory categories of a manufacture (claim 30) and a machine (claim 31), they recite nothing more than storing or performing abstract data analysis or generic instruments doing conventional tasks (See Electric Power Group, LLC v. ALSTOM SA, 830 F. 3d 1350). These tasks can still be performed by a human through mental processing and mathematical calculations as explained above according to claim 16. See Alice Corp. v. CLS Bank Int’l, 573 U.S. 208 (2014)). As a whole, the method depends on the naturally occurring relationship between protein concentration and spectral absorbance, which is a law of nature through natural correlation (Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66 (2012). The claims are therefore directed toward a judicial exception.
Step 2A/2: These judicial exceptions are not integrated into a practical application.
Providing an initial spectrum is merely data gathering (pre-solution activity, see MPEP 2106.05 (g)) only for the purpose of executing the abstract idea of the determination step. Simply outputting the result of a mental process by displaying the results of the determination step of protein content is considered post-solution activity (MPEP 2106.05 (g)). Claims 30 and 31 invoke a spectrophotometer, dosing materials, and an analysis system or computer. These are recited at a high level of generality and used only for their basic, routine functions: the spectrophotometer collects spectral data, the dosing step involves applying known reagents to shift equilibria in a conventional way, and the computer processes data mathematically. The claims simply apply the abstract idea of data analysis in the context of well-known laboratory tools. The processor is recited at a high-level of generality (i.e., as a generic processor performing a generic computer function of inputting data into a mathematic equation, drawing conclusions, displaying results, and drawing more conclusions) such that it amounts no more than mere instructions to apply the exception using a generic computer component. The processor does not carry out these steps using novel functionality, for example by use of artificial intelligence that trains an algorithm for deep learning, but rather automates a manual task of mathematical calculations and decision making (See MPEP 2106.05 (a)(I). The display of information does not provide a practical application. Additionally, predicting if a subject is at risk for a disorder, diagnosing a disorder, defining the stages of a disorder, qualifying or disqualifying a medical bag, and monitoring treatment of a disorder can be performed in the mind by comparing the output of protein content in the sample to known values. Once the comparisons are made, there is no further action. The results of the abstract ideas are not used in practical application, for example, treating the patient with a specific drug when bilirubin levels are above a threshold (See MPEP 2106.04(d)(2)). Accordingly, these additional elements do not integrate the abstract idea into a practical application because it does not impose any meaningful limits on practicing the abstract ideas. The claims are directed to an abstract idea with no practical application.
Step 2B: The claims do not include additional elements that are sufficient to amount to
significantly more than the judicial exception
Claims 16: The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As mentioned in Step 2A/2, the previous process steps of the claims are abstract ideas, mere data gathering, and are routine and conventional in the art. The claims fail to provide a specific improvement to a computer, technology, or a technical field resulting in a practical application of the judicial exception. There is no specific instrumentation (e.g. spectrophotometer) required in claim 16 to provide the initial spectrum, reference spectrum, or means for determining a protein content of the sample. Even though claims 30 and 31 recite a spectrophotometer for generating a spectrum and claim 30 recites a processor for carrying out the determination steps, the functioning of the spectrophotometer and the processor are unchanged. The processor is merely including instructions to apply the abstract idea and the spectrophotometer is performing as normal by generating a spectrum from a sample (See MPEP 2106.04(d) and 2106.05(f)). At most, the claims may offer an improvement in the use of mathematics which is an improvement to the abstract idea, but they fail to provide a practical application of the judicial exception.
Even so, the use of a ratio of second derivatives for normalization in spectral analysis is well-understood, routine and conventional in the art. A reference Myers (US 6473632 B1; 2002) measures the concentration of hemoglobin in blood samples by using a scaling factor created from a ratio of a second derivative value of a sample spectrum and a second derivative value at a reference wavelength (col. 4, ll. 66-67-col. 5, l. 1; Fig. 9). Myers also references Kuenstner (US 5377674 A; 1995, see 35 U.S.C. 103 rejection below) as teaching a similar methodology (col. 1, ll. 26-36; Myers)(column 7, lines 15-18; Kuenstner). These references establish that such mathematical derivative manipulation in regard to blood protein quantification was well-established. Likewise, iterative quantification of individual species in a mixture using reference spectrum subtraction with scaling coefficients was also well-known, routine and convention before the effective filing date of the instant application. A reference, Yaghoobi et al. (“Fast Sparse Raman Spectral Unmixing for Chemical Fingerprinting and Quantification”; 2016), teaches “The algorithm is based on iteratively subtracting the contribution of selected spectra and updating the contribution of each spectrum…The iteration terminates when the maximum number of expected chemicals has been found” (p. 99950E-1, para. 2). Reference Beyette applies a similar iteration to protein samples ([0013])(See 35 U.S.C. 103 rejection below). Finally, using chemical dosing of a sample (using CO, KCN, etc.) to quantify different blood protein species via spectroscopy is well-known, routine and conventional in the art (See claims 23-24 of reference Rieders et al., (US6194218B1; 2001) as well as Beyette and Kuenstner ‘674 in the 35 U.S.C. 103 rejection below. Accordingly, the claim limitations of iterative spectral subtraction, second-derivative ratio normalization, and chemical dosing of a sample do not amount to significantly more than the judicial exception, and the rejection of claim 16 under 35 U.S.C. 101 is maintained. Claims 17, 20-21, 23-29 are rejected upon dependency of all the limitations of claim 16.
