The History of Patenting Genetic Material.

The US Supreme Court's recent decision in Association for Molecular Pathology v. Myriad Genetics, Inc. declared, for the first time, that isolated human genes cannot be patented. Many have wondered how genes were ever the subjects of patents. The answer lies in a nuanced understanding of both legal and scientific history. Since the early twentieth century, "products of nature" were not eligible to be patented unless they were "isolated and purified" from their surrounding environment. As molecular biology advanced, and the capability to isolate genes both physically and by sequence came to fruition, researchers (and patent offices) began to apply patent-law logic to genes themselves. These patents, along with other biological patents, generated substantial social and political criticism. Myriad Genetics, a company with patents on BRCA1 and BRCA2, two genes critical to assessing early-onset breast and ovarian cancer risk, and with a particularly controversial business approach, became the antagonist in an ultimately successful campaign to overturn gene patents in court. Despite Myriad's defeat, some questions concerning the rights to monopolize genetic information remain. The history leading to that defeat may be relevant to these future issues.

International Divergence in Gene Patenting.

This review explores the recent divergence in international patent law relating to genes and associated subject matter. This divergence stems primarily from decisions of the highest courts in the United States and Australia on the eligibility of patent claims relating to the BRCA gene sequences. Patent offices, courts, and policy makers have struggled for many years to clearly articulate the bounds of patent claims on isolated and synthetic DNA and related products and processes, including methods for their use in genetic diagnostics. This review provides context to the current divergence by mapping key events in the gene patent journey from the early 1980s onward in five key jurisdictions: the United States, the member states of the European Patent Convention, Australia, Canada, and China. Early approaches to gene patenting had some commonalities across jurisdictions, which makes exploration of the recent divergence all the more interesting.There is insufficient empirical evidence to date to confidently predict the consequences of this recent divergence. However, it could potentially have a significant effect on local industry and on consumer access.

An Evaluation of Low-Cost Vision Processors for Efficient Star Identification.

Star trackers are navigation sensors that are used for attitude determination of a satellite relative to certain stars. A star tracker is required to be accurate and also consume as little power as possible in order to be used in small satellites. While traditional approaches use lookup tables for identifying stars, the latest advances in star tracking use neural networks for automatic star identification. This manuscript evaluates two low-cost processors capable of running a star identification neural network, the Intel Movidius Myriad 2 Vision Processing Unit (VPU) and the STM32 Microcontroller. The intention of this manuscript is to compare the accuracy and power usage to evaluate the suitability of each device for use in a star tracker. The Myriad 2 VPU and the STM32 Microcontroller have been specifically chosen because of their performance on computer vision algorithms alongside being cost-effective and low power consuming devices. The experimental results showed that the Myriad 2 proved to be efficient and consumed around 1 Watt of power while maintaining 99.08% accuracy with an input including false stars. Comparatively the STM32 was able to deliver comparable accuracy (99.07%) and power measurement results. The proposed experimental setup is beneficial for small spacecraft missions that require low-cost and low power consuming star trackers.

A diagnostically-challenging case of melanoma ex blue nevus with comprehensive molecular analysis, including the 23-gene expression signature (myPath melanoma).

Melanoma ex blue nevus (MEBN) is a rare, aggressive, and potentially lethal neoplasm. Distinguishing MEBN from an atypical cellular blue nevus can be very challenging. We report a diagnostically difficult case of MEBN with lymph node metastases, in which single nucleotide polymorphism array and fluorescence in situ hybridization were used to arrive at the correct diagnosis. It was also analyzed by the recently-introduced proprietary 23-gene expression signature test. To the best of our knowledge, this is the second reported case of MEBN analyzed by the 23-gene expression signature, which provided a false-negative result. More studies are needed to assess the sensitivity and specificity of this test in various melanocytic proliferations.

Performance of BRCA1/2 mutation prediction models in male breast cancer patients.

