Classifications

• • G—PHYSICS
  • G06—COMPUTING; CALCULATING OR COUNTING
  • G06Q—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES; SYSTEMS OR METHODS SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES, NOT OTHERWISE PROVIDED FOR
  • G06Q30/00—Commerce
  • G06Q30/02—Marketing; Price estimation or determination; Fundraising
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
• • G—PHYSICS
  • G06—COMPUTING; CALCULATING OR COUNTING
  • G06Q—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES; SYSTEMS OR METHODS SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES, NOT OTHERWISE PROVIDED FOR
  • G06Q40/00—Finance; Insurance; Tax strategies; Processing of corporate or income taxes
  • G06Q40/02—Banking, e.g. interest calculation or account maintenance

Definitions

• This invention relates to systems and methods for ordering custom designed biological molecules through networked electronic systems such as Internet. More specifically, this invention relates to electronic systems and methods for pricing, bidding, ordering, tracking and receiving custom-designed oligonucleotides.
• Custom made biologicals include, but are not limited to, macromolecule reagents such as DNA, RNA, or protein. Custom biologicals also include modified animals, and genomic data.
• oligonucleotide is short fragments of DNA.
• the use of oligonucleotides has grown significantly over the past decade as a consequence of the simultaneous burst of research and practical applications in the field of molecular biology - in particular genomic research, genetic testing and diagnostic applications- and the capacity to produce large numbers of synthetic oligonucleotides at a relatively low cost.
• Oligonucleotides along with enzymes and buffers, have become one of the most common and widely used laboratory reagents. However, oligonucleotides are different from other routine laboratory reagents in that they each have unique DNA sequences that are specific to their intended use.
• oligonucleotides are laboratory reagents that require a high degree of customization among an almost unlimited number of combinations.
• oligonucleotides are laboratory reagents that require a high degree of customization while being widely used on a daily basis.
• a sophisticated tool that facilitates the interactions between the oligonucleotide customers and the oligonucleotide vendors, as well as the interactions with the administrative systems of both parties would be a significant advantage over the systems currently available.
• the instant invention provides methods, software and apparati that enables a vast array of custom biologicals and biological information to be provided to the end user facilitating the design, pricing, ordering, tracking, and directing the production of customized biologicals in a novel unified platform.
• Embodiments of the invention relate to electronic systems and methods for ordering custom-designed biological compounds.
• aspects of the invention involve custom-designed oligonucleotides, other custom biologicals could be similarly ordered and processed within the system.
• custom antibodies, custom gene sequences, custom single nucleotide polymorphisms and the like can be ordered using embodiments of the present invention system.
• Bios include macromolecule reagents, modified animals, and genomic data.
• Macromolecule reagents include, but are not limited to oligonucleotides, polynucleotides, polypeptides, arrays of polynucleotides, arrays of polypeptides, both polyclonal and monoclonal antibodies, full-length and partial cDNA clones, mRNA, and genomic sequences. 3. Modified Animals
• Modified animals include, but are not limited to, animals which have been treated to produce antibodies to a specified polypeptide sequence as described below in the Antibody Embodiments section, and transgenic animals (including knock-outs, knock-ins, as well as genomic substitutions).
• Genomic data includes the identity and/or frequency of SNPs and other polymorphism, cDNA sequences, genomic sequences, the positions of introns, exons, promoters, open reading frames and regions of nucleotide and amino acid sequence homology.
• oligonucleotides include RNA, DNA, or RNA/DNA hybrid sequences of more than one nucleotide in either single chain or duplex form.
• nucleotide as used herein as an adjective to describe molecules comprising RNA, DNA, or RNA/DNA hybrid sequences of any length in single-stranded or duplex form.
• nucleotide is also used herein as a noun to refer to individual nucleotides or varieties of nucleotides, meaning a molecule, or individual unit in a larger nucleic acid molecule, comprising a purine or pyrimidine, a ribose or deoxyribose sugar moiety, and a phosphate group, or phosphodiester linkage in the case of nucleotides within an oligonucleotide or polynucleotide.
• nucleotide is also used herein to encompass "modified nucleotides" which comprise at least one modifications (a) an alternative linking group, (b) an analogous form of purine, (c) an analogous form of pyrimidine, or (d) an analogous sugar, for examples of analogous linking groups, purine, pyrimidines, and sugars see for example PCT publication No. WO 95/04064.
• the desired polynucleotide sequences are preferably chemically synthesized, but may also be prepared by any known method, including semi-synthetic, recombinant, ex vivo generation, or a combination thereof, as well as utilizing any purification methods known in the art.
• nucleotide sequence may be employed to designate indifferently a polynucleotide or a nucleic acid. More precisely, the expression “nucleotide sequence” encompasses the nucleic material itself and is thus not restricted to the sequence information (i.e. the succession of letters chosen among the four base letters) that biochemically characterizes a specific DNA or RNA molecule. 7. Polypeptide
• polypeptide refers to a polymer of amino without regard to the length of the polymer; thus, peptides, oligopeptides, and proteins are included within the definition of polypeptide. This term also does not specify or exclude post-expression modifications of polypeptides, for example, polypeptides which include the covalent attachment of glycosyl groups, acetyl groups, phosphate groups, lipid groups and the like are expressly encompassed by the term polypeptide.
• polypeptides which contain one or more analogs of an amino acid (including, for example, non-naturally occurring amino acids, amino acids which only occur naturally in an unrelated biological system, modified amino acids from mammalian systems etc.), polypeptides with substituted linkages, as well as other modifications known in the art, both naturally occurring and non-naturally occurring.
• amino acid including, for example, non-naturally occurring amino acids, amino acids which only occur naturally in an unrelated biological system, modified amino acids from mammalian systems etc.
• polypeptides with substituted linkages as well as other modifications known in the art, both naturally occurring and non-naturally occurring.
• Recombinant polypeptide is used herein to refer to polypeptides that have been artificially designed and which comprise at least two polypeptide sequences that are not found as contiguous polypeptide sequences in their initial natural environment, or to refer to polypeptides which have been expressed from a recombinant polynucleotide.
• the expression vector is any of the mammalian, yeast, insect or bacterial expression systems known in the art. Commercially available vectors and expression systems are available from a variety of suppliers including Genetics Institute (Cambridge, MA), Stratagene (La Jolla, California), Promega (Madison, Wisconsin), and Invitrogen (San Diego, California). If desired, to enhance expression and facilitate proper protein folding, the codon context and codon pairing of the sequence is optimized for the particular expression organism in which the expression vector is introduced, as explained by Hatfield, et al., U.S. Patent No. 5,082,767.
• antibody refers to a polypeptide or group of polypeptides which are comprised of at least one binding domain, where an antibody binding domain is formed from the folding of variable domains of an antibody molecule to form three-dimensional binding spaces with an internal surface shape and charge distribution complementary to the features of an antigenic determinant of an antigen, which allows an immunological reaction with the antigen.
• Antibodies include recombinant proteins comprising the binding domains, as wells as fragments, including Fab,
• an "antigenic determinant” is the portion of an antigen molecule, in this case a desired polypeptide, that determines the specificity of the antigen-antibody reaction.
• An “epitope” refers to an antigenic determinant of a polypeptide.
• An epitope can comprise as few as 3 amino acids in a spatial conformation which, is unique to the epitope. Generally an epitope consists of at least 6 such amino acids, and more usually at least 8-10 such amino acids. Methods for determining the amino acids which make up an epitope include x-ray crystallography, 2-dimensional nuclear magnetic resonance, and epitope mapping e.g. the Pepscan method described by H. Mario Geysen et al. 1984. Proc. Natl. Acad. Sci. U.S.A. 81 :3998-4002; PCT Publication No. WO
• transgenic animals or "host animals” used herein designate animals that have their genome genetically and artificially manipulated.
• Preferred animals are non-human mammals and include those belonging to a genus selected from Mus (e.g. mice), Rattus (e.g. rats) and
• Oryctogalus e.g. rabbits which have their genome artificially and genetically by the insertion of a nucleic acid according to the invention.
• the desired transgenic animals all include within a plurality of their cells a cloned recombinant or synthetic DNA sequence.
• Preferred transgenic animals according to the invention contain in their somatic cells and/or in their germ line cells a specified polynucleotide.
• the desired transgenic animals thus contain specific sequences of exogenous genetic material which are specified by the genomic sequence to be added, removed or modified in a suitably configured player module.
• the design of the desired transgenic animals may be made according to the conventional techniques well known for one skilled in the art. For more details regarding the production of transgenic animals, and specifically transgenic mice, one may refer to US Patents Nos. 4,873,191, issued Oct.lO, 1989, 5,464,764 issued Nov. 7, 1995 and
• Database A database includes indexed and freeform tables for storing data. Within each table are a series of fields that store data strings, such as names, addresses, chemical names, and the like. However, it should be realized that several types of databases are available. For example, a database might only include a list of data strings arranged in a column. Other databases might be relational databases wherein several two dimensional tables are linked through common fields. Embodiments of the invention are not limited to any particular type of database. 14. Input Devices
• An input device can be, for example, a keyboard, rollerball, mouse, voice recognition system, automated script from another computer that generates a file, or other device capable of transmitting information from a customer to a computer.
