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 .
Claim Status
Claims 1-22 are currently pending and under exam herein.
Claims 1-22 are rejected.
Claim 7 is objected to.
Priority
Applicant’s claim for the benefit of prior-filed application, U.S. Provisional Application No. 63/203,660 filed on July 27, 2021, under 35 U.S.C. 119(e) is acknowledged. At this point in examination, the effective filing date of claims 1-22 is July 27, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on July 26, 2022 is in compliance with
the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by
the examiner.
Drawings
Figures 4B-D, 5A-D, 6A, 7A-C, 8A-B, 9A-B, 10, and 11A-B are executed in color in the drawings of the instant application. Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Objections
Claim 7 is objected to because of the following informalities:
The claim recites: “The method of 6, …” in the preamble. The claim needs to be amended to clearly show its’ dependency to claim 6 (e.g., The method of claim 6, …); Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 12, 16, and 21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 12, it recites the limitation: “… the thermodynamic melting parameter…” in line 24. There is insufficient antecedent basis for this limitation in the claim. For the purposes of examination, it will be interpreted as the perturbation measurement is the thermodynamic melting parameter.
Regarding claim 16, it recites the limitation: “…comparing, using the computer system to a control sample thermogram…” in line 16. This claim element renders the claim indefinite because it is unclear what comparison is required by the claim. For the purposes of examination, it will be interpreted as the comparison is done on a computer and is between the analysis sample thermogram with added ligand and a control sample thermogram.
Regarding claim 21, it recites the limitation: “… the subsequent perturbation, or the one or more genomic or structural analyses.” in lines 25-26. There is insufficient antecedent basis for this limitation in the claim. For the purposes of examination, the limitation will be treated as the first recitation of the terms. It is suggested to amend the claim to depend from claim 20 to resolve the antecedent basis issue for the subsequent perturbation limitation and amend the claim to remove the article “the” before one or more genomic or structural analyses.
Therefore, the claims are indefinite and are rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
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 1-13, 15-18, and 21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
Step 1:
The first part of the eligibility analysis evaluates whether a claim falls withing any statutory category (See MPEP 2106.03). Claim 1-13, 15-18, and21 recite a series of steps to take to analyze fluid samples to detect and identify properties of molecules in the samples. The claims are directed to a method and fall within one of the statutory categories of invention (Step 1: YES).
Step 2A, prong 1:
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature, or natural phenomenon (Step 2A, prong 1). In the instant application, the claims recite the following limitations that equate to an abstract idea:
Claim 1 recites: (d) comparing… the analysis sample thermogram to a (i) control sample thermogram, the control sample comprising the complex fluid, the control sample being devoid of the target molecule, (ii) one or more reference library thermograms of samples comprising known target molecules in the complex fluid, or both (i) and (ii) to provide a comparison; (e) determining… based at least in part on the comparison, whether the analysis sample thermogram exhibits a perturbation; and (f) if a perturbation is present, identifying the target molecule as present in the complex fluid.
Claim 4 recites: The method of claim 1, wherein a perturbation is present, the method further comprising determining a mass of the target molecule in the complex fluid; comparing… the known sample thermogram to the control sample thermogram; determining, based at least in part on the comparison, a known perturbation measurement corresponding to the known amount of the target molecule or the standard molecule; comparing the known perturbation measurement to a perturbation measurement corresponding to the target molecule in the analysis sample to provide a measurement comparison; and determining, based at least in part on the measurement comparison, an amount of the target molecule in the analysis sample.
Claim 6 recites: comparing… the subsequent analysis sample thermogram to the analysis sample thermogram to provide a subsequent comparison; and determining… based at least in part on the subsequent comparison, whether the subsequent analysis sample thermogram exhibits a subsequent perturbation, wherein a subsequent perturbation indicates binding of the ligand to the target molecule.
Claim 7 recites: wherein a perturbation is present, the method further comprising: determining, based at least in part on the perturbation, a characteristic of an interaction of the ligand with the target molecule, wherein the characteristic is a binding constant, reaction enthalpy, binding stoichiometry, binding free energy, binding entropy, or any combination thereof.
Claim 10 recites: comparing… the analysis sample thermogram to (i) a control sample thermogram, the control sample comprising the complex fluid and the ligand, the control sample being devoid of the target molecule, (ii) a reference library of thermograms of samples comprising the ligand, or both (i) and (ii) to provide the comparison.
Claim 11 recites: wherein a perturbation is present, the method further comprising determining an amount of the target molecule in the complex fluid; comparing… the known sample thermogram to the control sample thermogram; determining, based at least in part on the comparison, a known perturbation measurement corresponding to the known amount of the target molecule or the standard molecule; comparing the known perturbation measurement to a perturbation measurement corresponding to the target molecule in the analysis sample to provide a measurement comparison; and determining, based at least in part on the measurement comparison, an amount of the target molecule in the analysis sample.
Claim 12 recites: wherein a perturbation is present, the method further comprising determining an amount of the target molecule in the complex fluid by: determining… based at least in part on the perturbation, a perturbation measurement of the target molecule; comparing… the thermodynamic melting parameter of the target molecule to a calibration curve comprising perturbation measurements of calibration solutions comprising varying amounts of a standard molecule, to provide a measurement comparison; and determining… based at least in part on the measurement comparison, an amount of the target molecule in the analysis sample.
Claim 13 recites: comparing… the modified analysis sample thermogram to the analysis sample thermogram; and determining… based at least in part on the comparison, whether the modified analysis sample thermogram exhibits a perturbation relative to the analysis sample thermogram, wherein a perturbation indicates that the additive (i) altered a structure of the target molecule, (ii) altered an interaction of the ligand, if present, with the target molecule, or (iii) both (i) and (ii).
Claim 15 recites: a perturbation indicates that the target molecule in the purified state has an altered characteristic compared to the target molecule in the unpurified state.
Claim 16 recites: comparing… to a control sample thermogram, the control sample comprising the complex fluid, the target molecule added in the purified state, and the ligand to provide a subsequent comparison; and determining… based at least in part on the subsequent comparison, whether the analysis sample exhibits a perturbation, wherein a perturbation indicates that the target molecule in the unpurified state exhibits different binding characteristics to the ligand compared to the target molecule in the purified state.
Claim 17 recites: wherein the perturbation comprises: (i) a change in height and/or width of a peak on the analysis sample thermogram relative to a corresponding peak on the control sample thermogram or reference library thermogram; or (ii) a shift in position of a peak on the analysis sample thermogram relative to a corresponding peak on the control sample thermogram or reference library thermogram; or (iii) presence of a peak on the analysis sample thermogram that is not present on the control sample thermogram or reference library thermogram; or (iv) absence of a peak on the analysis sample thermogram compared to a peak that is present on the control sample thermogram or reference library thermogram; or (v) any combination of (i), (ii), (iii), and (iv).
Claim 18 recites: the analysis sample thermogram is compared to a (i) control sample thermogram, the control sample comprising the complex fluid, the control sample being devoid of the virus, (ii) one or more reference library thermograms of samples comprising known viruses in the complex fluid, or both (i) and (ii) to provide a comparison; and a perturbation indicates the virus is present in the complex fluid.
Claim 21 recites: further comprising identifying the virus based at least in part on the perturbation, the subsequent perturbation, or the one or more genomic or structural analyses.