To establish whether existing mutation prediction models can identify which male breast cancer (MBC) patients should be offered BRCA1 and BRCA2 diagnostic DNA screening, we compared the performance of BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm), BRCAPRO (BRCA probability) and the Myriad prevalence table ("Myriad"). These models were evaluated using the family data of 307 Dutch MBC probands tested for BRCA1/2, 58 (19%) of whom were carriers. We compared the numbers of observed vs predicted carriers and assessed the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) for each model. BOADICEA predicted the total number of BRCA1/2 mutation carriers quite accurately (observed/predicted ratio: 0.94). When a cut-off of 10% and 20% prior probability was used, BRCAPRO showed a non-significant better performance (observed/predicted ratio BOADICEA: 0.81, 95% confidence interval [CI]: [0.60-1.09] and 0.79, 95% CI: [0.57-1.09], vs. BRCAPRO: 1.02, 95% CI: [0.75-1.38] and 0.94, 95% CI: [0.68-1.31], respectively). Myriad underestimated the number of carriers in up to 69% of the cases. BRCAPRO showed a non-significant, higher AUC than BOADICEA (0.798 vs 0.776). Myriad showed a significantly lower AUC (0.671). BRCAPRO and BOADICEA can efficiently identify MBC patients as BRCA1/2 mutation carriers. Besides their general applicability, these tools will be of particular value in countries with limited healthcare resources.

The difficulty in interpreting gene expression profiling in BAP-negative melanocytic tumors.

BACKGROUND: BAP-negative melanocytic tumors were unrecognized in the medical literature until 2011. While the clinical significance of these tumors is poorly understood, there is concern such lesions represent processes in transition, and malignant degeneration is a concern. We investigated use of a 23-gene expression profiling (23-GEP) test for distinction from melanoma with the aim of better characterizing the biologic potential of such tumors. METHODS: Twenty BAP-negative melanocytic tumors, subjected to 23-GEP (Myriad Genetic Laboratories, Inc. [Salt Lake City, Utah]) testing, were retrospectively analyzed. RESULTS: Tumors exhibited varying degrees of atypia and aberrant immunohistochemical profiles. 23-GEP testing revealed a "malignant" genetic signature in four cases, a "benign" signature in 15 cases, and an "indeterminate" signature in one case. Array-based comparative genomic hybridization (aCGH) testing was performed for two cases with a "malignant" 23-GEP signature, but the aCGH result conflicted with 23-GEP, and supported benignity. Conversely, in one case with a "benign" 23-GEP result, aCGH testing supported assessment as melanoma. Moreover, evolving melanoma could not be wholly excluded by histopathological analysis in 2 "benign" cases. CONCLUSIONS: BAP-negative melanocytic tumors remain a diagnostic dilemma for dermatopathologists. A widely marketed 23-GEP test may not be useful in distinguishing these tumors from spitzoid melanoma, at least in comparison to aCGH technology.

BRCA1 and BRCA2 mutation predictions using the BRCAPRO and Myriad models in Korean ovarian cancer patients.

OBJECTIVE: To evaluate the predictive efficacies including sensitivity and positive predictive value of the genetic risk prediction model BRCAPRO and the Myriad BRCA risk calculator in Korean ovarian cancer patients. METHODS: Individuals undergoing genetic testing for BRCA mutations from November 2010-August 2016 were recruited from the Department of Obstetrics and Gynecology at a single institute in Korea. The observed BRCA1 and BRCA2 mutation statuses were compared with the predicted carrier probabilities using BRCAPRO and the Myriad BRCA risk calculator. RESULTS: Two hundred thirty-two patients were recruited, of whom 99.1% (230/232) were of Korean ethnicity. Of the 232 individuals, 206 and 26 had ovarian and double primary breast/ovarian cancer, respectively. Thirty-six individuals had a family history of breast/ovarian cancer in first-degree relatives. Fifty-seven patients (24.6%) tested positive for BRCA mutation (41 BRCA1, 16 BRCA2). The mean BRCAPRO and Myriad scores for all patients were 6.4% and 7.7%, respectively. The scores were significantly higher for patients with positive BRCA mutation status (29.0% vs. 6.1%, P<0.001, 12.1% vs. 7.7%, P<0.001, respectively). For all patients, the respective areas under the receiver operating characteristics curves were 0.720 and 0.747 for the BRCAPRO and Myriad models to predict the risk of carrying a BRCA mutation. Both models overestimated the mutation probability in patients with a family history of breast/ovarian cancer (1.55-fold and 1.50-fold, respectively) and underestimated the probability in patients without a family history (both, 0.54-fold). CONCLUSION: BRCAPRO and Myriad seem to be acceptable risk assessment tools for determining the risk of carrying BRCA mutations in Korean ovarian cancer patients.