• the input device can also be a touch screen associated with the display, in which case the customer responds to prompts on the display by touching the screen. The customer may enter textual information through the input device such as the keyboard or the touch-screen.
• Instructions Instructions refer to computer-implemented steps for processing information in the system.
• Instructions can be implemented in software, firmware or hardware and include any type of programmed step undertaken by components and modules of the system.
• LAN One example of a Local Area Network may be a corporate computing network, including access to the Internet, to which computers and computing devices comprising the system are connected.
• the LAN conforms to the Transmission Control Protocol/Internet Protocol (TCP/IP) industry standard.
• TCP/IP Transmission Control Protocol/Internet Protocol
• the LAN may conform to other network standards, including, but not limited to, the International Standards Organization's Open Systems Interconnection, IBM's SNA, Novell's Netware, and Banyan VINES.
• a microprocessor as used herein may be any conventional general purpose single- or multi- chip microprocessor such as a Pentium ® processor, a Pentium ® Pro processor, a 8051 processor, a MIPS ® processor, a Power PC ® processor, or an ALPHA ® processor.
• the microprocessor may be any conventional special purpose microprocessor such as a digital signal processor or a graphics processor.
• the microprocessor typically has conventional address lines, conventional data lines, and one or more conventional control lines.
• each of the modules comprises various sub-routines, instructions, commands, procedures, definitional statements and macros.
• Each of the modules are typically separately compiled and linked into a single executable program. Therefore, the following description of each of the modules is used for convenience to describe the functionality of the preferred system.
• the processes that are undergone by each of the modules may be arbitrarily redistributed to one of the other modules, combined together in a single module, or made available in, for example, a shareable dynamic link library.
• the system may include any type of electronically connected group of computers including, for instance, the following networks: Internet, Intranet, Local Area Networks (LAN) or Wide Area Networks (WAN).
• the connectivity to the network may be, for example, remote modem, Ethernet (IEEE 802.3), Token Ring (IEEE 802.5), Fiber Distributed Datalink Interface (FDDI) or Asynchronous Transfer Mode (ATM).
• computing devices may be desktop, server, portable, hand-held, set-top, or any other desired type of configuration.
• an Ethernet IEEE 802.3
• Token Ring IEEE 802.5
• FDDI Fiber Distributed Datalink Interface
• ATM Asynchronous Transfer Mode
• computing devices may be desktop, server, portable, hand-held, set-top, or any other desired type of configuration.
• an ATM Asynchronous Transfer Mode
• Internet includes network variations such as public internet, a private internet, a secure internet, a private network, a public network, a value-added network, an intranet, and the like.
• DOS Operating System
• OS/2 Windows 3.X
• Windows 95 Windows 98
• Windows 2000 Windows NT
• Player refers to a compiled user interface program that displays information to a customer.
• a customer player is used to enter and view information relating to the custom biological that is being bid upon, ordered or tracked within the system.
• the player reads data from a standard format, such as XML, and displays the corresponding data to the customer.
• the player is based on an Internet browser that reads XML documents.
• the various software aspects of the system may be written in any programming language such as C, C++, BASIC, Pascal, Perl, Java, and FORTRAN and ran under the well-known operating system.
• C, C++, BASIC, Pascal, Java, and FORTRAN are industry standard programming languages for which many commercial compilers can be used to create executable code.
• SGML Standard Generalized Markup Language
• SGML "documents” usually consist of text, graphics, and hypertext links.
• SGML identifies and names the parts of the information so that these parts can be managed and manipulated to create a variety of products as diverse as typesetting, indexing, CD-ROM distribution, serving as hypertext over the Web, and translation into foreign languages.
• Information on the specification for SGML can be found on the Internet at http://www.w3.org.
• a standard data format includes a pre-determined definition of how data is to be sent from one system/module to another. By defining a standard data format for custom biologicals orders, the system can send the same data file to several vendors in order to obtain a bid.
• the standard data format can be based on the Extended Markup Language (XML), a Document Type Definition
• DTD Digital Time
• SGML Standard Generalized Markup Language
• a system is one or more computers and associated peripherals that carry out selected functions.
• a Customer system includes the computer hardware, software and firmware for executing the specific software instructions described below.
• a system should not be interpreted as being limited to be a single computer or microprocessor, and may include a network of computers, or a computer having mutiple microprocessors.
• Transmission Control Protocol is a transport layer protocol used to provide a reliable, connection-oriented, transport layer link among computer systems.
• the network layer provides services to the transport layer.
• TCP provides the mechanism for establishing, maintaining, and terminating logical connections among computer systems.
• TCP transport layer uses IP as its network layer protocol.
• TCP provides protocol ports to distinguish multiple programs executing on a single device by including the destination and source port number with each message.
• TCP performs functions such as transmission of byte streams, data flow definitions, data acknowledgments, lost or corrupt data re- transmissions and multiplexing multiple connections through a single network connection.
• TCP is responsible for encapsulating information into a datagram structure.
• the Extended Markup Language is a derivative dialect of SGML designed for use on the World Wide Web and in intranets.
• XML is a stripped-down version of SGML.
• Every valid XML document is also a valid SGML document.
• XML is therefore useful for implementing the most commonly-used SGML features.
• the specification for XML can be found on the Internet at http://www.w3.org.
• a customer can efficiently determine, bid and order a variety of custom biologicals.
• the customer enters a description of the molecule into a bidding module.
• the bidding module then sends the description, in a standard data format such as the Extended Markup Language (XML), to a transaction server.
• the transaction server analyzes the type of order and determines the appropriate vendors capable of developing the custom biological.
• the biological is a custom antibody, only vendors with the capability to provide antibodies will be contacted.
• the system sends a standard data format bid request to each vendor.
• the vendor system automatically or manually determines a bid for completing the required task.
• the task could be producing a custom antibody that binds to a selected peptide sequence.
• the order could include the amino acid sequence of the polypeptide, the required quantity of antibody, and other specific information necessary for each vendor to provide its bid.
• the transaction server orders the returned bid data by, for example, price or manufacturing times and then forwards that information to the customer that placed the order.
• the customer can then review the bids and select the most desirable bid from among those that have been returned.
• the system is used to order custom designed oligonucleotide sequences.
• the custom biological is the nucleotide sequence of the oligonucleotide.
• the nucleotide sequence is first entered manually or automatically into a customer module on the customer's computer.
• the customer module can be a stand alone program or a browser based application.
• the customer module can include software instructions for determining the actual sequence of the oligonucleotide to order.
• the customer module includes a primer determination program that designs oligonucleotide primer sequences that have homology to a known sequence.
• a primer determination program that designs oligonucleotide primer sequences that have homology to a known sequence.
• This primer determination software would assist the researcher in determining the appropriate primer sequence to order.
• Well known conventional primer determination programs are commercially available and can be incorporated within the system of the present invention by one of ordinary skill in the art.
• the custom oligonucleotide can also be entered. This information can be, for example, the types of bonds between each chemical group (nucleotide), or other side groups that are part of the composition to be ordered.
• This information is gathered by the customer module, it is converted into a standard data format.
• the standard data format is the Extended Markup Language (XML), but other types of standard data formats, such as the Hypertext Markup Language (HTML), SGML or other DTD could be substituted.
• the standard data format includes all of the information on the custom biological, plus other information, such as a unique identifier of the customer.
• the information is transmitted to the transaction server that connects a plurality of customers to a plurality of vendors.
• the transaction server are two interfaces that connect the customer to the transaction server.
• the first interface accepts data formats from the customer relating to pricing bids for a custom designed biological.
• the second interface accepts data formats from the customer relating to actual orders placed for the custom biologicals.
• these bids or orders Once these bids or orders have been placed by the customer, they are transmitted through the interfaces described above to each vendor.
• the vendors that have been sent a bid request return a price quote to the transaction server. Vendors that receive orders thereafter process the orders and send the custom biological to the customer.
• embodiments of this invention are extensible to delivery of genomic data in addition to actual chemical compounds.
• a customer could request a bid for providing every single nucleotide polymorphism (SNP) within particular nucleotide sequence.
• the customer could send a nucleotide sequence to a plurality of vendors. Each vendor would then match the customer's nucleotide sequence against their database of SNPs to determine if the had any data on the requested sequence. If such SNPs were found in their database, the vendor could return a price for revealing the SNPs of the customer's nucleotide sequence. In addition, the vendor could also return a price for performing additional experiments to discover additional SNPs of the customer's nucleotide sequence.
• embodiments of the invention relate to returning allelic variations of a particular sequence. Similar to the method described above for SNPs, the vendor can receive bids for providing a customer with allelic variations of a particular nucleotide sequence. The vendor would then look into its own database of genetic data to determine if such variants had already been determined. If so, the price for revealing the nucleotide sequences of such variants would be returned to the customer. Also, the vendor can provide a bid price for using the customer's nucleotide sequence to discover additional allelic variants in particular populations of individuals. If the customer accepts such a bid, the vendor then carries out the required experiments and returns the allelic gene data to the customer.