The limitations of comparing thermograms, determining the presence of a perturbation, identifying the presence of a target molecules, determining a mass of the target molecule, determining perturbation measurements, comparing perturbation measurements, determining a characteristic of an interaction of ligands and target molecules, determining different binding characteristics, screening ligands and capture moieties, and identifying viruses recited in claims 1, 4, 6-7, 10-13, 16, 18, and 21 encompass mental processes of observing, evaluating, and forming conclusions through data analysis and the mathematical calculations necessary to perform such tasks which can be done with pen and paper or in a generic computer environment. The recitation that these limitations are performed on a computer system does not does not preclude them by being performed by a human as claimed.
Specifically, the following limitations encompass mental processes: In claim 1, comparing the analysis sample thermogram to a control or reference thermogram, determining whether the analysis sample thermogram exhibits a perturbation, and identifying the target molecule as present in the complex fluid. In claim 4, comparing the known sample thermogram to the control sample thermogram. In claim 6, comparing the thermograms. In claim 10, comparing the thermograms. In claim 11, comparing the thermograms. In claim 13, comparing thermograms. In claim 16, comparing the thermograms. In claim 18, the comparison of thermograms. In claim 21, identifying the virus.
The following limitations encompass mathematical concepts: In claim 4, determining a mass of the target molecule in the complex fluid, determining a known perturbation measurement, comparing perturbation measurements to provide a measurement comparison, and determining an amount of the target molecule in the analysis sample. In claim 6, determining whether the subsequent analysis sample thermogram exhibits a subsequent perturbation. In claim 7, determining a characteristic of an interaction of the ligand with the target molecule. In claim 11, determining an amount of the target molecule in the complex fluid, determining a known perturbation measurement, comparing the perturbation measurements to provide a measurement comparison, and determining an amount of the target molecule in the analysis sample. In claim 12, determining an amount of the target molecule in the complex fluid, determining a perturbation measurement of the target molecule, comparing the thermodynamic melting parameter of the target molecule to a calibration curve to provide a measurement comparison, determining an amount of the target molecule in the analysis sample. In claim 13, determining whether the modified analysis sample thermogram exhibits a perturbation. In claim 16, determining whether the analysis sample exhibits a perturbation.
The limitations of a perturbation indicating that the target molecules have altered characteristics in a purified state versus in an unpurified state in claim 15 only further limits the conclusion reached after determining the presence of a perturbation in claim 1. In the same manner, the limitation that a perturbation indicates the presence of the virus in claim 18 only limits the conclusion when detecting a perturbation. Lastly, the limitations of claim 17 only further limit what evaluation takes place to determine a perturbation. Therefore, these limitations fall under the “Mathematical concepts” and “Mental processes” groupings of abstract ideas (Step 2A, prong 1: YES).
Step 2A, prong 2:
Claims found to recite a judicial exception under Step 2A, prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application (Step 2A, prong 2). The claims recite the following additional elements:
Claim 1 recites: A method, comprising: (a) obtaining an analysis sample comprising a quantity of a complex fluid, the complex fluid comprising one or more of proteins, peptides, lipids, and carbohydrates, the complex fluid further comprising or suspected of comprising a target molecule; (b) obtaining an analysis sample thermogram by differential scanning calorimetry; (c) inputting the analysis sample thermogram into a computer system; using the computer system.
Claim 2 recites: The method of claim 1, wherein the target molecule comprises a protein, peptide, nucleic acid, lipid, carbohydrate, virus, or any combination thereof.
Claim 3 recites: The method of claim 1, wherein the complex fluid is a biofluid, an environmental fluid, or any combination thereof.
Claim 4 recites: adding a known amount of the target molecule or a standard molecule to the control sample to provide a known sample; obtaining a known sample thermogram; inputting the known sample thermogram into the computer system; using the computer system.
Claim 5 recites: The method of claim 4, wherein: (i) the standard molecule has a different composition than the target molecule; or (ii) the standard molecule has a transition melting temperature of from 25 °C to 95 °C; or (iii) the standard molecule comprises a DNA or RNA oligomer; or (iv) the target molecule comprises a protein or a peptide; or (v) any combination of (i), (ii), (iii), and (iv).
Claim 6 recites: The method of claim 1 wherein the complex fluid comprises the target molecule, the method further comprising: adding a quantity of a ligand to the analysis sample; obtaining a subsequent analysis sample thermogram by differential scanning calorimetry; inputting the subsequent analysis sample thermogram into the computer system; using the computer system.
Claim 8 recites: The method of claim 6, wherein the ligand comprises a protein, a peptide, a nucleic acid, a lipid, a carbohydrate, an organic small molecule having a molecular weight less than 1,000 Daltons, a salt, an anion, a cation, a chelate, or any combination thereof.
Claim 9 recites: The method of claim 8, wherein the ligand comprises an organic small molecule therapeutic agent, an antibody, a CAR (chimeric antigen receptor) T cell, a nucleic acid probe, a CRISPR (clustered regularly interspaced short palindromic repeats) product, or any combination thereof.
Claim 10 recites: The method of claim 1, further comprising: combining a quantity of a ligand with the analysis sample prior to obtaining the analysis sample thermogram, the ligand capable of binding to the target molecule; using the computer system.
Claim 11 recites: Adding a known amount of a standard molecule to the control sample to provide a known sample; obtaining a known sample thermogram; inputting the known sample thermogram into the computer system; using the computer system.
Claim 12 recites: Using the computer system.
Claim 13 recites: The method of claim 1, further comprising: combining an additive with the analysis sample to provide a modified analysis sample, the additive comprising an inorganic salt, a protein, a carbohydrate, an amino acid, a vitamin, a peptide, a fatty acid, a lipid, a therapeutic agent, a solvent, or any combination thereof; obtaining a modified analysis sample thermogram; inputting the modified analysis sample thermogram into the computer system; using the computer system.
Claim 15 recites: The method of claim 1, wherein: the complex fluid comprises the target molecule in an unpurified state; the control sample comprises the complex fluid and the target molecule in a purified state.
Claim 16 recites: The method of claim 15, further comprising: combining a quantity of a ligand with the analysis sample prior to obtaining the analysis sample thermogram, the ligand capable of binding to the target molecule in the unpurified state; using the computer system.
Claim 18 recites: The method of claim 1, wherein: the analysis sample is obtained from a subject; the analysis sample comprises a quantity of a complex fluid comprising one or more of proteins, peptides, lipids, and carbohydrates, the complex fluid further comprising or suspected of comprising a virus.
The additional elements of obtaining an analysis sample, obtaining a thermogram, inputting the thermogram into a computer system recited in claims 1, 4, 6, 11, and 13 do not impose significant limits on the judicial exception because the additional elements are only tangentially related to the invention and amount to necessary data gathering and outputting since all uses of the recited judicial exception require such data gathering; These additional elements amount to insignificant extra-solution activity (MPEP 2106.05g). The additional elements of the type of target molecule present in the complex fluid, the specific type of complex fluid in an analysis sample, the state of the target molecule in the complex fluid and control sample, and the source of the analysis sample and its’ composition recited in claims 2-3, 15, 18 only further limit the insignificant extra-solution activity of data gathering to particular sources and data types. Likewise, the additional elements of adding known amounts of target or standard molecules to control samples, adding a quantity of ligand to analysis samples, and combining an additive with the analysis sample recited in claims 4, 6, 10-11, 13, and 16 also amount to insignificant extra-solution activity nominally related to the invention for the purpose of data gathering for use with the judicial exception. The additional elements of the properties of the standard molecule and target molecule, and the type of ligand used recited in claims 5, 8-9 further limit the data gathering steps in claims 4 and 6 to particular sources and types of data to be manipulated.
