Thank you and good afternoon, everyone. Welcome to today's call, during which we will provide an update on the company and review our fourth quarter and full year 2021 financial results. Earlier today, we issued a press release summarizing our financial results and progress across the company, which is available on our website at schrodinger.com. Here with me on our call today are Ramy Farid, Chief Executive Officer, Joel Lebowitz, Chief Financial Officer, and Karen Akinsanya, President of R&D Therapeutics. Following our prepared remarks, we'll open the call for Q&A.
I'd like to remind you that during today's call, management will make statements related to our business that are forward-looking and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including without limitation, statements related to our future financial performance, including our outlook for the full year 2022 and the quarter ending March 31, 2022. Our strategic goals for 2022 and 2023, the potential advantages of our platform, our strategic plans to accelerate the growth of our software business and advance our collaborative and internal drug discovery programs, risks relating to the COVID-19 pandemic, our expectations related to the use of our cash equivalents, and marketable securities, as well as our future operating expenses.
These forward-looking statements reflect our current views about our plans, intentions, expectations, strategies, and prospects, which are based on the information currently available to us and on assumptions we have made. Actual results may differ materially from those described in the forward-looking statements and are subject to a variety of assumptions, uncertainties, risks, and important factors that are beyond our control, including the demand for our software solutions, our ability to develop our computational platform, our reliance upon our drug discovery collaborators, and other risks detailed under the captioned risk factors and elsewhere in our most recent Securities and Exchange Commission filings and reports. Except as required by law, we undertake no duty or obligation to update any forward-looking statements discussed on this call as a result of new information, future events, changes in expectations, or otherwise.
These forward-looking statements should not be relied upon as representing our views as of any date subsequent to today. During this call, we will also discuss certain financial and operating metrics, which are further described in our financial results, press release, and SEC filings. With that, I'd like to turn the call over to Ramy.
Thanks, Karen, and thank you everyone for joining us today. We are extremely pleased with our execution across all elements of the business in 2021. We continue to drive scale up and adoption of our software, both life sciences and materials science companies. We also progressed our collaborative programs, seven of which are in the clinic, underscoring the impact of our platform. We nominated two development candidates in our wholly owned programs. Total revenue was $137.9 million, a 28% increase over the prior year, and this was capped by fourth quarter software revenue of $38.6 million, a 55% increase over the fourth quarter of 2020. We ended 2021 in a strong financial position with cash resources of approximately $579 million. These achievements set us up for high value milestones in 2022 and a very bright future ahead.
As you'll hear from Karen, we also made excellent progress on our internal pipeline. Our first three internal programs continue to advance toward the clinic, the most advanced of which is expected to enter the clinic later this year. We added two new programs to our pipeline in the areas of oncology and immunology. We now have five wholly owned programs and expect to initiate additional programs this year. To support our drug discovery efforts, we expanded our structural biology capabilities through the acquisition of XTAL BioStructures, a private company based in the Greater Boston area that provides structural biology services to the pharmaceutical and biotechnology industries. With this acquisition, we have access to more structures and will leverage our protein structure refinement methods to scale up production of high resolution structures, which are starting points for our physics-based computational platform.
We have also expanded our global footprint to support multiple areas of our business. In January, we established operations in Seoul, South Korea, to enhance competitive positioning and support both life sciences and material science customers in this region. In December, we expanded our operations in Hyderabad, India. Employees in Hyderabad are focused on a broad range of strategic initiatives across the company, including software development and support of our software platform and our drug discovery programs. I'm also very pleased to announce Karen's promotion to President of R&D Therapeutics. The promotion reflects Karen extraordinary contributions to leading our drug discovery team, as well as her strategic contributions to expanding and advancing our collaborative and wholly owned programs.
We are excited by the many advances we've made over the past year, and we expect continued progress across all aspects of our business, our internal pipeline, our collaborative and partnered programs, and our software business to support both drug discovery and materials design. Looking ahead, we will continue to invest in our computational platform, and we expect continued scale up and adoption of our software as our collaborators and customers continue to experience success in rapidly generating high-quality molecules to advance the next generation of therapeutics and materials.
Before I turn the call over to Joel, who recently announced his retirement at the end of February, I want to thank him for his incredible commitment and service over the past three years, during which time we debuted as a public company, secured additional financing in a follow-on offering, and strengthened our balance sheet to support continued investment across our business. During his tenure, Joel helped create our strong financial profile, contributed to the execution of our strategy, continued to build out our strong finance team, and established the investor relations and corporate affairs function. We wish him the very best in his future endeavors. We are actively searching for Joel's successor, and we are very pleased with the caliber of the candidates we have reviewed so far. I will now turn the call over to Joel to review our financial results.