• Embodiments of the invention include several methods for entering custom biological data.
• an stand-alone software "player” module can be run on the customer's computer that provides inputs for various types of custom biologicals.
• the player is designed to accept input relating to oligonucleotides, polynucleotides, arrays of polynucleotides, full-length and partial cDNA clones, mRNA, or genomic sequences.
• the entire nucleotide sequence(s) to be bid or ordered can be entered into the player module.
• entire sequences, as well as portions of a gene, or an Expressed Sequence Tag (EST) can be entered into the player module in order to obtain extended or full-length mRNA, cDNA, genomic sequences from a vendor.
• EST Expressed Sequence Tag
• the customer can enter nucleotide sequences so as to obtain information regarding the identity and/or frequency of polymorphisms, SNPs, splice variant or genetic homologues.
• polypeptides can be entered into the player module to obtain polypeptides, arrays of polypeptides, antibodies, or animals which have been treated to produce antibodies to a specified polypeptide sequence.
• vendors who own proprietary libraries or collections of custom biologicals are able to modify the pricing module to differentiate between biologicals which are already in the library and therefore cheaper to provide to the end user and those which must be custom synthesized.
• Embodiments which are able to deliver combinations of already existing biologicals and custom synthesized biologicals are explicitly contemplated.
• any of the desired polynucleotides can be labeled, if desired, by incorporating a label detectable by spectroscopic, photochemical, biochemical, immunochemical, or chemical means.
• useful labels include radioactive substances, fluorescent dyes or biotin.
• polynucleotides are labeled at their 3' and 5' ends.
• a label can also be used to capture the primer, so as to facilitate the immobilization of either the primer or a primer extension product, such as amplified DNA, on a solid support.
• a capture label is attached to the primers or probes and can be a specific binding member which forms a binding pair with the solid's phase reagent's specific binding member (e.g. biotin and streptavidin).
• a polynucleotide or a probe may be employed to capture or to detect the target DNA.
• the polynucleotides, primers or probes provided herein may, themselves, serve as the capture label.
• a solid phase reagent's binding member is a nucleic acid sequence
• it may be selected such that it binds a complementary portion of a primer or probe to thereby immobilize the primer or probe to the solid phase.
• a polynucleotide probe itself serves as the binding member those skilled in the art will recognize that the probe will contain a sequence or "tail" that is not complementary to the target.
• a polynucleotide primer itself serves as the capture label
• at least a portion of the primer will be free to hybridize with a nucleic acid on a solid phase.
• DNA Labeling techniques are well known to the skilled technician. Any of the desired polynucleotides, primers and probes can be conveniently ordered as immobilized on a solid support.
• Solid supports are known to those skilled in the art and include the walls of wells of a reaction tray, test tubes, polystyrene beads, magnetic beads, nitrocellulose strips, membranes, microparticles such as latex particles, sheep (or other animal) red blood cells, duracytes® and others.
• the solid support is not critical and can be selected by one skilled in the art. Thus, latex particles, microparticles, magnetic or non-magnetic beads, membranes, plastic tubes, walls of microtiter wells, glass or silicon chips, sheep (or other suitable animal's) red blood cells and duracytes are all suitable examples.
• a solid support refers to any material which is insoluble, or can be made insoluble by a subsequent reaction.
• the solid support can be chosen for its intrinsic ability to attract and immobilize the capture reagent.
• the solid phase can retain an additional receptor which has the ability to attract and immobilize the capture reagent.
• the additional receptor can include a charged substance that is oppositely charged with respect to the capture reagent itself or to a charged substance conjugated to the capture reagent.
• the receptor molecule can be any specific binding member which is immobilized upon (attached to) the solid support and which has the ability to immobilize the capture reagent through a specific binding reaction. The receptor molecule enables the indirect binding of
• ordered array of polynucleotides is designed to be "addressable" where the distinct locations are recorded and can be accessed as part of an assay procedure.
• Addressable polynucleotide arrays typically comprise a plurality of different oligonucleotide probes that are coupled to a surface of a substrate in different known locations. The knowledge of the precise location of each polynucleotides location makes these "addressable" arrays particularly useful in hybridization assays. Any addressable array technology known in the art can be employed with the desired polynucleotides.
• GenechipsTM One particular embodiment of these polynucleotide arrays is known as the GenechipsTM, and has been generally described in US Patent 5,143,854; PCT publications WO 90/15070 and 92/10092.
• arrays may generally be produced using mechanical synthesis methods or light directed synthesis methods, which incorporate a combination of photolithographic methods and solid phase oligonucleotide synthesis (Fodor et al., Science, 251 :767-777, 1991).
• the immobilization of arrays of oligonucleotides on solid supports has been rendered possible by the development of a technology generally identified as "Very Large Scale Immobilized Polymer Synthesis” (VLSIPSTM) in which, typically, probes are immobilized in a high density array on a solid surface of a chip. Examples of VLSIPSTM technologies are provided in
• Oligonucleotides comprising modified nucleotides are also included in the present invention. Oligonucleotides may, for example, contain one or more modified bases or DNA or RNA backbones modified for stability or for other reasons. "Modified" bases include, for example, tritylated bases and unusual bases such as inosine.
• Modifications of the present invention include, but are not limited to, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2- thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1 -methyl guanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,
• the first interface in a transaction server receives the bit request in a standard data format.
• the bid request includes bulk listing of the structure and features of the custom biological in order to calculate prices.
• the exact composition of the custom biological does not have to be transmitted across the Internet.
• the composition is an oligonucleotide
• information relating to the total number of nucleotides, identity and number of custom bonds and the total quantity of DNA required might be sufficient to prepare a bid.
• the actual sequence of the oligonucleotide would not need to be sent to the transaction server.
• conventional encrypton techniques can be employed to encrypt the transmission between the customer and the transaction server.
• digital certificates such as those available from Verisign Corporation (www.verisign.com) could be used by the customer and transaction server to encrypt messages and authenticate customers.
• the transaction server Once the bid request is received by the transaction server, it is transmitted to a plurality of vendors in order to obtain price quotes.
• the transaction server sends the standard data format to each vendor and tracks which vendor has been sent a quote request. Once a price quote has been received from each vendor, the transaction server forwards the price quotes to the requesting customer.
• this system thus provides an exchange or "reverse auction" that can be used by custom chemical composition buyers to determine the best price for synthesizing the requested product.
• the communication between the vendors and the transaction server is preferably encrypted and digitally signed to ensure that the data has not been tampered with or altered.
• each vendor can provide their own custom interface that reads this standard format and imports the necessary data into the vendor's quoting system.
• the transaction server reads the standardized incoming data and provides a pricing comparison for the customer.
• each vendor can be an "exchange vendor" that controls access to a subset of other vendors.
• each exchange vendor would receive the bid request and transmit it to its subset of vendor that would actually bid on providing the custom biological compound. Examples of these types of exchange vendors include Chemdex (www.chemdex.com) and SciQuest (www.sciquest.com).
• the vendor system in order for the vendors to properly quote prices for the custom compositions, includes a bid module that received the bid requests based upon the standard data format.
• the bid module provides three databases: 1) a customer name database, 2) a contract price database and 3) a standard price database.
• the customer name database preferably contains the names, preferences and unique customer identifiers for each customer that is authorized to request price quotes and orders in the system.
• the preferences can be for default parameters such as the normal delivery time requested, standard quantities ordered and preferred sample format (liquid, powder, etc.).
• the contract price database includes fields that store contract provisions for each customer so that specific customers can be provided with special prices. For example, a particularly good customer might be provided with a ten percent discount over the standard price. Other fields in the database store contract provisions for penalties or dollar value purchase limits.
• the standard price database includes fields corresponding to standard prices for each of the options available to the customers. Thus, if a contractual price for the customer is not found, the system will produce a price quote by reference to the standard price database. For example, the standard prices of each nucleotide sequence might be $1.00.
• the second interface in the transaction server receives the custom biological orders from a customer. These orders are sent in a standard data format that provides all of the necessary order information to a vendor. It should be realized that although this process has been described as providing a price bid before an order is placed, an order could be placed by a customer without ever requesting a price bid with a vendor. This might be appropriate, for example, when a customer desires to purchase their custom chemical composition from a particular vendor.
• the order is logged into an order tracking module within the transaction server so that the status of the order with the vendor can be tracked.
• the order is then sent in a standard data format to the predetermined vendor.
• the vendor computer then processes the order and sends a confirmation of order receipt to the transaction server.
• the transaction server logs the confirmation, and forwards the confirmation to the customer.
• the order has been entered into an order database in the vendor system, it also placed within a vendor tracking module.
• This module is used by the vendor to track the status of orders within the vendor system.
• the order is then transferred to a production module that is responsible for overseeing the actual production processing of the order. For example, if the order was for an oligonucleotide, the production module would send the desired nucleotide sequence to a data conversion module so that it is put in the proper data format for an oligonucleotide synthesizer. The converted data is then forwarded to the synthesizer so it can be manufactured. Because the process may not require human intervention, the chance of synthesis errors is greatly diminished.
