By Michael J. Moedritzer, Associate, Polsinelli (Special Guest Contributor)
For biotech founders, intellectual property (IP) can make or break a company. The life sciences industry is driven by innovation, but it is also crowded with patents. While it’s essential to build your own IP portfolio, it is just as critical to ensure that your product will not infringe on someone else’s. Overlooking this risk can expose your startup to costly lawsuits that could derail your business before it has a chance to grow.
What is an FTO Opinion?
An FTO Opinion is a legal review by an IP attorney that determines whether your startup can develop, manufacture, and sell a product without infringing existing patents. The attorney analyzes relevant patents and applications in your target markets and provides guidance on whether changes to your design or a licensing agreement might be necessary.
Why Founders Need It
For founders, an FTO Opinion provides more than legal coverage. It gives you peace of mind that you are not unknowingly putting your company at risk. It can also provide protection if litigation arises, helping you defend against claims of willful infringement and limiting potential increased damages. Most importantly, it strengthens your credibility with investors and partners by showing that you have done the due diligence to safeguard your innovations.
Where to Start
Securing an FTO Opinion requires working with an experienced IP attorney, who will tailor the analysis to your product and market strategy. While it is an investment, it is one that could save your company millions and ensure that your innovation makes it to market.
Michael Moedritzer is an Associate in Polsinelli’s Intellectual Property department. He focuses his practice on domestic and international patent prosecution and works with clients to revise, analyze and evaluate intellectual property-related issues to provide comprehensive overview of the portfolio.
Given the ‘pipeline in a product’ potential of drugs targeting this pathway, big pharma has shown considerable interest, with Genentech/Roche snapping up Jecure Therapeutics for an undisclosed amount, and both Novartis and Roche splashing out hundreds of millions of dollars for pioneer companies IFM Tre and Inflazome, respectively. In 2022, Novo Nordisk licensed Ventus Therapeutics’ peripherally restricted NLRP3 inhibitor in a deal worth up to $703 million, lending weight to pharmacological inhibition of NLRP3 as a complement to glucagon-like peptide-1 agonists (GLP-1s) in cardiometabolic disease. And with several programs now entering the clinic, investment activity in the area has continued, with Enveda’s announcement last week of a $150 million series D round to fund a phase 1 trial for ENV-6946, an orally delivered gut-restricted small molecule targeting the NLRP3/tumor necrosis factor-like cytokine 1A (TL1A) pathway in inflammatory bowel disease.
While drugmakers have traditionally targeted downstream extracellular mediators of the inflammasome pathway (canakinumab or rilonacept against IL-1β or anakinra to block IL-1 receptor), NLRP3 represents a key upstream intracellular signaling hub, activated by innate immune pattern-recognition receptor (Toll like receptors 2/4) signaling via MyD88 and NFkappaB. Once activated, NLRP3 monomers unfold and associate into a massive 1.2 MDa oligomeric supracomplex with three other proteins: ASC, NEK7 and caspase 1. The mature complex then cleaves and activates proinflammatory cytokines interleukin (IL)-1β and IL-18 and primes gasdermin D to instigate cell pore formation and cell death via pyroptosis.
Mechanisms of NLRP3 inflammasome activation and inhibition. In priming, lipopolysaccharide (LPS) or IL-1β activates NF-κB, and induces the expression of proinflammatory cytokines and NLRP3. Activation mediated by ATP, nigericin, and particulate matter causes ion fluxes, mitochondrial dysfunction, reactive oxygen species (ROS) generation, and DNA damage. NLRP3 binds to oxidized mitochondrial DNA (ox-mtDNA) released through the mitochondrial permeability transition pore (mPTP), leading to inflammasome assembly. Inhibition mechanisms are shown for drugs that prevent NLRP3 activation or inflammasome formation (red boxes). CARD, caspase activation and recruitment domain; LRR, leucine-rich repeat domain; MCU, mitochondrial calcium uniporter; MSU, monosodium urate; NACHT, nucleotide-binding and oligomerization domain. Source: TIPS.
But it has been less than straightforward to identify compounds with sufficient potency to target this pivotal innate immune signaling pathway without debilitating off-target effects. Indeed, several of the first wave of compounds entering the clinic have been dogged by serious toxicities, including liver problems (MCC950 and GDC-2394) and hypoglycemia (glyburide). Now, a team led by Rebecca Coll (Queen’s University Belfast) and Kevin Wilhelmsen (of BioAge Labs) reports in TheJournal of Experimental Medicine the discovery and characterization of BAL-0028, a novel and selective small-molecule inhibitor of the human NLRP3 inflammasome.
Unlike previously studied inhibitors, BAL-0028 acts through a unique mechanism of action; it binds NLRP3’s NACHT domain at a site distinct from other inhibitors that act by directly interfering with ATPase activity. BAL-0028 has nanomolar potency against human and primate NLRP3 but, remarkably, has weak activity against the mouse target, highlighting species-specific differences.
