wp biohal v1.4.5(20181113) fix - biohal open networkc ontents 1 message from the ceo and founder ......

2018WHITE PAPERMedical Ecosystem with the decentralized biometricsauthentication protocol for the securedand encrypted liquid biopsy data

Ver. 1.4.5

C ONTENTS

1

Message from the CEO and Founder ... 02

Executive Summary ... 03

... 14Components of BIOHAL Open Network

Chapter 123456789

1011

PROTEO® Approach for Problem-Solving ... 07

Solution for Transportation ... 13

... 17ICO Schedule

... 16PON Token

.. 18BIOHAL Platform Roadmap

... 19TEAM

... 21Marketing Plan

Super early cancer risk and screening tests ... 06

Appendix : Background of Today’s Medical and Healthcare ... 25

2

Have you ever developed or contracted a disease? Some of you may have had times when you felt uneasy about symptoms or almost lost hope. Don’t you feel encouraged if you know, people from all over the world will help you when you are suffering?

Your medical test and treatment data could help other patients, then their medical data could help more people. You could help anyone in need anywhere in the world regardless of where you are.

You may be a patient yourself. However, at the same time, you can provide data which could be used as a great indicator in treatment and help people suffering from diseases. If treatment saves your life, that means it could also save others’ lives. If treatment saves someone’ s life, that means it could also save your life. Let’ s participate in BIOHAL and save people all over the world together.

Our purpose is to create the world where people can help each other naturally. You survived disease maybe because someone else helped you. You can save your beloved family, someone special and/or friends, or maybe someone you don’ t yet know. An elderly patient might save a young life. There is no border. Age or gender doesn’ t matter.

It is still tough for anyone to fight against disease. We need your support through our project to create such a world.

BIOHAL blockchain can make it possible.

Yuki HasegawaBIOHAL CEO and Founder

01Chapter 1Message from the CEO and Founder

《Building a platform for preventive medicine》We st rongly hope to reduce bal looning medical expenses in the world, eliminate the need for nursing care and make a world free of severe diseases by building the BIOHAL platform with DNA biometric authentication as the core and establishing the ecosystem to change the existing medical system.

The BIOHAL platform can be used as a medical data center. By allowing patients, doc tors, hospitals, pharmaceutical companies and medical device manufacturers to safe ly share the data they have, we can provide an opportunity to receive medical examination to people at the BOP (Base of the Economic Pyramid), who could not afford for preventive me d i c i ne , be s t t r ea t men t t o pa t i en t s , accurate diagnost ic suppor t to doctors, efficient management solutions to hospitals, and business chances to pharmaceutical companies. The use of the BIOHAL platform will bring the benefits to consumers, patients, doctors, hospitals, pharmaceutical companies and medical device manufacturers.

《Building the future》We aim for a world where people at the BOP in developing countr ies can use medical testing for free. We plan to finance the cost to prov ide f ree test ing by encr ypt ing to anonymize the DNA data obtained from tests and sharing it for new drug research and development. Generally, test data belongs to the individual who took the test and only if the individual agrees to share the data for research and

study, then the data is encrypted to anonymize and provided to research institutions. Since individual users can access their own test data stored in the BIOHAL platform from the app, when they are seeing a doctor, by showing the data to the doctor, the users can accurately tell the medical history and test results to the doctor, reducing the risk for false diagnosis. Diagnostic data af ter a disease was found, post-operational data and more information can be stored on the BIOHAL blockchain and n o t o n l y u s e d f o r d i a g n o s i s a n d p o s t operational treatment, but also provided to institutions that need the data.

By using the BIOHAL platform as a medical da t a c en te r, h o sp i t a l s , p ha r mac eu t i c a l companies and research inst i tut ions can effectively obtain useful data for research on new drugs and therapies. Also, the burden of healthcare cost can be reduced and many precious lives can be saved, which could have been lost due to missing signs for diseases.

The profit from providing BIOHAL solutions for hospitals, proposing insurance and treatment plans based on pat ients’ test results, and displaying ads in the app wi l l be used for providing free tests and healthcare for people in BOP. The p ro f i t w i l l a l so be used fo r development of platform features and apps for users. This means that patients` data can be collected through PROTEO®.

