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Approximately 95% of FDA-approved drug targets are proteins, and yet today we still lack the ability to routinely read and quantify all of the proteins in our cells, or to fully map the downstream changes and modifications to those proteins which may define their biological function.
−Removed: By leveraging our novel design coupled with advanced machine learning software, we believe our Nautilus platform, which includes our end-to-end solution comprised of the proteome analysis system, consumables, and software, has the potential to rapidly and reproducibly identify up to approximately 95% of proteins in a sample from virtually any organism, and could have the ability to detect and map the diverse landscape of modifications on those proteins.
+Added: By leveraging our novel platform design coupled with advanced machine learning software, we believe our Nautilus platform, which includes our end-to-end solution comprised of the proteome analysis system, consumables, and software, has the potential to rapidly and reproducibly identify up to approximately 95% of proteins in a sample from virtually any organism, and could have the ability to detect and map the diverse landscape of modifications on those proteins.
We believe that unlocking proteomics has the potential to create a long-term transformation of basic science, translational research, and healthcare.
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For years, these methods have facilitated novel drug development and improved diagnostics.
−Removed: As with most technology platforms however, these also suffer from distinct limitations that make
−Removed: simple, high-throughput, ultra-deep characterization of the proteome challenging.
+Added: As with most technology platforms however, these also suffer from distinct limitations that make simple, high-throughput, ultra-deep characterization of the proteome challenging.
Mass spectrometry approaches have tremendous flexibility and thus have been applied to a wide range of applications, however their use requires a trade-off to be made between either depth or throughput;
meaning that a researcher can either look at one sample in a deep analysis or at many samples in a shallow analysis.
−Removed: Additionally, challenges in ease of use and sensitivity have limited the ability of mass spectrometry-based methods from easily, broadly and quickly characterizing the entirety of the proteome.
−Removed: Affinity-based approaches use the binding attraction of antibodies to proteins to capture and measure protein targets in parallel.
−Removed: These technologies can provide greater sensitivity, however this approach is directly dependent on the availability of high quality, highly specific and sensitive affinity reagents, which can limit the scale, reproducibility and accuracy.
+Added: Additionally, challenges in operational complexity and sensitivity have limited the ability of mass spectrometry-based methods from easily, comprehensively, and quickly characterizing the entirety of the proteome.
+Added: Affinity-based approaches use the binding attraction of antibodies to proteins to capture and measure protein targets.
+Added: Many of these legacy technologies measure only a single-target, or are multiplexed to cover a few specific protein targets per reaction.
+Added: Newer technologies have further expanded their multiplexing capability by using a next-generation sequencing readout.
+Added: However, affinity-based proteomics is inherently dependent on the availability of high quality, specific and sensitive affinity reagents, which can impact scalability, reproducibility and accuracy.
Consequently, we believe researchers are forced into an unattractive trade-off between the number of samples in a study and the depth and breadth of the analysis.
These trade-offs limit researchers’ ability to advance characterization of the proteome to match the current, and highly valuable, characterization of the genome.
−Removed: We believe the limitations of both platforms have prevented progress towards achieving comprehensive proteome and deep proteoform characterization.
+Added: We believe the limitations of both mass spectrometry and affinity-based technologies have prevented progress towards achieving comprehensive proteome characterization, including measurement of the many known modifications to proteins.
If detecting and quantifying the complexity of the human proteome were as simple and easy as detecting an entire human genome, we believe a new set of questions could be asked:
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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, The University of Texas MD Anderson Cancer Research Center, and the Translational Genomics Research Institute, among others.
−Removed: In the second phase we plan to launch an early access program to an expanded group of customers.
−Removed: We believe these customers will become important reference sites and key influencers that aid in the market adoption of our Nautilus platform, and will help us build a strong value proposition ahead of full commercial launch.
+Added: As of the date of filing this Annual Report, we have research collaborations with Genentech, Amgen, The University of Texas MD Anderson Cancer Research Center, and The Buck Institute for Research on Aging.
+Added: In the second phase of our product development and commercialization we plan to launch an early access program offering more standardized applications to an expanded group of collaborators.
+Added: We believe this growing group of collaborators will become important reference sites and key influencers that will aid in the market adoption of our Nautilus platform, and will help us build a strong value proposition ahead of full commercial launch.
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 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 future 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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Our management team also brings a unique combination of experiences from the fields of technology and life sciences, with a proven track record of building successful businesses based on novel technology.
−Removed: Our company is a highly interdisciplinary organization, and as of December 31, 2023 we were comprised of approximately 167 employees, with 59 of such employees holding a Ph.D.
+Added: Our company is a highly interdisciplinary organization with deep subject matter expertise across scientific disciplines in chemistry, molecular biology, physics and bioinformatics, and as of December 31, 2024 over one-third of our employees have a Ph.D.
Our organization is driven by the pursuit of deep, hard science, and our Scientific Advisory Board is comprised of world-renowned scientific leaders that support our vision.
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• Highly disruptive proteomics technology.
−Removed: Our Nautilus proteome analysis platform is designed to be a disruptive, single protein molecule analysis technology of extreme sensitivity, scale, and ease-of-use.
−Removed: Leveraging a novel system architecture, advanced machine learning and algorithms, we believe our Nautilus platform has the potential to identify substantially all proteins in a sample from almost any organism.
−Removed: We have designed our Nautilus platform technology by substantially reimagining methods of protein analysis, rather than an incremental or evolutionary advancement.
−Removed: We refer to Nautilus’ framework for what we believe to be a fundamentally different approach to protein analysis as Protein Identification by Short-epitope Mapping (PrISM).
−Removed: We believe that the prototype of our Nautilus proteome analysis system has also demonstrated the ability to detect the patterns of modifications made to proteins, while preserving the context of those modifications on the molecule where they exist, a capability that we do not believe is possible with existing affinity-based or shotgun mass spectrometry-based methods.
