[ACS Symposium Series] The Future of the History of Chemical Information Volume 1164 || Back to the Future: CAS and the Shape of Chemical Information To Come

Chapter 9

Back to the Future: CAS and the Shape ofChemical Information To Come

Roger J. Schenck* and Kevin R. Zapiecki

Chemical Abstracts Service, 2540 Olentangy River Road, Columbus,Ohio 43202

*E-mail: [email protected]

Chemical Abstracts Service (CAS), the only organization inthe world whose objective is to find, collect and organize allpublicly disclosed chemistry, has been a leader in providingscientists with access to chemical information for more than100 years. CAS relied on a group of globally situated volunteerabstractors from 1907 until the early 1990s. CAS now keepspace with the explosion in newly disclosed chemistry withmore than 500 scientists working at the CAS headquartersin Columbus, Ohio, who are supported in turn by thatsame number of scientists working in locations around theworld. CAS has designed computer applications both fordatabase-building efforts and service delivery. In 1984, STNwas developed for professional searchers to access scientificand technical databases. With the introduction of SciFinder in1995, CAS developed the first chemical information analysistool specifically targeted to help chemists working in the lab.Since then, CAS has leveraged rapid changes in technology andevolving sources of disclosed chemistry, to fulfill its missionto provide the world’s best digital research environment tosearch, retrieve, analyze and link chemical information. Thischapter describes how CAS has adapted to the phenomenalgrowth in published research to continuously support scientificdiscoveries and will close with some thoughts about the futureof chemical information.

© 2014 American Chemical Society

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In The Future of the History of Chemical Information; McEwen, L., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2014.

Overview of CAS

In 1907, E. J. Crane established the importance of indexes, not just abstracts,as part of Chemical Abstracts, starting with author and subject indexes (1). Sincethere was little control over nomenclature systems used in the early chemicalliterature, Carleton Curran and Austin Patterson of Chemical Abstracts deviseda systematic method of naming substances in 1916 (2). They surveyed organicchemical literature for common practices, established an order of precedence forchemical functionality and instituted the use of inverted index names. Invertednames became popular as a way to group similar classes of compounds in analphabetical printed index (3). Chemical Abstracts came to be recognized as aleader for chemical substance nomenclature development. In 1937, ChemicalAbstracts published its one-millionth abstract (4).

Around the time of the Seventh Collective period (1962-1966) ChemicalAbstracts staff was struggling to keep pace with substances reported in thechemical literature (5). Before 1965, structures were hand drawn and thesubstances were subsequently named. Manual comparisons were done todetermine if the incoming substance had been previously indexed. At thesame time computer technology was emerging, and Chemical Abstracts Serviceresearch staff brought computers to bear on the problem. The CAS ChemicalRegistry System was introduced in 1965 as an internal production system thatreplaced the redundant and very expensive task of naming known compounds.Using a unique CAS Registry Number to identify each chemical substance, thesystem proved to be a future benefit to chemical research, health and safetyinformation, and the communication of chemical information. There are nowmore than 85 million (April 2014) (6) organic and inorganic substances in CASREGISTRY, which makes it the world’s largest substance database.

Introduced in 1980, CAS ONLINE made it possible for users (primarilyinformation specialists) to search the CAS REGISTRY database (7). Using acommand language, users communicated their search strategies to the system.Users with a specific model of an intelligent graphics terminal could selectstructure features from a menu and then assemble them on the terminal monitorusing a graphics tablet and stylus. These terminals could display answers withconsistently drawn structure diagrams.

CAS content speeds the pace of scientific discovery through two platforms:STN and SciFinder. In 1983, CAS partnered with FIZ Karlsruhe (in Germany)and was represented in Japan by The Japan Science and Technology Agency(JST) to form an international online network. STN, the Scientific and TechnicalInformationinformation Network, was launched the next year. STN madedatabases accessible through distributed processing on a global scale. Initially,only CAS databases and Physics Briefs were accessible. Over time, STN grewto include many scientific databases from a range of information providers. STNdatabases are uniquely integrated so researchers can consult multiple databaseswith a single query. A new web-based platform, with a project-oriented workflow,and enhanced search power, precision and usability, was recentlyrecently releasedand continues to be developed.

