Evolving intellectual property landscape for AI-driven innovations in the biomedical sector: opportunities in stable IP regime for shared success.

Artificial Intelligence (AI) has revolutionized the biomedical sector in advanced diagnosis, treatment, and personalized medicine. While these AI-driven innovations promise vast benefits for patients and service providers, they also raise complex intellectual property (IP) challenges due to the inherent nature of AI technology. In this review, we discussed the multifaceted impact of AI on IP within the biomedical sector, exploring implications in areas like drug research and discovery, personalized medicine, and medical diagnostics. We dissect critical issues surrounding AI inventorship, patent and copyright protection for AI-generated works, data ownership, and licensing. To provide context, we analyzed the current IP legislative landscape in the United States, EU, China, and India, highlighting convergences, divergences, and precedent-setting cases relevant to the biomedical sector. Recognizing the need for harmonization, we reviewed current developments and discussed a way forward. We advocate for a collaborative approach, convening policymakers, clinicians, researchers, industry players, legal professionals, and patient advocates to navigate this dynamic landscape. It will create a stable IP regime and unlock the full potential of AI for enhanced healthcare delivery and improved patient outcomes.

Risk of Ischemic Stroke After Patent Foramen Ovale Closure.

BACKGROUND: Transcatheter patent foramen ovale (PFO) closure is the recommended treatment for patients age 18 to 60 years with cryptogenic stroke having a high probability of being PFO-related. Limited data exist on stroke recurrence after PFO closure outside clinical trials. OBJECTIVES: The purpose of this study was to examine stroke recurrence after PFO closure in routine clinical practice. METHODS: We used nationwide population-based Danish registries to conduct a cohort study of all patients with PFO closure during 2008 to 2021 (n = 1,162) and a birth year and sex-matched comparison cohort from the general population (n = 11,620). We calculated absolute and relative risks of ischemic stroke within 4 years after PFO closure. We used weighted Cox regression to estimate adjusted HRs of the association between PFO closure vs the general population and ischemic stroke. RESULTS: The absolute risks of ischemic stroke in patients with PFO closure and in the general population, respectively, were 1.4% (95% CI: 0.8%-2.3%) and 0.1% (95% CI: 0.0%-0.1%) at 1 year, 1.4% (95% CI: 0.8%-2.3%) and 0.2% (95% CI: 0.2%-0.4%) at 2 years, 2.2% (95% CI: 1.3%-3.5%) and 0.4% (95% CI: 0.2%-0.5%) at 3 years, and 2.5% (95% CI: 1.5%-4.0%) and 0.4% (95% CI: 0.3%-0.6%) at 4 years. Thus, the absolute 4-year risk of ischemic stroke was 2.1% (95% CI: 0.9%-3.3%) higher in patients with PFO closure than in the general population, corresponding to an adjusted HR of 6.3 (95% CI: 3.1-12.6). CONCLUSIONS: The 4-year risk of ischemic stroke after routine PFO closure for cryptogenic stroke was comparable to that observed in clinical trials, but remained higher than in the general population.

"Nerves Need Nourishment": Advertising Phospho-Energon Pills in Early Twentieth-Century Sweden.

This paper offers the first case study of Phospho-Energon - an early twentieth-century Swedish patent medicine believed to cure nervousness. Using a large dataset of newspaper advertisements, it explores how the product was presented through scientific and medical language, which drew upon a range of visual and verbal rhetoric to convince consumers of its benefits. It finds that pseudoscientific discourse focusing on self-help was regularly used to sell Phospho-Energon, with consumers warned that their nerves were "not allowed to fail" and required "protection" in order to remain healthy. Furthermore, the "science" supporting this discourse gradually shifted over time as neurosis replaced neurasthenia as a diagnostic category and the concept of spring lethargy became popularised. Overall, this study argues that Phospho-Energon stands as an important example of how partial scientific/medical claims can be used as a rhetorical device to sell products to consumers looking for a quick-fix cure for their perceived mental health conditions.

Cryptogenic HACEK (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, and Kingella) CNS Abscess in an Otherwise Healthy Patient With a Patent Foramen Ovale.

