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Interferon beta-1a - Avonex [recombinant] -- Product Record
Interferon beta-1a, rDNA/Biogen Idec
Merck & Co., Inc. -- Parent co.
Bayer HealthCare Pharmaceuticals -- Patent dispute
Abbott Laboratories, Inc. -- Former inv.
Upjohn Co. -- Patent dispute
Hoffmann-La Roche Inc. -- Patent dispute
Schering-Plough Corp. -- Europe mark. ; Former
Chiron Corp. -- Tech. ; Patent dispute
Biogen Corp. -- Tech. ; Former
Boehringer Ingelheim Pharma KG -- Patent dispute
Genzyme Corp. -- Japan mark.
Abbvie -- Latin Amer mark.
Triton BioSciences, Inc. -- Patent dispute
Cetus Corp. -- Patent dispute
Genesys Pharma -- Former
Amgen-Dompe Biotec S.p.A. -- Europe mark.
Packaging Coordinators, Inc. -- Manuf. other
Boehringer Mannheim GmbH -- Patent dispute
Cardinal Health, Inc. -- Parent
Japanese Foundation for Cancer Research -- Tech.
Columbia University -- Tech. ; Patent dispute
Bender & Co. GmbH -- Patent dispute
Novus Biopharma Inc. -- Europe mark.
Biogen Idec, Inc. -- Manuf. ; R&D ; Tech. ; USA mark.
Stanford University -- Tech. ; Patent dispute
Sanofi S.A. -- Parent co.
Bioferon Biochemische Substanzen GmbH & Co. -- Former
Bayer Healthcare AG -- Parent
Hoffmann-La Roche Ltd. -- Tech.
Rentschler Arzneimittel GmbH & Co. -- Tech. ; Patent dispute ; Former
Hoechst AG -- Patent dispute
Schering AG -- Parent
210 Interferon beta-1a, rDNA/Biogen Idec
Avonex [recombinant]
Status - approved; marketed
Biogen Idec, Inc. – Manuf.; R&D; Tech.; USA mark.
Biogen Corp. – R&D; Tech.; Former
Ben Venue Laboratories – Manuf. other
Schering-Plough Corp. – Europe mark.
Merck & Co., Inc. – Parent.
Dompe Biotec – Europe mark.
Bioferon Biochemische Substanzen GmbH & Co. – R&D; Tech.; Former
Rentschler Biotechnologie GmbH – Tech.; Former; Patent dispute
Boehringer Ingelheim Pharma KG – Patent dispute; Parent
Hoffmann-La Roche Ltd. – Tech.
Japanese Foundation for Cancer Research – Tech.
Abbott Laboratories – Former
Abbbvie – Latin Amer. mark.
ASTA Medica GmbH – Patent dispute
Berlex Laboratories – Patent dispute
Schering AG – Parent
Stanford University – Tech.; Patent dispute
Chiron Corp. – Tech.; Patent dispute
Genzyme Corp. – Japan mark.
Packaging Coordinators, Inc. – Manuf. other
Cardinal Health, Inc. – Parent
Columbia University – Tech.; Patent dispute
Cetus Corp. – Patent dispute
Triton Biosciences Inc. – Patent dispute
Hoechst AG – Patent dispute
Boehringer Mannheim GmbH – Patent dispute
Cross ref.: See the Interferon Products entry (#793) and the other interferon beta entries below.
Description: Avonex refers to lyophilized (freeze-dried) and aqueous formulations of recombinant interferon beta-1a glycoprotein expressed by Chinese hamster ovary (CHO) cells transformed with the human interferon beta-1a gene. The amino acid sequence of interferon beta-1a is identical to that of human fibroblast-derived interferon beta-1a (and identical to interferon beta-1a in Rebif from Merck Serono). CHO-expressed interferon beta-1a is a 166 amino acid glycoprotein with a predicted molecular weight of ~22,500 Daltons (~22.5 kDa). Its glycosylation is similar to that of human interferon beta-1a, and occurs at the asparagine (Asn) residue at position 80. The glycoprotein is ~89% protein and ~11% carbohydrate by weight, with an empirical formula of C908-H1406-N246-O252-S7.
Using the World Health Organization (WHO) natural interferon beta standard [Second International Standard for Interferon, Human Fibroblast (Gb-23-902-531)], an in vitro cytopathic effect bioassay using WISH cells and vesicular stomatitis virus, interferon beta-1a has a specific activity of ~200 million international units (IU)/mg, with 30 µg of Avonex containing 6 million IU of antiviral activity.
Avonex is packaged in single-use vials for intramuscular injection after reconstitution with supplied diluent; and as an Albumin (Human)-free liquid formulation in prefilled syringes. Vials are packaged along with two alcohol wipes, one gauze pad, one 3 mL syringe, one Micro Pin vial access pin, one needle, and one adhesive bandage. Each vial contains 33 µg (6.6 million IU; for withdrawal of a 30 µg dose) of interferon beta-1a; 16.5 mg Albumin (Human), USP; 6.4 mg sodium chloride, USP; 6.3 mg dibasic sodium phosphate, USP; and 1.3 mg monobasic sodium phosphate, USP. Avonex contains no preservatives.
AVONEX PEN is a sterile liquid for intramuscular injection in a prefilled glass syringe surrounded by an autoinjector. Each 0.5 mL (30 microgram dose) in the AVONEX PEN contains 30 micrograms of interferon beta-1a, 0.79 mg Sodium Acetate Trihydrate, USP; 0.25 mg Glacial Acetic Acid, USP; 15.8 mg Arginine Hydrochloride, USP; and 0.025 mg Polysorbate 20 in Water for Injection, USP at a pH of approximately 4.8.
Avonex vials are reconstituted with Sterile Water for Injection, with 1.0 mL withdrawn for administration. Diluent is supplied in a single-use vial (Sterile Water for Injection, USP, preservative-free). The dating period is 15 months from the date of manufacture at 2-8˚C (refrigerated). The date of manufacture is the date of final sterile filtration of the formulated bulk. The dating period for bulk intermediate is 12 months from the date of filling of bulk intermediate containers. In June 2006, Biogen Idec introduced prefilled syringes with new needle 20% shorter and thinner than the previously approved needle.
Avonex used in preclinical studies and various clinical trials, including its pivotal Phase III trial (for relapsing multiple sclerosis), was manufactured in Germany by Bioferon, then a joint venture of Biogen Corp., now Biogen Idec) and Rentschler Arzneimittlel GmbH & Co.. This involved use of Rentschler's BG9015 CHO cell line – cells which grew as an adherent (stick to surfaces) culture.
After the Bioferon joint venture disbanded and filed for bankruptcy, Biogen developed a new CHO cell line, BG9216, adapted to suspension culture (to more easily manufacture larger quantities). Various manufacturing-related changes to reduce immunogenicity were implemented by Biogen as it established its own cell line and manufacturing, including changes in oxidation, protein aggregation, and removal of moisture from vials. Subsequent pharmacokinetic bioequivalence trials showed that BG9015 product was not comparable to the BG9216 product. Biogen then developed yet another suspension culture interferon beta-1a expressing CHO cell line, BG9418. The purification process (extraction methods and column chromatography) for the BG9418 product also differed from that of BG9015. BG9418 has been extensively tested by biological, biochemical, and biophysical studies, and in human pharmacokinetic studies, and has been accepted by FDA as equivalent to the BG9015 product [allowing acceptance of the studies and trials using the BG9015 product for approval of BG9418-expressed interferon beta-1a (Avonex)]. Note, this change in cell line during development is often cited in discussions of follow-on biologics/biogenerics.
All AVONEX dosage forms are single-use (injection of reconstituted solution, prefilled syringe, and prefilled autoinjector). Dosage forms and strengths are: for injection: 30 micrograms lyophilized powder in a single-use vial; for injection: 30 micrograms per 0.5 mL solution in a single-use prefilled syringe and for injection: 30 micrograms per 0.5 mL solution in a single-use prefilled autoinjector
The AVONEX PEN (AVONEX 30mcg/0.5mL solution for injection) approved in 2012 is an automated injection device designed to be easier to use than the currently available AVONEX Prefilled Syringe - "the first single-use, once-a-week, fully integrated IM autoinjector for MS." AVONEX PEN also incorporates a substantially smaller needle, which may reduce injection anxiety and pain. AVONEX PEN was approved based on data from a Phase IIIb study in which approximately nine out of 10 patients used the device successfully. Ninety-four percent of patients in the study also expressed a preference for AVONEX PEN over the AVONEX Prefilled Syringe. AVONEX PEN was approved in the European Union and Canada in 2011.
Nomenclature: Interferon beta-1a, rDNA/Biogen Idec [BIO]; Avonex [TR]; Interferon beta-1a [FDA]; interferon beta-1a [USAN INN BAN]; interferon beta1 (human fibroblast protein reduced) [CAS]; 145258-61-3 [CAS]; BG9418 [SY]; BG-9418 [SY]; BG-9015 [SY]; BG9015[SY]; BG9216[SY]; Dompe (beta) [TR foreign]; Neoferon [TR foreign]
Biological.: Interferon beta-1a (Avonex) and other interferon beta products have both antiviral and immunoregulatory activities comparable to those of native human interferon beta species. The mechanisms by which interferon beta exerts its actions in multiple sclerosis (MS) are not clearly understood. Interferon beta exerts its biological effects upon binding to specific cell surface receptors. Binding initiates a complex cascade of intracellular events that leads to the expression of numerous interferon-induced gene products and markers. These include MHC Class I, Mx protein, 2',5'-oligoadenylate synthetase, beta2-microglobulin, neopterin, protein kinase, and indoleamine 2,3-dioxygenase, some of which are mediators of the biological actions of interferon beta. Some of these products have been measured in the serum and cellular fractions of blood collected from patients treated with Avonex. After a single intramuscular dose of Avonex, serum levels some of these products remain elevated for at least 4 days to 1 week.
The are no in vitro models for MS and no accepted animal model for MS in a species responsive to interferon beta. The activities of interferon beta-1b are highly species specific, and most preclinical pharmacologic information of Avonex was derived from studies in cultured human cells and, to a lesser extent, in rhesus monkeys.
In Oct. 2000, Biogen reported that an in vitro assay (developed by Dr. J. Oger, et al., Univ. of British Columbia) showed that Avonex is the most potent of the three available interferon beta products on a mass basis. This was the first in vitro assay for comparison of potency of interferon beta products based on mechanisms relevant to multiple sclerosis. Previously, the only potency assay was for antiviral effects. The assay is based on suppression of secretion of immunoglobulin G (IgG) antibodies, which are increased in MS patients. However, when potency of the three interferon beta products was expressed as a proportion of their weekly-injected dose, the overall effects were comparable. Since there have been no clinical trials comparing the interferon beta products, this is one of the few comparison studies of these products.
Companies.: Avonex was originally developed and manufactured by Bioferon Biochemische Substanzen GmbH & Co. (Germany), a former joint venture between Biogen Corp. (now Biogen Idec) and Rentschler Arzneimittlel GmbH & Co., now part of Boehringer Ingelheim Pharma KG. During late development, this collaboration was terminated, with Rentschler retaining the original cell line and manufacturing rights for product expressed by the BG9015 cell line and Biogen retaining clinical data.
Avonex is manufactured and marketed in the U.S. by Biogen Idec. It was originally commercially manufactured at Biogen facilities in Cambridge, MA, CBER/FDA est. lic. no. 1204. The FDA granted an establishment license to Biogen's large-scale Avonex manufacturing facility in Research Triangle Park, NC, on March 2, 1998. Cambridge facilities now produce products for clinical trials.
Formulation of the bulk and filling of Avonex for the U.S. market are performed by Ben Venue Labs., Inc., now a subsidiary of Boehringer Ingelheim Pharma KG. The product is labeled and packaged at Packaging Coordinators, Inc. and is distributed by Amgen Inc. Distribution Center (Louisville, KY).
In June 2000, Biogen opened a packaging facility in Hoofddorp, The Netherlands, initially for packaging of Avonex for distribution to all markets outside of the U.S. and Canada. This establishment is the manufacturer of record for Avonex for all international markets.
Marketing rights for certain central and eastern European countries are held by Schering-Plough Corp. (acquired by Merck in 2009). Marketing rights for South Africa are held by Pharmaplan. Rights for Turkey are held by GenIlac. Rights for the Middle East are held by Algorithm. Rights in Latin America and the Caribbean are held by Abbott Labs. Rights in Italy are held by Dompe Biotec in Italy. Rights in Greece are held by Genesys Pharma. Rights in Israel licensed are held by Medixon. Rights in India are held by Nicholas Piramal (NPIL), which launched Avonex in Nov. 2003.
In Sept. 1998, Biogen granted Genzyme General, a subsidiary of Genzyme Corp., rights to commercialize and exclusively distribute Avonex in Japan. Genzyme is responsible for clinical development, product registration, and reimbursement approvals for the product. Genzyme estimates that there are at least 5,000 multiple sclerosis patients in Japan.
Manufacture: The human interferon beta-1a gene was cloned by polymerase chain reaction (PCR) from human genomic DNA isolated from a human leukocyte cell line. The BG9015, BG9016 and BG9418 Chinese hamster ovary (CHO) cell lines were plasmid transformed to express interferon beta-1a. All tests of the BG9418 cell line, used for commercial production, for the presence of infectious agents were negative except for intracytoplasmic A-type retrovirus particles (common in CHO cells). Large scale suspension culture for product for the U.S. market is now performed at Biogen's dedicated large-scale facilities in Research Triangle Park, NC.
Following fermentation, cells and cell debris are removed, and the supernatant fluid is purified by a series of chromatographic separations. An unspecified viral inactivation step is performed (perhaps, nanofiltration). The purified product (bulk intermediate) is filtered, bottled and stored. This is shipped to Ben Venue Lab. in shipping containers packed in dry ice for final formulation and filling. Bulk intermediate is formulated with Albumin (Human), USP (for lyophilzed product packaged in vials) and diluent and sterilized by filtration. Vials are filled, lyophilized, and sealed. Labeling and packaging are performed by Packaging Coordinators, Inc., with distribution handled by the Amgen Inc. Distribution Center.
FDA class: Biologic PLA
CBER class: Biological Response Modifiers
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 19960517; first approval, PLA no. 95-0979/ELA no. 95-0975 granted to Biogen; orphan designation (expired 5/2003); Indication = treatment of multiple sclerosis
Date = 19980302; supplemental PLA/ELA; Indication = new manufacturing site in Research Triangle Park, NC
Date = 20021112; Indication = labeling change to indicate a 5% rate of developing neutralizing antibodies (from previously reported 24% rate)
Date = 20030131; BLA supplement (after conversion to BLA 103628); Indication = revised package insert to include safety and efficacy data from a study of patients who experienced a single clinical exacerbation of multiple sclerosis, and to provide a Medication Guide
Date = 20030528; BLA supplement; Indication = new Albumin (Human)-free liquid formulation of Avonex in pre-filled syringe
Date = 20070202; BLA supplement; Indication = additional intramuscular needle size Date = 20120228; BLA supplements (nos. 5189 and 5191); Indication = two separate dosing regimens/devices for once-a-week treatment of relapsing forms of multiple sclerosis
