Seer, Inc. 10-K

Item 1. Business Overview Our mission is to imagine and pioneer new ways to decode the secrets of the proteome to improve human health. Our first product, the Proteograph TM Product Suite (Proteograph), leverages our proprietary engineered nanoparticle (NP) technology to provide unbiased, deep, rapid and large-scale access to the proteome. The Proteograph Product Suite is an integrated solution that includes consumables, an automation instrument and software. The human proteome is incredibly complex, with multiple protein variants derived from each gene. This complexity arises from multiple biological steps required to create the functional proteome, including transcription, translation, post-translational modifications (PTMs) and protein interactions. While many protein variants may be benign, others can severely disrupt protein function and contribute to disease. The complexity of the proteome at a population level is huge. For example, a study by the UK Biobank published in late 2021 in Nature identified over 900,000 potential protein loss-of-function variants in a cohort of approximately 455,000 individuals, with each individual having an average of more than 200 such variants (Backman et al. ). It is essential to catalog the complexity of the proteome and understand the functions of protein variants to decode the links between the proteome, the genome and disease. This deeper understanding can lead to novel insights into disease mechanisms, the discovery of new biomarkers and the identification of potential therapeutic targets. We believe that broader access to the proteome is essential, not only to understanding its complexity and accelerating biological insights, but also to expanding end-markets. These markets may include basic research and discovery, translational research, diagnostics and applied applications. To comprehend the complexity and dynamic nature of the proteome, researchers must perform population-scale, deep, unbiased interrogation of biological samples over time. We believe that this level of interrogation was not previously feasible and that the Proteograph can enable researchers to perform these types of proteomics studies. Before the commercial launch of the Proteograph, we believe that the largest published deep unbiased plasma proteomics study, which measured at least 600 proteins, was conducted on just 48 samples. However, today, multiple customers have successfully completed, or are planning, deep unbiased plasma proteomics studies with thousands of proteins quantitatively measured across thousands of samples. This breadth and depth of unbiased plasma proteomics coverage was not previously achievable at scale. Proteins play a critical role in most biological processes and provide dynamic indicators of physiological changes across health, disease progression, and therapeutic response. However, compared to the genome, the discovered and cataloged body of proteomic data remains limited. Current proteomics approaches have not facilitated deep exploration at scale in samples with high dynamic range, because they are either: (i) unbiased but not scalable; or (ii) scalable but biased. Current deep, unbiased approaches require complex, lengthy, labor- and capital-intensive workflows that limit their application to small, under-powered studies. Targeted or biased methods are scalable but are limited to a specific number of predetermined proteins. These methods cannot distinguish between variants of the same proteins often present in the same biological samples, because they lack the necessary peptide-level resolution and accuracy needed to characterize the proteome. These limitations force a trade-off between the number of samples and the depth of protein coverage in a study. We believe that a more complete understanding of biology requires deep, unbiased, large-scale proteomic analysis with the peptide-level resolution and accuracy needed to distinguish protein variants. We are focused on driving adoption of the Proteograph by customers in the proteomics and genomics markets who recognize the value of large-scale, unbiased, and deep proteomics. Allied Market Research estimated the global proteomics market to be approximately $24 billion in 2021. The Proteograph’s unique capabilities now enable researchers to undertake first-of-their-kind, large-scale unbiased studies, which complement genomics studies by adding critical missing information that can provide functional context to genomic variation. With the advent of next-generation sequencing and improvement in cost and throughput, researchers have sequenced the equivalent of several million human genomes and human exomes. Across these studies, according to the dbSNP database, more than one billion individual genetic variants have been identified to date; however, less than 0.2% of those variants 1 have been cataloged in the ClinVar database with a reported relationship between variation and phenotype. This gap in functional annotation is in part due to the gross impedance mismatch between access to the proteome and genome. We believe that the Proteograph Product Suite will bridge this gap. Just as large-scale access to genomics has dramatically impacted that field, we believe large-scale access will do the same for proteomics, revealing new content, enabling mapping and cataloging of new protein variants, and driving new disease insights, diagnostics and treatments. Importantly, by impedance-matching researchers’ access to unbiased genomics content at the nucleotide level with proteomics content at the peptide and amino acid level, researchers can better connect genotype to phenotype. In this way, we believe customers will be able to develop more accurate biomarkers of disease for diagnostic and therapeutic applications, accelerating multi-omics driven precision medicine. We believe these capabilities will have broad appeal to researchers and entities undertaking large-scale genomics studies and should attract spending from the genomics market, which was estimated by Technavio to be approximately $26 billion in 2021. Additionally, we believe that the Proteograph will enable the discovery of novel content that will lead to the creation of value that will promote entirely new applications and market opportunities. The Importance of Proteomics Detailed and complex biological information resides within the proteome. Nearly all functions of an organism require the interaction of one or more proteins with each other and with other biological molecules. Proteins serve as dynamic indicators of health status, disease progression and therapeutic response. As depicted in Figure 1 below, the genome is a static indicator of an individual’s baseline physiology, while the proteome reveals the current physiological state. Despite its importance, the human proteome is relatively unexplored compared to the human genome. To link genomic information with phenotypes, understanding the functional context of proteins is critical. However, this connection is currently limited because the vast majority of genetic variants lack functional context at the protein level. We believe that enabling researchers to generate large-scale, integrated proteomic and genomic data will equip them to comprehend the relationship between variation, function and biology. Protein quantitative trait loci (pQTLs) are genomic variants that are associated with the levels or abundance of specific proteins. Because they influence protein expression or regulation, they are a genetic source of variation in the proteome. The term “protein quantitative trait loci” is used because protein abundance level is viewed as quantitative traits. To identify pQTLs, genome-wide association studies (GWAS) compare genetic variants across large populations and their association with differences in protein levels. These studies can provide valuable insights into the genetic basis of complex diseases, the molecular mechanisms that regulate protein expression, and the identification of potential therapeutic targets for drug development. However, the study of pQTLs requires large-scale acquisition of proteomic data, which is a challenge for traditional unbiased approaches. We believe that the Proteograph will bridge this gap. Moreover, the Proteograph allows for pQTL analysis at the peptide level, thus enabling the association of genomic variants with specific protein variants. 2 Figure 1: Utility of genomic vs. proteomic information. Over one million human genomes have been highly characterized with over one billion variants, but they have low utility and represent a static indicator of risk. The human proteome is far less characterized, but has a much higher utility as a dynamic indicator of health status. Challenges of Accessing the Proteome Complexity of the Proteome The human proteome is dynamic, diverse and complex, with approximately 23,000 genes giving rise to over one million protein variants. As shown in Figure 2 below, these variants arise from various mechanisms, including alternative splicing of RNA transcripts, genetic variations that alter the amino acid sequence of the protein, and post-translational modifications such as phosphorylation and glycosylation. It is estimated that our approximately 23,000 genes give rise to approximately 69,000 protein isoforms through alternative splicing. At a population level, a much larger number of protein isoforms exist because of genetic variants and somatic variants that alter RNA processing. Protein variants can have vastly different biological functions and be expressed in different tissues within the same individual. For example, two isoforms of the protein encoded by CD99L2 have different interacting proteins and those two proteins’ networks are related to distinct diseases (Yang et al. ). An example of a protein that has tissue-specific isoform abundance is FOX1, which has differential isoform presence in muscle and brain tissue (Nakahata and Kawamoto). Therefore, it is essential to study and understand proteins at the level of protein variants in the appropriate biosample, and this can be achieved only through large-scale analysis of the proteome at the peptide level. 3 Figure 2: Functional diversity exists through modifications and interactions of different molecules, from static indicators like the genome to increasingly numerous and complex indicators like the proteome and interactome. Modified from Bludau et al. Recently, a study by Backman et al. published in Nature revealed the genomic variation identified in a cohort of approximately 455,000 participants of the UK Biobank exome sequencing study. The study identified a vast amount of protein variation, including almost nine million protein variants, of which more than six million are potentially deleterious and 915,289 are protein loss-of-function variants. On the individual level, each participant had on average 9,506 protein variants, of which 2,945 were potentially deleterious and 214 were loss-of-function variants. However, these variants were only identified at the genomic level and did not account for alternative splicing or post-translational modifications. Considering these additional sources of protein variants, the actual number of protein variants at both individual and population-wide levels is significantly higher. These findings emphasize the unmet need to understand protein variants at the peptide level and underscore how little is currently known about the complexity of the proteome. We believe understanding protein variation at this level could revolutionize how we diagnose, treat, and monitor diseases. Figure 3: Summary of genetic variation across a population of approximately 455,000 participants of the UK Biobank (Backman et al.) Limitations of Transcriptomics to Infer Proteomics RNA sequencing (RNAseq) has been the established method for studying transcriptomics over the last decade. It is often assumed that transcript and protein abundance levels are highly correlated because of the central dogma of molecular biology describing how transcripts are translated into proteins. However, several studies have repeatedly demonstrated a poor correlation between transcript and protein levels (Buccitelli and Selbach). This discrepancy can arise from technical factors, such as noise and bias in methods for assessing both transcripts and proteins, and biological mechanisms such as mRNA translation and degradation. Although both transcriptomics and proteomics measurements have their uses, proteins are more closely linked to phenotype, making them more useful than 4 transcripts for understanding function. Therefore, we believe that direct analysis of the proteome via at-scale proteomics studies will provide unique biological insights for research, discovery and clinical applications. Limitations of Affinity-Based Approaches to Proteomics Proteins are highly variable in structure, chemistry and concentration, presenting technological challenges for their identification at low concentration levels. Due to the lack of a common amplification mechanism, researchers often use ligands to measure proteins. However, because ligands such as antibodies or aptamers were designed to bind to specific areas of proteins, approaches utilizing them are considered targeted, or biased. The average length of a human protein is approximately 470 amino acids, whereas the average binding site of a ligand is an epitope five to eight amino acids long. Panels of ligands used for protein interrogation have several shortcomings, including (i) they do not recognize differences in protein structure outside of the epitope binding site, so that all variants appear the same and cannot be differentiated from one another, (ii) conformational changes of the protein can affect epitope and ligand binding; for example, those induced by protein-protein interactions or post translational modifications, and (iii) certain protein isoforms may exclude entire protein domains and remove the epitope binding site, yielding false negative results. Figure 4: Sources of variation. Left panel is a graphical summary of factors contributing to variation in the affinity-based discovery of the plasma proteome. Right panel schematically describes reasons for differences in binding profile of aptamer and antibody-based proteomic profiling (PAV protein altering variant; SNV single-nucleotide variant). Adapted from Pietzner et al. In a paper published in Nature Communications, Pietzner et al. from the University of Cambridge experimentally demonstrated the limitations of two distinct commercially available affinity-based approaches. Specifically, the authors show that protein altering variants can affect ligand binding, i.e., each affinity-based platform interacts differently with the same protein, depending on the epitopes to which its ligands are binding. On average, the correlation between the two commercially available affinity-based methods was 0.38. The distribution of correlations across all proteins is bimodal, with some proteins having a very good correlation, and others have a correlation close to zero (as shown in Figure 5 below). The authors attribute this poor correlation to differences in epitope binding between platforms and interference from protein-altering variants. These limitations underscore the importance of studying proteins with peptide-level resolution using a technology that is quantitatively robust in identifying protein variants. 