Frontal burr hole approach for neuroendoscopic resection of craniopharyngioma with the NICO Myriad device: report of two cases.

OBJECTIVE: Craniopharyngiomas are challenging tumors to resect due to their deep location and proximity to vital structures. The perceived benefit of gross total resection may be tempered by the possibility of permanent disability. Minimally invasive techniques may reduce surgical morbidity while still allowing effective resection. The authors describe their initial experience with a neuroendoscopic transcortical, transventricular approach to two craniopharyngiomas. The surgeries were performed through a right frontal burr hole using the NICO Myriad, a side-cutting, aspiration device that fits through the working channel of a standard neuroendoscope. METHODS: The imaging and medical records of two children (a 5-year-old male and a 9-year-old female) undergoing endoscopic resection of a craniopharyngioma with this technique were reviewed. Outcomes, results, and complications were noted. RESULTS: A gross total resection was achieved in both patients. The operative time was 180 and 143 min, respectively. The estimated blood loss was 20 and 50 cm3, respectively. Both patients required a cerebrospinal fluid shunt. There were no surgical complications. CONCLUSIONS: The NICO Myriad is an effective tool that allows a safe minimally invasive endoscopic resection of craniopharyngiomas in patients with amenable anatomy. Surgeons with experience in neuroendoscopy may be able to achieve a gross total resection of these challenging tumors through a minimally invasive burr hole approach.

Ethical reasons for narrowing the scope of biotech patents.

Patents on biotech products have a scope that goes well beyond what is covered by the most widely applied ethical justifications of intellectual property. Neither natural rights theory from Locke, nor public interest theory of IP rights justifies the wide scope of legal protection. The article takes human genes as an example, focusing on the component that is not invented but persists as unaltered gene information even in the synthetically produced complementary DNA, the cDNA. It is argued that patent on cDNA holds this information captive, or illegitimately appropriates it in limiting other researchers and inventors' opportunity to explore new functions and uses based on this non-invented information. A tighter connection between legal IP protection and the use description stated in the patent claim is suggested. By binding protection to the product's foreseeable functions and use, instead of the product itself and all future uses of it, legitimacy of biotech product patents is restored.

Third ventricular choroid plexus papilloma: a pure neuroendoscopic approach.

Pure endoscopic technique in resection of intraventricular tumors is an emerging technology. This case demonstrates resection of a multicentric choroid plexus papilloma in a 2-month-old child. This child had two district tumors: one located in the left atrium and another in the third ventricle. Initial microsurgery was performed to resect the left atrial tumor. With the tumor noted to be not very vascular at initial surgery, the third ventricle tumor was resected with a GAAB neuroendoscope and NICO Myriad. A gross-total resection was achieved. At 3 years' follow-up, the child remains tumor free and developing without any functional deficits. The video can be found here: https://stream.cadmore.media/r10.3171/2023.1.FOCVID22145.

Aspirator-Assisted Endoscopic Third Ventriculostomy in an Infant: 2-Dimensional Operative Video.