• the transaction server monitors the status of the order and reports back to the customer via data transmission to the player.
• an accounting system within the vendor system prepares the appropriate invoice and billing options according to the terms of the purchase order that was sent with the order.
• the transaction server can be integrated into the accounting process so that a dollar amount from each order that is completed by a vendor is sent to the host (i.e. Genset, Sciquest, Chemdex or other exchange) of the transaction server.
• the host of the transaction server can be provided with a revenue stream for providing the bidding and ordering process to the customers and vendors.
• the system can be provided so that the actual bill for the custom designed product is sent from the host of the transaction server to the customer.
• the host of the transaction server then pays the vendor directly. In this manner, the host of the transaction server can charge one fee to the customer, and pay a lower fee to the vendor for manufacturing the product.
• a bid is not required prior to placing an order.
• a customer can simply place an order for a chemical compound through the order module and designate a particular vendor.
• the transaction server will pass the order directly to the particular vendor and begin the process of ordering the custom biological.
• the desired oligonucleotides are preferably synthesized chemically as directed by a standardized data file fed into the production module and utilizing various chemical methods well known in the art, e.g. by use of an automated DNA synthesizer (such as a 380B automatic DNA synthesizer (Applied Biosystems, Foster City, Calif.). As examples, the methods of Caruthers, M.
• oligonucleotides may be synthesized by the method of Stein et al. (Nucl. Acids Res. 16:3209, 1988), and methylphosphonate oligonucleotides may be prepared by use of controlled pore glass polymer supports (Sarin et al., Proc. Natl. Acad. Sci. USA 85:7448, 1988).
• Polypeptides may be synthesized by the method of Stein et al. (Nucl. Acids Res. 16:3209, 1988), and methylphosphonate oligonucleotides may be prepared by use of controlled pore glass polymer supports (Sarin et al., Proc. Natl. Acad. Sci. USA 85:7448, 1988).
• the desired polypeptides are preferably synthesized chemically as directed by a standardized data file fed into the production module and utilizing various chemical methods well known in the art including solid phase techniques such as those described in: Fields et al, Int. J.
• Polypeptides may also be produced by automated synthesis using the ABI 431 A Peptide Synthesizer (Perkin Elmer), for example.
• the newly synthesized peptide may be substantially purified by preparative high performance liquid chromatography (e.g., Creighton, T. (1983) Proteins, Structures and Molecular Principles, WH Freeman and Co., New York, N.Y.).
• composition of the synthetic peptides may be confirmed by amino acid analysis or sequencing (e.g., the Edman degradation procedure; Creighton, supra). Additionally, the amino acid sequence of the polypeptides, or any part thereof, may be altered during direct synthesis and/or combined using chemical methods with sequences from other proteins, or any part thereof, to produce a variant polypeptide.
• the desired polypeptides may be composed of amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres, and may contain amino acids other than the 20 amino acids naturally occurring in humans as specified in the standardized data file entered into the production module.
• the polypeptides may be modified by either natural processes, such as post-translational processing, or by chemical modification techniques which are well known in the art. Specific modifications may be made anywhere in the polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. The same type of modification may be made in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications.
• the polypeptides may be branched , for example, as a result of ubiquitination, and they may be cyclic, with or without branching.
• Cyclic, branched, and branched cyclic polypeptides may result from post-translation natural processes or may be made by synthetic methods. Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, s
• the desired polypeptides can also be made using routine expression methods known in the art.
• the polynucleotide encoding the desired polypeptide is hgated into an expression vector suitable for any convenient host. Both eukaryotic and prokaryotic host systems are used in forming recombinant polypeptides.
• the polypeptide is then isolated from lysed cells or from the culture medium and purified to the extent needed for its intended use. Purification is by any technique known m the art, for example, differential extraction, salt fractionation, chromatography, centrifugation, and the like. See, for example, Methods in Enzymology for a variety of methods for purifying proteins.
• Methods for purifying proteins include the use of detergents or chaotropic agents to disrupt particles followed by differential extraction and separation of the polypeptides by ion exchange chromatography, affinity chromatography, sedimentation according to density, and gel electrophoresis.
• Polypeptide may additionally be produced from the construct using m vitro translation systems such as the In vitro ExpressTM Translation Kit (Stratagene).
• Non-human animals or mammals whether wild-type or transgenic, which express a different species of the desired protein than the one to which antibody binding is desired, and animals which do not express desired protein (i.e. an knock out animal as described in herein) are useful for prepa ⁇ ng antibodies.
• the transgenic mice for example those developed by Abgenix or Medarex which are able to produce partially or totally humanized antibodies are also particularly useful for generating antibodies to be used as therapeutics and in vivo diagnostic reagents.
• Phage display technologies for example those developed by Dyax or Morphosys, are particularly useful in generating antibodies for use as low cost research tools.
• Substantially pure protein or polypeptide is chemically synthesized as desc ⁇ bed above in the Polypeptide Embodiments section, or isolated from transfected or transformed cells containing an expression vector encoding the desired protein or a portion thereof.
• the polypeptide antigens are preferably synthesized chemically as directed by a standardized data file fed into the production module and utilizing various chemical methods well known in the art.
• the concentration of protein in the final preparation is adjusted, for example, by concentration on an Amicon filter device, to the level of a few micrograms per ml.
• Monoclonal or polyclonal antibodies to the protein can then be prepared as follows:
• Monoclonal antibody to epitopes in the desired protein or a portion thereof can be prepared from murine hybridomas according to the classical method of Kohler and Milstein (Nature, 256:495, 1975) or derivative methods thereof (see Harlow and Lane, Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory, pp. 53-242, 1988). Briefly, a mouse is repetitively inoculated with a few micrograms of the desired protein or a portion thereof over a period of a few weeks. The mouse is then sacrificed, and the antibody producing cells of the spleen isolated.
• the spleen cells are fused by means of polyethylene glycol with mouse myeloma cells, and the excess unfused cells destroyed by growth of the system on selective media comprising aminopterin (HAT media).
• HAT media aminopterin
• the successfully fused cells are diluted and aliquots of the dilution placed in wells of a microtiter plate where growth of the culture is continued.
• Antibody- producing clones are identified by detection of antibody in the supernatant fluid of the wells by immunoassay procedures, such as ELISA, as originally described by Engvall, E., Meth. Enzymol. 70:419 (1980). Selected positive clones can be expanded and their monoclonal antibody product harvested for use. Detailed procedures for monoclonal antibody production are described in Davis, L. et al. Basic Methods in Molecular Biology Elsevier, New York. Section 21-2.
• Polyclonal antiserum containing antibodies to heterogeneous epitopes in the desired protein or a portion thereof can be prepared by immunizing suitable non-human animal with the desired protein or a portion thereof, which can be unmodified or modified to enhance immunogenicity.
• a suitable non-human animal is preferably a non-human mammal is selected, usually a mouse, rat, rabbit, goat, or horse.
• a crude preparation which, has been enriched for the desired protein concentration can be used to generate antibodies.
• Such proteins, fragments or preparations are introduced into the non-human mammal in the presence of an appropriate adjuvant (e.g. aluminum hydroxide, RTBI, etc.) which is known in the art.
• an agent which will increase antigenicity such agents are known in the art and include, for example, methylated bovine serum albumin (mBSA), bovine serum albumin (BSA),
• Booster injections can be given at regular intervals, and antiserum harvested when antibody titer thereof, as determined semi-quantitatively, for example, by double immunodiffusion in agar against known concentrations of the antigen, begins to fall. See, for example, Ouchterlony, O. et al., Chap. 19 in: Handbook of Experimental Immunology D. Wier (ed) Blackwell (1973).
• Plateau concentration of antibody is usually in the range of 0.1 to 0.2 mg/ml of serum (about 12 :M).
• Affinity of the antisera for the antigen is determined by preparing competitive binding curves, as described, for example, by Fisher, D., Chap. 42 in: Manual of Clinical Immunology, 2d Ed. (Rose and Friedman, Eds.) Amer. Soc. For Microbiol., Washington, D.C. (1980).
• Antibody preparations prepared according to either the monoclonal or the polyclonal protocol are useful in quantitative immunoassays which determine concentrations of antigen-bearing substances in biological samples; they are also used semi-quantitatively or qualitatively to identify the presence of antigen in a biological sample.
• the antibodies may also be used in therapeutic compositions for killing cells expressing the protein or reducing the levels of the protein in the body.
• transgenic animals are produced by the application of procedures which result in an animal with a genome that has incorporated exogenous genetic material.
• a recombinant polynucleotide is inserted into an embryonic or ES stem cell line.
• the insertion is preferably made using electroporation, such as described by Thomas et al. (Cell 51 :503-512, 1987).
• the cells subjected to electroporation are screened (e.g. by selection via selectable markers, by PCR or by Southern blot analysis) to find positive cells which have integrated the exogenous recombinant polynucleotide into their genome, preferably via an homologous recombination event.
• An illustrative positive-negative selection procedure that may be used according to the method is described by Mansour et al. (Nature 336:348-352, 1988).