+Added: Our Nautilus proteome analysis platform is designed to be a completely novel, single protein molecule analysis technology of extreme sensitivity, high throughput, and ease-of-use.
+Added: Leveraging a scalable and flexible system architecture, advanced machine learning and algorithms, we believe our Nautilus platform has the potential to identify substantially all proteins in a sample from almost any organism.
+Added: We also believe that by measuring single intact protein molecules, our platform has a highly differentiated and unique ability to also detect and quantify combinations and patterns of post-translational modifications, which are strongly suspected to be critical drivers of biology and have been largely invisible to legacy technologies to date.
• Novel end-to-end proteomics detection platform of extreme sensitivity.
−Removed: 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.
+Added: We aim to be the first commercially available proteomics detection platform technology and end-to-end solution to decode and quantify approximately 95% of the entire proteome, including the variations and modifications of proteins.
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.
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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.
−Removed: 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: Our platform is currently 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.
This design is also highly compatible with molecular barcoding, which may be introduced in the future to multiplex increasingly larger sample numbers per run.
−Removed: 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.
−Removed: 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.
+Added: Further, with the introduction of an affinity reagent labeling kit, our platform is also designed to be able to incorporate off-the-shelf affinity 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 reagent probes 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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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.
−Removed: As the proteomics
−Removed: 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.
+Added: 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.
• Our experienced, multidisciplinary team brings together a group of individuals with diverse backgrounds to disrupt the field of proteomics.
Nautilus’ leadership team represents a unique and valuable hybrid of technology and biotech experience.
−Removed: Several members of the executive team and board of directors held leadership roles at Illumina and Isilon, and helped to guide strategy and manage execution both before and throughout the rapid growth and success for those businesses.
+Added: Several members of the executive team and board of directors held leadership roles at Illumina, Agilent Technologies, and Isilon, and helped to guide strategy and manage execution both before and throughout the rapid growth and success for those
We view the core design thesis behind the Nautilus platform technology development as a non-traditional approach to new product development within life sciences that requires thinking at the intersection of three unique disciplines not often found together—life sciences, computer and data sciences, and physical sciences and engineering.
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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.
−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, 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.
+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 and The Buck Institute for Research on Aging, and others) and research organizations where we aim to jointly publish data utilizing the first versions of 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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• 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.
−Removed: Our Nautilus platform is compatible with a wide variety of protein affinity binding reagents, which we believe will allow us to create a broad menu of applications compatible with our technology.
+Added: Our Nautilus platform is compatible with a wide variety of protein affinity reagents, which we believe will allow us to create a broad menu of applications compatible with our technology.
Our Nautilus platform is also designed to be highly customizable, which we believe will allow us to create an infrastructure that enables our customers to design their own custom solutions and applications.
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We recognize that these opportunities extend into ancillary markets across life sciences, including clinical and translational research, and clinical diagnostics, where we believe there are substantial unmet needs our Nautilus platform can address in the future.
−Removed: We expect to drive expansion into these adjacent markets by developing and validating new product configurations and workflows targeting high impact applications, either by
−Removed: adapting our existing workflows or by partnering with leaders in those markets to develop workflows that address their immediate needs and will provide broader general value for other customers in that market segment.
+Added: We expect to drive expansion into these adjacent markets by developing and validating new product configurations and workflows targeting high impact applications, either by adapting our existing workflows or by partnering with leaders in those markets to develop workflows that address their immediate needs and will provide broader general value for other customers in that market segment.
A PRIMER ON PROTEOMICS
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Despite such investments, the number of new drugs approved each year has failed to increase proportionally.
−Removed: Additionally, it takes more than 10 years to bring a drug to market, and the cost has grown significantly in the past decade from approximately $1.2 billion in 2010 to approximately $2.0 billion in 2019.
+Added: It can take more than 10 years to bring a drug to market, and the cost has grown significantly in the past decade from approximately $1.2 billion in 2010 to approximately $2.0 billion in 2019.
The increasing cost, time and complexity of drug development have driven down the rate of return on R&D to less than 2% in 2019 for the 12 leading biopharmaceutical companies analyzed in a 2020 report by the Deloitte Center for Health Solutions.
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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 currently only approximately 168 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 only approximately 180 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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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 BCC Research, the global proteomics market was valued at approximately $27 billion as of 2022.
+Added: According to BCC Research, the global proteomics market was valued at
+Added: 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.
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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 researcher.
+Added: Affinity-based protein detection commonly utilizes affinity 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.
−Removed: Lastly, affinity-based approaches intended to target more than one protein at once in a sample commonly require a different affinity binding reagent for each target.
+Added: Lastly, affinity-based approaches intended to target more than one protein at once in a sample commonly require a different affinity reagent for each target.
Despite decades of ongoing efforts, there are still nowhere near the number of affinity reagents in existence today to attempt to measure the full proteome.
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We have designed the Nautilus platform to enable extreme sensitivity and scale, without compromising on ease of use.
−Removed: 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: 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.
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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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
−Removed: in-lane sample multiplexing to enable our customers to meet the high-volume data production needs of large-scale studies or core facilities.
+Added: 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.
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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An Integrated Multi-cycle Optical and Fluidics Instrument
−Removed: A Novel Class of Affinity Reagents for Efficient Whole Proteome Analysis
+Added: A Novel Class of Affinity Reagent Probes for Efficient Whole Proteome Analysis
Machine Learning Protein Decoding Analytics
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If one is able to identify each protein molecule, quantification arises simply from counting those identifications, and furthermore, single protein molecule counters are by definition the most sensitive detection modalities available.
−Removed: To break through these barriers, we have designed our Nautilus platform to measure billions of individual protein molecules at a time, in a massively parallel and efficient workflow.
−Removed: We refer to Nautilus’ framework for what we believe to be a fundamentally different approach to protein analysis as Protein Identification by Short-epitope Mapping (PrISM).