5 Figure 5: Distribution of correlation coefficients across 937 mapping aptamer–antibody pairs (n = 871 unique protein targets). Adapted from Pietzner et al. Affinity-based approaches have limitations when used for pQTL analysis. These ligands bind to a specific epitope of the protein, as depicted on the left side of Figure 6 below. However, protein variants can alter the ligands’ binding, as demonstrated in the middle panel of the figure. Such altered binding can lead to incorrect measurements of protein levels, resulting in false pQTL identifications or misinterpretation of true pQTLs. In contrast, the Proteograph readout offers multiple peptides per protein, some of which may contain variant peptides, while others may not, as shown in the right panel of the figure. We believe that the correlation of peptides with genomic variants enables accurate pQTL analysis. The Proteograph technology provides an advantage over affinity-based approaches in pQTL analysis by offering the necessary peptide-level resolution for detection of protein variants. Figure 6: Protein variants may cause false associations in affinity-based approaches for proteogenomic studies. Affinity-based approaches are effective when a known target and a specific epitope measurement is desired, but cannot cover the vast complexity of the proteome. We believe they are analogous to microarrays in genomics, where a specific DNA fragment is used in a targeted or biased manner to confirm the presence of a specific mutation or a 6 single nucleotide polymorphism (SNP). The fundamental limitation of affinity-based approaches is their inability to differentiate between protein variants and accurately survey the complexity of the proteome. Limitations of Current Unbiased Approaches to Proteomics Rather than relying on predefined epitopes, unbiased approaches can interrogate proteins at the peptide level, providing amino-acid level resolution to protein variants. However, traditional, deep, unbiased proteomic approaches rely on complex workflows that do not scale due to the wide range of protein concentrations in biological samples with high dynamic range. In human plasma, for example, the 22 most abundant plasma proteins account for 99% of the total protein mass, while the many thousands of less-abundant proteins comprise the remaining one percent. Given the important biological role of both high- and low-abundance proteins, it is critical to detect proteins accurately, precisely and reproducibly across the dynamic range. Mass spectrometry (MS) is a widely used technique for unbiased discovery, basic research and clinical applications, and is considered the gold standard for identification. However, the wide dynamic range of protein concentrations in plasma and other biological samples has previously required complex, upfront sample preparation workflows prior to MS analysis, involving depletion of abundant proteins and fractionation of the remaining proteins and peptides. Deep unbiased proteomics analysis of complex biosamples at scale have not been feasible for wide adoption by researchers due to the high complexity, cost and time requirements. For example, in a state-of-the-art deep unbiased plasma proteomics study in 2017 prior to commercial availability of the Proteograph Product Suite, Keshishian et al. depleted the most abundant proteins with immuno-affinity columns and then separated remaining peptides by multiple and complex chromatographic steps and mass spectrometer injections. The study identified 4,500 different proteins across 16 samples, but took months to complete. Prior to the commercial availability of the Proteograph Product Suite, we believe the critical unmet need in proteomic analysis was how to collect unbiased proteomic data in a sample on thousands of proteins in a sample spanning more than ten orders of magnitude in concentration (dynamic range), and to repeat this across thousands of samples in a reasonable amount of time and cost. Genomics faced a similar unmet need before the advent of NGS, which allowed for massively parallel sampling. The Importance of Unbiased, Peptide-level Resolution Proteomics Importance of an Unbiased Approach in the Discovery of Novel Content The ability to perform unbiased sampling at scale has transformed biological analysis. In genomics, unbiased sequencing of the genome enabled discovery of novel content, creating new end-market opportunities in basic research and discovery, translational research and clinical applications, including early cancer detection, recurrence monitoring and non-invasive prenatal testing. While there is no guarantee that the Proteograph Product Suite will have the same impact on proteomics that NGS had on genomics, we believe there is a significant market opportunity to provide unbiased, deep, rapid, and scalable access to the proteome. Figure 7 illustrates how content discovery increases as sample cohorts increase in size with an unbiased approach. 7 Figure 7: Unbiased approaches increase the identification of protein variants arising from genomic variants, isoforms and post-translational modifications as sample numbers increase, resulting in new biological insights, applications and utility. Targeted approaches are inherently unable to discover new protein variants. Importance of Peptide-Level Resolution in the Understanding of Biology We believe that peptide-level resolution is crucial to the discovery of novel content and new biological insights. One example is alternative protein isoforms arising from the same gene locus. At the transcriptome level, these alternative transcripts are known as spliceforms. The majority of human genes can produce more than one protein spliceform and, according to the Ensembl genome database project, as many as 69,000 protein spliceforms are generated by more than 23,000 human genes through alternative splicing. If we account for additional spliceforms at the population level, arising from genetic variants and somatic variants including those responsible for cancers (which affect RNA processing), the number is much larger. Affinity-based approaches generally cannot differentiate between spliceforms, whereas unbiased MS-based approaches survey proteins at the peptide level, enabling differentiation between spliceforms. Peptide-level resolution is critical for identifying biologically important novel cancer biomarkers, as we demonstrated in our Nature Communications paper (Blume et al. ). Using data from that paper, we identified several biomarkers at the peptide level that would have been missed if we had only focused on overall protein expression, including bone morphogenic protein 1 (BMP1). In a new paper currently in press with a peer-reviewed journal (Donavan et al. ), we find that the known spliceforms of BMP1 exhibit differential abundance in cases and controls; the single short form is more abundant in cancer cases, while the long forms are more abundant in controls. In that paper, we propose a mechanism to explain the differential abundance based on lack of domains in the short form. This highlights the importance of generating data at the peptide level, which is made possible by the Proteograph Product Suite. 8 Figure 8: Identification of peptide-level variants of BMP1 enabled by an unbiased approach. Peptide-level identification reveals individual BMP1 variants, showing an opposite pattern of differential expression in the short vs. long variants of BMP1 in individuals with non-small-cell lung cancer (NSCLC) compared to normal controls. Our Proprietary Engineered Nanoparticle Technology The Proteograph Product Suite leverages our proprietary engineered NP technology to overcome the limitations of existing methods, and enable an easy-to-use workflow for unbiased, deep, rapid and scalable proteomic analysis. Our proprietary engineered NPs provide unbiased sampling of intact proteins across the dynamic range of the proteome, capturing molecular information at the peptide-level, including protein variants. The NPs eliminate the need for complex workflows required by other unbiased approaches, which we believe will make proteomics more accessible to the broader scientific community. Typically, nanoparticles have a diameter in the tens to hundreds of nanometers, much smaller than a human hair, which has a diameter of 80,000 nanometers. When nanoparticles come into contact with a biological sample, a thin layer of intact proteins rapidly, selectively and reproducibly adsorbs onto their surface, forming what is called a protein “corona.” Additional intact proteins can also bind directly to proteins already attached to the nanoparticle through protein-protein interactions (PPIs), and intact protein complexes may also attach to the nanoparticle directly. Our engineered NPs capture intact proteins across the dynamic range without requiring prior knowledge of proteome composition or designing the assay for specific protein targets. In combination with an unbiased mass spectrometry readout, they reveal molecular information at the peptide level revealing protein variants. At binding equilibrium, which occurs within minutes after our NPs encounter a biosample, the selective sampling of proteins by our NPs is robust and highly reproducible. 9 Figure 9: Nanoparticles allow unbiased interrogation of proteoform diversity. Our nanoparticle technology leverages engineered physicochemical properties to reproducibly bind to proteins without prior knowledge, forming a protein corona. The binding of proteins to the nanoparticle surface and protein sampling are primarily driven by three factors: (i) the affinity of a particular protein for the physicochemical surface of a specific nanoparticle; (ii) the concentration of a specific protein in a biological sample; and (iii) the affinity of the proteins for other proteins on the surface of the nanoparticle, forming PPIs. A variety of materials and methods are used to create different nanoparticles with distinct physicochemical properties, which generate a unique protein corona pattern and a unique proteomic fingerprint. As the amount of proteomic data increases, we will continue to refine the unique physicochemical properties of our NPs with advanced machine learning. By combining nanoparticles in an assay, we can achieve a representative and thorough sampling across the dynamic range of the proteome, from high- to low-abundance proteins. In this way, we can replace complex biochemical laboratory workflows for the preparation of samples for deep, unbiased MS, enabling the capture of thousands of proteins from biofluids for large-scale proteomics studies. Nanoparticles can interrogate almost any solubilized biological sample, including cell or tissue homogenates, blood or blood components (such as plasma or serum), urine, saliva, cerebrospinal fluid and synovial fluid. This versatility, we believe, strongly suggests that a vast universe of different nanoparticles with different physicochemical properties could be employed across a broad range of sample types, to selectively, reproducibly and deeply sample the proteome in an unbiased way. The Proteograph Product Suite leverages the power of our proprietary engineered NPs to: • eliminate complex workflows required by other unbiased proteomic approaches; • enable unbiased sampling of a variety of biological samples across the dynamic range of the proteome; • identify and distinguish protein variants at the peptide level; • identify and quantify protein variants; • create a workflow that is compatible across a wide range of laboratory workflows, automation equipment, and sample processing and detection methods; and • facilitate broad product adoption. Using machine learning, we are able to design, synthesize and select different NPs and combinations of NPs to create multiple products and applications. We have validated our NP technology and the principle of protein corona formation as a robust and reproducible method to deeply and broadly profile the proteome in a high-throughput manner. We have characterized our technology and its performance in three peer-reviewed publications: Nature Communications (Blume et al. ), PNAS (Ferdosi et al. ), and Advanced Materials (Ferdosi et al. ). 