Partnering to advance global HealtH - Pacte PME · contents Partnering witH us partnering: ... quarter of 2016 as per the terms of the signed inal agreements and the ... aND aNtiboDy-DireCteD

Partnering to advance global HealtH

Partnering witH uscontents

partnering: SHARING EXPERTISE TO DRIVE INNOVATION

PARTNERING wITH SANOfI - 1

PARTNERING wITH US 01

SANOfI AT A GLANCE 02

OUR STRATEGIC PRIORITIES 03

AREAS Of INTEREST

OUR PARTNERING MODEL 14

ADDING VALUE fOR OUR PARTNERS 16

CONTACTS 18

Diabetes 04CarDiovasCular 05rare Diseases 06Neurobiology 07immuNology aND iNflammatioN 08oNCology 09saNofi Pasteur 10iNfeCtious Diseases 11Drug DisCoverybiologiCs Platforms

1213

Sanofi’s innovative solutions help to address a very diverse range of healthcare needs, from preventing diseases in large populations, to delivering treatments for rare life threatening conditions. A recognized world leader in vaccines and rare diseases, we make major contributions to diabetes management, and have a growing presence in specialty care. Our diversity is further supported by our strong track record in emerging markets.

Collaboration and partnership are critical for success in any pharmaceutical based R&D endeavor. No single institution, company, university or government has a monopoly on innovation.

At Sanofi, we know that good ideas can come from anywhere. This is why we are committed to share skills and projects with the best scientists and companies in each therapeutic area, wherever they are. In 2015 we signed over 75 research agreements with partners around the globe.

Today Sanofi is embarking on a new journey, guided by a strategic roadmap based on innovation, focus and simplification. All key activities critical to Business Development have been brought together into one global, integrated group. This provides a simple interface with Sanofi that supports rapid and effective dialogue.

MUZ MANSURIGlobal Head of Strategy & Business Development

SANOfI,A wORLD LEADER IN HEALTHCARE,committed to the prevention and treatment of diseases around the world

OUR STRATEGIC PRIORITIES

AGGREGATE GROUP sALEs

bILLION budget

invEsTEd in R&d in 2015.

WiTH OvER1 10 ,000 EMPLOYEEs

PREsEnT in MORE THAn

data in late 2015

HEALTHCARECOMPAnYWORLdWidE

5OURBUsinEss UniTsAnd MAJORTHERAPEUTiCAREAs

dIAbeteS &CARdIOVASCuLAR

SANOFI PASteuRVACCINES

SANOFI geNZYMeRARE DISEASES

MULTIPLE SCLEROSISONCOLOGY

IMMUNOLOGY

geNeRAL MedICINeS

ANd eMeRgINg MARKetS

CONSUMER HEALTHCARE,

GENERICS

MeRIAL*ANIMAL HEALTH

* In late 2015 a business swap was set up with Boehringer Ingelheim exchanging our Animal Health activity with their Consumer Healthcare business.The transaction is set to be inalized in the fourth quarter of 2016 as per the terms of the signed inal agreements and the acquisition of regulatory approvals.

#5 100 €37€5.2COuNtRIeS

bILLION

Deliver outstaNDiNg lauNChes

Innovation driven by and tailored to patients’ needs, such as Toujeo®, Praluent®, and Dengvaxia®

Prepare the introduction of sarilumab for rheumatoid arthritis, dupilumab for atopic dermatitis, and the insulin glargine/Lixisenatide combination (LixiLan) for diabetes

Successfully launch our major new products

reshaPe the Portfolio

Sustain leadership and consolidate operations in areas where Sanofi has substantial expertise and experience: Diabetes and Cardiovascular, Vaccines, Rare Diseases, and Emerging Markets

Build competitive positions and develop expertise in Multiple Sclerosis, Oncology and Immunology

Position Sanofi as a leader in self-care by collaborating with Boehringer Ingelheim*, to swap our Animal Health with their Consumer Healthcare business

Restructure our portfolio with a renewed emphasis on human health

sustaiN iNNovatioN iN r&D

Products that make a real difference to the doctors writing prescriptions, payers reimbursing their cost, and the patients who should, ultimately, receive the best possible care

Devote substantial resources to the most promising projects in our R&D portfolio

Foster existing R&D collaborations and increase capacity for external innovation

Enhance R&D innovation to develop our drugs and vaccines

simPlify the orgaNizatioN

Establish five global business units to improve collaboration between R&D and business operations, thereby fast-tracking the time to market for our innovations

Globalize and integrate all key functions including Research & Development and Strategy & Business Development

Streamline and simplify our organization teams

PARTNERING wITH SANOfI - 32 - PARTNERING wITH SANOfI

diabetes and cardiovascular

Sanofi Diabetes is a leader in delivering modern Diabetes Care to patients worldwide. Based on our rich history and pipeline as well as our global commercial and industrial footprint, our ambition is to expand Diabetes Care to the next level.