[full text of "INDICATIONS AND USAGE" section of product insert/labeling]: Indications: [full text of the "Indications and Usage" section of product insert/labeling; 6/2012]:
AVONEX (interferon beta-1a) is indicated for the treatment of patients with relapsing forms of multiple sclerosis to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations. Patients with multiple sclerosis in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis.
Status: The PLA was filed on May 22, 1995, received priority review (6 month target), and was approved on May 17, 1996; approval time of ~1 year. U.S. Orphan drug exclusivity for multiple sclerosis expired in May 2003.
Betaseron, a similar recombinant interferon beta from Chiron Corp./Berlex Labs., was approved with orphan status prior to the approval of Avonex (see entry below), and Berlex pressed for denial of FDA approval for Avonex for much the same multiple sclerosis indication based on substantial molecular and indication similarity. The interferon beta-2a in Betaseron has the same amino acid sequence as interferon beta-2a in Avonex, except for a single amino acid substitution. Despite this, under the regulations of the Orphan Drug Act, Avonex was essentially ruled to be a different and, thus, approvable product primarily based on it behaving differently in clinical trials, offering an improved safety profile relative to Betaseron. Specifically, Avonex "was determined by FDA to be a different product from Chiron's interferon beta-1a, because of a difference in safety profile involving the occurrence of injection site skin necrosis with the Chiron product, but not the Biogen product." No injection site necrosis was reported in the Avonex (BG9015 product) Phase III study in 158 patients, while an incidence rate of 5% was reported among 124 patients in Betaseron's Phase III study. The incidence of injection site reactions was 85% in the Betaseron's Phase III study, and only 4% in the Biogen Phase III study. Biogen's open label safety study of Avonex in 274 MS patients using BG9418 product reported zero injection site necrosis and 4% injection site reactions, consistent with results with earlier BG9015 product trials. Thus, although not identical in amino acid sequence, orphan drug exclusivity for Avonex was granted on the basis of its improved safety profile (indicative of the two being a different product). FDA approval of Avonex was conditioned on satisfactory completion of multiple Phase IV trials.
Avonex is exempt from CBER/FDA lot release requirements.
In "The FDA's assessment of follow-on protein products: a historical perspective," Nature Reviews Drug Discovery (published online April 13, 2007), FDA rationalized its prior approvals of biogeneric/follow-on products, including those with major manufacturing changes. FDA noted that Avonex "illustrates the major challenge associated with approvals of follow-on recombinant versions of approved recombinant products — that is, the amount and type of data needed to demonstrate that a product produced after major changes (for example, use of a new cell line) in the manufacturing process has safety and effectiveness that are comparable with the product manufactured before the change….To obtain approval for Avonex, Biogen had to develop its own manufacturing process for Avonex and demonstrate that the version of interferon beta-1a produced by that process was sufficiently similar to the Bioferon product that the data from the clinical studies using the Bioferon product could be relied on to support approval of the Biogen version…Biogen's initial effort to develop a new cell line and produce an interferon beta-1a that was comparable with the Bioferon product was unsuccessful. A subsequent effort using another new cell line was successful. Physicochemical testing (for example, peptide maps and glycoform characterizations) indicated that the structures were similar. Multiple bioassays (for example, antiproliferation and enhancement of major histocompatibility complex (MHC) class I expression) indicated that the products had comparable bioactivity, and pharmacokinetic data indicated that distribution and clearance of the products were comparable. On the basis of these data, the FDA concluded that the totality of the evidence indicated that the Bioferon product and Avonex were sufficiently comparable to rely on data from the major efficacy study using Bioferon's product to support licensure of Avonex. In a subsequent immunogenicity study, the Avonex product demonstrated decreased immunogenicity. Although decreased immunogenicity is advantageous, the fact that there were differences in immunogenicity between the two products highlights the importance of immunogenicity to product evaluations."
Despite having received full approval in the U.K., the National Institute of Clinical Excellence (NICE), which advises the National Health Service (NHS) on the cost-effectiveness of pharmaceuticals, originally (in June 2000) recommended that beta interferon not be offered by the NHS to MS patients in the UK. NICE considered the £10,000 annual cost per patient too high.
With the product's launch in France in Jan. 1998, Avonex became available in all major European markets.
Avonex received supplemental European Union (EU) approval on May 20, 2002 for use in the treatment of patients at high risk of developing Clinically Definite Multiple Sclerosis (CDMS). Avonex can be prescribed after a patient has a single MS attack and when alternative diagnoses have been excluded. The standard practice had previously been to start treatment only after patients had experienced two separate and distinct attacks or demyelinating events. This decision made Avonex the only MS treatment approved for earlier use, after the first attack, when patients are considered at high risk for developing MS. This indication is not approved in the U.S., but a supplemental BLA is pending with the FDA. This EU approval was based on Biogen's long-term clinical study, CHAMPS (Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study), which showed a 66% reduction in the risk of developing CDMS based on clinical measures and brain MRI scans in a high-risk subgroup of patients.
In May 2004, Biogen Idec reported potential shortages of Avonex, due to manufacturing problems with some prefilled syringes (formation of aggregates). This led to a $2.1 million inventory write-down (loss). Biogen Idec did not foresee supply problems, but requested that physicians prescribe the lyophilized powdered form to new patients until problems are resolved.
In June 2011, the EU approved Avonex Pen for patients with relapsing multiple sclerosis (MS) and patients who have had a single demyelinating event..
The Feb. 28, 2012 sBLA approval included AVONEX PEN, the first intramuscular (IM) autoinjector approved for MS. AVONEX PEN incorporates a smaller needle and easier administration to help patients reduce anxiety about AVONEX self-injection. A new dose titration regimen was also approved, which gradually escalates the dose of AVONEX at treatment initiation, reducing the incidence and severity of flu-like symptoms that can occur at the beginning of therapy..
In May 2012, Biogen-Idec launched 2 new Avonex delivery systems/methods in the U.S. -- AVONEX PEN (AVONEX 30mcg/0.5mL solution for injection), the first intramuscular (IM) autoinjector for chronic use, designed to enhance the self-injection process; and a new dose titration regimen, facilitated by the AVOSTARTGRIP titration devices, providing patients with the option to gradually increase the dose of AVONEX at treatment initiation to reduce the incidence and severity of flu-like symptoms that patients may experience with therapy. AVONEX PEN is the first IM autoinjector approved in MS treatment.
Tech. transfer: U.S. patent 4,530,901, Weissmann, C., assigned to Biogen N.V., filed Feb. 4, 1980, granted July 23, 1985, covers recombinant interferon beta-1a. Biogen has claimed that patent U.S. patent protection for Avonex extends for at least another decade, e.g., 5,326,859 (expires in 2011) and 5,514,567 (expires in 2013).
The Aug. 26, 2002 Wall Street Journal incorrectly stated the patent expiration date for Avonex is in 2003 (when orphan exclusivity expires). Also, DataMonitor and ABN Amro have reported that U.S. patent protection for Avonex expires in 2003.
The Juridical Foundation, Japanese Foundation for Cancer Research (JFCR), has received U.S. and foreign patents, the "Taniguchi patents," claiming the gene sequence of interferon beta. Taniguchi, et al., was the first to clone interferon beta. Biogen has nonexclusively licensed this technology, including 5,326,859 and 5,514,567, expiring in 2011 and 2013, respectively. The last of the Taniguchi patents expires in the U.S. in May, 2013, and related patents have expired already in other countries.
Berlex Labs., Inc., then a subsidiary of Schering AG, now Bayer Schering Pharma AG, manufacturer of a competing interferon beta product (Betaseron), filed suit against Biogen on July 3, 1996 alleging infringement of its "McCormick" U.S. patents concerning production of recombinant interferon beta in Chinese hamster ovary (CHO) cells, including 5,376,567 and a later continuation, 5,795,779. Biogen had previously filed suit against Berlex, Schering AG, and Stanford University seeking a judgement that it was not infringing 5,376,567 and that the patent was invalid. Biogen and Stanford University subsequently entered into an agreement voluntarily dismissing the university from the suit. In Sept. 2000, a U.S. District Court ruled in favor of Biogen, i.e., that Avonex does not infringe Berlex's patents (covering Betaseron), and Berlex appealed.
Final settlement of the "McCormick" dispute between the companies was announced in Jan. 2002. Biogen received a fully paid up, royalty-free, non-exclusive license to 5,376,567 in return for a payment to Berlex of $20 million. A second/final payment from Biogen to Berlex would be due, if the Court of Appeals for the Federal Circuit (CAFC) were to reverse the District Court's previous ruling granting summary judgment in favor of Biogen. The companies agreed not to pursue further litigation concerning these patents.
In Jan. 2003, the CAFC partially reversed the District Court's ruling concerning the "McCormick" patents. This included remanding the case to the District Court to decide whether Berlex patents were infringed under a redefinition of the "doctrine of equivalents." The District Court found in favor of Berlex (i.e., that Biogen was infringing). As stipulated in their prior settlement agreement, Schering AG received $55 million from Biogen, with this considered as nonexclusive licensing fees payable by Biogen Idec until 2007. Schering AG (keeping ~2/3rds) shared this with Stanford University and Chiron Corp. This payment was in addition to the $20 million received by Berlex from Biogen in Jan. 2002. In the worse case for Biogen, the final payment could have been ~$230 million.
In Oct. 1992, the European Patent Office (EPO) Boards of Appeal issued a final ruling in an oppostion filing against EPO patent application EP81300050 (EPO patent no. 32 134, granted Aug. 15, 1984), "DNA sequences, recombinant DNA molecules and processes for producing human interferon-alpha like polypeptides," concerning interferon beta, assigned to Biogen Corp. The opposition had been filed by . Hoffmann-La Roche AG; Upjohn Company (now Pfizer); Bender & Co. GmbH; Cetus Corp. (now Chiron Corp.) and Triton Biosciences Inc., a subsidiary of Schering AG; Hoechst AG (now Sanofi Aventis); and Boehringer Mannheim GmbH (merged into Hoffmann-La Roche); and Boehringer Ingelheim Zentrale GmbH and Boehringer Ingelheim Pharma KG. The EPO ruled in favor of the challengers, including that the patent "did not even disclose the successful preparation of beta-interferon from plasmids containing DNA-sequences coding for this protein."
In Oct. 1998, Biogen filed an opposition against then recently issued European Patent 529300 B1 ("Rentschler II Patent") assigned to Rentschler Biotechnologie GmbH (now part of Boehringer Ingelheim ) challenging the validity of this composition-of-matter patent concerning recombinant glycosylated beta-interferon. This patent covers a certain group of beta interferons with specific glycosylations resulting from genetic engineering. In Nov. 2002, the European Patent Office ruled in favor of Rentschler (upheld validity of its European patent). Rentschler filed an infringement suit against Biogen in Germany, and Biogen appealed.
Biogen has nonexclusively licensed interferon-beta technology from Hoffmann-La Roche Ltd., apparently including U.S. 4,921,699, granted May 1, 1990, and 4,816,566, with these patents expiring in May 2009, and having generally expired elsewhere in the world. These patents claim interferons, including interferon beta, with one cysteine replaced by another amino acid to prevent formation of intermolecular disulfide bonds.
In April 2003, Rentschler and Biogen settled their European patent disputes, with Rentschler granting Biogen a nonexclusive European license to EP 529300 for current and future interferon beta products, and Biogen paying Rentschler an initial $13.1 million payment and unspecified future royalties on sales. [Also in April 2003, BioPartners GmbH, a company developing a biogeneric human albumin-free version of interferon beta, nonexclusively licensed worldwide rights to EP 529300 and associated trade secrets and CMC information from Rentschler, and has contracted with Rentschler for manufacture of its interferon beta product]. Biogen reports that the Rentschler EU patent expires in July, 2012.
In Dec. 1998, Biogen settled a dispute with ASTA Medica GmbH relating to a terminated 1989 agreement between Biogen, ASTA and Bioferon under which ASTA had obtained a license to certain Biogen's patents related to recombinant beta interferon for a number of European countries. Under the terms of the settlement, ASTA dismissed its lawsuit against Biogen in the U.S. and released Biogen from all claims related to the 1989 agreement; and Biogen paid an undisclosed amount to ASTA.
Biogen was a licensee of Columbia University's patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. The original patents and license expired in 2000, but Columbia received another patent in 2002 and was again seeking royalties, which Biogen and other companies challenged in court. Recently, the University decided not to continue to press infringement suits and seek royalties, but the patent office is reexaming the relevant patent, and the university could against pursue infringement and royalties at a later date. See the "Tech. transfer" section of the Recombinant DNA Products entry (#100) for further information.
U.S. patent protection for Betaseron/Betaferon was projected by Decision Resources to expire in 2007, and in most European countries in 2008. However, with diverse entity/active agent, use, manufacturing process, formulation and other patents, this may well be an oversimplification of the patents that may be expected to be asserted against competitors.
