Recent Developments in

Liquid Biopsy“Research and Technology”

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Author, Data Collection Date, Notes

• The AuthorGary M. Oosta, holds a Ph.D. in Biophysics from Massachusetts Institute of Technology and a B.A. in Chemistry from E. Mich. Univ. He has 25 years of industrial research experience in various technology areas including medical diagnostics, thin-layer coating, bio-effects of electromagnetic radiation, and blood coagulation. Dr. Oosta has authored more than 20 technical publications and is an inventor on 77 patents worldwide. In addition, he has managed research groups that were responsible for many other patented innovations. Dr. Oosta has a long-standing interest in using patents and publications as strategic technology indicators for future technology selection and new product development.

• Data for this report was collected on August 15, 2018. – Annual values for 2018 were extrapolated from 2014-2017 data.– Three-year CAGR’s used data from 2015 and 2017.

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• This presentation is NOT management, legal or accounting advice. – While we believe that the results were accurate at the time of publication, the results are provided without warranty.

• © SelectBIO 2018. All rights reserved.

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You can estimate a CAGR by looking at the relative widths of the gray and blue bars

in the charts that follow.

Liquid Biopsy:Topic Introduction & the Analysis Process Summary

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The Study Process

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We begin with a broad, all-encompassing literature search(s). From the search, we create a database in SQLite. Next, with Python programs, SQLite queries and our pre-existing, keyword-based segment lists, we build multiple technical and market segments from which we can extract temporal trends. Often, we use Excel to visualize the trends.

Categorize and Segmentusing

ComprehensiveStudy Database

The Model

Hotspot Map

Segments, Categories & Model (Keywords/Phrases)

Broad Search

GraphsRank segment new vp val

1 EXOSOME 1.0002 OCCULT & CANCER 1.0003 GYNECOLOGIC & CANCER 0.8904 AMYOTROPHIC LATERAL SCLEROSIS 0.8545 CLOSTRIDIUM DIFFICILE 0.8546 ADENOCARCINOMA & CANCER 0.8357 FACTOR VIII 0.7818 MYOBLAST 0.7819 ROTAVIRUS, REOVIRUS 0.781

10 SCREEN PRINT 0.75511 GLIOBLASTOMA & CANCER 0.71112 AST/SGOT 0.67613 CORTISOL 0.67614 HEAD?AND?NECK & CANCER 0.67615 LIVER TRANSPLANT 0.67616 PARKINSON'S, PARKINSONS, GAIT DISORDER 0.67617 PAPER-BASED 0.67418 SOFT TISSUE & CANCER 0.66019 OVARIAN & CANCER 0.656

Tables

To Tell the Story

+Experiencefrom past projects

Literature &Process Flow Charts + Keyword Extraction

Natural Language+MarketingResearch + Text

Analysis

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Liquid Biopsy is a rapidly & newly expanding area.The Liquid Biopsy space as represented by our database of 4016 PubMed titles and abstracts is a rapidly expanding area. From 2015 to 2017, the CAGR was 37%, a significant growth rate even in biotech. We use this value (37%) as a benchmark to judge whether a specific segments is growing faster, slower or at the norm for the database.

ComprehensiveStudy Database

Broad Search Study Databaseof 4016 Papers

Journals in the Liquid Biopsy Database

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The Database contains 1397 journals, and the expected journals are at the top the list. One way to validate the utility of the database is to be sure that it contains journals that cover the Liquid Biopsy area. Our validation is by experience in the area. Note that cancer journals top the list, providing a hint at a key area of focus in Liquid Biopsy.

Regions in the Liquid Biopsy Database

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PubMed provides address information for most authors. Addresses can be mined to identify the location (country and region of the world) where the work is being done. Clearly , the US, Asia and Europe are the dominant areas with Europe as a leader. The same analysis can also be done by country.

Countries in the Liquid Biopsy Database

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PubMed provides address information for most authors. Addresses that are present can be mined to identify the location (country and region of the world) where the work is being done. A total of 82 countries were represented in our database. The top 25 countries are below. Europe, the dominant region, is more spread out in this analysis.

TOOLS USED IN LIQUID BIOPSY RESEARCH

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Samples for Liquid Biopsies

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True to PubMed’s definition of Liquid Biopsy, the major samples mentioned are blood, plasma and serum, but other samples area also being explored.

201820172016

Major Technology Tool Sets in Liquid Biopsy

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Traditional biotech tools are in play in this area. Most areas show growth rates below that of Liquid Biopsy itself.

PCR in Liquid Biopsy

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PCR is a tool that mirrors the growth of the Liquid Biopsy area. Watch digital PCR and sequencing and PCR for near-term growth.

Isolation and Purification Themes in Liquid Biopsy

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While the sample preparation is considered a key theme in liquid biopsy, it is not a major focus of research at this time. Apparently, methods necessary are mostly available.

Sample Prep is a Growing Segment of the Liquid Biopsy Space

Nucleic Acids in Liquid Biopsy

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A variety of DNA types are in play in Liquid Biopsy. The three year CAGR for DNA is ~50%, faster than the very rapid growth of the Liquid Biopsy area itself.

