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Marty Chilberg
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I'm a retired CPA who spent the majority of his working career in technology companies. My work included management stints at Atari Inc, Daisy Systems Corp, Symantec Corp and Visio Corp. My last position at Visio (VSIO) was as CFO and VP Finance and Operations.
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  • Proposed Amendments To EU Regulation On Medical Devices Are Counter To Patients' Interests And Unworkable, Says ESHG

    Recent amendments to the proposed Regulation on In Vitro Diagnostic Medical Devices (IVDs) currently before the European Parliament will restrict the rights of patients and doctors to carry out essential genetic testing, says the European Society of Human Genetics (OTC:ESHG) today (Monday 7 April 2014). Furthermore, an independent legal opinion now shows that the European Union (EU) has no competence to enact the Regulation as amended by the Parliament.

    The new Regulation was proposed by the European Commission in order to bring the regulation of diagnostic kits or IVDs up to date. The ESHG has welcomed the Commission's proposal as it will 'improve the quality, safety availability and oversight of IVDs marketed and used in the European Union.'

    However amendments, proposed by German MEP Peter Liese, call for mandatory detailed genetic counselling to accompany every genetic test and hold the person carrying out a genetic test responsible for the rights, safety and well-being of the test subjects. The amendments say that genetic counselling should be appropriate and comprehensible and that it should include medical, ethical, social, psychological and legal aspects. "These are praiseworthy objectives with which no-one would disagree, but they are well beyond the scope of a regulation on the safety of IVDs," said Dr David Barton, from the National Centre for Medical Genetics, Dublin, Ireland, speaking on behalf of the ESHG.

    "Medical practice, including genetic medicine, is organised and delivered in many different ways in different Member States. This proposed article encroaches on this diversity and seeks to dictate in detail the arrangements for every clinic where a genetic test may be ordered. It insists on the direct involvement of a medical doctor in every patient interaction, where, in reality, it is common practice for genetic tests to be ordered by other healthcare professionals such as genetic counsellors under the supervision of a medical doctor.

    "Marvellous advances in genetic science are bringing genetic testing into every area of medicine. The proposals set out here seek to impose a single restrictive template on all genetic tests; this is unworkable and can only impede the progress of medical practice in the EU," he said.

    The new legal opinion, from the respected life science law firms Lawford Davies Denoon and Axon Lawyers, says that because the proposed amendments are outside the competence of the EU, if a Regulation were to be enacted incorporating the new articles, it could be challenged on the grounds of 'infringement of the principle of subsidiarity by a legislative act.'

    "We hope that the European Council will now consider these proposals in the light of the competence of the EU", says Dr Barton "We are gravely concerned that these proposals, as they stand, restrict legitimate, ethically-acceptable genetic testing activities such as the screening of new-born babies. They infringe on accepted and acceptable clinical practice when they should simply be regulating IVDs, effectively hijacking a sound and important Regulation to interfere with carefully regulated clinical practice, and infringing on patients' autonomy."

    www.eshg.org/566.0.html

    Apr 14 12:00 PM | Link | Comment!
  • Sequenom IP 8K Filed

    April 14, 2014

    920 Interference

    In Interference No. 105,920, the PTAB concluded that Quake U.S. Patent No. 8,008,018 (the "Quake 018 Patent") lacked sufficient disclosure to meet the written description test for the patent claims. On that basis, the PTAB entered judgment canceling all four claims of the Quake 018 Patent and ending the interference, thus determining that Quake is not entitled to a patent on the subject matter of this interference.

    The Company intends to bring the PTAB judgment canceling all claims of the Quake 018 Patent to the attention of the Court in the N.D. Cal. Action, where the patent has been asserted against the Company. The Company also believes that the PTAB's decision in the 920 Interference is relevant to Quake U.S. Patent No. 7,888,017 (the "Quake 017 Patent"). The Quake 017 Patent is also asserted against the Company in the N.D. Cal. Action and is based upon the same disclosure as the Quake 018 Patent.

    923 and 924 Interferences

    In Interference Nos. 105,923 and 105,924, the PTAB concluded that the involved Quake Patent Application lacked sufficient disclosure to meet the written description test for the Quake Patent Application claims. On that basis, the PTAB refused the Quake Patent Application's claims and entered judgment ending both interferences, thus determining that Quake is not entitled to patents on the subject matter of the interferences.