In Sept. 2010, Biogen Idec received U.S. 7,588,755, "DNA sequences, recombinant DNA molecules and processes for producing human fibroblast interferon-like polypeptides," claiming certain interferon beta gene sequences (and later also 7,635,466). The company promptly filed patent infringement suits against Betaferon, Rebif and Extavia. This patent expires on Sept. 15, 2026, well after expiration of other patents in May 2013. Some might consider this a submarine patent, but the delay in obtaining the patent appears to lie with the USPTO, not Biogen Idec. The '755 patent claims priority to a first application filed in 1981 and a divisional application filed in 1989, both abandoned. The application that resulted in the '755 patent was filed on May 25, 1995, and thus has a patent term of 17 years from issue, determined by U.S. law prior to the adoption of the GATT provision limiting U.S. patent term to 20 years from the earliest priority date. During prosecution, there was a delay from March 12, 1998 to Jan. 15, 2003 -- almost five years -- while prosecution was suspended because of a potential interference. But no interference was declared. A second extensive period of delay involved the appeal of an asserted anticipation rejection, which was complicated by new rules for appeal briefs promulgated (and strictly enforced) by the USPTO. This delayed prosecution of the application to allowance by another 3 years, from June 24, 2005 to May 29, 2008. In addition to USPTO delays, the extended term of this patent is an artifact of the change in patent term in the U.S. The reason the term seems so long is that everyone has become accustomed to a 20-year maximum from the earliest priority date, with the prior norm of 17 years from grant date seeming anomalous, especially when the term is as extended as it is in this case (31 years from the application filing date, and 45 years from the earliest priority date). Something like this could not occur today. The ability of this patent to protect against biogeneric/biosimilar competition may depend in future understanding of the cause of MS, with claim no. 1 citing, "A method for immunomodulation or treating a viral conditions, a viral disease, cancers or tumors..." If MS treatment is not linked to viral infection or immune modulation, the patent may not apply
Trials: The CHAMPS study has shown that early treatment with Avonex significantly reduces the rate at which individuals at high-risk for MS developed clinically definite multiple sclerosis (CDMS). CHAMPS (Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study) was a longitudinal follow-up of the patient groups enrolled in an earlier Biogen MS treatment study conducted between April 1996 and April 1998. CHAMPS followed 383 patients given weekly injections of Avonex or placebo after experiencing a first MS-like symptom. CHAMPS was planned to last three years, but was stopped in Feb. 2000 after a pre-planned interim efficacy analysis found that the benefit of Avonex treatment was significant enough to halt the trial. Treatment with Avonex reduced the rate of development of CDMS by 44% versus placebo. Avonex also showed a highly significant positive impact on reducing the rate at which patients developed brain abnormalities or lesions visible on MRI scans. The increase in brain MRI T2 lesion volume (which reflects cumulative scarring) was 91% lower in the Avonex patients compared to the placebo group. CHAMPS results were published in the Sept. 2000 New England Journal of Medicine.
In early 2002, a Biogen-sponsored trial with Avonex in 795 relapse remitting MS patients treated for four years found that patients with interferon beta-neutralizing antibodies had a 34% higher annual relapse rate compared to patients without antibodies. This was the first demonstration of the effects of antibodies in MS clinical outcomes.
In Sept. 2005, Biogen Idec initiated GAP, an international, cross-sectional study of adherence to long-term MS treatment regimens in 1,800 patients. Patients taking Avonex, copaxone glatiramer from Teva, and Rebif from Serono were included.
In April 2007, one-year data were presented from the retrospective, claims-based, observational Multiple Sclerosis Benchmarks study in 10,000+-patients. Using a comprehensive analysis of medical and pharmacy costs, the study concluded that patients treated with Avonex have the lowest total one-year cost to a health plan when compared to other interferon beta treatments. Researchers analyzed 10,622 patients over one year to assess how demographic, administrative and clinical variables affect MS costs and utilization patterns and to examine the economic impact of treating MS. Avonex had the lowest average one-year cost compared to other interferon beta treatments. The total costs over one-year to MS patients on interferon beta therapy were: Avonex, $19,896.15; Rebif, $22,207.85; and Betaseron, $21,073.33. Avonex patients were also more likely to refill their prescriptions (average of 9.6/year vs. 8.1 and 8.2/year for the other interferon beta therapies) and were less likely to use certain concomitant medications. Use of disease-modifying therapies (interferon beta and glatiramer acetate) was almost always observed as monotherapy, reflecting little evidence of combination use or switching between products. In a separate study, Quality Assessment of Multiple Sclerosis Therapy (QUASIMS), reported at the same conference, it was shown that MS patients do not derive additional clinical benefit from switching among interferon beta therapies. QUASIMS was an open-label, retrospective, observational study conducted in 14 countries in 7,156 MS patients who had received two years of uninterrupted therapy with interferon beta as initial therapy or follow-up therapy.
In April 2008, results were published in Current Medical Research and Opinion from a Phase IV (post-marketing), open label, head-to-head study of intramuscular Avonex and high-dose, high-frequency subcutaneous Rebif (interferon beta-1a; see related entry) in patients with relapsing-remitting multiple sclerosis (RRMS). The two products showed similar efficacy over 18 to 30 months of continued therapy. The Prospective and Retrospective Long-Term Observational Study of Avonex and Rebif (PROOF), involved 217 patients with 136 completing a median of 25.9 months of AVONEX 30 µg once weekly (n=69) and a median of 22.2 months Rebif 44 µg three times weekly (n=67). T he study provides further clinical evidence that the dose and frequency of treatment shows no advantage on delivering better efficacy. So, with safety and efficacy being comparable, Biogen Idec expects Avonex, with its more convenient dosing, to have marketing advantage over Rebif.
Medical: The generally recommended dosage (for relapsing MS) is 30 µg (1.0 ml of reconstituted product) administered by intramuscular injection once weekly. (This compares to 250 µg every other day by subcutaneous injection for Betaseron).
AVONEX is administered intramuscularly. The recommended dose is 30 micrograms once a week. To reduce the incidence and severity of flu-like symptoms that may occur when initiating AVONEX therapy at a dose of 30 micrograms, AVONEX may be started at a dose of 7.5 micrograms and the dose may be increased by 7.5 micrograms each week for the next three weeks until the recommended dose of 30 micrograms is achieved . The AVOSTARTGRIP kit containing 3 titration devices can be used for titration and is to be used only with AVONEX Prefilled Syringes.
As discussed in the Interferon Products entry (in the Blood Products, Human section), administration of interferon products can result in induction of associated neutralizing antibodies which can reduce or even eliminate the activity and efficacy of the product. This is a particularly serious problem with interferon beta products used for treatment of multiple sclerosis. These patients must receive treatment for long periods, e.g., 10-30 years, often starting at an early age, so loss of the major treatment option (interferon beta) to induction of antibodies can be serious. Manufacturing-related changes can affect the development of neutralizing antibodies in the bulk and final products. The incidence of neutralizing antibodies due to Avonex (Manufactured by Biogen) is reported in the 2-6% range, is lower than for other interferon beta products, and is lower (~24%) than that for Avonex originally manufactured in Germany by Rentschler. FDA approved a label change reporting this lower incidence in Nov. 2002.
Market: Total worldwide sales of Avonex were $2.518 billion in 2010; $2.323 billion in 2009 and 2.226 billion in 2008. In 2008, U.S. sales of increased 18% to $1.3 billion and international sales increased 18% to $926 million..
Total worldwide sales of Avonex were $1,857 billion in 2007; $1.794 billion in 2006; $1.54 billion in 2005; $1.417 billion in 2004; $1.168 billion in 2003; and $1.3 billion in 2002 (achieving blockbuster status), $970.5 million in 2001, $761 million in 2000, $621 million in 1999, $395 million in 1998, and $240 million in 1997. In 2004, U.S. sales were $922 million and international sales were $495 million; and in 2003, were $800 million and $368 million, respectively.
The 2007 Average Wholesale Price (AWP) is $1,672.20 for four 30 µg/0.5 mL syringes, and also for four 33 µg vials (Red Book, 2007).
In April 2008, Biogen Idec reported that Avonex had become, "the number one most prescribed treatment for relapsing forms of MS worldwide, with more than 130,000 patients on therapy." Also, Avonex was "the number one prescribed treatment for relapsing forms of multiple sclerosis (MS) worldwide, and is the only once-a-week MS therapy that is effective after the first attack....The number one prescribed treatment for relapsing forms of multiple sclerosis (MS) worldwide, and is the only once-a-week MS therapy that is effective after the first attack."
In 2002, Avonex became the first multiple sclerosis treatment to attain $1 billion annual sales and with a market share above 50% in the U.S market (now down to about 31%). Avonex was reported in early 2002 to be the U.S. market leader, with a 56% U.S. market share among MS therapeutics, and 35% market share outside the U.S.
In June 2000, the National Institute of Clinical Excellence (NICE), which advices the U.K. National Health Service (NHS) on the cost-effectiveness of pharmaceuticals, recommended that beta interferon, including Avonex, not be offered by the NHS to MS patients. NICE considered the £10,000 (~$15,000) annual cost per patient to be too expensive. In early 2002 (after much criticism), NICE recommended use of beta interferon for MS, and estimated the annual cost (at the cost it had negotiated) for treatment of MS with Avonex (plus glaritamer acetate) to be $12,054.
Sales of Avonex are expected to increase as Biogen Idec promotes it as superior to Betaseron and as new MS patients begin interferon beta therapy, with increasing acceptance of the need to 'treat early' and treat all persons with MS, and with growing patient awareness of Avonex. Biogen Idec estimates that there are about 330,000 persons in the U.S. and Europe with relapsing forms of MS, with only about one-third receiving drug treatment (suggesting there may be a large potential for increased sales).
Avonex received approval in May 2002 from the Center for Medicare and Medicaid Services (CMS) for Medicare coverage for multiple sclerosis patients. In Dec. 2000, Congress clarified and expanded Medicare coverage of drugs and biologics by adding a provision (Section 112) to the Benefits Improvement and Protection Act of 2000 (BIPA). This reversed an August 1997 program memorandum by CMS, which had resulted in the termination of Medicare coverage for Avonex. Medicare had covered Avonex upon approval in the U.S. in 1996 until the 1997 program memorandum.
Avonex has been reported to be the most cost-effective of available interferon beta products for MS treatment, as discussed in the Trials section above.
Competition: In the MS therapeutics market, for comparison in 2003 Avonex total sales were $1.17 billion, Betaseron/Betaferon sales were ~$924 million (~$1 billion in 2004), Rebif sales were ~$819 million, and Copaxone (glutiramer acetate) sales by Teva (copromoted by Sanofi Aventis in the U.S) were $720 million.
Ongoing: Biogen (now Biogen Idec) has linked with Inhale Therapeutic Systems, Inc. for development of a dry powder formulation of Avonex for pulmonary (inhalation) delivery for treatment of multiple sclerosis. Inhale Therapeutic Systems received an upfront payment and may receive up to $25 million in R&D funding and milestone fees. Phase I trials began in April 2000. Biogen provides bulk interferon beta-1a for formulation by Inhale Therapeutic Systems. Biogen Idec retains full marketing rights, but has halted active development for MS and is exploring development for other indications:.
Aegis Therapeutics LLC (San Diego, CA) is in the early stages of developing intranasal formulations of interferon beta. Therapeutic Proteins Ltd. has reported it is developing a biogeneric interferon beta product. Nautilus Biotech S.A. is in preclinical development with a long-acting interferon beta mutein.
A generic (biogeneric, biosimilar, follow-on biologic, etc.) version of mammalian cell-expressed, glycosylated interferon beta-1a product developed and manufactured by the Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB (Stuttgart), Germany, in collaboration with CinnaGen (Tehran, Iran) is the first product from Fraunhofer to receive approval (as a biogeneric) – in Iran where it is marketed as CinnoVex by CinnaGen. A more soluble variant of interferon-beta also engineered by Fraunhofer is being developed by Vakzine Projekt Management (VPM) GmbH (Braunschweig, Germany).
In Nov. 2006, Stada Arzneimittel AG (Germany) abandoned its development of a biogeneric version of interferon-beta for multiple sclerosis, citing limited marketing opportunities.
Therapeutic Proteins, Ltd. (U.K.) is developing a biosimilar/biogeneric, Chinese hamster ovary (CHO) cell expressed interferon beta-1a (and also interferon beta-1b; similar to Avonex) for treatment of multiple sclerosis.
Interferon beta-1a, rDNA/Biogen Idec [BIO]
Avonex [TR]
Interferon beta-1a [FDA INN]
Interferon beta1 (human fibroblast protein reduced) [CAS]
145258-61-3 [CAS]
BG-9015 [SY]
Dompe (beta) [TR foreign]
Neoferon [TR foreign]
C908H1406N246O252S7 [MF USAN]
molecular weight (kDa) = 22.5
Annual sales (2012, $millions) = $2913.1 ; BLOCKBUSTER! (sales >$1 billion)
Annual sales (2011, $millions) = $2700 ; BLOCKBUSTER! (sales >$1 billion)
Biosimilars/biobetters-related U.S. Patents: 2013, based on 5,326,859 and 5,514,567, expiring in 2011 and 2013, respectively. But with these non-exclusviely licensed, it will be up to their owner, Juridical Foundation, Japanese Foundation for Cancer Research, to enforce its patents
2026, if 7,588,755 claiming use for antiviral-based treatment of MS is relevant.
2013 has been reported by IMS and a Nature Rev. Drug. Disc. article.
An MIT study (data from Visiongain 2009) reported U.S. and EU patents expired.
Decision Resources reported 2007.
The Aug. 26, 2002 Wall Street Journal incorrectly stated patent expiration is in 2003 (when orphan exclusivity expired).
DataMonitor and ABN Amro have also reported that U.S. patent protection for Avonex expired in 2003.
Biosimilars/biobetters-related EU Patents: 2011 (based on EP 0041313 and EP 0041767)
Had been reported by Decision Resources to expire in 2008,
hamster source materials
rodent source materials
BG9015/BG9216, Chinese Hamster Ovary cells
Chinese hamster ovary (CHO) cells
rodent cells <!-- rodentcells -->
antivenins
carbon dioxide (CO2 gas; dry ice)
Gb-23-902-531
lyophilized (freeze-dried)
polysorbate 20 (Tween 20)
sodium phosphate, dibasic
sodium phosphate, monobasic
viral inactivation, unspecified
Source/Host/Expression System: CHO mamrodhamcho
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
orphan status
priority review status