Actinomyces and HACEK (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, and Kingella) organisms are part of the oral microbiome and rarely affect the central nervous system (CNS). CNS infections with these agents can be caused by contiguous or hematogenous spread. We present a case of a 25-year-old immunocompetent male who presented with a one-week history of progressively worsening generalized headaches, photophobia, nausea, and vomiting. Despite a normal physical exam and the absence of leukocytosis, head imaging showed a right frontal lobe abscess. The patient was started empirically on vancomycin, ceftriaxone, and metronidazole, and surgery was performed. Surgical cultures grew organisms from the HACEK spectrum (Aggregatibacter, Eikenella), Gemella morbillorum, Streptococcus constellatus, and Actinomyces georgiae. Serial imaging studies showed a rapid increase in the size of the residual abscess, and the patient needed repeat intervention within five days. He was discharged five days after the repeat surgery on IV therapy prior to the transition to oral antibiotics. While the patient was found to have a small patent foramen ovale, there was no evidence of bacteremia or valvular vegetation, and no evidence of dental or sinus disease was seen on imaging. This case suggests that even in the absence of any clear sources of infection, cryptogenic brain abscesses can still occur sporadically in young, healthy patients.

A Patent Landscape on Methane Oxidizing Bacteria (MOB) or Methanotrophs.

Methane-oxidizing bacteria (MOB) or methanotrophs are a category of bacteria that rely on methane as their primary carbon and energy source. Methane is the second most abundant greenhouse gas after carbon dioxide and is comparatively far more potent in trapping heat in the atmosphere. MOBs are important microorganisms in the global carbon cycle where they play a crucial role in the oxidation of methane. The present review provides a comprehensive patent landscape on technology development using MOB. The first patent in this technology domain was recorded in 1971, with a notable surge in activity observed in 2020. A detailed patent analysis revealed that the early inventions were mainly focused on the production of various metabolites and bioremediation using MOB. In the later years, patents were filed in the area of identification of various species of MOB and their large-scale production. From 2010 onwards, consistent patent filing was observed in the genetic engineering of MOB to enhance their methane oxidizing capacity. The United States and China have emerged as the global leaders in terms of patent filing in this technology space. Precigen Inc. and Exxon Research Engineering Co., US were the top patent assignees followed by the University of Tsinghua and Calysta Inc. The Highest number of patent applications have claimed metabolite production by using MOB followed by their use in bioremediation. Methylosinus has emerged as the predominant microorganism of choice for methane oxidation applications.

A 'twice closed' patent foramen ovale: a case report of percutaneous management of a residual interatrial shunt in a patient with persistent migraine symptoms.

Background: Residual interatrial shunt following percutaneous patent foramen ovale (PFO) closure is a rare complication that can be associated with persistent migraine. Case summary: A 32-year-old woman with a history of percutaneous PFO closure due to a previous coronary paradoxical embolism and a condition of drug-refractory migraine underwent transoesophageal echocardiography (TOE) to investigate further recurrent migraine attacks. A partial displacement of a PFO occluder device was found, and it was successfully treated through the fluoroscopic and TOE-guided positioning of a second occluder in overlap with the previous one. The patient reported no more migraine attacks at the 6-month follow-up visit. Discussion: Residual interatrial shunt should be suspected in patients with persistent migraine and a history of percutaneous PFO closure. Fluoroscopic and TOE-guided closure of residual interatrial shunt with a second PFO occlude device seems to be a safe and clinically effective strategy to manage persistent migraine.

Device Closure of Hemodynamically Significant Patent Ductus Arteriosus in Premature Infants.

The patent ductus arteriosus is a very common condition in preterm infants, and a hemodynamically significant patent ductus arteriosus increases morbidity and mortality in these vulnerable patients. However, despite numerous randomized controlled trials, there is no consensus regarding management. Medical therapy is typically offered as first-line treatment, although it yields limited success and carries the potential for severe adverse events. In recent years, there has been rapid development in transcatheter patent ductus arteriosus closure primary with the use of the Amplatzer Piccolo Occluder, and this has gained widespread acceptance as a safe and effective alternative to surgical ligation in extremely low-birth-weight infants weighing over 700 g. This article aims to provide an appraisal of the patient selection process, a step-by-step procedural guide, and a comprehensive review of the outcomes associated with this approach.