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CAS introduced SciFinder in 1995 as a research tool to give scientists directaccess to CAS databases with no prerequisite to learn a command language (8).With its intuitive, graphical interface, SciFinder simplified the exploration ofthe world’s scientific literature, patents and substance information, making thisactivity part of the process for scientific research.

CAS recognized the possibilities of the Internet to speed and simplify accessto original journal articles and patents. CAS Full Text Options (originally calledChemPort) was introduced to CAS and STN electronic services in 1997. Todayit provides access to full-text journal articles and patents from more than 7,400electronic journals from nearly 360 participating publishers (9). CAS FullText Options also provides links to electronic patent documents from full-textpatents from five offices: USPTO (U.S. Patent and Trademark Office), Espacenet(European Patent Office), SIPO (State Intellectual Property Office of the P.R.C.),JPO (Japanese Patent Office) and KIPRIS (Korea Intellectual Property RightsInformation Service).

Addressing the Information Needs of Scientists

In the late 1960s, with the advent of computer technologies, CAS investigatedchemical information products and services beyond what was already available inCAS REGISTRY and the CA File on STN. The market drove CAS to consultchemists and information professionals to better understand their needs. Beyondthe need for access to chemical substance information and the literature fromwhichthose substances were selected, there was a clear opportunity for CAS to providescientists with much more targeted information. The desire for a collection ofchemical reactions that included both standard, trusted reactions as well as newand novel synthetic techniques was front and center among customers interviewed.This was the beginning of a rich suite of additional chemical information currentlyavailable to scientists in the CAS databases.

CAS is the only organization in the world whose objective is to find, collectand organize all publicly disclosed substance information. CAS currently coversmore than 10,000 active journals (10) and patents from 63 patent authorities(11). This scientific literature and these patents come from 180 countries in50 languages (12). CAS has developed seven core databases that cover themost current scientific information: chemical substances (CAS REGISTRY),references (CAplus), Markush (MARPAT), reactions (CASREACT), chemicalsuppliers (CHEMCATS), regulated chemicals (CHEMLIST) and ChemicalIndustry Notes (CIN).

CAplus covers international journals, patents, patent families, technicalreports, books, conference proceedings and dissertations from all areas ofchemistry, biochemistry, chemical engineering and related sciences from 1907 tothe present. There are more than 38 million records as of April 2014. In addition,over 180,000 records for pre-1907 patent and journal references are available,from sources such as the American Chemical Society (ACS), the Royal Societyof Chemistry (RSC) and Chemisches Zentralblatt (9). Other benefits of CAplus

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include abstracts of foreign language references (patent and journal) that aretranslated into English. CAplus also assures patent records, from nine majorpatent offices worldwide, are available online within two days of the patent’sissuance, and fully indexed by CAS scientists in 27 days or less from the date ofissue (13).

Voicing a clear need to leave no stone unturned when searching for priorart and freedom to operate, information professionals pushed CAS to developa database of generic structures selected from patent applications. To addressthis need, CAS developed MARPAT, a database of Markush structures derivedfrom patent applications. Introduced on STN in 1990, MARPAT was designedas an extension of the information provided in the CAS REGISTRY and CAplusdatabases to perform comprehensive patent substance searching.8 There are morethan one million searchable Markush structures derived from patents covered byCAS from 1988 to the present.

CASREACTwas introduced in 1988 on STN andmade available in SciFindersince the launch of the product in 1995. CASREACT offers access to currentreaction information found in literature covering synthetic organic chemistry.The literature includes journals and patents from 1840 to the present. There arecurrently more than 58 million single- and multi-step reactions, and more than 13million synthetic preparations in SciFinder (14).

CHEMCATS, introduced on STN in 1995, is a chemical catalog databasecontaining information about commercially available chemicals and worldwidesuppliers. It contains more than 65 million commercially available products, morethan 990 chemical catalogs, more than 880 suppliers and more than 27 millionunique CAS Registry Numbers (15).