    As a result of the PTAB judgments in the 920, 923, and 924 Interferences, the Company believes that several patents should issue from the Lo Patent Applications which were involved in those interferences. The PTAB's decisions may be appealed to United States District Court or the United States Court of Appeals for the Federal Circuit. If the PTAB's decisions are appealed, further action by the PTO with respect to the Lo Patent Applications involved in the interferences may be delayed. The Company cannot predict the final outcome of these matters and there can be no assurance that the final outcome of the matters will be favorable to the Company.

    922 Interference

    In Interference No. 105,922 (the "922 Interference"), the PTAB determined that the Lo U.S. Patent Application No. 13/070,266 (the "Lo 266 Application") has sufficient disclosure to meet the written description test for the Lo 266 Patent Application claims. The 922 Interference also involves Quake U.S. Patent No. 8,195,415 (the "Quake 415 Patent"), asserted by Verinata against the Company in the N.D. Cal. Action. The PTAB ordered the 922 Interference to proceed to the priority phase to determine which party (Lo or Quake) was the first to invent the subject matter of the interference. The inventors named on the Lo 266 Application were previously declared the senior party in the 922 Interference and are therefore presumed to be the first to invent, and entitled to a patent, on the invention that is the subject matter of the interference. In the priority phase, the inventors named in the Quake 415 Patent may seek to overcome that presumption and attempt to prove they invented the subject matter of the interference first.

    2.


    The Company also is separately challenging the validity of the Quake 415 Patent in an inter partes review proceeding currently pending before the PTAB (Case IPR 013-00390).

    The Company cannot predict the final outcome of the 922 Interference or the inter partes review and there can be no assurance that the final outcome of either matter will be favorable to the Company.

    Disclosure: I am long SQNM.

    Apr 14 7:49 AM | Link | Comment!
  • Switzerland Study Confirms: PrenaTest Reduces Invasive Procedures By 67%

    A new era in prenatal care: non-invasive prenatal testing in Switzerland

    Gwendolin Manegold-Brauer, Anjeung Kang Bellin, Sinuhe Hahn, Christian De Geyter, Johanna Buechel, Irene Hoesli, Olav Lapaire

    Women's Hospital, University of Basel, Switzerland

    Summary

    QUESTIONS UNDER STUDY: Prenatal care has been significantly influenced by the introduction of non-invasive prenatal testing (NIPT) for aneuploidies in 2012. The aim of this study was to describe the current impact of NIPT on prenatal care.

    METHODS: We performed a retrospective data analysis including all women with singleton pregnancies who presented for first trimester screening (FTS) between 1 October 2011 and 30 March 2013 and those seeking NIPT. According to the results of FTS the women were categorised into three risk groups: low risk for aneuploidy (<1:300), intermediate risk (1:300-1:50) and high risk (>1:50). They were counselled about the available options for invasive prenatal testing (IPT) and NIPT available at the time of FTS. The nine months before and after the introduction of NIPT were evaluated regarding further testing after FTS.

    RESULTS: In total, 951 women were included: 505 examinations (group 1) were carried out before NIPT became available, 446 (group 2) thereafter. In group 2, 9.0% (40/446) had NIPT. Here, 60.0% (24/40) had a low risk according to FTS. In group 2 there was an increase of 3.6% of additional prenatal tests after FTS. The greatest increase was noted in the intermediate-risk category (10.7%). The number of invasive prenatal tests decreased by 67.4%.

    CONCLUSIONS: We observed a notable increase in prenatal testing after the implementation of NIPT. NIPT is an additional test for women who need more reassurance. Since the options for pregnant women become more complex and the costs of NIPT are high, prenatal counselling has become more challenging.

    Key words: NIPT; cell-free foetal DNA in maternal blood; foetal aneuploidies; prenatal counselling;

    prenatal care

    Introduction

    The introduction of non-invasive prenatal testing (NIPT) for foetal aneuploidies, using cell-free foetal DNA extracted from maternal blood, offers a risk-free expansion of the prenatal tests for pregnant women [1]. The currently available cell-free DNA tests are based on the finding that cells of the placenta continuously release large amounts of nucleic acids into the maternal blood. Cell-free foetal DNA comprises about 10% of the total cell-free DNA (maternal and foetal), is only present during pregnancy and is cleared a few hours after birth [2].