Lastly, the additional elements of using a computer system recited in claims 1, 4, 6, 10-13, and 16 invokes computers to perform the judicial exception and amount to mere instructions to apply the exception to a generic computer (MPEP 2106.05f). Therefore, the judicial exception is not integrated into a practical application because the claims do not recite an additional element that reflects an improvement to technology or applies/uses the recited judicial exception in some other meaningful way and the claims are directed to the judicial exception (Step 2A, prong 2: NO).
Step 2B:
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims recite additional elements that equate to mere instructions to apply the recited judicial exception in a generic computing environment. Claims that amount to nothing more than instructions to apply the judicial exception using a generic computer do not render an abstract idea eligible. Alice Corp., 576 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. The claims recite computer functions and laboratory technique that the courts have ruled to be well-understood, routine and conventional (WURC) such as: Receiving or transmitting data over a network, e. g., using the Internet to gather data, Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362; buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014) (computer receives and sends information over a network) and Storing and retrieving information in memory, Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015); OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93.
Lastly, the additional elements of performing differential scanning calorimetry are well-understood, routine and conventional as taught by Fish et al. (Biophysical Chemistry, vol. 152, nos. 1-3, p. 184-90; IDS document 7/26/2022) and Garbett et al. (Methods, vol. 76, p. 41-50; IDS document 7/26/2022). Fish et al. teach differential scanning calorimetry (DSC) used as a diagnostic tool for analysis of complex biological mixtures such as plasma from human blood (p. 184, Introduction) and Garbett et al. teach DSC analysis of clinical samples has shown that, relative to control populations, thermograms are altered in shape and shifted to higher temperatures in a number of diseases and thermograms have been shown to be sensitive to disease burden and patient therapy (p. 2, 1. Introduction). In addition, paragraph 0128 of the published specification states that observed Tm shifts associated with ligand binding are a well-known manifestation of Le Chatelier’s principle.
As such, the combination of additional elements recited in the claims is well-understood, routine and conventional. The additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transform the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: NO) and claims 1-13, 15-18, and 21 are not patent eligible.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claims 1-3 and 17-18 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Monaselidze et al. (US20190003995A1). The italicized text corresponds to the instant claim limitations.
Regarding claims 1-3, Monaselidze et al. teach a method of detecting proteins and/or metabolites in a sample of whole blood, plasma, or serum by creating a thermogram of the sample in a differential scanning calorimeter, comparing the sample thermogram to a thermogram from a control sample, and determining the presence of the protein or metabolite when an alteration is present in the thermogram of the sample relative to the control and can be used to detect an infection (p. 1, paragraph 0008; p.4, paragraph 0048). Monaselidze et al. teach that the differential scanning calorimeter has processors, memory devices, and executes computer programs for actions such as calculating differential scanning calorimetry measurements (p. 6, paragraph 0064) and equipped with the relevant software (p. 12, paragraph 0129). These teachings taken together read on the claim 1 limitations of: A method, comprising: (a) obtaining an analysis sample comprising a quantity of a complex fluid, the complex fluid comprising one or more of proteins, peptides, lipids, and carbohydrates, the complex fluid further comprising or suspected of comprising a target molecule; (b) obtaining an analysis sample thermogram by differential scanning calorimetry; (c) inputting the analysis sample thermogram into a computer system; (d) comparing, using the computer system, the analysis sample thermogram to a … (ii) one or more reference library thermograms of samples comprising known target molecules in the complex fluid…; (e) determining, using the computer system and based at least in part on the comparison, whether the analysis sample thermogram exhibits a perturbation; and (f) if a perturbation is present, identifying the target molecule as present in the complex fluid. The teachings also read on the claim 2 limitations of: wherein the target molecule comprises a protein, peptide, nucleic acid, lipid, carbohydrate, virus, or any combination thereof and the claim 3 limitations of: wherein the complex fluid is a biofluid…
Regarding claims 17-18, Monaselidze et al. teach that the alterations present in the thermograms can be an increase in ΔTm at half max (integral melting width), an increase in main peak Tm (a shift in the position of a peak), or detection of a new shoulder or peak (p. 1-2, paragraph 0012) which reads on the claim 17 limitations of: wherein the perturbation comprises: (i) a change in height and/or width of a peak on the analysis sample thermogram relative to a corresponding peak on the control sample thermogram or reference library thermogram; or (ii) a shift in position of a peak on the analysis sample thermogram relative to a corresponding peak on the control sample thermogram or reference library thermogram; or (iii) presence of a peak on the analysis sample thermogram that is not present on the control sample thermogram or reference library thermogram… Monaselidze et al. teach that an embodiment of their invention includes diagnosing a subject as having a pathogenic (e.g., viral) infection based of alterations in the thermogram of a sample obtained from the subject (p. 2-3, paragraph 0028) which reads on the claim 18 limitations of: wherein: the analysis sample is obtained from a subject; the analysis sample comprises a quantity of a complex fluid comprising one or more of proteins, peptides, lipids, and carbohydrates, the complex fluid further comprising or suspected of comprising a virus; the analysis sample thermogram is compared to a (i) control sample thermogram, the control sample comprising the complex fluid, the control sample being devoid of the virus, … to provide a comparison; and a perturbation indicates the virus is present in the complex fluid.
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.
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Monaselidze et al. (US20190003995A1) as applied to claim 1 above, and further in view of Garbett et al. (Methods, vol. 76, pp. 41-50; IDS document 7/26/2022). The italicized text corresponds to the instant claim limitations.
The limitations of claim 1 have been taught by Monaselidze et al.
Regarding claims 4-5, Monaselidze et al. teach assessing the melting temperatures (Tm), the change in melting temperatures (ΔTm), enthalpy (ΔHm), and peak height (DCmax) of major plasma proteins (e.g., albumin) and quantifying suspected biomarkers, metabolites, proteins, lipids, saccharides via deconvolution of the thermogram curves (p. 4, paragraph 0048; Figure 7; Table 1) and, as taught for claim 1, performing the method on a computer system. The teachings read on the claim 4 limitations of: wherein a perturbation is present, the method further comprising determining a mass of the target molecule in the complex fluid… and the claim 5 limitations of: wherein: … (iv) the target molecule comprises a protein or a peptide.
Monaselidze et al. is silent to the claim 4 limitations of: adding a known amount of the target molecule or a standard molecule to the control sample to provide a known sample; obtaining a known sample thermogram; inputting the known sample thermogram into the computer system; comparing, using the computer system, the known sample thermogram to the control sample thermogram; determining, based at least in part on the comparison, a known perturbation measurement corresponding to the known amount of the target molecule or the standard molecule; comparing the known perturbation measurement to a perturbation measurement corresponding to the target molecule in the analysis sample to provide a measurement comparison; and determining, based at least in part on the measurement comparison, an amount of the target molecule in the analysis sample and the claim 5 limitation of: (ii) the standard molecule has a transition melting temperature of from 25 ℃ to 95 ℃. However, these limitations were known in the art at the effective filing date of the invention as taught by Garbett et al.