Our teams continually strive to develop the next generation of innovative insulins, peptides, oral agents and drug delivery technologies. We furthermore seek novel approaches that reach beyond glucose control and address onset and progression of Type 1 Diabetes and Type 2 Diabetes.

Novel insulins (long acting, oral delivery, glucose sensing, tissue selective)

Diabetic weight management (GI peptides, oral incretins, oral weight management)

Disease modifying agents for T1D and T2D

Beta cell replacement, regeneration & protection

Diabetic Nephropathy and NASH

Novel Drug Delivery Opportunities

Innovative solutions for patient self management

diabetes and cardiovascular

Cardiovascular disease is the number one cause of death globally, accounting for nearly 30% of all deaths. At Sanofi, we gained significant experience from the development of iconic brands in this therapeutic area, and we remain committed to developing new therapies by building on this strong legacy.

CarDiomyoPathies Including hypertrophic, dilated, and genetic cardiomyopathies

heart failure Acute and Chronic hyPerliPiDemia Orally bioavailable PCSK9 inhibitor and novel oral drugs to lower LDL Oral or injectable agents to reduce triglycerides Specific therapies for diabetes-related cardiovascular disease

Sanofi has developed Praluent® (alirocumab), an innovative treatment helping adult patients with hypercholesterolemia to reduce their level of bad choloesterol.

Sanofi has been leader in delivering modern Diabetes care to patients worldwide and benefits from a global commercial and industrial footprint in this area.

DIABETES CARDIOVASCULAR


oPhthalmologyLeber’s Congenital Amaurosis Type 1

PulmoNaryCystic FibrosisPulmonary Alveolar Proteinosis

eNDoCriNology & metabolismFamilial Amyloidotic CardiomyopathyLysosomal storage diseases, incl.

hematologyBeta-thalassemiaHemophiliaNiemann-Pick B DiseaseSickle cell anemia

musCleAlpha-dystroglycanopathiesDuchenne Muscular DystrophyFacioscapulohumeral muscular dystrophyMyotonic dystrophyPompe DiseaseSpinal Muscular Atrophy

boNe & reNalAlport SyndromeChondrodysplasiasCiliopathiesfabry DiseaseFocal Segmental GlomerulosclerosisHyperoxaluriaPolycystic Kidney DiseaseUrea Cycle Disorders

NeurologyAmyotrophic Lateral SclerosisAngelman SyndromeCharcot-Marie-Tooth diseaseFamilial Amyloidotic PolyneuropathyFriedrich’s ataxiaGangliosidosesGaucher-related ParkinsonismHuntington’s DiseaseMetachromatic LeukodystrophyRett SyndromeSynucleinopathies

sanoFi genZYMe

RARE DISEASES

For over three decades Sanofi Genzyme has discovered and developed transformative therapies for patients with rare and special unmet medical needs, providing hope where there was none before. We focus on diseases with well-defined mechanisms and high unmet needs.

Sanofi Genzyme has pioneered the development and delivery of transformative therapies for patients with rare and special unmet medical needs for over thirty years.

sanoFi genZYMe

NEUROBIOLOGY

NeuroDegeNeratioN

multiPle sClerosis

Debilitating neurogenerative diseases of the central nervous system such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis represent a growing unmet medical need, heavily impacting patients and their families.