10 The Proteograph Product Suite The Proteograph Product Suite is an integrated solution consisting of consumables, an automation instrument, and software to perform unbiased, deep proteomic analysis at scale in a matter of hours. We designed the Proteograph workflow to be efficient and easy-to-use, and to leverage common laboratory instrumentation to enable adoption in both centralized and decentralized settings, making deep, unbiased proteomics accessible to nearly any lab. The Proteograph consumables consist of our NPs and all other consumables necessary to assay samples in an automated workflow on our SP100 automation instrument. Our automated workflow is custom configured for researchers to assay samples in approximately seven hours, which includes 30 minutes of hands-on time and six and a half hours of automated instrument time. The output from the Proteograph workflow consists of peptides ready to be processed and evaluated on an MS instrument. The Proteograph Product Suite is detector agnostic and, we believe, will be adaptable to other protein detection instruments in the future. The MS component of the Proteograph workflow is either provided by the researcher’s laboratory or can be outsourced to a third-party provider. We estimate that there are approximately 16,000 MS instruments with configurations typically used to perform proteomic analysis installed worldwide and, therefore, we believe that MS systems are readily accessible to researchers. The Proteograph Analysis Suite, a data analytics software suite, provides quality control and allows researchers to analyze and interpret the output from the system to gain insights from their data. Figure 10: Proteograph Product Suite comprises consumables, an automation instrument, and software. Consumables For our first Proteograph assay, we employ a panel of five NPs, assay buffers and reagents for protein lysis and digestion, peptide purification, peptide quantification and the reconstitution of lyophilized materials. We designed the performance specifications of the Proteograph Product Suite to meet the core needs of the market in terms of protein coverage and sample throughput required for proteomic experiments that are unbiased and at-scale. The current product allows for the interrogation and processing of up to 16 samples in parallel on a single 96-well plate in approximately seven hours. Each sample incubates separately with each of the five nanoparticles, yielding 80 wells of peptides in a 96-well plate. The remaining 16 wells are reserved for integrated quality control samples to ensure consistent process performance and to aid in troubleshooting. The ready availability of non-particle reagents, combined with our ability to efficiently design and fabricate different NPs with different chemical properties, greatly facilitates the development and production of future iterations or additional versions of the Proteograph assays to address potential customer needs, such as expanded protein coverage or specialized assays. Additionally, we can introduce new assays that allow for higher throughput of samples or lower sample volumes. We expect our second Proteograph assay to be available in 2023. Automation Instrument We designed the Proteograph assay to be run in a robust and automated manner on our SP100 automation instrument, which is a custom-configured, industry-standard, liquid handling workstation. Our SP100 instrument is designed to enable studies of hundreds to thousands of samples, with an automated workflow that allows for rapid, highly-parallel sample processing with 30 minutes of set-up time. We believe the flexibility of our instrument, coupled with the inherent diversity of our NP technology, provides a runway for many future potential applications and workflows. The Proteograph workflow is driven by the Instrument Control Software (ICS) on the SP100 automation instrument. The workflow has been configured to process one full 96-well plate at a time, in just seven hours, processing 16 samples in parallel. Future workflows and products will be able to be run on the SP100 automation instrument with an accompanying software update. The output of the Proteograph workflow consists of peptides that are quantified, dried, and can be reconstituted when ready for injection into a mass spectrometer. MS provides quantitative unbiased detection, either on an instrument provided by the user, or sent out for MS analysis to a third-party provider. Software The Proteograph Analysis Suite (PAS) is designed for ease-of-use and efficiency to help users arrive at insights quickly. To accommodate varying customer needs, we have designed the PAS to be cloud-based and, in the future, to be available via more localized solutions that accommodate different customer types and geographies. The PAS offers a predefined workflow for data management and analysis, leveraging publicly available MS data analysis tools as well as our own proprietary analysis tools. Without the PAS, proteomics analysis requires expert knowledge and a scalable high-performance computer infrastructure. We believe that the PAS can accelerate adoption of the Proteograph among non-experts by providing an intuitive user interface that automates data handling, simplifies processing and analysis and provides access to a scalable infrastructure that can be used by any lab. Currently, one potential roadblock for researchers is understanding and evaluating the quality of their results. The Proteograph Assay Kit incorporates a series of controls for monitoring assay performance, and an integrated view of the results of these control runs via the PAS. Customers can evaluate trends over time and implement performance boundaries around the expected values that flag unexpected outcomes in the data. We believe providing a simple, consistent interface to evaluate the control data and generate a quality control (QC) report will help customers understand our approach to QC in the Proteograph workflow, simplifying support. In the third quarter of 2022, we launched the latest version of our Proteograph Analysis Suite, PAS 2.0, which incorporates a proteogenomic workflow that maps peptide-level data to genomic data to identify sample-specific variant peptides not captured in canonical reference databases. The workflow provides interactive tables and plots, enables visualization of identified peptides’ relationship to gene structure, protein domain information and functional regions; and creates amino acid-level browsable peptide data maps. We believe PAS 2.0’s intuitive visualizations make it faster and easier to discover protein targets for a wide range of applications. As we continue to improve and extend our product portfolio, we expect to continue to expand the capabilities and features in PAS. Some examples include large dataset management, advanced data analysis tools and applications such as PPI analysis, PTM mapping, transcriptomic, genetic polymorphisms, multi-omics integration and systems biology framework analysis. Proteograph Product Suite Performance The Proteograph Product Suite provides five essential capabilities: (i) broad protein sampling with peptide-level resolution; (ii) deep coverage; (iii) accurate and precise measurement; (iv) reproducibility and (v) scalability for high-throughput studies. We believe that our integrated solution is the only product in the market that combines all 12 of these technical and operational capabilities. Furthermore, we rigorously measure and evaluate each of these technical attributes, as we describe below. • Breadth of protein sampling. This capability refers to conducting unbiased, highly-parallel sampling of the proteome. Each uniquely engineered NP selectively captures hundreds of distinct intact proteins from a biosample based on their abundance and affinity for the NP surface. This sampling capability is particularly strong in complex biofluids such as plasma. Our unique NPs capture significantly more proteins than current methods of unbiased proteomic analysis, as shown in Figure 11 below. In a head-to-head experiment, we directly compared the breadth of the Proteograph Product Suite to other unbiased proteomics methods using the same biological sample. Neat plasma, which represents the simplest form of unbiased proteomic analysis requiring minimal processing time using another method, resulted in a breadth of coverage of 750 proteins. By adding processing steps such as depletion of high-abundance peptides and fractionation (separation of the remaining proteins into multiple fractions), the breadth of protein sampling increased to 1,596 proteins. However, using the Proteograph Product Suite, we detected 2,998 proteins in plasma, representing a major expansion in breadth of protein coverage. The Proteograph is not limited to a defined set of proteins, and samples across the dynamic range of proteins and protein variants that may be present in biosamples. We have exemplified the utility of the Proteograph in studying secreted proteins across several different sample types, including cell or tissue homogenates, blood or blood components (such as plasma or serum), urine, saliva, cerebrospinal fluid, synovial fluid and conditioned media. Across these studies, over 10,000 distinct proteins have been identified. When factoring in potential variants of these proteins, we believe the number of sampled proteins could be considerably larger. Importantly, the Proteograph protein data is obtained using an MS detector, which is the gold standard for proteomics, and data is conventionally reported with a one percent False Discovery Rate (FDR). This means that the reported proteins are identified with 99% confidence. • Depth of coverage. The Proteograph is able to evaluate the proteome across a wide dynamic range of protein abundance. Figure 11 compares our assay’s depth of coverage to that of other scalable unbiased proteomic methods (i.e., 4x versus neat digestion) and not scalable unbiased proteomic methods (i.e., 2x versus fractionation and 3.5x depletion workflows). The Proteograph assay samples proteins across the entire dynamic range of the plasma proteome, as defined in the Human Plasma Proteome Project database (Schwenk et al .). The dotted vertical line in the center panel represents the 75th percentile point of depth of coverage for each method. The Proteograph assay reaches further into low-abundance proteins than fractionation, depletion or neat plasma methods as noted by the dotted line being furthest to the right of all workflows. Lastly, Figure 11 describes the peptide level resolution of each approach and shows approximately the same relative ratios of peptide counts as the corresponding protein group counts. The 17,703 peptides quantitatively measured by Proteograph in this single experiment provide additional information and potentially significant biological insight into protein variants. Figure 11: The Proteograph identifies more proteomic content. The Proteograph workflow identifies 4x more protein groups than alternative MS-based workflows (left). Depth of the Proteograph captures protein groups spanning high to low abundance across the dynamic range versus alternative MS-based workflows (center). Additionally, the 13 Proteograph better resolves the complexity of the human plasma proteome at the peptide-level versus other MS-based methods (right). • Accuracy of measurement. This capability measures how close the measured abundance of a protein is to the true abundance in a sample. The true abundance of large number of proteins at a protein variant level at scale is not independently possible, so we use the ratio of abundances in two samples to demonstrate the accuracy of protein abundance measurement. We demonstrate the accuracy of protein abundance measurement by mixing two different plasmas in different ratios and measuring the relative MS signal intensity. By spiking human plasma with bovine plasma, the Proteograph can detect and quantify peptides that are unique to the bovine proteome. Peptides differ between the two species because of genetic differences that result in detectable changes at the amino acid level. By mixing the two plasma samples, the Proteograph can make measurements across thousands of peptides, highlighting the Proteograph Product Suite’s real-world accuracy. Panel A of Figure 12 shows how the change in MS intensity or intensity fold change varies when mixing the two plasmas at different ratios. Panel B of Figure 12 shows the results of this experiment, looking at threefold changes: 2X, 5.5X, and 11X. At each level, the dashed line is the expected fold change. The gray bars represent the distribution of bovine unique peptides for a neat plasma workflow, and the teal bars represent the unique bovine peptides detected by both the Proteograph and the neat workflow. In all cases, the median of each distribution is close to the dashed line, indicating the median fold change is close to the expected value. Figure 12: The Proteograph offers a high-degree of accuracy. (A) Three representative pairs of spiked-in samples and the expected fold changes of bovine proteins concentration in these pairs. (B) Distribution of observed fold changes of bovine proteins for three selected comparisons of spiked-in samples. The color indicates the data source: (i) neat digestion (gray), or (ii) Proteograph workflow constrained to proteins also identified in neat (teal). The horizontal dashed lines indicate the expected fold changes. 