First Flush is the first tea harvested annually, from the end of February until the end of April. It is bright in colour, has a light, flowery flavour and a light body. First Flush Darjeelings are sought after teas around the world.
All First Flush teas are certified organic by IMO Switzerland. The teas for our blends are selected from NATURLAND-certified tea gardens in Darjeeling.
Darjeeling Black Tea, First Flush, 250 g. Harvest 2018.
Darjeeling Black Tea, First Flush, 1000 g. Harvest 2018.


text:
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Proportionality – Further clarification on the application of Rule 44.3(5)
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SuperUser Account
In 2016 Master Rowley gave judgment in the case of May & May v Wavell & Bizarri [2016] EWHC B16 (Costs). proportionality. However, whilst the costs were still held to be disproportionate HHJ Dight CBE and Master Whalan have confirmed that the methodology in reaching the decision was not correct. Daniel Jones of Civil & Commercial Costs Lawyers discusses the judgment, which should give further clarity how the proportionality test is to be applied.
The main action and the SCCO
Queen guitarist, Dr Brian May and his actress wife, Anita Dobson's claim for costs, which was reduced from more than £200,000 to a mere £35,000 plus VAT following application of the new test of proportionality, has been successfully appealed.
By way of brief background, the substantive action arose by way of Dr May bringing proceedings against his neighbour for nuisance caused by their "super basement" development. Following acceptance of a Part 36 offer, in the sum of £25,000, the claim proceeded to detailed assessment with Dr May submitting a Bill of Costs totalling £208,236.54. It came as no surprise that the parties were unable to reach an agreement in respect of costs so the matter proceeded to a hearing.
Master Rowley, sitting at the SCCO, applied a two stage test; firstly he conducted a line by line assessment of the Bill and arrived at a figure of £99,655.74. He thereafter reduced these "reasonably and necessarily incurred" costs to a meagre £35,000 plus VAT following application of the new test of proportionality.
In reaching his decision Master Rowley gave consideration to the five factors listed in CPR 44.3(5) and advised that:-
"In summary, this is a case worth in the region of £25,000 and for which there was a modest prospect of an injunction at least early in the case. There was no noteworthy complexity in the litigation of either a legal or factual nature. There were no additional costs caused by the defendant's conduct nor were there any wider factors to be considered. In these circumstances the reasonable costs allowed of £99,655.74 are undoubtedly disproportionate".
Master Rowley considered a global approach appropriate and advised that the figure he considered to be a proportionate one for the first defendant to pay, bearing in mind all of the factors in 44.3(5), was £35,000 plus VAT.
In concluding his finding the learned Master declared that:-
"There is only so much finesse that can be employed when using a broadsword rather than a rapier. A concluding global assessment of proportionality as envisaged by the new approach involves the court wielding a blunt instrument rather than a precision tool."
Unsurprisingly, a blunt broadsword is not the appropriate tool for the Court to wield.
The central issue on the appeal was whether the new test of proportionality had been correctly interpreted and properly applied. The appeal was confined to four specific aspects of Master Rowley's decision namely:-
1. The sums in issue in the proceedings - CPR 44.3(5)(a)
In reaching his decision Master Rowley had advised that the sum of £25,000 (the settlement value) reflected the sums in issue in the proceedings. The paying party stated that the claim was worth the sum for which it settled - an all too common adage enthusiastically resonated by paying parties.
It was Dr May's case however that the learned Master had failed to give proper consideration to all factors affecting the sums in issue including the diminution of rental value of the property (c. £500,000 pa).
Upon review it was found that whilst the Master was entitled to have regard to the figure at which the case settled, this was not the singular element to be derived from CPR 44.3(5)(a).
It was found that it would not have been unreasonable to note that the annual letting value of each house was £500,000 and that a reduction due to the alleged nuisance for the period claimed would have been in the range pleaded by Dr May and Mrs Dobson, namely £50,000 - £100,000.
In essence the learned Master had erred in having no regard to the value upon the claim form, the pleadings and the entirety of the evidence before him.
In his judgement HHJ Dight stated that:-
"A settlement figure might provide some indication of the former battle ground but it is the battle ground which is to be identified when looking at the "sums in issue" and not the final figure which brought the battle to an end."
HHJ Dight provided further helpful guidance as to the method to be adopted by the Court:-
"The task of the court is, in my judgement, to undertake an objective evaluation of the sums which are in issue having regard to all the material before it, including the highest figure put on his claim by the claimant and the lowest figure, if any, admitted by the defendant."
2. The complexity of the litigation - CPR 44.3(5)(c)
Master Rowley had found the case neither legally nor factually complicated.
HHJ Dight, in consideration of CPR 44.3(5)(c), juxtaposed this case with road traffic accident claims of a similar value (£50,000 - £100,000) but less complex and lower value clinical negligence claims which would be more complex.
In essence if one compared a claim of this nature to the range of claims frequently made in the County Court it could be readily seen that this matter was towards the more complex end of the range.
Whilst this case was not complex within its category it was complex when compared with other claims of similar value.
3. The relevance of the stage reached at settlement
In applying the global reduction to proportionality Master Rowley had applied an additional reduction on the basis that the claim settled at an early stage. In his judgement Master Rowley stated that:-
"The proportionate amount of costs must inevitably be smaller for a case which concludes early than one which reaches a final hearing."
Whilst a Court is entitled to take into account all the factors of the case, HHJ Dight respectfully disagreed that early settlement required a greater reduction in the overall costs.
4. The global approach
Finally, it found that a global reduction to the costs, without having regard to the component parts and providing a specific mathematical calculation of specific explanation of how consideration of the various factors resulted in the final figure, was a misapplication of the rules.
FFollowing consideration of the four specific issues raised by Dr May, HHJ Dight found that the learned Master had misinterpreted and misapplied the new proportionality test. In particular he found that he had undervalued the sums in dispute, had given too little weight to the complexity of the litigation, had incorrectly reduced the costs because of early settlement and had incorrectly utilised a global reduction.
His Honourable Judge Dight and Master Whalan gave greater weight to the sums in issue and to the factor of complexity and after taking all matters into consideration concluded that a proportionate figure was £75,000 (plus VAT). HHJ Dight did not apply a global proportionality reduction by not reducing either the Court fees or the costs of preparing the Bill.
The judgement stands as further guidance as to how to new test of proportionality is to be applied having regard to the four specific issues raised in the appeal.
It is doubtful that Dr May will be picking up his guitar for a rousing rendition of We are the Champions as this decision will no doubt be regarded as a pyrrhic victory.
If you would like to discuss this issue in more detail, or any other Costs matters, contact Daniel Jones on 0161 255 2788 or our Head of Costs Anil Virji on 0207 842 5950 or email us.
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Welcome to B2B summit 2019!
As a B2B-focused, cross-border VC fund, Draper Nexus has been involved in the B2B scene in the US and Japan since 2011.
B2B Summit is an opportunity for you to showcase your company to Japanese corporate executives and startup entrepreneurs and envision the future of where our society is headed.
This year, our main themes are "Industry Cloud", "AI Implementations", "5G/ Tele-communication" .
We are thrilled to support entrepreneurs that are keen to collaborate with the largest Japanese corporations and expand the business into Japanese market.
AI Implementations: What worked and what didn't?
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We're the largest and oldest student drama society in Cambridge and the resident company at the ADC Theatre.
The Cambridge University Amateur Dramatic Club is the oldest student dramatic society in the country and the resident company at the ADC Theatre. We offer membership to anybody aged 17 or over who is a student in higher educational institution and residents within the city of Cambridge. We put on around 20 shows every year and has an obligation to spread interest in the theory and practice of theatre and to encourage the active involvement of students regardless of previous experience.