Thank you, Ramy, and hello, everyone. I'm very pleased to discuss our 2021 financial results and provide our outlook for 2022. I'll start with a review of the fourth quarter. Total revenue was $46.2 million, up 40% compared to the fourth quarter of 2020. Software revenue was $38.6 million, representing 55% growth compared to the fourth quarter of 2020. As was the case throughout the year, the growth in software revenue was primarily driven by increased adoption of our solutions by large customers, as well as the addition of new customers during the quarter. Drug discovery revenue was $7.6 million, compared to $8.1 million in the fourth quarter of 2020.
Operating expense was $48.9 million compared to $35.6 million in the fourth quarter of 2020, reflecting our investment in R&D to advance the science underlying our platform and to progress our internal drug discovery programs, as well as costs required to support a public company infrastructure. We recorded a net loss of $30.7 million compared to a loss of $11.6 million in the fourth quarter of 2020. For the full year, total revenue was $137.9 million, a 28% increase over 2020. Software revenue was $113.2 million, up 22% over 2020, with strong growth in both life sciences and material science. Discovery revenue was $24.7 million compared to $15.6 million in 2020, primarily due to revenue recognized from our collaboration with BMS.
Software gross margin was 77% in 2021 compared to 81% in 2020, reflecting our investment to expand capabilities to drive and support large-scale adoption of our solutions. Full-year operating expense was $177.1 million versus $124.4 million in 2020 as we continue to invest in R&D and in the infrastructure to support our operations. In 2021, we recorded other income of $10.6 million compared to $34.6 million in 2020, driven by changes in the mark-to-market value of our strategic investments. Overall, these results demonstrate the ongoing value creation opportunity of our collaboration strategy. Net loss for the year was $101.2 million compared to a loss of $26.6 million in 2020.
We ended 2021 with cash equivalents, marketable securities, and restricted cash balances of approximately $579 million, compared to approximately $600 million on September 30, 2021. In addition to the financial results we just reviewed, I'd like to report on our key software performance indicators for 2021. Total software annual contract value, or ACV, reached $112.1 million in 2021 compared to $92.1 million in 2020, an increase of 22% year-over-year. For comparison, we also saw a 22% growth in 2020 and 18% growth in 2019. The number of customers with ACV of more than $1 million was 15 compared to 16 in 2020. It's important to note that this change was driven by timing.
Even with this change, the total ACV in this category increased to $40.2 million in 2021, up from $35.5 million in 2020. The total ACV of our top 10 customers was $34.1 million compared to $28.5 million in 2020 for growth of 20%. Customers with ACV over 100,000 increased to 190 from 153 in 2020, a 24% increase. We reported 98% customer retention in this cohort, similar to the 99% retention rate we reported for 2020. Finally, the number of total active customers, those over $1,000 in ACV, in 2021 was 1,647 compared to 1,463 in 2020, a 13% increase year-over-year. We are pleased with the performance across our business.
As we look ahead to this year, we are focused on executing on our strategy and generating long-term growth. At this time, I'll provide our financial outlook for 2022. We expect total annual revenue to be in the range of $161 million-$181 million, corresponding to 17%-31% growth over 2021. Software revenue is expected to range from $126 million-$136 million, representing 11%-20% growth over 2021, approximately 16% at the midpoint. With regard to software, we are very pleased with our track record and excited about the opportunity for continued expansion. Consistent with prior years, we anticipate that revenue will vary from quarter to quarter.
Similar to 2021, we expect the first and fourth quarters to be our largest two revenue quarters, with a larger proportion of the annual revenue coming in the fourth quarter, as was the case in each of the last two years. Accordingly, we expect the second and third quarters to be our lowest revenue quarters, also consistent with previous seasonality patterns. For the first quarter, specifically, we expect software revenue to range from $28 million-$30 million. The range reflects approximately 10% growth over the first quarter of 2021 at the midpoint. We expect drug discovery revenue to range from $35 million-$45 million, reflecting 42%-82% growth over the last year. A significant portion of this revenue is driven by the timing of collaboration programs achieving certain milestones and can therefore vary from period to period.
We are pleased with the continued strong outlook anticipated this year, which reflects progress across our collaborative pipeline and our intention to progress our lead internal programs into phase I clinical development independently. In 2022, we expect the first two quarters to be at revenue levels similar to the first two quarters of 2021, with most of the growth coming in the second half of the year and in particular, in the fourth quarter. I would also like to comment on how we expect operating expense and software gross margin to trend for the year. We anticipate that operating expense growth will be similar to the 42% annual growth rate we saw in 2021, as we invest in advancing our internal programs into the clinic. We also anticipate the software gross margin percentage to be in the mid-70s%.
