AT THE ROOTS OF AN INTERDISCIPLINARY INNOVATION: preliminary insights from the patenting activity in the Bioinformatics industry APPIO F.P., APREDA R., FANTONI G., MARTINI A. Università di Pisa 15 th International CINet Conference Budapest, 7-9 September 2014 _____________________________________________________________________

Outline Aim of the paper Background Methodology Preliminary Results Conclusions and future research Appio F.P., Martini A. - 15th International CINet Conference 2

Aim of the paper Appio F.P., Martini A. - 15th International CINet Conference 3 Investigating the antecedents that led to the birth of the bioinformatics industry 3 aspects will be discussed; Trends Players Scientific/technological bases

Background Appio F.P., Martini A. - 15th International CINet Conference 4 Bioinformatics is a radical interdisciplinary innovation relying on significant new biotechnology and IT knowledge and the development of ‘super’ computing capabilities. Transversal applications in many fields; enormous economic potential. Companies are aggressively seeking patent protection however, large scale investigations on patenting activity in Bioinformatics are almost non existing.

Methodology Appio F.P., Martini A. - 15th International CINet Conference 5 Analysis of USPTO-EPO-WIPO bioinformatics patents 5 phases: 1 st large scale extraction of patents with existing technology classes/subclasses Multiple keywords search to check for content consistency 2 nd large scale extraction with refined searching routine Seriation, hierarchical clustering, and dissimilarity analysis Final review of extracted patents Logit Regression Total patents: 90,064

Trends : patents and scientific publications Appio F.P., Martini A. - 15th International CINet Conference 6

Trends : interdisciplinary technological knowledge 7 Main technological classes: Cluster 1 : G06F, C07K, C40B, A61P, C12P; Cluster 2 : C12N, A61K; Cluster 3 : G01N, C12M; Cluster 4 : B01L, G06G, C07D, B29C; Cluster 5 : C12Q; Cluster 6 : C07H; Cluster 7 : A01H. Main technological sub-classes (number of related patents in brackets) : C12Q 1/68 (5501) C07H 21/04 (3499) G06F 19/00 (2106) A61K 39/395 (1758) A01H 5/00 (1584) C12N 15/82 (1542) G01N 33/53 (1485) C12N 15/63 (1420) Domains: 1. Information and Communication Technology (ICT) 2. Agri-food 3. Biomedicine

Players and interaction dynamics Appio F.P., Martini A. - 15th International CINet Conference 8 Geographical distribution Agents of the quadruple helix

Players and interaction dynamics 9 Most dissimilar* technological classes (A): C12M, G01N (bottom), and G06F, C07K, C40B, A61P, C12P, C12N, A61K, C07H (top). Most dissimilar* assignees (B): Xencor Inc., Genentech Inc., Amgen Inc., Schering Corp., Zymogenetics Inc., Smithkline Beecham Corp., Bristol-Myers Squibb Company, Novozymes A/S, Codexis Inc., Verenium Corp., Ceres Inc., Monsanto Technology Llc, Dharmacon Inc. (row above), and Affymetrix Inc., IBM Corp., The Regents of the University of California, Agensys Inc., Corixa Corp., Basf Plant Science Gmbh, Pioneer Hi- Bred International Inc., E I Du Pont De Nemours And Company (row below). *Euclidean distance used as dissimilarity measure.