I love the aroma of apples and cinnamon cooking together; it excites the senses as it permeates my home and brings back memories memories of my Mother, baking "Apple Crisp" when I was young. Apple desserts rate right up there with chocolate as my favorite sweets! I have been trying to come up with a recipe that has a good apple to crust ratio, apples that aren't too sugary, and a crust that is, of course, crisp! So this is the result of trying different recipes through the years and finally coming up with this one on my own. Be sure to use a firm, tart apple. Don't over bake the crisp or it will be dry and maybe burn, especially the nuts. This recipe fills a 9x13 pan when assembled, but will ,of course, cook down during baking. Enjoy my "Apple Crisp"!
Mix above ingredients together and place in a greased 9x13 baking dish.
With a pastry blender work the topping until it is crumbly. Add 1/2 cup of sliced almonds or chopped pecans to the topping and work the nuts in with your fingers until you have a fine crumb. Sprinkled evenly over the apples. Bake in a preheated 375 degree for 35-40 min. until brown. A toothpick inserted in the apples will tell you how done the apples are. Remove from the oven, let cool if you want . It's best served warm with whipped cream or ice cream, of course!


Evidence one of the most despicable and treasonous examples of profiteering in human history.
Bankers in Allied countries worked hand in hand with Hitler, including the Bank of England, who not only lent money to Hitler, even as Germany was invading Europe and bombing London, but also leaked valuable intelligence information to the Third Reich directly resulting in the shedding of Allied blood.
[Editor's Note: For more than 100 years, people have sensed a sinister & malevolent power stealthily encroaching on their freedom and security. The following is an excerpt from a French book now suppressed: "La Conjuration Juive Contre Les Peuples" (1909) by Paul Copin-Albancelli (1851-1939.) While it focuses exclusively on the Jewish role, we should remember two points.
1. The Illuminati (Cabalist) Jewish bankers have empowered a proxy Gentile elite, with whom they have intermarried. The Gentile leadership, organized in Freemasonry, is a full partner in this diabolical plan. (For anyone in doubt, I recommend the book, "Unholy Alliances" by Dr. James Wardner.) The Illuminati cult began as a satanic Jewish heresy that took over Judaism and Freemasonry; and used them to inspire Communism, Zionism, Socialism, Liberalism, Fascism, feminism etc.
Human history and political life are a charade conjured by these Cabalist magicians using the mass media.
Humanity is the political and mental prisoner of the Illuminati . We are being inducted into their cult via the media and education. All of our "leaders" belong to this cult. Advancement is based on witting or unwitting cooperation with the Illuminati agenda.
2. The majority of Jews, and people in general, are kept in the dark, the better to dupe/entice them into advancing it.
Copin-Albancelli says that publicly-held companies and "democracies" ("Republics") are ways of disguising Illuminati wealth and power which has been dominant for more than a hundred years.
Produced by Michael Tsarion and Blue Fire Film, Architects of Control: Program One explores humankinds future and the posthuman world.
Will the perfect human be a dumbed down, regimented inhabitant of a cyber purgatory created by unseen elites? Will the children of tomorrow be smiling depressives of a technocratic dystopia?