Regarding claim 4-5, Garbett et al. teach, “DSC thermograms are directly related to the mass of proteins present. For example, if the weight concentration of a protein is doubled, the calorimetric heat response will also double. Likewise, in a solution containing a mixture of proteins, the relative heat response will correspond to the total mass of proteins present” (p. 3, 2. Principle of plasma thermograms, paragraph 1). Garbett et al. have demonstrated deconvoluting thermograms of protein mixtures into characteristic melting curve of individual protein components and that the thermogram of a mixture can be represented as the sum of all constituent individual protein thermograms weighted according to their relative molar mass and concentration (Id.). To calculate protein concentrations from a plasma sample, Garbett et al. teach using a matrix (R) of excess specific heat capacities of reference proteins at each temperature for each protein component and calculating a least-squares solution to deconvolute vector (T) of excess specific heat values measured over a range of temperatures observed in experimental thermograms to determine the concentrations of proteins in the plasma samples (p. 3, 2. Principle of plasma thermograms, paragraph 2; Figure 1). One in the art would recognize that creating the matrix of the reference proteins implies adding a known amount of the proteins to a control sample and obtaining their individual thermograms, therefore the teaching reads on the claim 4 limitations of: adding a known amount of the target molecule or a standard molecule to the control sample to provide a known sample; obtaining a known sample thermogram; inputting the known sample thermogram into the computer system; comparing, using the computer system, the known sample thermogram to the control sample thermogram; determining, based at least in part on the comparison, a known perturbation measurement corresponding to the known amount of the target molecule or the standard molecule; comparing the known perturbation measurement to a perturbation measurement corresponding to the target molecule in the analysis sample to provide a measurement comparison; and determining, based at least in part on the measurement comparison, an amount of the target molecule in the analysis sample. As shown in Figure 1, several of the proteins have a transition melting temperature between 50 ℃ to 90 ℃ (i.e., the peaks of the melting curves) and so the teachings of Garbett et al. read on the claim 5 limitation of: (ii) the standard molecule has a transition melting temperature of from 25 ℃ to 95 ℃.
The methods of Monaselidze et al. taught quantifying molecules in samples of plasma via deconvolution analysis of the sample thermograms, but did not teach the exact process performed. The components of claim 4 of obtaining a known sample thermogram by adding a known amount of a molecule to make a reference thermogram used to quantify a target molecule in a sample was known in the art as taught by Garbett et al. As such, the prior art contained each claimed element albeit not in a single reference and the difference between the prior art and the claimed invention is the lack of actual combination of the claimed elements. One of ordinary skill in the art could have combined the reference matrix of known sample thermograms with the method used by Monaselidze et al. by known methods to quantify the target molecules present in the sample and the results of the combination would have been predictable in resulting of a measurement of the concentration of a target molecule in the analysis sample because all prior art references teach using a differential scanning calorimeter in its’ normal mode of functioning. Additionally, a person having ordinary skill in the art would be motivated to perform the combination because Garbett et al. teach the relationship between protein concentration and the calorimetric heat response is the fundamental basis for DSC-based diagnostic application (p.3, 2. Principle of plasma thermograms, paragraph 1). The invention is therefore prima facie obvious.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Monaselidze et al. (US20190003995A1) as applied to claim 1 above, and further in view of Kholodenko et al. (Analytical Biochemistry, vol. 270, no. 2, pp.336-38). The italicized text corresponds to the instant claim limitations.
The limitations of claim 1 have been taught by Monaselidze et al.
Regarding claim 12, Monaselidze et al. teach assessing the melting temperatures (Tm), the change in melting temperatures (ΔTm), enthalpy (ΔHm), and peak height (DCmax) of major plasma proteins (e.g., albumin) and quantifying suspected biomarkers, metabolites, proteins, lipids, saccharides via deconvolution of the thermogram curves (p. 4, paragraph 0048; Figure 7; Table 1) and, as taught for claim 1, performing the method on a computer system. This teaching discloses the limitation wherein a perturbation is present, the method further comprising determining an amount of the target molecule in the complex fluid by: determining, using the computer system and based at least in part on the perturbation, a perturbation measurement of the target molecule…
Monaselidze is silent to the limitations of …comparing, using the computer system, the thermodynamic melting parameter of the target molecule to a calibration curve comprising perturbation measurements of calibration solutions comprising varying amounts of a standard molecule, to provide a measurement comparison; and determining, using the computer system and based at least in part on the measurement comparison, an amount of the target molecule in the analysis sample. However, these limitations were known in the art prior to the effective filing date of the invention as taught by Kholodenko et al.
Regarding claim 12, Kholodenko et al. teach measuring the absolute heat capacity of a protein (CP) at varying concentrations and plotting the data which shows the relationship between mass and absolute heat capacity (pp. 336-37, Figure 2). Kholodenko et al. also teach because absolute heat capacity is obtained from the protein concentration dependence of the calorimetric data, it is possible to evaluate deviations (p. 338, last paragraph). These teaching demonstrate the ability to determine the concentration of a target molecule by comparing its’ experimental absolute heat capacity to a plot comprising measurements of the target molecule at different concentrations and therefore teach the claim 12 limitation of: …comparing, using the computer system, the thermodynamic melting parameter of the target molecule to a calibration curve comprising perturbation measurements of calibration solutions comprising varying amounts of a standard molecule, to provide a measurement comparison; and determining, using the computer system and based at least in part on the measurement comparison, an amount of the target molecule in the analysis sample.
The methods of Monaselidze et al. taught quantifying molecules in samples of plasma via deconvolution analysis of the sample thermograms, but did not teach the exact process performed. The component of claim 12 of creating a calibration curve by measuring perturbations of a known molecule at different concentrations was known in the art as taught by Kholodenko et al. As such, the prior art contained each claimed element albeit not in a single reference and the difference between the prior art and the claimed invention is the lack of actual combination of the claimed elements. One of ordinary skill in the art could have combined the plot of absolute heat capacities vs. protein concentration with the method used by Monaselidze et al. by known methods to quantify the target molecules present in the sample and the results of the combination would have been predictable in resulting of a measurement of the concentration of a target molecule in the analysis sample because all prior art references teach using a differential scanning calorimeter in its’ normal mode of functioning. The invention is therefore prima facie obvious.
Claims 6-10 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Monaselidze et al. (US20190003995A1) as applied to claim 1 above, and further in view of Chaires et al. (WO2012109383A2). The italicized text corresponds to the instant claim limitations.
The limitations of claim 1 have been taught by Monaselidze et al.
Monaselidze et al. is silent on the limitations of claims 6-10 and 13 of adding a ligand (of various types) to the analysis sample and determining if the ligand binds to the target molecules, comparing the analysis sample with added ligand to a control sample that only has the ligand or a reference library of thermograms of samples of the ligand, or combining an additive with the analysis sample and determining if the additive altered a structure of the target molecule or interaction of the ligand molecule with the ligand. However, these limitations were known in the art at the effective filing date of the invention as taught by Chaires et al.