After the passage of the Toxic Substances Control Act (TSCA) by the U.S.Congress in 1976, regulatory officers began asking CAS for access to an electronicversion of the TSCA Inventory and other national inventories like the EINECSInventory in Europe. CHEMLIST, the regulated chemicals database, is availableon STN and in SciFinder. It was originally built from data in the 1985 TSCAinventory of more than 308,000 regulated substances (16). It is the most accuratesource of substance and regulatory information with validated CAS RegistryNumbers and the world’s most extensive collection of chemical names, consistingof systematic, trade and common names from 14 national chemical inventories.

Seeking current business information from the chemical enterpriseworldwide, CAS introduced a database called Chemical Industry Notes (CIN) onSTN in 1989. It was built from 100 trade journals (including bibliographic data,abstracts, indexing and CAS Registry Numbers). CIN offers chemical businessnews related to production, pricing, sales, facilities, products and processes,corporate activities, government activities and people. Today, CIN contains anestimated 1.7 million records drawn from 80 sources from 1974 to the present,including both domestic and foreign journals, trade magazines, newspapers andnewsletters (17).

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Trusting CAS for Current and Comprehensive Information

As well as covering chemistry in its broadest sense, the CAS databases arecurrent and up-to-date so chemists can discover information sooner than from otherscientific information providers. While the identification and approval processfor new projects within research organizations typically requires a comprehensivereview prior to moving forward, it still remains possible that, during the lifetime ofa project, information can become available that could alter the scope of the projector even ruin it. Specific types of information affecting these efforts include:

• Recent publication of parallel or more advanced research efforts bycompetitors using the same approach and goals as the current project.

• Recent publication of key processes in the project by academicresearchers or companies that limit patentability of the approach and/orenables competitor workarounds.

• New patent filings by competitors preventing freedom-to-operate for keyprocesses in the project.

• Identification of old publications or patents (not identified previously)that limit the patentability of current efforts (i.e., prior art).

It is important that scientists have access to up-to-date information. There isintense competition to publish research first. The sooner the research is publishedby reliable sources, the more it provides scientists the help they need to plan andgenerate new scientific ideas and concepts.

In the mid-1960s, as CAS REGISTRY was being designed and implemented,chemists and computer scientists at CAS needed to estimate the pace and size offuture growth – how many substances might chemists ultimately synthesize, andhow fast? Initial estimates ranged from six to twelve million substances. Somepredicted that when chemists had finally synthesized all possible substances; whenthey had combined all atoms in all synthetically accessible combinations, CASREGISTRY might reach 25 million substances. While it took CAS 33 years toregister its first ten million substances in published literature (18), in December of2012, just 18 months after reaching 60 million small molecules, CAS registered its70millionth substance (19). Where are CAS analysts seeing these new substances?Patents, especially from the Asia Pacific region, have exploded during the pasteleven years. In 2012, CAS saw a spike in Chinese patent applications unlike anyin its history.

Covering 63 patent authorities, the CAS databases reflect patent activityaround the globe through the years. Figure 1 shows Chinese patent growth as amajor force in the Asia Pacific region and worldwide. In 2013 alone, the numberof patents from the Asia Pacific countries was responsible for more than 67percent of the patent publications seen by CAS, and China contributed around 65percent of that region’s patent output.

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Figure 1. Asian patent growth over the past 11 years. The black bars show totalworldwide patent growth; the grey bars show the contribution to worldwide

growth from the Asia Pacific region (China included); the white bars show Chinaonly. Source: CAplus database.

For drug discovery scientists, knowing what’s being patented for freedom-to-operate and intellectual property concerns is important. Every day, CAS scientistsadd more than 3,000 substances fromChinese patent applications alone. SciFinderand STN searchers have access to this novel patent information up to three monthssooner than their competition.

The Future of Chemistry Research

At the inception of any research effort, whether it is a commercial drugdevelopment project or the potential subject for a PhD dissertation, researchersneed to know what has been done in the past. They must find out what hasworked, what hasn’t worked and who else is working in the area of research.Before the 1970s, days, sometimes weeks, were spent in the library searchingprinted Chemical Abstracts indexes, and other compendia, to uncover whathad been accomplished in the past. Extensive notes documenting the literaturesearch were kept. Original journals articles, if not held in the local library, wereacquired through interlibrary loans or document delivery services. Figure 2 is avisual representation of the relative time spent fetching (search and acquisition)relevant chemistry research and original literature versus the time spent readingand absorbing that literature (evaluation).