Claims 30 and 31. None of the additional parts add significantly more to the judicial exceptions. Claim 30 includes additional computer parts (computer readable medium, computer program that is “loadable,” into a data processing unit. Claim 31 includes a spectrophotometer. All of these claim limitations especially at the level of generality claimed— are well understood, routine and conventional (WURC) in the art and therefore do not add significantly more to the judicial exceptions. See Step 2B assessment for claim 16 above and MPEP 2106.05 (d). The rejection of claims 30-31 under 35 U.S.C. 101 is maintained.
Claims 17, 20-21, 23-29 are rejected upon dependency of rejected claims 16, 30-31.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Beyette (US 20060034730 A1) in view of Gentinetta (US 20200237652 A1, EFD 2018-08-08).
Regarding claim 30, Beyette teaches a computer program product comprising a non-transitory computer readable medium (a processor; [0016]), storing instructions that, when executed by a processor cause the processor to perform steps (subjects the output signal to an algorithm; [0016]), the computer program being loadable into a data-processing unit (the algorithm is functionally capable of performing the intended use of being loadable into a data-processing unit) of a method for determining a content of proteins or heme-derived pigment in a biological sample ("spectral content of the CSF obtained from LP," wherein "the analytes in the CSF sample to be analyzed comprise methemoglobin, oxyhemoglobin, bilirubin, or a combination thereof"; [0064])(Beyette defines CSP and LP to be cerebral spinal fluid and lumbar puncture, respectively), the method for determining comprising the steps of:
a) providing an initial spectrum of the sample on a wavelength range of interest (obtaining a sample of the fluid and generating a measured spectral absorption curve (F) of the sample over each wavelength range determined in step (d); [0067])("Spectrophotometer results of CSF following SAH obtained from LP" shown in Fig. 1 includes a wavelength),
b) setting a current spectrum that is iteratively updated at step d) as the initial spectrum (Paragraph [0066] explains that scaled spectrum is subtracted from the SAH spectrum and “The process goes on iteratively, until it converges to some methemoglobin curve”),
c) iterating the following steps:
c1) determining the content of first a protein or heme-derived pigment in the sample independently of a content of a second protein or heme-derived pigment, wherein the first and second proteins or heme-derived pigment are chosen among which oxyhemoglobin (oxyhemoglobin; [0064]), methemoglobin (methemoglobin; [0064]), heme bound to serum albumin, heme bound to hemopexin and bilirubin (bilirubin; [0064])(Paragraph ([0096] describes using standard curves for the first and second protein as shown in Fig. 4a and 4b wherein the methemoglobin is fixed with varying amounts of bilirubin and bilirubin is fixed with varying amounts of methemoglobin, respectively)(Holding the first protein constant while varying the second protein and vice versa results in an independent determination of the protein content of interest) the determination being carried out by using a spectral analysis of the current spectrum ("These standard curves are used as quantization levels for estimating the bilirubin or methemoglobin values in a CSF/SAH sample"; [0098]) or/and a chemical dosing (The limitation of "or/and a chemical dosing" is not being considered due to the optional “or” statement),
c2) deducing an overall spectral component on the wavelength range of interest (over the specified wavelength region; [0098]) associated to the first protein or heme-derived pigment based on the determined content for the first protein or heme-derived pigment ("(a) using a spectrophotometer to generate at least one standard spectral absorption curve for the analyte; (b) using a spectrophotometer to generate at least one standard spectral absorption curve for the contaminant; (c) computing a sum spectral absorption curve (F.sub.sum) for the fluid by adding the spectral absorptions curves generated in steps (a) and (b); ); (d) comparing the spectral absorption curves generated in steps (a) and (b) to determine a wavelength range wherein the analyte dominates and a wavelength region wherein the contaminant dominates," wherein the analyte is the first protein and the contaminant is the second protein)(Under broadest reasonable interpretation, the Examiner interprets “deducing” to mean determining or estimating a spectral component based on available data, including scaling, fitting, or calculation), and
