Profile

Biométhodes, based in Evry, near Paris, France, since 1997, first gained a wide technical expertise in protein engineering that was highlighted by dozens of service contracts with a diversity of industries (ABEnzymes, GSK, Roquette, Sanofi-Aventis,…). Biométhodes is now an industrial biotechnology company which exploits its validated technologies to improve enzymes that are critical in major industrial process. A sister company, Biométhodes Therapeutics develops next generation biologicals, with an initial focus on haemophilia.

We created and patented two highly original and complementary technologies. Massive Mutagenesis^® is the only combinatorial site-directed mutagenesis technique. It allows us to semi-rationally design and construct vast yet focused genetic libraries. One billion nature- and position-controlled mutations are routinely generated within a 36 hour time-frame. THR^™ is a unique en masse selection scheme we invented in 2006 that for the first time allows to directly select for thermostable variants among protein repertoires. We constantly upgrade our technological toolkit and are now working on integrating both in-licenced and in-house invented whole-cell diversity creation and screening techniques. These latest technological development should soon prove particularly relevant in the biofuels domain and should be highly visible publicly by late 2008.

Along these constant technological efforts, most of our efforts are focused towards the development of a limited number of selected major products for the following enzyme markets: biofuels, biocatalysis and animal feed.

Business Strategy

We welcome industrial input in our internal products pipelines in the form of strategic partneurship or exclusive licences. When possible, we believe that a carefully-conceived collaboration at the earliest stages is by far the most profitable route for both contractants. Alternatively Biométhodes is willing to discuss new projects in these fields with industrial partners, convinced that our highly focused team and unique technology platform can find solutions to many industry challenges.

News

June 23, 2008 :

Virginia Tech biofuel processes to be developed by French biotechnogy company, Biomethodes

Blacksburg, Va., June 23, 2008 -- Biométhodes, a French biotechnology company in Evry, has signed an exclusive and worldwide option-to-license multiple technologies for converting biomass to bioethanol and biohydrogen from Virginia Tech Intellectual Properties Inc. (VTIP).

The processes were invented by Percival Zhang, assistant professor of biological systems engineering in the College of Agriculture and Life Sciences at Virginia Tech. An integrated biorefinery pilot plant in Virginia is envisioned to advance the process for the conversion of biomass into ethanol and valuable co-products, focusing especially on biomass pretreatment. The process for transformation of biomass into hydrogen will be developed in France and will be validated through a biohydrogen fuel cell prototype and small-scale model car.

Zhang developed a novel and innovative process for releasing sugars that can be fermented into ethanol from non-food sources into sugars that can be converted to ethanol. His process uses enzymes and mild and recyclable physicochemical conditions that do not require high pressure or high temperature. The gentle pretreatment process also results in no sugar degradation and separates other highly profitable products, such as lignin and acetic acid. “More revenues from lignocellulose components other than sugars would be vital to the success of biomass refineries,” said Zhang.

According to Gilles Amsallem, Biométhodes chief executive officer, “The pilot plant will integrate two major technologies – Virginia Tech’s pretreatment process, which breaks down the biomass, and Biométhodes’ hydrolysis enzyme optimization technology to improve the cellulose degradation into fermentable sugars.”

Goals are to increase hydrolysis efficiency, optimize production of enzymes, reduce enzyme cost, and then do industrial scale testing with a commercial process deployment. “Our strategy is to enable next generation of biocatalysts and biofuels by co-developing pre-industrial processes, to be further integrated by industrial partners,” Amsallem said. John Talerico, VTIP licensing associate, said, “We have a process with the potential to economically produce ethanol from biomass on the scale of billions of gallons per year scale.”

Locating the plant in Virginia will enhance the collaboration with Zhang as the process is optimized, Amsallem said. A U.S. based-plant is also important because, “In the United States, the time to market is shorter for ethanol,” said Amsallem. “The U.S. and Brazil already have first generation technologies based on ethanol as a fuel.”

However, the European Union is very active in funding and developing hydrogen as a fuel, Amsallem said. “All the conditions for the success of the hydrogen project exist in Europe and Biométhodes technologies are the most appropriate to develop this process.” Using synthetic biology approaches, Zhang and colleagues from Oak Ridge National Lab and the University of Georgia proved that a combination of 13 enzymes never found together in nature will completely convert polysaccharides into hydrogen when and where that form of energy is needed.

