Executive summary 14

DNA SEQUENCING PART 55

Context 56

Market forecasts 70

• Installed base of sequencers
• Flow cell market (units and 8” equivalent wafers)
• Sequencing consumable market ($M)
• Sequencing consumable fab market ($M)
• Sequencing consumable raw material market ($M)

Market trends 83

• Applications of NGS
• Evolution of sequencing revenue by application
• Applications driving the use of NGS
• Leveraging semiconductor technologies
• The value will switch from the optics to the chip
• Clonal vs. single molecule technologies – A difficult road to market
• Consumables and sample preparation
• Penetration of the clinical market
• Why has Illumina won the sequencing race so far?
• Why will Illumina be challenged at some point?
• Competition on price
• Advice to newcomers

Market shares and supply chain 104

• Installed base of sequencers
• Number of flow cells per player and per material
• Potential sequencing output per player
• Sequencing consumable revenue per player and per flow cell material
• 8” equivalent wafers, per flow cell material
• Flow cell fab market, per flow cell material
• Flow cell raw material market, per flow cell material
• Comments and conclusion
• Supply chain analysis:
  – DNA sequencing flow cell manufacturing
  – Glass substrate providers

Technology trends 124

• Methods for DNA sequencing
• Clonal amplification vs. single molecule technologies
• Sample preparation
• Drivers for technology development: an endless race
• Clonal vs. single molecule technologies – which ones are solid-state?
• Which substrates are used?
• Detection methods
• Use of semiconductor substrates
• Size of the chips
• Flow cell cost and price breakdown
• Quality scores in sequencing
• Performances comparison of sequencing technologies
• Technology focus: Illumina, Oxford Nanopore, Pacific Biosciences, Ion Torrent
• Conclusion

Profiles of over 50 companies developing sequencing technologies 161

DNA SYNTHESIS PART 193

• Definition
• Rapid growth in base pairs
• A massive divergence in capacity
• History of DNA writing
• What can be synthesized?
• How can DNA be synthesized?
• Current DNA synthesis methods
• Geographical location of DNA synthesis companies
• Mergers and acquisitions
• Market data and forecasts
• Writing synthetic DNA on silicon chips
• Company profiles
• Applications for DNA synthesis
• New types of DNA suppliers
• Market opportunities and current developments
• Adoption of silicon chip-based DNA synthesis technology

Conclusion of the report 215

SEQUENCING IS A VERY DYNAMIC MARKET AND HAS APPLICATIONS IN MANY FIELDS, HOWEVER IT IS ONLY THE BEGINNING OF THE STORY

DNA sequencing has many applications in healthcare and life sciences and it is increasingly used in myriad areas as cost reduction starts to permit it. Research is progressing and enabling a better understanding of the genetic content of life. Sequencing therefore holds a bright future in clinical applications, enabling clinical decisions on the basis of sequencing information. Increasing adoption paves the way for personalized medicine, helping to better understand cancers and rare genetic diseases. Sequencing even has potential for non-invasive early cancer detection with liquid biopsies. It is also increasingly used in other applications, such as forensics, agricultural sciences and drug development. Furthermore, the possibility of encoding vast amounts of information in DNA could replace our current data storage solutions, offering an insanely space efficient storage at low cost in the future.

The sequencing market is dominated by a handful of players, all with their own sequencing technology, and associated advantages and drawbacks. However, Illumina currently holds more than 80% of the sequencing market, leaving only crumbs to its competitors. Nevertheless, newcomers such as China’s BGI and the UK’s Oxford Nanopore have the potential to change this along with other technologies in development, some of which might reach the market as soon as 2019. In total, Yole Developpement’s (Yole) analysts identified more than 50 companies developing sequencing technologies. In the report, Yole’s analysts provide our analysis of how the sequencing landscape will evolve in the coming years and how these new technologies could change the game. Cost, throughput, read length, accuracy, speed, portability, ease of interpretation are criteria on which there is room for improvement, and Illumina might win some but not all of these races.

One thing remains clear: we are still in the early days of sequencing and tremendous growth is expected as the use of sequencing spreads. This is why Yole’s analysts expect that the fleet of sequencing instruments will more than double by 2024, from almost 30,000 sequencers today. As a consequence of the razor/razor-blade business model of sequencing consumables, the number of sequencing flow cells, the disposable chips used to perform and sometimes detect the sequencing reaction, is poised to grow at a 21% Compound Annual Growth Rate (CAGR), from 1.28 million units in 2018 to 4.19 million units in 2024. But this is only a first step: the $1,000 genome was achieved years ago, and we’re now heading towards the $100 genome. The continuous improvement of sequencing technologies will someday lead to a much more affordable and practical sequencing, the $10 genome or even below. At this point, it is not millions of flow cells per year but hundreds of millions that one needs to consider, representing an immense opportunity for the entire semiconductor supply chain.