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Figure 2. Content innovation and technology have significantly simplifiedscientific literature searches and provided a new area of opportunity:EVALUATION. Note: This graph is qualitative not quantitative.

With the advent in the 1970s of computer-based searching systems, timespent in the library began to shrink. Not all major reference works were availableelectronically, so library time was still necessary. Because of the intricacies ofonline searching systems, researchers often had to explain their questions toinformation experts who would then query online databases. As the secondaryinformation industry moved through the 1980s and into the 1990s, searchingbecame more efficient. More and more chemical information products were madeavailable in electronic form. The primary literature was beginning to be deliveredelectronically in formats like PDF. In the mid-nineties, CAS developed SciFinder,a researcher’s tool that was simple to use. Chemists were no longer required tounderstand the nature of arcane printed indexes or the sometimes complex searchcommands necessary to use online databases – they could search for themselves,find useful answers quickly, and access electronic versions of patents and journalarticles – all from their own computer. So, today, the time required to searchand acquire scientific information has been greatly reduced. A new problemhas arisen – too many answers are resulting from the explosion in worldwidescientific publishing. CAS is currently developing features and functions in itsproducts that take advantage of that content to reduce the time it takes scientiststo evaluate a collection of patents and literature articles. The problem that CASneeds to solve now is not getting more answers but getting the best answers.

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So what is CAS doing to aid researchers in getting to the most relevantliterature quickly? CAS is adding more context to its records so scientists havemore information that points to the right answers. Access to comprehensive andtimely scientific information is vital. CAS, with its comprehensive, timely andhigh quality content, helps organizations eliminate or avoid wasted, unproductiveefforts by quickly discovering business critical information as soon as possible.The search and acquisition time has been reduced and now CAS is finding waysto drastically cut the evaluation time. Let’s describe some of those enhancements.

Experimental Procedures and Reaction Transformations

CAS provides access to more than 58 60 million single- and multi-stepreactions and synthetic preparations (20), as well as associated experimentalprocedures for reactions, through SciFinder. Experimental procedures helpscientists find useful reactions and the most relevant publications. CAS providesaccess to millions of experimental procedures from other sources includingEnglish-language translations from German and Japanese patents, the ShanghaiInstitute of Organic Chemistry, Chinese Journal of Organic Chemistry andActa Chimica Sinica, hundreds of Springer journals and all ACS Publicationsjournals in addition to English-language patents from the United States Patent andTrademark Office, European Patent Office, and the World Intellectual PropertyOrganization (2000 to the present).

The group by reaction transformation feature in SciFinder saves users timereviewing reaction answer sets by speeding evaluation synthesis options andpreferred pathways by grouping single-step reaction answers by transformationtype. It classifies answers in a way that is meaningful to synthetic chemists andallows a user to easily manage and evaluate large, comprehensive answer sets.

Bioactivity and Target Indicators

Scientists working in the drug discovery arena, such as medicinal chemists,are experts in diseases, the protein pathways involved in those diseases, andsmall molecules or biologics that may inhibit, or enhance, protein expression.The essence of drug discovery is in identifying and validating druggable proteintargets, designing lead molecules that affect their behavior and decorating thatdrug lead to maximize its efficacy.

In 2011, CAS began adding bioactivity indicators and target indicators to thesmall molecules in CAS REGISTRY. Bioactivity indicators are a defined set ofapproximately 260 bioactivity terms, much like therapeutic indications. A termis assigned to a substance in CAS REGISTRY when there is a high probabilitythat the bioactivity indicator was reported for that substance in a journal article orpatent. For instance, Velcade (CAS Registry Number 179324-69-7) is associatedwith bioactivity terms like antitumor agents and biological radio sensitizers. Targetindicators are assigned by the same manner. Thus, Velcade is associated with thetarget indicators Akt kinase and 26S proteasome. These bioactivity and targetindicators guide drug discovery scientists to new uses for known drugs, possible

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side effects and the original literature where this pharmaceutical information wasreported.