Regarding claims 6 and 7, Chaires et al. teach determining ligand binding by comparing differential scanning thermograms with and without the added ligand (p. 8, paragraphs 0062-0063) which reads on all the limitations of claim 6. Chaires et al. teach their methods provide determining binding free-energy and separating it into enthalpic and entropic components, measuring melting enthalpy, and using additional techniques to verify and complement the thermogram to evaluate binding constants and the number of binding sites (p. 6-7, paragraphs 0058-0059) which read on the claim 7 limitations of: wherein a perturbation is present, the method further comprising: determining, based at least in part on the perturbation, a characteristic of an interaction of the ligand with the target molecule, wherein the characteristic is a binding constant, reaction enthalpy, binding stoichiometry, binding free energy, binding entropy, or any combination thereof. Determining the number of binding sites is interpreted as the claimed binding stoichiometry because knowing the number of binding sites of a ligand on a molecule allows the calculation of the molar ratio of ligands to target molecule.
Regarding claims 8-10, Chaires et al. teach the ligand being analyzed can be any class of drug, drug composition (e.g., chemical or biological), a chemical compound, binder, biopolymer, or biomolecule that affects the function of one or more other biomolecules including: insulin, NSAIDs, statins, aminoglycosides, calcium supplements, antacids, bisphosphonates, receptors, fragments of peptide or nucleotide sequences, or other molecules whether organic, inorganic, synthetic, or natural (p. 15-17, paragraphs 0093-0096). These teachings read on all the limitations of claims 8 and 9. Chaires et al. teach that the embodiments of their invention employ a differential scanning calorimeter for comparing and ranking physical transformation data for a first combination of compounds and/or biomolecules to data for a second combination of compounds and/or biomolecules (p. 8, paragraph 0062) which reads on the claim 10 limitations of: combining a quantity of a ligand with the analysis sample prior to obtaining the analysis sample thermogram, the ligand capable of binding to the target molecule; and comparing, using the computer system, the analysis sample thermogram to …(ii) a reference library of thermograms of samples comprising the ligand… to provide the comparison.
Regarding claim 13, in the broadest reasonable interpretation of the teachings from Chaires et al. recited above for claims 6-10, a ligand is equivalent to the claimed additive comprising an inorganic salt, a protein, a carbohydrate, an amino acid, a vitamin, a peptide, a fatty acid, a lipid, a therapeutic agent, a solvent, or any combination thereof. Additionally, Chaires et al. teach using their differential scanning calorimetry method in a drug screening process where DMSO was added in one sample to improve ligand solubility and it was shown that the DMSO additive did not alter any melting curve parameters (p. 19-20, paragraphs 00109-00111), thus teaching all the limitations of claim 13.
The prior art at the effective filing date of the invention included each claimed element, although not in a single reference. The teachings of Monaselidze et al. taught detecting a target molecule in a complex fluid whereas the teachings of Chaires et al. show probing ligand-target molecule interactions and effects of additives on melting curve parameters. One of ordinary skill in the art could combine the elements of Monaselidze et al. with the elements of Chaires et al. by known methods since both utilize differential scanning calorimetry and utilize the same principles of analyzing thermograms, and the separate elements would merely perform the same function when combined as they do separately. An ordinary artisan would have recognized the results of the combination would be predictable because both teachings involve analyzing complex fluids and molecular interactions with only the intended purpose of the analysis differing (i.e., detecting and quantifying molecules versus characterizing ligand/additive interactions). The invention is therefore prima facie obvious.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Monaselidze et al. (US20190003995A1) in view of Chaires et al. (WO2012109383A2) as applied to claims 1 and 10 above, and further in view of Garbett et al. (Methods, vol. 76, pp. 41-50; IDS document 7/26/2022). The italicized text corresponds to the instant claim limitations.
The limitations of claims 1 and 10 have been taught by Monaselidze et al. and Chaires et al.
Monaselidze et al. and Chaires et al. are silent on the limitations of claim 11. However, these limitations were known in the art at the effective filing date of the invention, as taught by Garbett et al.
Regarding claim 11, Garbett et al. teach, “DSC thermograms are directly related to the mass of proteins present. For example, if the weight concentration of a protein is doubled, the calorimetric heat response will also double. Likewise, in a solution containing a mixture of proteins, the relative heat response will correspond to the total mass of proteins present” (p. 3, 2. Principle of plasma thermograms, paragraph 1). Garbett et al. have demonstrated deconvoluting thermograms of protein mixtures into characteristic melting curve of individual protein components and that the thermogram of a mixture can be represented as the sum of all constituent individual protein thermograms weighted according to their relative molar mass and concentration (Id.). To calculate protein concentrations from a plasma sample, Garbett et al. teach using a matrix (R) of excess specific heat capacities of reference proteins at each temperature for each protein component and calculating a least-squares solution to deconvolute vector (T) of excess specific heat values measured over a range of temperatures observed in experimental thermograms to determine the concentrations of proteins in the plasma samples (p. 3, 2. Principle of plasma thermograms, paragraph 2; Figure 1). One in the art would recognize that creating the matrix of the reference proteins implies adding a known amount of the proteins to a control sample and obtaining their individual thermograms, therefore the teaching reads on the limitations of claim 11.
The methods of Monaselidze et al. taught quantifying molecules in samples of plasma via deconvolution analysis of the sample thermograms, but did not teach the exact process performed (paragraph 0048). The components of claim 11 of obtaining a known sample thermogram by adding a known amount of a molecule to make a reference thermogram used to quantify a target molecule in a sample was known in the art as taught by Garbett et al. As such, the prior art contained each claimed element albeit not in a single reference and the difference between the prior art and the claimed invention is the lack of actual combination of the claimed elements. One of ordinary skill in the art could have combined the reference matrix of known sample thermograms with the method used by Monaselidze et al. by known methods to quantify the target molecules present in the sample and the results of the combination would have been predictable in resulting of a measurement of the concentration of a target molecule in the analysis sample because all prior art references teach using a differential scanning calorimeter in its’ normal mode of functioning. Additionally, a person having ordinary skill in the art would be motivated to perform the combination because Garbett et al. teach the relationship between protein concentration and the calorimetric heat response is the fundamental basis for DSC-based diagnostic application (p.3, 2. Principle of plasma thermograms, paragraph 1). The invention is therefore prima facie obvious.
Claims 14 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Monaselidze et al. (US20190003995A1) as applied to claims 1 and 18 above, and further in view of Koslen et al. (Advances in Biological Chemistry, vol. 09, no. 03, pp. 110-34; IDS document 7/26/2022), Tetala et al. (Journal of Separation Science, vol. 33, no. 3, pp. 422-38), and Wooster et al. (Journal of Immunological Methods, vol. 464, pp. 22-30). The italicized text corresponds to the instant claim limitations.
The limitations of claims 1 and 18 have been taught by Monaselidze et al.
Monaselidze et al. appears to be silent on the limitations of claims 14 and 19. However, these limitations were known in the art at the effective filing date of the invention, as taught by Koslen et al., Tetala et al., and Wooster et al.