Smaller Nucleic Acid Segments in Liquid Biopsy

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A variety of DNA types are in play in Liquid Biopsy. DNA (not surprisingly) in the most often mentioned. Among the smaller segments cell-free- DNA and microRNAs (3-year CAGR’s of 51% and 60%, respectively) are the most often mentioned.

MicroRNAs in Liquid Biopsy

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Because the naming of microRNA is fairly standard, we can reasonably easily extract and count the mentions of specific microRNAs in the Liquid Biopsy database. There were a total of 79 specific microRNA names found in our Liquid Biopsy database. Below are the most prominent. MIR-21 is often linked with cancer. MIR-200 is often linked to metastasis. MIR-483 is another linked to cancer.

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Breakout of the Liquid Biopsy Space by Biomarker Class

Circulating molecules and bodies play a key role in diagnostics based on blood, plasma, serum and other body fluids. The chart below shows the relative proportions of selected circulating bodies. Note that some terms may legitimately belong to multiple segments.

Biomarkers are key to Liquid Biopsies

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Assay of appropriate biomarkers are key to Liquid Biopsy. This is represented in this slide where the 3-Year CAGR of the Biomarker area within the Liquid Biopsy database is nearly 58%, well above the 3-Year CAGR for the Liquid Biopsy space itself.

Major Gene or Gene Product Targets Mentioned in LQ DB

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We have searched for all human gene names in the Liquid Biopsy database. The graph show the number of papers in which major gene targets are mentioned. The table shows minor gene targets mentioned in 5 or more papers. Cancer related genes top the list in agreement with the vocabulary analysis presented earlier.

Other Gene TargetsMentioned in between 5 & 9

papers.ACT & GENEATMBASBRCA1BRMS1C3CBSCD34CD4CD44CD63COPDCPCRPCST6DAPK1ERGFGFR3

GAPDHGRASPHPHRASMCM2MGMTMSCMYCNMYD88NOTCH1PCA3RESTSFRP1SMAD4SOX17TIMP1TKTL1TOP2A

Enzymes in Liquid Biopsy

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Enzyme names follows specific naming rules (ending in –ase), making it fairly easy to form single and multiple word enzyme names using our Python and natural language tools. There were 189 Enzyme Classes and 519 multi-word Enzyme Names found. Below are the top 25 enzyme classes and names from the Liquid Biopsy database. It is the author’s belief that these could become useful biomarkers in Liquid Biopsies.

Enzyme Classes Count Enzyme Names Count1 KINASE 205 POLYMERASE 632 POLYMERASE 199 TYROSINE KINASE 473 DEHYDROGENASE 63 ANAPLASTIC LYMPHOMA KINASE 264 UREASE 42 EGFR TYROSINE KINASE 235 AMINOTRANSFERASE 32 RAPID UREASE 176 SYNTHASE 28 TELOMERASE 167 OXIDASE 27 EGFR-TYROSINE KINASE 138 TELOMERASE 26 PROTEASE 129 PHOSPHATASE 22 DIGITAL POLYMERASE 12

10 PROTEASE 21 LACTATE DEHYDROGENASE 1111 TRANSCRIPTASE 17 ALANINE AMINOTRANSFERASE 1112 DECARBOXYLASE 14 ASPARTATE AMINOTRANSFERASE 1113 DNASE 11 NITRIC OXIDE SYNTHASE 1014 REDUCTASE 10 XANTHINE OXIDASE 1015 DISMUTASE 10 REVERSE TRANSCRIPTASE 1016 3-KINASE 10 REAL-TIME POLYMERASE 1017 PEROXIDASE 10 RECEPTOR TYROSINE KINASE 918 LIPASE 9 DNASE 919 IMMUNOPEROXIDASE 9 HUMAN TELOMERASE 920 ATPASE 9 ALKALINE PHOSPHATASE 821 HYDROXYLASE 8 SYNTHASE 722 TRANSFERASE 8 MYELOPEROXIDASE 723 TRANSCRIPTASE-POLYMERASE 8 AROMATASE 724 HEXOKINASE 8 HEPARINASE 725 TRANSAMINASE 8 TYROSINASE 6

CLINICAL TRIALS & DISEASES IN LIQUID BIOPSY

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Liquid Biopsy- Clinical Trials

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There are a small but rapidly growing number of papers that mention clinical trails in recent years.

Cancer a Major Theme in Liquid Biopsy

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Cancer (of all types) is a major theme in Liquid Biopsy research. Its growth rate parallels the growth of the Liquid Biopsy database itself – a growth driver.

Cancer in Liquid Biopsy

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Our vocabulary analysis shows that cancer is a major theme in Liquid Biopsy. We track several major cancer types through keywords (and synonyms). The relative length of the blue and gray bars (2017 and 2015 data) give hints to CAGRs.

Cardiovascular Disease in Liquid Biopsy

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It is clear that some research interest exists in cardiovascular themes in Liquid Biopsy, but the interest is very small compared to cancer.

Reproductive and Neurodegenerative Diseases

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Reproductive and neurodegenerative diseases are mentioned in the Liquid Biopsy database, but the number of papers in these areas are miniscule compared to the interest in cancer.

Immunotherapy in Liquid Biopsy

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The cross connection between immunotherapy and liquid biopsy makes sense to the author. The segments are fairly large and growing at robust rates that are above the CAGR for the liquid biopsy area itself.

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