PROTEO® was featured in the online scientific magazine “Scientific Reports” published by the Nature Publ ishing Group on May 21, 2015.( ”https://www.nature.com/articles/srep10455” )

It is performed by directly absorbing cancer related substances only. Even low concentrat ion of target substance can be detected since there

is no inf luence by other substances. H igh ly p rec ise detec t ion and d i rec t quantitative detection are performed by omitting complicated pre-processes.PROTEO® is used as a current product which detects cancer and Alzheimer 's disease at the ealier stage. Its inspection t ime is about 10 minutes, and f rom viewpoints of i ts cost and technique, PROTEO® is super ior than the similar t e c h n i c a l p r o d u c t s . A l s o d a t a t o specimens of PROTEO® can be collected a l l o v e r t h e w o r l d b y d r i e d s e r u m technology which is the most productive i n s p e c t i o n m e t h o d t o t h e b i g d a t a construction of biodata.

3

02Chapter 2Executive Summary










Benefits for Patients

4

In the first development step, risk tests for cancer and Alzheimer’s will be available to B I O H A L u s e r s a t s u b s t a n t i a t i v e experiment for free. More types of tests will gradually become available to users as more companies jo in the BIOHAL platform.










For the users who had the tests and agreed to share the result to medical institutions, PON coins will be distributed via the wallet of the BIOHAL app. The users can access the test result using PON coins. If an user does not need to access the test data, the user can sell PON coins.In the BIOHAL app, users can col lect exerc ise data such as running, b lood pressure, other health data to manage daily exercise as well as to be used in risk judgement. The col lected data wi l l be safely recorded to the BIOHAL blockchain to be accessed. The B IOH A L app c an c a l cu la te and display estimated five-year and ten-year survival rates from the collected data.More features including test schedule and drug management will be added to the BIOHAL in the future.

BIOHAL app features▶ Data of fitness trackers▶ Data on medical consultation and examinations▶ Individually recorded data

Patients

Pharmasceutical

Institutes/Companies

Doctors

Hospitals

MedicalResults(data)

PON PON PON

PON

Medical services(ex:2nd opinion,etc)

Data Data

cancer test

Data

＊Take cancer test of PROTEO®＊Get PON when result is shared＊Collect exercise data from BIOHAL app

＊Access patients’ data＊Store surgical diagnostic data＊Reduce inventories of medicines and reaccommodation

＊Make use of clinical data＊Manage delivering and restocking medicine ＊Automatic processing order delivery system＊Access results of patients

Medical Big Data

BIOHAL OPEN NETWORK

®

5

Benefits forPharmaceutical Companies

Benefits toHospitals

B y m a n a g i n g t h e i n v e n t o r y d a t a o f pharmaceuticals and medical supply using the BIOHAL platform, joint purchasing and shared use of pharmaceuticals are possible among par t ic ipating hospitals, which can optimize inventory and eliminate disposal to reduce expenses. For shared use, using the BIOHAL blockchain, reaccommodate excess pharmaceuticals in a hospital to another by ut i l izing the empty space in the delivery vehicles after delivery and automatically manage the network of reaccomodation among hospitals.

Fo r r e a c c u m u l a t e d p h a r m a c e u t i c a l s , payment will be adjusted at the time of joint purchasing.A lso, i f a disease is found in a r isk test , B IOHAL w i l l au tomat ica l l y p rocess the pat ient admission to the hospital. (I f the

Pharmaceutical companies can access the da t a i nc l u d i n g te s t r e su l t s , us a g e o f pharmaceuticals, number of patients, drug administration data for a fee. As for data, we a re p lann ing to charge fo r c anc er surgery and treatment records by doctor. Clinical study data management can also be done using the BIOHAL blockchain. It would use monitoring test of drugs and its result can be made use of development to better new drugs. All pharmaceutical orders from hospitals us ing the BIOHAL p lat form can be put together and mass processed. Additionally, since the BIOHAL platform can manage the inventory of delivered pharmaceuticals, it wil l automatically process orders for the pharmaceuticals that need to be restocked, a n d i f exc e s s i nve n t o r y n e e d s t o b e accommodated to another hospital, it will automatically determine the available space of delivery vehicles and schedule delivery.

Insurance companies can access the result of cancer test for a fee to use i t in r isk assessment such as underwriting. Data access can be purchased using PON co ins. In addi t ion to cancer test data, post-operative data, survival rate, other health data can also be utilized. (Data from users who agreed to share only.)