Overall, we are very pleased with the progress we made last year, which we believe positions us for continued momentum as we look ahead. In addition to the financial outlook for 2022 that we provided today, we have outlined key strategic goals for the next two years. This includes our expectation that we will see further adoption of our software platform with our goal of ACV growth of over 20% in 2023. We also expect an inflection in our drug discovery business with 2023 revenue of at least $100 million. Notably, the drug discovery revenue goal excludes potential revenue from partnering any of our three lead internal programs. I'd like to wrap up on a personal note. I'll be retiring at the end of the month, and I'm looking forward to spending more time with my family before deciding what's next.
It's been an absolute pleasure to be a member of the Schrödinger team over the past three years, working with so many great people, and to be a part of the company's IPO to help advance our strategy over this time and to build the capabilities required to support a global public company. I've greatly appreciated the opportunity to work with all of you as well in the investment community, and I look forward to tracking the company's continued success. I'll now turn the call over to Karen for an update on our drug discovery programs.
Thank you, Joel, and good morning, everyone. In 2021, we continued to make important advances on many fronts across our portfolio of collaborative programs and our internal drug discovery pipeline. We are pleased to see multiple programs advance into preclinical and clinical development. A total of seven collaborative programs are in the clinic, which underscores the impact of our platform. We are excited about Nimbus's recent announcements highlighting the initiation of a phase IIB study of the company's TYK2 inhibitor and initiation of a phase I/II study in their HPK1 program. Our computational software relies upon high-quality 3D protein structures that are obtained from techniques such as X-ray crystallography and cryo-EM. Because accurate structures are also core to our drug discovery business, our strategy includes scaling up our structural biology capabilities and our access to high-quality target structures that are fully enabled for our computational platform.
As part of this strategy, last month we acquired XTAL BioStructures, a private company based in the Boston area that provides structural biology services to the biopharmaceutical industry. Structure-based drug design continues to have a transformative impact on drug discovery, and this acquisition provides a tremendous opportunity for Schrödinger to be at the forefront of this field by combining experimental and computational methods. Additionally, this acquisition will augment our ability to produce high-quality target structures for our drug discovery programs and, in the future, expand our offerings to include an advanced and differentiated service that provides customers access to protein structures that have been computationally validated and are ready for structure-based virtual screening and lead optimization. Now, I will highlight the progress made on our three most advanced internal programs, MALT1, CDC7, and Wee1. Starting with our MALT1 inhibitor program. We have made significant progress in the last year.
MALT1, a regulator of NF-κB that is downstream of BTK, has emerged as a potential therapeutic strategy to treat certain relapsed or resistant B-cell lymphomas and chronic lymphocytic leukemia. In December, we presented preclinical data from this program at the American Society of Hematology annual meeting. The data presented suggest that targeting MALT1 may expand therapeutic options for patients with certain subtypes of non-Hodgkin's B-cell lymphomas, such as ABC- DLBCL, with the possibility of expanding into other B-cell lymphomas, such as mantle cell lymphoma. Furthermore, our preclinical data has shown that our compounds have strong antitumor activity, both alone and in combination with BTK inhibitors to overcome drug-induced resistance in samples derived from patients with relapsed and resistant B-cell lymphomas. We are on track to submit the IND to the FDA for our MALT1 development candidate in the first half of this year.
Subject to regulatory clearance, we expect to initiate our first phase I clinical study of our MALT1 inhibitor in patients with relapsed and resistant lymphoma in the second half of 2022. As our wholly owned programs advance toward the clinic, we have enhanced our team in key areas, including early clinical development, CMC, and regulatory affairs. We have also initiated a search for a chief medical officer to support our clinical development strategy and activities. Now I'll turn to our CDC7 program. CDC7 is a protein kinase that is required for DNA replication initiation. CDC7 is also thought to be linked to cancer cells' proliferative capacity and ability to bypass normal DNA damage responses. Targeting proteins that play important roles in DNA replication and replication stress is gaining momentum as a therapeutic approach for cancer. Last year, we selected a development candidate for our CDC7 program.
We are very pleased with the profile of our molecule, which has demonstrated strong antitumor activity in preclinical models of AML in combination with venetoclax and other marketed agents. IND-enabling studies are progressing. However, the timing of some required toxicology studies, which are performed by a CRO, have been delayed due to COVID-19 related issues. We have secured slots to complete these tox studies later this year, and we now expect to submit the IND to the FDA for our CDC7 candidate in early 2023 and to initiate a phase I clinical study later that same year. I'll now move on to our Wee1 inhibitor program, which also targets cancer through replication stress and DNA repair mechanisms. We have identified multiple highly selective Wee1 inhibitors with desirable drug-like properties that show strong pharmacodynamic responses and antitumor activity in preclinical models.
We believe the profile of our compound supports evaluation in the clinic as monotherapy as well as in combination with other agents. We are on track to select a development candidate later this year and expect to submit an IND to the FDA next year. We are also planning to present preclinical data from our Wee1 program in the first half of this year. As our first three internal programs advance towards the clinic, we are adding new programs to our pipeline. In 2021, we added two new programs, one in oncology and the other in immunology. We now have five wholly owned programs and expect to initiate additional programs this year. In summary, our diverse portfolio of collaborative and internal programs is rapidly advancing towards the clinic.
