BACKGROUND OF BUSINESS COMBINATION
−Removed: On June 9, 2021 (the “Closing Date”), Nautilus Biotechnology, Inc., a Delaware corporation (f/k/a ARYA Sciences Acquisition Corp III, a Cayman Islands exempted company and our predecessor company (“ARYA”)), consummated its previously announced business combination (the “Business Combination”) pursuant to the terms of that certain Business Combination Agreement, dated as of February 7, 2021 (the “Business Combination Agreement”), by and among ARYA, Mako Merger Sub, Inc., a Delaware corporation and wholly-owned subsidiary of ARYA (“Mako Merger Sub”), and Nautilus Subsidiary, Inc., a Delaware corporation (f/k/a Nautilus Biotechnology, Inc.) (“Legacy Nautilus”).
+Added: On June 9, 2021 (the “Closing Date”), Nautilus Biotechnology, Inc., a Delaware corporation (f/k/a ARYA Sciences Acquisition Corp III, a Cayman Islands exempted company and our predecessor company (“ARYA”)), consummated the previously announced business combination (the “Business Combination”) pursuant to the terms of that certain Business Combination Agreement, dated as of February 7, 2021 (the “Business Combination Agreement”), by and among ARYA, Mako Merger Sub, Inc., a Delaware corporation and wholly-owned subsidiary of ARYA (“Mako Merger Sub”), and Nautilus Subsidiary, Inc., a Delaware corporation (f/k/a Nautilus Biotechnology, Inc.) (“Legacy Nautilus”).
Pursuant to the terms of the Business Combination Agreement, on the Closing Date, (i) ARYA changed its jurisdiction of incorporation by deregistering as a Cayman Islands exempted company and continuing and domesticating as a corporation incorporated under the laws of the State of Delaware (the “Domestication”), upon which ARYA changed its name to “Nautilus Biotechnology, Inc.” (together with its consolidated subsidiary, the “Company” “New Nautilus” or “Nautilus”) and (ii) Mako Merger Sub merged with and into Legacy Nautilus (the “Merger”), with Legacy Nautilus as the surviving company in the Merger and, after giving effect to such Merger, Legacy Nautilus becoming a wholly-owned subsidiary of New Nautilus.
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We were founded on the belief that incremental advancements of existing technologies are inadequate, and that a bold scientific leap would be required to radically reinvent proteomics and revolutionize precision medicine.
−Removed: Our vision is to integrate our breakthrough innovations in computer science, engineering, and biochemistry to develop and commercialize a proteome analysis platform of extreme sensitivity and scale.
−Removed: To accomplish this, we have built a prototype of our proteome analysis system, an instrument to perform massively parallel single protein molecule measurements which will be further developed to deliver the speed, simplicity, accuracy, and versatility that we believe is necessary to establish a new gold standard in the field.
+Added: Our vision is to integrate our breakthrough innovations in computer science, engineering, and biochemistry to develop and commercialize a proteomic analysis technology of extreme sensitivity and scale.
+Added: To accomplish this, we have built a prototype of a proteome analysis system, an instrument to perform massively parallel single protein molecule measurements which will be further developed to deliver the speed, simplicity, accuracy, and versatility that we believe is necessary to establish a new gold standard in the field.
The human proteome, the make-up of all the proteins in a human, is among the most dynamic and valuable sources of biological insight in modern-day science.
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Due to the extensive applications and broad potential of large-scale proteomic characterization, we believe the proteomics market is currently among one of the largest untapped opportunities in the biological sciences today.
−Removed: The existing proteomics research market is currently estimated to be approximately $25 billion annual spend as of 2021, made up primarily of mass spectrometry and affinity-based quantification methods.
−Removed: Over the longer-term, the proteomics market is expected to reach approximately $50 billion by 2027, representing a compound annual growth rate, or CAGR, of 12% over the six-year period.
−Removed: Further, we believe there are substantial adjacent opportunities across translational research, drug target discovery, precision medicine development, clinical diagnostics, and other disciplines such as food and environmental science.
+Added: According to BCC Research, the existing proteomics research market is currently estimated to be approximately $27 billion annual spend as of 2022, made up primarily of mass spectrometry and affinity-based quantification methods.
+Added: Over the longer-term, the proteomics market is expected to reach approximately $55 billion by 2027, representing a compound annual growth rate, or CAGR, of 15% over the five-year period.
+Added: Further, we believe there are substantial adjacent opportunities across translational research in drug target discovery, precision medicine development, clinical diagnostics, and other disciplines such as food and environmental science.
We plan to initially target the life sciences proteomics research market and are currently entering the first phase of our product development and commercialization strategy.
In this first phase, we are focused on developing partnerships with key biopharma companies and leading academic institutions to create a founding group of collaborators that will gain experience with our technology, jointly publish research using our Nautilus platform, and generally help validate our initial applications.
−Removed: As of the date of filing this Annual Report, we have partnerships with Genentech, Amgen, and The University of Texas MD Anderson Cancer Research Center.
+Added: As of the date of filing this Annual Report, we have partnerships with Genentech, Amgen, The University of Texas MD Anderson Cancer Research Center, and the Translational Genomics Research Institute, among others.
In the second phase we plan to launch an early access program to an expanded group of customers.
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In our third phase of commercialization, we intend to execute a broad commercial launch of our Nautilus platform including the introduction of our proteome analysis system, which is an integrated fluidics and optics system for massively parallel single protein molecule detection, accompanied by consumable reagents and analysis software, in direct sales to customers across academia and industry.
−Removed: The launch of our proteome analysis system is expected to be done with a multi-year product roadmap of system enhancements and new applications designed to help our customers achieve their research objectives and expand the
−Removed: utility of our Nautilus platform.
+Added: The launch of our proteome analysis system is expected to be done with a multi-year product roadmap of system enhancements and new applications designed to help our
+Added: customers achieve their research objectives and expand the utility of our Nautilus platform.
We also plan to leverage our machine learning software to build a data analysis and insights engine that improves over time as we grow our data sources and the analysis learns to deliver better accuracy and identify new potential discoveries.
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We aim to be the first commercially available proteomics detection platform technology and end-to-end solution to decode and quantify virtually the entire proteome, including the variations and modifications of proteins.
−Removed: Our Nautilus platform consists of instruments, reagents and software that we believe has the potential to deliver broad proteomic profiling to the market and potentially unlock the vast, dynamic, and valuable biological information contained in the proteome.
−Removed: Not only would this enable us to have a significant technical advantage, but we believe it may also allow us to leverage a diversified revenue model that could be highly recurring in nature.
−Removed: With each instrument sale, there is expected to be an accompanying recurring stream of consumable sales, in addition to service, support and software creating a comprehensive proteomics solution.
−Removed: • Open and customizable technology platform.
−Removed: Our Nautilus platform is designed to be compatible with a wide variety of affinity binding reagents.
−Removed: We believe that this flexibility allows the system to be ‘tuned’ in response to the profile of binding reagents introduced.
−Removed: With a labeling kit, our system is designed to be able to use a wide range of reagents that have been created by biopharma, academia, or leading commercial affinity reagent manufacturers.
−Removed: It also creates the opportunity to partner with third-parties on the development and supply of affinity reagents.
−Removed: To that end, in the fourth quarter of 2021 we initiated a strategic partnership with Abcam, a world leader in the design and production of assay kits, reagents, and antibodies.
−Removed: This type of development and supply agreement is expected to provide Nautilus with antibodies additive to the affinity reagents we are creating internally and serves to highlight the flexible nature of our technology.
+Added: Our Nautilus platform consists of instruments, reagent consumables and software that we believe has the potential to deliver broad proteomic profiling to the market and potentially unlock the vast, dynamic, and valuable biological information contained in the proteome.
+Added: With each instrument sale, there is expected to be accompanying recurring revenue comprised of reagent consumable sales, instrumentation service, support, and software that creates a comprehensive proteomics solution.
+Added: • Open, flexible and customizable technology platform.
+Added: Our Nautilus platform is designed to allow our customers to analyze their samples in a variety of run configurations by utilizing flow cells which each contain 4 discrete and independent lanes, analyzed on an instrument that can be loaded with up to 3 flow cells per run.
+Added: At launch, our platform is designed to either maximize analysis depth by running all 12 lanes on 1 sample, or maximize analysis throughput by running a single sample per lane.
