Beijing Children's Hospital Licenses LCH Prognostic Testing Kit with RMB 30 per Test Royalty

Recently, the State-Owned Scientific and Technological Achievement Trading System released a public notice stating that Beijing Children's Hospital, Capital Medical University, and the Beijing Institute of Pediatrics plan to jointly transfer their co-developed invention patent.“Langerhans Cell Histiocytosis Prognostic Testing Kit”Authorize the industry party for commercialization. Both parties intend to enter into an implementation license agreement, with“Sales commission of 30 yuan per test”agreed-upon pricing method. The patent is held byZhang Rui, Cui Lei, Wu Jian, Li Zhigang, Wang Tianyouet al. invented.

The core innovation of this patent lies inFirst establishment of a high-depth targeted sequencing method based on peripheral blood for dynamic prognostic monitoring of Langerhans cell histiocytosis.It achieves efficient enrichment and ultra-deep sequencing of key mutation regions in the BRAF gene through three pairs of carefully designed specific amplification primers, enabling not only the simultaneous detection of multiple variant types, such as multi-point mutations and insertions/deletions, but alsoMinimum 0.01%Its ultra-high sensitivity captures trace amounts of tumor signals in the blood. This technological breakthrough transforms prognosis assessment, which originally relied on tissue biopsies and was difficult to repeat, into a convenient, non-invasive blood test, providing an unprecedentedly precise tool for clinical judgment of treatment response and early warning of recurrence.

Langerhans Cell Histiocytosis (LCH), as a disease closely associated with BRAF gene mutations, has long faced three core dilemmas in clinical prognostic monitoring. First,Clinical Limitations of Tissue Sampling Are Prominent:The traditional gold standard relies on lesion tissue biopsy, which is not only invasive but also poses challenges in sampling multiple, deep-seated, or hard-to-reach lesions. Furthermore, it does not allow for repeated, dynamic monitoring during treatment, making it difficult for physicians to assess therapeutic efficacy in real time and detect early signs of recurrence.

Secondly,The molecular complexity of BRAF mutations itself poses challenges for detection.BRAF mutations in Langerhans Cell Histiocytosis (LCH) are not confined to a single hotspot; rather, they exhibit diverse types (including V600E point mutations, in-frame deletions, and splice site mutations) and dispersed loci (involving multiple regions such as exons 12 and 15), with some mutations occurring at very low frequencies. This heterogeneity demands that detection technologies possess “broad-spectrum” coverage capabilities, a requirement that commonly available commercial assays struggle to meet. For instance, while digital PCR and quantitative fluorescent PCR offer high sensitivity, they typically target only one known locus per assay; covering all potential mutations would require multiple sets of primers and probes, resulting in prohibitive costs and cumbersome workflows. Sanger sequencing lacks sufficient sensitivity to detect low-frequency mutations below 20%. Meanwhile, whole-exome sequencing is hindered by complex workflows, high costs, and insufficient depth of coverage at target regions, making it unsuitable for routine monitoring.

Finally, and most critically,Prognostic monitoring imposes near-exacting demands on sensitivity.Unlike diagnosis, prognostic monitoring—particularly minimal residual disease (MRD) monitoring—requires the identification of trace amounts of tumor signals against a massive background of normal DNA, imposing sensitivity requirements on detection technologies that far exceed diagnostic standards. False negatives may delay timely intervention, while false positives can lead to overtreatment.

The emergence of this patented technology directly addresses the aforementioned three major pain points. It aims to simultaneously resolve these issues through a single blood test,“Non-invasive and repeatable,” “broad-spectrum coverage of multiple mutations,” and “ultra-high sensitivity”clinical needs, shifting the prognostic management of LCH from reliance on static, invasive tissue samples to a new era of dynamic and convenient liquid biopsy, thereby providing clinicians with crucial molecular evidence for formulating and adjusting treatment plans.

Faced with the challenges of complex mutations and low abundance in LCH, the research team pioneered a novel approach by proposing"High-Depth Targeting"This technical strategy is specifically tailored for prognostic scenarios in Langerhans Cell Histiocytosis (LCH). By concentrating limited sequencing data on the most critical hotspot regions of the BRAF gene, this approach achieves ultra-deep sequencing coverage—ranging from hundreds of thousands to millions of folds—in the target regions while maintaining cost-effectiveness. This establishes the physical foundation for detecting ultra-low-frequency mutations with variant allele frequencies below 0.1%.

The most core innovation of this patent lies inThree pairs of specific amplicon primers, rigorously designed and validated through multiple rounds of screening.Amplicon primers precisely anchor to three key regions on chromosome 7, comprehensively covering known hotspots in exons 12 and 15 (such as V600E and various in-frame deletions) as well as potential novel mutation sites.

In primer design, the team thoroughly accounted for various mutations that could occur within the binding regions, ensuring effective amplification even when mutations were present near the primer ends, thereby avoiding “false negatives” caused by such mutations. Furthermore, from multiple sets of candidate primers, the team selected the final combination with the highest amplification efficiency based on the hard metric of experimentally measured target region read proportion (all exceeding 95%), thus guaranteeing library preparation quality and data validity.