Who was at the beginning of the field? Jim Ostell : MSc in Zoology, University of Massachusetts : collector of live materials for a biological supply house : going back to school. MSc thesis describing the anatomy and late-stage development of the male cricket accessory gland. I had no plans for what my career goal after graduate school might be. While I do not necessarily recommend this as a career strategy, I felt tremendous freedom to pursue any avenue that looked interesting to me. BIG QUESTION: HOW ALL THIS COMPLEXITY COULD ARISE FROM SUCH A SIMPLE BEGINNING? His MSc adviser: ‘Look into the new field of molecular biology for an answer by pursuing a Ph.D.’ 1979 : began his doctoral studies in the laboratory of Kafatos in Harvard’s Department of Cellular and Development Biology. He begun to experiment with MOLGEN system for analyzing his sequences. He found the tools it provided unsatisfactory for his purposes. As a result, he began to write his own sequence analysis software in FORTRAN : Ostell’s colleague soon began asking to use his programs. When he published a description of the programs in Nucleic Acids Research, offering free copies to anyone who wanted it, he was overwhelmed with requests. Ostell’s programs constituted one of the most complete software packages available for molecular biology and the only one that would function on a microcomputer. However, not everyone shared his view, including some members of Ostell’s PhD committee at Harvard. “ It wasn’t something that biologists should be doing,” according to the reaction of some members of his committee. Ostell could not get his PhD : Ostell was approached by International Biotechnologies, Inc. (IBI), which wanted to license his software and develop it into a product. Since Ostell had done the work while a graduate student at Harvard, the university had a legal claim to the intellectual property rights. But it saw no commercial value in Ostell’s work and agreed to sign over all rights. The IBI/Pustell Sequence Analysis Package was release in August 1984, ready to use on an IBM personal computer, at a cost of $800 for academic and commercial users. In the meanwhile, Ostell embarked on applying his software to various biological problems, resulting in significant success : Ostell’s committee allowed him to submit his thesis. Phd in Molecular Biology at Harvard University : Selling the rights to his software so as not to create a conflict of interest, Ostell began to work at the NCBI in November as the chief of information engineering : Dr. Ostell was inducted into the United States National Academies, Institute of Medicine : Dr. Ostell made an NIH Distinguished Investigator. Currently : Dr. Ostell is the Chief of the Information Engineering Branch (IEB) of the National Center for Biotechnology Information (NCBI). He has been responsible for designing, developing, building, and deploying almost all production resources at NCBI from its beginning including PubMed, GenBank, BLAST, Entrez, RefSeq, dbSNP, PubMed Central, dbGaP, and many others.

Scientific (NPRs) and Technological (PRs) bases of patenting in Bioinformatics 11 MODEL SPECIFICATION Logit (probability of generating radicalness) Pr(Y=1 │X 1, …, X 7 )= β 0 + β 1 *NPRs_# + β 2 *PRs_# Controlling for: -NPRs diversity: Shannon-Wiener diversity index accounting for the diversity of scientific sources (journals, books, proceedings, etc.); -number of SCI-covered journals; -impact factor of SCI-covered journals; -PRs diversity: Shannon-Wiener diversity index accounting for the diversity of technological sources (technological classes and subclasses); -PRs forward citations: weighted number of FCs.

12 Scientific (NPRs) and Technological (PRs) bases of patenting in Bioinformatics With outliers Without outliers Mean VIF Correctly classified Sensitivity Specificity False + False % 91.29% 97.05% 2.95% 8.71% 95.25% 91.43% 97.11% 2.89% 8.57% Mean VIF Correctly classified Sensitivity Specificity False + False % 91.51% 97.05% 2.95% 8.49% 95.32% 91.72% 97.12% 2.88% 8.28%

Scientific (NPRs) and Technological (PRs) bases of patenting in Bioinformatics 13 Quadrant count analysis: to understand whether points tend to cluster or randomly distribute. Cluster analysis (k-means), excluding outliers. Different ways of recombining science and technology emerge (7 clusters).

Concluding remarks Appio F.P., Martini A. - 15th International CINet Conference 14 Bioinformatics is an interdisciplinary field (ICT, Agri-food, biomedicine). A quadruple-helix of agents (strong presence of single very prolific inventors) determines its evolution. Bioinformatics is a science-driven field (historical evidence plus #NPRs>#PRs). However, even though science prevails, technology has more predictive power. Recombination, both on science and technology sides, increases the chances to get radicalness. Different ways of recombining science and technology emerge (7 clusters).

Thanks for your attention … questions/suggestions … Appio F.P., Martini A. - 15th International CINet Conference 15