AlzHeImeR’S DISeASe AND OTHeR TAuOPATHIeS

ImmuNOmODulATION

TeCHNOlOGy

PARkINSON’S DISeASe

NeuROPROTeCTION & RemyelINATION

Tau-targeting biologics or small molecules that reduce spread of pathologyApoE4 approaches not directed at deposition of amyloid plaquesNew approaches in neuroinflammation and innate immunity

Drug candidates targeting lymphocytes with novel mechanisms of actions, with potential for high efficacy and manageable safety

Biomarkers to predict disease course, stratify patient populations, monitor therapeutic interventionsMethods for quantifying synaptic plasticity and synaptic loss, neuroprotection, or assessing remyelination in vivoMethods of enhancing transit of therapeutics across the BBB

Compounds modulating pathways affected by genetic variations or that cause human disease

Synuclein pathology blockers

Drug candidates targeting neurodegeneration, neuroinflammation or neuroprotection and remyelination Symptom Management

Drug candidates targeting MS-related symptoms, preferably at clinical stage

Our team includes internationally recognized scientists in neurology, rare diseases, and neuroimmunology, working on slowing neurodegeneration, modulating neuroinflammation, and facilitating neuroprotection, repair and remyelination.


DermatologiCal aND PulmoNary DisorDers

gastroiNtestiNal-DisorDers

bioiNformatiC CaPabilities to exPaND uNDerstaNDiNg of Disease aND resPoNse to theraPy

rheumatologiCal DisorDers

immuNe system-targeteD theraPy

Atopic Dermatitis Psoriasis Vitiligo Severe asthma

Crohn’s Disease Ulcerative ColitisEosinophilic esophagitis

Identification, characterization and validation of biomarkers in for patient stratification and clinical monitoring

Rheumatoid arthritis Psoriatic arthritis Systemic Lupus Erythematosus Ankylosing spondylitis Gout

Normalization of imbalanced immune responses in allergic disease including the ‘atopic march’ Induction of long-term immunological non-responsiveness (tolerance) to allergens & auto-antigens

sanoFi genZYMe

Sanofi Genzyme seeks new therapeutics to normalize aberrant immune responses in immune-mediated disorders such as rheumatic and respiratory diseases, and inflammatory skin and gastro-intestinal diseases.

Biologic, small molecule and nucleic acid-based approaches for the following:

Sanofi Genzyme is pioneering development of dupilumab, a first-in-class biologic drug in allergic dermatological and pulmonary disorders

sanoFi genZYMe

Cancer remains a leading cause of death world-wide. At Sanofi Genzyme, we are building on our strong heritage in oncology research to pursue curative approaches. Collaborations focusing on novel therapeutic approaches are a key part of our strategy.

overComiNg immuNosuPPressioN

other iNterests

aCtive immuNizatioN aND aNtiboDy-DireCteD tumor targetiNg

CaNCer DePeNDeNCy-relateD theraPies Translational Medicine and biomarkers

to support pipeline Immune profiling methodologies in pre-clinical and clinic (immuno-monitoring)Novel-novel combinations Preclinical platform to test and validate immuno-oncology combinationsMolecular entities with potential for transformative benefits Commercial opportunities synergistic with current portfolio (prostate cancer, colorectal cancer, hematological malignancies)

Drugs or novel targets targeting: K-RAS directly or cancers where K-RAS is implicated Oncogenic pathways currently lacking therapy Co-dependency or synthetic lethality CRISPR/CAS9 based target identification platform Targeted therapy resistance (induced or intrinsic)Novel lineage targets and drugs targeting them

Stimulation of functional activity of antigen presenting cells. Redirection of immunity against tumors using cell engagers & immuno-conjugates Innovative cancer vaccine platforms and adjuvantsDevices for direct intra-tumoral/intra-nodal injection.

Modulation of immunosuppressive components in the tumor microenvironmentSuppressive mechanisms within myeloid lineage cell typesT cell invasion and expansion Modalities outside “classical” immune checkpoints

Our portfolio contains a range of innovative therapeutic agents including Immuno-Oncology and targeted therapies.