Delivery systems for transcatheter therapies of congenital heart disease.

INTRODUCTION: Delivery systems are crucially important for the implantation of medical devices in patients with congenital heart disease. However, very little data is available comparing the advantages and disadvantages of the various delivery systems. AREAS COVERED: This article describes the delivery systems and methods used for delivery of atrial septal occluder devices, ventricular septal occluder devices, devices to occlude patent arterial ducts, and transcatheter pulmonary valves. Delivery systems are compared relating to prepping and loading, positioning of the delivery sheath/catheter, deployment, ability to recapture and reposition, as well as device release. EXPERT OPINION: For most ASD/VSD/PDA occluder devices, the basic delivery mechanism has changed very little over the preceding 20 years. Future modifications may focus on meaningful modifications to the cable systems that reduce stiffness and improve angulation at the connection to the device. Over the next 5-10 years, it is expected to see significant changes to delivery systems used for transcatheter pulmonary valve implantation, that result in improvements in the ability to recapture and reposition self-expandable transcatheter valves during the deployment process, combined with kink resistant sheaths that facilitate easy tracking across often complex right ventricular outflow tracts.

Pricing dynamics of anti-seizure medications in the U.S.

BACKGROUND: The median cost of anti-seizure medications (ASM) in the United States (U.S.) nearly doubled per person between 2006 and 2021. This increase, combined with shifts in ASM usage and the impact of the COVID-19 pandemic on drug supply chains amid rising inflation, underscored the urgent need to scrutinize ASM pricing dynamics. This study aimed to analyze the complex dynamics of ASM pricing in the U.S. over the past decade (2013-2023); this included how the entry of generic ASMs influenced the pricing of brand-name counterparts and what impacted price variations across different ASM formulations (e.g., significant inflation, the COVID-19 pandemic). METHODS: This study utilized National Average Drug Acquisition Cost (NADAC) data from November 2013 to July 2023. We adjusted ASM prices for inflation using the Consumer Price Index for Medicinal Drugs - Seasonally Adjusted (CPI-MDS). Statistical analyses included fixed effects regressions and multivariable regression analysis to evaluate the impact of inflation, the number of medication labelers, and the COVID-19 pandemic on ASM prices. RESULTS: Our study analyzed 23 ASMs approved by the U.S. Food and Drug Administration (FDA), which encompassed 223 oral formulations:112 brand-name and 111 generics. From 2013-2016 to 2020-2023, accounting for standard deviations (SD), the average price of brand-name ASMs increased from $8.71 (SD 5.9) to $15.43 (SD 10.7), while generic ASMs saw a slight decrease from $1.39 (SD 1.8) to $1.26 (SD 1.6). Consequently, the price gap between brand-name and generic ASMs surged from 1452.39 % to 3399.26 %. The proportion of matched brand-name and generic ASMs with a price difference of 1000 %-9999 % increased from 32.88 % (2013-2016) to 41.43 % (2020-2023), while those exceeding 10,000 % rose from 16.44 % to 20 % in the same period. Generic immediate-release (IR) formulations were significantly less expensive than extended-release (ER) or delayed-release (DR) counterparts, with cost differences reaching up to 7751.20 %. The number of medication labelers was inversely related to generic ASM prices, which decreased by 5.45 % (p = 0.001) with each additional generic labeler, while brand-name ASM prices increased by 2.46 % (p < 0.001) with each additional generic labeler. The COVID-19 pandemic led to a 24.4 % increase in brand-name ASM prices and a 23.1 % decrease in generic ASM prices. CONCLUSIONS: The findings reveal an expanding price disparity between brand-name and generic oral ASMs. An inverse relationship was observed between the number of medication labelers and generic ASM prices, with additional labelers driving down generic prices. However, introducing more generic labelers led to a significant increase in brand-name ASM prices. Furthermore, following patent expirations, brand-name ASM prices rose-a trend explained by the "generics paradox," where, contrary to expectations, brand prices do not decrease and may even increase when generics enter the market. These findings underscore the need for targeted interventions in drug pricing policies to manage the rising costs associated with epilepsy treatment. To ensure equitable access to ASMs, stakeholders must understand and address the factors driving these pricing dynamics.