Benefits forDoctors

Benefits forInsurance Companies

Doctors can access the test data of a patient, even i f i t is a new pat ient , stored on the blockchain, ut i l ize i t to accurately review medical condi t ion of the pat ient wi thout missing any al lergies and other medical history, diagnose the patient and determine courses of treatment.Also, by storing surgical and diagnostic data on the BIOHAL b lockchain, doc tors can provide information to the patients who wants a second opinion. Registered doctors wil l receive PON coins for storing data. When a doctor’s affiliated hospital changes, just by changing the affiliation on the BIOHAL b l o c kc h a i n , p a t i e n t s w i l l b e i n f o r m e d au tomat i c a l l y. I t i s pos s ib l e to de l i ve r information to pharmaceutical companies, etc as well if needed.

pat ient wants a second opinion, i t wi l l instead provide doctor/hospital information to the patient.) If no bed is available for admission, the system will f ind a hospital w i t h a v a i l a b l e b e d s o n t h e BIOHAL blockchain, and if the patient agrees, then it will process the admission.

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6

PROTEO® Background of Test DevelopmentEar ly de tec t i on w i th a more ac cura te method and early treatment are the most effective for “cancer” that is one of the top terminal illnesses in the world.Especially, it is very difficult to predict what kind of course the disease condition of a metastatic cancer will take.

In the current cancer examination, even the latest PET scan has dif f iculty in detecting lesions of several millimeters. Since it only provides visual information, a biopsy must be performed, which puts a heavy burden on patients with prolonged time and cost.Further, existing blood tests (tumor marker tests), which have been widely spread as simple tests, have low organ specificity and have not been ab le to ident i f y cancer primary sites yet.

A l though diagnost ic endoscopy for the digest ive system is sui table for gastr ic epithelial tumors, it is also visual exam and dif f icult to detect a non-epithelial tumor (tumor on the surface) early.

A progression of cancer is t radi t ional ly determined by visually evaluating a size of t u m o r w i t h i m a g i n g s t u d i e s a n d supplementarily measuring serum tumor markers (the concentration of a specif ic protein present in the serum).However, it is unable to find the biological information of the tumor, or whether the tumor cel ls are act ively prol i ferat ing or dormant.

In addi t ion, the examinat ion is general ly per formed at inter vals of several months since it is difficult to grasp changes in the size of the tumor in a short period of time. Tumor markers are commonly known to rise due to inf lammation and such ir respective of the tumor size or the cancer pathology, and it is said to have little correlation with treatments and changes in the pathology of cancer.

If a test method that can quantitatively and quickly detect cancer related or Alzheimer related substances from blood components is deve loped, i t can cont r ibute not on ly to treatmentof cancer and Alzheimer but also great ly to reduc t ion of medica l expense worldwide.

Challenges of Liquid BiopsyL iqu id b iopsy i s idea l as i t i s min ima l ly i n v a s i v e ; h o w e v e r , i t h a s n o t b e e n implemented for practical use despite the fact that it has been known as “cancer markers” in the research pub l icat ions of exosomes, circulating tumor cells (CTCs), and circulating t u m o r D N A ( c t D N A ) . T h e s e m a r k e r substances begin to be inactivated as soon as they are taken out of blood. I t is also unsuitable for quantitative detection since it is terribly dif f icult to directly extract the target substance only because the available amount in the blood is extremely small. Moreover, it has been kept away from practical use since the protocol up to the detection is complex and requires a long period of time.

03Chapter 3Super early cancer risk screening tests

04

7

Model of multistep carcinogenesis

Size

10µm

Normal GeneticabnormalitiesPrecancerous

lesions

MetastasizeManifestations

PET・CT, MRI

5-20 Years 3-5Years

Autoimmune exclusion

Diagnostic imaging

PROTEO® Risk Test Level

CancerStartGrowth

1cm5mm

Chapter 4PROTEO® Approach for Problem-Solving

P R OT EO® i s t h e “ ve r y e a r l y c a n c e r screening test” that has been featured in t h e v a r i o u s m e d i a i n c l u d i n g J a p a n B roadc as t ing C or po ra t i on (NH K ) and received sensational media coverage as groundbreaking, cutting-edge technology capable of detecting cancer from stage 0, and it has been gathering much attention from all over the world.

U p u n t i l n o w , t h e m i n i m u m s i z e o f detectable cancer has been from 5 mm to 1 cm. There are as many as 1 billion cancer cells in a 1cm tumor, and it can still be “too la te” even i f i t i s found a t t h i s s t age. T h e r e f o r e , s t u d i e s h a v e b e e n d o n e throughout the world in search of a method that can detect cancer much earlier.