−Removed: Our internal testing has demonstrated that our hyper-dense single-molecule protein nanoarray contains 10 billion landing pads.
+Added: To break through these barriers, we have designed our Nautilus platform with a fundamentally different approach:
+Added: to measure billions of individual protein molecules at a time, in a massively parallel and efficient workflow.
+Added: Our internal testing has demonstrated that our hyper-dense single-molecule protein nanoarrays contain over 3 billion landing pads per chip.
Our team has developed a process for manufacturing our nanoarray as the foundational component of our flow cell consumable.
The flow cell itself is comprised of a nanometer-scale fabricated chip that holds the individual protein molecules in place on the surface in a landing pad, encapsulated by a fluidics channel that allows for reagents to flow across the surface.
−Removed: Our design includes the isolation of individual proteins in a protein library preparation by binding them to a much larger scaffold which has been created to hold exactly one protein molecule.
−Removed: 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.
+Added: Our design includes the isolation of individual proteins in a protein library preparation by binding them to a much larger nanoparticle scaffold which has been created to hold exactly one protein molecule.
+Added: These nanoparticle 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.
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).
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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 approximately 95% of the proteome.
−Removed: Nautilus Platform Multi-Cycle Affinity Probe Reagent Binding, Imaging, Washing, and Re-Binding
+Added: Nautilus Platform Multi-Cycle Affinity Reagent Probe 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.
−Removed: Our affinity reagents are labeled with proprietary fluorescent labels that help improve both the signal-to-noise and speed of our assay chemistry.
−Removed: The instrument introduces labeled affinity reagents into our flow cell, allowing them to briefly incubate, then rinse off unbound molecules, and then rapidly images the entire surface.
+Added: Our affinity reagent probes are labeled with proprietary fluorescent labels that help improve both the signal-to-noise and speed of our assay chemistry.
+Added: The instrument introduces labeled affinity reagent probes into our flow cell, allowing them to briefly incubate, then rinse off unbound molecules, and then rapidly images the entire surface.
During the imaging process, a laser system is used to excite and illuminate the fluorescent labels.
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A typical full scale proteome run will generate approximately 35 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 Multi-Affinity Probe Reagents for Efficient Whole Proteome Analysis
−Removed: 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.
−Removed: Historically, affinity binding reagents have been qualified for use based on their specificity to a given protein target, and showing the ability to bind strongly to that specific target.
+Added: Multi-Cycle Binding and Detection using Affinity Reagent Probes Enables an Entirely New Way to Detect Proteins and their Modifications
+Added: Our Nautilus platform technology is designed with fundamentally different principles of how to use and exploit the properties of affinity reagents compared to prior methods.
+Added: Historically, affinity reagents have been qualified for use based on their specificity to a given protein target, and showing the ability to bind strongly to that specific target.
In order to see and measure a single protein target, a researcher would require an affinity reagent of sufficient specificity to detect it.
−Removed: These high specificity affinity reagents are commonly used for bulk measurements, and are typically only used for one single bulk measurement event (or cycle) and then discarded.
−Removed: By using these same high specificity reagents in our system, we believe it is possible to detect each specific protein target now at the single-molecule level, enabling digital quantitation.
+Added: These higher specificity affinity reagents are commonly used for bulk measurements, and are typically only used for one single bulk measurement event (or cycle) and then discarded.
+Added: By using these same high specificity reagents in our multi-cycle system, we believe it is possible to detect each specific protein target now at the single-molecule level, enabling digital quantitation.
We further believe it is possible to expand this concept, and use our Nautilus platform with a wide variety of “off-the-shelf” affinity reagents that are highly specific to multiple individual protein targets.
Also and of particular importance, is these off-the-shelf affinity reagents can often also target very specific sites on the protein itself, such as post-translational modification sites.
−Removed: Using reagents that target very specific locations and features of proteins will allow the Nautilus platform to detect and quantify the different patterns and varieties of post-translational modifications (i.e.
+Added: Using affinity reagent probes that target very specific locations and features of proteins will allow the Nautilus platform to detect and quantify the different patterns and varieties of post-translational modifications (i.e.
the proteoforms).
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Identifying the tens-of-thousands of different proteins in a proteome would require a prohibitively large 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 probes and binds to many different proteins that contain the short linear epitope target, each we describe as a “multi-affinity probe”.
−Removed: 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.
−Removed: 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.
−Removed: 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 probes.
−Removed: Nautilus Platform Technology Protein Identification with Increasing Multi-Affinity Probe Cycles
+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 binding reagent probes and binds
+Added: to many different proteins that contain the short linear epitope target, each we describe as a “multi-affinity reagent probe”.
+Added: While the binding of a single multi-affinity reagent probe is not sufficient to identify a given protein, sequential binding events using a series of multi-affinity reagent 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 reagent probe that is introduced in a cycle of binding and imaging provides additional evidence and gradually narrows the list of possible protein identities.
+Added: Hereafter, we refer to this approach as Protein Identification by Short-epitope Mapping (PrISM).
+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 reagent probes.
+Added: Nautilus Platform Technology Protein Identification with Increasing Multi-Affinity Reagent Probe Cycles
A theoretical framework for proteome-scale single-molecule protein identification using multi-affinity protein binding reagents.
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Among the most unique aspects of our Nautilus platform is the integration of a proprietary machine learning-based protein identification analysis software engineered to work with the type of data our system generates.
−Removed: 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 therefore an exceedingly large number of cycles to measure every protein in the proteome.
−Removed: 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 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.
+Added: As discussed, more typical measurements for high specificity affinity reagent probes can be used in our system to identify, and thereby quantify, each protein from a single binding and imaging step.
+Added: These high specificity affinity reagent probes 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 reagent probes and therefore an exceedingly large number of cycles to measure every protein in the proteome.