14 • Reproducibility of measurement. Reproducibility, also referred to as precision, is a measure of the consistency of protein abundance measurements (i.e., MS measured intensity) between repeated measurements of the same sample. A higher reproducibility indicates lower noise, which reduces the number of samples required to observe a true fold change in the study. Reproducibility is usually measured as the coefficient of variation (CV%), which is the standard deviation divided by the mean multiplied by 100. A lower CV% represents a more precise measurement. The CV across individual components of the workflow, including the Proteograph instrument and the mass spectrometry instrument, aggregate to form the overall CV% of the workflow (Figure 13; left panel). The typical CV% of MS instrumentation, derived by running the same peptide mixture in consecutive MS injections, is approximately 10%. Using the Proteograph assay to make protein measurements within a single plate adds approximately 7%, for a total CV of about 17%. Running a study across multiple plates and days adds further MS and Proteograph variability for a total system CV% of approximately 20%. Using data acquired over a long-running study, the Proteograph can derive power curves illustrating the power to detect fold changes of different sizes (Figure 13; right panel). For example, 1.5-fold and two-fold changes in protein abundance can be detected with 90% power in sample sizes of 192 and 66, respectively. Typical biological cohorts are much larger than this to capture biological variability and so we believe that the reproducibility of the Proteograph is well-calibrated for biomarker discovery and clinical proteomics. Figure 13: (A) contributors to CV; (B) smaller fold changes can be detected with increased power with larger study sizes. • Scalability . The Proteograph Product Suite enables rapid and large-scale proteomic sample processing in a seven-hour workflow, compared to other unbiased solutions that can take days to weeks. With our current assay, we can process sixteen samples in a single run of the Proteograph SP100 instrument. Therefore, a single Proteograph Product Suite coupled with two MS instruments can process 48 samples in approximately two and a half days for unbiased and deep proteomic analysis. In comparison, the unbiased workflows developed by leading proteomics labs can take weeks for sample preparation and MS measurement to reach an equivalent depth of proteomic coverage. We believe that the Proteograph will be attractive to researchers who are looking for an easy-to-use, scalable approach with a unique combination of attributes spanning breadth, depth, accuracy, reproducibility and precision of measurement, and the speed and throughput necessary for large-scale proteomics studies. Furthermore, the peptide-level data that the Proteograph Product Suite provides at scale are crucial for gaining novel biological insights. Markets We believe that the Proteograph Product Suite has two primary near-term markets: the approximately $24 billion global proteomics market, and the $26 billion global genomics market, as reported by Allied Market Research and Technavio, respectively. Potential applications of the Proteograph could span several areas, including basic research and discovery, translational research, diagnostics and applications. The proteomics market is estimated by Allied Market Research to have spent $18 billion on reagents, $4 billion on instruments, and $1.5 billion on services in 2021. We believe that we will be competing in both the proteomics reagent and instrument markets in the near term, 15 while our service provider customers and Centers of Excellence (COEs) will be accessing the services component. According to Technavio, the genomics market consists of approximately $16 billion spent on products and $9.5 billion spent on services. We believe that we will similarly be able to attract spending on both products and services as genomic customers link genotype to phenotype by supplementing existing genomic data with proteomics data. These applications can be used across basic research, translational research, pharmaceutical, commercial and contract research organization (CRO) customer segments. We currently sell and market the Proteograph Product Suite for research use only (RUO). However, we believe that the capabilities of the Proteograph Product Suite may enable other applications in the future. We may in the future seek premarket approval or clearance for the Proteograph Product Suite in order to allow our customers to use the Proteograph in other product offerings. We expect that the Proteograph Product Suite’s unique value proposition will appeal to proteomics researchers who value deep and unbiased proteomic information and seek to scale experiments to much larger sample sizes with greater speed and efficiency. Moreover, we believe that as more genomics researchers incorporate other -omics approaches to elucidate key genomic findings, the Proteograph will uniquely provide large-scale, unbiased and deep proteomic information to complement genomic information, and enable researchers to gain a clearer picture of both biology and genomic risk factors. We anticipate that in the longer term, the capabilities of the Proteograph and future products may yield new end-markets, applications and business models that complement existing proteomics and genomics markets. Proteomics According to Allied Market Research, the global proteomics market was valued at approximately $24 billion in 2021, and is expected to grow to $49 billion in 2026, representing a 15% compound annual growth rate. The market is divided into three categories, 61% focused on drug discovery, 34% on disease diagnosis and 5% on other applications. Products in the proteomics market include spectrometry, microarray and chromatography instruments as well as reagents, for both unbiased and biased proteomics. However, most proteomic analyses of high dynamic range samples to date rely on biased or targeted methods or expensive, complex, and laborious unbiased or de novo deep methods, which are limited to analyzing only tens of samples instead of the thousands needed to power large-scale studies. Few methods are based on capture of intact proteins that enable analysis of proteome complexity at the level of amino acid variants, PTMs and PPIs, all of which have the potential to generate important biological insights. We believe that the unique capabilities of the Proteograph Product Suite will appeal to researchers, either as a complement or alternative to current approaches, or as a wholly-novel way to survey the proteome. We estimate that there are approximately 16,000 MS instruments with configurations typically used to perform proteomic analysis installed worldwide. By leveraging the installed base of MS instruments, we believe we can accelerate adoption of the Proteograph’s technology. The Proteograph could be a robust alternative to both unbiased and biased proteomics approaches, particularly in the discovery of new biology insight. As a result, the Proteograph has the potential to grow the proteomics market by enabling new applications for unbiased proteomics spanning research, translational and clinical settings. Genomics According to Technavio, the global genomics market was valued at approximately $26 billion in 2021, and is expected to reach $42 billion by 2026, representing a compound annual growth rate of approximately 10%. We believe that large-scale deep, unbiased proteomics studies enabled by the Proteograph could provide important missing biological information to improve the functional characterization of genomic variants, enabling large-scale proteogenomics. Complementing large-scale genomics analysis with large-scale proteomic analysis could enhance and accelerate our understanding of biology and human health, and ultimately the treatment of disease. Therefore, we believe the Proteograph solution can attract an increasing number of genomics customers, especially those in translational settings, who are looking to leverage multi-omics approaches to further annotate genomic variants in terms of function and connect genotype to phenotype. New Markets We also believe that the Proteograph Product Suite, similarly to the commercial impact of a broadened access to genomics products, will enable novel applications and insights, leading to new end-markets. For example, non- 16 invasive prenatal testing and precision oncology currently make up a significant part of the current genomics market, which would have been difficult to predict a decade ago. We anticipate that the same dynamic of new market creation will occur in proteomics, with one such application for proteomics being early disease detection. In the third quarter of 2020, we spun out a new entity, PrognomiQ, Inc. (PrognomiQ), which is developing novel early detection diagnostic tests that leverage the Proteograph Product Suite in combination with other -omics, including genomics, metabolomics and lipidomics. More broadly, we believe the Proteograph solution has the potential to further stimulate growth of new applications and end-markets in additional ecosystems. The Advantages of the Proteograph Product Suite We believe the Proteograph Product Suite and its underlying NP technology have unique advantages: • The first commercially available solution to combine unbiased, deep, rapid and large-scale access to the proteome. Other proteomics technologies currently exist, but we believe that the Proteograph Product Suite fills a gap by providing all four attributes in a single solution with an easy-to-use workflow. • Provides unique insight into protein variation at the peptide level, with a depth and scale that sets a new standard for unbiased and deep proteomics. The Proteograph’s ability to capture protein variations at scale enables synergistic insights when combined with genomic variations, yielding informative individualized models of biology at population scale. • Allows for wide adoption by customers in both decentralized and centralized settings. The Proteograph Product Suite is an integrated solution that includes consumables, an automation instrument and software, and was designed to deliver ease-of-use, efficiency, robustness and reproducibility of results and to complement existing laboratory infrastructure. Its simple and integrated workflow enables the customer to use their own MS instrument or leverage a widely available installed base of MS instruments. We believe these features will facilitate broad adoption of the Proteograph solution across a variety of laboratories and institutions in both decentralized and centralized settings. • Offers a core technology with the potential for development of a range of products, applications and platforms. Our diverse and expanding library of NP surfaces can support the development of new products catering to various applications and customer needs. We are using machine-learning techniques and conducting large-scale analyses to understand relationships between NP surfaces and protein binding in order to design our future products. • Provides core technology with significant operational leverage in research and development, manufacturing and commercialization. NP-based products are efficient to design, develop and manufacture. We believe that by leveraging our understanding of NP surfaces, software and analytics capabilities, we can rapidly develop new products. Our NP manufacturing process uses well-characterized inputs and methods, which require relatively modest investments in capital equipment and space. This capital-efficient and labor-efficient model has high operating leverage potential. • Presents a solution with sustainable differentiation. The Proteograph is uniquely capable of generating robust, reproducible, deep and unbiased proteomic data. As this data is used by more customers to generate insights, we believe this cycle will fuel further adoption of the Proteograph Product Suite throughout the industry. The Proteograph workflow is fully integrable with customer workflows and provides a unique user experience with the support of our software packages, making it a sustainable solution within customer organizations. Our NP technology, SP100 automation instrument, and software are protected by numerous issued patents and pending patent applications worldwide, covering improvements in NPs, assay methods and ways to leverage proteomic data and information for life sciences research, clinical diagnostic and drug discovery applications. 17 Our Strategy Our mission is to imagine and pioneer new ways to decode the secrets of the proteome to improve human health. Our growth strategy is to: • Drive adoption of the Proteograph Product Suite to enable researchers to create large-scale unbiased proteomic datasets that generate transformative scientific insights. Our Proteograph Product Suite uniquely enables researchers and clinicians to generate unbiased, deep proteomic information at speed and scale not previously possible. These capabilities have broad application, spanning basic research and discovery, translational research, diagnostics and applied applications. • Invest in market development activities to demonstrate the importance of large-scale proteomic data and the ability to access it . To expand and accelerate demand for our products, particularly as new applications are developed and adopted by customers, we plan to invest in market development activities to educate prospective customers, funding bodies, commercial entities, government-sponsored -omics programs, and other stakeholders of the importance of large-scale unbiased and deep proteomic data. This effort will likely include collaborations with key opinion leaders, generation of peer-reviewed publications, sponsorship of targeted projects, joint publications and seminars, and industry partnerships. We plan to demonstrate the value of large-scale unbiased and deep proteomic data, as well as the unique capabilities offered by our products. • Innovate continuously to develop and commercialize additional transformative products to access the proteome and accelerate our understanding of biology. We aim to continuously innovate and develop new products, applications, workflows and analysis tools that simplify and accelerate researchers and clinicians’ ability to generate proteomic data and to connect proteomic data to genomic and transcriptomic data that drive novel biological insights. As leaders in NGS have demonstrated, our sustainable advantage will come from continual development and commercialization of new products and applications based on our technology. We will drive innovation through both internal R&D projects and from collaborations with customers and partners. • Build our commercial infrastructure and manufacturing capabilities to enable expansion of our global customer base. We are establishing our commercial infrastructure to sell and support our products directly in the United States, the European Union,and United Kingdom. We are expanding access to our products in other geographies, starting with select countries in Asia Pacific through distributors, and eventually to the rest of the world. We are also scaling our manufacturing capabilities in our facility in Redwood City, California, and will continually evaluate and optimize our manufacturing and supply chain footprint to meet our business objectives. • Foster the creation of an ecosystem of customers, partners and collaborators whose expertise and offerings complement and enhance the power and utility of our products. We intend to seed and develop a new ecosystem of applications and organizations based upon large-scale proteomic analysis. This ecosystem could include areas such as disease detection, large-scale population studies, agriculture, environmental monitoring and food safety. To help seed the growth of this ecosystem, we spun-out PrognomiQ, which is developing and will commercialize diagnostic tests for early disease detection, leveraging the Proteograph Product Suite in combination with