Endoscopic third ventriculostomy (ETV) is an effective treatment for hydrocephalus in carefully selected patients.1 Studies have shown that larger ostomy size may be associated with higher ETV success and reduced ostomy closure in pediatric and adult patients.2-5 Therefore dilation of the ostomy is a key step in this procedure, which is traditionally accomplished with a balloon catheter, leaving behind loose redundant tissue at the ostomy site. In this 2-dimensional endoscopic operation (Video 1), we demonstrate the technique of using an aspiration device to enlarge the ETV ostomy in a controlled and efficient manner while eliminating redundant tissue. The patient is a 6-month-old girl with newly developed triventricular hydrocephalus seen on head ultrasound, manifested as upward gaze palsy, fontanelle fullness, and rapidly increasing head circumference. We chose to treat her with an ETV, given an ETV success score of 70.6,7 She underwent an ETV augmented with the NICO Myriad aspirator (NICO Corporation, Indianapolis, Indiana, USA) and achieved excellent clinical outcome. No intraoperative or postoperative complication occurred. Postoperative magnetic resonance imaging demonstrated an 8.4-mm ostomy on the third ventricular floor, nearly twice the size of a typical ETV ostomy.5 The key considerations in using this device include setting a low aspiration limit to avoid oversuction and using only mediolateral motion to avoid damage to the basilar artery. Future comparative studies are needed to investigate the efficacy, safety, and long-term outcome in aspirator-assisted ETV versus traditional techniques, as well as to evaluate ostomy size as an independent variable for long-term ETV success.

Alternative academic approaches for testing homologous recombination deficiency in ovarian cancer in the MITO16A/MaNGO-OV2 trial.

BACKGROUND: The detection of homologous recombination deficiency (HRD) can identify patients who are more responsive to platinum and poly ADP ribose polymerase inhibitors (PARPi). MyChoice CDx (Myriad) is the most used HRD test in ovarian cancer (OC). However, some limitations of commercial tests exist, because of the high rate of inconclusive results, costs, and the impossibility of evaluating functional resistance mechanisms. PATIENTS AND METHODS: Two academic genomic tests and a functional assay, the RAD51 foci, were evaluated to detect HRD. One hundred patients with high-grade OC enrolled in the MITO16A/MaNGO-OV2 trial and treated with first-line therapy with carboplatin, paclitaxel, and bevacizumab were analyzed. RESULTS: The failure rate of the two genomic assays was 2%. The sensitivity in detecting HRD when compared with Myriad was 98.1% and 90.6%, respectively. The agreement rate with Myriad was 0.92 and 0.87, with a Cohen's κ coefficient corresponding to 0.84 and 0.74, respectively. For the RAD51 foci assay, the failure rate was 30%. When the test was successful, discordant results for deficient and proficient tumors were observed, and additional HRD patients were identified compared to Myriad; sensitivity was 82.9%, agreement rate was 0.65, and Cohen's κ coefficient was 0.18. The HRD detected by genomic assays and residual tumor at primary surgery and stage was correlated with progression-free survival at multivariate analysis. CONCLUSIONS: Results suggest the feasibility of academic tests for assessing HRD status that show robust concordance with Myriad and correlation with clinical outcome. The contribution of the functional information related to the RAD51 foci test to the genomic data needs further investigation.

Establishing a Standardized Method for the Effective Intraoperative Collection and Biological Preservation of Brain Tumor Tissue Samples Using a Novel Tissue Preservation System: A Pilot Study.

BACKGROUND: Glioblastoma (GB) is an aggressive tumor showing extensive intertumoral and intratumoral heterogeneity. Several possible reasons contribute to the historical inability to develop effective therapeutic strategies for treatment of GB. One such challenge is the inability to consistently procure high-quality biologically preserved specimens for use in molecular research and patient-derived xenograft model development. No scientifically derived standardized method exists for intraoperative tissue collection specifically designed with the fragility of RNA in mind. METHODS: In this investigation, we set out to characterize matched specimens from 6 GB patients comparing the traditional handling and collection processes of intraoperative tissue used in most neurosurgical operating rooms versus an automated resection, collection, and biological preservation system (APS) which captures, preserves, and biologically maintains tissue in a prescribed and controlled microenvironment. Matched specimens were processed in parallel at various time points and temperatures, evaluating viability, RNA and protein concentrations, and isolation of GB cell lines. RESULTS: We found that APS-derived GB slices stored in an APS modified medium remained viable and maintained high-quality RNA and protein concentration for up to 24 hours. CONCLUSIONS: Our results showed that primary GB cell cultures derived in this manner had improved growth over widely used collection and preservation methods. By implementing an automated intraoperative system, we also eliminated inconsistencies in methodology of tissue collection, handling and biological preservation, establishing a repeatable and standardized practice that does not require additional staff or a laboratory technician to manage it.