+Added: To enable broad protein identification on our system, we instead use our multi-affinity reagent probes that can bind to hundreds or even thousands of individual proteins in a given cycle.
+Added: Protein identification and quantification can be extended to proteoform-resolution by incorporating high specificity affinity reagent probes against protein targets of interest.
+Added: 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.
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 binding events to uniquely identify a protein.
+Added: On average, it takes roughly 15 cycles of multi-affinity reagent probe binding events to uniquely identify a protein.
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 Probe Binding Event with High Probability.
+Added: Nautilus Platform Technology Can Identify a Protein by Analyzing Data from Multiple Cycles of Affinity Reagent Probe Binding Event with High Probability.
Internal Data
−Removed: The machine learning protein identification analysis is run for each of the 10 billion protein molecules captured on the flow cell in parallel to identify each protein molecule present.
−Removed: Following this, each identification is counted to produce a cumulative, absolute quantification.
−Removed: As the algorithm learns more and more about each multi-affinity probe’s binding characteristics, both within and across Nautilus platform data sets, it is able to adapt and update its confidence in each protein identification, essentially getting “smarter” over time.
+Added: The machine learning protein identification analysis is run for each of the 10 billion protein molecules captured across three flow cells in parallel to identify each protein molecule present.
+Added: Following this, identifications are coalesced to infer an estimate of the quantity of each protein.
+Added: As the algorithm learns more and more about each affinity reagent probe’s binding characteristics, both within and across Nautilus platform data sets, it is able to adapt and update its confidence in each protein identification, essentially getting “smarter” over time.
As a result, the machine learning protein identification analysis is able to re-analyze data collected in the past and continuously improve upon its ability to identify proteins within that 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 during the library preparation process, which requires approximately 2-3 hours of hands-on time over a 2-day protocol.
+Added: Internal tests demonstrate that substantially all of the proteins are attached to the scaffold during the library preparation process, which requires minimal hands-on time over a 2-day protocol.
• Step 2 – Sample Deposition onto the Flow Cell
−Removed: The protein library is then deposited onto the flow cell capable of holding up to 10 billion intact single protein molecules.
+Added: The protein library is then deposited onto the three flow cells capable of holding up to 10 billion intact single protein molecules.
The landing pads on the flow cell are matched to the size of the protein-attached scaffold, thus allowing only one protein to be deposited per site.
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 Processing Multiple Cycles of Affinity Reagents
+Added: • Step 3 – Integrated Imaging and Fluidics System Processing Multiple Cycles of Affinity Reagent Probes
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.
−Removed: 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.
−Removed: 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.
+Added: This process entails introducing fluorescent dye labeled affinity reagent probes into the flow cell, rinsing out the unbound fraction, imaging the surface area, and then stripping and washing the affinity reagent probes 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 affinity reagent probes intended to identify a set of targets.
• 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 multi-affinity probe 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 affinity reagent probe binding events, effectively digitizing up to approximately 35 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 multi-affinity probe 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 affinity reagent probe binding event at each location to determine protein identity and quantity.
Nautilus Platform Technology Performance
4 unchanged sentences
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 with approximately 2-3 hours of hands-on time completed over a 2 day period.
−Removed: 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.
−Removed: An analysis of nearly 1,000 flow cells showed typical sample loading of single protein libraries yielded near complete flow cell occupancy, which demonstrates the speed and efficiency of our sample handling process.
+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 minimal hands-on time completed over a 2 day period.
+Added: 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 cells.
+Added: An analysis of nearly 1,000 flow cells showed typical sample loading of nanoparticle scaffold libraries yielded near complete flow cell occupancy, which demonstrates the speed and efficiency of our sample handling process.
Nautilus Platform Stability in Multi-Cycle Experiments
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Last, we demonstrated that after extended exposure to washing, and rinsing, that the protein detection remained nearly identical to the initial measurement.
−Removed: These results suggest
−Removed: that our wash conditions are highly effective and that our process of reagent cycling does not significantly damage the protein and thereby interfere with the probability of its measurement accuracy.
−Removed: Protein Library Remains Bound to Flow Cell During Repetitive Probe Binding and Wash Cycles
+Added: These results suggest that our wash conditions are highly effective and that our
+Added: process of reagent cycling does not significantly damage the protein and thereby interfere with the probability of its measurement accuracy.
+Added: Protein Library Remains Bound to Flow Cell During Repetitive Affinity Reagent Probe Binding and Wash Cycles
Nautilus Platform Sensitivity
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We are also able to use this sensitivity in flexible way, for example we can perform an extremely deep analysis of a single protein library sample across all lanes of a flow cell, or we can perform a multiplexed analysis by processing a batch of samples together (each sample protein library individually barcoded) during one proteome analysis system run.
−Removed: Development and Characterization of Multi-Affinity Probes
−Removed: 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.
−Removed: These pipelines employ multiple candidate discovery methods to identify and select antibody, antibody fragment, or nucleic acid based candidate multi-affinity probes.
−Removed: Promising candidates are 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.
−Removed: Multi-Affinity Probe Discovery and Development Pipeline
+Added: Development and Characterization of Multi-Affinity Reagent Probes
+Added: Multi-affinity reagent probe discovery and development pipelines have been built that generate multi-affinity reagent 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 reagent probes.
+Added: Promising candidates are further screened in assays to determine EC50 values off-platform (example results for two candidate multi-affinity reagent probes shown below), and then leads are evaluated in detail for their performance on the Nautilus proteome analysis platform.
+Added: Multi-Affinity Reagent Probe Discovery and Development Pipeline
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: 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.
−Removed: 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.
−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 isoform and phosphorylated patterns) of the same Tau protein.
+Added: Illustrating this concept in the diagram below, during the first cycle we use an anti Tau affinity reagent probe 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 probe that targets a different isoform or phosphorylation modification on the Tau protein.
