(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`
`
`(43) International Publication Date
`2 August 2001 (02.08.2001)
`
`(10) International Publication Number
`
`pCT
`
`WO 01/56216 A2
`
`(51)
`
`International Patent Classification7:
`
`H04L
`
`(81)
`
`(21)
`
`International Application Number:
`
`PCT/USOl/02316
`
`(22)
`
`International Filing Date: 24 January 2001 (24.01.2001)
`
`(25)
`
`Filing Language:
`
`(26)
`
`Publication Language:
`
`English
`
`English
`
`(84)
`
`(30)
`
`Priority Data:
`60/178,077
`
`25 January 2000 (25.01.2000)
`
`US
`
`(71)
`
`except US):
`(for all designated States
`Applicant
`AFFYMETRIX,
`INC.
`[US/US]; 3380 Central
`EX—
`pressway, Santa Clara, CA 95051 (US).
`
`(72)
`(75)
`
`Inventors; and
`Inventors/Applicants (for US only): CRAFORD, David,
`M. [US/US]; 1027 Ray Avenue, Los Altos, CA 94022 (US).
`NORVIEL, Vernon, A. [US/US]; 1155 El Abra Way, San
`Jose, CA 95125 (US).
`
`(74)
`
`Agent: SHERR, Alan, B.; Affymetrix, Inc., 34 Commerce
`Way, Woburn, MA 01801 (US).
`
`Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ,
`DE, DK, DM, DZ, EE, ES, FT, GB, GD, GE, GH, GM, HR,
`HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR,
`LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ,
`NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM,
`TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW.
`
`Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FT, FR, GB, GR, IE,
`IT, LU, MC, NL, PT, SE, TR), OAPl patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`without international search report and to be republished
`upon receipt of that report
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes andAbbreviations" appearing at the begin—
`ning ofeach regular issue ofthe PCT Gazette.
`
`(54) Title: METHOD, SYSTEM AND COMPUTER SOFTWARE FOR PROVIDING A GENOMIC WEB PORTAL
`
`(57) Abstract: Systems, methods, and computer program products are de—
`
`scribed that process inquiries or orders regarding purchase of biological de—
`vices, substances, or related reagents. In some implementations, a user se—
`lects probe—set identifiers that identify microarray probe sets capable of en—
`abling detection of biological molecules. Corresponding genes or EST’s are
`identified and are correlated With related product data, which is provided to
`the user. Further, the user may select products for purchase based on the
`product data. If so, the user’s account may be adjusted based on the pur—
`chase order. In the same or other implementations, a local genomic database
`is periodically updated. In response to a user selection of probe—set identi—
`fiers, data related to corresponding genes or EST’S is provided to the user
`from the local genomic database.
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`WO 01/56216
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`PCT/US01/02316
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`METHOD, SYSTEM, AND COMPUTER SOFTWARE FOR PROVIDING A
`GENOMIC WEB PORTAL
`
`RELATED APPLICATION
`
`The present application claims priority from U.S.
`
`Provisional Patent Application Serial No. 60/178,077,
`
`entitled “METHOD, SYSTEM, AND COMPUTER SOFTWARE FOR
`
`PROVIDING A GENOMIC WEB PORTAL,” filed January 25, 2000,
`
`incorporated herein by reference in its entirety for all
`
`purposes.
`
`BACKGROUND
`
`The present invention relates to the field of,
`
`bioinformatics.
`
`In particular,
`
`the present invention
`
`relates to computer systems, methods, and products for
`
`providing genomic information over networks such as the
`Internet.
`
`Research in molecular biology, biochemistry, and
`
`many related health fields increasingly requires
`
`organization and analysis of complex data generated by
`
`new experimental techniques. These tasks are addressed
`
`See,
`by the rapidly evolving field of bioinformatics.
`
`e.g., H. Rashidi and K. Buehler, Bioinformatids Basics:
`
`Applications in Biological Science and Medicine (CRC
`
`Press, London, 2000); Bioinformatics: A Practical Guide
`
`to the Analysis of Gene and Proteins (B.F. Ouelette and
`
`A.D. Bzevanis, eds., Wiley & Sons, Inc., 1998), both of
`
`which are hereby incorporated herein by reference in
`
`their entireties. Broadly, one area of bioinformatics
`
`applies computational techniques to large genomic
`
`databases, often distributed over and accessed through
`
`networks such as the Internet, for the purpose of
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`illuminating relationships among gene structure and/or
`
`location, protein function, and metabolic processes.