c3) removing the deduced spectral component from the current spectrum ("computing a residual curve over all measured wavelengths," wherein the residual curves are computed for both the first and second protein; [0067][0066]),
d) outputting the determined contents in first [sic] protein or heme-derived pigment, wherein each of steps c1), c2), and c3) is performed for the first protein, and step c) is iterated successively (iteratively repeating steps (h)-(k) until a standard contaminant curve and a standard analyte curve are selected in consecutive iterations)(Since the method comprises "the step of obtaining sequential cerebrospinal fluid samples from the individual," the method meets the limitation of the iteration of step c)) until the content is determined for at least oxyhemoglobin, methemoglobin, and bilirubin (the analytes in the CSF sample to be analyzed comprise methemoglobin, oxyhemoglobin, bilirubin, or a combination thereof; [0064])("The iterative procedure is continued until M.sub.i and B.sub.i converge," for the result of "estimating bilirubin and methemoglobin in the SAH data," wherein M.sub.i and B.sub.i are the absorption curves of methemoglobin and bilirubin, respectively with an index of "i" iterations; [0098])(See Figs. 8a, 8b, 9,14-19).
wherein each of steps c1), c2), and c3) is performed for the first protein or heme-derived pigment, and step c) is iterated successively (iteratively repeating steps (h)-(k) until a standard contaminant curve and a standard analyte curve are selected in consecutive iterations; [0013]) until the content is determined for at least oxyhemoglobin, methemoglobin, heme bound to serum albumin and hemopexin and bilirubin (the algorithm is functionally capable of performing the intended use of iterating until the content of these proteins are determined).
Beyette fails to teach determining the content of heme bound to serum albumin, heme bound to hemopexin.
Gentinetta teaches:
Determining the content of heme bound to serum albumin, heme bound to hemopexin (the different spectral characteristics of heme when it is bound to albumin or to hemopexin can be used to determine the concentration of the heme-hemopexin complex in the solution; [0169]) via chemical dosing by
dosing total hemopexin by adding heme (met-Hb (Fe.sup.3+) (15 μM in PBS) or hemin bound to human albumin (25 μM in PBS) was incubated with 10 μM human Hpx,” wherein under broadest reasonable interpretation dosing is achieved since a reagent (met-Hb or hemin bound to human albumin) is added that delivers heme to Hpx, revealing Hpx content via spectral analysis (“in order to follow the transition of met-Hb/hemin to heme-Hpx over time”); [0193])( the concentrations of met-Hb/hemin and heme-Hpx in the reaction mixtures were resolved by deconvolution of the full spectrum; [0193]) ,
Gentinetta is considered to be analogous to the claimed invention because it is in the same field of endeavor for determining the protein content in a biological sample. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Beyette by incorporating the teachings of Gentinetta by further determining the content of heme-HSA and heme-HPX and subtracting these peaks from the current spectrum. These proteins are natural, clinically relevant heme-protein complexes that interfere spectrally in blood. Beyette states that “a potential pitfall in the clinical usefulness of a bilirubin assay to detect an SAH is the interference caused by hemoglobin concentrations” ([0077]). A person of ordinary skill in the art would have been motivated to modify Beyette’s iterative subtraction method to quantify these analytes since they are spectroscopically distinguishable and the extension would have been a predictable use of the same methods (See MPEP 2143(I)(C)).
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Beyette (US 20060034730 A1).