+Added: In this simple workflow using only 4 position-specific Tau affinity reagent probes, our technology is able to distinguish up to 16 different proteoforms (4 position-specific targets = 2 4 possible forms of Tau based on variation in protein length or site phosphorylation status).
Workflow for the Detection of Tau Proteoform Patterns
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Nautilus Platform Development Plan Key Areas of Focus
−Removed: In order to achieve our goal of broad commercialization in 2025, 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 commercialize our platform, we plan to advance the development of our technology 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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We plan to focus on the continued improvement of our flow cell designs.
−Removed: Having initially demonstrated that prototype versions of our flow cell can functionally achieve 10 billion discrete single protein molecule landing pads, we plan to further optimize the landing pad spacing, density, manufacturing process and chemistries of the first commercially available flow cells.
+Added: Having initially demonstrated that prototype versions of our flow cells can functionally achieve approximately 10 billion discrete single protein molecule landing pads per instrument run, we plan to further optimize the landing pad spacing, density, manufacturing process and chemistries of the first commercially available flow cells.
We also intend to focus on the completion of the final engineering design of our proteome analysis system, where we plan to complete the development of manufacturing processes to integrate and test all completed sub-systems including the high-speed optical subsystem, fluorophore excitation laser, and micro-fluidics system in combination with our flow cell.
−Removed: We also plan to continue expanding the number of affinity binding reagents and chemistries that can be used within our proteome analysis system for both broad scale proteomics quantification and target quantification of proteoforms at the single molecule level.
−Removed: Our aim is to create a broad portfolio of affinity binding reagents through in-house reagent development efforts and through strategic partnerships where we qualify already developed reagents for compatibility with our technology.
+Added: We also plan to continue expanding the number of affinity reagent probes and chemistries that can be used within our proteome analysis system for both broad scale proteomics quantification and target quantification of proteoforms at the single molecule level.
+Added: Our aim is to create a broad portfolio of affinity reagent probes through in-house reagent development efforts and through strategic partnerships where we qualify already developed reagents for compatibility with our technology.
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 in 2025.
APPLICATIONS OF OUR TECHNOLOGY
The Nautilus platform technology is an open platform that is designed to leverage a wide variety of reagents to read and quantify the proteome and proteoforms
−Removed: We believe that our Nautilus platform technology is designed to represent one of the first truly novel technologies for the detection and quantitation of proteins and proteoforms by leveraging the creation of our single protein molecule flow cell in combination with a broad range of affinity binding reagents.
−Removed: By design, our Nautilus platform technology is open to the use of virtually any affinity binding reagent, where each reagent can be efficiently chemically labeled and used in our multi-cycle process to identify and quantify a protein library.
+Added: We believe that our Nautilus platform technology is designed to represent one of the first truly novel technologies for the detection and quantitation of proteins and proteoforms by leveraging the creation of our single protein molecule flow cell in combination with a broad range of affinity reagent probes.
+Added: By design, our Nautilus platform technology is open to the use of virtually any affinity reagent, where each reagent can be efficiently chemically labeled and used in our multi-cycle process to identify and quantify a protein library.
We further believe one of the inherent strengths of the open design of our Nautilus platform is the ability to use reagents across a range of different binding profiles to create unique applications that unlock different types of important biological information.
−Removed: On one end of the spectrum (above left), our technology is designed to harness the power of low specificity multi-affinity binding reagents that will potentially allow us to detect substantially all of the proteome.
−Removed: On the other end of the spectrum (above right), we believe we can apply high specificity affinity binding reagents that detect and quantify individual target proteins of interest, and the post-translational modifications of these target proteins to detect and quantify the various proteoforms that may exist.
−Removed: We believe it is this inherent flexibility of reagent applications on our Nautilus platform that will enable a broad suite of uses across research, discovery, translational and clinical applications.
+Added: On one end of the spectrum (above left), our technology is designed to harness the power of low specificity multi-affinity reagent probes that will potentially allow us to detect substantially all of the proteome.
+Added: On the other end of the spectrum (above right), we believe we can apply high specificity affinity reagent probes that detect and quantify individual target proteins of interest, and the post-translational modifications of these target proteins to detect and quantify the various proteoforms that may exist.
+Added: We believe it is
+Added: this inherent flexibility of reagent applications on our Nautilus platform that will enable a broad suite of uses across research, discovery, translational and clinical applications.
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 for use on our instrument.
+Added: The open nature of the Nautilus platform creates the opportunity to partner with third-parties on the development and supply of affinity reagent probes for use on our instrument.
Basic Research and Discovery Applications
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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.
−Removed: 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.
+Added: We believe discovery focused proteoform specific reagents could be used in combination with our multi-affinity reagent probe broad protein detection method to enhance the output of our analyses.
Multi-Omic Systems Biology and Proteogenomics
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Our Nautilus platform represents an entirely new single protein molecule data source for proteogenomics, which we believe could contribute significantly to the field by increasing the scale of proteomic data accessible for these analyses, and ultimately increasing the discovery potential of the integrated dataset.
−Removed: Given the current level of access to genomic and transcriptomic information enabled by NGS, we believe the
−Removed: research community could rapidly integrate data from our Nautilus platform technology into these studies to leverage matched genomic and proteomic data.
+Added: Given the current level of access to genomic and transcriptomic information enabled by NGS, we believe the research community could rapidly integrate data from our Nautilus platform technology into these studies to leverage matched genomic and proteomic data.
Translational Research and Discovery Applications
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It has been published that approximately 95% of FDA-approved drug targets are proteins.
−Removed: The Human Protein Atlas collaborative research project identified that FDA-approved drugs are targeting up to 854 separate human proteins and that there are 4,906 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 854 separate human proteins and that there are 4,906 genes in
+Added: 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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Our proteome analysis system is a high-resolution optical imaging system coupled with integrated fluidics and liquid handling sub-systems.