    With the development of massively parallel genomic sequencing, testing for foetal aneuploidies from maternal blood has now become clinically available [3-5]. Several validation studies from high-risk populations now have reported detection rates for foetal trisomy 21 of >99%, 98% for trisomy 18 and 89% for trisomy 13, with false positive rates of 0.1%, 0.1% and 0.4%, respectively [4-11]. Recently, NIPT has become clinically available for other aneuploidies such as trisomy 16, 22, 45 X0 and 47 XXX, but the published study reports only a small number of each aneuploidy and therefore experience is still very limited [11].

    Currently, most pregnant women in industrialised countries have access to a detailed sonographic examination of their foetus's anatomy at 11-14 gestational weeks and are offered a risk assessment for aneuploidies using first trimester screening (FTS). FTS combines the statistical background risk of the mother, foetal anatomy, nuchal translucency measurement and biomarkers in the maternal blood (pregnancy-associated plasma protein A [PAPP-A], free beta human chorionic gonadotropin [HCG]). FTS can achieve a sensitivity of 90% for trisomy 21 with a false positive rate of 3%-5% [12].

    In high risk populations, NIPT has been shown to have a higher sensitivity and specificity than FTS with respect to the detection of trisomy 21 [4-10]. It can be started from as early as ten weeks of pregnancy and is not limited to a defined "time window". However, NIPT only offers information on the aneuploidies that are specifically tested, it is not yet implemented in twin pregnancies in Europe and there are only very few studies from low-risk populations [13].

    The only diagnostic test today to exclude chromosomal abnormalities with a near 100% accuracy is invasive prenatal testing (IPT) by means of amniocentesis or chorionic villus sampling (CVS). IPT, however, carries a significant risk of miscarriage, estimated to vary around 0.5%-1% [14, 15].

    In the light of these facts, the exact role of NIPT in prenatal care remains to be defined. Although the technology is available today and the test can be requested by the patients at their own expense (approximately 1200 CHF), the indications for NIPT are still debated controversially. Here, we report on the experiences of the implementation of NIPT in clinical practice after its formal introduction in July 2012 in Switzerland. The aim of this study was to describe the current impact of NIPT on prenatal care.

    Material and methods

    The Praena Test®, the first available NIPT-test, became clinically available at the University Hospital of Basel on 13 July 2012. From July 2012 until February 2013, the Praena Test® (Lifecodexx, Konstanz, Germany) offered the detection of trisomy 21 only. Since February 2013, analysis for trisomies 13 and 18 also became available and the Praena Test® was the only NIPT test used in the study group.

    The present retrospective data analysis included all singleton pregnancies between 1 October 2011 and 30 March 2013, who presented for FTS at the University Hospital of Basel between 11-14 weeks of gestation and all women seeking NIPT based on the results of internal and external FTS. FTS was offered as a combined test including nuchal translucency measurement, PAPP-A and free beta-HCG. Biochemical markers were not offered to women who had a HCG injection for induction of ovulation or for other reasons. Some women also declined to take the additional blood test. The risk derived from FTS according to the combined test or according to age risk and nuchal translucency measurement was analysed. The data were analysed anonymously in retrospect from our database and therefore informed consent was not obtained. All internal FTS were conducted according to the guidelines of the Foetal Medicine Foundation (FMF), London with GE Voluson E8 Expert ultrasound machines (GE Medical Systems, Zipf, Austria). Risk calculation was performed with the Viewpoint software (GE, Viewpoint Bildverarbeitung Version 5.6.12.601, Wessling, Germany). Experienced FMF-certified sonographers performed all internal ultrasound examinations and invasive procedures. As a standard of care, all women were counselled about the different methods available at the time of investigation and were presented with the various options of both invasive and non-invasive prenatal diagnostic procedures. The individual risk of aneuploidy was discussed based on the results of FTS.

    The women were categorised into three risk groups according to the results of FTS: low risk for aneuploidy <1:300; intermediate risk 1:300-1:50; high risk >1:50. Nuchal translucency >95th percentile or the presence of foetal structural abnormalities were considered as high risk, regardless of the risk calculation. Risk calculation was always performed for trisomy 21, 13 and 18 individually. The women were grouped according to their highest risk for aneuploidy (trisomy 21, 13 or 18).

    All statistical analyses were performed using the R system for statistical computation Version 2.15.1. A p-value <0.05 was considered significant. Frequencies in the tables were compared using the chi-square test. If the expected frequency was less than 5, the Fisher test was used.