Regarding claim 31, Beyette teaches an apparatus for determining a content of proteins or heme-derived pigment in a biological sample("spectral content of the CSF obtained from LP," wherein "the analytes in the CSF sample to be analyzed comprise methemoglobin, oxyhemoglobin, bilirubin, or a combination thereof"; [0064])(Beyette defines CSP and LP to be cerebral spinal fluid and lumbar puncture, respectively), wherein the apparatus at least comprises a spectrophotometer (A spectrophotometer; [0067]), dosing materials ("A 22 gauge spinal needle,", wherein under broadest reasonable interpretation, the examiner understands a dosing material to be any solid, fluid, or gas that can be used in the process of dosing; [0131]) and an analysis system (a processor which subjects the output signal to an algorithm which yields an estimated value of the concentration of the analyte; [0016]), the apparatus being adapted to carry out a method for determining the content in proteins or heme-derived pigment in a biological sample (The examiner interprets “adapted to” as non-limiting and the intended use of the algorithm, See MPEP 2114), the method for determining comprising the steps of:
a) providing an initial spectrum of the sample on a wavelength range of interest (obtaining a sample of the fluid and generating a measured spectral absorption curve (F) of the sample over each wavelength range determined in step (d); [0067])("Spectrophotometer results of CSF following SAH obtained from LP" shown in Fig. 1 includes a wavelength),
b) setting a current spectrum that is iteratively updated at step d) as the initial spectrum (Paragraph [0066] explains that scaled spectrum is subtracted from the SAH spectrum and “The process goes on iteratively, until it converges to some methemoglobin curve”),
c) iterating the following steps:
c1) determining the content of a first protein or heme-derived pigment in the sample independently of a content of a second protein or heme-derived pigment ([0096] describes using standard curves for the first and second protein as shown in Fig. 4a and 4b wherein the methemoglobin is fixed with varying amounts of bilirubin and bilirubin is fixed with varying amounts of methemoglobin, respectively)(Holding the first protein constant while varying the second protein and vice versa results in an independent determination of the protein content of interest), wherein the first and second proteins or heme-derived pigment are chosen among which oxyhemoglobin (oxyhemoglobin; [0064]), methemoglobin (methemoglobin; [0064]), carboxyhemoglobin, heme bound to serum albumin, heme bound to hemopexin and bilirubin (bilirubin; [0064]), the determination being carried out by using a spectral analysis of the current spectrum ("These standard curves are used as quantization levels for estimating the bilirubin or methemoglobin values in a CSF/SAH sample"; [0098]) or/and a chemical dosing (The limitation of "or/and a chemical dosing" is not being considered due to the optional “or” statement),
c2) deducing an overall spectral component on the wavelength range of interest (over the specified wavelength region; [0098]) associated to the first protein or heme-derived pigment based on the determined content for the first protein or heme-derived pigment ("(a) using a spectrophotometer to generate at least one standard spectral absorption curve for the analyte; (b) using a spectrophotometer to generate at least one standard spectral absorption curve for the contaminant; (c) computing a sum spectral absorption curve (F.sub.sum) for the fluid by adding the spectral absorptions curves generated in steps (a) and (b)(Under broadest reasonable interpretation, the Examiner interprets “deducing” to mean determining or estimating a spectral component based on available data, including scaling, fitting, or calculation); and
c3) removing the deduced spectral component from the current spectrum ("computing a residual curve over all measured wavelengths," wherein the residual curves are computed for both the first and second protein; [0067]; [0066]),
d) outputting the determined contents in first [sic] protein or heme-derived pigment,
wherein each of steps c1), c2), and c3) is performed for the first protein or heme-derived pigment, and step c) is iterated successively (iteratively repeating steps (h)-(k) until a standard contaminant curve and a standard analyte curve are selected in consecutive iterations; [0013])(the algorithm is functionally capable of performing the intended use of iterating until the content of these proteins are determined)(The examiner interprets “adapted to” as non-limiting and the intended use of the algorithm, See MPEP 2114).
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Myers, 2002 (instant PTO-892) measures the concentration of hemoglobin in blood samples by using a scaling factor created from a ratio of a second derivative value of a sample spectrum and a second derivative value at a reference wavelength
Rieders et al., 2001 (instant PTO-892) teaches using chemical dosing of a sample to quantify different blood protein species via spectroscopy
Yaghoobi et al., 2016, (instant PTO-892) teaches an algorithm based on iteratively subtracting selected spectra and updating the contribution of each spectrum until all analytes are quantified.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Myers, 2002 (instant PTO-892) measures the concentration of hemoglobin in blood samples by using a scaling factor created from a ratio of a second derivative value of a sample spectrum and a second derivative value at a reference wavelength
Rieders et al., 2001 (instant PTO-892) teaches using chemical dosing of a sample to quantify different blood protein species via spectroscopy
Yaghoobi et al., 2016, (instant PTO-892) teaches an algorithm based on iteratively subtracting selected spectra and updating the contribution of each spectrum until all analytes are quantified.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/V.S./Examiner, Art Unit 1758
/MARIS R KESSEL/Supervisory Patent Examiner, Art Unit 1758
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