• the positive cells are generally isolated, cloned and injected into 3.5 days old blastocysts from mice, such as described by Bradley ("Production and Analysis of Chimaeric
• the positive ES cells are brought into contact with embryos at the 2.5 days old 8-16 cell stage (morulae) such as described by Wood et al. (Proc. Natl. Acad. Sci. U.S.A. 90:4582-
• Embodiments of the system include a series of executable software programs that interact with each other through communication protocols over a network utilizing standard data formats.
• Features of the system include:
• the system 10 includes several systems and modules.
• a set of customer systems 15A,B are linked to administration systems 20A,B.
• a bid module 25A,B Within each customer system is a bid module 25A,B and an order module 27A,B.
• the customer systems 15A,B can include sequence analysis modules 28A,B that provide programs for creating, ordering and analyzing nucleotide or peptide sequences. Such sequence analysis modules are discussed previously in relation to determining custom primers that bind to a particular nucleotide sequence.
• the customer systems are linked through a network, such as the Internet, to a transaction server 30 which processes data transactions from the customer computers.
• the transaction server 30 is linked to three vendor systems 35A-C which provide the custom biologicals that are ordered by each customer.
• each vendor system is a vendor order module 37A-C for processing actual orders and a vendor bid module 40A-C for processing price quotes to customers.
• a synthesizer 45A-C is linked to each of the vendor systems.
• the synthesizer 45 can produce nucleotide sequences, or in another embodiment, synthesize peptide sequences.
• the customer system 15 includes several modules for carrying out the tasks described below. These modules are preferably compiled into a single executable "player" that is installed on the customer's computer, however one of ordinary skill could separate these modules into two or more stand-alone executable programs.
• the customer system is a standard computer system such as that based on an Intel Pentium processor and running a Microsoft Windows operating system, such as Windows 98, Windows 2000 or Windows NT.
• the customer system 15 can be run in a stand alone, disconnected mode to perform local functions including without limitation: the preparation of new orders, and the management of archived orders and all related data. It should be understood that when in this mode, the player can "burst" data to the transaction server 30 when the customer system 15 becomes linked to the transaction server.
• a data queue is provided within the player that stores and tracks which messages need to be sent to the transaction server once a connection is detected.
• the customer system 15 can also be run in an interactive, connected mode to perform online, real-time communication tasks with the Administration system 20 and the vendor system 35, through the transaction server.
• This communication includes, without limitation, the transmission of bid requests to the vendor system, the transmission of purchase order approval requests and purchase order number requests to the administration system, the transmission of orders to the vendor system, the receipt of quotes from the vendor system and the reception of tracking order information from the vendor system.
• the customer system 15 includes a customer profiles database that stores data relating to the customer that is entering data into the system.
• the customer profile database verifies access privileges with the assistance of an authentication module 110 and provides customer information, such as name and identification numbers to the other modules of the customer system.
• the authentication module 110 provides secured access to the ordering process by requiring a password from the customer. This prevents unauthorized customers from placing orders into the system.
• a data entry module 105 accepts data that has been input manually or automatically into the customer system. It should be realized that this data entry module preferably accepts data directly from integrated or third party oligonucleotide analysis software programs that are commercially available. These third party programs are used by customers to determine the proper oligonucleotide sequence to be synthesized.
• Oligonucleotide data is then fed into an analysis module 115 which confirms that the nucleic acid sequence and composition provided by the data entry module will produce the desired oligonucleotide.
• the data analysis module is fed chemical bond information by a bond database 118 so that all of the potential bond types are analyzed by the analysis module 115.
• information on labels or other options can also be included. Examples of types of oligonucleotide information is provided below:
• a standard data conversion module 120 that converts all of the oligonucleotide data into a standard data format 125.
• One example of a preferred format for the standard data format 125 is and XML document, as shown below.
• Information sent from the standard data format conversion module 120 concerns Bid requests and actual orders for oligonucleotides.
• the customer sends directly an order to the vendor "without quote", that means without having sent a bid request before and 2).
• the customer sends first a bid request, then, after receiving an answer from the vendor(s), sends the order "with quote”. Accordingly, three possible functions need to be addressed:
• oligonucleotide packaging, form, shipment, .... These "parameters" may concern only orders, only oligonucleotide, or both.
• the determination of how much information to send is preferably as follows:
• the letters authorized for entry are: A , C , G, T , U, I, R, Y, M, K, S, W, H, B, V, D, N to which are added, according to the international code for degenerate bases (i.e. when the customer user desires a mix of two, three or four bases at a position):
• This second format is more usual, but might be too restricted if we want to deal with new types of monomers. For this reason, the first format is preferred.
• a link can be described by a type:
• the exact sequence descriptions will not be send at bid request time.
• Nb Number (Nb) of bases by type: Nb of A, C, G, T (global sum) Nb of degenerate bases (N, X, Y%) Nb of Inosines Nb of ADN bases Nb of ARN bases Nb of 2'O-Methyl bases Nb of "Other" bases ("Other" must be specified)
• Nb for each type
• a standard data format reception module 130 within the customer system reads incoming standard data formats and displays the received data through a standard data format display module 135.
• the customer system is preferably associated with custom chemical analysis programs that help the customer design the appropriate molecule. For example, if the customer wants to design an oligonucleotide that uniquely binds to a particular fragment of DNA, software programs exist for determining unique short stretches of DNA within the particular fragment. Such programs, for example, are available on the Internet at http://www.gcg.com from the University of Wisconsin
• the Transaction server is illustrated in Figure 3, and includes a collection of executable software programs and databases that link to the Vendor's (or exchange vendor's) information system and regulates the interactions between the customer, the Administration, the Suppler and the Manufacturer.
• the transaction server includes a bid interface module 200 for receiving and processing XML formatted bid requests from customers.
• a bid interface module 200 for receiving and processing XML formatted bid requests from customers.
• an authentication module 202 that provides secured access to the transaction server from the customer system.
• Data that is sent from the customer system is preferably encrypted by conventional public key/private key infrastructure methods, or other ciphers that are well known in the art.
• the XML documents from the customer system are logged into a bid tracking module 205 that includes commands and data storage for tracking the progress of a particular bid after it has been sent to a plurality of vendors through a vendor bid interface module 210.
• a vendor bid interface module 210 Integrated with the vendor module 210 is an encryption module 212 that provides secured access to each vendor system.
• the transaction server waits until each vendor system returns an XML formatted bid response.
• timeout features allows the transaction server to return a set of bids to the customer even if all of the vendor system has not returned a bid
• Each bid that is returned to the transaction server is decrypted by the encryption module 212 and then forwarded to a bid compilation module 215 which reads the XML bid data and orders each bid according to a predefined c ⁇ te ⁇ a. For example, most customers would want the bids ranked m order of price, however the system could also provide rankings according to speed of delivery, purity of compound or other factor desired by the customer.
• the bid compilation module 215 Once the bid compilation module 215 has received and ranked each bid, the bids for the customer are formatted back into an XML format at an Standard data format conversion module 220 and then transmitted to the customer. If a customer decides to accept one of the bids, a purchase order is thereafter received by an order module interface 225 in the transaction server.
• the order includes all of the data necessary for the vendor to synthesize the custom oligonucleotide
• it is preferably send through an authentication module 227 which verifies the identity of the ordering customer through, for example, an authorized digital certificate.
• an order tracking module 230 that tracks the status of all orders in the system.
• the order is then sent through a vendor order module interface 235 to the designated vendor so that the custom compound will be synthesized.
• the vendor order module interface 235 returns order information to a transaction processing module 240 that completes any necessary post- production processing.
• the transaction processing module can include an internal or external accounting system for directly billing the customer for the custom product.
• the transaction processing module can also notify the customer of the status of the completed order, with, for example, shipping tracking numbers or other relevant information.
• the Transaction server allows, without limitation, to save tempora ⁇ ly information, data or queries received from any of the Administration, Manufacturer or customer modules while the recipient is not connected and keep them available until its next connection.
• the transaction server includes modules that perform the following features:
• the Administration system 20 includes executable software and is mainly used in an interactive connected mode to perform through the Transaction server to communicate tasks between the Administration's information system, the vendor system and the customer system.
• the administration system preferably includes modules that perform the following functions:
• the Vendor System Referring to Figure 4, one example of a vendor system 35 is illustrated.
• the vendor system is illustrated.
• 35 includes a series of programs/commands and modules for performing the various necessary functions outlined below.
• a transaction server interface 300 that accepts incoming XML documents from the transaction server 30 and converts those documents into data formats that are read by the remaining modules of the vendor system. If the incoming document is a bid request, the request is sent to the vendor bid module 40.
• Linked to the vendor bid module 40 are several databases and data storages that are used to price the various custom compounds that are being bid by the customers.
• a contract pricing database 310 holds the name of customers and whether any special pricing rules apply to those customers. Thus, customers that order large quantities of products can be given special pricing by reference to the contract price database.
• the proper price for a customer is determined by first comparing a unique customer identifier that was sent by the customer to a customer database 315. The customer database can then determine the proper pricing options for that customer by linkage to the contract price database 310. For example, a first customer might be granted contract pricing from the "Group A" contract price sheet, whereas a second more regular customer might be granted contract pricing from a lower priced "Group B" contract price sheet.