Activities to support expansion of our pipeline into additional disease areas are well underway, and we have acquired internal structural biology capabilities that will allow us to produce high-quality target structures that are fully enabled for our computational platform. We are excited about the progress that we and our collaborators are making and look forward to updating you on our R&D activities throughout the year. I will now turn the call back over to Ramy.
Thanks, Karen. 2022 has the potential to be another strong year for Schrödinger. Our long-term strategy leverages synergies across our business, and we have laid out several key objectives over the next two years that can generate value and position us for continued success. These objectives include ongoing growth in adoption and scale up of our software platform with ACV growth of over 20% in 2023. Inflection in our drug discovery business with 2023 drug discovery revenue of at least $100 million, which does not include potential revenue from partnering our three lead internal programs. IND submission for our MALT1 program in the first half of 2022 and IND submissions for our CDC7 and Wee1 programs in 2023.
Phase I clinical study initiation for our MALT1 program in the second half of 2022 and phase I clinical study initiation of our CDC7 and Wee1 programs in 2023. Publication of data from internal programs in peer-reviewed forums. Initiation of multiple new internal programs that leverage our structural biology capabilities. Initiation of material science collaborations in multiple verticals such as clean energy and sustainable materials. We have an exceptional team committed to transforming the way therapeutics and materials are discovered, and we look forward to providing updates on our progress throughout the year. At this time, we'd be happy to take your questions. Operator.
As a reminder, if you have a question at this time, please press star one on your telephone keypad. If your question has been answered or you wish to remove yourself from the queue, press the pound key. Once again, that's star one to ask a question. Your first question comes from the line of Do Kim with Piper Sandler. Please go ahead.
Great. Thanks for taking my questions. First, Karen, congrats on the promotion, and Joel, I wanted to wish you well on your retirement. On the fourth quarter earnings, Joel, is there anything specific that you could point to in the quarter that drove the strength in software revenue? As we look at the number of customers with over $1 million in ACV, you said the difference from 2020 to 2021 was a timing. What does that exactly mean?
Sure. Thanks, Do, and thanks for those comments. Appreciate it. With regard to software, we're obviously very pleased with the quarter of 55% growth, the year 22% growth. In the fourth quarter, in particular, we continue to see the trends that we've been seeing all along, which is continued progress of our existing customers, many of whom are our largest customers continuing to increase adoption of our solutions. In the fourth quarter, we saw some really good examples of that, and some of them were pretty large. That really did help drive the business. I'd say the performance in the business in the quarter and the year was also broad-based. We had growth in both life sciences and materials.
If you look at our customers that are over $100,000 in ACV, we had 24% growth, not just in customer count, but also in spend. We clearly had broad-based growth leading to the and culminating in the really strong fourth quarter that we reported. I'd also point out that fourth quarter and the full year was on top of a base year in 2020 that was also very strong. Really good performance, and we're really pleased about the momentum there. With regard to the timing aspect that you asked about with regard to customers over $1 million, it happens to be a contract that was, r enewed in late 2020, and then was renewed again in very early 2022. Just by virtue of a couple of weeks, slipped from that count. It's still a customer and a significant customer.
Okay, got it. I also wanted to ask about the drug discovery revenue guidance for 2023 about at least $100 million. How confident are you on that number? Could you provide some details on the number of underlying programs that it accounts for?
Sure. Thanks, Do. We're, you know, confident in any time we give guidance. We are pretty thorough when we try to look at our business and forecast it out, both in 2022 and 2023. Obviously, there's a number of things that can vary, particularly as you go further out. However, what I would say is, we have a portfolio of collaboration programs that's about 20 programs now, more, plus or minus. The portfolio is pretty broad. We also have seven that are now in the clinic, that's collaboration programs. And then we have a host of programs behind that in the collaboration portfolio that are approaching the clinic. In general, the opportunity to earn larger and larger milestones comes as these programs progress.
We map out program by program what our opportunities are, and we risk adjust and we're providing an outlook that we believe that we will achieve. It's really important to note that that's really the baseline for the collaboration business, that goal that it does not include any potential revenue from if we partner any of our three lead internal programs.
Okay, that's great. A question for Karen. What's left in the MALT1 IND filing before you get to that? Have you done a pre-IND meeting with the FDA as planned?
Thanks, Do. We are complete with our GLP tox studies, and we are in that last phase of planning for the IND submission. We have actually had an opportunity to interact with the agency as you're pointing out. We think that gives us a lot of opportunity to submit a package that's well considered, and we expect that to happen, as we said, in the first half of this year.
Great. Thanks for taking my questions and congrats on the quarter.