`
`SUMMARY OF THE INVENTION
`
`The expanding use of microarray technology is one of
`
`the forces driving the development of bioinformatics.
`
`In
`
`particular, microarrays and associated instrumentation
`
`and computer systems have been developed for rapid and
`
`large—scale collection of data about the expression of
`
`genes or expressed sequence tags (EST’s)
`
`in tissue
`
`samples.
`
`The data may be used, among other things,
`
`to
`
`study genetic characteristics and to detect mutations
`
`relevant to genetic and other diseases or conditions.
`
`More specifically,
`
`the data gained through microarray
`
`experiments is valuable to researchers because, among
`
`other reasons, many disease states can potentially be
`
`characterized by differences in the expression levels of
`
`various genes, either through changes in the copy number
`
`of the genetic DNA or through changes in levels of
`
`transcription (e.gz,
`
`through control of initiation,
`
`provision of RNA precursors, or RNA processing) of
`
`particular genes. Thus, for example, researchers use
`
`microarrays to answer questions such as: Which genes are
`
`expressed in cells of a malignant
`
`tumor but not expressed
`
`in either healthy tissue or tissue treated according to a
`
`particular regime? Which genes or EST’s are expressed in
`
`particular organs but not in others? Which genes or
`
`EST’s are expressed in particular species but not in
`
`others? Data collection is only an initial step,
`
`however,
`
`in answering these and other questions.
`
`Researchers are increasingly challenged to extract
`
`biologically meaningful
`
`information from the vast amounts
`
`of data generated by microarray technologies, and to
`
`design follow—on experiments.
`
`A need exists to provide
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`researchers with improved tools and information to
`
`perform these tasks.
`
`Systems, methods, and computer program products are
`
`described herein to address these and other needs.
`
`In
`
`some implementations, a web portal processes inquiries or
`
`orders regarding purchase of biological devices or
`substances, or related reagents.
`The user selects
`
`“probe—set identifiers” (a broad term that is described
`
`below)
`
`that may be associated with probe sets of one or
`
`more probes.
`
`These probe sets are capable of enabling
`
`detection of biological molecules. These biological
`
`molecules include, but are not limited to, nucleic acids
`
`including DNA representations or mRNA transcripts and/or
`
`representations of corresponding genes
`
`(such nucleic
`
`acids are hereafter, for convenience, referred to simply
`
`as “mRNA transcripts”).
`
`The corresponding genes or EST’s
`
`are identified and are correlated with related data,
`
`which is provided to the user.
`
`In some aspects,
`
`the user
`
`may select products for purchase based on the data.
`
`If
`
`the user decides to make a purchase,
`
`the user’s account
`
`may be adjusted based on the purchase order.
`
`An advantage of some of these implementations is
`
`that a user may be presented with product suggestions for
`
`follow—up experiments based on results from an initial
`
`experiment. These initial results are represented by the
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`user’s selection of probe—set identifiers by, for
`example, designating those probe—set identifiers
`
`corresponding to probes indicating a relatively high
`
`degree of differential expression in control and
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`experimental samples.
`
`In the same or other implementations, a local
`
`genomic database is periodically updated.
`
`In some
`
`aspects,
`
`this updating may be made from remote databases.
`
`In response to a user selection of probe—set
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`identifiers, data related to genes or EST’s are provided
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`to the user from the local genomic database.
`
`In other
`
`aspects, data related to genes or EST’s are provided to
`
`the user from the local genomic database in response to a
`
`user selection of gene and/or EST identifiers.
`
`Advantages of some of these implementations include
`
`the ability of the user to initiate a data request based
`
`on the results of experiments. As only one example,
`
`the
`
`user may indicate these results by selecting probe—set
`
`identifiers corresponding to relatively high differential
`
`gene expression. These implementations may also be
`
`advantageous because the genomic data is locally
`
`available at the time of the user’s request and generally
`
`need not
`
`involve the querying of a remote database in
`
`response to the user's request. Rather,
`
`the querying of
`
`remote databases is done periodically as, for example,
`
`weekly.