As BAL-0028 showed very high plasma protein binding in mice, limiting its use in vivo, the team developed a derivative, BAL-0598, with improved pharmacokinetic properties. In a humanized NLRP3 mouse peritonitis model, BAL-0598 effectively reduced IL-1β and IL-6 production, confirming its anti-inflammatory activity in vivo. Importantly, both BAL-0028 and BAL-0598 inhibited hyperactive NLRP3 mutants associated with autoinflammatory diseases, in some cases more effectively than Vertex’s VX-765, a caspase 1 inhibitor, and compounds like MCC950, one of the best characterized NLRP3 inhibitors available.
The novel mechanism of action of BAL-0028 and BAL-0598 would suggest their off-target effects may be different from those associated with other NLRP3 inhibitors blocking ATP hydrolysis. The concern that such compounds might also bind other members of the NOD/NLR family (e.g., NLRP1, NLRP4 or AIM2 inflammasomes) is mitigated by most published studies indicating that NLRP3’s unique fold around the ATP binding site makes small-molecule binders selective for this family member alone. The most likely explanation from trials published to date is that the observed toxicities are associated with small molecule chemotype rather than any NLRP3 class-specific problem. In any case, the findings from this study support further investigation of these compounds as candidates for treating inflammatory and age-related diseases where NLRP3 plays a role. The race to develop a safe and effective NLRP3 inhibitor is on, with big pharma billion-dollar bets and startups jostling to create best-in-class assets across cancer, cardiovascular, neurodegenerative and metabolic disease.
By Max Braht, Director of Business Development, LSN
Life Science Nation (LSN) invites early-stage life science and healthcare companies to a free, in-person pre-conference event designed to equip founders and executives with the knowledge and tools to build a successful venture in the U.S. market.
Structuring Your Startup: Legal, Tax, Funding, and Other Strategic Decisions will be held on Tuesday, September 16, from 1:00–5:00 PM at CIC Cambridge, Havana Room, One Broadway, Cambridge, MA. Taking place the day before RESI Boston 2025 (September 17–19), this workshop is a valuable opportunity for companies in town for Biotech Week Boston to gain practical insights and make new connections.
Attendees will hear from leading organizations, including Polsinelli, Eva Garland, LabCentral, Savills, and EisnerAmper, along with LSN, on the critical decisions that shape an emerging life science company. Topics will span legal frameworks, risk mitigation, tax considerations, fundraising approaches, deal structuring, operational planning, and pathways for life science companies entering or looking to scale within the U.S. market.
The program also features time dedicated to networking, giving founders and executives the chance to connect with peers, advisors, and potential partners before the RESI conference begins.
This pre-conference session is part of LSN’s ongoing effort to support life science entrepreneurs in landing their companies in the Boston innovation ecosystem and expanding into the U.S. market.
Registration is free, but space is limited. Don’t miss your chance to join.
By Joey Wong, Director of Investor Research, Hong Kong BD, LSN
Many large corporations establish ventures or innovation arms to invest in and partner with life science and healthcare startups. Unlike traditional institutional VCs, corporate venture capital (CVC) groups bring unique strategies, goals, and ties to their parent organizations. Some CVCs focus closely on opportunities that align with the corporation’s core businesses, while others pursue innovation beyond existing portfolios, creating broader avenues for collaboration.
This 50-minute discussion will bring together leaders from corporate venture arms of global pharma, biotech, medtech, and healthcare corporations. Panelists will share how they evaluate early-stage opportunities, what distinguishes their investment criteria from institutional VCs, and how they balance strategic alignment with financial return. Startups will also gain valuable perspective on how to approach CVCs, what additional benefits they can expect beyond funding, and how relationships and collaboration may evolve post-investment.
For entrepreneurs seeking strategic partners, this session offers a chance to hear directly from active CVC investors about how they drive innovation, accelerate R&D, and bring transformative solutions to the market.
Andrew Merken Shareholder Polsinelli PC
(Moderator)
Komeil Nasrollahi Sr. Director Innovation & Venture Partnerships Siemens Healthineers
Claire Leurent Managing Director AbbVie Ventures
Jeffrey Moore President MP Healthcare Venture Management (MPH)
Alex de Winter VP of New Ventures Danaher Corporation
Join us at RESI Boston this September to take part in this discussion and connect with investors across the life science and healthcare ecosystem.