PROTEO® is the technology which can theoretically detect the very early cancer of approx . 1 mm, and i t has obta ined an i n te r n a t i o n a l p a te n t f o r m e a su r i n g a “nuc leosome.” “ PROTEO® ” has been successful in detecting “molecular- level cancer” for the first time in the world.Th i s i s t he on ly tes t method tha t c an

quant i f y the amount of cancer- re lated substances.Th is i s t he on ly tes t method tha t c an conduct cancer examinat ion for a wide range of age f rom the infant (chi ldhood cancer) to the elderly.S a m p l e s c a n b e s e n t t o t h e m e d i c a l laboratory via international mail; therefore, the area the international mail covers is the target area for this test. This means that its potential demand can be the whole world’ s population of 7.6 billion people.

This screening test can detect the following solid malignant tumors: pancreatic, lung, breast , gast r ic , umbi l ica l , l i ver, co lon, thyro id, k idney, p rostate, u ter ine, and ovarian cancers. A very small amount of cancer- re la ted substances, wh ich get d isso lved in the b lood when a cancer occurs, are measured and quantified using a n e w b i o c h i p , P R O T E O® . I t t h e n determines and classif ies the cancer risk into three stages, A (low risk), B (followup required), and C (high risk).

8

The blood required for this test is as little as 10μL, and it is not affected by meals and such. Thus, this test method is safe with very little physical strain.

Fur thermore, the PROTEO® very early cancer screening test shows the dif ferences in measured values so clearly that the results are easily interpreted, which gives a characteristic of very little possibility of misinterpretation.

It can be useful not only as a tool for early detection of cancer but also as a useful test for risks of progression, recurrence/metastasis, treatment effect, etc.

Diagnosis of Stage 0 CancerA human body is said to have “60 trillion” cells, and “300 billion (0.5%)” of them die daily. “Apoptosis” is a process of “programmed death” of cells that occurs when cells are damaged, not required anymore, or become abnormal.

Cancer cells indefinitely proliferate doubling in number. The size of the tumor that can be found in imaging studies is about 1 cm, but this is why detectable tumors grow quickly. An early stage of cell abnormalities is known to be protected by the mechanism of apoptosis.

Cancer cells are believed to be fragmented to chromatin and nucleosomes, and then to be released in the blood. Since cancer- related substances in the blood contain var ious information, analysis of those information becomes useful against tumor progression, diagnosing cancer recurrence, determining treatment effects, etc. Thus, its usefulness is attracting attention as a noninvasive test.

10µm Double

5-10 Years 3-5 Years

1cm 2cm

Cancer cells Chromatin Nucleosomes Released Cancer-Related substances

9

Benefits of PROTEO®1.Very early detection of cancer from stage 0 (treatment is effective).2.Minimally invasive (very little physical distress).3.No medical radiation exposure (safe for those who are pregnant or with possibility of pregnancy).4.No fasting or diet restriction required before the test. (can be tested any time)5.Blood sample taken at home with self-testing kit (can eliminate disparities in quality of health care).

《Stable Markers》PROTEO® uses nucleosomes (a section of DNA that is wrapped around a core of p rote ins) as a marker. Nucleosomes are released in the blood by apoptosis (autoimmune); however, the state of nucleosomes, in which proteins and DNA are bound together, is very stable. Therefore, transportation of nucleosomes can be done easily from anywhere in the world.

《Highly Sensitive Detection》Biochips used in PROTEO® measure cancer-related substances by directly absorbing cancer-related substances only. It is possible to detect the target substances at low concentration because there is very little influence of other substances.

《Label-Free》Green fluorescent protein (GFP) is a protein with fluorescence of jellyfish Aequorea victoria and was discovered along with aequorin by Osamu Shimomura in the 1960s. Dr. Shimomura was awarded the Nobel Prize in Chemistry in 2008 for this discovery. Although the discovery of green f luorescent prote in (GFP) has great ly cont r ibuted to the development of biotechnology, PROTEO® is the world’ s first technology of label-free detection which does not require GFP (green fluorescent protein) or any other pigment.

It was featured in “Nanotechnology, Biology, and Medicine” in April, 2014.It was featured in the online scientific magazine “Scientific Reports” published by the Nature Publishing Group on May 21, 2015.

PROTEO® is performed by directly absorbing cancer-related substances only. Even low concentration of target substance can be detected since there is no inf luence by other substances. Highly precise detection and direct quantitative detection are performed by omitting complicated pre-processes.

Chromatin Apoptosis

PROTEO® INSPECTION IMAGE

Serum

Nucleosomes

Methylated histone

Silver peroxide PROTEO®MYTECH

charges

charges

10

Place one drop of blood component (serum) from the centrifuged blood on the metal chip.

SERSClinicalserumsample

Autofluorescence of absorbed nucleosomes are observed by applying light.