Regarding claim 14, Koslen et al. teach a technique of capturing ligands that bind human serum albumin (HSA) which can then be analyzed in further processes (p. 116-118, Capture Strategy, paragraph 1, Components, paragraphs 1-5; Figures 1-2). These teachings read on the limitations of combining, in a vessel, a capture moiety and a complex fluid comprising a target molecule or suspected of comprising a target molecule, the capture moiety comprising biotin covalently attached to a ligand capable of binding to the target molecule; incubating the complex fluid and capture moiety whereby the target molecule, if present, binds to the capture moiety to form a conjugate; removing the conjugate, if present, from the complex fluid… removing the target molecule… Under the broadest reasonable interpretation of the claims, a target molecule can itself be a ligand and, although HSA is not typically interpreted as a ligand by definition, it can act functionally as a ligand in a molecule capture system that binds target molecules to capture them. Additionally, MPEP 2144.04(VI)(A) states reversal of parts is an obvious modification, so the teaching of using biotin labeled HSA to capture target ligands prompts the idea of biotin labeled ligands that bind HSA to capture it.
Koslen et al. teach thermogram analysis in combination with the capture strategy provides validation for the use of differential scanning calorimetry (DSC) in diagnostic applications and analytes can be isolated from plasma and independently assessed (p. 128-129, Applications of Thermogram Analysis in Diagnostics, paragraphs 2-5). These teachings disclose the limitation of …combining the removed target molecule with a quantity of a control sample to provide the analysis sample, wherein the control sample comprises the complex fluid, the control sample being devoid of the target molecule. Additionally, Figure 2 step (f) shows retrieved ligands were further analyzed by liquid chromatography/mass spectrometry which demonstrates the captured molecules can be used for further experimentation such as differential scanning calorimetry as suggested by Koslen et al. (p. 112, 1. Introduction, paragraph 8).
Further regarding claim 14, Wooster et al. teach using PMMA beads conjugated to streptavidin to collect biotinylated peptide/MHC molecules in the proper orientation for use in downstream applications (p. 25, 2.10 Flow cytometry; p. 27-28, 3.4 Multimerization and functional assessment of eukaryotic-derived peptide/MHC). This teaching discloses the claim 14 limitation of … a device comprising (i) a body comprising a substrate material, a poly (methyl methacrylate) (PMMA) coating on at least a portion of a surface of the body, and a plurality of retrieval moiety molecules covalently bound to the PMMA coating, the retrieval moiety molecules comprising streptavidin, and removing the target molecule from the device.
Regarding claim 19, the teachings of Koslen et al. and Wooster et al. applied to claim 14 also disclose the claim 19 limitations of combining a capture moiety with the analysis sample, the capture moiety comprising biotin covalently attached to a ligand … incubating the complex fluid and capture moiety … to form a conjugate, removing the conjugate, if present, from the complex fluid with a device comprising (i) a body comprising a substrate material, a poly(methyl methacrylate) (PMMA) coating on at least a portion of a surface of the body, and a plurality of retrieval moiety molecules covalently bound to the PMMA coating, the retrieval moiety molecules comprising streptavidin… The previous teachings don’t mention isolating a virus, however, Tetala et al. teach that streptavidin-biotin interactions were used to isolate a virus and the system can be used by immobilizing a ligand with streptavidin or biotin termination on the stationary phase coated with biotin or streptavidin (p. 432, 3.3 Streptavidin-biotin system, paragraph 1; Figure 11). Thus, disclosing the limitations of claim 19 of a ligand capable of binding to the virus, whereby the virus binds to the capture moiety to form a conjugate, and removing the virus from the device.
Monaselidze et al. teach the motivation for their invention is to address the need for sensitive and non-invasive diagnostic methods for disease and infections in patients (paragraph 0003). Koslen et al. teach ligand binding associated with various disease states is thought to induce perturbations in plasma thermograms which can be verified by isolating ligands (p. 112, 1. Introduction, paragraph 7). A person having ordinary skill in the art would be motivated to combine the teachings of Koslen et al. with those of Monaselidze et al. in order to accurately diagnose patients using differential scanning calorimetry and avoid invasive procedures. There would be a reasonable expectation of success because both references utilize differential scanning calorimetry to show differences between samples with varying constituents and Koslen et al. demonstrated that ligands can be captured and retrieved.
Additionally, the prior art teaching of Koslen et al. contained beads of unknown material with streptavidin linked to them used to capture and retrieve target molecules, which differs from the claimed device. Wooster et al. taught the components of the claimed device and their functions. One of ordinary skill in the art could have substituted the PMMA beads coated with streptavidin taught by Wooster et al. for the streptavidin coated beads used by Koslen et al. and the results of the modification would be predictable because the beads perform the same function, thereby capturing and retrieving target molecules that are bound by a ligand tagged with biotin. The invention of claim 14 is therefore prima facie obvious.
A person having ordinary skill in the art would be motivated to modify the combined teachings of Monaselidze et al., Koslen et al., Wooster et al.to capture viruses because Tetala et al. teach there is a demand for faster and more sensitive analyses of various molecules in decreasing sample volumes and affinity chromatography is particularly suitable for highly selective enrichment of trace organic molecules (p. 422, 1 Introduction, paragraph 1) and Monaselidze et al. teach there is a need for sensitive methods to effectively detect and assess risk for disease or infection in patients (paragraph 0003). There would be a reasonable expectation of success because Tetala et al. taught viruses can be enriched by affinity chromatography and Monaselidze et al. taught detecting a viral infection in a patient by differential scanning calorimetry (paragraph 0008, 0010). The invention of claim 19 is therefore prima facie obvious.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Monaselidze et al. (US20190003995A1) as applied to claims 1 and 18 above, over Koslen et al. (Advances in Biological Chemistry, vol. 09, no. 03, pp. 110-34; IDS document 7/26/2022), Tetala et al. (Journal of Separation Science, vol. 33, no. 3, pp. 422-38), and Wooster et al. (Journal of Immunological Methods, vol. 464, pp. 22-30) as applied to claim 19 above, and further in view of Chaires et al. (WO2012109383A2). The italicized text corresponds to the instant claim limitations.
The limitations of claims 1 and 18 have been taught by Monaselidze et al. and the limitations of claim 19 have been taught by Koslen et al., Tetala et al, and Wooster et al.
Monaselidze et al., Koslen et al., Tetala et al., and Wooster et al. appear to be silent on the limitations of claim 20. However, these limitations were known in the art at the effective filing date of the invention as taught by Chaires et al.
Regarding claim 20, Chaires et al. teach determining ligand binding by comparing differential scanning thermograms with and without the added ligand (p. 8, paragraphs 0062-0063). Furthermore, Chaires et al. teach in various embodiments the goal is to identify a ligand that affects the function of other biomolecules in an organism via a potential molecular interaction (p. 16, paragraph 0095). Chaires et al. teach the target biomolecule may be found in a disease-causing organism such as a virus (Id.). Together the teachings of Chaires et al. disclose the limitations screening a ligand … to determine whether the ligand … is capable of binding to the virus, wherein screening comprises: combining the virus with a complex fluid devoid of the virus to provide a subsequent analysis sample; adding a quantity of the ligand … to the subsequent analysis sample; obtaining a subsequent analysis sample thermogram by differential scanning calorimetry; inputting the subsequent analysis sample thermogram into the computer system; comparing, using the computer system, the subsequent analysis sample thermogram to a control sample thermogram, the control sample comprising the complex fluid and the virus, the control sample being devoid of the ligand …; and determining, using the computer system and based at least in part on the comparison, whether the subsequent analysis sample thermogram exhibits a subsequent perturbation, wherein a subsequent perturbation indicates binding of the ligand … to the virus.
