EPHEMER TM From CELEBRITY TM : World s 1st technology of macroalgae cell culture. Sourcing the EPHEMER TM for a long lasting anti-aging effect

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1 EPHEMER TM From CELEBRITY TM : World s 1st technology of macroalgae cell culture Sourcing the EPHEMER TM for a long lasting anti-aging effect

2 CELEBRITY World s 1 st technology of macroalgae cell culture EPHEMER is the 1 st active ingredient for cosmetic application, worldwide, from macroalgae cell biotechnologies Innovation : > Isolation of macroalgae in cellular form > Culture in photo-bioreactors in cellular form 2

3 EPHEMER Sourcing the EPHEMER for a long lasting anti-aging effect Undaria Pinnatifida A brown algae, known as wakame in Japan & sourced in Brittany by BiotechMarine Life cycle: 2 morphologic forms 1 > sporophyte (macroalgae form) 2 > gametophyte: source of EPHEMER (cellular form) branched filaments formed of elongated cells BiotechMarine 3

4 Sourcing the EPHEMER EPHEMER is an extract of gametophytes: macroalgae cells in the lifecycle of the Undaria Pinnatifida brown algae. Gametophytes: are autotrophic cells. They produce organic compounds from CO 2 & minerals, using energy from light. only live a few weeks in the ocean, before giving a different form. are unstable in the ocean & not available in large quantities. The culture of gametophytes, as a rare & precious type of macroalgae cells, in a laboratory is a World first for cosmetic applications. 4

5 Benefits from this technology Growing gametophytes in the laboratory Technical interest of Gametophytes > Gametophytes are stable in our process in the laboratory (not in the ocean) > Gametophytes from Undaria Pinnatifida contain antioxidants molecules Marketing interest of Gametophytes > The Value of an ephemeral stage in the life cycle of Undaria Pinnatifida. 5 BiotechMarine & HEOS MARINE > Essential role as the Source of Life of Undaria Pinnatifida, for the survival of the species

6 Extraction method 1 > Extraction solid / liquid (biomass + solvant) 2 > Extraction liquid / liquid (triphasic association, allowing migration of lipophilic molecules) 3 > Separation of the phases > Isolating the lipophilic extract of gametophytes: - carotenoïds (ex :fucoxanthin), Fucoxanthin: quality tracer in standard - chlorophylles (6 different types), - triterpenes BiotechMarine 6

7 Concept of Ephemeral Art An ephemeral moment gives intense & unforgettable memories An ephemeral experience, a brief moment with a long lasting impact Ephemeral beach art for the launch of EPHEMER TM, Britanny, March 2015 BiotechMarine & K. RACCAH 7

8 Concept of Ephemeral Art Brief & Memorable Fragile & Precious Ephemeral & Essential FOTOLIA Mickael LEVY - FOTOLIA Achenes crested dandelion Buddhist Mandala 8

9 Protection of the Genes of EVE thanks to a protected source of life (gametophytes) Protection of the energetic source that women inherit from their mother & transmit to their children EPHEMER protects the genes of Eve (mitochondrial DNA), inherited from mom* Mitochondrial DNA is inherited from mom whereas Nucleus DNA is inherited from mom & dad Fotolia EPHEMER protects mitochondrial DNA integrity +63% Aconitase, a mitochondrial enzyme involved in cell homeostasis and known for its protective role towards mitochondrial DNA. (after 8 days, versus control in skin explants - histological evaluation) *The genetic patrimony is located in the nucleus & the mitochondria. In the nucleus, all genes are equally inherited from mom & dad. In the mitochondria, genes are inherited from mum. Mitochondria are the energy factory (ATP) of the cells. 9

10 Ephemeral & long lasting antioxidant 10 BiotechMarine

11 Scientific data Studies in human skin explants > Histologic study results (1/3) General morphology at D8 (Trichrome s Masson coloration) Control Vehicle Vehicle +EPHEMER TM Histological targets (immunostaining confirmations) SIRT-1: to confirm a long-term activation Catalase: to confirm the antioxidant long-term regulation Aconitase mt: mitochondrial marker to ensure no mitochondrial damages Qualitative & quantitative evaluations 11

12 Scientific data Studies in human skin explants > Histologic study results (2/3) Immunostainings > SIRT-1 Vehicle Vehicle + EPHEMER TM epid.area % effect vs V: +101%*** p<