• a standard price database 320 that contains the standard prices for each component in the custom oligonucleotide. If a customer does not have a contract price, or there is no contract price for a particular compound in the contract price database 315, the price is retrieved from the standard price database 320. Examples of pricing for various oligonucleotide components are illustrated below. Examples of Pricing for Oligonucleotide Components
• That price is converted into a predetermined XML format, as described above, and transmitted through the transaction server interface 300 to the transaction server.
• a purchase order (in XML format) is forwarded through the transaction server to the transaction server interface in the vendor system.
• the vendor system preferably stores a reference (bid identifier) to previous bids so that any new orders can reference a bid that was made. This ensures that the proper price is charged for the ordered product.
• the transaction interface module receives the new order, the order is sent to the vendor order module 37.
• This module includes an order database 330 that stores each new order coming into the system.
• an order tracking module 335 within the vendor order module provides the customer and the transaction server with updated information on the status of the order.
• a vendor accounting system 340 that is responsible for receiving the incoming purchase order, and billing the customer or host of the transaction server for production of the custom oligonucleotide.
• the accounting system can be a custom designed system, but is preferably based on one of the standard billing, ordering, purchasing, tracking and reporting systems widely available through vendors such as SAP, Oracle and others.
• the vendor order module 37 also includes a production module 350 that reads the incoming XML production data from the transaction server and sends a production order to a data conversion module 355.
• the data conversion module 355 converts the XML order data into a data format that is appropriate for synthesis on a nucleic acid synthesizer, such as a PE Biosystems (Foster City, CA) Model ABI 3948 Nucleic Acid Synthesis and Purification System.
• synthesizer interface module 360 which is linked to the synthesizer.
• the process 400 begins at a start state 402 and then moves to a state 404 wherein oligonucleotide data is received in the customer system.
• the oligonucleotide data might be received through the player software described previously.
• the process 400 moves to a decision state 410 to determine whether a bid has been requested by the customer. If a bid has been requested, the data is converted into an XML format at a state 412. The process 400 then moves to a state 414 wherein the XML data is transmitted from the customer system to the transaction server. As discussed previously, this transmission preferably includes encrypting the data as it is sent to the transaction server. The process 400 then moves to a state 416 wherein the transaction server forwards bid requests in XML format to a plurality of vendors so that each vendor can respond to the big request. Similarly, the transaction server preferably encrypts the data sent to the each vendor so that unauthorized individuals cannot determine what molecules are being ordered or bid by a particular customer.
• the process 400 then moves to a process state 418 wherein each vendor determines a price for the oligonucleotide order they have received.
• This process of pricing oligonucleotides is described more specifically with reference to Figure 6.
• the process 400 moves to a state 422 wherein the prices from each vendor are converted into an XML document and transmitted to the transaction server.
• the transaction server then compiles each of the bid prices from each vendor at a state 424.
• the bids can be listed by vendor identifier, price, delivery date or any other data type.
• the process 400 then moves to a state 426 wherein the bids are forwarded from the transaction server to the customer systems. A determination is then made at a decision state 428 whether any bid was accepted by the customer. If a bid was accepted by the customer, the process 400 moves to a process state 430 in order to process the order for the custom oligonucleotides.
• the process state 430 is described in more detail with reference to Figure 6 below.
• the process 400 then moves to a state 432 wherein an invoice is received by the customer from the selected vendor that has been chosen to process the order. The process 400 then terminates at an end state 434.
• the process 418 begins at a start state 450 and then moves to a state 452 wherein the XML data corresponding to the number of nucleotide bases, types of modifications to the ordered oligonucleotide, specific linkages between oligonucleotides and other features of the oligonucleotide sequence are received by the vendor systems. It should be realized that this process is normally undertaken by several vendors simultaneously in order to provide a variety of prices to the customer.
• the process 418 then moves to a state 454 wherein the identity of the customer ordering the oligonucleotide is identified.
• the process 418 then moves to a state 456 wherein the specific pricing data for the identified customer is retrieved from a customer pricing database.
• the number of bases within the oligonucleotides sequence, identification of spacers and internal modifiers and other features of the sequence are then determined at a state 458 by the vendor system.
• a determination is then made at a decision state 464 whether custom pricing has been found for the particular customer that is ordering the product. If custom pricing is found, that price is retrieved from a customer pricing database at a state 470.
• the sum of all prices for each component of the oligonucleotide sequence is then determined at a state 472 and the process 418 terminates at an end state 476.
• the process 418 moves to a state 478 wherein standard pricing for each component of the ordered oligonucleotide product is retrieved from a database. The process 418 would then continue at the state 472 wherein the sum of all prices for the oligonucleotide is determined.
• the process 430 begins at a start state 500 and then moves to a state 502 wherein a XML order is transmitted by the customer to the selected vendor that has provided the appropriate bid.
• the process 430 then moves to a state 504 wherein a new order file is opened by the vendor within their vendor order database.
• the order is then transmitted to a production module at a state 506.
• the oligonucleotide In order for the oligonucleotide to be processed, it is preferably converted from the XML format into a data format that is compatible with the synthesizer that will create the actual oligonucleotide sequence.
• the XML document is converted into a synthesizer compliant data format so that it can be immediately transmitted into a conventional oligonucleotide.
• a similar scheme could be utilized for ordering custom peptides, wherein the XML document is converted into a file format that is compatible with a protein synthesizer.
• the data is then transmitted to the nucleotide synthesizer at a state 512.
• a determination is then made at a decision state 516 whether the oligonucleotide has been completely synthesized.
• the process 430 moves to a state 520 wherein an order tracking module within the vendor system is updated to indicate that the oligonucleotide sequence has been completely synthesized.
• the process then moves to a state 524 wherein the accounting system within the vendor system is updated to indicate that the order has been completed and the customer's bill can be generated.
• the process 430 then moves to a decision state 526 to determine whether the product has been shipped to the customer. Once the produce has been shipped, the order tracking module is updated at a state 530 to indicate that the order is in transit to the customer. An invoice is then transmitted either electronically or via paper to the customer at a state 532. The process then terminates at an end state 534.
• the customer computer 15 includes a polymorphic "player" program that manages communication between the various systems. Using the player, the customer system is used in a stand-alone local mode disconnected from any external system, or in a connected mode where it manages communication with one or several external systems.
• the customer system includes bid and order modules which are compiled and displayed in the player so that the player appears on the customer's computer screen under different shapes depending on the task it is required to perform. This player provides an intuitive interface for inputting and manipulating ordering data. Three basic shapes correspond to the three basic functioning status of the player.
• the Icon shape corresponding to the idle status. • The console shape corresponding to the mode selection status.
• the screen shape corresponding to the different working modes. The navigation from one status to another is always possible by different types of actions on the mouse or on the keyboard.
• the player In the Idle Status mode, the player is not active. However, if it is connected to the transaction server, it works as a passive receiver. If and when information is received, a colored indicator flashes in the center of an icon to inform the customer that information is ready to be read. The customer can activate the player and access the selection status by clicking their mouse cursor on the flashing indicator.
• the choice of accessible functional modes includes without limitation:
• a player 600 is illustrated.
• the player 600 is a "polymorphic" program that changes shapes depending on its status.
• the player is in an idle mode which resembles a small oval shape.
• an indicator 602 which changes colors depending on the status of orders within the system. For example, if desired information has been received, the indicator 602 might flash red. However, in all other circumstances, the indicator might be a steady yellow color.
• buttons that are used in other modes of the player device.
• buttons 604, 606, 608, 610, 612 and 614 are enabled so that clicking a mouse on each button will open the corresponding display screen.
• a create order button 604 which causes the player to enter the mode illustrated below in Figure 10.
• the player 600 includes a edit order button 606 which causes the player to enter the mode illustrated in Figure 11.
• the player 600 also includes a bid request button 608 which results in the player entering the mode illustrated in Figure 12.
• a send order button 610 which transmits pending orders to the transaction server.
• An order status button 612 is also provided which retrieves a screen illustrating the status of pending orders as illustrated in Figure 13. Note that in this polymorphic shape a text display 620 for displaying the mode selected by the mouse is shown.
• the create order display window is opened to the customer.
• the create order window includes a text box 650 for entering text corresponding to the oligonucleotide sequence that is to be ordered.
• display boxes 652 and 653 show the order number and oligonucleotide name for the present order being modified.
• each nucleotide of the sequence is displayed graphically by a different color and shape.
• the label of each nucleotide is provided within the graphical element corresponding to the particular nucleotide.
• the nucleotide sequence TAG is illustrated as a first graphical element 658 which provides a label of a letter "T" in the center.
• a straight graphical line 660 which connects to a second graphical element 662 which provides a label of a letter "A” in the center.
• the graphical 662 is connected through a straight graphical bar 664 to a third graphical element 668 which provides a label of a letter "G" in the center.
• a sound indicator 680 is provided on the create order screen which results in a voice synthesized output of the nucleotide sequence, including all modifications to that sequence.