other -omics technologies. • Expand our proprietary engineered NP technology to analyze molecules beyond proteins. We intend to expand the scope of our proprietary engineered NP technology to analyze other biomolecules, such nucleic acids and metabolites. As we continue to work closely with our customers, we will better understand their needs and requirements, which will inform our product development pathway and development of our library of NPs and our software capabilities to address other -omics applications. The Applications of the Proteograph Product Suite We believe the ability to generate unbiased, deep, proteomic data at scale, with rich content at the protein variant level, will have a wide range of applications in proteomics, including basic research and discovery, translational research, diagnostics and applied markets. This data can be used in many of the same application areas as genomics 18 data, as well as proteomics applications that are uniquely possible with unbiased proteomic data, and in new applications that the field will develop in the future. In addition, the Proteograph Product Suite’s versatility allows it to analyze not only plasma and serum, but also other biofluids across humans and model organisms. For example, when we compared the performance of the Proteograph Product Suite workflow with that of neat biological samples across model organism plasma, urine, cerebral spinal fluid, and conditioned media, we noted superior protein group identification by the Proteograph of 4x, 1.5x, 1.5x, and 8.6x, respectively. Importantly, in each sample, we measured tens of thousands of data points at the peptide level, providing information on thousands of proteins. We believe this extensibility offers researchers a powerful and flexible tool to utilize across a variety of applications and sample types. Basic Research and Discovery Applications We believe that the Proteograph will be a valuable tool for researchers across a wide range of basic research and discovery applications, including cataloging protein diversity, proteogenomics and exploring the interactome. Studies in these areas are currently limited in scale by the complexity of unbiased methods or the limited set of affinity-based reagents available for biased methods. The Proteograph Product Suite is designed to enable the use of unbiased proteomic data at scale, which we believe will greatly accelerate these areas of basic research and discovery. Cataloging protein diversity The Proteograph Product Suite is designed to enable researchers to explore the complexity and diversity of the proteome with peptide level resolution. We anticipate that researchers will use the Proteograph solution to catalog protein variants in a manner similar to the cataloging of genetic variants over the past 15 years, providing functional context at a scale that is not currently accessible with other proteomics methods. We believe that the identification of protein variants, including those resulting from PTMs such as glycosylation and phosphorylation, has the potential to significantly transform the life sciences field. Proteogenomics Proteogenomics is a rapidly growing field of research that integrates genomic and transcriptomic information with proteomic information, using personalized protein sequence databases to identify novel peptides. The Proteograph generates large-scale unbiased proteomic data, enabling researchers to map protein variants to genomic variants, advancing the field of proteogenomics. We anticipate that as researchers conduct large-scale proteomics studies with the Proteograph, proteogenomic content will rapidly increase, providing functional information to existing genomics and gene expression information. Translational Research Applications Researchers can use the Proteograph for translational research applications aimed at shortening the time from early discovery research to clinical application. The Proteograph Product Suite allows clinical and translational researchers an opportunity to perform unbiased, deep and large-scale proteomics studies in therapeutic and diagnostic research and clinical trials, which can allow for significant advances in biomarker discovery, target identification and exploration and clinical trial applications. Biomarker Discovery Currently, de novo biomarker discovery research is limited by the size of unbiased studies or is targeted in nature. These approaches have yet to uncover the large number of potential single biomarkers or combinations of markers for a range of clinical applications. The Proteograph has the potential to enable the discovery of biomarkers through large-scale, unbiased and deep proteomics studies. Target Identification and Exploration We believe that large-scale access to protein variant information that map to different states of health and disease, as enabled by the Proteograph and concurrent advances in proteogenomics, could lead to the discovery of personalized 19 drug targets that could number in the hundreds of thousands. We believe that the translational application of the Proteograph for potential biomarker development may also be applied to the identification of novel targets for therapeutic development. Components of classifiers may themselves become targets for drug development, or they may point to new knowledge with respect to disease mechanisms, which could then aid in the exploration of additional targets and/or help to elucidate the function of potential targets, particularly if these targets are discovered with genomics approaches, but lack protein functional context. Clinical Trial Applications The Proteograph Product Suite provides clinical researchers with the opportunity to perform deep and broad proteomic profiling of subjects in therapeutic clinical trials, enabling the real-time monitoring of protein-related drug effects, distribution and metabolism. These attributes are essential in virtually all clinical drug trials. Current methods use biased or targeted panels of proteins. It is currently impractical to do this type of monitoring with unbiased proteomic methods, given the inability of these methods to scale to the hundreds or thousands of samples that are evaluated in clinical trials. The Proteograph Product Suite may also enable patient selection and grouping based on patients’ proteomics profiles, leading to improved ability to confirm efficacy for novel therapies in complex diseases that involve multiple physiological systems. While genomic approaches are widely used to select patients in cancer and rare genetic disease clinical trials, their use in other indications has been limited by a lack of genetic understanding of these diseases. We believe that the Proteograph has the potential to generate useful proteomic signatures that can complement genomic and other patient selection criteria, improving patient selection and segmentation for clinical trials, particularly for indications outside of cancer and rare genetic diseases. Diagnostic Applications We believe that the Proteograph Product Suite also holds significant diagnostic potential. The unbiased, deep and scalable proteomic data generated by the Proteograph has the potential to create ecosystems, similar to the way in which NGS enabled genomics-based diagnostics for cancer and rare genetic diseases. We expect that companies in the healthcare testing space, including our spin-out PrognomiQ, will utilize the Proteograph solution, and we are committed to supporting all of our customers as the ecosystem grows, not only in their basic research and translational research applications but also as they develop their own diagnostic applications. Applied Applications in Agriculture, Animal Health, Environmental Monitoring and Food Safety We see significant opportunities for the Proteograph solution to be applied in areas beyond human health, including areas where broad-scale genomics is being widely applied today, and applications where proteomics can uniquely enable the creation of end-markets. We believe that unbiased, deep and large-scale proteomic information, which can be enabled by the Proteograph, can complement and extend the value of genomics, transcriptomics and metabolomics information in fields such as agriculture, animal health, environmental monitoring and food safety. Given the robustness of the Proteograph Product Suite and the ability of its core NP technology to work across species, we believe there is significant interest and an attractive market opportunity for implementation of the Proteograph Product Suite in model organisms and the animal health markets to pursue opportunities in diagnostic and therapeutic development. We have already demonstrated the application of the Proteograph Product Suite in projects in mouse, pig, feline, chicken, canine, baboon and bovine plasmas. PrognomiQ In August 2020, we made a strategic decision to transfer certain assets related to disease testing to PrognomiQ, a wholly owned subsidiary of the Company, in exchange for all of its outstanding equity interests. Following the transfer, we completed a pro-rata distribution to our stockholders of most of the shares of capital stock of 20 PrognomiQ. Following the distribution and two subsequent financings of PrognomiQ totaling approximately $102 million, we hold approximately 15% of the outstanding equity in PrognomiQ. The rationale for this transaction was to enable the growth of ecosystems around new applications that leverage unbiased, deep and large-scale proteomic information. The transaction allows us to remain focused on our core strategy of providing proteomics solutions to all customers across these ecosystems, rather than potentially competing with, or creating the perception that we are competing with, our customers. Our relationship with PrognomiQ does not preclude us from selling the Proteograph Product Suite to any customer in any geography, nor does it preclude our customers from using the Proteograph in any way. PrognomiQ seeks to combine the protein data from the Proteograph with genomics and other -omics data, to develop a multi-omics approach to health and disease testing. We believe this initiative will increase the adoption of the Proteograph Product Suite in these applications. Omid Farokhzad, our Chief Executive Officer and President, and Chair of our board of directors, also serves as the Chair of PrognomiQ’s board of directors. Philip Ma, Ph.D., our former Chief Business Officer, serves as the Chief Executive Officer and President of PrognomiQ. While Dr. Ma has fully transitioned to PrognomiQ, he will continue to consult until April 2023 at which time, Dr. Ma’s consulting agreement will automatically renew for subsequent one year terms unless and until terminated. Commercial Commercial Strategy We are focused on developing the market for deep, unbiased, rapid proteomics at scale by improving accessibility to our technology and growing the installed base of the Proteograph across a wide variety of customer types. We believe that enabling breakthrough science, demonstrating the power of our technology and catalyzing new applications and markets will lead to increased utilization of the Proteograph Product Suite by our customers. We are initially focused on research applications for the Proteograph Product Suite and selling and marketing the Proteograph for RUO. We started broad commercialization of the Proteograph Product Suite in January 2022 and shipped 22 instruments in 2022, bringing our total system shipments to 39 as of December 31, 2022. Our market development efforts are focused on creating a body of evidence to support unbiased, deep proteomics at-scale by establishing relationships with key thought leaders and driving programs that make it easier for labs of all types to undertake first-of-their-kind studies. We believe that paving the way with standards, methods and proof in the form of published data empowers the scientific community to move forward more rapidly. • Centers of Excellence (COE) Program: We have partnered with select service facilities and core labs globally to be Centers of Excellence for the Proteograph. These sites have become our customers and provide fee-for-service capabilities that allow interested parties to access and evaluate the Proteograph Product Suite using their own samples. We expect that these COEs will actively promote the Proteograph solution and its capabilities, help us further raise awareness, and increase the accessibility of the Proteograph to a wider range of customers. • Proteogenomics Consortium: We have formed the Proteogenomics Consortium (PGC) to accelerate access to proteogenomic studies in partnership with Discovery Life Sciences (Discovery) and SCIEX, with the stated eventual goal of developing capacity to analyze 100,000 samples annually. Discovery announced in December 2022 that it is accepting customer samples for analysis. • Key Opinion Leader (KOL) Relationships: The generation of publications and scientific presentations is a core pillar of our market development strategy and is important for establishing validity and utility of new disruptive products in the life sciences community. We are working closely with our customers, including KOLs, to generate clear use-cases, as well as peer-reviewed publications that illustrate the Proteograph’s performance claims and value proposition. • Commercial Partnerships: We have partnered with leading mass spectrometry instrumentation providers, including Thermo Fisher Scientific, Bruker Corporation and SCIEX to establish partnerships that include 21 lead sharing, co-marketing, and co-development of end-to-end workflows to enable broad education of the market as well as easy-to-implement workflows. • Geographic Partnerships: As we expand geographically, we have partnered to enable access in key regions, such as China, where Enlight Medical is our distribution partner and they educate, develop and expand the market for the Proteograph Product Suite. We are initially targeting potential customers who value unbiased and deep proteomic information and are performing proteomic or genomic analysis at academic institutions, translational research groups and biopharmaceutical companies. Our direct sales and marketing efforts are focused on the principal investigators, researchers, department