`
`Thus, even if the user’s selection involves
`
`numerous probe—set identifiers indicative of the
`
`expression or differential expression of numerous genes
`
`or EST’s, a response may be provided rapidly to the user
`
`from the local genomic database. Significant delays due
`
`to multiple or batch interrogations of remote databases
`
`are thus generally avoided.
`
`Also,
`
`in the preceding or other implementations, a
`
`method is described by which a user places a computer—
`
`implemented inquiry or order regarding purchase of one or
`
`more products.
`
`The user selects a first set of probe—set
`
`identifiers, and this selection is sent over the Internet
`
`to a portal system capable of correlating data with one
`
`or more genes or EST’s corresponding to the probe sets
`
`identified by the user—selected probe—set identifiers.
`
`The user receives the correlated data from the portal
`
`system.
`
`The user may select some or all of the data or
`
`otherwise indicate a desire to purchase products related
`
`to the data.
`
`If the user elects to purchase a product,
`
`the user’s account may be adjusted accordingly.
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`In some implementations a system is described for
`
`providing data related to one or more genes or EST’s,
`
`wherein each gene or EST has at least one corresponding
`
`probe set identified by a probe—set identifier and
`
`capable of enabling detection of a biological molecule.
`
`The biological molecule may be a nucleic acid or an mRNA
`
`transcript of a corresponding gene. As noted above, one
`
`or more of the probe—set identifiers may include a gene
`or EST identifier, such as an accession number.
`The
`
`system includes an input manager that receives a user
`
`selection of a first set of probe—set identifiers; a gene
`
`determiner that identifies genes or EST’s corresponding
`
`to the probe sets identified by the first set of probe—
`
`set identifiers; a correlator that correlates the genes
`
`or EST's with data; and an output manager that provides
`
`the data to the user.
`
`The input and output managers of
`
`these implementations may be coupled to the user via the
`Internet.
`
`The first set of probe—set identifiers may be a
`
`subset of a second set of probe—set identifiers of probe
`
`sets that have enabled detection of the expression or
`
`differential expression of their corresponding genes or
`
`EST’s.
`
`For example,
`
`the user may have selected the
`
`subset using a graphical user interface provided by a
`
`probe—array software application. This selection may be
`
`made, for instance, by drawing a loop around out—liers in
`
`a scatter plot representation of probe sets, where the
`
`out—liers indicate probe sets having a relatively high
`
`degree of differential expression. As another of many
`
`possible examples,
`
`the user may select the subset by
`
`highlighting entries of probe—set identifiers in an
`
`ordered table.
`
`The probe sets typically are disposed on one or more
`
`probe arrays that, as noted, may be any of various types
`
`of microarrays such as those synthesized using VLSIPSTM
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`technology (described below) or spotted arrays.
`
`Thus,
`
`the term “probe set” generally will be understood to
`
`include not only a set of synthesized probes in
`
`accordance, for example, with VLSIPSTM technology, but
`
`also one or more spots as deposited in accordance with
`
`various spotted array technologies (also described
`
`below).
`
`The spots may, as one example, be
`
`oligonucleotides or in another be cDNA clones or PCR
`
`products generated from those clones.
`
`The data may
`
`include product data about the availability, pricing,
`
`composition, suitability, or ordering of various products
`
`including a biological device or substance, or a reagent
`
`that may be used with a biological device or substance or
`
`additional information such as nucleotide or protein
`
`sequence information or locational or functional
`
`annotation information. As some examples,
`
`the device may
`
`be a probe array or a microscope slide, or the substance
`
`may be a clone, oligonucleotide, antibody, or protein.
`
`Other implementations are directed to methods for
`
`providing data related to one or more genes or EST’s,
`
`wherein each gene or EST has at least one corresponding
`
`probe set identified by a probe—set identifier and
`
`capable of enabling detection of a biological molecule.
`
`The biological molecule may be a nucleic acid or an mRNA
`
`transcript of a corresponding gene.
`
`The method includes
`
`the steps of: receiving a user selection of a first set
`
`of probe—set identifiers;
`
`identifying genes or EST's
`
`corresponding to the probe sets identified by the first
`
`set of probe—set identifiers; correlating the genes or
`
`EST’s with data; and providing the data to the user. Yet
`
`other implementations are directed to a computer program
`
`product that implements the preceding methods.