Thanks, Do.
Thanks.
Thank you. Your next question comes from the line of Vikram Purohit with Morgan Stanley. Please go ahead.
Great. Thanks for taking my questions. The first one was on the software sales guidance for 2022. You guided to a range of an 11% to, I believe, a 20% increase over 2021 at the bookends. Could you just talk about what you think drives performance to either side of those bookends of guidance? Then I have a follow-up.
Sure, Vikram, we can talk about that. Again, we're coming off of a strong year. We see these underlying trends in both our large existing customers continuing to increase adoption of our solutions. We have had pretty steady addition of new customers for a long time now. We think we can continue growing at a strong pace over a multiple year period. In 2022, as you said, we've guided to a range of that equates to 11%-20% growth. The bookends, as we've described before, really center around how much progress we can make in getting our largest customers to really significantly commit fully and extensively to our approach to drug discovery.
As we've talked about in the past, the gap between even our largest customers' deployment of our solutions, though they're getting larger and larger, but the gap between their deployment of our solutions and the level at which we deploy our solutions on our internal programs and our collaboration programs is still very large. It's still at a fraction of what we think is optimal, that is the deployment by our customers. We're working continuously to move customers along that path. We're making great progress. We showed a lot of that in the fourth quarter, and we're excited about the conversations we're having around that, and we think there's a lot of opportunity there.
Obviously, the more that happens, the more towards the top end of the bookend you are, but it's unpredictable. If for whatever reason, those decisions take a little longer or the upsizing is not quite as extensive as we will be working towards, you know, that sends you towards the bottom end. That's kind of the natural variation in the software outlook.
Okay. Understood.
I would also add, Vikram, we're very pleased with the track record of execution we've had, though, over the last two years. You know, I think we're confident that we can continue to have these discussions and succeed in getting them to move along that path, not just this year, in 2022, but over the longer term as well.
Great. Understood. That's helpful. I had a follow-up on your wholly-owned pipeline. You mentioned that there were two molecules added recently, I think one in immunology, one in oncology. I'd just be curious to get your thoughts on how you prioritize which mechanisms and which molecules you decide to add to your pipeline? And how you weigh kind of the mix of scientific rationale, development pathways, and commercial opportunity when making these decisions? On a related note, what is the cadence at which you think you could be expanding this pipeline further in 2022 and 2023?
Vikram, thanks for the question. In terms of the selection of programs, we're really focused on targets and mechanisms that we believe have preclinical and more importantly, human evidence. That means some evidence from initial clinical studies for a particular mechanism or indeed human genetics or both. We don't think it's appropriate for us to take a lot of risk on the biology. The targets that we select are both well-positioned for our platform in terms of our ability to solve specific design challenges. We also look very closely at the clinical landscape, the biomarker opportunities, our ability to generate compelling clinical data in early trials, and obviously the longer term potential of the mechanism as it relates to the broader landscape for the indication.
All of that goes into consideration, and as I said, the key design challenges that we think we can solve with our platform. I think your second question was regarding capacity, and growth of the pipeline. We have added the two programs in immunology and oncology. We're looking at a number of programs right now, in feasibility, that we believe will be replacements for the programs that are graduating out of the pipeline or the discovery pipeline, into IND enabling and clinical studies. That means that we'll be keeping a steady state of around five wholly owned programs. Over time, that may change, but for now, we think that's a good number for us, in the discovery portfolio.
Understood. Thanks a lot. Appreciate it.
Thank you. Your next question comes from the line of Michael Yee with Jefferies. Please go ahead.
Okay. Thanks, everyone. This is Andrew Tsai for Michael Yee. First question is on the software guidance again for 2022. I'm just trying to gauge whether you think your current guidance is conservative. So maybe talk about whether, you know, you think your business is fundamentally accelerating and maybe to kind of discuss, whether there's even more upside to what you've guided to, or, you know, do you think the bookends that you provided is fair based on what you're seeing out there? Thanks. That's my first question.
Thanks, Andrew. Yes, we establish our guidance based on what we believe our outlook is, and we're confident in our guidance. I'd say that at the same time, as we look at the business over a longer period of time and what we think is possible over a multi-year period. We think that, as I said, the pathway for our largest customers to continue to upsize their deployment is significant. It and we have a lot of opportunity for growth there. We have proven that we're able to attract new customers to the business pretty consistently. We anticipate that both those trends is evidenced by the overall ACV growth of 22% in 2021 will have the opportunity to continue over a long period of time.
If you look at 2023, the strategic goal that we've outlined of greater than 20% ACV in 2023, that's an indicator that we are confident in the strong continued growth in the business.
Thanks. On the drug discovery, again, I know you expect that inflection there in 2023, which excludes, you know, partnerships for your lead compounds. I'm curious what your latest thinking actually is for these lead compounds? Do you have any intention to partner them out even in 2022, if not 2023? You know, would you be considering like a multi-target thing like the Bristol deal? Or would you know, at this stage, partner out a specific program? Just your latest thinking would be helpful. Thank you.