13 Scientific data Studies in human skin explants > Histologic study results (3/3) Immunostainings Vehicle Vehicle + EPHEMER TM Mitochondrial ACONITASE epid.area % effect vs V: +63%* 0.01<p<0.05 CATALASE epid.area % effect vs V: +19%*0.01<p<

14 Clinical results IN VIVO: antioxidant capacity of the skin after 28 days > Evaluation of the antioxidant capacity of the skin FRAP method (Ferric Reducing Antioxidant Parameter) method commonly used in measuring antioxidant power from fruits Study synopsis: - 20 healthy Caucasian volunteers (men & women), mean age of 37years old - Randomized application of a 1% EPHEMER TM formulation vs placebo formulation vs no treatment on 30cm² zones on thighs, twice a day -1 month treatment Parameter: - Strippings Evaluation were of performed the antioxidant in order capacity to collect of stratum the skin corneum layers using Corneofix TM UVA stress Treatment with EPHEMER twice a day D0 Skin stripping Skin stripping D28 FRAP evaluation & lipoperoxidation D29 Skin stripping Residual oxidation evaluation (lipoperoxidation) after UVA stress 14 - Study conducted at Farcoderm, Italy, nov./dec

15 Clinical results IN VIVO: antioxidant capacity of the skin after 28 days > Evaluation of the antioxidant capacity of the skin Results: Formulation with 1% EPHEMER Variation after 28 days (% versus D0 ) +15% > After 28 days, EPHEMER reinforces the antioxidant capacity of the skin +15% observed versus D0 (p<0.001) versus the placebo (p=0.005) versus non-treated zone (p<0.001) - Study conducted at Farcoderm, Italy, nov./dec

16 Better recovering response to oxidative stress After end of the treatment % variation D29-D28 of basal lipoperoxidation On Day 29, once treatment finished, treated skin with EPHEMER for 28 days has a better recovering Response to oxidative stress. & After UVA stress, lipoperoxidation is lower on treated skin with EPHEMER than on non treated skin

17 Clinical results IN VIVO: effect on skin relief after 56 days > Evaluation of skin relief on the crow s feet region Study synopsis: - 25 healthy Caucasian women, older than 45 years old, presenting a wrinkle score of 3 to 6 (ProDerm score) on the crow s feet area - Randomized application of a 1% EPHEMER TM formulation vs placebo formulation, twice a day, on half-face - 2 month treatment Parameters: - Evaluation of the skin relief: AEVA fringe projection method (Ra) skin microrelief (Rz) skin roughness, characterizing the average depth of wrinkles 17 - Study conducted at ProDERM, Germany, nov./dec

18 Clinical results IN VIVO: effect on skin relief after 56 days > Evaluation of skin relief on the crow s feet region Results: EPHEMER decreases the microrelief versus placebo (p=0.08), Formulation with 1% EPHEMER Microrelief variation after 56 days (% versus D0) -7% (p=0.02) Roughness variation after 56 days (% versus D0) -5% (p=0.02) Benefits from EPHEMER TM 1% on microrelief & roughness after 56days treatment D0 EPHEMER decreases the microrelief (-7%) effect observed versus D0 (p=0.02) D56 EPHEMER decreases skin roughness (-5%), effect observed versus D0 (p=0.02) 18 - Study conducted at ProDERM, Germany, nov.-dec

19 EPHEMER TM Sourcing the EPHEMER for a long lasting anti-aging effect INCI Name: Caprylic/Capric Triglyceride - Undaria Pinnatifida Extract QUALITY TRACER: SOLUBILITY: FORMULATION: PRESERVATIVE: RECOMMENDED USE: 1% APPROVALS: fucoxanthin liquid & liposoluble easy none CHINA COMPLIANT* * * RSPO* GREEN PALM PROGRAMME * CHINA COMPLIANT: INCI name listed on IECIC list of June * ECOCERT: raw material approved by ECOCERT GREENLIFE, in conformity with Ecocert natural and organic cosmetic standard. * COSMOS: raw material approved by ECOCERT GREENLIFE, in conformity with Cosmos standard. * RSPO GREEN PALM PROGRAMME: supports the production of substainable palm oil through the green palm programme (book and claim)

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21 Annex Environmental sustainability aspects BiotechMarine Scientific datas: Studies on human skin