`
`Further implementations are directed to a method for
`
`placing a computer—implemented inquiry or order regarding
`
`purchase of one or more products. This method includes
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`the steps of: receiving at a user computer a user
`
`selection of a first set of one or more probe—set
`
`identifiers, wherein each probe—set identifier identifies
`
`a probe set that has enabled detection of the expression
`
`of a corresponding gene; providing the user selection
`
`over the Internet to a portal system capable of
`
`correlating data with one or more genes or EST’s
`
`corresponding to the probe sets identified by the first
`
`set of probe—set identifiers; and receiving the
`
`correlated data from the portal system.
`
`The user may
`
`also select product data for purchase.
`
`Yet another implementation is directed to a system
`
`for providing data related to one or more genes or EST’s,
`
`wherein each gene or EST has at least one corresponding
`
`probe set identified by a probe—set identifier and
`
`capable of enabling detection of a biological molecule.
`
`The biological molecule may be a nucleic acid or an mRNA
`
`transcript of a corresponding gene.
`
`The system includes
`
`a database manager that periodically updates a local
`
`genomic database comprising data related to the genes or
`
`EST's; an input manager that receives a user selection of
`
`probe—set identifiers; a user—service manager that
`
`constructs from the local genomic database data related
`
`to genes or EST's corresponding to the probe—set
`
`identifiers; and an output manager that provides the data
`
`to the user.
`
`In the preceding implementations,
`
`the database
`
`manager may periodically update the local genomic
`
`database,
`
`for example, weekly, with sequence data, exonic
`
`structure or location data, splice—variants data, marker
`
`structure or location data, polymorphism data, homology
`
`data, protein—family classification data, pathway data,
`
`alternative—gene naming data,
`
`literature—recitation data,
`
`annotation data, other genomic or proteomic data, or any
`
`combination thereof. This updating may be accomplished
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`by periodic communication with remote databases, possibly
`
`over the Internet. Any of hundreds of public or
`
`proprietary remote databases may be included, such as
`
`GenBank, GenBank New, SwissProt, GenPept, DB EST,
`
`Unigene, PIR, Prosite, PFAM, Prodom, Blocks, PDB,
`
`PDBfinder, EC Enzyme, Kegg Pathway, Kegg Ligand, OMIM,
`
`OMIM Map, OMIM Allele, DB SNP, and/or PubMed. Whereas
`
`the database manager periodically communicates with
`
`remote databases,
`
`typically (but not necessarily) not in
`
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`response to a user’s request,
`
`the input manager typically
`
`(but not necessarily) dynamically receives the user’s
`
`selection of probe—set identifiers.
`
`The word
`
`“dynamically,” as used in this context is intended to
`
`indicate an essentially real—time response to a user
`
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`
`inquiry.
`
`In yet further implementations, a system is
`
`described for providing product data, which may include
`
`biological product data.
`
`The system has an input manager
`
`that receives from a user a gene, EST, and/or probe—set
`
`identifier.
`
`For example,
`
`the user may specify one or
`
`more gene accession numbers.
`
`The system also has a user—
`
`service manager that correlates or associates the gene,
`
`EST, and/or probe—set identifier with one or more product
`
`data.
`
`The user—service manager further causes,
`
`optionally in cooperation with a database manager,
`
`the
`
`product data to be obtained from one or more local and/or
`
`remote databases or other local or remote source of data,
`
`e.g., a web page.‘ Also included in the system is an
`
`output manager that provides the product data to the
`
`user.
`
`In some aspects, a User account may be adjusted
`
`based on the purchase, or a vendor account may be
`
`adjusted for referring the user to the vendor.
`
`The
`
`receipt of information from, and provision of information
`
`to,
`
`the user may be done over a network, such as the
`
`Internet.
`
`In other aspects, a method is described for
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`providing product data, e.g., biological product data.
`
`The method includes the steps of: receiving from a user a
`
`gene, EST, and/or probe—set identifier; correlating the
`
`gene, EST, and/or probe—set identifier with one or more
`
`product data; causing the product data to be obtained
`
`from a local and/or a remote database or other local
`
`and/or remote source of data; and providing the product
`
`data to the user.
`
`The method may optionally include
`
`adjusting a user account based on the purchase, or
`
`adjusting a vendor account for referring the user to the
`vendor.