IMMUNOLOGY AND INfLAMMATION ONCOLOGY


VACCINES, MONOCLONAL aNtiboDies & suPPortiNg teChNologies

vaCCiNe immuNe RESPONSES’ ENHANCERS

Adjuvants and immunomodulatorsVaccine vectors and delivery systems Biological and immunological studies to further characterize adjuvants and immunomodulators

Novel antigens and methods for antigendiscovery

Novel conjugation technologies

Vaccine vectors suitable for nasal or oral use

New ways to administer vaccines

sanoFi Pasteur

A world leader in its industry, Sanofi Pasteur, the vaccines division of Sanofi, offers a broad range of vaccines protecting against 20 infectious diseases. In the field of prevention, we focus on developing safe and effective vaccines with a single or combined target against complex diseases. In the infectious diseases area, our goal is to address severe bacterial and parasitic infections as well as acute and chronic viral infections.

otHer areas

Innovative small molecules or biologics (including natural products) Bacterial infections: anti-gram negative with a new MoA for severe hospital infectionsTuberculosis active agents (MDR/XDR), with potential to shorten treatmentViral infections: Antiviral agents against HBV, influenza, HIV, and chikungunyaNovel bacterial or viral targets with proof of conceptAdjunct therapies: immuno-modulation, anti-virulence Bacterial infections: biologics against bacterial toxins or other virulence factors Viral infections: host target approach (immuno-stimulation/-restoration) for cure of HBV, or HIV Technologies under patent protection

CharaCterizatioN aND assay of immuNe resPoNses aND Disease markers

tools for imProviNg vaCCiNe aND MONOCLONAL ANTIBODy RESEARCH, DeveloPmeNt aND ProDuCtioN

Genomics and proteomics technologiesProkaryotic or eukaryotic cell lines for antigen productionFermentor and bioreactor technologyDisposable systemsDownstream processingProcess automationPreservatives and stabilizersBioinformatics techniques

Animal models of human diseases

In vitro models of human tissues, including the immune system

Biological markers

As a world leader, Sanofi Pasteur provides more than 1 billion doses of vaccine each year, making it possible to immunize more than 500 million people across the globe.

As a world leader, Sanofi Pasteur provides more than 1 billion doses of vaccine each year, making it possible to immunize more than 500 million people across the globe.

INfECTIOUS DISEASESSANOfI PASTEUR


Next generation screening techniquesInnovative chemical matter: small molecules, peptides, macrocycles, natural productsTarget validation: gene editing, compound de-orphaning technologiesAdvances in computational chemistry and structural biologyNovel drug delivery Prediction of stability, toxicity & pharmacokinetics in silico, in vitro or in vivoDisease relevant 3D tissue culturesSystems biology/pharmacology/toxicology models Identification of drug efficacy biomarkersTarget engagement in living systems

otHer areas

Sanofi’s Drug Discovery platforms identify bioactive synthetic molecules and advance them to the clinic.

otHer areas

We research, develop and manufacture recombinant enzymes, mAbs, antibody-drug conjugates, insulins, fusion proteins, gene and nucleic acid therapeutics.

mabs aND alterNative sCaffolDs DeveloPmeNt aND maNufaCturiNg of biologiCs

Delivery of biologiCs

Technologies and platforms to improve the generation and manufacturing of bi- and multispecifics mAbs and cell engagersNew technologies for mAb optimization, i.e. Fc engineering, enhancing antibody valency, improving developability, viscosity reduction, extending half-lifeNovel and future biologics: non-mAbs scaffolds, modular biologics, advanced structure based design, synthetic biologics Prediction of immunogenicity and biophysical liabilities: aggregation, high viscosity, etc.

Improving biophysical properties of mAbs: aggregation, viscosity, syringeability, solubility, etc.Mammalian cell technologies to improve expression & production of recombinant proteinsPredictive tools for biomanufacturing: behavior under process conditions, process simulation, technologies for on-line analysis and process controls for production of biologicals (Up-Stream and Down-Stream Processing, DSP), breakthrough technologies in protein purification, e.g. column free downstream processingProduction of AAV-based gene therapies, especially expression and packaging

Tissue-specific delivery of nucleic acid therapeutics to organs other than liver Alternatives to Gal-Nac ligand for liver targeting Cell penetrating biologics, mAbs and protein therapeutics Delivery of biologics across physiological barriers: BBB, GI, skin, lungs

DRUG DISCOVERY BIOLOGICS PLATfORMS

Biologics make up more than 50% of Sanofi’s development pipeline. Accessing external innovation is key to ensure that we remain on the cutting edge of discovery, development and manufacturing.

Our platforms cover fields such as lead generation biology, structural biology, computational design, medicinal chemistry and pharmacokinetics.