While most parts of biotech early-stage financing have been in the doldrums in the past two or three years, so-called tech-bio startups have been thriving. Since the posterchild $1.0 billion mega series A round last April of Xaira Therapeutics, which was founded by scientists out of Nobel prize winner David Baker’s group at the University of Washington, several startups seeking to develop machine learning models for designing miniproteins or peptide binders of challenging or ‘undruggable’ targets have emerged, including Enlaza Therapeutics, Vilya, and UbiquiTx. All of these have been developing their own proprietary models based on Alphafold 3, Boltz-1 or Chai-1 for structure prediction and tools based off RFdiffusion, Bindcraft and ProteinMPNN for peptide design. Predicting CDR loops for de novo antibody design is a considerably more challenging task than for simple peptides, but Nabla Bio, founded last year by scientists out of George Church’s lab at Harvard, claims it is doing just that for GPCRs and ion channels. Earlier this month, Chai Discovery also launched with a $100 million series A from Menlo Ventures to optimize multimodal generative models such as Chai-2, which, according to the company, already “achieves a 16% hit rate in de novo antibody design.”
Designing peptides that can selectively bind to a protein target and show therapeutic activity remains a challenge, however, as it often depends on the availability of high-quality structural information about the target molecule, which is seldom available for many disease-relevant proteins that are unstructured or conformationally disordered. Similarly modeling protein-protein interactions like antibody-antigen interactions that are extremely dynamic and floppy also poses problems. All of which raises the question as to whether binders could be predicted simply using amino acid sequence information instead of structural data.
Now, a team led by Pranam Chatterjee from Duke University has addressed this question. In a recent paper in Nature Biotechnology, Chatterjee and his collaborators report the creation of PepMLM, a peptide binder design algorithm based on masked language modeling. A key feature of the algorithm is that it depends exclusively on protein sequence, not structure. Built upon the ESM-2 (Evolutionary Scale Modeling 2) protein language model, PepMLM masks and reconstructs entire peptide regions appended to target protein sequences. This design compels the model to generate context-specific binders. To train PepMLM, the team used high-quality curated datasets from PepNN and Propedia comprising ~10k putative peptide-protein sequence pairs. PepMLM output was consistently found to outperform RFDiffusion on held-out/structured targets, with a higher hit rate (38% to 29%) and low perplexities that closely matched real binders, with generated sequences showing target specificity, even in stringent permutation tests.
The PepMLM model is trained by labeling with ~10k putative target protein-peptide sequence pairs and is built with a target protein sequence and a masked binder region. During the generation phase, the model has a target protein sequence and then mask the binder to facilitate the prediction of peptides of specified lengths. (Source: Nature Biotechnology)
The model generated binders predicted to have higher binding scores than native and structure-based binders designed through other methods. Indeed, in vitro validation experiments confirmed the high affinity and specificity of PepMLM-generated binders.
Structural comparison of PepMLM-designed binders (red) and experimental test binders (blue), with contact residues in target proteins H-2Kb MHC complex (2OI9)and Lck tyrosine kinase (1LCK) (gray) shown in corresponding colors. (Source: Nature Biotechnology).
Chatterjee and his colleagues went on to turn their binders into degraders by fusing them to E3 ubiquitin ligase domains, such as CHIP/STUB1. When tested in vitro, over 60% of these degraders knocked down their target proteins. PepMLM peptides achieved nanomolar binding affinity on the drug targets neural cell adhesion molecule 1 (NCAM1), a key marker of acute myeloid leukemia, and anti-Müllerian hormone type 2 receptor (AMHR2), a critical regulator of polycystic ovarian syndrome (where RFDiffusion-predicted peptides failed to bind). The authors also demonstrated that PepMLM-predicted peptides fused to E3 ubiquitin ligases not only degraded MSH3 but completely eliminated mutant huntingtin protein exon 1 containing 43 CAG repeats in Huntington disease patient-derived fibroblast cells. Similar results were obtained for a PepMLM-predicted peptide binder of MESH1, a protein controlling ferroptosis, in collaboration with Ashley Chi Jen-Tsan’s group at Duke University (RFDiffusion again gave no hits). And with Madelaine Dumas and Hector Aguilar-Carreno’s group, in collaboration with Matt Delisa’s group at Cornell University, PepMLM-derived peptides bound and reduced levels of viral phosphoproteins from Nipah, Hendra, and human metapneumovirus (HMPV); indeed, in live HMPV infection models, the PepMLM peptide mediated high levels of P protein clearance.
The ability of PepMLM to design binders purely on the basis of target-protein sequence is an important advance towards designing therapeutic peptides against hitherto inaccessible targets that lack structural data. Future work should explore how to incorporate chemical modifications such as cyclization or stapling to enhance stability of the binders, as well as the evaluation of the strongest candidates in vivo. Another challenge will be to ameliorate the immunogenicity of these foreign de novo proteins. The use of protein engineering approaches, such as incorporation of mirror amino acids that can cloak foreign peptides from the immune system, may offer solutions. But it is likely that candidates discovered using sequence or structure prediction tools will still require lengthy development programs to be turned into safe and effective drugs, despite the hype.