Yeah. I can take that, Andrew. We continue speaking with potential companies who would partner with us in the way that we did with BMS. There's obviously a lot of interest in accessing this platform at scale as we have done across our existing collaborative portfolio. As you know, for the BMS collaboration, we partnered some programs really early on in the life cycle of those efforts. Yeah, there's obviously potential for us to do similar partnerships. With regard to our wholly owned advanced assets, we have intentions to take those into the clinic, as you've heard today. We do, though, continue to talk to companies who have synergistic agents, PARP inhibitors, BCL-2 inhibitors, for example, that we think will combine well or BTK inhibitors for that matter for MALT1.
Our intentions, as I said, are to generate initial clinical data with these. In the event that a partner that we think makes sense for us is interested in partnering earlier than that, we certainly have those conversations and make the right decision for the company at that time.
Thanks. Last question is just the inflection in 2023. Is that gonna be like a one-off thing, or, you know, is that like the new sustained level beyond 2023? Thanks.
Yeah. Andrew, we're not providing guidance beyond 2023 at this point, but what we'll say is that we do see because of the business and the portfolio progressing that you know, there's a real opportunity to drive very strong revenue in the discovery business. We've indicated a level for you in 2023 to think about. I think that shows you the kind of business that we think it can be both in terms of the very strong growth rate that would imply but also just in terms of the size of that business as our portfolio continues to mature. Remember I said that we have seven programs that are collaboration programs that are already in the clinic and a whole slew that are right behind them.
It's a robust business that is starting to emerge, and we're excited about the revenue growth opportunities going forward.
Okay. Thank you everyone for all the color. Appreciate it. Congrats.
Thanks.
Thank you. Your next question comes from the line of Matt Hewitt with Craig-Hallum Capital. Please go ahead.
This is Lucas on for Matt Hewitt. I guess for my first question, you know, when we look at the large expansions that were signed in Q4, did all of that revenue get recognized during the quarter, or do some of those licenses not switch on until January?
Sure, Lucas. Yes. The four-
You want to?
Yeah, I will. Thanks. Thanks, Ramy. Fourth quarter is our largest volume quarter in terms of renewals. Also, we did have some large expansions as well this quarter. Some of those are for fourth quarter recognition and fourth quarter contract starts, and some are for contract starts that flip over to the new year and therefore get recorded in deferred revenue at the end of the year. You can see that our deferred revenue software balance increased by 22% year-over-year versus the fourth quarter of 2020. That also shows us a large increase, and that's reflective of the fact that some of the bookings that we have in the fourth quarter do in fact get recognized in the first quarter as revenue.
Excellent. That's helpful. For my second question, historically, customers have had to do some crystallography work on their own before adopting your software? Now that you've acquired XTAL and can do that work for them, do you foresee an increase in adoption for the software?
Yeah, that's a really great question. This is Ramy. I'll answer that. That's a really great question. Absolutely. That's a big part of the strategy that, you know, we saw when acquiring the company. That's not necessarily something that you'll see right away, of course. I mean, that will take time. Our expectation is not just also from the acquisition, but it's from many efforts that we've undertaken in increasing the availability of high quality structures. As we succeed in that endeavor, then we will certainly see an increase in the demands of the software.
Thanks. That's all I had.
Thanks.
Thanks, Lucas.
Thank you. Your next question comes from the line of Gary Nachman with BMO Capital Markets. Please go ahead.
Hi, good afternoon and nice quarter, guys. On your software growth-
Thanks.
In 2022, in an inflationary environment, can you take price on your software programs? Is that baked in there at all to your guidance and the growth in the ACV, I guess, that we saw in 2021, and maybe that would spill over into 2022? And how much of the growth should be from new business versus existing customers? You're talking, you know, at a high level, maybe you could specify that a little bit more. And how much in terms of the life sciences versus the materials, how much is the materials really accelerating maybe over the next year or two?
Sure. Thanks, Gary. I can take that. With regard to new versus existing business, when we see these opportunities for really large increases in a particular quarter or a year, it tends to be more driven by the upsizing decisions of some of our largest customers. You can imagine, you know, a $1 million customer can, you know, if they triple the size of the contract, then obviously that's a pretty big increase and has an outsized impact on the overall growth rate. And that has been a steady pattern for the last couple of years. But we shouldn't ignore the fact that we are attracting new customers, and it's been really steady.
We are seeing growth in both life science and materials, and in 2021, even though we have a lot of life science customers, we did attract new customers on that side of the business as new biotech's were formed. A lot of them were formed. We're also focusing on different geographic markets as well. We're growing both sides. We're pursuing both strategies for growth. We haven't really broken out the two separately. I would say that the opportunities for these real big jumps though are primarily driven by existing customers deploying our solutions at a much higher level. Can you just remind me what your first question was, Gary? Sorry.