`
`A further aspect isAa system for providing product
`
`data related to one or more genes or EST's.
`
`Each gene or
`
`EST has at least one corresponding probe set identified
`
`by a probe—set identifier and capable of enabling
`
`detection of a biological molecule.
`
`The system includes
`
`an input manager that receives one or more of the probe—
`
`set identifiers; a correlator that correlates the probe—
`
`set identifiers with a first set of one or more product
`
`data; and an output manager that provides the first set
`
`of data to the user. Yet another aspect is a system for
`
`providing product data related to one or more genes or
`
`EST’s.
`
`The system includes an input manager that
`
`receives one or more gene and/or EST identifiers; a
`
`correlator that correlates the identifiers with a first
`
`set of one or more product data; and an output manager
`
`that provides the first set of data to the user.
`
`An additional aspect is a method for providing
`
`product data related to one or more genes or EST’s.
`
`Each
`
`gene or EST has at least one corresponding probe set
`
`identified by a probe—set identifier and capable of
`
`enabling detection of a biological molecule.
`
`The method
`
`includes the steps of receiving one or more of the probe—
`
`set identifiers; correlating the probe—set identifiers
`
`with a first set of one or more product data; and
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`providing the first set of data to the user. Yet another
`
`aspect is a method for providing product data related to
`
`one or more genes or EST's.
`
`The method includes the
`
`steps of receiving one or more gene and/or EST
`
`identifiers; correlating the identifiers with a first set
`
`of one or more product data; and providing the first set
`
`of data to the user.
`
`According to another aspect, a system is described
`
`for providing product data related to one or more genes
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`or EST’s.
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`The system includes receiving means for
`
`receiving one or more gene or EST identifiers over the
`
`Internet; correlating means for correlating the gene or
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`EST identifiers with one or more product data; and
`
`providing means for providing the product data to the
`user.
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`According to yet another aspect, a system is
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`described for providing product data related to one or
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`more genes or EST’s, wherein each gene or EST has at
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`least one corresponding probe set identified by a probe—
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`set identifier and capable of enabling detection of a
`
`biological molecule.
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`The system includes receiving means
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`for receiving from a user a selection of a first set of
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`one or more of the probe—set identifiers; correlating
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`means for correlating the first set of probe—set
`identifiers with a first set of one or more product data;
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`and providing means for providing the first set of data
`to the user.
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`In an additional aspect, a system is described for
`
`providing data related to one or more genes or EST’s,
`
`wherein each gene or EST has at least one corresponding
`
`probe set identified by a probe—set identifier and
`capable of enabling detection of a biological molecule.
`
`The system includes updating means for periodically
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`updating a local genomic database comprising data related
`
`to the genes or EST’s;
`
`input managing means for receiving
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`from a user a selection of a first set of one or more of
`
`the probe—set identifiers; data managing means for
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`periodically updating from the local genomic database a
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`first set of data related to genes or EST’s corresponding
`
`to the first set of probe—set identifiers; and providing
`
`means for providing the first set of data to the user.
`
`The above implementations are not necessarily
`
`inclusive or exclusive of each other and may be combined
`
`in any manner that is non—conflicting and otherwise
`
`possible, whether they be presented in association with a
`
`same, or a different, aspect or implementation.
`
`The
`
`description of one implementation is not
`
`intended to be
`
`limiting with respect to other implementations. Also,
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`any one or more function, step, operation, or technique
`
`described elsewhere in this specification may,
`
`in
`
`alternative implementations, be combined with any one or
`
`more function, step, operation, or technique described in
`
`the summary.
`
`Thus,
`
`the above implementations are
`
`illustrative rather than limiting.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`The above and further advantages will be more
`
`clearly appreciated from the following detailed
`
`description when taken in conjunction with the
`
`accompanying drawings.
`
`In the drawings,
`
`like reference
`
`numerals indicate like structures or method steps and the
`
`leftmost one or two digits of a reference numeral
`
`indicates the number of the figure in which the
`
`referenced element first appears (for example,
`
`the
`
`element 180 appears first in Figure l and element 1020
`
`first appears in Figure 10).