+Added: This design is also highly compatible with molecular barcoding, which may be introduced in the future to multiplex increasingly larger sample numbers per run.
+Added: Further, with the introduction of an affinity binding reagent labeling kit, our platform is also designed to be able to incorporate off-the-shelf affinity binding reagents that have already been created by biopharma, academia, or commercial affinity reagent manufacturers.
+Added: We believe that the ability to customize the type of analysis performed by adding or combining these affinity binding reagents with our Nautilus provided reagent kits could provide a very powerful and desirable analysis for our customers.
• Immense data production capacity coupled with machine learning can unlock new proteomic insights.
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• Commercial model with clear market entry point, designed to support a wide variety of customers and applications.
−Removed: Many successful life sciences research tools companies with disruptive technology have employed a business model similar to our planned commercial model.
−Removed: However, we believe a key advantage for us is the near-term commercial
−Removed: opportunity of capitalizing on the existing mass spectrometry-based proteomics marketplace estimated at over 16,000 installed systems.
+Added: Many successful life sciences research tools companies with disruptive technology have employed a business model
+Added: similar to our planned commercial model.
+Added: However, we believe a key advantage for us is the near-term commercial opportunity of capitalizing on the existing mass spectrometry-based proteomics marketplace estimated at over 16,000 installed systems.
Our price point is expected to be in-line with mass spectrometry system budgets allocated for broad scale proteomics applications, and thus with a premium instrumentation average selling price, or ASP, we plan to operate with a very efficient sales model.
Further, since the early days of our product development, we have consulted with biopharma companies, academic institutions and research organizations to inform our product development plan and specifically address our target customer needs.
−Removed: These customer segments were estimated to spend approximately $195 billion in 2021 in R&D activities across a variety of settings, from basic sciences to translational and clinical research.
• Our Nautilus platform technology could position us as a leader in a large initial life sciences research market and provide a path to the clinical diagnostics.
−Removed: The global proteomics market is estimated to be approximately $25 billion annually as of 2021 and is expected to grow at an estimated 12% CAGR from 2021 to 2027.
+Added: The global proteomics market is estimated to be approximately $27 billion annually as of 2022 and is expected to grow at an estimated 15% CAGR from 2022 to 2027 according to BCC Research.
Furthermore, we believe our Nautilus platform has the potential to facilitate a broader transformation across life sciences and healthcare, and therefore significantly augment our total addressable market over time.
−Removed: We believe there are multiple high-value applications in precision and personalized medicine, drug discovery, and clinical diagnostics that can be unlocked by accurate, reproduceable, and cost effective proteomic profiling.
+Added: We believe there are multiple high-value research applications in precision and personalized medicine, drug discovery, and clinical diagnostics that can be unlocked by accurate, reproduceable, and cost effective proteomic profiling.
As the proteomics market continues to mature, and if our technology is validated across translational research applications, we believe our Nautilus platform could transfer well into the clinical setting prior technologies have thus far been unable reach.
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We believe our Nautilus platform has the potential to provide value across the life sciences ecosystem as the first end-to-end solution capable of substantially quantifying the proteome.
−Removed: The utility and potential applications are expected to be broad and serve basic research and discovery, translational and clinical research, and clinical diagnostic market segments.
−Removed: We intend to drive adoption of our Nautilus platform through a three-phase commercial strategy that begins with an initial partnership and collaboration phase with biopharma companies (such as our existing relationships with Genentech and Amgen), academic institutions (such as our existing relationship with The University of Texas MD Anderson Cancer Center and others) and research organizations where we aim to jointly publish data and validate our Nautilus platform, followed by a pre-sales or early access program to drive awareness and demand, and finally culminating in a full commercial launch.
+Added: The utility and potential applications are expected to be broad and serve basic research and discovery, translational and clinical research, and ultimately enable clinical diagnostic market segments.
+Added: We intend to drive adoption of our Nautilus platform through a three-phase commercial strategy that begins with an initial partnership and collaboration phase with biopharma companies (such as our existing relationships with Genentech and Amgen), academic institutions (such as our existing relationship with The University of Texas MD Anderson Cancer Center, the Translational Genomics Research Institute and others) and research organizations where we aim to jointly publish data and validate our Nautilus platform, followed by a pre-sales or early access program to drive awareness and demand, and finally culminating in a full commercial launch.
• Continuously innovate and scale our Nautilus platform’s capabilities to enable further advancement of proteomic research.
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We have established a manufacturing process for our technology utilizing a combination of both external contract manufacturers and internal resources based in our San Carlos, CA facility, with the ability to support substantially all of our current core activities during development.
−Removed: We believe there are many potential options we can use in order to increase the manufacturing and production capabilities
−Removed: for our products, including expanding our outsourced manufacturing and supply to multiple suppliers to ensure our quality and production capacity will meet our commercial plan.
+Added: We believe there are many potential options we can use in order to increase the manufacturing and production capabilities for our products, including expanding our outsourced manufacturing and supply to multiple suppliers to ensure our quality and production capacity will meet our commercial plan.
• Build long-term value by leveraging the open design of our Nautilus platform to create an ecosystem of products and services based on our core technology.
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However, the detailed and complex information provided from proteomics has the potential to help in identifying novel and causal drug targets and to enable more efficient and effective drug development.
−Removed: A few examples of the way proteomics may lead to novel insights are highlighted below.
+Added: A few examples of the way proteomics may lead to novel insights in research are highlighted below.
• Better understanding of biology .
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We believe that our Nautilus platform has the potential to be uniquely positioned in the proteomics market.
−Removed: In our mission to democratize proteomics, we see initial applications in precision and personalized medicine, clinical diagnostics, as well as in machine-learning powered drug discovery.
+Added: In our mission to democratize proteomics, we see initial research applications in precision and personalized medicine, with a natural growth path into clinical diagnostics, as well as in machine-learning powered drug discovery.
However, we believe that the opportunity could extend far beyond this.
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As existing approaches only allow us to routinely quantify a fraction of the proteome, biopharmaceutical companies have become increasingly adept at identifying possible targets within what is currently observable, and as such, many viable targets have been exhausted.
−Removed: Despite the many hundreds of thousands of biomarker research studies estimated to have been published to date, there are only approximately 100 unique pharmacogenomic biomarkers with FDA approval for use with therapies today.
+Added: Despite the many hundreds of thousands of biomarker research studies estimated to have been published to date, there are currently only approximately 140 unique pharmacogenomic biomarkers with FDA approval for use with therapies today.
This number of approved biomarkers is alarmingly low, and further highlights the shortfall of attempting to predict a protein biomarker’s expression level and function primarily from genetic data.
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With an advancement such as the Nautilus platform, we believe researchers will have the power to deeply and comprehensively measure the physical proteins at the root of disease, dramatically increasing the potential to identify more clinically meaningful biomarkers with greater precision in the practice of medicine.
−Removed: A breakthrough increase in throughput will enable researchers to more deeply measure large cohorts, thereby powering studies at the scale required to quickly and cost-effectively discover new critically important biomarkers.
+Added: We believe a breakthrough increase in throughput would enable researchers to more deeply measure large cohorts, thereby powering studies at the scale required to quickly and cost-effectively discover new critically important biomarkers.
The inability to easily and reliably quantify the proteins that drive every aspect of human physiology has been a fundamental hindrance to a greater understanding of cellular and molecular biology.
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Scientists have estimated that there may be as many as 70,000 or more human protein isoforms.
−Removed: The resulting proteome is not only highly dynamic and in a constant state of flux by regulating the quantity and type of each protein isoform, but it also
−Removed: exhibits great diversity across cells and tissues.
+Added: The resulting proteome is not only highly dynamic and in a constant state of flux by regulating the quantity and type of each protein isoform, but it also exhibits great diversity across cells and tissues.
This complexity, which governs all biological processes, both healthy and sick, cannot be captured or characterized routinely by current methods.
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Furthermore, shortfalls in the ability of bioinformatics to predict the existence as well as the function of genes have further illustrated the need for enhanced protein analysis techniques.
−Removed: Today, we believe the field of proteomics is at
−Removed: the very beginning of a significant growth phase.
+Added: Today, we believe the field of proteomics is at the very beginning of a significant growth phase.
We are of the firm belief that every scientist should have access to the proteome, including proteoforms, in the same way that access to the genome has been made broadly available over recent years.