Partnering Model

ChaNgiNg the Way SANOfI PARTNERS

Deal makiNg fLEXIBILITY

NeW ORgANIZAtIONAL MOdeL TO dRivE FOCUs And siMPLiFiCATiOn

2015-2020 StRAtegIC ROAdMAP TO CREATE LOnG TERM vALUE

ACCeLeRAte bd ACtIVItIeS ANd StRAtegIC ALLIANCeS sTREnGHTEn And GROW THE PORTFOLiO

Licensing, Collaborations and M&A (upfront, milestones, royalties etc.)Target products and technologies supportive to R&DEarly to late stage technology/products

Equity participation within a syndicate, strategic interest,business drivenNo strategic rights for SanofiSpecific investement guidelines and boundaries

Company creation and co-creation equity investementsStrategic rights for Sanofi and deep collaborationFund to plan approach: Deal size varies and is tailored to r&D plan

SANOfI BUSINESS DEVELOPMENT & LICENSINGBuSINeSS DeVelOPmeNT & lICeNSING, the corporate partnering arm of Sanofi, invests in opportunities in alignment with Sanofi’s strategic priorities to maximize value creation. Our objective is to seek and execute external growth and collaboration opportunities to reshape our portfolio and support R&D innovation. Business Development & licensing has global scope, across all business units and therapeutic areas.

Business Development & licensing has the flexibility to pursue a broad range of deal structures to support the strategic intent of the partnership; from traditional approaches such as in- and out-licensing, R&D collaborations and m&A (asset/company acquisitions and divestitures), to alternative models such as joint ventures, commercial collaborations and other creative types of strategic alliance. Business Development & licensing can leverage all Sanofi capabilities and expertise across the value chain, from discovery to commercial and across geographies, to enable an efficient decision making process, fast negotiation and successful deal execution.

SANOfI GENZYME BIOVENTURESBIOVeNTuReS, the corporate venture capital arm of Sanofi, invests in early stage companies with promising new products that may be future Sanofi pipeline candidates. As a strategic fund, BV invests globally and directly in promising innovative private companies aligned with Sanofi’s areas of interest including rare genetic diseases, vaccines, immune-mediated diseases, and other breakthrough therapies. BV has an expedited decision-making process enabling rapid and clear decisions.

In addition to equity financing, BV provides strategic and technical input by leveraging the established expertise of Sanofi teams in science, preclinical and clinical development and regulatory strategy when helpful. BV’s success is driven by our ability to invest in areas where we have a unique voice and insight, and then to engage actively at the board level as well to facilitate meaningful interactions within Sanofi that could lead to future strategic collaborations and product opportunities.

SUNRISESuNRISe, Sanofi’s company co-creation and incubation vehicle, has a primary goal of accelerating the delivery of transformative treatments to patients in need while adding innovative products to the Sanofi pipeline. Sunrise invests in disruptive innovations that are best developed through focused efforts by entrepreneurs in new start-up biotech companies, and works globally and across all therapeutic areas.

Through Sunrise, Sanofi is both an equity investor and a foundational and committed first partner. Sunrise takes a risk-sharing, science-driven investment approach captured in a jointly developed 3-5 year research and development plan. Direct Sunrise investment in the company focuses on aligned interests of all involved parties. Through Sunrise, Sanofi secures product rights, but notably the new company retains significant rights and independent value creation opportunities. Sanofi’s strategic interests, supported by strong internal sponsorship, drive a close partnership with the entrepreneurs. Further, Sunrise bridges innovative science with expert capabilities and committed resources from Sanofi.Our close and collaborative relationships accelerate time to clinic and value creation, while providingimportant validation to any nascent life sciences company.

Partnering Model


alliance ManageMent

ADDING VALUE TO OUR PARTNERS

At Sanofi, we believe that Alliance management is the keystone of any sound and successful collaboration. For this reason, we have a dedicated team of Alliance managers, working across the globe, to materializing the value that Business Development groups intend to build into each contract.

Our Alliance managers are not only a key point of contact for the partner, they also promote fairness for all concerned parties, manage complexity and enhance communications. They ensure contractual understanding on all sides, and help to de-risk and leverage our alliances. To achieve this, we use health checks with follow up action plans for individual alliances and systematically seek feedback from our partners to identify general areas for improvement.