Tissues Harvested Using an Automated Surgical Approach Confirm Molecular Heterogeneity of Glioblastoma and Enhance Specimen's Translational Research Value.

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Designing effective individualized therapies for GBM requires quality fresh tissue specimens, and a comprehensive molecular profile of this highly heterogenous neoplasm. Novel neuro-surgical approaches, such as the automated resection NICO Myriad™ system, are increasingly used by neurosurgeons to better reach the invasive front of tumors. However, no information exists on how harvesting GBM tissue using this approach may impact the translational research value of the sample. Here, we set out to characterize matched specimens from 15 patients, where one tissue sample was obtained using traditional tumor de-bulking (herein referred to as "en bloc" sample), and the other sample was obtained using the MyriadTM System (herein referred to as "Myriad" sample). We investigated the fidelity of patient derived xenografts (PDXs) for each sample type to the corresponding human tissues and evaluated the added value of sequencing both samples for each patient. Matched en bloc and Myriad samples processed in parallel, were subjected to the following assays: cell viability, self-renewal, in vivo tumorigenicity using an orthotopic model of glioma, genomic sequencing, and pharmacological testing using PI3K-MTOR pathway inhibitors. Our results demonstrate that primary GBM cultures derived from matched specimens grew at similar rates (correlation coefficient R = 0.72), generated equivalent number of neurospheres, and had equivalent tumorigenic potential in vivo (mouse survival correlation coefficient R = 0.93). DNA Sequencing using the Illumina tumor panel amplicons revealed over 70% concordance in non-synonymous mutations between matched human GBM specimens. PDX genomic profiles were also highly concordant with the corresponding patient tissues (>70%). RNA sequencing of paired GBM samples revealed unique genomic variants and differential gene expression between the en bloc and Myriad specimens, with the former molecularly resembling the "tumor core" and the latter resembling the "invasive tumor front" signature. Functionally, we show that primary-derived GBM cells-obtained after fresh specimen's dissociation-are more effectively growth-inhibited by co-targeting non-overlapping mutations enriched in each sample type, suggesting that profiling both specimens more adequately capture the molecular heterogeneity of GBM and may enhance the design accuracy and efficacy of individualized therapies.

Patenting nature-a comparative perspective.

The landscape for patenting products and processes tied to the natural world has changed dramatically in recent times as a result of a series of decisions of the US Supreme Court, particularly Mayo Collaborative Services v Prometheus Laboratories 566 U.S. 66 (2012) and Association for Molecular Pathology v Myriad Genetics, Inc. 569 U.S. 576 (2013) (Myriad). This article critically analyses these decisions and the multitude of lower court decisions that have followed them. This analysis provides support for the growing concern in the United States that it will be increasingly difficult to use the patent system to encourage the development of therapies and research intermediates useful in developing new therapeutic interventions. One option being posited in the industry to deal with this problem is to lobby Congress to reform the threshold patent eligibility standard in US patent law. It is argued in this paper that a more nuanced approach is preferable. Using the experience in Australia as a case study, this paper argues that such an approach is feasible. Australia has been chosen for analysis because the threshold patent eligibility standard is similar in both countries, much more so that with the European Union, and because the highest court in Australia has ruled on essentially the same patent as in Myriad, in D'Arcy v Myriad Genetics, Inc [2015] HCA 35. In addition to the nuanced approach to eligibility currently exercised by the Australian courts and patent office, Australia also has a number of post-grant options for addressing the dynamics of patent monopolies. These include experimental use, compulsory licensing, and government use. It is concluded that, while it would be impractical to attempt to replicate the Australian environment in the United States, there is no reason why some lessons can't be learned from the Australian experience with patenting nature.