Relevancy Ranking

Relevancy ranking speeds access to desired results for researchers. Userssometimes performed multiple searches and refined them to obtain a moremanageable answer set size. By using relevancy ranking in both STN andSciFinder, the best answers are pushed to the top, which leads to fewer follow-upsearches.

Conclusion

Access to comprehensive and timely scientific information is vital for theadvancement of science. For centuries scientists have routinely published theirresearch; their conclusions may then be reviewed, confirmed and used by otherscientists. Discoveries lead to more discoveries and science advances. CAS hasbeen the repository of that research for more than 100 years.

CAS is cognizant of the fact that along with more information available inits databases comes the concern of navigating too many answers. CAS analystsare not only indexing and abstracting the important chemical content in reputablescientific publications including articles and patents, but also offering new contentand functionality that aids searchers to quickly winnow a large collection ofCAS records down to a useful and manageable set for their research. Recentnotable content additions include graphical abstracts, experimental procedures forreactions, experimental and predicted properties, bioactivity and target indicators,citations and relevancy ranking capabilities.

In some sense, CAS has come full circle. The first issue of ChemicalAbstracts, published on January 1, 1907 (8) contained 502 abstracts. Its purposewas more than raising the visibility of the American chemical enterprise. Itwas to summarize the growing volume of research papers being publishedworldwide for quick review. For many years, Chemical Abstracts was producedby a team of volunteer abstractors located around the world. Today, althoughCAS indexes well over a million documents on an annual basis, it continues todo so with the support of a team located around the globe. And, from the CAScustomers’ perspective, strives to develop database content and features thatenable researchers, information professionals and patent searchers to winnow amassive collection of published information down to what’s important for theproblem at hand…just like what happened in 1907.

Many generations of scientists, information professionals, educators andstudents have used services from CAS, from printed Chemical Abstracts to STNand SciFinder. With knowledge gleaned from the CAS databases, scientists havebegun their research efforts knowing what has been done before them, and intime, have contributed their own discoveries. In turn, CAS continues to includethose discoveries in its databases.

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References

1. Schenck, R. J. Back to the Future. Presented at the Fall 2012 ACS NationalMeeting.

2. Patterson, A.; Curran, C. J. Am. Chem. Soc. 1917, 39, 1623–38.3. Crane, E. J. The Chemical Abstracts, Service - Good Buy or Good-by. Chem.

Eng. News 1955, 33 (26), 2753.4. Crane, E. J. Why Indexers Turn Gray. Chem. Eng. News 1937, 15 (8), 175.5. CAS Report Highlights Progress. Chem. Eng. News 1962, 40 (22), 90–97.6. REGISTRY counter on the www.cas.org website (accessed April 2014).7. CAS offers new online service. Chem. Eng. News 1980, 58 (40), 34–35.8. Shively, E. CAS Surveys Its First 100 Years. Chem. Eng. News 2007, 85

(24), 41–53.9. http://www.cas.org/fulltext/cas-full-text-options (accessed April 2014).10. http://www.cas.org/content/references (accessed April 2014).11. http://www.cas.org/content/references/patworld (accessed April 2014).12. http://www.cas.org/about-cas/cas-fact-sheets/registry-fact-sheet (accessed

April 2014).13. http://www.cas.org/content (accessed April 2014).14. http://www.cas.org/content/reactions (accessed April 2014).15. http://www.cas.org/content/chemical-suppliers (accessed April 2014).16. http://www.cas.org/File%20Library/Training/STN/DBSS/chemlist.pdf

(accessed April 2014).17. http://www.cas.org/File%20Library/Training/STN/DBSS/cin.pdf (accessed

April 2014).18. Toussant, M. A Scientific Milestone. Chem. Eng. News 2009, 87 (37), 3.19. http://www.cas.org/news/product-news/70-millionth-substance (accessed

April 2014).20. http://www.cas.org/products/scifinder/content-details (accessed April 2014).

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Documents

[ACS Symposium Series] The Future of the History of Chemical Information Volume 1164 || Back to the Future: CAS and the Shape of Chemical Information To Come