• the process of outputting voice is illustrated below in Figure 15.
• an edit order display screen 700 is shown.
• the edit order display screen 700 is activated by depressing the edit order button 606.
• a table 704 is provided in the display screen 700 which lists the sequence number, name, base number, utilization, priority and nucleotide sequence of oligonucleotides that have been ordered.
• selecting, for example, line 706 will return the customer to the create order display shown in Figure
• the bid request display 750 that is activated by the bid request button 608 is illustrated.
• the bid request display 750 includes a table 754 having the following categories: selected, ID number, name, creation date, oligo number, utilization, priority, and number of bases.
• the selection field 756 provides checkboxes which indicate which of the ordered oligonucleotides should be sent out for a bid.
• the customer chooses which of the ordered oligonucleotides should be bid by selecting checkboxes 756 corresponding to the proper oligonucleotides.
• the customer can then press the send order button 610 to begin the process of transmitting bid requests to the various vendors.
• send order button 610 can provide options for which vendors, or groups of vendors, should receive the bid requests. This allows the customers to designate certain vendors as preferred over other vendors within the system.
• an order status display screen 800 that is activated by the button 612 is illustrated.
• a table 802 which lists each of the orders that have been sent out for bid.
• Within the table 802 are fields for the oligonucleotide identifier, name, creation date, oligonucleotide number, utilization, and quote number for each oligonucleotide that has been ordered.
• selecting a particular order within the table 802 results in a detailed display of the status on that order within a table 804.
• the table 804 shows the status of each order as it progresses through the system.
• indicators 806 provide graphical indicia of the status of a particular order. For example, when an order has been sent but not received, the indicator 806 might be green. However, once a bid has been received, the indicator might turn yellow. Thus, a customer can visually determine the status of each order within the system.
• a process 900 of creating an oligonucleotide using the create order display ( Figure 10) is illustrated.
• the process 900 begins at a start state 902 and then moves to a state 904 when the order entry screen is displayed to the customer.
• a determination is then made at a decision state 906 whether a new nucleotide has been entered into the nucleotide text box. If a nucleotide was not entered, the process 900 moves to a decision state 908 to determine whether a modified base has been entered into the system.
• a modified base can be entered through a selection of menu choices that provide a series of base modifications. These modifications can then be illustrated graphically or through text to the customer.
• the process 900 moves to a decision state 912 to determine whether a custom linkage has been entered in the system.
• a custom linkage can be provided between two nucleotide bases by selecting the appropriate linkage through a series of menu choices within the create order display window. If a determination is made that a custom linkage has not been entered, a determination is made at a decision state 916 whether any other element has been entered in the display window. Other elements can be various types of modifications, labels, or other alterations to the nucleotide sequence that might make up part of an oligonucleotide order. If no other elements have been entered, the process terminates at an end state 920.
• the process 900 moves to a state 922 wherein the nucleotide that was entered is graphically displayed within the create order window. This graphical representation of the nucleotide base is provided to the customer so that the customer can easily identify the oligonucleotide that has been ordered. The process then terminates at the end state 920.
• the process 900 moves to a state 926 wherein the modified base is displayed as a graphical object within the create order display.
• the graphical object could be, for example, of a different shape or color than the standard nucleotide base thereby providing an indicator to the customer that a modified base has been ordered. For example, if the normal base is displayed as a circle, the modified base might be displayed as a square.
• the process 900 moves to a state 930 wherein the custom linkage is displayed as a graphical object on the create order display window.
• the custom linkage might be displayed as, for example, a curved, zigzag or jagged line between the graphical objects indicating oligonucleotide bases.
• a customer reviewing the order could easily determine that a custom linkage had been provided between two bases by the shape of the graphical line running between each base.
• varying colors can be used within the graphical indicator of the modified base to show differences between a standard linkage and a custom linkage.
• the process then terminates at the end state 920. If a determination was made that another element was entered at the decision state 916, the process 900 moves to a state 934 wherein the appropriate graphical element indicating the chosen element is displayed to the customer. The process then terminates at the end state 920.
• the process 950 begins at a start state 952 and then moves to a state 954 wherein the first nucleotide in the sequence is read by the system.
• a start state 952 and then moves to a state 954 wherein the first nucleotide in the sequence is read by the system.
• several types of text readers are available that retrieve a string and, beginning at the first letter, output each letter of the string to a voice synthesizer.
• the name of the nucleotide is output to the voice synthesizer. As is known, conventional voice synthesizers will verbalize text that is sent to them by a program. Thus, sending the character "a" to the voice synthesis system will cause the computer to output the "a” sound through the computer speakers.
• the process 950 moves to a state 960 wherein the type of linkage between the currently output nucleotide and the next nucleotide is read. The process then moves to a decision state 962 to determine whether the linkage is standard or not. If the linkage is not standard, the process 950 moves to a state 964 wherein the proper voice text describing the nonstandard linkage is determined. Thus, for each modified linkage, the system stores the text equivalent of that linkage so that it can be output to the voice synthesis system. Once the proper text for the modified linkage is determined at the state 964, the text is output to the voice synthesizer at a state 966. A determination is then made whether other nucleotides are within the sequence at a decision state 968. If no more nucleotides are available in the sequence, the process terminates at an end state 970
• the process 950 moves to a state 972 to determine the appropriate text to output to the voice synthesis system to describe the modified base. Once the appropriate text has been determined, the process 950 returns to the state 966 to output the text to the voice synthesizer.
• This example provides a desc ⁇ ption of one embodiment of a system for designing, orde ⁇ ng, pricing, tracking and directing production of custom oligonucleotides. This system relies on an
• the OhgoPlayer is a versatile module that can adapt to three possible states, the Standby Mode, the Console Mode and the Display Mode.
• the OhgoPlayer When the OhgoPlayer is in Standby Mode (FIG. 8), it appears as an oval shaped icon displaying: (1) a central heart button indicator 602, (2) six lights representing the available function modes 604, 606, 608, 610, 612, and 614, (3) a reduction button 616 and (4) a close button 618.
• the Console Mode offers the user access to all the function modes of the OhgoPlayer.
• the OhgoPlayer When the OhgoPlayer is in Console mode it appears as an oval shaped icon displaying: (1) a text display screen 620, (2) a return to Standby Mode button 622, (3) a close button 618, (4) central heart indicator 602, (5) a reduction button 616, (6) six "keys", or functionality buttons, that allow the user to (a) create an order 604, (b) edit an order 606, (c) make a bid request 608, (d) send an order 610, (e) check an order's status 612, and (f) view toolbox 614.
• Display Mode When the OhgoPlayer is in Console mode it appears as an oval shaped icon displaying: (1) a text display screen 620, (2) a return to Standby Mode button 622, (3) a close button 618, (4) central heart indicator 602, (5) a reduction button 616, (6) six "keys", or functionality buttons, that allow the user to (a)
• the Console Mode can be converted into a Display Mode, which provides access to several features of the OhgoPlayer.
• the Display Mode allows the user access to all of the functional modes, pass from one functional mode to another, and program the OhgoPlayer. While in the Display Mode, the user has access to four other modes: (1) Create Order Mode, (2) Edit Order
• the OhgoPlayer displays: (1) a reduction button 616, (2) a close button 618, (3) an order zone 619, (4) a current functional mode display 621, (5) control paddles 623a, 623b, 623c, (6) tabs to access other functional modes 604, 606, 608, 610, 612, 614 and (7) a light that indicates new replies to bids 625. Clicking on a functional mode tab with a mouse cursor will take the user into the corresponding functional mode. The tab that corresponds to the functional mode in current use will be green to distinguish it from the red tabs that are not in use.
• the control paddles 623a, 623b, 623c allow the user to access the following functionalities: (1) preferences, (2) profiles, (3) tools, (4) search, (5) return to the console mode.
• FIG. 10 shows an illustration of the Create Order Mode, which allows the user to create an order.
• the OhgoPlayer displays: (1) an order number display box 652, (2) an oligonucleotide ID display box 653, (3) navigation buttons 654a, 654b and wheels 656a, 656b for the order number display box, and the oligonucleotide ID display box, (4) a menu and tools zone,
• a refining zone (6) an alphanumeric sequence box 650, (7) a graphic display box 655, (8) a nucleotide base selection paddle 657, (9) a vocal verification button 680, (10) a modifications button 661 and (11) a panel of oligonucleotide statistics and measurements 659.
• the user can navigate through the order number display box 652 and the oligonucleotide ID display box. 653.
• the navigation buttons 654a, 654b allow access to tables with detailed information on orders or sequences.
• the navigation wheels 656a, 656b allow for sequential scrolling of the orders or sequences. Orders and oligonucleotide sequences in these fields are labeled with numbers and names.
• a scrolling menu allows the user to access the list of orders in progress and the sequences of the order in progress.
• the menu and tools zone offers tools to operate the current order and/or sequence of the current order.
• the menu and tools zone displays three buttons: (1) Orders, (2) Sequences and (3) Tools.
• the Orders button allows the user to create, save, open, validate, or print an order.
• the Sequence button allows the user to create a new sequence, start a primer design, or import a file from a hard disk.