Our strategic alliance with Regeneron: the most visible part of this success Since 2007, Regeneron and Sanofi have collaborated to discover, develop, manufacture and commercialize fully human monoclonal antibodies. In 2015, Sanofi and Regeneron entered into a new global collaboration in the emerging field of immuno-oncology. This long-standing, broad alliance has enriched our pipeline with products such as “Praluent”, dupilumab, sarilumab and a PD-1 inhibitor.

A dedicated Alliance management team ensures that strategic objectives and value creation are achieved and manages decision-making through an appropriate governance structure, encompassing research, development, commercialization and manufacturing.

alliance ManageMent

Hanmi Pharmaceutical Co., Ltd.: A license agreement to develop a portfolio of long-acting diabetes treatments including a) efpeglenatide, a late-stage long-acting glucagon-like peptide-1 receptor agonists (GLP1-RA), b) a weekly insulin and c) a fixed-dosed weekly GLP-1-RA/insulin drug combination.

Alnylam: An exclusive alliance to develop and commercialize RNAi therapeutics targeting transthyretin (TTR) for the treatment of transthyretin-mediated amyloidosis (ATTR) in Japan and other Asia-Pacific countries, that has been extended in January 2014 by forming a transformational alliance focused on the advancement of RNAi therapeutics as genetic medicines.

Voyager Therapeutics: An agreement to develop gene therapies for severe CNS disorders combining our experience in the field of adeno-associated virus (AAV) gene therapy and Voyager’s AAV product engine to develop therapies for multiple programmes, including Parkinson’s disease, Friedreich’s ataxia and Huntington’s disease.

BioNtech: Research collaboration leveraging the scientific expertise of the two organizations to discover and develop up to five cancer immunotherapies, each consisting of a mixture of synthetic messenger RNAs (mRNAs)

Innate Pharma: Research collaboration and licensing agreement for new bispecific antibodies using Innate Pharma’s technology and Sanofi’s technology and tumor targets

VALUE CREATION THROUGH PARTNERSHIPSThe portfolio managed by our Alliance managers includes major alliances in various geographies and a wide range of partners such as Pharma, Biotech, Academics, Foundations, consortia and also companies from other industries. The team manages alliances from very early Research stage up to the Commercial phase.

This list only represents a number of selected alliances and is therefore non exhaustive.

Regeneron: Various agreements including an antibody discovery and development originally signed in 2007, where the partners collaborate to discover, develop, manufacture and commercialize fully human monoclonal antibodies utilizing Regeneron’s proprietary VelociSuite® of technologies, and an Immuno-Oncology Discovery and Development collaboration signed in 2015 to discover, develop and commercialize new antibody cancer treatments in the emerging field of immuno-oncology.

Lexicon Pharmaceuticals: A Collaboration on Sotagliflozin, an Investigational New Oral Medicine (inhibitor of sodium-glucose cotransporters 1 and 2) in Phase 3 studies for people with Diabetes.


OUR CONTACTS

Diabetes & CarDiovasCular

saNofi geNzyme

We invite you to contact Sanofi to inquire about our partnership opportunities.email your opportunity according to your area of interest.

loic Hameon: [email protected]

mark BARReTT : [email protected]

DIABETES Ulrich Wendt - [email protected]

RARE DISEASES AND MULTIPLE SCLEROSIS Daguang Wang - [email protected] françois besnard - [email protected]

CARDIOVASCULAR Michael Draper - [email protected]

ONCOLOGY Loic Vincent - [email protected] AND INfLAMMATION Brendan Classon: [email protected]

saNofi Pasteur

geNeral meDiCiNes & emergiNg markets

other r&D areas

Jean-louis GRuNWAlD: [email protected]

VACCINES Roman Chicz - [email protected]

ASIA Matthieu Merlin - [email protected] AMERICA Nicolas Gobeill - [email protected]

INfECTIOUS DISEASES Anne Dagallier - [email protected]

AfRICA, MIDDLE EAST, EURASIA & SOUTH ASIA Eric Sol - [email protected]

DRUG DISCOVERY Peter Hamley - [email protected] Shiv Krishnan - [email protected]

For more informations visit our website : http://en.sanofi.com/partners/partners.aspx


54, rue de La Boétie, 75008 Paris, Francewww.sanofi.com

Documents

Partnering to advance global HealtH - Pacte PME · contents Partnering witH us partnering: ... quarter of 2016 as per the terms of the signed inal agreements and the ... aND aNtiboDy-DireCteD