22 Environmental sustainability aspects CELEBRITY, sustainable technology of macroalgae cell culture > Protection of macroalgae EPHEMER : - protects the Source of Life (gametophyte) of Undaria Pinnatifida, - reduces the environmental footprint (local sourcing & manufacturing) & contributes to the sustainable sourcing of raw material from renewable raw material origin, - enables a constant supply. No problems related to lack of raw materials, pollution, or stock, - process to grow is totally natural. The production is handled in natural sea water. > RSPO - SEPPIC is member of RSPO (Roundtable on Sustainable Palm Oil). - EPHEMER TM is covered by Book & Claim certification (Ephemer supports the production of sustainable palm oil through the green palm programme) - SEPPIC intends to get certification for the BiotechMarine Pontrieux plant according to mass Balance criteria within current year and to propose Ephemer MB (Mass Balance certified) in

23 Scientific data Studies in human skin explants - Bio-EC/Genex > Protocol +/- daily treatment (2mg/explant): > vehicule (hydroalcoholic gel 2,5%-topic & ethanol 1%-systemic) > EPHEMER TM (1% in hydroalcoholic gel 2,5%-topic & 0.1% EPHEMER in 1% ethanol-systemic) 24 h D8 Human abdominal skin explant ( 10mm) : > from a 50year old caucasian woman (transcriptomic study) > from a 47year old caucasian woman (histologic study) 23 n=3/condition Transcriptomic study & histological quality control RNA extraction & qualification RNA amplification & hybridization on human full genome chip Relative quantification of gene expression variation (vs vehicule) Histologic study General morphology (Masson strichrom coloration) + immunostaining : Aconitase + Catalase + SIRT-1 + Qualitative & quantitative evaluation

24 Scientific data Studies in human skin explants - Bio-EC/Genex > Full genome transcriptomic study results (1/4) Histologic quality control at 24h Control Vehicule (placebo) EPHEMER TM Global profile of transcriptomic regulations Upregulated genes: 635 (fold change 1.25) Downregulated genes: 263 (fold change 0.8) (results between replicates) 24

25 Scientific data Studies in human skin explants (Bio-EC/Genex) > Full genome transcriptomic study results (2/4) Some relevant upregulated genes Upregulated targets (fold change) HIF-1α 2.61 HSPA MT1E 1.51 Antioxidant KLF Heat HSPA elements CAT 1.69 Shock SIRT AHSA Proteins TXNL LAMB ID HSPD Laminins LAMA FLG SERPINB Some relevant downregulated genes Downregulated targets (fold change) 25 Mitochondrial respiratory chain elements ROMO COX5B 0.69 COX6A NDUFA11 & 13 + B2 & ATP5E 0.58

26 Ephemeral antioxidant Mechanism of action: after 24 hours > Full genome transcriptomic study results (3/4) Free radicals Ephemeral antioxidant Mitochondria have an ephemeral ability to produce energy in anaerobic conditions, leading to a reduction of free radicals release. With EPHEMER HIF-1α gene expression is up regulated (2.6x more than control, in skin explants) leading to a switch from aerobic to anaerobic metabolism. BiotechMarine SIRT-1 gene expression is up regulated (1.4x more than control, in skin explants) : retrocontrol on HIF-1α for a balanced regulation of its effects. 26

27 Long lasting antioxidant Mechanism of action: after 8 days > Long lasting antioxidant EPHEMER : protects the cells against free radicals +19% Catalase (Detoxyfying enzyme in histologic evaluation) thanks to SIRT-1 long term activation SIRT-1 gene expression is up regulated at 24h (1.4x more than control), regulation maintained after 8 days (+101% Sirt-1 versus control in epidermis staining). SIRT-1 is also known as the protein of longevity protects mitochondrial DNA integrity +63% Aconitase a mitochondrial enzyme involved in cell energy production and also known for its protective role towards mitochondrial DNA. (after 8 days, versus control in skin explants - histological evaluation) 27

28 IN VIVO antioxidant protocol FRAP analysis: study details (1) Evaluation of the antioxidant capacity of the skin: FRAP method, ferric reducing antioxidant power The FRAP method gives information about the global antioxidant power of samples. It is used: in vitro to measure the antioxidant profile of food products (fruits, plant extracts, etc...) as well as in vivo on biological samples like human plasma & skin samples (for measuring the effect of food supplements or topical products) FRAP is one method to target oxidation in biological samples, as are ORAC, DPPH, ABTS methods 300cm² zones were defined on the thighs for products application Strippings were performed in order to collect stratum corneum layers using Corneofix TM The 1 st stripping was discarded; following 2 other strippings were kept frozen at -20 C for further analysis. Fe(III)-complex antioxidants from stripped stratum corneum samples ph=3.6 T=37 C blue colored Fe(II)-complex (absorption measured at 595 nm) 28