• the Tools button allows the user to search, copy selected elements, or import sequences from the clipboard.
• the refining zone is a menu bar that offers ways to specify characteristics of the current order and/or the sequences of the current order.
• the refining zone displays three buttons: (1) Applications, (2) Options, and (3) Priorities.
• the Applications button allows the user to select one of several envisioned uses (e.g., PCR, sequencing, hybridization).
• the Options button allows the user to define the packaging, quantity, documentation, and the field of the application.
• Priorities button allows the user to prioritize an order based on variables such as price, turn-around, or purity.
• the alphanumeric sequence box 650 has two ends, labeled, 5' and 3', to allow for polarization of the sequence.
• the user can enter the desired nucleotide sequences into the box by using the authorized letters: A, C, G, T, U, I, R, Y, M, K, S, W, H, B, N, D and ⁇ .
• the user can control the entry of nucleotides by using the mouse.
• the graphic display box 655 provides an illustrative representation of the entered oligonucleotide sequence.
• This box comprises a ruler to allow the user to know the position in the chain of each visible base.
• the box displays the sequence itself which is composed of: (1) the bases 658, 662, 668, 672, 676, (2) the links between the bases 660, 664, 670, (3) the modifications of insertion, and (4) the HO and OH left and right end components.
• Arrows 771a, 771b, 773a, 773b allow the user to navigate towards the right and left of the displayed sequence.
• the nucleotide base selection paddle 657 is in the form of a cross and displays the letters
• the modification button 661 allows the user to modify a selected portion of a sequence in the alphanumeric sequence box 650.
• the modifications available to the user are dependent upon how many bases the user selects. If the user selects one base, the base may either be modified or deleted. If two or more bases are selected, the user can modify links in addition to modifying and deleting bases.
• the panel of oligonucleotide statistics and measurements 659 displays a certain number of physicochemical indicators and other measurements e.g., molecular weight, size, and % GC. Edit Order Mode
• FIG. 11 shows the Edit Order Mode as a tabular presentation of all the sequences associated with an order.
• the OhgoPlayer displays: (1) a menu bar, (2) an order identifier 705, (3) the current sequence 706, and (4) mechanisms of selection and identification of the order and current sequences 652, 653, 654a, 654b, 656a, 656b.
• the table is divided into columns that display all of the characteristics of a particular sequence, including the: (1) Oligo ID number 701, (2) Oligo name 702, (3) base number 703, (4) utilization 705, (5) priority 706 , and (6) sequence 704.
• a scroll bar 707 allows the user to view hidden orders.
• Selecting a column name will sort the entire table in alphabetical or numerical order. There is always a blue-highlighted "current sequence” in the table. By default it is the first entry in the table, but the "current sequence” may be changed by (1) using the navigational wheel, (2) directly selecting another sequence, or (3) using the Up and Down displacement arrows.
• the "current sequence” is the sequence that will be graphically displayed when the user leaves the Edit Order
• the user may click on the desired cell and type in a modified entry.
• the user may click on the desired cell, thereby transforming the cell into a scrolling menu that presents the user with available options. For example, clicking on a cell in the priority column will display the following options to the user: price, turn-around, purity, control, or alt.
• the menu bar allows the user to operate on the entire order or the current order.
• the menu bar is comprised of three buttons: (1) Order button, (2) Sequences Button, and (3) Tool Button.
• the Order button allows the user to create, validate, save, open, and print an order.
• the Sequences button allows the user to create a new sequence, start a primer design, or import a file on the hard disk.
• the Tool button allows the user to search the orders or edit, delete, print, copy, or paste a sequence.
• FIG. 12 shows an illustration of the Bid Request Mode. This mode displays a tabular presentation of all the orders that are validated and thus capable of price quote or an order request.
• the Bid Request Mode comprises: (1) a menu bar, (2) a current order 758, (3) mechanisms of selection of the current order 654a, 656a, 652 and (4) the current order 770.
• the table is divided into columns representing the following characteristics of an order: (1) order ID number 758, (2) order name 760, (3) creation date 762, (4) number of Oligos 764, (5) utilization 766, (6) priority 768, and (7) number of bases 754. There is also a special column 756 that serves as a mechanism to select various orders.
• the table also includes a vertical scrolling bar 772, which allows the user to view hidden orders.
• the special column allows the user to bid on (get a price quote), or definitively order multiple orders in one transaction. All orders that are checked in the special column will be ordered or receive a price quote.
• the user may change an entry in the order name, creation date, number of Oligos, or number of bases column by clicking on the desired cell and typing in a modified entry.
• the user may change an entry in the utilization or priority column, by clicking on the desired cell, thereby transforming the cell into a scrolling menu that presents the user with available options.
• the menu bar makes it possible to start operations on: (1) the entire order list, (2) the selected order list, and (3) the current order.
• the menu bar comprises an Order button and a Tools button.
• the Order button allows the user to send the selected orders for a bid proposal or an order.
• the Tools button allows the user to edit, delete, or print orders.
• FIG. 13 provides an illustration of the Order Status mode.
• This mode displays a tabular presentation of all the orders being processed.
• the table is divided into two sections: (1) characteristics of the order 808 and a (2) status of the order section 810.
• the characteristics of the order section 808 contains the following information: (1) order ID number 812, (2) order name 813, (3) creation date 814, (4) utilization 816, (5) number of Oligos 815, (6) quote number 802, (7) order date, (8) shipment date, (9) production report, and (10) status.
• This section has both vertical and horizontal scrolling bars 817, 818 to visualize all the orders and all the fields of each order.
• the status of the order section 810 is divided into three columns: (1) status 804, (2) waiting for 805, and (3) news 807.
• the status column 804 shows the current state of the order: (1) validated, (2) bid request, (3) quote available, (4) send order, (5) order acknowledge, and (6) completed.
• the waiting for column 805 displays the next step that will occur in the ordering process. For example if the status column shows that an order was sent out, the waiting for column will signify that the product will be sent.
• the news column 807 will indicate to the user whether new information regarding an order is available. Selecting a column name sorts the entire table in alphabetical or numerical order. There is always a blue-highlighted "current order" 819 in the table. By default it is the first entry in the table, but the "current order" may be changed by (1) using the navigational wheel, (2) directly selecting another order, or (3) using the Up and Down displacement arrows. The user may access additional information about an order by opening a tabular presentation of the order, the quotation document, or the production report.
• the menu bar makes it possible to start operations on: (1) the entire order list, (2) the selected order list, and (3) the current order.
• the menu bar comprises an Order button and a Tools button.
• the Order button allows the user to send the selected orders for a bid proposal, an order, or to the archive if the order is in the completed state.
• the Tools button allows the user to visualize the order, print the order list, and print the current order.
• Custom antibodies could be ordered by having the customer enter in the amino acid sequence of the desired antigen into the bid module 25.
• the bid module would convert the amino acid sequence data into a standard data format that could be read by multiple vendors.
• the transaction server would then forward a bid request to vendors that had signed up with the transaction server to bid on production of custom antibodies.
• Those vendors would then receive the XML data corresponding to the custom antigen and price producing the antibody as discussed above.
• the vendor would take into account the cost of synthesizing the antigen, similar to the system described above, for pricing the cost of synthesizing an oligonucleotide sequence. The cost of then manufacturing that antigen and producing either polyclonal or monoclonal antibodies from the antigen would be added into the bid price.
• the techniques for developing polyclonal and monoclonal antibodies from a known antigen are well known in the art, and normally involve injecting a rabbit or mouse with the antigen in order to purify an antibody that is raised against the injected antigen. Once a bid is accepted by a customer, it is sent to the appropriate vendor who would receive the order and process the request.
• a commercially available peptide synthesizer such as a PE Biosystems (Foster City, CA) Model 431 A peptide synthesizer, the customer data can be directly transferred to the synthesizer for production. Once production of the peptide was complete, the product would be introduced into a rabbit, and polyclonal or monoclonal antibodies, depending on the customer's order, would be generated.
• the customer could enter or import nucleotide sequences corresponding to gene fragments, and request bids for production of the full-length gene.
• the vendors would accept XML documents having a the DNA sequence of the gene fragment, and then search internal and external databases for information on the full length gene that was requested by the customer. If the vendor found that its system included the complete DNA sequence of the gene of interest, a price would be estimated back to the customer for providing this data. If the vendor determined that it only had some, but not all, of the DNA sequence of the gene of interest, it could estimate a price for discovering the DNA sequence of the full length gene and a time estimate for that process.
• the system can also be used to bid prices for single nucleotide polymorphisms (SNPs) corresponding to a known gene.
• SNPs single nucleotide polymorphisms
• the customer would enter a DNA sequence in the bid module and then request bids for determining SNPs of the DNA sequence. Vendors could search their internal and external gene databases to determine if they had SNPs corresponding to the requested DNA sequence. If one or more SNPs were found by the vendor, the price for identifying these SNPs would be sent to the customer.
• the customer would accept bids through the transaction server from a plurality of vendors and could choose to accept data from a particular vendor based on a desired parameter, such as price, deliver, etc.

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• 2001
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