3

1 2

Cancer-related substances, nucleosomes, react with and get absorbed by silver peroxide meso crystals.

CCD camera

power-requlatedlamp

band pass filter

grid

PZTtranslation

stage

PZTdriver

PZT vertical stage

water-immersionobjective lens

Autofluorescence of Substacesbonded on the Surface of the Biochip

Magnified imageof a nucleosome

BenignDiseases

EsophagealAchalasia

Gastrointestinal stromaltumor in the stomach

Benign tumor ofduodenal papilla

Cancer

Gastric Cancer Colon Cancer Pancreatic Cancer

Fluorescence image of the cancer-related substances.Because crystals of cancer-related substances released in the blood are derived from cells related to apoptosis, the contained amount in a healthy body or a benign tumor is small while a large amount is contained in the blood of the diseased. Therefore, there is a characteristic that fluorescence appears much more in malignant tumors.

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《A Simple Procedure》PROTEO® requires no complex procedures, and all protocols can be completed within 10 minutes.

Since the PROTEO® biochip is a new highly sensitive assay method, cancer-related substances (nucleosomes) can be quantified and detected quantitatively.

Unlike tradit ional DNA, microarray and microf luidic chips, cancer-related substances (nucleosomes) in the blood were directly detected label-free successfully w i t hou t us ing p robes suc h as D N A , an t i b o d ies , fluorescent substances, etc.

The detec t ion of cancer- re lated substances at an extremely early stage, which exceeds the existing test methods, is expected to bring breakthrough results in the field of cancer diagnosis such as physical examination, treatment effect, and diagnosis of cancer recurrence.

1

2

3

4

5

6

Peripheral blood sampleBlood samole is drawn intotubes containing clot activatorand polyolefin gel

Silver thiosulfate complexesSilver thiosulfate complexesis dropper on the chip andheld 4 minutes.

Clinical serum sampleEach 20 ul of 1:10 dilutedserum sample is droppedon chip.

Sodium hypochloriteSilver nanoscale hexagonalcolumns on chip is ionizedwithin 2 minutes.

Blood serumStored at -20℃

1600 g. 7 min.

Silver thiosulfatecomplexes are directlyconverted to nanoscalehexagonal columns.

Example: Healthy person Example: Cancer patient

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We succeeded in the world’ s first synthesis of “quantum crystals” and “silver peroxide meso crystals” (three-dimensional self-assembled crystals), which has the effect of specifically absorbing proteins on the surface of biochip. This is a novel substance with a new concept.

Novel substances that absorb nucleosomes

PROTEO® biochip

Size: Thickness 1.2 mm,Dimensions 26 mm x 76 mm

Silver Peroxide Meso CrystalsQuantum Crystals (three-dimensional self-assembled crystals)Results of PROTEO®’ s Clinical Trials

05There are international regulations on every means of transportation of infectious substances (air, rail, road and marine transport as well as mail), and they are released as a form of model regulations based on the recommendation of the United Nations Committee of Experts on the Transport of Dangerous Goods (UNCETDG) which is the committee of the United Nations Economic and Social Council. The UN model rules are reflected in the international laws through the international model agreements.

For these reasons, global medical testing services have not been actualized so far.

We have established the dried serum technology by separating serum from the blood as a way to solve these problems. This enables safe transport of dried serum.

By enabling transport of dried serum, it is possible to perform a stable test whose accuracy is not adversely affected by the condition of transportation.

Permission by Individual CountriesThere is nothing in the category of medical equipment in Japan that is equivalent to a biochip used for PROTEO®, and it has been implemented as a doctor-led clinical trial (Effectiveness Tr ia l). As the cur rent appl icat ion status of overseas biochip medical devices, the classif ication of DNA biochips is approved for category 1 and 2. We aim for obtaining approvals corresponding to qualifications for medical device application in each country.

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Chapter 5Solution for Transportation

Articles of PROTEO®

May 2015 “Scientific Reports” published by the Nature Publishing Group ( ”https://www.nature.com/articles/srep10455” )April 2014 “Nanotechnology, Biology, and Medicine”, Volume 10, Issue 3 ( ”https://www.sciencedirect.com/science/article/pii/S1549963413005406” )July 2013 “Royal Society of Chemistry” ( ”https://pubs.rsc.org/en/content/articlelanding/2013/cp/c3cp52564c#!divAbstract” )

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06Chapter 6BIOHAL Open Network : BON Technical Architecture

Structure of BONBON consists of the following two layers:

　- BON data management layer, and 　- BON access management layer.