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Due to the extensive applications and broad potential, we believe that the proteomics market represents one of the largest untapped opportunities in the biological sciences today.
−Removed: According to Allied Market Research, the global proteomics market was valued at approximately $25 billion as of 2021.
+Added: According to BCC Research, the global proteomics market was valued at approximately $27 billion as of 2022.
This encompasses only the fraction of the proteomics market that is currently available to us via mass spectrometry and other quantification methods and does not include diagnostics.
−Removed: The overall proteomics market is projected to reach approximately $50 billion in 2027, representing a CAGR of 12% for the six-year period.
+Added: The overall proteomics market is projected to reach approximately $55 billion in 2027, representing a CAGR of 15% for the five-year period.
We believe that as the proteomics market evolves, substantial adjacent opportunities will arise due to the potential applications in not only precision and personalized medicine, clinical diagnostics, and machine-learning powered drug discovery, as well as other disciplines such as food and environmental science.
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This detection method can only measure the individual protein fragments, and is therefore unable to identify specific patterns of post-translational modifications and proteoforms visible on intact proteins across a sample.
−Removed: Despite these challenges, there has still been a strong appetite for protein data given its importance in biology and drug development, and the proteomics research marketplace is estimated to have over 16,000 installed mass spectrometry systems today.
+Added: Despite these challenges, there has still been a strong appetite for protein data given its importance in biology and drug development, and the proteomics research marketplace is estimated to have over 16,000 installed mass spectrometry systems.
Limitations with Affinity-based Approaches
Where mass spectrometry-based approaches have been widely used for broad scale protein discovery applications, affinity-based approaches have generally been used for targeted protein measurements.
−Removed: Affinity-based protein detection commonly utilizes affinity binding reagents that are designed to be very specific to an individual protein target that is already known to the
+Added: Affinity-based protein detection commonly utilizes affinity binding reagents that are designed to be very specific to an individual protein target that is already known to the researcher.
Additionally, the ability of an affinity reagent to selectively bind to its target may also be impacted by protein specific factors, such as the protein’s folded structure and orientation.
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We have designed the Nautilus platform to enable extreme sensitivity and scale, without compromising on ease of use.
−Removed: Leveraging a unique architecture and advanced machine learning software, we believe our Nautilus platform has the potential to identify substantially all proteins in a sample from almost any organism.
+Added: a unique architecture and advanced machine learning software, we believe our Nautilus platform has the potential to identify substantially all proteins in a sample from almost any organism.
We view many of the core ideas underlying the Nautilus platform as “counterintuitive”, as it required innovations at the intersection of three distinct disciplines not often found in harmony:
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To achieve our ambitious goals, and to meet the unmet needs of scientists and researchers, we recognized early on that we would need to tackle the deep, hard, novel science required to innovate and commercialize a fundamentally new detection technology capable of reading and quantifying the proteome and associated proteoforms.
−Removed: As such, we designed the Nautilus platform – from the ground up – to accomplish the following objectives:
−Removed: Nautilus Platform Attribute:
−Removed: Nautilus Platform Benefit:
−Removed: Easy-to-Use è Any Lab Can Run It
−Removed: Sensitivity and Dynamic Range è Comprehensive Measurement
−Removed: Rapid Run Time è Days Not Weeks
−Removed: Reproducible and Robust è Path to the Clinic
−Removed: Scalable and Flexible è Accommodates Low & High Throughput
−Removed: Complete è No Missing Data
−Removed: A core design criterion was that the Nautilus platform needed to be sufficiently easy-to-use so that virtually any lab could benefit from using it, not just labs that are explicitly focused on proteomics or analytical chemistry.
+Added: As such, we designed the Nautilus platform – from the ground up – to accomplish the following goals:
+Added: A core design criterion was that the Nautilus platform needed to be comprehensive.
+Added: One of the largest challenges with existing “shotgun” proteomics technologies is that replicate analyses are likely to sample different subsets of the proteome.
Next, the Nautilus platform needed to be ultra-sensitive.
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To achieve the goal of measuring the complete proteome, scientists and researchers needed a new analysis method with unprecedented sensitivity.
+Added: The Nautilus platform was designed to cover a very large dynamic range in a simple workflow in order to scale to the full proteome.
In addition, the process needed to be reproducible and robust, maximizing the chance that the results derived in one experiment are the same as the results derived in subsequent experiments.
−Removed: It must also be complete.
−Removed: One of the largest challenges with existing “shotgun” proteomics technologies is that replicate analyses are likely to sample different subsets of the proteome.
−Removed: In order to fully support the wide-ranging needs of our future customers, the platform can also support multiple run configurations.
−Removed: Our design accommodates both low throughput and high throughput run configurations, and will also employ in-lane sample multiplexing to enable our customers to meet the high-volume data production needs of large-scale studies or core facilities.
Importantly, the Nautilus platform needed to be fast and able to analyze tens of thousands of samples in a reasonable time period.
−Removed: It also needed to be integrated, allowing a biologist to put a sample in the instrument and get data out without additional intervention.
+Added: It also needed to be sufficiently easy-to-use so that virtually any lab could benefit from using it, not just labs that are explicitly focused on proteomics or analytical chemistry.
+Added: In order to fully support the wide-ranging needs of our future customers, the platform can also support multiple run configurations.
+Added: Our design accommodates both low throughput and high throughput run configurations, and will also employ
+Added: in-lane sample multiplexing to enable our customers to meet the high-volume data production needs of large-scale studies or core facilities.
With these objectives identified as our core design criteria, we set out to create a transformative technology with the potential to achieve all of these criteria.
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These scaffolds can be reliably made to precise sizes, and the flow cell nanoarray surface can then be generated by well understood manufacturing processes to create surface features, which we call landing pads, that match the dimension of the scaffold.
−Removed: As each landing pad can only hold one scaffold, and each scaffold can only hold one protein molecule, the introduction of scaffold-protein complex onto the nanoarray surface generates a self-assembling, high-density single protein molecule array (as seen in the below illustration).
+Added: As each landing pad can only hold one scaffold, and each scaffold can only hold one protein molecule, the introduction of scaffold-protein complex onto the nanoarray surface generates a self-assembling, high-density single protein molecule array (as seen in the above and below illustrations).
The attachment between the scaffold and the nanoarray surface is extremely robust, enabling scaffolds to persist through extensive reagent washing across many cycles.
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With our platform, each protein molecule has a unique coordinate address on the flow cell, and repeated probing enables deeper characterization of each individual molecule with each cycle, unlocking the ability to characterize proteoforms and ultimately decode the whole proteome.
−Removed: Nautilus Platform Multi-Cycle Affinity Reagent Probing, Imaging, Washing, and Re-Probing
+Added: Nautilus Platform Multi-Cycle Affinity Probe Reagent Binding, Imaging, Washing, and Re-Binding
To achieve extreme sensitivity and scale, we have designed a novel instrument that integrates reagent fluidics with a sensitive high-resolution optical imaging system to cyclically measure all single protein molecules captured on the flow cell.
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A typical full scale proteome run will generate approximately 20 terabytes of data, which is then compressed to a digital binding matrix for downstream analysis by our cloud-based software-as-a-service, SaaS, analytics suite.
−Removed: A Novel Class of Affinity Reagents for Efficient Whole Proteome Analysis
+Added: A Novel Class of Multi-Affinity Probe Reagents for Efficient Whole Proteome Analysis
Our Nautilus platform technology is designed with fundamentally different principles of how to use and exploit the properties of affinity binding reagents compared to prior methods.
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In a highly innovative and counterintuitive way, our Nautilus platform has also been designed to exploit low specificity affinity reagents.
−Removed: Identifying the tens-of-thousands of different proteins in a proteome would require a prohibitively large
−Removed: number of traditional highly specific affinity reagents.
−Removed: We therefore explored the possibility of using affinity reagents that bind short, linear epitopes (e.g., target protein sequences of 3-4 amino acids each) with moderate specificity, such that each affinity reagent binds many proteins that contain the short linear epitope target, each a “multi-affinity reagent”.
−Removed: While the binding of a single multi-affinity reagent is not sufficient to identify a given protein, sequential binding events using a series of multi-affinity reagents can create enough information that it is sufficiently powerful to accurately identify an exceptionally broad number of proteins present in a sample.
