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GAME-CHANGERS Some Papers Have a Profound and Obvious Influence on Future Research and Industry Applications

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GAME-CHANGERS Some Papers Have a Profound and Obvious Influence on Future Research and Industry Applications INNOVATION | NATURE INDEX David Lipman, who co-authored the BLAST paper, which has been cited in at least 4,900 inventions according to patent documents in the Lens database. GAME-CHANGERS Some papers have a profound and obvious influence on future research and industry applications. Patents citing these life science papers indicate their bearing on developments which have widespread health implications. ists of the most highly cited academic patents are a general indicator of the dynamic selected from the Lens platform, based on articles garner considerable attention between science and technology, and can articles cited in patents. Each paper had been from the research community. But infer that a piece of research has influenced cited in more than 1,000 patent families by Larticles that are highly cited in patents don’t an invention (see Patently clear). Here, the 2016. Patent families represent a single inven- BILL REITZEL receive the same attention. This is surprising index profiles three life science articles that tion. Inventors often file patents in multiple given the demand from governments that sci- have been highly cited in patents. Each arti- countries, which is why the number of citing entists demonstrate the societal or economic cle has had profound impact on industry and, patents is larger than the number of patent value of their research. Citations of articles in eventually, consumers. These papers were families. NATURE INDEX 2017 | INNOVATION | S9 NATURE INDEX | INNOVATION Basic Local Alignment Search Tool (BLAST) THE GOOGLE OF GENOMES used pattern recognition software to perform ANTIBODIES AS THERAPY faster sequence comparisons. It could calculate Basic Local Alignment Search Tool the statistical level of similarity between two Replacing the complementarity- published in the Journal of Molecular sequences, says Lipman, who recently left the determining regions in a human Biology in 1990. NCBI after 28 years as its director. antibody with those from a mouse Within 10 years automated DNA sequenc- published in Nature in 1986. › CITED IN 4,900 PATENT FAMILIES ing machines had also gained a foothold and some 50,000 nucleotide sequences from plants › CITED IN 2,089 PATENT FAMILIES nferring the function of a protein 40 years and animals were stored in the NCBI-owned ago required finding a related protein with genetic sequence database known as Genbank. n 1986, Greg Winter and colleagues at the a known function. To determine the simi- BLAST enabled researchers to search for, or UK’s Medical Research Council (MRC) Ilarity between two proteins meant comparing compare, DNA sequences. Just five years after described in Nature a method for swapping their amino acid sequences using a time- its release, BLAST was handling about 200,000 Ipieces of a mouse antibody with those from a consuming algorithm. queries a week. These comparisons could human to create a chimeric antibody. This was In 1983, biologist David Lipman and col- yield several types of clues: what organism the the second essential step in the development of league W. John Wilbur reported a faster sequence probably came from, its evolutionary antibody-based therapies for human disease, method to identify the similarity between origin, and potential function. which represented more than 40% of total sales two unrelated sections of DNA or protein. A BLAST has since evolved into a family of free of biopharmaceutical products in 2016. year later, a global team of scientists used the web-based bioinformatics search tools that are The first step occurred a decade earlier when technique to show that amino acid sequences still widely used. Since 1990, the BLAST paper Nobel prize winning researchers Georges from a human growth factor closely resembled has been cited by at least 4,900 new inventions, Köhler and César Milstein developed mouse sequences from a cancer gene in a chicken according to patent documents in the Lens antibodies that recognize a single foreign virus. The paper marked significant progress database. Chemical giant Dupont and several molecule. While such monoclonal antibod- in the basic understanding of cancer develop- of its subsidiaries own the most patents that ies, had a wide range of applications in medical ment and revealed the value of computational cite the paper. research and diagnostics, their use in medicine tools for making biological discoveries. The NCBI team have created a new pro- was limited. Mouse antibodies are different Lipman, then based at the National Institute gramme within the BLAST toolkit that they from human ones — even when they target of Arthritis, Diabetes, and Digestive and Kid- hope to publish by September that will assist and bind to the same part of a protein. “Anti- ney Diseases, says this unexpected discovery with finding small genetic variations in bacte- bodies that are generated in another species prompted him to find how to detect more dis- ria, which may be linked