Protecting essential information about genetic variants as trade secrets: a problem for public policy?

In 2013, the U.S. Supreme Court held that naturally occurring human genes are not patentable subject matter. This decision, invalidating patents held by Myriad Genetics involving genes affecting breast cancer, appeared to further the constitutional policy behind intellectual property protection to promote scientific progress and to make genetic testing more readily available to patients. However, the decision's ironic aftermath is continuing assertion by genetic testing companies of trade secrets protections over information about the significance of genetic variants. This article analyzes possible approaches to the assertion of trade secret protections over information about the significance of genetic variants. Specifically, we consider five approaches: voluntary responses from the scientific community; Food and Drug Administration (FDA) or CMS regulation; creation of additional march-in rights as under the Bayh Dole Act; compulsory licensing as under patent law; and creation of a public policy exception to trade secret protection. We explore what each approach would require legally if applied to break trade secret barriers, together with their advantages and disadvantages. While our analysis concerns genetic information, we conclude with some thoughts about its relevance to other types of big data now protected by trade secrets such as information about innovations in quality of care.

Recent Advances in High-throughput Platforms with Engineered Biomaterial Microarrays for Screening of Cell and Tissue Behavior.

In the last decades, bioengineers have developed myriad biomaterials for regenerative medicine. Development of screening techniques is essential for understanding complex behavior of cells in the biological microenvironments. Conventional approaches to the screening of cellular behavior in vitro have limitations in terms of accuracy, reusability, labor-intensive screening, and versatility. Thus, drug screening and toxicology test through in vitro screening platforms have been underwhelming. Recent advances in the high-throughput screening platforms somewhat overcome the limitations of in vitro screening platforms via repopulating human tissues' biophysical and biomchemical microenvironments with the ability to continuous monitoring of miniaturized human tissue behavior. Herein, we review current trends in the screening platform in which a high-throughput system composed of engineered microarray devices is developed to investigate cell-biomaterial interaction. Furthermore, diverse methods to achieve continuous monitoring of cell behavior via developments of biosensor integrated high-throughput platforms, and future perspectives on high-throughput screening will be provided.

"The Google of Healthcare": enabling the privatization of genetic bio/databanking.

PURPOSE: 23andMe is back on the market as the first direct-to-consumer genetic testing company that "includes reports that meet Food and Drug Administration (FDA) standards…." But, whereas its front-end product is selling individual genetic tests online, its back-end business model is amassing one of the largest privately owned genetic databases in the world. What is the effect, however, of the private control of bio/databases on genetic epidemiology and public health research? METHODS: The recent federal government notices of proposed rulemaking for: (1) revisions to regulations governing human subjects research and (2) whether certain direct-to-consumer genetic tests should require premarket FDA review, were reviewed and related to the 23andMe product, business model, and consumer agreements. RESULTS: FDA regulatory action so far has focused on the return of consumer test reports but it should also consider the broader misuse of data and information not otherwise protected by human subjects research regulations. CONCLUSIONS: As the federal government revises its decades-old human subjects research structure, the Executive Office of the President (EOP) should consider a cohesive approach to regulating private genetic bio/databanks. This strategy should allow the FDA and other agencies to play a role in expanding current regulatory coverage.

Mayo, Myriad, America Invents Act and BPCIA: how has the United States biopharmaceutical market been affected?

This paper discusses how the United States biopharmaceutical market has been affected by recent changes in patent law resulting from United States legislations (Biologics Price Competition and Innovation Act and the Leahy-Smith America Invents Act) and Supreme Court precedents (Mayo Collaborative Services v. Prometheus Laboratories, Inc. and Molecular Pathology v. Myriad Genetics). The authors interviewed eight key opinion leaders from the United States knowledgeable in biopharmaceuticals, including industry veterans, patent counsel, senior scientists and jurists. This paper summarizes the opinions of the key opinion leaders. This paper explains the impact of these Supreme Court decisions - i.e., broadening the exceptions to patent eligibility for law of nature and natural phenomenon - on biopharmaceutical innovations and provides future perspectives.