−Removed: In this approach, each new affinity reagent that is introduced in a cycle of binding and imaging provides additional evidence and gradually narrows the list of possible protein identities.
+Added: Identifying the tens-of-thousands of different proteins in a proteome would require a prohibitively large number of traditional highly specific affinity reagents.
+Added: We therefore explored the possibility of using affinity reagents that bind short, linear epitopes (e.g., target protein sequences of 3-4 amino acids each) with moderate specificity, such that each affinity reagent probes and binds to many different proteins that contain the short linear epitope target, each we describe as a “multi-affinity probe”.
+Added: While the binding of a single multi-affinity probe is not sufficient to identify a given protein, sequential binding events using a series of multi-affinity probes can create enough information that it is sufficiently powerful to accurately identify an exceptionally broad number of proteins present in a sample.
+Added: In this approach, each new multi-affinity probe that is introduced in a cycle of binding and imaging provides additional evidence and gradually narrows the list of possible protein identities.
Hereafter, we refer to our proposed approach as Protein Identification by Short-epitope Mapping (PrISM).
−Removed: Our Nautilus platform technology is estimated to achieve the detection of the vast majority of proteins in the proteome using a combination of approximately 300 unique multi-affinity reagents.
−Removed: Nautilus Platform Technology Protein Identification with Increasing Multi-Affinity Reagent
+Added: Our Nautilus platform technology is estimated to achieve the detection of the vast majority of proteins in the proteome using a combination of approximately 300 unique multi-affinity probes.
+Added: Nautilus Platform Technology Protein Identification with Increasing Multi-Affinity Probe Cycles
A theoretical framework for proteome-scale single-molecule protein identification using multi-affinity protein binding reagents.
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As discussed, more typical measurements for high specificity reagents can be used in our system to identify, and thereby quantify, each protein from a single binding and imaging step.
−Removed: These high specificity affinity reagents can provide a lot of information about a small number of proteins, and as such it would take an exceedingly large number of highly specific affinity reagents and therefor an exceedingly large number of cycles to measure every protein in the proteome.
+Added: These high specificity affinity reagents can provide a lot of information about a small number of proteins, and as such it would take an exceedingly large number of highly specific affinity reagents and therefore an exceedingly large number of cycles to measure every protein in the proteome.
To enable broad protein identification on our system, we instead use our multi-affinity probes that can bind to hundreds or even thousands of individual proteins in a given cycle.
−Removed: Our proprietary algorithm is thereby trained using experimental data from our probe development process that provides a baseline estimate of how likely each probe is to bind to each protein in a reference proteome database.
+Added: Our proprietary algorithm is thereby trained using experimental data from our multi-affinity probe development process that provides a baseline estimate of how likely each probe is to bind to each protein in a reference proteome database.
As data is collected, a binding matrix is generated for each protein coordinate.
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The illustration below provides a view of our machine learning protein identification analysis at work by observing the confidence the algorithm has with respect to each protein as additional cycles of data are collected.
−Removed: On average, it takes roughly 15 cycles of multi-affinity probe biding events to uniquely identify a protein.
−Removed: Prior to 15 cycles, there is a lot of variability in which the protein is likely to be at a given spot, but then after 15 cycles, the algorithm locks in on a precise protein and becomes increasingly more confident in its identification.
+Added: On average, it takes roughly 15 cycles of multi-affinity probe binding events to uniquely identify a protein.
+Added: Prior to 15 cycles, there is a lot of variability in which protein is likely to be at a given spot, but then after 15 cycles, the algorithm locks in on a precise protein and becomes increasingly more confident in its identification.
Further, with each additional cycle the other potential proteins become increasingly less likely.
−Removed: Nautilus Platform Technology Can Identify a Protein by Analyzing Data from Multiple Cycles of Multi-Affinity Reagent Probing with High Probability
+Added: Nautilus Platform Technology Can Identify a Protein by Analyzing Data from Multiple Cycles of Multi-Affinity Probe Binding Event with High Probability.
Internal Data
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This process was designed to be simple, robust, and rapid.
−Removed: Internal tests demonstrate that substantially all of the proteins are attached to the scaffold within two hours, creating the prepared protein library.
+Added: Internal tests demonstrate that substantially all of the proteins are attached to the scaffold during the library preparation process, which requires approximately 2-3 hours of hands-on time over a 2-day protocol.
• Step 2 – Sample Deposition onto the Flow Cell
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This element of the process was specifically designed to enable massively parallel, rapid, single-molecule sampling of proteins, as shown in the flow cell occupancy figure below.
−Removed: • Step 3 – Integrated Imaging and Fluidics System using Multi-Cycle Affinity Reagents
−Removed: Once the proteins are deposited onto the flow cell, it is then loaded into the proteome analysis system to measure each individual molecule in a multi-cycle system run.
−Removed: The process entails introducing affinity reagents into the flow cell, rinsing out the unbound fraction, imaging the surface area, and then stripping and washing the affinity reagent away.
−Removed: This step is then repeated sequentially to collect data on the desired number of cycles.
+Added: • Step 3 – Integrated Imaging and Fluidics System Processing Multiple Cycles of Affinity Reagents
+Added: Following protein library deposition, the proteome analysis system then initiates the multi-cycle interrogation of each single-molecule bound to the surface of the flow cell.
+Added: This process entails introducing fluorescent dye labeled multi-affinity probes into the flow cell, rinsing out the unbound fraction, imaging the surface area, and then stripping and washing the multi-affinity probe away.
+Added: This entire process is then repeated sequentially to collect data on the desired number of cycles in the system run, where each cycle is a unique batch of multi-affinity probes intended to identify a set of target epitopes.
• Step 4 – Processing of Digitalized Proteomic Data
−Removed: After the proteins on the flow cell have been iteratively imaged over the determined number of cycles, the resulting raw images are converted into a coordinate map with corresponding illumination signals indicating positive affinity reagent binding events, effectively digitizing up to approximately 20 terabytes of raw image analyzed proteomic data.
+Added: After the proteins on the flow cell have been iteratively imaged over the determined number of cycles, the resulting raw images are converted into a coordinate map with corresponding illumination signals indicating positive multi-affinity probe binding events, effectively digitizing up to approximately 20 terabytes of raw image analyzed proteomic data.
• Step 5 – Machine Learning Analytics - Decoding, Protein Identification, and Quantity
In the final step of the workflow, the digital proteomic data is analyzed by our cloud-based machine learning protein identification analysis software.
−Removed: The data is converted to protein identities during this analysis, evaluating the characteristics of each affinity reagent binding event at each location to determine protein identity and quantity.
+Added: The data is converted to protein identities during this analysis, evaluating the characteristics of each multi-affinity probe binding event at each location to determine protein identity and quantity.
Nautilus Platform Technology Performance
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The process has been designed to be accessible to virtually any life sciences researcher.
−Removed: In addition, our forthcoming sample protein library preparation instrument is expected to further simplify the workflow by introducing automation.
−Removed: Also, unlike existing shotgun proteomics methods, no sample protein digestion is required in our method which in turn makes the workflow very simple.
−Removed: The result is a process that is expected to effectively prepare a sample into a library ready to load on the flow cell in approximately 2 hours.
+Added: In addition, the protocol is highly compatible with standard lab automation equipment and workflows, which is expected to further minimize the effort required while increasing laboratory processing throughput.
+Added: Also, unlike existing shotgun proteomics methods, no sample protein digestion is required in our method which in turn makes the workflow very
+Added: The result is a process that is expected to effectively prepare a sample into a library ready to load on the flow cell with approximately 2-3 hours of hands-on time completed over a 2 day period.
A key feature of our Nautilus platform is the large scale (up to billions) of protein molecules that we believe can be measured massively in parallel on our single-molecule flow cell.
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Extreme Sensitivity Quantified by 10 -16 LOD (Limit of Detection)
+Added: Development and Characterization of Multi-Affinity Probes
+Added: Multi-affinity probe discovery and development pipelines have been built that generate multi-affinity probe candidates that target short peptides, typically three amino acids in length.
+Added: These pipelines employ multiple candidate discovery methods to identify and select antibody, antibody fragment, or nucleic acid based candidate multi-affinity probes.
+Added: Promising candidates are
+Added: further screened in assays to determine EC50 values off-platform (example results for two candidate probes shown below), and then leads are evaluated in detail for their performance on the Nautilus proteome analysis platform.