[Pharmacovigilance guidelines for clinical application of oral Chinese patent medicines].

Oral Chinese patent medicine is the essence of effective prescriptions created and summarized by Chinese medical scientists through thousands of years of medical practice. It is portable and convenient, with an obvious curative effect and other characteristics. However, at present, oral Chinese patent medicine is rich in dosage forms, various in types, complex in mechanism of action, and broad in clinical positioning. In clinical application, there are often cases of drug use without reference to instructions,repeated drug use, and prolonged drug use, which highlights safety problems such as adverse reactions and hepatorenal toxicity. Oral Chinese patent medicine pharmacovigilance is facing challenges. World Health Organization(WHO) has issued the WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems, and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use(ICH) has issued the ICH E2 pharmacovigilance guidelines. The United States has issued the Pharmacovigilance management standards and pharmacoepidemiological assessment guidelines, and the European Union has issued the Guidelines on good pharmacovigilance practices. Japan, South Korea, and other countries in the Asia Pacific region have established their own pharmacovigilance systems, but currently, there are no pharmacovigilance guidelines related to oral Chinese patent medicine in China. Therefore, experts from many disciplines and fields in China were invited to jointly develop the Pharmacovigilance guidelines for clinical application of oral Chinese patent medicines, which aims to develop pharmacovigilance guidelines for clinical application that are consistent with China's national conditions and highlight the characteristics of oral Chinese patent medicine, and provide guidance for clinically safe and rational drug application in medical institutions.

[Pharmacovigilance guidelines for clinical application of Chinese patent medicines for external use].

There are many kinds and dosage forms of Chinese patent medicines for external use on the market, which are widely used in clinical departments. The common adverse reactions of Chinese patent medicines for external use are skin reactions, and those for the rare severe diseases include palpitation, chest tightness, dyspnea, and anaphylactic shock. At present, World Health Organization(WHO), International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use(ICH),the United States, the European Union, and Asia-Pacific countries(such as Japan and South Korea) have not issued any pharmacovigilance guideline of Chinese patent medicines for external use. China has not issued any pharmacovigilance guideline for these medicines, only releasing the standard Evaluation of skin adverse reactions caused by Chinese patent medicines for external use(T/CACM 005-2017). To standardize the safe and reasonable use of Chinese patent medicines for external use, Pharmacovigilance guidelines for clinical application of Chinese patent medicines for external use was developed with the joint efforts of experts in diverse disciplines. The guideline provides guidance on the monitoring and reporting of adverse reactions/events, identification and assessment of risk signals, and risk control measures in the clinical application of Chinese patent medicines for external use to guide the rational use of these medicines in clinical practice. At the same time, the possible risks and risk control measures in clinical application of Chinese patent medicines for external use are listed for clinical reference. In addition, the guideline provides guidance for risk minimization plans and the standardization of activities related to pharmacovigilance of Chinese patent medicines for external use in China.

[Pharmacovigilance guidelines of Chinese patent medicines].

