# US 7,407,810 B2 · Methods and apparatus for characterizing polymeric mixtures > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 7,407,810 B2 - Document ID: US7407810B2 - Status: Granted - Kind: B2 - Application number: 10/931,939 - Filed: 2004-09-01 - Published: 2005-03-24 - Granted: 2008-08-05 - Earliest claimed: 2003-09-04 - Assignees: Momenta Pharmaceuticals, Inc. - Inventors: Sasisekharan Raguram - Web page: https://patentgrep.com/patent/US7407810B2 ## CPC - G01N 33/48: Biological material, e.g. blood, urine (G01N33/02, G01N33/26, G01N33/44, G01N33/46 take precedence); Haemocytometers (counting blood corpuscules distributed over a surface by scanning the surface G06M11/02) - G16C 20/20: Identification of molecular entities, parts thereof or of chemical compositions - Y10T 436/107497: Preparation composition [e.g., lysing or precipitation, etc.] - Y10T 436/143333: Saccharide [e.g., DNA, etc.] - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) - G16C: COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE - Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION ## Abstract The invention provides methods and apparatus for characterizing complex polymeric mixture of interest. Candidate solutions are eliminated from a solution space using one or more experimental measurements of a polymeric mixture of interest. The elimination step can be repeated one or more times using different experimental measurements produced by various chemical and physical protocols, so that the remaining candidate solutions converge to describe the actual polymeric mixture under investigation. Once the composition of the complex polymeric mixture has been characterized, the information thus generated can be used to facilitate, for example, the manufacture of a bio-equivalent of the complex polymeric mixture. ## Claims ### Claim 1 A method of characterizing a polymeric mixture, the method comprising the steps of: (a) generating a solution space comprising a plurality of candidate solutions; (b) providing an experimental measurement of a first attribute of a polymeric mixture of interest; (c) determining for each of at least a subset of the candidate solutions a value of the first attribute; and (d) characterizing the polymeric mixture at least in part by eliminating at least one of the candidate solutions from the solution space whose determined value does not correspond to the experimental measurement of the first attribute. ### Claim 2 (depends on 1) The method of claim 1, wherein each of the plurality of candidate solutions is characterized by a quantity of components, and wherein each component is characterized by (i) an abundance of the component in the candidate solution, (ii) a composition defined by one or more members of a set of primary units, and (iii) an arrangement of the one or more primary units in the component. ### Claim 3 (depends on 2) The method of claim 2, wherein the abundance in element (i) is a relative abundance. ### Claim 4 (depends on 1) The method of claim 1, wherein step (d) comprises eliminating candidate solutions from the solution space in a step-wise manner according to a comparison between an experimental measurement of each of a plurality of attributes of the polymeric mixture and a value of the respective attribute determined for each of at least a subset of the remaining candidate solutions in the solution space. ### Claim 5 (depends on 1) The method of claim 1, wherein in step (c), determining a value of the first attribute for a candidate solution comprises evaluating a model that predicts the first attribute for a mixture characterized by the candidate solution. ### Claim 6 (depends on 1) The method of claim 1, wherein in step (c), determining a value of the first attribute for a candidate solution comprises obtaining a value of the first attribute from a database. ### Claim 7 (depends on 1) The method of claim 1, wherein the polymeric mixture comprises at least one biopolymer. ### Claim 8 (depends on 1) The method of claim 1, wherein the polymeric mixture comprises at least one polysaccharide. ### Claim 9 (depends on 8) The method of claim 8, wherein the polymeric mixture comprises at least one linear polysaccharide. ### Claim 10 (depends on 8) The method of claim 8, wherein the polymeric mixture comprises at least one branched polysaccharide. ### Claim 11 (depends on 1) The method of claim 1, wherein the polymeric mixture comprises at least one member selected from the group consisting of a polysaccharide, an oligosaccharide, a peptide, a protein, a glycoprotein, a nucleic acid, a polynucleotide, a lipid, a lipopolysaccharide, a proteoglycan, a glycolipid, and a lipoprotein. ### Claim 12 (depends on 1) The method of claim 1, wherein the experimental measurement comprises at least one member selected from the group consisting of a physical measurement, a chemical measurement, and a biological assay. ### Claim 13 A method of characterizing a polymeric mixture, the method comprising the steps of: (a) generating a solution space comprising a plurality of candidate solutions, wherein each candidate solution is characterized by a quantity of components, and wherein each component is characterized by (i) an abundance of the component in the candidate solution, (ii) a composition defined by one or more members of a set of primary units, and (iii) an arrangement of the one or more primary units in the component; (b) providing an experimental measurement of a first attribute of a polymeric mixture of interest; (c) determining for each of at least a subset of the candidate solutions a value of the first attribute; and (d) characterizing the polymeric