+Added: Multi-Affinity Probe Discovery and Development Pipeline
+Added: Model Protein Decoding
+Added: Bringing multiple aspects of the platform together, we created a control sample library using model synthetic proteins that were designed to be multi-epitope controls to demonstrate the PrISM decoding method in action on the Nautilus platform.
+Added: A multi-cycle run was completed using 24 unique multi-affinity probes.
+Added: Shown below is the detection of Model Protein 1 (MP1) across two replicate datasets.
+Added: The relative count of MP1 identifications within the library was generated by decoding the pattern of binding events at each location present on the flow cell over the course of the multi-cycle run.
+Added: In the figure below, the observed binding events (yellow) for each cycle of multi-affinity probes matched the expected binding events unique to the MP1 epitopes present (top orange) vs the MP2 epitopes (bottom orange).
+Added: Model Protein 1 Decoded by PrISM
Mapping Proteoforms
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We do this by measuring individual proteins at each specific post-translational modification site over multiple cycles, each cycle targeting a different specific site or feature of the protein.
−Removed: For example in the diagram below, during the first cycle we use an EGFR affinity reagent to identify all of the EGFR proteins present on the flow cell.
−Removed: Then over the next 4 cycles we detect each EGFR molecule again, only now with a slightly different affinity reagent that targets each different location of a phosphorylation modification on the EGFR protein.
−Removed: Looking at this data together over 5 cycles, our technology is potentially able to distinguish up to 16 different proteoforms (in this case, different phosphorylated patterns) of the same EGFR protein and the quantity of each proteoform in a sample.
−Removed: We demonstrated this principle of proteoform detection by looking at three samples on our Nautilus platform.
−Removed: These three samples were designed from purified protein to detect different proteoforms of the same basic protein.
−Removed: The first sample was primarily a protein in Proteoform 1 form.
−Removed: The second sample was primarily a protein in a mix of Proteoform 1 and Proteoform 2 forms.
−Removed: The third sample was primarily a protein in Proteoform 2 form.
−Removed: As shown in the figure below, the Nautilus platform is not only able to both differentiate between these forms, but is also able to do so quantitatively and therefore determine how much of each proteoform is in each sample.
−Removed: Nautilus Platform Proteoform Pattern Detection and Quantitation
+Added: Illustrating this concept in the diagram below, during the first cycle we use an anti Tau affinity reagent to identify all of the Tau proteins present on the flow cell.
+Added: Then over the next 4 cycles we detect each Tau molecule again, only now with a slightly different affinity reagent that targets a different isoform or phosphorylation modification on the Tau protein.
+Added: Looking at this data together over 5 cycles, our technology is potentially able to distinguish up to 16 different proteoforms (in this case, different isoform and phosphorylated patterns) of the same Tau protein.
+Added: Workflow for the Detection of Tau Proteoform Patterns
+Added: The protein counts in the image above are for illustration purposes only.
+Added: Demonstrating this workflow in action, on a single chip we deposited positive control Tau proteins, a negative control (ubiquitin), and a mixture of four Tau proteoforms.
+Added: After correcting for non-specific binding and antibody false negative rates, we detected all four proteoforms in the complex mixture.
+Added: Over 500k molecules were analyzed.
+Added: Nautilus Platform Proteoform Pattern Detection
+Added: Further demonstrating the ability of this workflow to identify increasingly lower levels of Tau protein in complex mixtures, below recombinant 0N4R Tau (exogenously phosphorylated by the ERK2 kinase) was spiked in to a K562 cell lysate.
+Added: Tau was added at 0 (no spike control), 5%, 10%, or 20% of total protein.
+Added: Tau protein was then enriched by immunoprecipitation and detected with the Tau anti-0N antibody.
+Added: Detection of Low Tau Levels in a Cell Lysate Background
Nautilus Platform Development Plan Key Areas of Focus
−Removed: In order to achieve our goal of broad commercialization by the end of 2023 or beginning of 2024, we plan to advance the development of our Nautilus platform across all components including chemistries, reagents, consumables, instrumentation and analysis software.
+Added: In order to achieve our goal of broad commercialization by mid-2024, we plan to advance the development of our Nautilus platform across all components including chemistries, reagents, consumables, instrumentation and analysis software.
The prototype of our proteome analysis system has generated all of our internal data to date, and we are continuing the development process to optimize, improve upon, and validate the final designs, formulations, protocols, manufacturing processes, and software code comprising our Nautilus platform.
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Lastly, we intend to continue the development of our analysis software, where we expect improvements to our algorithms and analysis that will help with the speed, accuracy, and reliability of our commercial proteome analysis system performance.
−Removed: Assuming the completion of our development across these focal areas on our currently anticipated timeline, as well as additional related development activities, we believe we will be in position to achieve our goal of broad commercialization by the end of 2023 or beginning of 2024.
+Added: Assuming the completion of our development across these focal areas on our currently anticipated timeline, as well as additional related development activities, we believe we will be in position to achieve our goal of broad commercialization by mid-2024.
APPLICATIONS OF OUR TECHNOLOGY
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Because of this inherent flexibility, we also believe our Nautilus platform will spark the creation of new and unforeseen applications, in a similar market expansion and innovation trend that was experienced in the years following the launch of open and flexible NGS platform technologies.
−Removed: The open nature of the Nautilus platform creates the opportunity to partner with third-parties on the development and supply of affinity reagents.
−Removed: To that end, in the fourth quarter of 2021, we initiated a strategic partnership with Abcam, a world leader in the design and production of assay kits, reagents, and antibodies.
−Removed: This type of development and supply agreement is expected to provide us with antibodies additive to the affinity reagents we are creating internally and serves to highlight the flexible nature of our technology.
+Added: The open nature of the Nautilus platform creates the opportunity to partner with third-parties on the development and supply of affinity reagents for use on our instrument.
Basic Research and Discovery Applications
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A deeper level of detail and molecular complexity also clearly exists beyond the estimated 20,000 proteins in the human proteome, and we expect our customers to utilize proteoform specific reagents for the profiling, mapping, and characterization of post-translational modification patterns on proteins of interest.
−Removed: It is estimated there are as many as 6,000,000 different
−Removed: proteoforms produced through protein modification pathways that hold critical biological and contextual information on the function and purpose of the proteins in our cells.
−Removed: We believe our customers could show strong interest in this important field of research given the lack of technologies and tools in existence today capable of mapping multiple features on a single protein in one analysis workflow.
+Added: It is estimated there are as many as 6,000,000 different proteoforms produced through protein modification pathways that hold critical biological and contextual information on the function and purpose of the proteins in our cells.
+Added: We believe our customers could show strong interest in this important field of research given the lack of technologies and tools in existence today capable of mapping multiple features on a single protein in
+Added: one analysis workflow.
We believe discovery focused proteoform specific reagents could be used in combination with our multi-affinity broad protein detection method to enhance the output of our analyses.
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It has been published that approximately 95% of FDA-approved drug targets are proteins.
−Removed: Currently, FDA-approved drugs are targeting 812 separate human proteins and there are 4,514 genes in the UniProt database that have experimental evidence for being involved in disease.
+Added: The Human Protein Atlas collaborative research project identified that FDA-approved drugs are targeting up to 812 separate human proteins and that there are 4,514 genes in the UniProt database that have experimental evidence for being involved in disease.
We believe that the drug development and diagnostic industries have suffered from an inability to access the low frequency and rare proteins present in biological samples due to the tremendous dynamic range present across proteins in a specimen.
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Individual or small panel protein surveillance tools have existed in the healthcare market for decades using traditional assay methods across a range of biospecimen, all of which have the same inherent limitations as those in the research space.
−Removed: Also, cell-free nucleic acid methods have emerged recently as amongst the first molecular surveillance tools in oncology for the
−Removed: emergence of disease progression post treatment or surgery, and may also prove to enable the detection of disease at earlier stages in some cancers where cell-free nucleic acids are present at higher levels.
−Removed: However, the same fundamental challenges exist in this setting.
+Added: Also, cell-free nucleic acid methods have emerged recently as amongst the first molecular surveillance tools in oncology for the emergence of disease progression post treatment or surgery, and may also prove to enable the detection of disease at earlier stages in some cancers where cell-free nucleic acids are present at higher levels.