Showcase your innovation to active life science investors
By Max Braht, Director of Business Development, LSN
Life Science Nation (LSN) is now accepting applications for the Innovator’s Pitch Challenge (IPC) at both RESI London and RESI JPM. The IPC provides early-stage life science and healthcare companies with the opportunity to pitch directly to a panel of active investors, receive interactive feedback, and showcase their technology in the RESI Exhibition Hall.
RESI London – December 2025
The first week of December marks the largest life science partnering and venture week in the UK. For companies raising pre-seed through Series B, or those in Phase II or earlier development, RESI London—alongside One Nucleus’ Genesis and ELRIG/SLAS events—offers a stronger fit compared to the late November healthcare week held concurrently with Jefferies. While Jefferies tends to focus on IPO-ready or Phase III+ companies, RESI London is designed for venture-stage entrepreneurs seeking investment and strategic partnerships.
The conference takes place in person on December 4 at No.11 Cavendish Square, London, with virtual partnering continuing on December 8–9.
The RESI Conference will return to San Francisco during JP Morgan Healthcare Week, providing entrepreneurs with access to the largest gathering of early-stage life science investors in the world. Taking place January 12–13 at the Marriott Marquis San Francisco, the conference will be followed by three days of virtual partnering on January 14, 19, and 20.
RESI JPM draws more than a thousand participants, including 500+ global investors, innovators, and industry experts. The Innovator’s Pitch Challenge allows selected companies to pitch live, engage in Q&A with investors, and participate in dedicated partnering meetings throughout the week.
Apply today to secure your place in the Innovator’s Pitch Challenge at RESI London or RESI JPM and take advantage of the opportunity to showcase your innovation directly to active investors.
By Claire Davies, Shareholder, Polsinelli (Special Guest Contributor)
Life sciences companies are constantly innovating with the goal of developing groundbreaking medical products. Unfortunately, the most novel products often face more uncertainty about their regulatory pathway to market—with several factors heightening that uncertainty today. These include the loss of many FDA policy and scientific staff over the past six months and multiple changes in leadership, such as at the head of the agency’s drug and biologics programs. Although significant personnel change may present opportunities for companies that would benefit from a change in the agency’s historic regulatory approach, it also unsettles precedent for the FDA’s expectations. In addition, as numerous companies explore applications of generative AI, the agency itself has indicated that generative AI-enabled products present challenges to existing (often decades old) laws that govern FDA’s regulatory framework.
With these factors in play, companies may be tempted to hold off on spending resources to map out their regulatory strategy and get feedback from the agency. But incorporating regulatory considerations into early business plans remains key for a number of reasons:
Efficient Product Development: Whether and how FDA will regulate your product determines the level of evidence and type of application needed to enter the market. (Does your AI-enabled product fall within an exception from regulation as a medical device? If not, it may require an FDA application supported by significant data.) An early understanding of the regulatory pathway can help companies budget development costs more accurately. It can also help them anticipate and proactively address regulatory hurdles, ultimately shortening the time it takes to get the product to market.
Raising capital: Regardless of scientific promise, companies that underestimate the regulatory complexity of getting a medical product to market or that lack an experienced in-house or external advisory team in this area may be viewed as a risky proposition for investors. In contrast, a thorough understanding of the regulatory pathway and plan for navigating the challenges to commercialization can help distinguish a company from the crowd.
Ultimately, an early and proactive approach to your regulatory strategy is a critical investment that can help shorten time to market and increase your company’s attractiveness to investors.
Claire Davies is a Shareholder in Polsinelli’s FDA practice where she provides strategic counsel to help clients navigate FDA regulatory and compliance challenges. Claire has handled a wide range of issues involving medical devices, biological products, drugs and human cells, tissues and cellular and tissue-based products (HCT/Ps). Prior to joining Polsinelli, Claire spent nearly a decade as an attorney in the FDA’s Office of the Chief Counsel. Her work at FDA often involved advising agency leadership on high-profile and significant matters, such as responses to emerging public health threats and user fee negotiations with industry.
About Polsinelli
Polsinelli is an Am Law 100 firm with more than 1,200 attorneys in over 25 offices nationwide. Recognized as one of the top firms for excellent client service and client relationships, Polsinelli is committed to meeting our clients’ expectations of what a law firm should be. Our attorneys provide value through practical legal counsel infused with business insight, offering comprehensive corporate, transactional, litigation and regulatory services with a focus on health care, real estate, finance, technology, private equity and life sciences. Polsinelli PC, Polsinelli LLP in California, Polsinelli PC (Inc) in Florida.
For biotech founders, intellectual property (IP) can make or break a company. The life sciences industry is driven by innovation, but it is also crowded with patents. While it’s essential to build your own IP portfolio, it is just as critical to ensure that your product will not infringe on someone else’s. Overlooking this risk can expose your startup to costly lawsuits that could derail your business before it has a chance to grow.