mixture at least in part by eliminating at least one of the candidate solutions from the solution space whose determined value does not correspond to the experimental measurement of the first attribute. ### Claim 14 (depends on 13) The method of claim 13, further comprising the steps of: (e) providing an experimental measurement of a second attribute of the polymeric mixture of interest; (f) determining for each of at least a subset of the candidate solutions a value of the second attribute; and (g) characterizing the polymeric mixture at least in part by eliminating at least one of the candidate solutions from the solution space whose determined value does not correspond to the experimental measurement of the second attribute. ### Claim 15 (depends on 13) The method of claim 13, wherein step (d) comprises eliminating candidate solutions from the solution space in a step-wise manner according to a comparison between an experimental measurement of each of a plurality of attributes of the polymeric mixture and a value of the respective attribute determined for each of at least a subset of the remaining candidate solutions in the solution space. ### Claim 16 (depends on 15) The method of claim 15, wherein step (d) proceeds by preferentially eliminating candidate solutions having different quantities of components than the polymeric mixture before eliminating candidate solutions having the same quantities of components as the polymeric mixture but having different component compositions. ### Claim 17 (depends on 16) The method of claim 16, wherein step (d) proceeds by preferentially eliminating candidate solutions having different abundances of components than the polymeric mixture before eliminating candidate solutions having the same abundances of components as the polymeric mixture but having different component compositions. ### Claim 18 (depends on 17) The method of claim 17, wherein step (d) proceeds by preferentially eliminating candidate solutions having different component compositions than the polymeric mixture before eliminating candidate solutions having the same component compositions as the polymeric mixture but having different primary unit arrangements. ### Claim 19 (depends on 15) The method of claim 15, further comprising the step of computing a measure of difference between at least two of the candidate solutions remaining in the solution space following an elimination. ### Claim 20 (depends on 19) The method of claim 19, wherein step (d) comprises eliminating candidate solutions in a step-wise manner until the measure of difference is below a predetermined threshold. ### Claim 21 (depends on 19) The method of claim 19, wherein the measure of difference indicates a difference in biological activity. ### Claim 22 (depends on 19) The method of claim 19, wherein the step of computing a measure of difference comprises: (i) ordering the components of the at least two candidate solutions to identify analogous components; (ii) evaluating a first distance metric that accounts for a difference between the quantity of components of the at least two candidate solutions and a difference between the abundance of the analogous components of the at least two candidate solutions; (iii) evaluating a second distance metric that accounts for a difference between the composition of the analogous components of the at least two candidate solutions; (iv) evaluating a third distance metric that accounts for a difference between the arrangement of the primary units of the analogous components; and (v) computing the measure of difference using the first distance metric, the second distance metric, and the third distance metric. ### Claim 23 (depends on 19) The method of claim 19, wherein step (d) further comprises using the measure of difference to suggest an attribute of the polymer mixture to provide in a subsequent elimination step. ### Claim 24 (depends on 13) The method of claim 13, wherein in step (c), determining a value of the first attribute for a candidate solution comprises evaluating a model that predicts the first attribute for a mixture characterized by the candidate solution. ### Claim 25 (depends on 13) The method of claim 13, wherein in step (c), determining a value of the first attribute for a candidate solution comprises obtaining a value of the first attribute from a database. ### Claim 26 (depends on 13) The method of claim 13, wherein the polymeric mixture comprises at least one biopolymer. ### Claim 27 (depends on 13) The method of claim 13, wherein the polymeric mixture comprises at least one member selected from the group consisting of a polysaccharide, an oligosaccharide, a peptide, a protein, a glycoprotein, a nucleic acid, a polynucleotide, a lipid, a lipopolysaccharide, a proteoglycan, a glycolipid, and a lipoprotein. ### Claim 28 (depends on 13) The method of claim 13, wherein the polymeric mixture comprises at least one polysaccharide. ### Claim 29 (depends on 28) The method of claim 28, wherein the polymeric mixture comprises at least one linear polysaccharide. ### Claim 30 (depends on 28) The method of claim 28, wherein the polymeric mixture comprises at least one branched polysaccharide. ### Claim 31 (depends on 28) The method of claim 28, wherein the set of primary units comprises a plurality of disaccharide units. ### Claim 32 (depends on 13) The method of claim 13, wherein the set of primary units comprises at least one member selected from the group consisting of a monosaccharide, a disaccharide, and an oligosaccharide. ### Claim 33 (depends on 13) The method of claim 13, wherein the known set of primary units comprises more than 4 primary