+Added: However, the same fundamental challenges
+Added: exist in this setting.
Nucleic acids are still only a proxy for measuring the biological consequences of the functional proteins, and further the sensitivity needed to find early-onset molecular features of disease before it presents clinically is incredibly high.
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Prior proteomic profiling technologies have struggled to make an impact in prospective clinical settings due to a lack of run-to-run data reproducibility, slow turn-around-time, and overall complexity of practical implementation.
−Removed: We believe our Nautilus platform design is ideally suited for the quality,
−Removed: stability, and speed required to fully realize the value of accessing deep proteomic profiling data to identify biomarkers that stratify patients for clinical trials and improve drug development.
−Removed: Our primary business model is anticipated to be focused on the commercialization of our Nautilus platform through the sale of instrumentation, consumables, and software.
−Removed: Our proteome analysis system is our detection instrument at the center of our product suite, supported by reagent consumables for the preparation and analysis of proteins, and followed by sophisticated machine learning software architecture for the analysis of our data in the cloud.
−Removed: Proteome Analysis System & Reagent Kits
−Removed: Our proteome analysis system is a high-resolution optical imaging sub-system coupled with an integrated fluidics sub-system in order to process multi-cycle labeled affinity reagent binding and imaging runs.
−Removed: System run reagent kits are comprised of two main components:
−Removed: the flow cell(s), and the affinity binding reagents used to perform multi-cycle analysis runs.
−Removed: Our initial flow cell design includes 4 physically separated and independent fluid channels, or “lanes”, such that a customer can introduce a unique biological sample in to each lane for multi-cycle analysis.
−Removed: Our proteome analysis system is designed to hold and concurrently analyze up to three flow cells in a single system run, for a total of 12 lanes.
−Removed: Additional sample throughput may also be achieved by the use of a molecular barcode in our reagent kits that will enable the multiplexing of more than one barcoded sample library together within a single lane for analysis.
−Removed: Our high-throughput multiplexed reagent kits are expected to support up to 24 samples per run, and may be further scaled in the future.
−Removed: Affinity binding reagents will also be included within each system run reagent kit.
−Removed: Reagent kits will be offered in configurations that cover a catalog of proteomic content desired by our customers by supplying different combinations of reagents together within a given kit.
−Removed: We intend to supply a standardized set of affinity binding reagents for the broad-scale detection of proteins, or “proteome kits”, as well as protein-specific or proteoform-specific reagent content sets, or “targeted proteoform kits”, focused on high interest areas of disease research.
−Removed: Additionally, custom affinity reagent labeling kits are expected to be supplied to enable customers to label their own in-house developed affinity reagents to be compatible with Nautilus chemistry for use on the system.
−Removed: Sample Preparation Kits
−Removed: Our proprietary sample preparation kits are expected to be intended for the isolation and library preparation of proteins from a variety of input materials including cell cultures, tissues and biospecimen.
+Added: We believe our Nautilus platform design is ideally suited for the quality, stability, and speed required to fully realize the value of accessing deep proteomic profiling data to identify biomarkers that stratify patients for clinical trials and improve drug development.
+Added: Our primary business model is anticipated to be focused on the commercialization of our Nautilus platform through the sale of instrumentation, reagent consumables, and software.
+Added: Our proteome analysis system is our detection instrument at the center of our product suite, supported by reagent consumables for the preparation and analysis of proteins, and followed by sophisticated machine learning software architecture for the analysis and reporting of our data in the cloud.
+Added: Proteome Analysis System
+Added: Our proteome analysis system is a high-resolution optical imaging system coupled with integrated fluidics and liquid handling sub-systems.
+Added: The system is designed to deposit protein libraries onto a flow cell and to process labeled multi-affinity probe binding and imaging cycles rapidly in order to decode and quantify the vast majority of proteins present in biological samples.
+Added: After the reagent kits, samples (protein libraries), and flow cells are loaded onto the system, the remainder of the workflow is automated.
+Added: System run reagent kits are comprised of four main components:
+Added: sample preparation, flow cell(s), multi-affinity probe reagents, and instrument buffers used to perform multi-cycle analysis runs.
+Added: Our proprietary sample preparation kits will be designed for the isolation and preparation of a library of proteins from a variety of input materials including cell cultures, tissues and biospecimen.
The library preparation includes an automatable workflow consisting of chemically labeling target proteins and attaching them to a scaffold used to deposit proteins on our flow cell.
−Removed: Given the breadth and depth of data output capability planned for our proteome analysis system, it is not expected that additional protein sample enrichment, enhancement or pre-treatments of samples will be required for processing, but we do intend to be compatible with such input materials.
−Removed: We also expect our customers and partners may intend to design their own custom process to target specific proteins prior to creating a library with them, and we intend to ensure our kits will be compatible with pre-treated or enriched protein samples.
+Added: Given the breadth and depth of data output capability planned for our proteome analysis system, it is not expected that additional protein sample enrichment, enhancement or pre-treatments of samples will be required for processing, however we do intend to be compatible with such pre-treated samples.
+Added: We also expect our customers and partners may wish to design their own custom process to target specific proteins prior to creating a library with them, and we intend to ensure our kits will be compatible with pre-treated or enriched protein samples.
Our protein library preparation process is designed to be simple, efficient, and robust, all features which are expected to allow for easy automated processing for high throughput applications.
+Added: In an effort to provide maximum flexibility, our initial flow cell design includes four physically separated and independent fluid channels, or “lanes,” such that a customer can introduce a unique biological sample in to each lane for multi-cycle analysis.
+Added: Our proteome analysis system is designed to hold and concurrently analyze up to three flow cells in a single system run, for a total of 12 lanes.
+Added: Additional sample throughput may also be achieved by the use of a molecular barcode in our reagent kits that will enable the multiplexing of more than one barcoded sample library together within a single lane for analysis in the future.
+Added: Affinity binding reagents will also be included as a reagent kit.
+Added: Kits will be offered in configurations that cover a catalog of proteomic content.
+Added: We intend to supply a standardized set of multi-affinity probe reagents for the broadscale detection of proteins, or “proteome kits,” as well as protein-specific or proteoform-specific kits, or “targeted proteoform kits,” focused on high interest protein targets in key disease areas.
+Added: Additionally, custom affinity reagent labeling kits are expected to be supplied in the future to enable customers to label their own in-house developed or purchased affinity reagents to be compatible with Nautilus workflows for use on the system.
Software & Analysis
−Removed: Our machine learning protein identification analysis software suite also is expected to be utilized as the secondary analysis engine to decode the proteome analysis system raw data.
−Removed: Our software is expected to be a SaaS based service, utilizing Nautilus’ machine learning computational algorithms required to identify and quantify the proteins or proteoforms present on the system run.
−Removed: Our software is a learning and evolving system, which we are designing to improve in accuracy over time as the protein feature profiles are refined and trained across a growing database and our software has demonstrated this potential ability in our internal tests.
+Added: Our machine learning analysis software suite also is expected to be utilized as the analysis engine to decode the proteome system raw data into protein identifications and counts.
+Added: Our software is expected to be a SaaS based service, utilizing Nautilus’ machine learning computational algorithms required to identify and quantify the proteins or proteoforms present in a sample run on the system.
+Added: Our software is a learning and evolving system, which we are designing to improve in accuracy over time as the multi-affinity probe binding profiles are refined and trained across a growing database.
We expect our software enhancements in performance will also be accessible to customers who wish to re-analyze prior run data with later versions to deliver new insight and discovery value.
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the ongoing sale of consumables covering a broad suite of applications run on our system;
−Removed: a SaaS analytics and insights software subscription to
−Removed: capture long term value created by our machine learning-based analysis enhancements;
+Added: a SaaS analytics and insights software subscription to capture long term value created by our machine learning-based analysis enhancements;
and a service warranty plan to maintain our install base and support our customers in the field.
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We expect many of our customers will already have high complexity molecular analysis laboratories which include high throughput proteomic or genomic analysis capabilities on site.
−Removed: These customers represent a segment of the greater than 16,000 system install base of mass spectrometry detection systems already in use, many of which are dedicated to proteomic analyses.
+Added: We believe these customers represent a segment of the greater than 16,000 system install base of mass spectrometry detection systems already in use, many of which are dedicated to proteomic analyses.