Yes. Yeah, it was on pricing in an inflationary
Right.
environment. Like, are you able to-
Right.
take price on your software programs? Also if there are input costs maybe that go up. We hear other companies that are doing it.
Sure, you know, we have a product offering that is quite valued in the discovery activities, and scientists really need it. We're the largest player in our field, and we're recognized for being able to charge a, you know, a fair price that reflects the value of our products. We do have the ability to increase price, and we do marginal increases generally from time to time. We don't see that though as the primary strategy to drive growth, because the idea is that we really want our customers to just increase the number of licenses to the level that we believe they should.
If they do that, we'll see a multiple effect on our revenue line. That is really our strategy.
Okay, great. Then just a couple more for Karen. Can you talk about what the phase I will look like for MALT1 that you're gonna start in the second half of the year, you mentioned for relapsed and resistant lymphoma. If you could give some specifics on that if you have it. And then just back to you, Ramy. Just you know on expanding operations into South Korea. I'm assuming that's to serve not just South Korea, but maybe the whole Asia PAC region. So maybe you could just talk a little bit about the type of opportunity that you're seeing there. Thanks.
Yep. Karen, you wanna take the MALT1 program?
Sure. Yeah. Gary, we'll be discussing the design of our phase I study in more detail as we progress through the year. What I can tell you is that, this study is focused on safety, tolerability, as you can imagine, in, all comers with, B-cell lymphomas. That's gonna be the initial focus of the study. We are also, of course, thinking about the cohort expansion and, how we'll be assessing, proof of target engagement, as well as proof of biology, in this trial. Again, I think we'll reserve comments on the design of the phase I until we're a little bit further along, at some point this year.
Yeah. Thanks, Karen. Just really quick on the question about South Korea. We already had actually a few distributors in South Korea. So we've been there. We understand the opportunity both on the life science and material science business. We saw the opportunity and recognized the obvious thing that if we established our own operation there, we can capitalize on the significant opportunity there more effectively. We already have operations in a number of other Asian countries. We have K.K., of course, we have distributors in China. We do have a pretty significant operation in India, you know, and other countries in that region through distributors. So I hope that answers the question. The South Korea was specific to the South Korea market for now.
Oh, okay. Just in general, when do you think we'll see more of an inflection, I guess, from that overall region in general? Could that happen this year or will it take a couple of years for that to get going?
Oh, yeah. Yeah. It does take a little bit of time to, you know, establish your presence there and build up the team. We're not guiding to any particular inflection, you know, in a certain region. We've seen, for example, what happened in Japan when we did the same thing a number of years ago when we replaced in some sense, you know, the distributors we had there. This was quite a while ago with our own operation there. We've seen that through investment over many years, we can see pretty significant growth there. It does take some time to build up our presence and when, you know, when you're entering in a new country.
Okay, great. I also wanted to wish the best of luck to Joel, and also congrats to Karen.
Thanks.
Thanks, Gary. I appreciate that.
Thank you.
Okay.
Thank you. Once again, if you would like to ask a question, please press star one on your telephone keypad and wait for your name to be announced. Your next question comes from the line of Derik De Bruin with Bank of America. Please go ahead.
Hey, good evening, and thank you for taking my questions. Just to go back on the, sorry to beat the 2022 guide, for software and circle back on that, but I'm just sort of curious, it's what do you think is the driver to get your customers to spend more and to, you know, how do you upsell them and how they scale up with it, right? I mean, you've got a number of programs currently in the clinic. There's clear need, you know, there's clear use case for using structural biology. The methods are getting better. You've got, you know, you've got AlphaFold, you've got other things out there. So what is sort of that inflection point that drives your customers to say, "Okay, now we have to do this on a much larger scale"?
Yeah. There are a couple of things. One thing is that we think we've really accomplished is what you were talking about, which is it's clear that the technology works and it's having the kind of, you know, the impact that we, I think had always hoped that, you know, computational methods would have. And you see that in our own programs, you see it in collaborative programs, and customers are definitely starting to see it in their own projects. That's kind of, you know, check that box off. Now what remains is a couple of things.
One is that you need people to run the software, and this is software, and we're working hard to do this, to make it as easy to use as possible, and I think we've made a lot of progress in that, but you still need experts. You need computational chemists to run the software. You know, that's something that's gonna take some time. It doesn't happen overnight. We're seeing, by the way, an interesting trend where more and more chemists are transitioning into that field, which is I think a really great sign. That's one thing.