    Table 1: Baseline characteristics of the patients included in the two respective study groups. Group 1: before the introduction of NIPT; group 2: after the introduction of NIPT. The maternal age is presented as mean value (± standard deviation).
     Group 1 n = 505Group 2 n = 446p-overall
    Risk group according to FTS
    Low risk (n)431(85.3%)391(87.7%)0.180
    Intermediate risk (n)37(7.3%)35(7.9%)
    High risk (n)37(7.3%)20(4.5%)
    Mode of conception
    Natural conception (n)437(86.5%)382(85.7%)0.764
    After assisted reproduction (n)68(13.5%)64(14.3%)
    Maternal age (y)31.8(±5.8)31.4(±5.6)0.247
    FTS = first trimester screening; NIPT = non-invasive prenatal testing

    Results

    During the observational period, 951 women presented for a routine 11-14 week ultrasound scan. Five hundred and five sonographic examinations were carried out before NIPT became available, whereas 446 sonographic examinations were conducted after the formal introduction of NIPT. Of the patients, 13.9% (133/951) were pregnant after infertility treatment. The comparison of the baseline characteristics between both groups revealed no statistically significant differences (table 1). In the study population, 13.6% (129/951) were screened positive after FTS according to a cut-off of >1:300.

    Experience with NIPT and characteristics of the women who opted for NIPT

    Nine percent of all patients (40/446) decided to take advantage of the Praena Test®. The mean interval between the blood collection and the test result was 14 business days (range: 10-40 days). We did not have any samples that could not be analysed because of a low foetal cell-free DNA fraction. The median gestational time at testing was 16 weeks. One test screened positive for trisomy 18 and was confirmed by CVS. In the women who had negative NIPT test results there were no aneuploidies detected at birth. We also did not have any false positive NIPT tests.

    Of these 40 women, 62.5% (25/40) were ≥35 years old (table 2). The median age of the women opting for NIPT was 35.4 years; 15.0% (6/40) had previously undergone infertility treatment and 60.0% (24/40) had a low risk for aneuploidy according to FTS (table 2).

    Changes in prenatal care after introduction of NIPT

    Since the introduction of NIPT, there has been an overall increase of 3.6% of additional prenatal tests including both IPT and NIPT after FTS (8.5% vs 12.1%, p = 0.068). In the low risk category this increase amounted to 4.7% (2.2% vs 6.9%, p <0.149), whereas in the intermediate risk category this increase was 10.7% (35.1% vs 45.8%, p = 0.016). In the high risk category an increase of 1.8% (55.0% vs 56.8%, p = 0.149) was noted (table 3).

    In contrast, the overall decrease of IPT was 5.5% (8.8% vs 3.1%, p = 0.001). The decrease was 1.1% in the low-risk group, 29.4% in the intermediate-risk group and 16.8% in the high-risk group (table 3). Since the introduction of NIPT, the total number of invasive prenatal procedures decreased by 67.4% (43 vs 14).

    Table 2: Baseline characteristics of the women who opted for NIPT. The maternal age is presented as mean value (± standard deviation).
     NIPT n = 40
    Risk groups according to FTS
    Low risk (n)24(60.0%)
    Intermediate risk (n)14(35.0%)
    High risk (n)2(5.0%)
    Mode of conception
    Natural conception (n)34(85.0%)
    After assisted reproduction (n)6(15.0%)
    Maternal age (y)35.4(±4.91)
    FTS = first trimester screening; NIPT = non-invasive prenatal testing
    Table 3: Differences in prenatal testing according to risk category before and after the introduction of NIPT. Group 1: before the introduction of NIPT; group 2: after the introduction of NIPT.
    Risk group according to FTSnNo further testsIPTNIPTIPT special indication / termination
    Low riskGroup 143141195.36%92.09%00%112.55%
    Group 239136292.58%41.02%235.88%20.51%
    p-value 0.9970.372<0.001 
    Intermediate riskGroup 1372464.86%1335.14%00%00%
    Group 2351954.29%25.71%1440.00%00%
    p-value 0.8350.018<0.001 
    High riskgroup 1371540.54%2156.75%00%12.71%
    Group 220840.00%840.00%315.00%15.00%
    p-value 0.3330.0540.103 
    FTS = first trimester screening; IPT = invasive pregnancy testing; NIPT = non-invasive prenatal testing

    Discussion

    Our study summarises the first experience with NIPT in Switzerland. We compared the first nine months since the introduction of NIPT with the nine months after NIPT became available. The baseline characteristics were similar in both groups. The higher number of patients that "screen positive" in FTS in our population is explained by a mixed collective constituted of low risk patients and referred higher risk patients.