`
`In functional block
`
`diagrams, rectangles generally indicate functional
`
`elements, parallelograms generally indicate data,
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`rectangles with curved sides generally indicate stored
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`data, rectangles with a pair of double borders generally
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`l2 -
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`indicate predefined functional elements, and keystone
`
`shapes generally indicate manual operations.
`
`In method
`
`flow charts, rectangles generally indicate method steps
`
`and diamond shapes generally indicate decision elements.
`
`All of these conventions, however, are intended to be
`
`typical or illustrative, rather than limiting.
`
`Figure l is a functional block diagram of a probe—
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`array analysis system including a scanner and a computer
`
`system on which may be executed computer applications
`
`suitable for providing probe—set identifiers and for
`
`receiving user selections of probe—set identifiers for
`
`processing;
`
`Figure 2 is a functional block diagram of one
`
`embodiment of probe~array analysis applications as
`
`illustratively stored for execution in system memory of
`
`the computer system of Figure 1;
`
`Figure 3 is a functional block diagram of a
`
`conventional system for obtaining genomic information
`
`over the Internet;
`
`Figure 4 is a functional block diagram of one
`
`embodiment of a genomic portal coupled over the Internet
`
`to remote databases and web pages and to clients
`
`including networks having user computer systems including
`
`that of Figure 1;
`
`Figure 5 is a functional block diagram of one
`
`embodiment of the genomic portal of Figure 4 including
`
`illustrative embodiments of a database server, portal
`
`application computer system, and portal—side Internet
`
`server;
`
`Figure 6 is a simplified graphical representation of
`
`one embodiment of computer application platforms for
`
`implementing the genomic portal of Figures 4 and 5 in
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`communication with clients such as those shown in Figure
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`4;
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`Figure 7 is a flow chart of one embodiment of a
`
`method for providing a user with genomic product
`
`information related to gene expression, or differential
`
`expression, experimental results;
`
`Figure 8 is a functional block diagram of one
`
`embodiment of a user—service manager application as may
`
`be executed on the portal application computer system of
`Figure 5;
`‘
`
`Figure 9 is a simplified graphical representation of
`
`one embodiment of a gene or probe—set identifier to
`
`database such as may be by the user—service manager of
`
`Figure 8 in connection with the method of Figure 7;
`
`Figure 10 is one embodiment of a graphical user
`
`interface that may be generated by a probe—array analysis
`
`application of Figure 2; and
`
`Figure 11 is another embodiment of a graphical user
`
`interface that may be generated by a probe—array analysis
`
`application of Figure 2.
`
`DETAILED DESCRIPTION
`
`Systems, methods, and computer products are now
`
`described with reference to an illustrative embodiment
`
`referred to as genomic portal 400. Portal 400 is shown
`
`in an Internet environment in Figure 4, and is
`
`illustrated in greater detail in Figures 5—11.
`
`In a typical implementation, portal 400 may be used
`
`to provide a user with information related to results
`
`from experiments with probe arrays.
`
`The experiments
`
`often involve the use of scanning equipment to detect
`
`hybridization of probe—target pairs, and the analysis of
`
`detected hybridization by various software applications,
`
`as now described in relation to Figures 1 and 2.
`
`Probe Arrays 103
`
`Various techniques and technologies may be used for
`
`depositing or synthesizing dense arrays of biological
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`materials on a substrate or support.
`
`For example,
`
`Affymetrix® GeneChip® arrays, manufactured by Affymetrix,
`
`Inc. of Santa Clara, California, are synthesized in
`
`accordance with techniques sometimes referred to as
`
`VLSIPSTM (Very Large Scale Immobilized Polymer Synthesis)
`
`technologies.
`
`Some aspects of VLSIPSTM technologies are
`
`described in the following U.S. Patents: 5,143,854 to
`
`Pirrung, et a1.; 5,445,934 to Fodor, et a1.; 5,744,305 to
`
`Fodor, et al.; 5,831,070 to Pease, et a1.; 5,837,832 to
`
`Chee, et a1.; 6,022,963 to MCGall, et al.; and 6,083,697
`
`to Beecher, et a1.
`
`Each of these patents is hereby
`
`incorporated by reference in its entirety.
`
`The probes
`
`of these arrays consist of oligonucleotides, which are
`
`synthesized by methods that include the steps of
`
`activating regions of a substrate and then contacting the
`
`substrate with a selected monomer solution.