−Removed: 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: The system is designed to deposit protein libraries onto a flow cell and to process labeled multi-affinity reagent probe binding and imaging cycles rapidly in order to decode and quantify the vast majority of proteins present in biological samples.
After the reagent kits, samples (protein libraries), and flow cells are loaded onto the system, the remainder of the workflow is automated.
System run reagent kits are comprised of four main components:
−Removed: sample preparation, flow cell(s), multi-affinity probe reagents, and instrument buffers used to perform multi-cycle analysis runs.
+Added: sample preparation, flow cell(s), multi-affinity reagent probes, and instrument buffers used to perform multi-cycle analysis runs.
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.
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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.
−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.
+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
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.
−Removed: Affinity binding reagents will also be included as a reagent kit.
+Added: Affinity reagent probes will also be included as a reagent kit.
Kits will be offered in configurations that cover a catalog of proteomic content.
−Removed: 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.
−Removed: 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.
+Added: We intend to supply a standardized set of multi-affinity reagent probes for the broad-scale 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 probe 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
1 unchanged sentence
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.
−Removed: 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.
+Added: Our software is a learning and evolving system, which we are designing to improve in accuracy over time as the multi-affinity reagent 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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We believe a comprehensive solution could offer a compelling value proposition across multiple market segments due to the substantial enhancements it will create in speed and scale of data creation, single protein molecule quantitation, sensitivity, and reproducibility.
−Removed: We initially intend to target customers with a history of strong performance in proteomic research, and a substantial annual research budget allocation for proteomics technologies and proteomic data.
−Removed: 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: 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.
−Removed: 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.
−Removed: As our Nautilus platform is introduced into these customer segments, we further intend to expand our commercialization into clinical settings, where our target customers are expected to include pharma and biotech clinical development groups, contract research organizations, and ultimately, diagnostic laboratories.
+Added: We initially intend to target customers with a history of strong focus in proteomic research, and a substantial annual research budget allocation for proteomics technologies and proteomic data.
+Added: We expect many of our customers will already have access to existing proteomic or genomic analysis capabilities including a segment of the greater than 16,000 system install base of mass spectrometry detection systems.
+Added: Our early customers are expected to span laboratories focused on basic and translational research in large pharma and biotech research groups, academia, and large-scale commercial and academic multi-omics research laboratories.
+Added: As our Nautilus platform becomes established in these customer segments, we further intend to expand our commercialization into clinical settings, where our target customers are expected to include pharma and biotech clinical development groups, contract research organizations, and ultimately, diagnostic laboratories.
Our proteome analysis system is expected to be priced in-line with mass spectrometry peptide detection equipment, or high-throughput NGS equipment, making the capital expense for our system within the budget for our initial customers.
Our consumables are expected be priced at a level that provides comparable market value for full proteome analysis.
−Removed: The use of multiplexed run configurations will continue to grow over time, which we believe will help to reduce our costs and the price-
−Removed: per-sample of our reagent kits such that we are able to support customers with very high-throughput applications of our systems.
+Added: The use of multiplexed run configurations will continue to grow over time, which we believe will help to reduce our costs and the price-per-sample of our reagent kits such that we are able to support customers with very high-throughput applications of our systems.
We expect these high-throughput run configurations and economics to accelerate the initiation of large-scale proteomics and multi-omics research projects, and also to be much more compatible with centralized core lab facility operations with requirements for proteomic data generation that can support an entire organization or user base.
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Our publication strategy is a key component of our overall go-to-market plan, and we expect to spend considerable time and resources building these fundamental proof-sources to accelerate adoption of our proteome analysis system.
−Removed: We further believe that once our proteome analysis system is launched, a key performance indicator of our success will be the rate of new publications generated using our technology.
+Added: We further believe that once our proteome analysis system is launched, key performance indicators of our success would include publications and references to our platform technology.
We intend to track this closely, and we expect to invest both internally and externally to accelerate the pace of new research and publications leveraging our Nautilus platform pre- and post- proteome analysis system launch.
Go-To-Market Strategy
−Removed: We expect our proteome analysis system technology will be highly disruptive to the current proteomics technology and market landscape, and as a result, we have designed our go-to-market plan with a similar strategy to the highly successful NGS platform technology introduction and commercialization in genomics.
+Added: We expect our proteome analysis system technology will be highly disruptive to the current proteomics technology and market landscape, and as a result, we have designed our go-to-market plan with a strategy that combines elements of highly successful mass
+Added: spectrometry and NGS platform technology introductions and commercialization.
We also believe that engaging with the market early is a critically important activity in building confidence and awareness of our technology and its capabilities.
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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 Milestone
Collaborations & Partnerships
−Removed: We believe that directly engaging the market early, well before system launch, has the potential to be a very important differentiator to raise awareness of our novel Nautilus platform as it matures throughout the formal development process, and to build credibility as we educate the community on our scientific approach through the value of our data.
−Removed: We believe the most effective way to engage our future customers now is through partnerships and collaborations, with the primary purpose of driving new and meaningful biological insights while demonstrating our technology’s performance, unique characteristics, and capabilities.
−Removed: We have launched a formal partnering program with the goal of establishing multiple research collaborations generating data and publications in high impact research areas.
+Added: We believe that directly engaging our future customers early, well before system launch, will have the potential to be a very important differentiator to raise awareness of our platform technology as it matures throughout the formal development process, and to build credibility as we educate the community on our scientific approach.
+Added: We believe the most effective way to engage our future customers now is through research collaborations, with the primary purpose of driving new and meaningful biological insights while demonstrating our technology’s performance, unique characteristics, and capabilities.
+Added: We continue to maintain a formal program for identifying collaborative research partners and establishing new relationships in specific research areas where we wish to generate data and publications highlighting the value of single-molecule proteomics.
We also believe we can use these collaborations to improve the performance characteristics of our technology during development, and we can shape the system and run parameters to more precisely meet our customer’s needs.