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Nathan Ward (November 21, 1804 – November 24, 1860) was a physician born in Plymouth, New Hampshire who worked as a religious and medical missionary in Jaffna, Ceylon (now Sri Lanka) from 1833 to 1846. Ward is most remembered for his work as the head physician of the Batticotta Seminary where he served as a prominent educator and was influential in handling the cholera outbreak of 1846.

Early life and education
Nathan Ward was born on November 21, 1804, in Plymouth, New Hampshire. His mother was Sarah Ward and his father was Samuel Ward. He received his primary and secondary schooling in his birth town. Later, he attended Bowdoin College Medical School, the "Medical School of Maine" and graduated in 1832. After schooling, he moved to live in Vermont where he met his wife and later settled to have kids.

Personal life
Ward married Hannah Ward on January 8, 1833. They met in Vermont where Hannah was born. They lived in North Troy, Vermont for a couple of years before eventually settling in Burlington, Vermont. Nathan and Hannah Ward traveled to Ceylon together where the eventually conceived and raised all of their children. In 1834, the Wards had their first child William H. Ward. Later, they had their second son Edward C. Ward and in 1842 they had Samuel R. Ward. At some point in between the births of William and Samuel, the Wards also had a baby girl who died before turning one.

Missionary service
After graduating from medical school Ward worked as a physician. After a couple of years, he tired of this work and decided to pursue a calling to work abroad. Hannah Ward's brother was a missionary of the American Board of Commissioners for Foreign Missions (A.B.C.F.M). He helped Ward get involved with the program and, ultimately, get sent on a mission to Ceylon. Luckily for Ward, his timing could not have been better. A new governor of Jaffna had just been elected who permitted the presence of American missionaries while the previous governor had not. This resulted in a sudden increase in demand for missionaries, including Ward.

Journey
On June 30, 1833, Ward met the other voyagers that would be accompanying him on his journey to Ceylon, which included Reverend William Todd, Samuel Hutchins, Henry R. Hoisington, George H. Apthorp and their respective wives. The group received an embarkation ceremony in the Park-Street Church of Boston. Only July 1, 1833 they departed from Boston on a ship called the Israel. An audience of Bostonians accumulated to watch as a hymn was sung to grace the missionaries with good fortune on their journey. On October 28, 1833, the group arrived at the Jaffna Peninsula.

Service
Ward was only the second capable and qualified physician to be sent to the Batticotta Seminary and was, therefore, much needed and appreciated. The physician that was at the seminary before Ward was Dr. Scudder. After Ward arrived, he was able to open new stations in the peninsula and was eventually relocated to Madras in 1836. Scudder left Ward in charge of the seminary. He lived with other missionaries, Daniel Poor, Henry Woodward, James Read Eckard and their wives. At that point, Ward was the only American A.B.C.F.M physician in all of Jaffna.

Scudder commented on some of the benefits of having Ward at the Batticotta Seminary. He explained how Ward helped keep the hospital regulated, train students, and engage in new fields of research. As well as a physician, Ward was a teacher of Natural Philosophy and Medicine at the school. Additionally, he worked with and helped train a group of 8-10 native men in medicine by having them shadow him and help him with tasks in the hospital. He was observed to treat his men with respect by referring to them as "Dr." in his letters.

The most notable and trying aspect of Ward's mission was the cholera outbreak of 1846. Before Ward's arrival the natives did not understand how cholera is transmitted. They believed that simply being around a person with cholera would put someone at risk for getting the disease. In reality, the disease is transmitted through feces and often is common in places with poor sanitation. Ward helped educate the population while also providing medication. Many of the natives were opposed to taking medication, but Ward was able to treat around 900 patients and save around 600 people to give him a 60% success rate.

Return
After thirteen years of working in Ceylon under the A.B.C.F.M, the Wards finally returned to the states in the year 1846. Both Nathan and Hannah Ward had experienced deteriorations in their health and decided it was time to return to Vermont. For a time, Ward continued to work as a physician in Burlington, Vermont. Later in 1853, he decided to become a member of the clergy. He had been a member of the Browington Church for several years. Throughout his membership the Church had been lacking a pastor. Therefore, at the request of the Church, Ward obtained his preacher's license and later in 1855 was ordained as an evangelist.

Death
After about a decade in Vermont, Ward was again overcome by the calling of overseas missionary work. His health had improved since he left and so on October 30, 1860, Nathan and Hannah Ward departed on their second journey from Boston to Ceylon. Unfortunately, Ward was never able to make it back to Ceylon. On November 24, 1860, Ward died of a heart attack at sea. In a letter written by Hannah Ward she states that he died peacefully in his sleep. Hannah Ward continued on to Jaffna despite her husband's passing and worked there for five years before returning home. She later died in 1884.

References

1804 births
1860 deaths
American Protestant missionaries
Bowdoin College alumni
Medical School of Maine alumni
Christian medical missionaries
Protestant missionaries in Sri Lanka

redpajama_set_name: RedPajamaWikipedia


text:
Soyuz MS-02 launch delayed for technical reasons
September 18, 2016 / Derek Richardson
The flight of Soyuz MS-02, which will carry NASA astronaut Shane Kimbrough, left, and Russian cosmonauts Sergey Ryzhikov, center, and Andrei Borisenko to the International Space Station has been postponed. Photo Credit: Victor Zelentsov / NASA
The next crewed flight to the International Space Station, Soyuz MS-02, has been postponed "for technical reasons after tests at the Baikonur Space Center," according to the Roscosmos State Corporation.
The flight was scheduled for a Sept. 23 launch and subsequent two-day rendezvous with the orbital outpost.
This vehicle is the second of the newly upgraded Soyuz MS variant. Soyuz MS-01, which launched July 7, was also postponed due to a technical issue. In its case, there were flaws in the control system that could have affected a successful docking to the ISS. However, the flaws were fixed, and the spacecraft docked without flaw July 9.
For Soyuz MS-02, Roscosmos has not officially revealed what the technical issue was. However, according to RIA Novostri, an industry source said a test identified a short circuit.
"Preliminary data revealed that a short circuit occurred while testing the new series Soyuz MS-02 spacecraft, docked to a carrier rocket, at Baikonur," the source said. "The date of the new launch will be announced later, but the launch is unlikely to take place before the beginning of October, 2016."
Soyuz MS-02, when it does launch, will send Russian cosmonauts Sergey Ryzhikov and Andrei Borisenko and NASA astronaut Shane Kimbrough to the ISS for a roughly six-month stay at the orbital complex.
After docking with the station, the trio will join the crew of Expedition 49 currently aboard the station. Russian cosmonaut Anatoli Ivanishin, Japanese astronaut Takuya Onishi and NASA astronaut Kate Rubins launched aboard Soyuz MS-01.
The new crew arrival will increase the station's crew complement back to six. However, the size increase may be short-lived as the Soyuz MS-01 crew is expected to land back on Earth Oct. 30. This will once again decrease the crew count to three.
The crew count will again increase a couple weeks later when Soyuz MS-03 launches with cosmonaut Oleg Novitskiy, European Space Agency astronaut Thomas Pesquet and NASA astronaut Peggy Whitson.
Whether or not the MS-02 delay will affect the departure of MS-01 or launch of MS-03 is unclear.
Recently, two other ISS visiting vehicle flights have been delayed. The Japanese Kounotori cargo ship was postponed from its Oct. 1 launch due to a pipe leaking. Additionally, the OA-5 Cygnus, which will launch atop an upgraded Antares 230 rocket, was also delayed to October for an unspecified reason.
While a delay has not been officially announced, SpaceX's CRS-10 Dragon cargo capsule was slated to launched in November. However, due to the Sept. 1 Falcon 9 launch pad explosion, that mission will likely slip. How long will depend on the results of the ongoing investigation into the cause of the failure.
September 18, 2016 / Derek Richardson/ Comment
Visiting Vehicle, Launches
Soyuz MS-02, Roscosmos
NASA Video: A Gut Feeling
Orbital Velocity Space Bytes