`
`The regions
`
`are activated with a light source shown through a mask in
`
`a manner similar to photolithography techniques used in
`
`5
`
`10
`
`15
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`the fabrication of integrated circuits. Other regions of
`
`2O
`
`the substrate remain inactive because the mask blocks
`
`them from illumination.
`
`By repeatedly activating
`
`different sets of regions and contacting different
`
`monomer solutions with the substrate, a diverse array of
`polymers is produced on the substrate. Various other
`
`steps, such as washing unreacted monomer solution from
`
`the substrate, are employed in various implementations of
`
`.
`these methods.
`These probes typically are used in conjunction
`
`with tagged biological samples such as cells, proteins,
`
`genes or EST’s, other DNA sequences, or other biological
`
`elements.
`
`These samples, referred to herein as
`
`“targets,” are processed so that they are spatially
`
`associated with certain probes in the probe array.
`
`For
`
`example, one or more chemically tagged biological
`
`samples, i.e., the targets, are distributed over the
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`probe array.
`
`Some targets hybridize with at least
`
`partially complementary probes and remain at the probe
`
`locations, while non—hybridized targets are washed away.
`
`These hybridized targets, with their “tags” or “labels,”
`
`are thus spatially associated with the targets’
`
`complementary probes.
`
`The hybridized probe and target
`
`may sometimes be referred to as a “probe—target pair.”
`
`Detection of these pairs can serve a variety of purposes,
`
`such as to determine whether a target nucleic acid has a
`
`nucleotide sequence identical to or different from a
`
`specific reference sequence.
`
`See, for example, U.S.
`
`Patent No. 5,837,832, referred to and incorporated above.
`
`Other uses include gene expression monitoring and
`
`evaluation (see, e.g., U.S. Patent No. 5,800,992 to
`
`Fodor, et al.; U.S. Patent No. 6,040,138 to Lockhart, et
`
`al.; and International App. No. PCT/US98/15151, published
`
`as WO99/05323,
`
`to Balaban, et a1.), genotyping (U.S.
`
`Patent No. 5,856,092 to Dale, et a1.), or other detection
`
`of nucleic acids.
`
`The ‘992,
`
`‘138, and ‘092 patents, and
`
`publication WO99/05323, are incorporated by reference
`
`herein in their entirety for all purposes.
`
`Other techniques exist for depositing probes on a
`
`substrate or support.
`
`For example, “spotted arrays” are
`
`commercially fabricated on microscope slides. These
`
`arrays consist of liquid spots containing biological
`
`material of potentially varying compositions and
`
`concentrations.
`
`For instance, a spot in the array may
`
`include a few strands of short oligonucleotides in a
`
`water solution, or it may include a high concentration of
`
`long strands of complex proteins.
`
`The Affymetrix® 417TM
`
`Arrayer is a device that deposits a densely packed array
`
`of biological material on a microscope slide in
`
`accordance with these techniques, aspects of which are
`
`described in PCT Application No. PCT/US99/OO73O
`
`(International Publication Number WO 99/36760), hereby
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`incorporated by reference in its entirety. Other
`
`techniques for generating spotted arrays also exist.
`
`For
`
`example, U.S. Patent No. 6,040,193 to Winkler, et a1.
`
`is
`
`directed to processes for dispensing drops to generate
`
`spotted arrays.
`
`The ‘193 patent, and U.S. Patent No.
`
`5,885,837 to Winkler, also describe the use of micro—
`
`channels or micro—grooves on a substrate, or on a block
`
`placed on a substrate,
`
`to synthesize arrays of biological
`
`materials.
`
`These patents further describe separating
`
`reactive regions of a substrate from each other by inert
`
`regions and spotting on the reactive regions.
`
`The ‘193
`
`and ‘837 patents are hereby incorporated by reference in
`
`their entireties. Another technique is based on ejecting
`
`jets of biological material to form a spotted array.
`
`Other implementations of the jetting technique may use
`
`devices such as syringes or piezo electric pumps to
`
`propel the biological material. Various other techniques
`
`exist for synthesizing, depositing, or positioning
`
`biological material onto or within a substrate.
`
`To ensure proper interpretation of the term “probe”
`
`as used herein, it is noted that contradictory
`
`conventions exist in th