−Removed: We intend to target projects with these engagements that will help to define and validate our product applications, which we expect will further aid in the rapid adoption of such applications once directly commercialized as products.
+Added: We further intend to target projects within these engagements that will help to define and validate our first launched product applications, which we expect will further aid in the rapid adoption of such applications once directly commercialized as products.
Early Access Program
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Using this Early Access Program, we intend to begin building a pipeline of customer engagements, supporting their evaluations of our technology through proof of concept and pilot studies, and giving them access to our data to begin establishing interest in our proteome analysis system leading up to launch.
−Removed: We further intend to build on the momentum of our Early Access Program by expanding it to include a small group of target customers for the sales and subsequent testing of our first generation proteome analysis system on site at their facilities.
+Added: We further intend to build on the momentum of our Early Access Program by expanding it to include a small group of target customers to evaluate of our first generation proteome analysis system on site at their facilities.
Our goal in the planned proteome analysis system Early Access Program is to establish this influential group of customers as reference sites ahead of our broader commercial launch, and to integrate the learnings from our system performance outside of our own laboratories to improve the performance and robustness of our system and process design.
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 proof of concept and pilot projects for an extended
−Removed: period of time 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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• Expanding our impact in translational research for clinical applications, precision medicine and diagnostics.
−Removed: In December of 2020, we signed a research collaboration agreement with Genentech to engage in a pilot study using our technology.
−Removed: 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: 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 December of 2020, we signed a research collaboration agreement with Genentech to engage in a pilot study using our technology to investigate proteoforms of the Tau protein, an important biomarker of neurodegenerative disease.
+Added: In October 2021, we entered into a research collaboration agreement with Amgen in which the Nautilus platform may be used across a number of projects to investigate proteins and proteoforms of interest to the both organizations.
In October 2021, we signed a research agreement with The University of Texas MD Anderson Cancer Center.
−Removed: 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.
−Removed: 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.
−Removed: 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: And, in February of 2025, we entered into a research collaboration with The Buck Institute for Research on Aging where the Nautilus platform may be used across a number of projects focused both on proteoform analysis of the Tau protein, as well as new projects and analysis methods exploring other platform applications.
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.
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The life sciences market is highly competitive.
−Removed: There are other companies, both established and early-stage, that have indicated that they are designing, manufacturing and marketing products for, among other things, multiplexed or high-throughput proteomic analysis.
+Added: There are other companies, both established and early-stage, that have indicated that they are designing, manufacturing and marketing products for, among other things, multiplexed or high-throughput proteomic
Nautilus currently competes with technology and diagnostic companies that supply components, products, and services to customers engaged in proteomics analysis.
−Removed: These companies include Agilent Technologies;
−Removed: Becton, Dickinson and Company;
+Added: Major competitors include Thermo Fisher Scientific (including Olink);
Bruker Corporation;
−Removed: Olink Proteomics;
+Added: Agilent Technologies;
+Added: Danaher (SCIEX);
+Added: Becton, Dickinson and Company;
Standard Biotools (formerly known as Somalogic ) .
−Removed: and Thermo Fisher Scientific.
Nautilus also competes with a number of emerging companies that are developing proteomic products and solutions.
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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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Devices deemed to pose lower risk to the patient are placed in either class I or II, which, unless an exemption applies, requires the manufacturer to submit a pre-market notification requesting FDA clearance for commercial distribution pursuant to Section 510(k) of the FDC Act.
−Removed: This process, known as 510(k) clearance, requires that the manufacturer demonstrate that the device is substantially equivalent to a previously cleared and legally marketed 510(k) device or a “pre-amendment” class III device for which pre-market approval applications (PMAs) have not been required by the FDA.
+Added: This process, known as 510(k) clearance, requires that the manufacturer demonstrate that the device is substantially equivalent to a previously cleared and legally marketed 510(k)
+Added: device or a “pre-amendment” class III device for which pre-market approval applications (“PMAs”) have not been required by the FDA.
This FDA review process typically takes from four to twelve months, although it can take longer.
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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: The FDA has issued warning letters to genomics labs for illegally
−Removed: 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.
+Added: 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.
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.
−Removed: 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.
−Removed: In October 2023, through rulemaking, the FDA proposed to amend the definition of “in vitro diagnostic products” in FDA regulations to include laboratories that manufacture such products and to phase out the FDA’s general enforcement discretion approach for LDTs so that IVDs manufactured by a laboratory would be regulated similarly to IVDs.
−Removed: It is unclear when the FDA will finalize and begin enforcing such rule and how current and future judicial challenges and legislation by the federal and state governments will impact the industry, including our business and that of our customers.
−Removed: As laboratories and manufacturers develop more complex genetic tests and diagnostic software, FDA may increase its regulation of LDTs.
−Removed: Any future legislative or administrative rule making or oversight of LDTs and LDT manufacturers, if and when finalized, may impact the sales of our products and how customers use our products, and may require us to change our business model in order to maintain compliance with these laws.
+Added: To date, Congress has not passed the VALID Act.
+Added: In May 2024, the FDA issued a final rule that phases out its enforcement discretion for most laboratory-developed tests (LDTs) and amended the FDA’s regulations to make explicit that in vitro diagnostics are medical devices under the Federal Food, Drug, and Cosmetic Act, including when the manufacturer of the diagnostic product is a laboratory.
+Added: This final rule is being challenged in federal courts.
+Added: In June 2024, the U.S.
+Added: Supreme Court overruled the Chevron doctrine, which gives deference to regulatory agencies’ statutory interpretations in litigation against federal government agencies, such as the FDA, where the law is ambiguous.
+Added: This landmark Supreme Court decision may invite various stakeholders to bring lawsuits against the FDA and other federal agencies to challenge longstanding decisions and policies, including this LDT final rule.
+Added: Further, the new administration, including changes in the leadership at the FDA and other federal agencies, may issue new policies and regulations that can impact the compliance status of our products or that of our customers.