BON data management layer

BON data management layer is a distributed database that manages securely encrypted EHRs. Since only the data owner can decrypt the data in the BON data management layer, no one can access the content wi thout permission f rom the data owner. Access to the BON data management layer is controlled via the BON access management layer.

BIOHAL Open Network (BON) is a foundation to support the BIOHAL ecosystem. BON can

provide unif ied management and secure effective use of users’ healthcare information, i.e.

Electronic Health Record (EHR).

BON access management layer

Using the blockchain technology, the BON access management layer controls the access to BON in the BIOHAL ecosystem. All access logs for the EHRs in the BON data management layer, including data registration, viewing request and access permission, will be clearly and securely recorded on the blockchain.

BON features1. Data security 2. Reliability3. Transparency4. Self-data control by data owner5. Unified data management 1 6. Unified data management 2

Medical ins�tu�onrecords

QIP(Quality Indicator/

Improvement Project)

records

Health records

Traffic records

PROTEO® records

BIOHAL blockchainDNA ID

Authentication

Insurance records

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EHR accessRoles in the BIOHAL system can be divided into General User, Service Provider (medical profess ionals and inst i tu t ions, medica l information advisors, healthcare suppor t centers , e tc .) , and Data User (medica l researchers, pharmaceutical companies, insurance companies, etc.) based on the intended use. Each role has a different data access level in BON.

《General Users》General Users are authorized to view and register their own medical data. They can’t generally view or register other people’ s medical data. However, in case ofemergency, with prior permission from data owners, they can be author ized to v iew partial data of other people.

EHR ManagementSince there is a wide range of variations in EHR type and storage capacity, which still continues widening, it is inappropriate to store all the data on the blockchain.Therefore, in BON, the data encrypted using data owner (user)’ s key is saved in the BON data management layer. When that happens, the access pointer of the corresponding EHR on the BON data management layer and the hash value of registered data will be stored o n t he b l o c kc ha in i n t he BO N ac c e s s management layer.

EHRs in the BON data management layer is accessed v ia BON access management layer. The access pointer will verify the data location and hash value will verify the data identity.

《Service Providers》Ser v i c e p rov i de r s w i l l have t he s ame author i t y for the i r own medical data as General Users.In order to view other people’ s data, they need to obtain permission from the data owner. V iew ing requests f rom Ser v ice Providers and permission from data owners are managed and recorded in the BON access management layer. S e r v i c e P r ov i d e r s c a n r e g i s t e r o t h e r people’ s data only if they obtain permission from the data owner. Registered data will be digitally signed by Service Provider to clearly show who registered the data.

《Data Users》Data users will have the same authority for their own medical data as General Users.In order to view other people’ s data, they need to obtain permission from the data owner. Viewing requests from Data Users and pe r m iss i on f r om da t a owner s a re managed and recorded in the BON access management layer. Data Users can purchase and view anonymize data with prior permission for use and sales from data owners.

BIOHAL Traffic Records O p e r a t i o n s c h e d u l e s a n d r e c o r d s o f associated businesses that come in and out of the hospitals.T h e s e c a n b e u s e d f o r opt im izat ion o f de l i ve r y even bet ween businesses and contributing to reduction of f reight expense.

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PON Token is a utility token for users, clinic, medical doctors and researchers etc.The usage of the token are the below.

1. To take Super Early Screening2. To buy and sell medical data for a research3. To access personal medical data by Biometrics Authentication4. To access DNA big data based on the approval of the owner5. To join our ecosystem as a player

07Chapter 7PON Token

08 Token Release ScheduleAll the tokens purchased during the pre-ICO, pre-sale and crowdsale will be temporarily locked. Below is the token release schedule:・January, 2019 (20%), main reason: ICO done・February, 2019 (20%), main reason: α-version release・March, 2019 (20%)・May (20%), main reason: β-version release・June (20%), main reason: project launch

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Chapter 8ICO Schedule

ICOFunds planned to be raised via the ICO token sale: $550,000,000.Soft Cap: $5,000,000.Tokens will be sold via a smart contract on Ethereum acc ord ing to the USD/ETH exchange rate that is in forcefor the token purchase date.ICO is terminated i f : al l the tokens are purchased or two calendar months have passed.

Pre-ICODuring Pre- ICO, tokens are sold with a discount.1 PON = $0.06. Hard cap: $6,000,000. Tokens are sold via a smar t contract on Ethereum acc ord ing to the USD/ETH exchange rate for the Pre-ICO launch date.