Furthermore, in terms of performance, this technology has achieved the realization of"Ultra-High Sensitivity" and "Broad-Spectrum Detection"of unity. Traditional methods often struggle to achieve both “sensitivity” and “multi-target coverage.” This patent successfully unifies these two major advantages through the aforementioned innovations:

Sensitivity Reaches New Heights:In rigorous dilution validation, the assay achieved a limit of detection (LoD) of 0.01% and a lower limit of quantification (LLoQ) of 0.03% for the BRAF V600E mutation, fully meeting the requirements for monitoring minimal residual disease.

One Test, Comprehensive Scan:A single assay can simultaneously detect multiple types of variants, including point mutations and insertions/deletions (indels), within the target region, eliminating the need to design separate tests for each mutation. This approach overcomes the limitations of traditional molecular diagnostics, which typically require “one test per mutation,” thereby significantly improving detection efficiency and cost-effectiveness.

The most profound innovation of this patent lies in its driving a paradigm shift in clinical management. It transforms the samples for prognostic monitoring from tissues that are “difficult to obtain and non-reproducible” to“Easily accessible and dynamically trackable” peripheral blood. Clinical cases (such as patients LCH-22 and LCH-23) have confirmed that changes in plasma BRAF mutation levels detected by this method can accurately reflect patient treatment responses, even providing early warnings prior to clinical signs of recurrence. This enables physicians to proactively adjust treatment regimens based on molecular evidence, achieving a transition from “empirical” follow-up to “data-driven” precision management.

In summary, the innovation of this patent is not merely a simple application of a single technology, but rather a comprehensive solution that originates from clinical needs, proceeds through original strategic design, core reagent development, and rigorous performance validation, and ultimately returns to creating clinical value. It successfully transforms cutting-edge sequencing technology into an actionable and trustworthy clinical decision-making tool for physicians.

Although the successful commercialization of this patent marks a critical step forward in precise prognostic monitoring for Langerhans Cell Histiocytosis (LCH), its competitive landscape and differentiated advantages warrant equal attention when viewed within the broader context of the global and domestic liquid biopsy and companion diagnostics markets.

In the field of liquid biopsy for oncology, several mature and commercially successful blockbuster products have emerged abroad, forming a landscape dominated by“Breadth” and “Universality”market landscape centered around. For example,Foundation Medicine's FoundationOne Liquid CDxis an FDA-approved blood test product that analyzes over 300 genes for companion diagnostics in multiple solid tumors, helping to match corresponding targeted therapies. Its tissue-based test, FoundationOne CDx, is the first broad-panel companion diagnostic approved for all solid tumors, with more than 35 FDA-approved companion diagnostic indications. Another giantGuardant Health’s Guardant360 CDxAlso FDA-approved, it is one of the key players in the liquid biopsy market.

These products share the common characteristic of being based onLarge Panel Design, aiming toComprehensive genotyping for the most common solid tumors (such as lung cancer, breast cancer, and colorectal cancer) to guide initial treatment selection.However, while the sequencing depth of such “broad-spectrum” products (typically ranging from thousands to tens of thousands of reads) may meet the requirements for companion diagnostics, their sensitivity may be insufficient for dynamic monitoring of ultra-low-frequency mutations in rare diseases such as Langerhans Cell Histiocytosis (LCH). Furthermore, the high cost per test limits their routine application in long-term, dynamic prognostic monitoring.

China’s liquid biopsy market is experiencing rapid growth, driven by both policy support and capital investment, yet product strategies still closely follow international mainstream trends. Recently,Burning Rock Biotech's "Human Tumor Multi-Gene Mutation Combined Detection Kit (High-Throughput Sequencing Method)"Public notice of entry into the priority review channel indicates that this product is classified as a “medical device urgently needed for clinical use, with no same-variety product approved for registration in China.” In addition to Burning Rock,3D Medicines, 3DMed DiagnosticsLeading companies also possess similar multi-gene testing panels, which have been approved by the NMPA for companion diagnostics in certain cancer types.

Domestic products offer the advantage of closer alignment with China’s local healthcare system and payment capabilities, along with greater flexibility in rapid iteration and service responsiveness. However, similar to the international landscape, mainstream products currently approved or fast-tracked for approval in the Chinese market predominantly focus on high-incidence cancers such as lung cancer and gastrointestinal cancers, striving to balance broader genomic coverage with more effective cost control. For rare pediatric hematologic malignancies such as Langerhans cell histiocytosis (LCH), there remains a clear market gap due to the lack of specialized, clinically validated ultra-high-sensitivity products for prognostic monitoring.

In summary, the strategic focus of mature liquid biopsy and NGS testing products currently available both domestically and internationally lies in “breadth” (covering multiple cancer types and genes) and “versatility,” aiming to capture market share through economies of scale. In contrast, the patented technology being commercialized here adopts a distinctly different path emphasizing “depth” and “specialization.” Rather than engaging in homogeneous competition with established giants in the “red ocean” market, it precisely targets the “blue ocean” niche of “precision prognostic monitoring for pediatric rare tumors.” Its core competitiveness resides in:Targeting the single, well-defined driver gene BRAF, customized primers and a proprietary library preparation method are employed to achieve sequencing depth and sensitivity far exceeding those of conventional products, ultimately serving the specific clinical scenario of dynamic, long-term efficacy management.

* Patent transaction information is provided by CSTT