Our early customers are expected to include large pharma and biotech research groups, sophisticated proteomic translational research laboratories in academia, and large-scale commercial and academic multi-omics research laboratories.
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Our strategy to utilize our Nautilus platform early in its formal development cycle through partnerships is an important component, and in part can be attributed to the inherent flexibility we have to employ commercially available reagents for targeted applications of single-molecule proteomics that drive new and significant discovery value.
−Removed: Further, as we advance from low-cycle targeted applications towards longer runs with increasing data output, we believe each of the milestones on our development plan are potentially new and unprecedented advancements we can leverage to build commercial momentum.
−Removed: Aligning Go-to-Market Strategy with Research and Development Milestones
+Added: Further, as we advance from low-cycle targeted applications towards longer runs with increasing data output, we believe each
+Added: of the milestones on our development plan are potentially new and unprecedented advancements we can leverage to build commercial momentum.
+Added: Aligning Go-to-Market Strategy with Research and Development Milestone
Collaborations & Partnerships
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Proteome Analysis System Launch and Commercial Scale Up
−Removed: At full commercial proteome analysis system launch, we expect to continue offering our Proteomic Data Early Access Program, and to maintain the laboratory services to continue supporting POC and pilot projects for an extended period of time
−Removed: to continue building our sales funnel.
+Added: At full commercial proteome analysis system launch, we expect to continue offering our Proteomic Data Early Access Program, and to maintain the laboratory services to continue supporting proof of concept and pilot projects for an extended period of time to continue building our sales funnel.
Our proteome analysis system launch is expected to be coupled with a substantial scale up of our commercial sales and marketing workforce.
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• Implementing a proven commercial model with an efficient direct salesforce;
−Removed: • Expanding our impact into clinical applications, precision medicine and diagnostics.
+Added: • Expanding our impact in translational research for clinical applications, precision medicine and diagnostics.
In December of 2020, we signed a research collaboration agreement with Genentech to engage in a pilot study using our technology.
−Removed: This partnership is consistent with our objectives in Phase I of our commercial go-to-market strategy to build external collaborations and relationships that produce data and publications based on the application of our Nautilus platform technology to deliver a meaningful biological insight.
We are collaborating with Genentech using our proteome analysis system to analyze and map the proteoform landscape of a Genentech protein target of interest.
−Removed: We aim to submit results for publication in early 2022.
−Removed: In October 2021, we entered into a research collaboration agreement with Amgen in which the Nautilus platform will be used across a number of projects to investigate proteins and proteoforms of interest to the Company.
−Removed: Also in October 2021, we signed a research agreement with The University of Texas MD Anderson Cancer Center.
−Removed: The Nautilus platform will be applied in measuring the quantity and patterns of post-translational modifications on specific oncology protein targets of interest across different settings, such as pre- and post treatment.
+Added: In October 2021, we entered into a research collaboration agreement with Amgen in which the Nautilus platform will be used across a number of projects to investigate proteins and proteoforms of interest to the both organizations.
+Added: In October 2021, we signed a research agreement with The University of Texas MD Anderson Cancer Center.
+Added: In this research collaboration the Nautilus platform will be applied in measuring the quantity and patterns of post-translational modifications on specific oncology protein targets of interest across different settings, such as pre- and post treatment.
+Added: And, in January of 2023, we entered into a research collaboration with the Translational Genomics Research Institute, which is a Phoenix, Arizona-based nonprofit organization dedicated to conducting groundbreaking research with life-changing results.
+Added: Translational Genomics Research Institute is part of City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases.
+Added: All of the above research collaborations are consistent with our objectives in Phase I of our commercial go-to-market strategy to establish external collaborations and relationships that produce data and publications exploring the utility and strengths of our Nautilus platform technology.
Commercial Organization
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We currently source base nanoarray chips and flow cell components, sample preparation and assay reagents.
−Removed: We believe that our suppliers have sufficient capacity to meet our near-term development needs through to commercialization.
+Added: We believe that our suppliers have sufficient
+Added: capacity to meet our near-term development needs through to commercialization.
We believe it may be advantageous to have multiple sources for our consumable components and reagents in the future, to help reduce the risk of production delays or quality issues that may cause a disruption to our development timelines or pre-commercial activities.
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The current system is an early-stage design, used for optimization of the function and design of each component.
−Removed: We currently source components for our systems from external manufacturers and assemble them in-house at our San Carlos, CA facility.
+Added: We currently source components for our systems from external manufacturers and assemble them in-house at our San Carlos, CA facility or at our manufacturing partner facilities.
Once development is completed, we will determine the most appropriate path for high volume production.
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GOVERNMENT REGULATION
−Removed: The development, testing, manufacturing, marketing, post-market surveillance, distribution, advertising and labeling of certain of medical devices are subject to regulation in the United States by the Center for Devices and Radiological Health of the U.S.
+Added: The development, testing, manufacturing, marketing, post-market surveillance, distribution, advertising and labeling of certain medical devices are subject to regulation in the United States by the Center for Devices and Radiological Health of the U.S.
Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act (FDC Act) and comparable state and international agencies.
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Not for use in diagnostic procedures.” – the regulations do not subject such products to the FDA’s jurisdiction or the broader pre- and post-market controls for medical devices.
−Removed: In November 2013, the FDA issued a final guidance on products labeled RUO, which, among other things, reaffirmed that a company may not make any clinical or diagnostic claims about an RUO product, stating that merely including a labeling statement that the product is for research purposes only will not necessarily render the device exempt from the FDA’s clearance, approval, or other regulatory requirements if the totality of circumstances surrounding the distribution of the product indicates that the manufacturer knows its product is being used by customers for diagnostic uses or the manufacturer intends such a use.
+Added: In November 2013, the FDA issued a final guidance on products labeled RUO, which, among other things, reaffirmed that a company may not make any clinical or diagnostic claims about an RUO product, stating that merely including a labeling statement that the product is for research purposes only will not necessarily render the device exempt from the FDA’s clearance, approval, or other regulatory requirements if the totality of circumstances surrounding the distribution of the product
+Added: indicates that the manufacturer knows its product is being used by customers for diagnostic uses or the manufacturer intends such a use.
These circumstances may include, among other things, written or verbal marketing claims regarding a product’s performance in clinical diagnostic applications and a manufacturer’s provision of technical support for such activities.
−Removed: If FDA were to determine, based on the totality of circumstances, that our products labeled and marketed for RUO are intended for diagnostic purposes, they would be considered medical devices that will require clearance or approval prior to
−Removed: commercialization.
+Added: If FDA were to determine, based on the totality of circumstances, that our products labeled and marketed for RUO are intended for diagnostic purposes, they would be considered medical devices that will require clearance or approval prior to commercialization.
Further, sales of devices for diagnostic purposes may subject us to additional healthcare regulation.
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However, on October 3, 2014, the FDA issued two draft guidance documents that set forth the FDA’s proposed risk-based framework for regulating LDTs, which are designed, manufactured, and used within a single laboratory.
−Removed: In January 2017, the FDA announced that it would not issue final
−Removed: guidance on the oversight of LDTs and LDT manufacturers, but would seek further public discussion on an appropriate oversight approach and give Congress an opportunity to develop a legislative solution.
+Added: In January 2017, the FDA announced that it would not issue final guidance on the oversight of LDTs and LDT manufacturers, but would seek further public discussion on an appropriate oversight approach and give Congress an opportunity to develop a legislative solution.
More recently, the FDA has issued warning letters to genomics labs for illegally marketing genetic tests that claim to predict patients’ responses to specific medications, noting that the FDA has not created a legal “carve-out” for LDTs and retains discretion to take action when appropriate, such as when certain genomic tests raise significant public health concerns.
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International sales of medical devices are subject to foreign government regulations, which vary substantially from country to country.
−Removed: In the future, if we decide to distribute or market our diagnostic products as IVDs in Europe, such products will be subject to regulation under the European Union (EU) IVD Directive and/or the IVD Medical Device Regulation (IVDR) European Union (EU) 2017/746.
−Removed: The IVDR was published in 2017, will replace the IVD Directive, is significantly more extensive than the IVD Directive, including requirements on performance data and quality system, and will become fully enforceable in 2022.
−Removed: Outside of the EU, regulatory approval needs to be sought on a country-by-country basis in order to market medical devices.