10%

PRE-ICO

Start

2018/8/15 12:00 UTC

2018/9/18 12:00 UTC

2018/10/15 2:00 UTC

2018/11/15 2:00 UTC

End Rate Bonus

30%

20%

15%

0.06USD

0.10USD

0.10USD

0.10USD

2018/9/18 00:00 UTC

2018/10/15 00:00 UTC

2018/11/15 00:00 UTC

2018/12/15 00:00 UTC

PRE-SALE

1st CROWDSALE

2st CROWDSALE

09

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Chapter 9BIOHAL Platform Roadmap

2018 2020 2021 2022 20232019

BIOHAL Platform

BIOHAL Dapp

Cancer Screening

Medical Device

Medical Device

Big Data Business

Cancer Insurance

AlzheimerRheumatism

Alzheimer InsuranceRheumatism Insurance

Development

Development

Operation

Operation

Operation

Apply

Apply

Preparation

Operation

Operation

Operation

OperationClinical Trial

Token Sale Budget

Fundraising Targets

Pre ICOPre SaleCrowd Sale (1st)Crowd Sale（2nd)

1PON =＄0.061PON = ＄0.11PON = ＄0.11PON = ＄0.1

＄6M＄100M＄230M＄200M

PRICE USD

Pre-ICO(Secret) 0.5%

Team 20%

Bounty 3%

Referral program 5%

Advisor 2%

ICO 26.5%

Secondary TokenOffering Pool 15%

Bonuses(max) 4.7%

System Fund 20%

Community Development Fund 3.3%

20BPON

26.5%

3.3%

20%15%

4.7%

20%

2%

3%5%

0.5%

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Chapter 10TEAM

Yuki Hasegawa BIOHAL CEO and Founder　Let ’s par t ic ipate in BIOHAL and save people al l over the wor ld together. Our purpose is to create the world where people can help each other naturally. You survived disease maybe because someone else helped you. It is stil l tough for anyone to f ight against disease. We need your support through our project to create such a world.BIOHAL blockchain can make it possible.

Dr. Yoshitaka Fukuzawa Medical Adivisor M.D. / Ph.D. / Bio Technical Officer　JSPCM：Japan Society of Preemptive and Clinical Medicine /Chairman 　JSCSF:Japan Society of Clinical Study for Frontier-Medicine /Vice Chairman

Now all people want that their personal future health conditions could be detectable by a risk screening from the stage the potential diseases that not appear yet.BIOHAL will realize the desire.

Dr. Akinobu Gotoh Medical Adivisor M.D. / Ph.D / Bio Technical Officer

　Chairman : Foundation for Kobe International Medical Alliance 　Professor and Director: Laboratory of Cell and Gene Therapy　Institute for Advanced Medical Sciences　JSPCM：Japan Society of Preemptive and Clinical Medicine/ Vice Chairman

Patients, doctors, hospitals, pharmaceutical companies, etc. need to cooperate more than ever. Therefore, the data between them can be connected through BIOHAL blockchain as the best architecture.

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Dr. Kensho Yorozu CTO / Medical Adivisor M.D. / Bio Technical Officer　Yorozu Clinic / President　JSCSF:Japan Society of Clinical Study for Frontier-Medicine /Director　The Association for Clinical Research of Fecal Microbiota Transplantation Japan　Managing Director

How can we better support our patients?For that purpose,ear ly detec t ion of d isease and appropr iate treatment suitable for that person are more important than anything.BIOHAL not only makes it possible, everyone in the world can take inspections.

Raj S. Davé Dr. Sc. Legal Advisor　President & Founder Davé Law Group, LLC / Patent Attorney of in the United States　Gujarat Council on Science and Technology (GUJCOST) Chair Professor for IPR　Excellence at Gujarat National Law University (GNLU).

Although science and technology has advanced dramatically, human being have to be a l ive wi th d iseases. An innovat ive architecture, BIOHAL could save people from the sufferings and anxiety of the diseases. Everyone would want it. I am also one of them. I wish for the happiness of all people, I will join in this project.

Mr. Youichi Chikamoto Healthcare Medical Advisor / Bio Technical Officer President: Fukuyama Medical Laboratory

Because everyone in the world can take an inspection by BIOHAL ecosystem which can detect a disease at early stage.The ear l ier you concentrate on treatment, the less burden of disease you have. And your family can contribute your energy to society.This new approach will be a savior for people all over the world.