heads, research laboratory directors and core facility directors who control the buying decisions. We expect these customers to purchase the Proteograph Product Suite and associated consumables in line with typical purchases of other life science instrumentation and consumables. We believe that we have priced the Proteograph Product Suite to be affordable to most researchers who can direct buying decisions, without the need for additional levels of approval, simplifying our sales process. For example, we price the SP100 automation instrument comparably to other similar automated fluid handling systems currently available. We price the Proteograph consumables, on a per-sample basis, in a range similar to that of other life sciences consumables that provide deep and unbiased -omics information. To service our Proteograph customers, we provide multiple levels of technical service for the Proteograph Product Suite, depending upon the customer's needs. We recognize that excellent customer support can be a critical part of a customer experience, and we will invest accordingly in our technical and application support to achieve the desired levels of service. Commercial Organization We are currently building out our commercial organization across Marketing, Sales, and Customer Experience functions to support demand, with the goal of delivering an exceptional customer experience. We believe that coupling an exceptional customer experience with a transformative product will allow us to deliver substantial value to our customers, build long-term customer loyalty, enhance our competitive differentiation and, importantly, use our customer relationships to gain insights that inform our product development to grow our offerings in ways that will benefit our customers. In North America, the United Kingdom and select countries of the European Union, we have direct sales and customer experience personnel, including Regional Business Managers (RBM), Field Application Scientists and Field Service Engineers. In addition to these direct personnel, we have significant marketing, customer experience and technical support personnel located in our offices in Redwood City and San Diego, California. The RBM are focused on identifying potential customers who have a strong interest in deep, unbiased proteomics and access to sufficient sample cohorts and capital to help drive long-term usage. They work closely with our marketing personnel to identify, qualify and close these customer opportunities. The Field Application Scientists also help in the sales process, they are primarily responsible for ensuring that customers have an exemplary experience once a purchase has been made. This ranges from providing customer training to working with each customer to help them optimize their methods and applications. Our Field Service Engineers perform installation and provide on-site service support for any technical problems or repairs that are needed. In China, we have entered the market through our distribution partner, Enlight Medical, who provides sales, marketing, distribution and customer support services. We will continue to evaluate entering other geographies and countries over time and will likely initially enter those markets through distribution partners. 22 Suppliers and Manufacturing Our overall manufacturing strategy is to continuously develop and refine our processes to achieve our objectives of continuity of supply, quality of supply and margin enhancement. Over time, this may lead to in-sourcing or outsourcing certain functions, including manufacturing, in various geographic locations in order to achieve our objectives. Consumables We leverage well-established unit operations to formulate and manufacture our NPs at our facilities in Redwood City, California. We procure certain components of our consumables from third-party manufacturers, which includes the commonly-available raw materials needed for manufacturing our proprietary engineered NPs. We are currently manufacturing using our production-scale and pilot lines and continue to build out our manufacturing capabilities to support broad commercial availability of our products. We obtain some of the reagents and components used in the Proteograph workflow from third-party suppliers. While some of these reagents and components are currently sourced from a single supplier, these products are readily available from numerous suppliers. While we currently perform some filling and packaging of the Proteograph assay and the related consumables, we may eventually have our filling and packaging outsourced to a third party. We conduct vendor and component qualification for components provided by third-party suppliers and quality control tests on our NPs. Automation Instrument We designed the SP100 automation instrument and have outsourced its manufacturing to Hamilton Company, a leading manufacturer of automated liquid handling workstations. We have entered into a non-exclusive agreement with Hamilton that covers the manufacturing of the SP100 automation instrument and its continued supply on a purchase order basis. The agreement has an initial term that runs three years following our commercial launch. We have the option to extend the term of the agreement with Hamilton upon written notice at the end of the initial term; provided that prices are only fixed during the initial term of the agreement. Hamilton has represented to us that it maintains ISO 9001 and ISO 13485 certification. Competition The life sciences technology industry is highly dynamic, marked by rapidly advancing technologies, intense competition and a strong focus on intellectual property. In the proteomics market, companies offer a range of analytical instruments, such as chromatography and MS instruments, and associated reagents. Competition in the proteomics market is based on proprietary technologies, rapid product development capabilities, applications and intellectual property. We believe that no currently commercially available products offer the capability to conduct unbiased, deep proteomics studies of high dynamic range samples at the same scale and throughput as the Proteograph Product Suite. However, given the potential market opportunity and scientific promise of proteomics, we expect the competition to increase and, as a result, one or more competing products to emerge in the future. Competing products may emerge from various sources, including life sciences tools, diagnostics, pharmaceutical and biotechnology companies, third-party service providers, academic research institutions, governmental agencies, and public and private research institutions. Current companies that provide proteomics products include Agilent Technologies, Bruker Corporation, Danaher, DiaSorin and Thermo Fisher Scientific. There are also a number of companies that provide proteomic analysis services. In addition, multiple emerging growth companies have developed, or are developing, proteomics products, services and solutions, such as Nautilus Biotechnology, Olink Proteomics, Quanterix, Quantum-Si and SomaLogic. Government Regulation The development, testing, manufacturing, marketing, post-market surveillance, distribution, advertising and labeling of certain of medical devices are subject to regulation in the United States by the Center for Devices and Radiological Health of the U.S. Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act (FDC Act) and comparable state and international agencies. FDA defines a medical device as an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent or other similar or related article, including 23 any component part or accessory, which is (i) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or (ii) intended to affect the structure or any function of the body of man or other animals and which does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes. Medical devices to be commercially distributed in the United States must receive from the FDA either clearance of a premarket notification, known as 510(k), or premarket approval pursuant to the FDC Act prior to marketing, unless subject to an exemption. We label and sell our products for RUO and expect to sell them to academic institutions, life sciences and research laboratories that conduct research, and biopharmaceutical and biotechnology companies for non-diagnostic and non-clinical purposes. Our products are not intended or promoted for use in clinical practice in the diagnosis of disease or other conditions, and they are labeled for research use only, not for use in diagnostic procedures. Accordingly, we believe our products, as we intend to market them, are not subject to regulation by FDA. Rather, while FDA regulations require that research use only products be labeled with – “For Research Use Only. Not for use in diagnostic procedures.” – the regulations do not subject such products to the FDA’s jurisdiction or the broader pre- and post-market controls for medical devices. In November 2013, the FDA issued a final guidance on products labeled RUO, which, among other things, reaffirmed that a company may not make any clinical or diagnostic claims about an RUO product, stating that merely including a labeling statement that the product is for research purposes only will not necessarily render the device exempt from the FDA’s clearance, approval, or other regulatory requirements if the totality of circumstances surrounding the distribution of the product indicates that the manufacturer knows its product is being used by customers for diagnostic uses or the manufacturer intends such a use. 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. 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. We continue to monitor the changing legal and regulatory landscape to ensure our compliance with any applicable rules, laws and regulations. In the future, certain of our products or related applications could become subject to regulation as medical devices by the FDA. If we wish to label and expand product lines to address the diagnosis of disease, regulation by governmental authorities in the United States and other countries will become an increasingly significant factor in development, testing, production, and marketing. Products that we may develop in the molecular diagnostic markets, depending on their intended use, may be regulated as medical devices or in vitro diagnostic products (IVDs) by the FDA and comparable agencies in other countries. In the U.S., if we market our products for use in performing clinical diagnostics, such products would be subject to regulation by the FDA under pre-market and post-market control as medical devices, unless an exemption applies, we would be required to obtain either prior 510(k) clearance or prior premarket approval from the FDA before commercializing the product. The FDA classifies medical devices into one of three classes. 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. 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. This FDA review process typically takes from four to twelve months, although it can take longer. Most class I devices are exempted from this 510(k) premarket submission requirement. If no legally marketed predicate can be identified for a new device to enable the use of the 510(k) pathway, the device is automatically classified under the FDC Act as class III, which generally requires PMA approval. However, FDA can reclassify or use “de novo classification” for a device that meets the FDC Act standards for a class II device, permitting the device to be marketed without PMA approval. To grant such a reclassification, FDA must determine that the FDC Act’s general controls alone, or general controls and 24 special controls together, are sufficient to provide a reasonable assurance of the device’s safety and effectiveness. The de novo classification route is generally less burdensome than the PMA approval process. Devices deemed by the FDA to pose the greatest risk, such as life-sustaining, life-supporting, or implantable devices, or those deemed not substantially equivalent to a legally marketed predicate device, are placed in class III. Class III devices typically require PMA approval. To obtain PMA approval, an applicant must demonstrate the reasonable safety and effectiveness of the device based, in part, on data obtained in clinical studies. All clinical studies of investigational medical devices to determine safety and effectiveness must be conducted in accordance with FDA’s investigational device exemption (IDE) regulations, including the requirement for the study sponsor to submit an IDE application to FDA, unless exempt, which must become effective prior to commencing human clinical studies. PMA reviews generally last between one and two years, although they can take longer. Both the 510(k) and the PMA processes can be expensive and lengthy and may not result in clearance or approval. If we are required to submit our products for pre-market review by the FDA, we may be required to delay marketing and commercialization while we obtain premarket clearance or approval from the FDA. There would be no assurance that we could ever obtain such clearance or approval. All medical devices, including IVDs, that are regulated by the FDA are also subject to the quality system regulation. Obtaining the requisite regulatory approvals, including the FDA quality system inspections that are required for PMA approval, can be expensive and may involve considerable delay. The regulatory approval process for such products may be significantly delayed, may be significantly more expensive than anticipated, and may conclude without such products being approved by the FDA. Without timely regulatory approval, we will not be able to launch or successfully commercialize such diagnostic products. Changes to the current regulatory framework, including the imposition of additional or new regulations, could arise at any time during the development or marketing of our products. This may negatively affect our ability to obtain or maintain FDA or comparable regulatory clearance or approval of our products in the future. In addition, regulatory agencies may introduce new requirements that may change the regulatory requirements for us or our customers, or both. As noted above, although our products are currently labeled and sold for research purposes only, the regulatory requirements related to marketing, selling, and supporting such products could be uncertain and depend on the totality of circumstances. This uncertainty exists even if such use by our customers occurs without our consent. If the FDA or other regulatory authorities assert that any of our RUO products are subject to regulatory clearance or approval, our business, financial condition, or results of operations could be adversely affected. For example, in some cases, our customers may use our RUO products in their own laboratory-developed tests (LDTs) or in other FDA-regulated products for clinical diagnostic use. The FDA has historically exercised enforcement discretion in not enforcing the medical device regulations against LDTs and LDT manufacturers. 