A person having ordinary skill in the art would be motivated to combine the teachings of Chaires et al. with the combined teachings of Monaselidze et al., Koslen et al., Tetala et al., and Wooster et al. in order to discover potential drug candidates against viral pathogens because Chaires et al. teach differential scanning calorimetry can be used to predict drug efficacy and there have been many unsuccessful attempts in the pharmaceutical industries to obtain information about properties of new drug candidates (p. 1, paragraph 0002, 0005). There would be a reasonable expectation of success because Chaires et al. teach that part of the drug candidate assessment process may involve determining which plasma proteins bind to the drug candidate (p. 1, paragraph 0004) and their methods are used to analyzing ligand-protein binding interactions. The invention of claim 20 is therefore prima facie obvious.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Monaselidze et al. (US20190003995A1) as applied to claims 1 and 18 above, and further in view of Ren et al. (Quantitative Biology, vol. 8, no. 1, pp. 64-77). The italicized text corresponds to the instant claim limitations.
The limitations of claims 1 and 18 have been taught by Monaselidze et al.
Monaselidze et al. is silent on the limitations of claim 21. However, these limitations were known in the art at the effective filing date of the invention as taught by Ren et al.
Regarding claim 21, Ren et al. teach identifying viruses from sequences using a convolutional neural network (p. 66, Results, paragraph 1) which reads on the claim 21 limitations of: identifying the virus based at least in part on the perturbation…, or the one or more genomic … analyses.
The prior art at the effective filing date of the invention included each claimed element, although not in a single reference. The teachings of Monaselidze et al. show detecting target molecules and viruses in a complex fluid by differential scanning calorimetry and the teachings of Ren et al. show a technique of identifying viruses from genomic analysis. One of ordinary skill in the art would know that after detecting a virus by differential scanning calorimetry as taught by Monaselidze et al. they could obtain the sequence of the virus and attempt to identify it. An ordinary artisan could combine the elements taught by Monaselidze et al. and with the elements taught by Ren et al. by known methods since they would merely input the sequence of the virus into the neural network of Ren et al. The results of the combination would be predicable to a person skilled in the art because the separate elements perform the same function together as they do separately and do not prevent performing the individual steps in the separate teachings. The invention is therefore prima facie obvious.
Claims 22 is rejected under 35 U.S.C. 103 as being unpatentable over Monaselidze et al. (US20190003995A1) in view of Koslen et al. (Advances in Biological Chemistry, vol. 09, no. 03, pp. 110-34; IDS document 7/26/2022), Wooster et al. (Journal of Immunological Methods, vol. 464, pp. 22-30), and Chaires et al. (WO2012109383A2). The italicized text corresponds to the instant claim limitations.
Regarding claim 22, Monaselidze et al. teach detecting the presence of proteins and/or metabolites in a sample of whole blood, plasma, or serum by creating a thermogram of the sample in a differential scanning calorimeter, comparing the sample thermogram to a thermogram from a control sample, and determining the presence of the protein or metabolite when an alteration is present in the thermogram of the sample relative to the control (p. 1, paragraph 0008; p.4, paragraph 0048) and using a computer system with appropriate software (p. 6, paragraph 0064; p.12, paragraph 0129). The teaching reads on the claim 22 limitations of: …obtaining an analysis sample thermogram by differential scanning calorimetry; inputting the analysis sample thermogram into a computer system; comparing, using the computer system, the analysis sample thermogram to (ii) a reference library of thermograms of samples … to provide a comparison; determining, using the computer system and based at least in part on the comparison, whether the analysis sample thermogram exhibits a perturbation; and if a perturbation is present, identifying the target molecule as present in the complex fluid.
Monaselidze et al. is silent on the claim 22 limitations of: combining, in a vessel, (i) a complex fluid, comprising one or more of proteins, peptides, lipids, and carbohydrates, the complex fluid further comprising or suspected of comprising a target molecule, and (ii) a capture moiety comprising biotin covalently attached to a ligand capable of binding to the target molecule; incubating the complex fluid and capture moiety whereby the target molecule, if present, binds to the capture moiety to form a conjugate; removing the conjugate, if present, from the complex fluid with a device comprising (i) a body comprising a substrate material, a poly(methyl methacrylate) (PMMA) coating on at least a portion of a surface of the body, and a plurality of retrieval moiety molecules covalently bound to the PMMA coating, the retrieval moiety molecules comprising streptavidin; removing the target molecule from the device; combining the removed target molecule with a quantity of a control sample to provide an analysis sample, wherein the control sample comprises the complex fluid, the control sample being devoid of the target molecule… and that the reference library thermograms are comprising the ligand. However, these limitations were known in the art at the effective filing date of the invention as taught by Chaires et al., Koslen et al., and Wooster et al.
Regarding claim 22, Chaires et al. teach a method of using a differential scanning calorimeter for comparing and ranking physical transformation data for a first combination of compounds and/or biomolecules to data for a second combination of compounds and/or biomolecules for profiling ligand and target molecule interactions (p. 8, paragraph 0062). These various combinations of analysis include embodiments which read on the claim 22 limitations of: the reference library thermograms are comprising the ligand.
Koslen et al. teach a technique of capturing ligands that bind human serum albumin (HSA) which can then be analyzed in further processes (p. 116-118, Capture Strategy, paragraph 1, Components, paragraphs 1-5; Figures 1-2). These teachings read on the limitations of combining, in a vessel, (i) a complex fluid, comprising one or more proteins, peptides, lipids, and carbohydrates, the complex fluid further comprising or suspected of comprising a target molecule, and (ii) a capture moiety comprising biotin covalently attached to a ligand capable of binding to the target molecule; incubating the complex fluid and capture moiety whereby the target molecule, if present, binds to the capture moiety to form a conjugate; removing the conjugate, if present, from the complex fluid… removing the target molecule… Under the broadest reasonable interpretation of the claims, a target molecule can itself be a ligand and, although HSA is not typically interpreted as a ligand by definition, it can act functionally as a ligand in a molecule capture system that binds target molecules to capture them. Additionally, MPEP 2144.04(VI)(A) states reversal of parts is an obvious modification, so the teaching of using biotin labeled HSA to capture target ligands prompts the idea of biotin labeled ligands that bind HSA to capture it.
Koslen et al. teach thermogram analysis in combination with the capture strategy provides validation for the use of differential scanning calorimetry (DSC) in diagnostic applications and analytes can be isolated from plasma and independently assessed (p. 128-129, Applications of Thermogram Analysis in Diagnostics, paragraphs 2-5). These teachings disclose the limitation of …combining the removed target molecule with a quantity of a control sample to provide the analysis sample, wherein the control sample comprises the complex fluid, the control sample being devoid of the target molecule. Additionally, Figure 2 step (f) shows retrieved ligands were further analyzed by liquid chromatography/mass spectrometry which demonstrates the captured molecules can be used for further experimentation such as differential scanning calorimetry as suggested by Koslen et al. (p. 112, 1. Introduction, paragraph 8).