Drug administration law of the People's Republic of China(2019 revised edition), which came into effect on December 1, 2019, proposed that " the state shall establish a pharmacovigilance system". Pharmacovigilance work of Chinese patent medicines is more difficult, and it is necessary to carry out Pharmacovigilance activities that are in line with the characteristics of Chinese patent medicines. Pharmacovigilance guidelines of Chinese patent medicines(T/CACM 1563. 1-2024), based on the principles of Drug Administration Law of the People's Republic of China(2019 revised edition) and Pharmacovigilance quality management standards(No. 65 of 2021) of the National Medical Products Administration, draws on the EU Pharmacovigilance regulation and the secondary guidelines of International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use(ICH), and it is drafted in accordance with the provisions of Guidelines for standardization work part 1: structure and drafting rules of standardization documents(GB/T1. 1-2020) based on the characteristics of Chinese patent medicines. It serves as a general document for a series of pharmacovigilance guidelines of Chinese patent medicines, such as Guidelines for construction of traditional Chinese medicine pharmacovigilance system in medical institutions(T/CACM 1563. 2-2024), Pharmacovigilance guidelines for clinical application of oral Chinese patent medicines(T/CACM 1563. 3-2024), Pharmacovigilance guidelines for clinical application of traditional Chinese medicine injections(T/CACM 1563. 4-2024), Pharmacovigilance guidelines for clinical application of Chinese patent medicines for external use(T/CACM 1563. 5-2024), and Pharmacovigilance guidelines for clinical application of Chinese patent medicines for mucosal administration(T/CACM 1563. 6-2024), including four major elements of pharmacovigilance monitoring and reporting of Chinese patent medicines, signal identification, risk evaluation, and risk control, as well as pharmacovigilance activities for Chinese patent medicines, ensuring the safety of public drug use.

[Pharmacovigilance guidelines for clinical application of Chinese patent medicines for mucosal administration].

The group standard Pharmacovigilance guidelines for clinical application of Chinese patent medicines for mucosal administration was released on January 16, 2024, on the national group standards information platform by the Institute of Basic Research in Clinical Medicine of China Academy of Chinese Medical Sciences and School and Hospital of Stomatology of Peking University, under the centralized management by the China Association of Chinese Medicine. The standard number is T/CACM 1563.6-2024. It aims to propose key elements and specify technical methods for safety monitoring and reporting, signal identification, risk assessment, and risk control based on the Drug administration law of the People's Republic of China(revised in 2019), which establishes normative pharmacovigilance guideline of Chinese patent medicine for mucosal administration that is in line with the characteristics of traditional Chinese Medicine(TCM) based on the pharmacovigilance content for clinical application of Chinese patent medicine for mucosal administration. The group standard has been discussed by internal and external experts through multiple rounds of consultation. It serves as a guiding document for stakeholders involved in pharmacovigilance activities, including pharmaceutical license holders, drug manufacturers, medical institutions, research institutes, and pharmaceutical trading enterprises.

[Research strategy for homogenization feeding of Chinese patent medicines].

Chinese patent medicine constitutes a vital segment of the traditional Chinese medicine(TCM) industry and stands as a significant emblem of TCM modernization. At present, the quality stability between batches of Chinese patent medicine preparations has become a pivotal factor directly restricting the high-quality development of the TCM industry. Consequently, addressing the homogeneity of Chinese patent medicines, this paper proposes a research scheme of homogenization feeding. It systematically elaborates on the object and pretreatment of homogenization, operational procedures of homogenization feeding, selection of homogenization evaluation indices, homogenization feeding algorithm, and homogenization feeding process. With the key quality control indicators as the homogenization target, the homogenization feeding process and its quality analysis were discussed. Finally, a demonstration strategy for homogenization feeding of Chinese patent medicine was formed, providing the scientific basis for advancing the research of quality consistency across batches of Chinese patent medicine preparations.

[Network Meta-analysis of oral Chinese patent medicine combined with conventional western medicine in treatment of gastro-esophageal reflux disease].