29 IN VIVO antioxidant protocol Lipoperoxidation analysis: study details (2) Evaluation of the cutaneous lipoperoxidation, 24 hours after a UVA stress, through MDA measurement Malonyldialdehyde (MDA) is one of the main products resulting from lipid peroxidation process. Its concentration in a biological matrix is a good index of the lipoperoxidation level of the system. 300cm² zones were defined on the thighs for products application. Strippings were performed in order to collect stratum corneum layers using Corneofix TM. The first 10 strippings were discarded; stripping #11 was kept frozen at -20 C for further analysis. MDA From stripped stratum corneum samples + NMPI (*) Added reactive compound Stable chromophore (absorption peak at 586 nm) (*) N-methyl-2-phenylindole 29

30 Contacts Nota The analytical specifications warranted are only those mentioned on the certificate of analysis supplied with each delivery of the product. Except as set forth above, SEPPIC* makes no warranties, whether express, implied or statutory, as to the product which is the subject of this document. Without limiting the generality of the foregoing, SEPPIC* makes no warranty of merchantability of the product or of the fitness of the product for any particular purpose. Buyer assumes all risk and liability resulting from the use or sale of the product, whether singly or in combination with other goods. The information set forth herein is furnished free of charge and is based on technical data that SEPPIC* believes to be reliable. It is intended for use by persons having technical skill and at their own discretion and risk. Since conditions of use are outside SEPPIC*'s control, SEPPIC* makes no warranties, express or implied, and assumes no liability in connection with any use of this information. Nothing herein is to be taken as a license to operate under or a recommendation to infringe any patents. * SEPPIC being: SEPPIC S.A. 22 Terrasse Bellini Puteaux FRANCE Tel. : +33 (0) info.seppic@airliquide.com USA - SEPPIC Inc. 30, Two Bridges Road, suite 210 Fairfield, New Jersey USA Tel. : us.seppic@airliquide.com POLAND - SEPPIC Poland Office CCIF Ul. Widok Varsovie POLAND Tel : poland.seppic@airliquide.com SEPPIC Castres 27, chemin de la poudrerie BP CASTRES CEDEX FRANCE Tél. +33 (0) Fax. +33 (0) SINGAPORE - SEPPIC Asia Singapore 3 HarbourFront Place # HarbourFront Tower Two Singapore P.O. Box SINGAPORE Tel : singapore.seppic@airliquide.com DUBAI - SEPPIC Dubai East Wing 5, Block-A, 3rd Floor Dubai Airport Free Zone UNITED ARAB EMIRATES Tel : +971 (0) dubai.seppic@airliquide.com BiotechMarine Zone Industrielle B.P Pontrieux FRANCE Tel : +33 (0) contact.biotechmarine@airliquide.com JAPAN - SEPPIC Japan Office Air Liquide Japan's office Granpark Tower Shibaura Minato-ku, Tokyo JAPAN Tel : japan.seppic@airliquide.com Air Liquide India Holding Pvt Ltd O2 Commercial Twin Tower B/1304, Asha Nagar Road Mulund (W) Mumbai INDIA Tel : india.seppic@airliquide.com Head Office 75, quai d'orsay Paris FRANCE CHINA - SEPPIC China Room 2909 Nan Zheng Building 580 West Nan Jing Road Shanghai CHINA Tel : +86 (21) china.seppic@airliquide.com BRASIL - SEPPIC Brasil Alameda Santos 745/ cj 72 / 7ºfloor Cerqueira Cesar São Paulo SP BRAZIL Tel : brasil.seppic@airliquide.com BiotechMarine / BM-0100-slides-EPHEMER-GB-01-APRIL2015 GERMANY - SEPPIC Gmbh Martinstrasse Köln GERMANY Tel : +49 (0) germany.seppic@airliquide.com ITALIA - SEPPIC Italia Srl Via Quarenghi Milano ITALY Tel : italy.seppic@airliquide.com COLOMBIA - SEPPIC Colombia SAS Calle 71 n Edificio Orbe 71 of 401 Bogota COLOMBIA Tel : colombia.seppic@airliquide.com