Polysaccharides like starch and cellulose are used by plants for energy storage and building blocks. They are very stable until exposure to enzymes, which degrade them into carbon dioxide and hydrogen through a very efficient artificial metabolic chain. The vision is for the hydrogen to be used by fuel cells to create electricity. Water byproduct would then be recycled to the starch reactor, to create a very clean process. Laboratory tests also confirm that it all takes place at low temperature--about 86 degrees F--and normal atmospheric pressure.

Biométhodes will scale up the proven laboratory-scale process to deliver fuel cells, a model car as an initial prototype, a battery prototype, and, in the end, a car prototype. According to the company’s plan, the goal is to enter into co-development agreements with hydrogen fuel cell companies. These agreements will aim to develop the Biométhodes hydrogen-on demand technology implemented into prototypes that can be tested with, and ultimately incorporated into, the design of commercial fuel cells for portable and other mobile applications.

“Our technologies and Biométhodes’ expertise in enzyme optimization should create best conditions for success of commercial development of biohydrogen and second generation biofuels in Europe and the U.S.,” said Talerico.

December 21, 2007 :

Biométhodes granted U.S. and European Patents on Massive Mutagenesis^®

Biométhodes that it has been granted U.S. Patent N° 7,202,086 and EP Patent N° EP1311670 for its Massive Mutagenesis^® technology.

Massive Mutagenesis^® technology allows the generation of a large genetic diversity from any gene, mimicking natural evolution but at an accelerated laboratory scale. Massive Mutagenesis^® allows the improvement of enzyme activity, stability and specificity. The technology is responsible for several successful Biométhodes projects and thereby a number of natural enzymes have been adapted for industrial use.

Massive Mutagenesis^® has been adapted a number of times and one adaptation was patented and published two years ago (Saboulard et al., Biotechniques 2005), thus preceding the present revolution in synthetic biology. This technology, and its application to protein engineering, were published in several articles and have also been the subject of a chapter in a reference book.

« Biométhodes was founded with this technology » declares Marc Delcourt, Founder and Head of R&D of Biométhodes. « Nine years after its conception, Massive Mutagenesis^® has become the Golden Standard in the genetic diversification of proteins. This technology gives us a competitive advantage in conducting our projects. Massive Mutagenesis^® also contributes to the implementation of our “green” processes in pharmaceutical chemistry, animal feed and biofuels fields ».

Gilles Amsallem, Chief Executive Officer of the company, adds : « we attributed non-exclusive licence agreements of this technology and concluded several collaborations based on its use. We will continue to exploit this technology to generate assets for Biométhodes and its partners ».

December 3, 2007 :

Biométhodes announces the publication in the journal Nature Methods of an article which describes its proprietary technology, THR^™, to resolve the issue of protein stability

Biométhodes announces the publication of a scientific paper in the prestigious journal Nature Methods entitled “An activity-independent selection system of thermostable protein variants”.

Marc Delcourt, Founder of Biométhodes and Head of R&D explains: “the stability of therapeutic proteins and industrial enzymes is a major issue. Many groups have previously worked on this subject using technologies based on labour-intensive high-throughput screening. Thanks to our technology, we are able to achieve the same objectives with at least a 10-fold improvement in productivity. This technology also opens new horizons that we are just beginning to explore”.

The THR^™ Technology, developed by Biométhodes, in association with the Laboratory of Dr. Berenguer – Madrid University – is based on the direct selection, using a particular naturally-occurring bacterial strain, of stabilized proteins among millions of variants. “Nature is working with us” concludes Marc Delcourt. THR^™ is protected by the patent FR2886943 granted in France and its international extension (WO2006/134240).

November 23, 2007 :

Biométhodes announces its refinancing and appoints a new Chief Executive Officer

Biométhodes announced the company’s refinancing and the appointment of Gilles Amsallem as Chief Executive Officer.

Gilles Amsallem brings more than 20 years of expertise in managing biotechnology companies. He has founded and successfully headed the Mixis Genetics company in the 90’s. Throughout his career, he has acquired a broad expertise serving at Dupont, Sorin Biomedica and Eurobio Laboratories. From 2004 to 2006, Gilles held the functions of Chief Operating Officer at Avesthagen in India.

“I am enthousiastic that Gilles has joined our team” said Marc Delcourt, Founder, President and Director R&D of Biométhodes. “His experience and global market vision will allow the company to accelerate its growth”.