The other thing is what we've been, you know, sort of touching on, which is the availability of structures and the prioritization of programs that are structurally enabled, you know, prioritizing those programs. That, again, is something that takes time, but we're seeing that trend occurring very clearly. You see now essentially every pharma company investing in all sorts of structural biology technologies, including cryo-EM, right? You know, pharma companies are buying their own electron microscopes to do cryo-EM. They're continuing to invest in methods including, you know, methods that we provide in structurally enabling projects. But that obviously also takes time.
Got it. I mean, that certainly makes sense, I mean, based on some of the other-
Mm-hmm.
technologies that we cover.
Yeah.
As a CRO analyst as well, I have to ask the question about the delays in sort of like booking space and like that. Could you just talk a little bit more about that? This is something that you've seen, is it with multiple clients that you're seeing this? Just some sense of what's going on in that area right now in terms of like what really is sort of like the underlying driving it? Just not enough availability, people coming in on top of you, spending more? Just in curiosity.
Sorry. Were you asking about the delays that-
Yes.
Karen mentioned?
Yeah.
Yes.
Yes. The delays that Karen mentioned, right? You mentioned you're having access-
Yeah. Yeah.
At the beginning of this year. Yes. Yes. Yeah. Yeah. Yeah. Yeah. Go ahead, Karen.
Yeah.
Do you wanna? Yeah
Yeah. This has been an emerging story, I think across all of biotech over the last six or so months. We've been along with everyone else, there's a couple of species that are required for GLP tox studies that are simply backlogged around the world. The supply of some of these species is limited, and that's pushing a sort of queue, as it were, for access to a smaller cohort of animals for those studies. We and I think a lot of other companies have been in queue and we're slowly getting access to those slots. As you can imagine, a lot of this work has been going on in China, for example.
Some of the restrictions that have been imposed around COVID-19 have also had an impact. We feel we're on top of it, and we, as I mentioned, have access to our slots for our current DC.
Thanks. Just one final question. It's again on the $100 million in 2023 target. I mean, is that a floor number for 2023, right? I mean, is it or it's basically like what's the bookend on your confidence level around that?
Yeah. Well, the way we've described it is at least $100 million for our collaboration business. We see the portfolio continuing to advance. As I talked earlier, it's a pretty large portfolio now, so we have some diversification and can forecast out with some degree of confidence that we're gonna hit that level that we said at least $100 million. We obviously have the opportunity, if we choose to do so, to capture additional value throughout licensing or partnering any of our lead three internal programs, which is not included in that $100 million.
Great. Thank you very much.
Thank you. Your next question comes from the line of Gaurav Goparaju with Berenberg Capital Markets. Please go ahead.
Hey, guys. How's it going? Thanks for taking my question. Just a quick one from me. You know, of the 190 customers that you guys recorded that, you know, had over $100,000 ACV, how many of them are new customers versus, you know, customers who may increase their software consumption to exceed that $100,000 Level? I'm just really trying to get an idea of, you know, how many customers are actually increasing the consumption versus new customers that are acquiring licenses that are? You know, I guess, exceeding that level.
Thanks, Gaurav. Yes, good question. We don't actually break that out, but I will say this, I mean, if you look at the total active customers, clearly the customer count continues to increase. I know, we certainly know the customer list that's included in that 190, and there are new customers. There are a lot of biotech companies that were formed in 2021.
We definitely signed up some of those, and those are new customers. Interestingly, we're seeing some of them come in at fairly sizable levels relative to levels that maybe new customers might have started at in the past. Certainly that's the case on the material side as that's dominated by new customers. Although our largest customers on the material side are getting pretty large as well. Really it is both. As I said, upsizing does play a large role among our largest customers and also in this broader group.
Got it. I guess just piggybacking off of that, right, just generally, are you seeing, you know, new customers come in, you know, regardless of size, just on average, are they coming in and, you know, I guess coming in with a large ACV or are they gradually increasing their ACV year to year?
You know, I mean, it really depends. Interesting.
Oh, go ahead, Joel.
Oh, sorry, Ramy. Go ahead.
No, no. Please. Go ahead, Joel. No, go ahead.
Okay. I was just gonna say that it really depends because I think we would have answered that question a couple of years ago that they start lower and then they start to gradually upsize. As I said before, we've seen examples this year where there were new customers that came in at a much higher level than had been typically the case. Now clearly there are smaller companies with maybe one program or two programs that will come in at the lower end of the range, and as they achieve success and build out their discovery efforts, we'll continue to upsize.
I think there's a broad understanding in the marketplace of the power of our technology. As people move around and as people form new companies, sometimes the initiation levels are higher than they have been in the past. I don't know, Ramy, if you had other things to add there.
That's exactly what I was. Yeah, exactly. Yeah. Well said.
Perfect. Thanks, guys, for the color and again, best of luck, Joel, and congrats, Karen, again. Thanks.
Thanks, Gaurav.
Thank you.
Thank you. I'm showing no further question at this time. This concludes today's conference call. You may now disconnect.