The effectiveness and safety of various oral Chinese patent medicines combined with conventional western medicine in treatment of gastro-esophageal reflux disease(GERD) were evaluated using network Meta-analysis. CNKI, Wanfang, VIP, SinoMed, PubMed, Cochrane Library, EMbase, and Web of Science were searched for randomized controlled trial(RCT) of oral Chinese patent medicines combined with conventional western medicine in treatment of GERD from inception to September 2023. The quality of the included studies was assessed using the Cochrane risk-of-bias tool, and data analysis was conducted using RevMan 5.4 and Stata 16 software. Forty-seven RCTs were included, involving 10 oral Chinese patent medicines, including Jianwei Yuyang Tablets, Qizhi Weitong Granules, Dalitong Granules, Liuwei Anxiao Capsules, Kangfuxin Liquid, Weisu Granules, Zhizhu Kuanzhong Capsules, Xiaochaihu Granules, Xiaoyao Pills, and Danweikang Capsules. Network Meta-analysis showed that:(1)in terms of effective rate of clinical symptoms, intervention measure ranked first by SUCRA was Dalitong Granules + conventional western medicine.(2)In terms of endoscopic effective rate, intervention measure ranked first by SUCRA was Liuwei Anxiao Capsules + conventional western medicine.(3)In terms of increasing serum gastrin levels, intervention measure ranked first by SUCRA was Weisu Granules + conventional western medicine.(4)In terms of increasing plasma motilin level, intervention measure ranked first by SUCRA was Xiaoyao Pills + conventional western medicine. In terms of symptom scores, quality of life and recurrence rate, only descriptive analyses were performed due to the heterogeneity of the studies, but all studies reported that oral Chinese patent medicines combined with conventional western medicine improved the outcome indicators better than conventional western medicine alone, and the differences were statistically significant. In terms of adverse reactions, there was no significant difference between oral Chinese patent medicine combined with conventional western medicine and conventional western medicine alone. Through cluster analysis, it was found that the comprehensive efficacy of Dalitong Granules + conventional western medicine, Danweikang Capsules + conventional western medicine, Qizhi Weitong Granules + conventional western medicine, Kangfuxin Liquid + conventional western medicine, and Liuwei Anxiao Capsules + conventional western medicine were more prominent, and could improve clinical symptoms and endoscopic inflammation at the same time. The results indicated that oral Chinese patent medicines combined with conventional western medicine in treatment of GERD could improve comprehensive efficacy, alleviate clinical symptoms, and regulate gastrointestinal motility. However, due to limitations such as sample size and quality of the included literature, the conclusions need to be further verified by more large-sample, high-quality studies.

The risk of intraoperative venous air embolism from neurosurgical procedures performed in the lounging position: an in-depth analysis of detection, management, and outcomes of 1000 consecutive cases.

OBJECTIVE: The overall benefit of employing a sitting/semisitting position for neurosurgical procedures remains under criticism due to concerns for additional risk, especially the risk of intraoperative venous air embolism (VAE). The aim of this single-center cohort study was to evaluate the frequency and severity of VAEs and associated complications in patients undergoing neurosurgery in the lounging position. METHODS: From 2010 to 2020, 1000 patients, including 172 patients with a patent foramen ovale, underwent surgery in the lounging position for different neurosurgical pathologies. All patients were monitored intraoperatively using continuous transesophageal echocardiography (TEE). The anesthesia team documented any observed incidences of VAEs and scored their severity according to the Tuebingen classification system (TCS) for VAE (TCS-VAE). The patients' clinical condition, radiological findings, and hospital course were subsequently analyzed to assess complications in a retrospective analysis of prospectively collected data. RESULTS: In the cohort of 1000 patients, 5 underwent cervical spine surgery and 995 underwent suboccipital craniotomy. VAE was detected by TEE in 51.4% (95% CI 48.4%-54.5%) of patients, with synchronous changes in end-tidal CO2 (grade 2-5 TCS-VAE) noted in 10.2% (95% CI 8.3%-12.3%). None of the patients presented with hemodynamic instability (grade 5 TCS-VAE). Patients with high-grade VAEs were significantly older (p = 0.02) and had lower BMIs (p = 0.001) than the respective mean value of the cohort. VAE grade was not associated with any of the outcome measures such as Karnofsky Performance Scale score, duration of ventilation, length of intensive care unit stay, and length of hospital stay. Postoperative acute respiratory distress syndrome (ARDS) was diagnosed in 0.3% (95% CI 0.0%-0.7%, n = 3) of all cases, and ARDS was associated with perioperative VAE grade (p = 0.001). No patient suffered a new permanent neurological deficit due to a paradoxical VAE. CONCLUSIONS: In this large cohort, the risk of an intraoperative VAE during neurosurgery in the lounging position was assessed, and contrary to the general perception in the field, no permanent sequelae or fatal adverse events attributable to VAEs were observed. Furthermore, the overall incidence of ARDS was very low. This study clearly establishes that experienced interdisciplinary teams can safely use the lounging position for neurosurgical procedures.