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FaithFaith in Focus
"Set the world on fire"? Sorry, St. Ignatius never said that (or these other famous Jesuit quotes)
Barton T. Geger, S.J.April 06, 2017
Mother Teresa did not write, "People are often unreasonable, illogical and self-centered; forgive them anyway. If you're kind, people may accuse you of selfish, ulterior motives; be kind anyway." A 19-year-old Harvard student wrote that in 1968, in a booklet for high school students.
Archbishop Oscar Romero did not say, "We are prophets of a future not our own." Bishop Kenneth Untener of Saginaw wrote it in a homily for deceased clergy.
St. Francis of Assisi did not pray, "Lord, make me an instrument of your peace." Honor for that gem goes to an anonymous French writer and a Catholic publication called La Clochette in 1912.
Dorothy Day did not complain, "I feed the poor and they call me a saint; I ask why they're poor and they call me a communist." That comes from Dom Hélder Câmara, the archbishop of Recife.
In the last decade, numerous pundits have written about a phenomenon conspicuous on the internet—but surely also with roots as old as the written word—of famous persons being credited with quotations that they never said.
Among the saints, Ignatius Loyola is something of a "quote magnet."
Among the saints, Ignatius Loyola is something of a "quote magnet," a term coined by the Yale librarian Fred Shapiro to denote individuals who, for whatever reason, attract more misquotes than usual.
Ignatius did not say, with reference to Jesuit schools, "Give me the child for the first seven years, and I will give you the man." Or again, when a Dominican visitor purportedly asked Ignatius where he kept the holding cells for wayward Jesuits—a common practice among religious orders at that time—Ignatius did not respond, "I have no need of prisons when I can show them the door."
Some Ignatian misquotes do little harm, such as "Go and set the world on fire." Circumstantial evidence suggests that Olivier Mannaerts, one of the last surviving Jesuits to have known Ignatius personally, credited him with a saying that was popular among the Jesuits of Father Mannaerts's own time.
"Laugh and grow strong" will not injure anyone, although Jesuits and friends who wish Ignatius to be taken seriously do him no favors by promoting it. An undiscriminating reader lifted it from a life of Ignatius by the English poet Francis Thompson. The latter was being facetious when he reworked an old saying, "Laugh and grow fat," to summarize advice that Ignatius had given to Jesuits.
Other misquotes are more consequential.
Lord, teach me to be generous, and to serve you as you deserve/ to give and not to count the cost/ to fight and not to heed the wounds/ to labor and not to seek for rest/ to toil and not to seek any reward/ except that of knowing that I do your will.
The prayer is romantic, but otherwise quite opposed to Ignatius' spirituality. He urged his brother Jesuits to rest regularly, eat healthily, moderate their asceticism and resist the quixotic temptation to choose difficult works for their own sake. He wanted Jesuits to accomplish the most good that they could over the course of a long lifetime—not to burn themselves out in a brief blaze of zeal.
"Laugh and grow strong" will not injure anyone. Other misquotes are more consequential.
In the same vein, Ignatius did not ask, "What more can I do for Christ?" but rather poses this question in the Spiritual Exercises: "What ought I to do for Christ?" It was never a question of working harder but of choosing the one option that will serve God's greater glory and then having the courage to let the other good options go—for which reason discernment and indifference were so central to Ignatius' spirituality.
Finally, Jesuits and friends might reconsider a quotation attributed to Pedro Arrupe, S.J., but which in fact was written by Joseph Whelan, S.J., an American Jesuit who died in 1994:
Nothing is more practical than finding God, than falling in love in a quite absolute, final way. What you are in love with, what seizes your imagination, will affect everything. It will decide what will get you out of bed in the morning, what you do with your evenings, how you spend your weekends, what you read, whom you know, what breaks your heart, and what amazes you with joy and gratitude. Fall in love, stay in love, and it will decide everything.
Beautiful prose, to be sure, but if one takes it literally, I doubt that Ignatius would have endorsed it. He knew from experience, as perhaps most of us do, that falling in love—whether with God or with anyone else—does not make decisions clearer. It usually makes them more difficult. True Ignatian discernment presupposes that one already loves God and therefore desires to identify the course of action that will serve his greater glory. Even after Ignatius had attained heroic sanctity, he wrestled for months, and with many tears, over various discernments that he had to make.
St. Ignatius knew from experience that falling in love—whether with God or with anyone else—does not make decisions clearer.
In November 2016, a Jesuit wrote me to confess that he "may have had a hand" in perpetuating the Arrupe misquote. He found it attributed to Father Arrupe in a vocations calendar for women religious and then posted it on the website of the university where he was working. Years later, he noticed that it was posted on numerous other websites as well. By then, he had doubts about its authenticity, and so he contacted these websites, asking for their source. He discovered, much to his wonder, that all of them could be traced to his original post.
One can blame the prevalence of misquotes on an internet culture of clickbait and cut-and-paste, but I see no evidence that they were any rarer in the past. The more interesting question is whether people will continue to cut-and-paste them if they have someone else's name at the end of them. Soon we will see whether Mick Jagger spoke the truth—and yes, he really did say this—that it's the singer, not the song.
More: Spirituality / Saints
Barton T. Geger, S.J.
Barton T. Geger, S.J., is the editor of Studies in the Spirituality of Jesuits.
Bruce Snowden
Thanks Father Geger for your article on "misquotes." As a Secular Franciscan professed 38 years, I'm disappointed that St. Francis of Assisi did not say, "Lord, make me an instrument of your peace." Instead, the prayer is that of an anonymous French person. "You shall know the truth and the truth shall set you free," Scripture says. I do feel freed in knowing the truth, but as said, disappointed. I've probably attributed erroneously quotes of saints and others over the years, in conversation and in writing. Your corrected Ignatian misquotes are all good to know. May I call you an historical unsmudger?
Franklin Uroda
Jesus: I have come to set the earth on fire... Lk12,49. Natural for Jesuits to attempt the same.
Julian Irias
Father Geger, Mick Jagger may well have used the expression you mention, but was he the first? In 1953, when he would have been about 9 1/2 years old, Audrey Erskine Lindop published a book titled The Singer Not the Song.


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Start selecting reading materials based on his/her own interests.
Identify the "who," "what," "when," "where," "why" and "how" of the text.
While the goals of second Grade English and Language Arts are numerous, Reading Street will help you craft engrossing lessons. Your child will garner important English and Language Arts skills while completing a workbook, reading stories and poems, and taking assessments. Planning these lessons will be easier than ever, as all Reading Street systems are broken down into weekly Big Ideas. All the work your child does on a given week is formulated around that single concept for an organized and challenging curriculum.
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Saffron Walden Town FC
Saffron Walden Life
A concert called Inspired by Nature will be given by Saffron Walden Symphony Orchestra at Saffron Hall on Saturday, May 11.
PUBLISHED: 16:16 01 May 2019 | UPDATED: 16:16 01 May 2019
Angela Singer
Saffron Walden Symphony Orchestra. Picture: SAFFRON PHOTO
Saffron Photo 2018
A concert called Inspired by Nature, will be given by Saffron Walden Symphony Orchestra at Saffron Hall on Saturday, May 11.
A concert, called Inspired by Nature will be given by Saffron Walden Symphony Orchestra at Saffron Hall on Saturday, May 11.
They will play Antonin Dvořák's In Nature's Realm, Gustav Mahler's Blumine and Symphony No 1 and Peter Sculthore's Kakudu.
The concert opens with Dvořák's overture In Nature's Realm, resembling a landscape painting. It was completed just before Dvořák left Europe to settle in the United States.
Mahler's Blumine (meaning floral or flower) follows. This was part of Symphony No 1, but was omitted from the score by Mahler after it received harsh criticism. It was rediscovered in 1966, and has been described as a sensitive, impassioned and sentimental piece.
Sculthorpe's Kakadu, evokes the sounds and feelings of the outback.
Mahler's Symphony No 1, composed between 1887 and 1888, includes cuckoo calls and birdsong.
7.30pm. Tickets, £18, £15, under 18s, £3 from 0845 548 7650) or www.saffronhall.com or Tourist Information, 01799 524002).
Car on fire prompts road closure
Firm confirms plans to open new hotel and restaurant by 2020
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Dunmow Broadcast Royston Crow