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. In January 2017, the FDA announced that it would not issue final guidance on the oversight of LDTs and LDT manufacturers, but would seek further public discussion on an appropriate oversight approach and give Congress an opportunity to develop a legislative solution. More recently, the FDA has issued warning letters to genomics labs for illegally marketing genetic tests that claim to predict patients’ responses to specific medications, noting that the FDA has not created a legal “carve-out” for LDTs and retains discretion to take action when appropriate, such as when certain genomic tests raise significant public health concerns. As laboratories and manufacturers develop more complex genetic tests and diagnostic software, FDA may increase its regulation of LDTs. 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. 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. 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. International sales of medical devices are subject to foreign government regulations, which vary substantially from country to country. In the future, if we decide to distribute or market our diagnostic products as IVDs in Europe, such products will be subject to regulation under the IVD Medical Device Regulation (IVDR) European Union (EU) 25 2017/746, which replaces the IVD Directive, is significantly more extensive than the IVD Directive, including requirements on performance data and quality system, and went into application in May 2022. Recently, the European Parliament voted to extend the transition timelines for IVDR. Outside of the EU, regulatory approval needs to be sought on a country-by-country basis in order to market medical devices. Although there is a trend towards harmonization of quality system, standards and regulations in each country may vary substantially which can affect timelines of introduction. In August 2020, the Department of Health and Human Services (HHS) announced rescission of guidance and other informal issuances of the FDA regarding premarket review of LDT absent notice-and-comment rulemaking, stating that, absent notice-and-comment rulemaking, those seeking approval or clearance of, or an emergency use authorization, for an LDT may nonetheless voluntarily submit a premarket approval application, premarket notification or an Emergency Use Authorization request, respectively, but are not required to do so. In November 2021, HHS under the Biden administration issued a statement that withdrew the August 2020 policy announcement stating that HHS does not have a policy on LDTs that is separate from FDA’s longstanding approach. 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). In September 2022, Congress passed the FDA user fee reauthorization legislation without substantive FDA policy riders, including the VALID Act, but Congress may revisit the policy riders and enact other FDA programmatic reforms in the future. 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. Any restrictions or heightened regulatory requirements on LDTs, IVDs, or RUO products by the FDA, HHS, Congress, or state regulatory authorities may decrease the demand for our products, increase our compliance costs, and negatively impact our business and profitability. We will continue to monitor and assess the impact of changing regulatory landscape on our business. In the future, to the extent we develop any clinical diagnostic assays, we may pursue payment for such products through a diverse and broad range of channels and seek coverage and reimbursement by government health insurance programs and commercial third-party payors for such products. In the United States, there is no uniform coverage for clinical laboratory tests. The extent of coverage and rate of payment for covered services or items vary from payor to payor. Obtaining coverage and reimbursement for such products can be uncertain, time-consuming, and expensive, and, even if favorable coverage and reimbursement status were attained for our tests, to the extent applicable, less favorable coverage policies and reimbursement rates may be implemented in the future. Changes in healthcare regulatory policies could also increase our costs and subject us to additional regulatory requirements that may interrupt commercialization of our products, decrease our revenue and adversely impact sales of, and pricing of and reimbursement for, our products. For further discussion of the risks we face relating to regulation, see the section titled “Risk factors—Risks related to our business and industry.” The federal Health Insurance Portability and Accountability Act of 1996 (HIPAA), as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 (HITECH), and their implementing regulations, which impose obligations, including mandatory contractual terms, with respect to safeguarding the transmission, security and privacy of protected health information by covered entities subject to HIPAA, such as health plans, health care clearinghouses and healthcare providers, and their respective business associates that access protected health information. HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates in some cases, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions. In addition, in the U.S., numerous federal and state laws and regulations, including state data breach notification laws, state health information privacy laws, and federal and state consumer protection laws, govern the collection, use, disclosure, and protection of health-related and other personal information. For example, in June 2018, the State of California enacted the CCPA, which came into effect on January 1, 2020 and provides new data privacy rights for consumers and new operational requirements for companies. 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 26 liability. 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. The GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data, including requirements relating to processing health and other sensitive data, obtaining consent of the individuals to whom the personal data relates, providing information to individuals regarding data processing activities, implementing safeguards to protect the security and confidentiality of personal data, providing notification of data breaches, and taking certain measures when engaging third-party processors. The GDPR also imposes strict rules on the transfer of personal data to countries outside the EEA, including the United States, and permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million or 4% of annual global revenues, whichever is greater. The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the GDPR. In addition, the GDPR includes restrictions on cross-border data transfers. 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. 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. Further, the United Kingdom’s decision to leave the EU, often referred to as Brexit, has created uncertainty with regard to data protection regulation in the United Kingdom. As of January 1, 2021, and the expiry of transitional arrangements agreed to between the United Kingdom and EU, data processing in the United Kingdom is governed by a United Kingdom version of the GDPR (combining the GDPR and the Data Protection Act 2018), exposing us to two parallel regimes, each of which potentially authorizes similar fines and other potentially divergent enforcement actions for certain violations. Pursuant to the Trade and Cooperation Agreement, which went into effect on January 1, 2021, the United Kingdom and EU agreed to a specified period during which the United Kingdom will be treated like an EU member state in relation to processing and transfers of personal data for four months from January 1, 2021. This period may be extended by two further months. Furthermore, following the expiration of the specified period, there will be increasing scope for divergence in application, interpretation and enforcement of the data protection law as between the United Kingdom and EEA. For further discussion of the risks we face relating to regulation, see the section titled “Risk factors—Risks related to our business and industry.” Intellectual Property Our success depends in part on our ability to obtain and maintain intellectual property protection for our products and technology. We use a variety of intellectual property protection strategies, including patents, trademarks, trade secrets and other methods of protecting proprietary information. As of December 31, 2022, we owned or exclusively licensed over 125 issued patents and patent applications worldwide. Our intellectual property portfolio includes patents and patent applications directed to proteomic assays, nanoparticle chemistry, data analysis and automation instruments. Our owned or exclusively licensed patents and patent applications, if issued, are expected to expire between 2023 and 2043, in each case without taking into account any possible patent term adjustments or extensions and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees. We exclusively license U.S. patents and patent applications, as well as ex-U.S. patents and pending patent applications from The Brigham and Women’s Hospital (BWH). These patents and patent applications are directed to methods for identifying a biological state, including classification and early detection of cancers and other diseases, using nanoparticle and biosensor compositions, as well as other nanoparticle compositions. Our in-licensed patents and patent applications, if issued, are expected to expire between 2027 and 2037, in each case without taking into 27 account any possible patent term adjustments or extensions and assuming payment of all appropriate maintenance, renewal, annuity, or other governmental fees. In addition to licensing patents and patent applications from BWH, we have also non-exclusively licensed certain of our patents and patent applications to PrognomiQ for use in the field of human diagnostics. Pursuant to our agreement with PrognomiQ, we also assigned a patent application related to lung cancer biomarkers to PrognomiQ. In connection with our agreement with PrognomiQ, we have granted PrognomiQ a non-exclusive sublicense to certain patents and patent applications that we license from BWH under our license agreement with BWH for use in the field of human diagnostics. For further information on the intellectual property transfer and license agreement with PrognomiQ and the license agreement with BWH, see the section titled “Business —Collaboration and License Agreements.” We intend to pursue additional intellectual property protection to the extent we believe it would be beneficial and cost-effective. Our ability to stop third parties from making, using, selling, offering to sell, importing or otherwise commercializing any of our patented inventions, either directly or indirectly, will depend in part on our success in obtaining, defending and enforcing patent claims that cover our technology, inventions, and improvements. With respect to both our owned and in-licensed intellectual property, we cannot provide any assurance that any of our current or future patent applications will result in the issuance of patents in any particular jurisdiction, or that any of our current or future issued patents will effectively protect any of our products or technology from infringement or prevent others from commercializing infringing products or technology. Even if our pending patent applications are granted as issued patents, those patents may be challenged, circumvented or invalidated by third parties. Consequently, we may not obtain or maintain adequate patent protection for any of our products or technologies. In addition to our reliance on patent protection for our inventions, products and technologies, we also rely on trade secrets, know-how, confidentiality agreements and continuing technological innovation to develop and maintain our competitive position. For example, some elements of manufacturing processes, analytics techniques and processes, as well as computational-biological algorithms, and related processes and software, are based on unpatented trade secrets and know-how that are not publicly disclosed. Although we take steps to protect our proprietary information and trade secrets, including through contractual means with our employees, advisors and consultants, these agreements may be breached or may be unenforceable and we may not have adequate remedies. In addition, third parties may independently develop substantially equivalent proprietary information and techniques or otherwise gain access to our trade secrets or disclose our technology. As a result, we may not be able to meaningfully protect our trade secrets. For further discussion of the risks relating to intellectual property, see the section titled “Risk factors—Risks Related to our Intellectual Property.” Collaboration and License Agreements The Brigham and Women’s Hospital In December 2017, we entered into an exclusive patent license agreement with BWH, pursuant to which we obtained an exclusive, royalty-bearing, sub-licensable (with approval from BWH) license to certain U.S. and foreign patents and patent applications in one patent family related to methods for identifying a biological state using nanoparticle and biosensor compositions and other nanoparticle compositions to develop, manufacture, use and commercialize products and processes in all fields, including