units. ### Claim 34 (depends on 13) The method of claim 13, wherein the known set of primary units comprises more than 20 primary units. ### Claim 35 (depends on 13) The method of claim 13, further comprising the step of identifying the set of primary units. ### Claim 36 A method of characterizing a biological preparation comprising a plurality of biopolymers, the method comprising the steps of: (a) generating a solution space comprising a plurality of candidate solutions, wherein each candidate solution is characterized by a quantity of components, and wherein each component is characterized by (i) an abundance of the component in the candidate solution, (ii) a composition defined by one or more members of a set of primary units, and (iii) an arrangement of the one or more primary units in the component; and (b) characterizing a biological preparation at least in part by eliminating candidate solutions from the solution space in a step-wise manner according to a comparison between an experimental measurement of each of a plurality of attributes of the biological preparation and a value of the respective attribute determined for each of at least a subset of the remaining candidate solutions in the solution space. ### Claim 37 (depends on 36) The method of claim 36, wherein the biological preparation is a pharmaceutical preparation or a nutraceutical preparation. ### Claim 38 (depends on 36) The method of claim 36, wherein the method further comprises the step of: (c) producing a composition that is defined by at least one of the remaining candidate solutions in the solution space following step (b). ### Claim 39 (depends on 38) The method of claim 38, wherein the composition produced in step (c) is a bio-equivalent of the biological preparation. ### Claim 40 (depends on 38) The method of claim 38, wherein the method further comprises the step of: (d) characterizing the composition by performing a step-wise candidate elimination procedure. ### Claim 41 A method for determining a measure of difference between at least two mixtures, the method comprising the steps of: (a) describing each of at least two mixtures having known components, wherein each component of each mixture is characterized by (i) an abundance of the component in the candidate mixture, (ii) a composition defined by one or more members of a set of primary units, and (iii) an arrangement of the one or more primary units in the component; (b) ordering the components of each of the at least two mixtures to identify analogous components; (c) evaluating a first distance metric that accounts for a difference between the quantity of components of the at least two mixtures and a difference between the abundance of analogous components of the at least two mixtures; (d) evaluating a second distance metric that accounts for a difference between the composition of analogous components of the at least two mixtures; (e) evaluating a third distance metric that accounts for a difference between the arrangement of the primary units of the analogous components; and (f) determining a measure of difference using the first distance metric, the second distance metric, and the third distance metric. ### Claim 42 (depends on 41) The method of claim 41, wherein the step of determining the measure of difference comprises using a predetermined functional relationship between the first, second, and third distance metrics. ### Claim 43 (depends on 42) The method of claim 42, wherein the predetermined functional relationship is a weighted sum of the first, second, and third distance metrics. ### Claim 44 (depends on 42) The method of claim 42, further comprising the step of determining the functional relationship by relating experimental measurements indicating biological activity to at least one of the first, second, and third distance metrics. ### Claim 45 (depends on 41) The method of claim 41, wherein the measure of difference indicates a difference in biological activity. ### Claim 46 (depends on 41) The method of claim 41, wherein the measure of difference indicates whether one mixture is bioequivalent of the other mixture. ### Claim 47 A system for characterizing a polymeric mixture, the system comprising: (a) a candidate generation module that generates a solution space comprising a plurality of candidate solutions; (b) a computation module that determines for each of at least a subset of the candidate solutions a value of a first attribute; (c) a comparison module that determines for each of the candidate solutions in (b) whether the value of the first attribute for the candidate matches an experimentally-measured value of the first attribute for a polymeric mixture of interest; and (d) an elimination module that eliminates at least one of the candidate solutions from the solution space whose first attribute value does not match the experimentally-measured value. ### Claim 48 An apparatus for characterizing a polymeric mixture, the apparatus comprising: (a) a memory for storing code that defines a set of instructions; and (b) a processor adapted to execute the set of instructions to: (i) generate a solution space comprising a plurality of candidate solutions; (ii) determine for each of at least a subset of the candidate solutions a value of a first attribute; (iii) determine for each of the candidate solutions in (ii) whether the value of the first attribute for the candidate matches an experimentally-measured value of the first attribute for a polymeric mixture of interest; and (iv) eliminate at least one of the candidate solutions from the solution space whose first attribute value does not match the experimentally-measured value.