to traits such as anti- cause side-effects in humans,” says vaccinolo- tant relationships between proteins. In 1990, biotic resistance. ■ gist, Ursula Wiedermann, of the Medical Uni- Lipman and colleagues Stephen Altschul and versity of Vienna. Indeed, the first US Food Warren Gish, along with collaborators Webb By Branwen Morgan and Drug Administration (FDA) approved Miller, at Pennsylvania State University, and therapeutic antibody, CD3, is no longer used Eugene Myers at the University of Arizona, pub- 1. Altschul et al. Journal of Molecular Biology for this reason. lished details of a more advanced algorithm. The 215,403-410 (1990) Winter’s method for creating chimeric PAPERS IN 1,200 PATENTS Lines represent 1,100 the number Source: Lens.org Source: of patent 1,000 documents that The 1990 paper by Lipman and cited one of three 900 life science colleagues has been cited in papers by 2016. 6,807 patent documents to 2016, The number of 800 totalling 4,900 new inventions. patent families refers to the 700 number of new inventions. 600 The 1986 paper by Winter and colleagues has been cited in 500 3,182 patent documents, totalling 2,089 new inventions. Lipman-citing 400 patents Number of citing patents per year 300 Winter-citing The 1999 paper by Golub has been patents cited in 2,031 patent documents, 200 totalling 1,278 new inventions. Golub-citing patents 100 0 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016 Year Figures represent applications and granted patents from 95 jurisdictions. S10 | NATURE INDEX 2017 | INNOVATION INNOVATION | NATURE INDEX in cancer research, he faced a dilemma: “The PATENTLY CLEAR question was, what’s the right experiment to do to really highlight its potential?” If Golub’s group, working out of MIT’s How patents and their citations work Whitehead Institute, chose a problem that was too easy to demonstrate, no-one in the research community would care. If they made • Patent filings signal the holder's • Front pages of most patents include the problem too hard, they might diminish intent to commercialize an bibliographic information, including their chances of success. invention, or to stop others from citations to earlier patents or The team, which included geneticist and commercializing such a product. scientific documents. mathematician, Eric Lander, chose to look • Patents are only valid in the • Citations to science literature provide at how using the microarrays to profile gene jurisdiction in which they're evidence that the invention is in some expression could help classify cancers. It was sought and granted. There are no way related — or initiated or stimulated among the earliest attempts to move the iden- international patents. — by research activities. However cited tification of specific cancers beyond symptoms, • Patents are expensive to prepare, file, papers are rarely the key source of the responsiveness to treatment, and appearance. and prosecute (advance to granting); idea that led to the invention. To achieve this, the researchers selected two and require regular payments • Applicants or patent attorneys cancers — acute myeloid leukaemia and acute to maintain their validity during and examiners can add citations lymphoblastic leukaemia — for which there their typical 20-year lifetime. How to patent documents; although, were existing diagnostic tests. If gene expres- much an applicant is willing to pay studies have found most non-patent sion profiling enabled them to distinguish indicates how much they think the citations (NPCs) were supplied by between the two malignancies, they would be invention is worth. the applicant/inventor. able to show the accuracy of the new method, • Patent applications are published • There is no standard method for says Golub, now director of the MIT/Harvard 18 months after submission with all references in patents between Broad Institute. supporting files. They are typically jurisdictions, which may affect Golub and his colleagues were successful, open access and not copyrighted. qualitative analysis of citations. and could distinguish between the cancers on the basis of the expression of just 50 genes. Source: Richard and Osmat Jefferson; Robert Tijssen; Michael Meyer Nearly 20 years later, the experiment they settled on has become one of the most cited life sciences papers in global patents in the Lens database. Patents range from diagnostic antibodies meant they were less likely to be rec- officer of Australian biotech company, Imu- technology for cancer, to skin substitutes for ognised as a foreign protein and destroyed by gene, says much of the current interest in industry use, anti-inflammatory treatments, the human immune system. But, it was more monoclonal antibodies comes from the rapid and algorithms for genomic data analysis. than ten years after the Nature paper that chi- development of cancer immunotherapies. “We The study provided a framework for the use meric therapeutic antibodies were approved are in the middle of an exciting era,” she says. of the new DNA microarray technology to for treating conditions such as rheumatoid “A lot has changed in the last 15 years.” Major classify other diseases besides cancers, includ- arthritis and non-Hodgkin lymphoma.
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