CHEAPER, BETTER, FASTER, LONGER SEQUENCING READS: SEMICONDUCTOR TECHNOLOGIES HAVE A KEY ROLE TO PLAY IN DRIVING THIS ENDLESS RACE

Most sequencing technologies are using, to some extent, microstructures. Beads, wells, membranes, patterned surfaces and nanopores are all examples of microstructures that can be found in sequencing consumables. Sequencing consumables from most players leverage semiconductor technologies to manufacture these microstructures in a reproducible and scalable manner. The key to scaling sequencing power is always increasing flow cells’ density to generate more data on the same surface area. It is no coincidence that the cost of sequencing has dropped much faster than Moore’s law over the past 15 years.

While glass is often used when optical detection is the method of choice, the advent of electrical detection methods has led to the increased use of silicon and CMOS substrates. Silicon, especially CMOS, is the material of choice for the flow cells used by most technologies currently in development. The expected market introduction of several of these technologies in the next few years will boost the associated number of wafers. Sequencing companies need, or will need, to mass-manufacture these flow cells, creating opportunities at all the levels of the semiconductor supply chain. Indeed, most sequencing players have made the choice to outsource this production to specialized players. However, some start-ups struggle in the development phase because foundries seem not to realize the potential volumes sequencing flow cells could represent in the future. Consequently it is difficult for them to get access to the equipment and processes they need. In this report, Yole analyzes the supply chain and also focuses on several leading and emerging flow cell technologies from key and upcoming players including the type of microstructures, process flow, and evolution over time. Yole’s analysts also talk about the limitation of optical detection technologies leading to ever larger glass flow cells, which represents a significant opportunity for glass players as well.

THE TIME FOR NEW DNA SYNTHESIS TECHNOLOGIES BASED ON SEMICONDUCTOR CHIPS HAS ARRIVED

Gene synthesis technology has revolutionized both the understanding of DNA functions and the ability to manipulate DNA for experimental, medical, and industrial purposes. Until recently, DNA was synthesized using enzymatic and chemical processes. These methods include random errors, making the DNA useless, and finding error-free DNA is a timeconsuming mission requiring further analysis and sequencing.

Semiconductor chips are allowing important advancements in the field of genomic research by enabling the synthesis of thousands of genes in parallel. This is revolutionizing the way DNA synthesis is performed, enabling faster and more efficient synthesis. Such technology leverages semiconductor processing techniques to greatly increase throughput and has the potential to make oligonucleotide synthesis cost 1000 times lower. On the other hand, the throughput can be increased even further by scaling down the chips’ feature size. In this context, Yole’s analysts estimate that the global market of semiconductor chips used for DNA synthesis will reach $213.2M in 2024 with a CAGR of 40% over the period 2018-2024.

A wide range of applications such as drug discovery, agriculture and data storage will increasingly rely upon gene synthesis to solve problems related to healthcare, food supplies and storage modalities respectively. In the report, Yole’s analysts explore the possibilities envisioned thanks to emerging semiconductor-based DNA synthesis technologies, identify the key players leading the market, highlight the new needs for each application and discuss the technology’s evolution.

AGC [Asahi Glass Co.], Agilent Technologies, Advanced Liquid Logic (Illumina), Apton Biosystems, Armonica Technologies, Atum, Base4 Innovation, BGI [Beijing Genomics Institute], Bio Basic, Biocat, Bioneer, Bio-Rad Laboratories, Biosearch Technologies, Caerus Molecular Diagnostics, Catalog, Centrillion Technologies, Complete Genomics (BGI), Corning, Cygnus Biosciences, Depixus, Desktop Genetics, Direct Genomics, DNA Electronics, DNA Script, Electronic Biosciences, Electron Optica, Electroseq, Eurofins, Eve Biomedical, Evonetix, Gen9 Bio (Gingko Bioworks), Genapsys, GeneArt, GeneOracle, Geneseque, Genewiz (Brooks Automation), Genia Technologies, Genome Surveilllance, GenScript, Gingko Bioworks, GnuBio (Bio-Rad), Grail, Helixworks, Heraeus, Hoya, Integrated DNA Technologies (Danaher), Illumina, IMT AG, IMT MEMS, iNanoBio, inSilixa, Intelligent Biosystems (Qiagen), Invenios, Ion Torrent (Thermo Fisher), Iridia, Jilin Zixin Pharma, Kilobaser, LabGenius, LaserGen (Agilent), Lightspeed Genomics, Little Things Factory, MGI (BGI), Micralyne, Micronit, Mir Enterprises, Molecular Assemblies, Nabsys, NanoString Technologies, NorthShore Bio, Novati (Skorpios Technologies), Ohara Corporation, Omniome, Origene, Oxford Nanopore Technologies [ONT], Pacific Biosciences (Illumina), Plan Optik, Personal Genomics, Powerchip Technologies, Quantapore, Qiagen, QuantuMDx, QuantumSi, Roche, Roswell Biotechnologies, Schott AG, SeqLL, Silex Microsystems, SingularBio, Singular Genomics, Solexa (Illumina), Stratos Genomics, Synthomics, Thermo Fisher Scientific, TSMC [Taiwan Semiconductor Manufacturing Company], Twist Bioscience, Two Pore Guys, Universal Sequencing Technology Corporation, Xgenomes, ZS Genetics, and more.