Further regarding claim 22, Wooster et al. teach using PMMA beads conjugated to streptavidin to collect biotinylated peptide/MHC molecules in the proper orientation for use in downstream applications (p. 25, 2.10 Flow cytometry; p. 27-28, 3.4 Multimerization and functional assessment of eukaryotic-derived peptide/MHC). These teachings disclose the claim 22 limitation of … a device comprising (i) a body comprising a substrate material, a poly (methyl methacrylate) (PMMA) coating on at least a portion of a surface of the body, and a plurality of retrieval moiety molecules covalently bound to the PMMA coating, the retrieval moiety molecules comprising streptavidin, and removing the target molecule from the device.
Monaselidze et al. teach the motivation for their invention is to address the need for sensitive and non-invasive diagnostic methods for disease and infections in patients (paragraph 0003). Koslen et al. teach ligand binding associated with various disease states is thought to induce perturbations in plasma thermograms which can be verified by isolating ligands (p. 112, 1. Introduction, paragraph 7). A person having ordinary skill in the art would be motivated to combine the teachings of Koslen et al. with those of Monaselidze et al. in order to accurately diagnose patients using differential scanning calorimetry and avoid invasive procedures. There would be a reasonable expectation of success because both references utilize differential scanning calorimetry to show differences between samples with varying constituents and Koslen et al. demonstrated that ligands can be captured and retrieved.
Additionally, the prior art teaching of Koslen et al. contained beads of unknown material with streptavidin linked to them used to capture and retrieve target molecules, which differs from the claimed device. Wooster et al. taught the components of the claimed device and their functions. One of ordinary skill in the art could have substituted the PMMA beads coated with streptavidin taught by Wooster et al. for the streptavidin coated beads used by Koslen et al. and the results of the modification would be predictable because the beads perform the same function, thereby capturing and retrieving target molecules that are bound by a ligand tagged with biotin. Lastly, the prior art at the effective filing date of the invention included each claimed element, although not in a single reference. The teachings of Monaselidze et al. show detecting target molecules in a complex fluid by differential scanning calorimetry and the teachings of Chaires et al. taught probing ligand-target molecule interactions with various combinations of samples containing a target molecule and/or a ligand. One of ordinary skill in the art could combine the elements of Monaselidze et al. with the elements of Chaires et al. by known methods since both utilize differential scanning calorimetry and utilize the same principles of analyzing thermograms and the separate elements would merely perform the same function when combined as they do separately. An ordinary artisan would have recognized the results of the combination would be predictable because both teachings involve analyzing complex fluids and molecular interactions with only the intended purpose of the analysis differing (i.e., detecting and quantifying molecules versus characterizing ligand/additive interactions). The invention of claim 22 is therefore prima facie obvious.
Claims 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Monaselidze et al. (US20190003995A1) as applied to claim 1 above, and further in view of Chaires et al. (WO2012109383A2) and Takeno et al. (Sen’i Gakkaishi, vol. 68, no. 9, pp. 248-52). The italicized text corresponds to the instant claim limitations.
The limitations of claim 1 has been taught by Monaselidze et al.
Monaselidze et al. is silent on the limitations of claims 15-16. However, these limitations were known in the art at the effective filing date of the invention as taught by Chaires et al. and Takeno et al.
Regarding claims 15-16, Takeno et al. teach comparing the thermograms of the same target molecule in a purified and unpurified state and detecting differences (p. 249, 2.1 Sample and samples preparation, 2.2 Differential scanning calorimetry (DSC), 3.1 Melting and formation of crystalline fibers). This teaching shows the concept of comparing a molecule in a purified vs. an unpurified state that is applicable to any molecule and therefore reads on the claim 15 limitations of: wherein: the complex fluid comprises the target molecule in an unpurified state; the control sample comprises the complex fluid and the target molecule in a purified state; and a perturbation indicates that the target molecule in the purified state has an altered characteristic compared to the target molecule in the unpurified state. Chaires et al. teach a method of using a differential scanning calorimeter for comparing and ranking physical transformation data for a first combination of compounds and/or biomolecules to data for a second combination of compounds and/or biomolecules for profiling ligand and target molecule interactions (p. 8, paragraph 0062). Chaires et al. teach small variations in a complex composition may alter the melting temperature, transition temperature, as well as other chemical and physical characteristics as compared to a pure substance (p. 11, paragraph 0076). These teachings of Chaires et al. read on the claim 16 limitations of: combining a quantity of a ligand with the analysis sample prior to obtaining the analysis sample thermogram, the ligand capable of binding to the target molecule in the unpurified state; comparing, using the computer system to a control sample thermogram, the control sample comprising the complex fluid, the target molecule added in the purified state, and the ligand to provide a subsequent comparison; and determining, using the computer system and based at least in part on the subsequent comparison, whether the analysis sample exhibits a perturbation, wherein a perturbation indicates that the target molecule in the unpurified state exhibits different binding characteristics to the ligand compared to the target molecule in the purified state.
The prior art at the effective filing date of the invention included each claimed element, although not in a single reference. The teachings of Monaselidze et al. show detecting target molecules and viruses in a complex fluid by differential scanning calorimetry and the teachings of Chaires et al. taught probing ligand-target molecule interactions with various combinations of samples containing a target molecule and/or a ligand. One of ordinary skill in the art could combine the elements of Monaselidze et al. with the elements of Chaires et al. by known methods since both utilize differential scanning calorimetry and utilize the same principles of analyzing thermograms and the separate elements would merely perform the same function when combined as they do separately. An ordinary artisan would have recognized the results of the combination would be predictable because both teachings involve analyzing complex fluids and molecular interactions with only the intended purpose of the analysis differing (i.e., detecting and quantifying molecules versus characterizing ligand/additive interactions). In the same manner, the teachings of Takeno et al. of investigating differences in a purified target molecule vs. an unpurified target molecule could be combined to the combined teachings of Monaselidze et al. and Chaires et al. by one or ordinary skill in the art using known methods of purifying one sample with the target molecule and keeping another sample unpurified. The results of such a combination would be predicable because differential scanning calorimetry techniques are based on the comparison of two samples that are different in composition and/or content and the results of such a combination would demonstrate whether or not there are changes in the thermodynamic properties of molecules. The invention is therefore prima facie obvious.
Conclusion
No claims are allowed.
Claims 14, 19-20, and 22 are patent eligible subject matter under Step 2B of the eligibility analysis. The combination of capturing target molecules by affinity isolation and then performing differential scanning calorimetry on the collected target molecules is not well-understood, routine, or conventional because the prior art does not demonstrate that such a combination of techniques is widespread and ubiquitously known by persons of ordinary skill in the art (e.g., no review articles published before the effective filing date of the invention teach the combination). An article by Koslen et al. (Advances in Biological Chemistry, 9, pp. 110-34; IDS document 7/26/2022) teaches the combination, which the inventors of the instant application are coauthors. Another article by Brudar et al. (Acta Chimica Slovenica, pp. 564-70) explored a similar combination of immunoaffinity chromatography and differential scanning calorimetry to investigate plasma samples (p. 565, 1. Introduction). Claim 20 is eligible because it depends from claim 19.
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/T.Y.O./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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