Israel Adesanya put together yet another scintillating performance at UFC 230 with a first-round knockout of No. 6-ranked Derek Brunson to run his MMA record to 15-0 with his 13th knockout. As entertaining as Adesanya was when his fist and feet were flying, the Nigerian-New Zealander is just as exceptional with his words.
His penchant for a snappy quip is just as crisp as his striking. With four straight victories as a member of the UFC roster in less than a calendar year, Adesanya certainly has the makings of MMA's next big thing.
It's almost unfortunate that people are already quick to peg him as the next iteration of another brash striking dynamo, who made a swift ascent up the ladder before breaking into the mainstream as a crossover celebrity.
The parallels cannot be totally dismissed as McGregor had an astronomical rise upon his arrival in the UFC. After beating Marcus Brimage and a very young Max Holloway in 2013, McGregor was sidelined for a year. Upon his return, he reeled off four straight victories in 12 months, with the final victory during that timeframe being a second-round knockout of Chad Mendes to claim the interim UFC featherweight title. His mouth was just as lethal as his hands during his well-documented ascent and helped thrust him to the top of UFC cards and into the mainstream.
Both McGregor and Adesanya are recognized for their devastating striking and questions have hovered regarding their respective ground games. But that's where the comparisons should end.
McGregor made it very clear upon his arrival that his goal was to make top dollar and he would say whatever it would take to sell a fight. The Irishman has always been calculated in his approach to trash talking and has often taken upon the role of a crazy-eyed maniac with an insatiable appetite for mind games.
Adesanya has yet to share those same sentiments in terms of consciously selling a fight. Instead, Adesanya's personality is one that welcomes verbal confrontation, but doesn't necessarily seek to verbally shred his opponents prior to a fight. He's outspoken and confident, but not crude with his approach to combat. He's expressive and enjoys the spotlight, but it is something that he does in the dark as well as in the light.
When it comes to striking, Adesanya is a kickboxing dynamo whose technique is among the best in mixed martial arts. Where McGregor has often relied upon his vaunted right hand, Adesanya looks to terrorize his opponents with all of his appendages. Against Brunson, Adesanya sniffed out his opponent's takedown attempts with a standing knee, flicked a range-finding jab and set up a beautiful high kick before sending his opponent to dream street with a straight right hand.
The Last Stylebender's technique has derived from his exceptional pro kickboxing career, where he went 75-5-1. He has also tried his hand as a professional boxer, where he won six straight fights after losing his pro debut by decision in 2014.
He's already shown tremendous growth in his ground game and takedown defense. After squeezing out a split-decision victory over Marvin Vettori, who often put Adesanya on his back when the clashed earlier this year, Adesanya was paired with two exceptional wrestlers in Brad Tavares and the aforementioned Brunson. The result was far different as Adesanya demonstrated exceptional takedown defense and showed some much-improved ability to control the distance in an MMA fight, while showcasing the explosiveness that has become his calling card.
Like McGregor, he's already seeking a title shot. However, that has become the case for many unique talents who have made a swift climb to the top. Jon Jones rampaged through the UFC's light heavyweight division that was stuffed full of future hall of famers before finding himself competing for a world title on relatively short notice against Shogun Rua. Cody Garbrandt is another fighter who tore up the scene in 2016 with four straight wins before snatching away the UFC bantamweight title from Dominick Cruz to cap off his torrid run.
McGregor isn't the first to make a swift rise, but is certainly the most memorable. Adesanya has proven to be a very different beast in terms of his approach, technique and magnetic personality. We often like to find the closest thing to compare a fighter to, but Adesanya should live on his own merit. He's earned that right thus far. And he may only be scratching the surface of his spectacular ability as both a mixed martial artist and a bonafide star.
White has made it clear that he's not willing to push Adesanya to the top of the division as quickly, as the Nigerian-born fighter would like to see. However, White says a lot of things that don't necessarily come to fruition.
He certainly knows what he has with Israel Adesanya and mentioned that he has his next opponent in mind. The middleweight division where the 29-year-old resides has an intriguing array of talent. Robert Whitaker sits atop the division with the pecking order behind him including Jacare Souza, Kelvin Gastelum, Yoel Romero and Luke Rockhold.
What's interesting is that White might suggest not rushing Adesanya up the ladder, but he may have no choice. With Adesanya decimating Brunson in impressive fashion, Weidman's (No. 3) knockout loss to Jacare (No. 5), Rockhold's (No. 2) ongoing injury issues and Yoel Romero's (No. 1) weight problems, the path to a world title shot may not be able to be avoided. With Robert Whitaker set to defend his title against the No. 4-ranked Gastelum, there's very little room for White to maneuver. The only possible opponent that may make sense is against Paulo Costa, but that's putting two touted prospects together with an effort to eliminate one of them.
Nevertheless, Adesanya's star is shining extraordinarily bright and there's potential for him to become a breakout star in the world of mixed martial arts. Obviously, there are still many hurdles for him to clear that end up being the difference between Cody Garbrandt (fast rise, swift fall), Conor McGregor (one of a kind talent with a meteoric rise) and Sage Northcutt (pushed too hard, too fast).
Who knows exactly where he will end up by this time next year. One thing is for sure, he has the "It" factor and the arrow on his stock watch is pointing straight to the roof.
But, please, let's not try to make Israel Adesanya the next Conor McGregor because The Last Stylebender is truly one of a kind.


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MotoringLatest Launches
With the Genesis G90, Hyundai is taking on the Mercedes S-Class
By Motoring Staff Nov 30, 2021
Seoul - Hyundai's luxury division Genesis has pulled the covers off its new flagship sedan. With the Genesis G90, the carmaker is seeking to mount a better challenge to German contenders like the Mercedes-Benz S-Class and BMW 7-Series, which currently dominate this aristocratic automotive class.
Sadly, apart from revealing the exterior design, Genesis is keeping quiet about the rest of the vehicle and the technologies that lie beneath its modernised design. What we do know is that the company will offer it in both standard and long-wheelbase guises, the latter stretching out a further 190mm to possibly give Genesis a true rival to the Mercedes-Maybach S-Class.
According to Car and Driver, the new flagship sedan is likely to offer Hyundai's 3.5-litre twin-turbo V6 engine as well as an electric powertrain, but at this stage there's no word on whether the current G90's normally aspirated 5.0-litre V8 will continue to be offered.
The exterior design of the new G90 takes inspiration from other contemporary Genesis models such as the GV80 and the GV70, as you'll see in the imposing 'Crest Grille' and double-decker headlights. As for its three-box silhouette, dare we imply that there's a hint of Bentley and Jaguar in its stately lines. Furthermore, the long-wheelbase model will be available with exclusive 20-inch wheels.
"The G90 will redefine the flagship luxury design experience in a unique way only offered by Genesis." said Genesis design head SangYup Lee. "The G90 is the ultimate expression of Athletic Elegance that carefully balances dynamic driving and an elegant rear seat experience."
Hyundai enters premium electric SUV game with new Genesis GV60
Hyundai develops cruise control with artificial intelligence
Hyundai's Genesis reveals tech-laden flagship SUV
With this vehicle, Genesis is also planning to expand its luxury sedan presence, not only in its Korean home market, but across the globe, the company said. But please, Genesis, tell us more about it and show us inside...
IOL Motoring
SedanLuxury CarsHyundai


text:
Well-Safe Secures $85MM for Next Phase of Growth
by Andreas Exarheas
Well-Safe Solutions secures a new $84.7 million investment for its next phase of growth.
Well-Safe Solutions revealed Monday that it has secured a new $84.7 million (GBP 66 million) investment for its next phase of growth.
MW&L Capital Partners led the new round of investment, bringing together a consortium of private investors to acquire a major stake in the business.
"This significant investment marks the beginning of our next phase of planned growth. The initial private funding from our original shareholders has enabled us to build strong foundations," Well-Safe Chief Executive, Phil Milton, said in a company statement.
"With the backing of MW&L and existing shareholders, we'll be bringing the Well-Safe Guardian into operation in the first half of 2020 and looking to acquire further assets as planned to accelerate the delivery of our campaign-based approach to the plug and abandonment of wells in the North Sea and Continental Europe," he added.
Julian Metherell, a founding partner of MW&L, said, "decommissioning is one of the greatest industrial challenges we face and a sector with massive global potential".
"Well-Safe, with its wealth of well decommissioning experience, dedicated marine P&A assets and associated equipment, is the first-of-its-kind tier one company with a complete P&A capability and is ideally placed to capitalize on this opportunity," he added.
Following the deal, Alasdair Locke and Paul Warwick will remain as chairman and non-executive director, respectively. Metherell will join the board, which also comprises Well-Safe's senior management and Scottish Enterprise. Founding executive director, Mark Patterson, will be stepping down.
"I am proud to have been involved in establishing a business that has the potential to revolutionize how we tackle well decommissioning safely, responsibly and cost-effectively," Patterson stated.
"When embarking on this venture, I wanted to get the business onto the best footing, launching the brand and creating the right environment to attract the most experienced people in the industry to form a center of excellence in P&A," he added.
"With these accomplished and the first tranche of major external investment in place, the time is now right for me to step down and leave the business in safe and expert hands," Patterson continued.
Back in June, Well-Safe revealed that it would be moving headquarters after outgrowing its offices at Hill of Rubislaw in Aberdeen. During the same month the company announced the award of a "major" contract to decommission up to 21 wells on the Schooner and Ketch fields in the UK Continental Shelf.
Launched in 2017, Scotland-based decommissioning company Well-Safe now employs 70 staff and around 20 contractors. MW&L describes itself as a private investment vehicle providing flexible, long term capital to growth businesses.
To contact the author, email andreas.exarheas@rigzone.com
Andreas Exarheas
Editor | Rigzone
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Their music just gets it, man. I always keep coming back to them: their imagination, live sound, creativity, just dope vibes! So good, my soul sings every time I play their stuff - punk, wave, psychedelic afriki rhythmic deliciousness. Seriously favourite.
Nothing than positive vibes from this gifted musicians.
Dub and Punk and Wave and house in their minds makes some surprising evolutions in our beloved dance music.
Perhaps the best "band" in the elctronic bussines nowadays.


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how we came to be our happy little power switching selves. The thing we particularly liked about Norman is that you never have to question where he stands on an issue. He just kind of lays it all out there and tells it like it is. Ah, now that's so refreshing in this world of political correctness (which I clearly don't subscribe to), and particularly in the midst of all of this presidential election tussling, where people are talking out of both sides — and the top and the bottom — of their mouths. He has some interesting things to say, so we think you should give him a little listen… and you might even hear a P2S commercial in the next week or two!
Thanks again Norm! And a special thanks to Melissa Ryzy, the digital queen and marketing maven of WCPT, for setting this up for us!


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Masseur loses appeal against indecent assault conviction
By court reporter Candice Marcus
Updated August 20, 2013 13:09:52
Related Story: Masseur appeals indecent assault conviction
Related Story: Masseur jailed for indecent assault
Map: SA
An Adelaide masseur jailed for groping a young woman during a full body massage has lost an appeal against his conviction.
Jamie Steven England, 43, is serving a minimum six-month sentence for indecently assaulting the 20-year-old he massaged at a healing centre at Prospect in November 2010.
The prosecution alleged that England reached under a towel that was covering the victim and had massaged her breasts for about 15 minutes, despite male therapists being banned from doing so under company policy.
It was also alleged that England touched her close to her genital area.
The court heard victim did not complain to England during the massage nor to reception staff as she left the centre, but later told her mother and a friend about the incident.
The woman's mother gave evidence that her daughter provided details about how she was touched during the massage.
England tried to have his conviction overturned and argued on appeal that the woman felt intimidated and vulnerable because she had never had a massage before.
He claimed she may have misinterpreted a form of Chakra massage.
His lawyer also argued the trial judge failed to adequately direct the jury about the reliability of the victim's evidence.
Three judges sitting on the Court of Criminal Appeal unanimously dismissed England's appeal against his conviction, ruling that there was no miscarriage of justice.
England was sacked as a result of the incident and was jailed in April for 12 months with a non-parole period of six months.
The sentencing judge said England had shown no remorse, and had taken advantage of a nervous young woman for his own sexual gratification.
He will be eligible for release in October.
Topics: courts-and-trials, massage, prisons-and-punishment, sa, prospect-5082, adelaide-5000
First posted August 20, 2013 12:46:26
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