+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.
+Added: Any future legislative or administrative rule making or oversight of LDTs and LDT manufacturers, if and when finalized, may impact the sales of our products and how customers use our products, and may require us to change our business model in order to
+Added: maintain compliance with these laws.
We would become subject to additional FDA requirements if our products are determined to be medical devices or if we elect to seek 510(k) clearance or premarket approval.
−Removed: If our products become subject to FDA regulation as medical devices, we would need to invest significant time and resources to ensure ongoing compliance with FDA quality system regulations and other post-market regulatory requirements.
+Added: If our products become subject to FDA regulation as medical devices, we would need to invest significant time and resources to ensure ongoing compliance with FDA quality system regulations and other post-market regulatory requirements, including U.S.
+Added: healthcare fraud and abuse laws, such as the federal Anti-Kickback Statute and the False Claims Act, as well as reporting and transparency laws, such as the Sunshine Act.
International sales of medical devices are subject to foreign government regulations, which vary substantially from country to country.
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While we are not currently subject to the CCPA, we may in the future be required to comply with the CCPA, which may increase our compliance costs and potential liability.
−Removed: Furthermore, the CCPA could mark the
−Removed: beginning of a trend toward more stringent state privacy legislation in the U.S., which could increase our potential liability and adversely affect our business.
+Added: Furthermore, the CCPA could mark the beginning of a trend toward more stringent state privacy legislation in the U.S., which could increase our potential liability and adversely affect our business.
Furthermore, the collection, use, storage, disclosure, transfer, or other processing of personal data regarding individuals in the European Economic Area (EEA), including personal health data, is subject to the GDPR, which became effective on May 25, 2018.
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The GDPR may increase our responsibility and liability in relation to personal data that we process where such processing is subject to the GDPR, and we may be required to put in place additional mechanisms to ensure compliance with the GDPR, including as implemented by individual countries.
−Removed: Compliance with the GDPR will be a rigorous and time-intensive process that may increase our cost of doing business or require us to change our business practices, and despite those efforts, there is a risk that we may be subject to fines and penalties, litigation, and reputational harm in connection with our European activities.
+Added: Compliance with the GDPR will be a rigorous and time-intensive process that may increase our cost of doing
+Added: business or require us to change our business practices, and despite those efforts, there is a risk that we may be subject to fines and penalties, litigation, and reputational harm in connection with our European activities.
Further, with the end of the United Kingdom’s transition period to leave the European Union, or the Brexit transition period, on December 31, 2020, there is uncertainty with regard to medical device and data protection regulations as well as other regulations that may apply to our industry in the United Kingdom, including new guidance, rules, and regulations by the Medicines and Healthcare products Regulatory Agency (“MHRA”).
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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, 2023, we owned seventeen issued U.S.
−Removed: patents, approximately thirty-eight pending U.S.
−Removed: non-provisional patent applications, approximately twenty-three pending U.S.
−Removed: provisional patent applications, approximately four granted foreign patents, and approximately eighty-two pending foreign patent applications, including nineteen 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 2044, 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, 2024, we owned or held exclusive licenses to thirty one issued U.S.
+Added: patents, approximately sixty pending U.S.
+Added: non-provisional patent applications, approximately nineteen pending U.S.
+Added: provisional patent applications, approximately twenty five granted foreign patents, and approximately one hundred thirty six pending foreign patent applications, including twenty four international patent applications filed under the Patent Cooperation Treaty (PCT application).
+Added: Our owned and exclusively licensed patents and patent applications, if issued, are expected to expire between 2026 and 2044, in each 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;
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In addition to patents, we utilize trade secrets and proprietary know-how to boost our competitive position.
−Removed: Specifically, we rely on trade secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for,
−Removed: patent protection.
+Added: Specifically, we rely on trade secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.
We protect trade secrets and know-how by establishing confidentiality agreements and invention assignment agreements with our employees, consultants, scientific advisors, contractors and partners.
1 unchanged sentence
These agreements also generally provide that all inventions resulting from work performed for us or relating to our business and conceived or completed during the period of employment or assignment, as applicable, shall be our exclusive property.
−Removed: As of December 31, 2023, we owned approximately nine registered trademarks in Australia, China, Israel, the United Kingdom, and Europe.
−Removed: In addition, we have approximately thirty-four pending trademark applications covering seven different marks in the U.S., Australia, Brazil, Canada, China, the European Union, India, Israel, Japan, Korea, Mexico, Singapore, Switzerland, and the United Kingdom.
+Added: As of December 31, 2024, we owned approximately thirty four registered trademarks covering four different marks in Australia, Brazil, Canada, China, the European Union, India, Israel, Japan, Mexico, Singapore, Switzerland.
+Added: In addition, we have approximately twenty pending trademark applications covering seven different marks in the U.S., Brazil, Canada, China, India, Japan, Korea, and Mexico.
Collaboration Agreements
−Removed: 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.
−Removed: 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.
−Removed: These agreements are for research only and we will not generate any revenue under the agreements.
+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 The Buck Institute for Research on Aging in February 2025.
+Added: Under each of these agreements, respective research collaboration teams are using prototype versions of the Nautilus platform in pilot projects to learn about it’s capabilities and accelerate the development process to meet the needs of our future
+Added: These agreements are for research only and are not expected to generate any revenues, however they may provide opportunities for the parties to jointly apply for and secure grants, awards, or other government or non-profit research funding
Scientific Advisory Board
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Employees and Human Capital
−Removed: As of December 31, 2023, we had 167 employees, all based in the United States, 59 of whom hold doctorate degrees.
+Added: As of December 31, 2024, we had 155 employees, all based in the United States, over one-third of whom hold doctorate degrees.
Of these employees, 110 were engaged in research and development activities, and 45 were engaged in general and administrative activities.
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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.