but not limited to therapeutic, diagnostic, or other uses, on a worldwide basis. In addition, we were also granted an exclusive, royalty-bearing, sub-licensable (with approval from BWH) license to certain U.S. pending patent applications in another patent family to develop, manufacture, use and commercialize products and processes in all fields, including but not limited to therapeutic, diagnostic, or other uses, other than for the treatment of cancer through antigen-specific immune stimulation or the treatment of disease through immune tolerance or immune switching of lymphocyte subclasses. We may sublicense the patent rights licensed under the agreement subject to certain conditions, including obtaining the review and approval by BWH of such sublicense and any such sublicense must be consistent with and subject to the terms of the agreement. In consideration for the licenses granted under the agreement, we must pay BWH annual license fees and a low single digit royalty on net sales of licensed products in any country during the term of the agreement, which is credited against the annual license fees. In the event we commercialize a product in the therapeutic space, we are 28 also required to make certain drug-approval regulatory and commercialization milestone payments to BWH of up to a mid-seven digit figure in the aggregate for licensed products. In the event we sublicense any of the licensed intellectual property, we must pay BWH a percentage of any sublicense income received by us, which on a going-forward basis will be in the high single digits. Under the terms of the agreement, we are required to use commercially reasonable efforts to develop and commercialize the licensed products, including in accordance to certain developmental, funding, regulatory and commercialization milestones. BWH controls the prosecution, maintenance and enforcement of all licensed patents and patent applications under the agreement. Unless earlier terminated, the agreement continues until the expiration of the last to expire patent right licensed under the agreement. Subject to an applicable cure period, BWH may terminate the agreement if we fail to comply with applicable payments or diligence obligations or upon a breach of our obligation under the agreement, or for certain insolvency-related events. PrognomiQ In August 2020, we entered into an intellectual property transfer and license agreement and, in October 2020, we entered into an intellectual property sublicense agreement, in each case with PrognomiQ in connection with the spin-out of PrognomiQ. Under the intellectual property transfer and license agreement, we granted PrognomiQ a non-exclusive, perpetual, irrevocable (subject to termination for breach) license to certain patents and patent applications that we own and, under the intellectual property sublicense agreement, we granted a non-exclusive sublicense to certain patent applications exclusively licensed from BWH, in each case, relating to our core technology to develop, manufacture and commercialize licensed products for the field of human diagnostics on a worldwide basis. In addition, we assigned a patent application relating to lung cancer biomarkers, and transferred certain clinical samples, contracts and other related assets to PrognomiQ. PrognomiQ may extend such licensed and sublicensed rights to customers of licensed products. PrognomiQ is not required to pay us any royalties or fees pursuant to the intellectual property transfer and license agreement. In consideration of the non-exclusive sublicense to certain patent applications licensed from BWH, PrognomiQ paid us a low-five digit figure, and would pay a low single digit royalty, in an amount equivalent to what we would have to pay under our license with BWH, on net sales of sublicensed products beginning with the first commercial sale of a sublicensed product during the term of the intellectual property sublicense agreement. In the event we elect to grant an exclusive license to a third party in the field of human diagnostics for any of the patents and patent applications licensed or sublicensed, as applicable, to PrognomiQ under the respective agreements, we are required to first negotiate with PrognomiQ for a period of sixty days for a license or sublicense, as applicable, to such rights on reasonable terms. Furthermore, for a period of two years after the effective date, we are required to negotiate in good faith with PrognomiQ for a license or sublicense, as applicable, to any improvements to the patents and patent applications assigned or licensed or sublicensed, as applicable, under the intellectual property transfer and license agreement and the intellectual property sublicense agreement. In an amendment to the intellectual property transfer and license agreement on July 28, 2022, we agreed to extend this negotiation period to three years after the effective date. Neither party may assign the intellectual property transfer and license agreement nor any rights or obligations under the agreement without the other party’s prior written consent, other than to an affiliate or pursuant to an acquisition. PrognomiQ may not assign the intellectual property sublicense agreement or any rights or obligations under the agreement without our prior written consent, other than to an affiliate or pursuant to an acquisition, and in any event only with BWH’s prior written consent. Our right to assign the intellectual property sublicense agreement and any rights or obligations under the agreement is subject to the terms and conditions of our license with BWH. Unless terminated earlier, the terms of both agreements continue until the expiration of the last to expire intellectual property right granted under such agreement. Either party may terminate either agreement for an uncured breach of the other party, upon which all licenses granted under such agreement to the breaching party will terminate. 29 Collaborators As part of the initial Collaboration phase of our completed three-phase commercial strategy for the Proteograph Product Suite, we entered collaboration agreements with Oregon Health & Science University (OHSU), an academic health center, The Broad Institute of MIT and Harvard (Broad Institute), a biomedical and genomic research center, the Salk Institute for Biological Studies, a multi-disciplinary research institute focused on addressing challenging health issues, including cancer, Alzheimer’s and diabetes, and Discovery Life Sciences, a provider of biomedical and genomic research services. We have worked closely with our collaborators to help exemplify applications for the Proteograph Product Suite. For example, researchers at OHSU are using our products to facilitate various research efforts focused on proteomic profiling of various oncology versus control samples to determine protein signatures common between various cancer samples versus signatures found in control samples. Additionally, researchers at the Broad Institute use our products to analyze protein signatures in diseased vs. non-diseased samples undergoing drug perturbations in various clinical applications including cardiovascular disease. Proteogenomics Consortium In January 2022, we entered into an agreement to form the PGC with Discovery and SCIEX. Through this multi-year effort, Discovery will expand and offer deep, unbiased proteomics capabilities to their existing genomics customers using the Proteograph Product Suite and the SCIEX ZenoTOF 7600 platform. The consortium has the objective to build capacity to analyze 100,000 samples per year to enable large-scale, unbiased plasma proteomic studies. In December 2022, Discovery announced the launch of its Proteomics Services Division, which includes services offered by the PGC, and that it is accepting customer samples from pharmaceutical and biotech companies, government, and non-profit and academic research centers. The PGC will offer unbiased, high resolution proteogenomic services to help uncover novel biomarkers that can be mapped back to underlying genetic variations. Scientific Advisory Board We have assembled a highly-qualified scientific advisory board composed of advisors who have deep expertise in the fields of nanotechnology, proteomics, genomics, medicine, regulatory compliance and data science. Our scientific advisory board is composed of Robert Langer, Sc.D., Mostafa Ronaghi, Ph.D., Erwin Böttinger, M.D., Charles Cantor, Ph.D., Bradley Hyman, M.D., Steve Carr, Ph.D., Joshua Coon, Ph.D., Luis Diaz, M.D., Josh Elias, Ph.D., Vivek Farias, Ph.D., Wolfgang Parak, Ph.D. and Ralph Weissleder, M.D. Employees Our employees are guided by our mission to imagine and pioneer news ways to decode the secrets of the proteome to improve human health. Our core values Better Together, Customer Centric, Difference Makers, People First and Trailblazers guide us toward achieving our mission. Our core values set the foundation for how we conduct business, interact with each other and our customers and evaluate employee performance. As of December 31, 2022, we had 164 employees; 160 employees were based in the United States, one employee was based in Canada and three employees were based in the United Kingdom. Many of our employees are highly educated, holding masters and doctorate degrees. Of these employees, 80 were engaged in research and development activities, 21 were engaged in manufacturing and operations and 63 were engaged in selling, general, and administrative activities. We consider our relationship with our employees to be good. None of our employees are represented by a labor union or covered under a collective bargaining agreement. Diversity, equality and inclusion awareness and training were an important part of our 2022 human capital strategy. As of December 31, 2022, 66% of our employees were women and people of color. Our human capital resources objectives include identifying, recruiting, retaining, incentivizing and integrating our existing and new employees, advisors and consultants. The principal purposes of our equity and cash incentive plans are to attract, retain and reward personnel through the granting of stock-based and cash-based compensation awards, in order to increase stockholder value and the success of our company by motivating such individuals to perform to the best of their abilities and achieve our objectives. 30 Corporate Information and History We were incorporated in Delaware on March 16, 2017, under the name Seer Biosciences, Inc., and changed our name to Seer, Inc. on July 16, 2018. Our principal executive offices are located at 3800 Bridge Parkway, Suite 102, Redwood City, California 94065. Our telephone number is 650-543-0000. Our website address is http://seer.bio. Information contained on, or that can be accessed through, our website should not be considered to be part of this Annual Report. We use Seer and Proteograph as trademarks in the United States and other countries. This Annual Report contains references to our trademarks and service marks and to those belonging to other entities. Solely for convenience, trademarks and trade names referred to in this Annual Report, including logos, artwork and other visual displays, may appear without the ® or TM symbols, but such references are not intended to indicate in any way that we will not assert, to the fullest extent under applicable law, our rights or the rights of the applicable licensor to these trademarks and trade names. We do not intend our use or display of other entities’ trade names, trademarks or service marks to imply a relationship with, or endorsement or sponsorship of us by, any other entity. References Published studies referenced throughout this Annual Report are cited below. These studies are not a part of this prospectus and are not incorporated by reference in this Annual Report. Backman, J.D. et al. Exome sequencing and analysis of 454,787 UK Biobank participants. Nature 599, 628–634 (2021) Bludau, I. et al. Proteomic and interactomic insights into the molecular basis of cell functional diversity. Nat Rev Molec Cell Biol 21, 327–340 (2020). Blume, J.E. et al. Rapid, deep and precise profiling of the plasma proteome with multi-nanoparticle protein corona. Nat. Commun. 11 (2020). Buccitelli C. and Selbach M. mRNAs, proteins and the emerging principles of gene expression control. Nat Rev Genet. 21(10):630-644 (2020). Donovan M. et al. Functionally distinct BMP1 isoforms show an opposite pattern of abundance in plasma from non-small cell lung cancer subjects and controls (in press; bioRxiv). Ferdosi, S. et al. Engineered nanoparticles enable deep proteomic studies at scale by leveraging tunable nano-bio interactions. PNAS . 119(11) (2022). Ferdosi, S. et al. Enhanced competition at the nano-bio interface enables comprehensive characterization of protein corona dynamics and deep coverage of proteomes. Advanced Materials . 34, 2206008 (2022). Keshishian, H. et al. Quantitative, multiplexed workflow for deep analysis of human blood plasma and biomarker discovery by mass spectrometry. Nat. Proc. 12 1683-1701 (2017). Keshishian, H. et al. Multiplexed, quantitative workflow for sensitive biomarker discovery in plasma yields novel candidates for early myocardial injury . Molec & Cellular Proteomics 14(9) 2375-2393 (2015). Nakahata and Kawamoto. Tissue-dependent isoforms of mammalian Fox-1 homologs are associated with tissue-specific splicing activities. Nucleic Acid Research 33(7) 2078-2089 (2005). Pietzner, M. et al. Synergistic insights into human health from aptamer- and antibody-based proteomic profiling. Nat Commun. 12, 6822 (2021). Schwenk, J.M. et al. The Human Plasma Proteome Draft of 2017: Building on the Human Plasma Peptide Atlas from Mass Spectrometry and Complementary Assays. J. Proteome Res. 16, 4299-4310 (2017). 31 Yang X. et al. Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell. 164(4):805-17 (2016). Available Information We make our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, and amendments to those reports, available free of charge at our website as soon as reasonably practicable after they have been filed with the SEC. Our website address is http://seer.bio. Information on our website is not part of this report. The SEC maintains a website that contains the materials we file with the SEC at www.sec.gov.