+Added: In the future, if we decide to distribute or market our diagnostic products as IVDs in Europe, such products will be subject to regulation under the IVD Medical Device Regulation (IVDR) European Union (EU) 2017/746.
+Added: The EU IVDR was entered into application on May 26, 2022, which replaced the IVD Directive and aims to improve the quality, safety and reliability of in vitro diagnostic medical devices with a new risk-based device classification system, provide for more detailed and stringent rules on the evaluation of device performance, and to enhance vigilance and post-market surveillance, among other changes.
+Added: Outside of the EU, regulatory authorization needs to be sought on a country-by-country basis in order to market medical devices.
Although there is a trend towards harmonization of quality system, standards and regulations in each country may vary substantially which can affect timelines of introduction.
−Removed: As part of the Trump Administration’s efforts to combat COVID-19 and consistent with President Trump’s direction in Executive Orders 13771 (Executive Order on Reducing Regulation and Controlling Regulatory Costs) and 13924 (Executive Order on Regulatory Relief to Support Economic Recovery), the Department of Health and Human Services (HHS) announced rescission of guidance and other informal issuances of the FDA regarding premarket review of LDT absent notice-and-comment rulemaking, stating that, absent notice-and-comment rulemaking, those seeking approval or clearance of, or an emergency use authorization, for an LDT may nonetheless voluntarily submit a premarket approval application, premarket notification or an Emergency Use Authorization request, respectively, but are not required to do so.
−Removed: Although the Biden administration has not taken affirmative steps to rescind this announcement issued by the previous administration, this 2020 HHS policy statement is no longer posted on the HHS website.
−Removed: Further, Congress has recently proposed legislation to create a new LDT and in vitro diagnostic regulatory framework for all in vitro clinical tests that would be separate and distinct from the existing medical device regulatory framework.
−Removed: In June 2021, members of the U.S.
−Removed: House of Representatives formally introduced the VALID Act (Verifying Accurate Leading-edge IVCT Development Act of 2021) and an identical version of the bill was introduced in the U.S.
−Removed: If passed, the VALID Act would create a new category of medical products separate from medical devices called “in vitro clinical tests,” or IVCTs, and bring all such products within the scope of FDA’s oversight.
−Removed: It is unclear whether the VALID Act or any other legislative proposals would be passed by Congress or signed into law by the President.
−Removed: Any restrictions on LDTs by the FDA, HHS, Congress, or state regulatory authorities may decrease the demand for our products.
−Removed: The adoption of new restrictions on RUOs, whether by the FDA or Congress, could adversely affect demand for our specialized reagents and instruments.
+Added: In August 2020, the Department of Health and Human Services, or HHS, announced rescission of guidance and other informal issuances of the FDA regarding premarket review of LDT absent notice-and-comment rulemaking, stating that, absent notice-and-comment rulemaking LDTs are not required to obtain FDA premarket authorization.
+Added: In November 2021, HHS under the Biden administration issued a statement that withdrew the August 2020 policy announcement stating that HHS does not have a policy on LDTs that is separate from the FDA’s longstanding approach.
+Added: Legislative and administrative proposals to amend the FDA's oversight of LDTs have been introduced in recent years, including the Verifying Accurate Leading-edge IVCT Development Act of 2021 (VALID Act), which aims to create a new category of medical products separate from medical devices called “in vitro clinical tests,” or IVCTs, and bring all such products within the scope of the FDA’s oversight.
+Added: To date, Congress has not passed the VALID Act, but may revisit the VALID Act or similar policy riders and enact other FDA programmatic reforms in the future.
+Added: It is unclear how future legislation by federal and state governments and FDA regulation will impact the industry, including our business and that of our customers.
In the future, to the extent we develop any clinical diagnostic assays, we may pursue payment for such products through a diverse and broad range of channels and seek coverage and reimbursement by government health insurance programs and commercial third-party payors for such products.
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The federal Health Insurance Portability and Accountability Act of 1996 (HIPAA), as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 (HITECH), and their implementing regulations, which impose obligations, including mandatory contractual terms, with respect to safeguarding the transmission, security and privacy of protected health information by covered entities subject to HIPAA, such as health plans, health care clearinghouses and healthcare providers, and their respective business associates that access protected health information.
−Removed: HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business
−Removed: associates in some cases, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.
+Added: HITECH also created
+Added: new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates in some cases, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.
In addition, in the U.S., numerous federal and state laws and regulations, including state data breach notification laws, state health information privacy laws, and federal and state consumer protection laws, govern the collection, use, disclosure, and protection of health-related and other personal information.
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We strive to obtain and maintain intellectual protection for our products and technology by using a variety of intellectual protection strategies, such as patents, trademarks, trade secrets and other methods of protecting proprietary information.
−Removed: As of December 31, 2021, we owned four issued U.S.
−Removed: patents, approximately twenty pending U.S.
−Removed: non-provisional patent applications, approximately fourteen pending U.S.
−Removed: provisional patent applications, and approximately forty-two pending foreign patent applications, including four international patent applications filed under the Patent Cooperation Treaty (PCT application).
−Removed: Our owned patents and patent applications, if issued, are expected to expire between 2037 and 2042, in each case absent any patent term adjustments or extensions and assuming payment of all appropriate maintenance, renewal, annuity, or other governmental fees.
+Added: As of December 31, 2022, we owned eight issued U.S.
+Added: patents, approximately twenty-nine pending U.S.
+Added: non-provisional patent applications, approximately twenty-two pending U.S.
+Added: provisional patent applications, and approximately fifty-five pending foreign patent applications, including twelve international patent applications filed under the Patent Cooperation Treaty (PCT application).
+Added: Our owned patents and patent applications, if issued, are expected to expire between 2037 and 2043, in each
+Added: case absent any patent term adjustments or extensions and assuming payment of all appropriate maintenance, renewal, annuity, or other governmental fees.
Our solely owned patents and patent applications contain, among others, claims directed to our core platform technology, such as compositions, methods, and systems directed to identifying and quantifying proteins utilizing probes that can bind different epitopes of the proteins with different degrees of binding non-specificity;
reagents and materials;
+Added: arrays and other consumables;
sample preparation;
−Removed: and high throughput decoding algorithms amongst other things.
+Added: high throughput decoding algorithms, and algorithms for secondary analysis of proteins and proteomes, amongst other things.
Trade Secrets
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As of December 31, 2022, we owned approximately six registered trademarks in China, the United Kingdom, and Europe.
−Removed: In addition, we have three pending trademark applications in the U.S., China and Canada.
+Added: In addition, we have seven pending trademark applications in the U.S., Australia, Brazil, Canada, China, the European Union, India, Israel, Japan, Korea, Mexico, Singapore, Switzerland, and the United Kingdom.
Collaboration Agreements
−Removed: We have entered into research collaboration agreements with Genentech in December 2020, with Amgen in October 2021, and with The University of Texas MD Anderson Cancer Center in October 2021.
+Added: We have entered into research collaboration agreements with Genentech in December 2020, with Amgen in October 2021, with The University of Texas MD Anderson Cancer Center in October 2021, and with Translational Genomics Research Institute in January 2023.
Under each of these agreements, respective research collaboration teams are using the Nautilus platform to analyze and map proteoforms of interest to the specific collaborator.
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Employees and Human Capital
−Removed: As of December 31, 2021, we had 113 employees, all based in the United States, many of whom hold doctorate degrees.
+Added: As of December 31, 2022, we had 134 employees, all based in the United States, 51 of whom hold doctorate degrees.
Of these employees, 95 were engaged in research and development activities, and 39 were engaged in general and administrative activities.
3 unchanged sentences
Corporate and Available Information
+Added: We were incorporated as a Cayman Islands exempted company in March 2020 as a blank check company under the name ARYA Sciences Acquisition Corp III.
+Added: On June 9, 2021, we consummated the Business Combination pursuant to the terms of the Business Combination Agreement.
+Added: Pursuant to the terms of the Business Combination Agreement, on the Closing Date, (i) we changed our jurisdiction of incorporation by deregistering as a Cayman Islands exempted company and continuing and domesticating as a corporation incorporated under the laws of the State of Delaware, upon which we changed our name to Nautilus Biotechnology, Inc.
Our principal executive offices are located at 2701 Eastlake Avenue East Seattle, Washington, 98102, and our telephone number is (206) 333-2001.
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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.