“I am delighted to be part of this new challenge”, declared Gilles Amsallem before adding “the company now holds all the assets to reap the benefits of the innovative research efforts it has made in recent years to apply its unique technological platform to therapeutic proteins, animal feed, biocatalysis and biofuels fields”

Ultra-High Throughput Semi-Rational Mutagenesis

Massive Mutagenesis^® is a robust, scalable, versatile technique allowing the creation of custom mutant libraries of up to 109 mutants. Massive Mutagenesis^® allows for any type of mutagenesis strategy; from wide combinatorial randomisation of the gene (e.g. all the double mutants of a gene) to semi-rational, knowledge-based design of a smart library.

Associated with appropriate selection or Biométhodes’ HTS platform, Massive Mutagenesis^® allows tailoring all types of proteins including enzymes and biopharmaceuticals. The technology has been widely validated through over 30 projects and has delivered improved enzymes, antibodies and other proteins.

A Direct Selection Scheme for Stability

THR^™ is a unique technique that allows to directly select thermostable variants among very large protein repertoires. The issue of thermostability, which often correlates with stability in a wider sense, is particularly relevant to the field of biocatalysis, where high-temperature process are sought, allowing faster reaction rates, decreased viscosity and much lower risks of contamination. THR^™ was developed in collaboration with J. Berenguer, a world-class Thermus thermophilus specialist at Madrid University.

Ongoing Technological Developments

We currently pursue an ambitious R&D program in the domain of whole-cell directed evolution. We hope it will deliver before 2009 and help us gain a significant advance in the race for next generation biofuels.

Publications

“An activity-independent selection system of thermostable protein variants” Nature Methods 2007. 4:919-21

“Directed Evolution of biocatalysts” Organic Process Research & Development. 2006. 10(3):562-71.

“High-throughput site-directed mutagenesis using oligonucleotides synthesized on DNA chips” BioTechniques (2005) 39, 3: 363-68

“Massive Mutagenesis^® high-throughput, high-precision library creation” DrugPlusInternational – Nov. 2005

Patents

Method for selecting stable proteins in non-standard physicochemical conditions EP1894014, WO2006134240

Method for massive directed mutagenesis US7202086B2, EP1311670B1

Method for obtaining soluble or better expressed variants of a protein of interest WO2006106193

Method of massive mutagenesis EP1544296, US2005153343

Biofuels

Food-crop based bioethanol and biodiesel do not scale up sustainably and efficiently. Hence the need for a new generation of biofuels to progressively substitute fossil fuels as liquid energy. Biométhodes addresses a central problem in the vast lignocellulosic biomass recalcitrance issue by developing new cost-efficient enzyme systems enable to hydrolyse microcrystalline cellulose. We pursue both whole-cell approaches and the improvement of enzyme cocktails. One of our projects aims at expressing three carefully selected and improved enzymes in a plant.

Biocatalysis

The dream of replacing energy- and water-consuming, polluting chemical catalysts by highly specific, process-stable, bespoke enzymes is coming true. The main issue we are currently addressing is the regeneration of nicotidamine cofactors involved in numerous industrial reactions. Another important element of our pipeline in green chemistry is an enzyme that could catalyse the synthesis of a dozen major chemical intermediates. We develop assays for our enzymes both immobilized and in whole-cell systems.

Animal Feed

We have started fine-tuning the properties of a promising microbial phytase to make it an ideal candidate to solve all remaining issues on this market of growing ecological and economical value. The product we develop aims to be naturally thermostable (90s at 90°C), optimally active at both pig and poultry upper digestive tracts pH (2-5) and potent enough to avoid any inorganic phosphate supplementation. First animal trials are due to start S2 2009 and we are willing to discuss options by major industry players in the meanwhile.

Our Team

Gilles Amsallem, MD - Chief Executive Officer

Stéphane Blesa, Ph.D. - Chief Technical Officer

Xavier Liju - Chief Financial Officer

Board of Directors

Gilles Amsallem, CEO

Ingrid Rayez, CDC Innovation

Robert Leon, Qualis

Eric Claus, CFO of the MASA group

Stéphane Huguet, CEO of Smaxy

Non-voting members :

Michel Lurquin

Jean-Christophe Barale, Researcher at the CNRS/Pasteur Institute

Careers

Biométhodes is currently seeking talented and highly motivated individuals to complete its multidisciplinary team in the fields of molecular biology, microbiology, computational biology and to prepare for the creation of a bioproduction unit.

Please send a resume, cover letter and your salary requirements to careers[at]Biométhodes.com or fax to +33 (0) 160 91 21 52

Contact

Biométhodes

Genavenir 8
5, Rue Henri Desbruères
91030 Evry cedex
France

Tel: +33 (0) 160 91 21 21
Fax: +33 (0) 160 91 21 52

E-mail : info[at]biomethodes.com