    As the Swiss guidelines for pregnancy care recommend offering FTS after counselling to all women, NIPT was not used as a first-line prenatal test in the study group [16, 17].

    Experience with NIPT

    Conclusive test results with NIPT were obtained in all cases. This is probably due to the low number of patients in the study group and the late median gestational age for testing, since it has been reported that about 2.2% of all tests do not reach the minimal requirement for quality or amount of foetal cell-free DNA in the sample [13]. More than half of the patients who opted for NIPT were over 35 years of age. This might be in part due to a higher statistical risk of aneuploidy at this age, but may also reflect the financial situation of this age group. One could speculate that women after infertility treatment would choose NIPT more frequently than others, mainly because of a higher maternal age and a more attentive position towards pregnancy, but this was not confirmed here. Surprisingly, most of the women that decided to take advantage of NIPT did not have an increased risk in FTS. Here NIPT seems to be a risk-free reassurance test for women who can afford to take the test and who want to take advantage of the higher test sensitivity compared with FTS.

    Changes in prenatal care

    In low risk pregnancies, the proportion of women taking IPT was 2.1% before the advent of NIPT. After the introduction of NIPT, almost 6% chose NIPT despite outcome data in low risk populations being scarce [16, 17]. Although false positive rates of around 0.5% for trisomy 21 are reported [18], the consequences and associated risks of a false positive test in a low risk population, which will finally lead to unnecessary IPT and possible miscarriage should not be underestimated.

    For the women with an intermediate risk, the increase of additional testing with NIPT was most significant (10.7%) resulting in a drop of IPT of 29.4%. It is not surprising that these women, who had an intermediate risk after FTS before NIPT became available, decided not to undergo IPT (64.9%) because of the risk of miscarriage. It can easily be explained that, on the other hand, the number of women willing to gain more assurance in this group is high. We hypothesise that the number of test takers in this group will continue to rise as the awareness of NIPT grows. It is likely that the intermediate-risk group will benefit most from risk-free testing. As such, coverage of the costs of NIPT testing by health insurance would seem most appropriate in this risk group.

    In high risk cases after FTS, an invasive procedure is still recommended [18, 19], especially in those cases with increased nuchal translucency over the 95th percentile, where we know that the risk of structural or genetic anomalies is about 20% [20]. Here the risk for other aneuploidies and genetic syndromes as a result of deletions or duplications that cannot be detected by NIPT should not be underestimated and counselling in this situation should be performed by a specialist. Another benefit is that IPT provides accurate information on the karyotype within 24-48 hours. However, even in this group some women opted to have NIPT despite having been informed about its limitations. This confirms prior studies, in which women had a high preference for those tests that help to avoid any risk of miscarriage [21].

    Decrease in IPT

    Overall, the total number of invasive preterm tests decreased by almost 70%. This was a goal of prenatal research for many years and there certainly will be a further expansion of the screening opportunities given by NIPT in the near future. However, IPT will still be necessary for testing in special indications (inherited risks, infections, etc.) and for positive findings by NIPT. As a result of this trend, we must be aware that expertise in this field will dramatically decline.

    Although a long desired goal in prenatal diagnostics, the ability to analyse the foetus with a simple maternal blood sample, has finally become reality [22], prenatal counselling is becoming even more complex. This study shows first experiences in Switzerland with NIPT. It shows the important impact of these tests and their rapid uptake in our society. It also illustrates new challenges in our counselling process and clearly demonstrates the decrease in invasive prenatal tests already. The limitations of this study certainly are the small number of patients with NIPT, which allows only a description of the experiences without the ability to make any statements on the reliability and quality of the NIPT test used.

    The challenge now is to develop a new algorithm for prenatal care and to integrate NIPT into national guidelines to allow general access covered by health insurance for all women who, from a public health perspective, could really benefit from NIPT.

    www.smw.ch/content/smw-2014-13915/

    Disclosure: I am long SQNM.

    Apr 12 9:56 AM | Link | Comment!
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