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Anyone planning to create a DApp knows what opportunities the blockchain technology has to offer. We want to help our users concentrate their efforts on the main advantages of their DApps and not bother with their own medical data infrastructure development, which can be easily replaced with the BIOHAL.We offer secure decentralized medical authentication infrastructure for your DApps.Our transaction fees will lower, cutting your expenses and increasing your DApps market competitiveness.Our main marketing objective is not only to let developers know about BIOHAL infrastructure capabilities, but also to persuade regular users that using BIOHAL for DApps is the new way of medical data sharing that guarantees their data security and confidentiality.

To make our marketing plan clear to everyone, we decided to organize it into separate blocks. They show how we are going to promote BIOHAL, cover our progress, f ind new team members and manage our community. This is how we try to make our marketing spending of the funds raised during the PRE-ICO and ICO more transparent.We pay close attention to community management. We will do everything we can to make our replies prompt, detailed and clear, and we will take your replies into account and make the necessary changes.

Chapter 11Marketing Plan

What makes BIOHAL attractiveWe would like to create a medical big data s o l u t i o n f o r DA p p s o p e r a t i n g o n a ny blockchain plat form with smar t contract c a p a b i l i t i e s a s we l l a s f a c i l i t a t e t h e development of projects in the blockchain industry.

BIOHAL promotionThe t a rge t aud ienc e o f B IOH A L uses var ious med ic a l se r v i c es not on ly fo r themself but also their family.We want to make the most ou t o f th i s chance to tell the widest range of people about our project.

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Targeted advertising on social networksAs you already know, Facebook has over 2 billion users, Instagram has 1000 millions and Telegram has 200 million. We believe a l l these soc ia l net works ser ve as the perfect marketing platforms with a variety of e f f e c t i v e a d v e r t i s i n g t o o l s s u c h a s advertising posts and videos. We have to thinks that these social networks are the pr imary way to te l l the wor ld about the concept and ideas BIOHAL is based on.

Messengers ads Messengers are get t ing more and more popular nowadays, with a lot of or iginal channels prov id ing interest ing content which attracts many observant and active subscribers. One of the most popular messengers in the world is the Chinese app WeChat with over 1040 million active users.It has become more than a messenger – a whole ecosystem with payment and booking services etc. L INE – i s t he most popu la r Japanese messenger with 217 million active users. Telegram – is a popular messenger actively used by 200 million people worldwide. These are modern and relevant marketing tools used to provide your information to the audience that prefers to consume and engross itself in original content.

Contextual advertisingSome of our marketing team members have p r e v i o u s l y w o r k e d a t g l o b a l d i g i t a l m a r k e t i n g a g e n c y i n c o n t e x t u a l advertisement. We understand that contextual advertisement is an ideal and effective way to reach target audience on the Internet. It might be clear that people usually hesitate to invest in recent blockchain projects, so it is important to hit the potential users with as many impressions as possible for them to notice our service among all the data noise on the Internet. The world leading search engines Google, Yahoo and Baidu are the best for contextual advertising.

ICO listsTheare are various platforms that provide potential users with information about dates, t oken p r i c e s , s t age s and b o nuse s o f upcoming ICOs worldwide. There are many global and local lists helping users to think through al l the pros and cons, d iscuss p r o j e c t s w i t h o t h e r u s e r s a n d m a ke decisions.

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IT, Blockchain and cryptocurrency mediaAs you know, we c annot i gno re some detailed and thorough reviews of our project made by major online outlets covering the world of IT, blockchain and cryptocurrencies on a daily basis. The qualif ied opinions of journalists will help both to draw attention of BIOHAL target audience and to get some feedback from people reviewing projects professionally.

Meetups, conferences and exhibitionsAf ter the ICO, we wil l make a l ist of the most impor tant global conferences and exhibi t ions dedicated to the blockchain techno logy, B io techno logy and L iqu id Biopsy. Our team will par ticipate in them a n d w i l l b e r e a d y t o a n s w e r a l l t h e questions.Besides, it is a great opportunity to convey our main ideas to the potential partners and DApp developers. We will both find partners as well as assure and encourage other teams, showing how we c an s o l ve s o m e o f t he i r p r o j e c t s ’ development issues with the BIOHAL open network.

Communitymanagement

BIOHAL social media accountsTo make i t more convenient, we plan to c r e a te o f f i c i a l B I O H A L s o c i a l m e d i a accounts to post all the relevant information on project development as well as answer your questions. We w i l l c rea te: - A Fac ebook page in English, as it is the most popular social network worldwide; - A Twitter account in English, as i t is very convenient to post updates on BIOHAL project development.

Official BIOHAL chats in Telegram

Project blog on MediumThe of f ic ial BIOHAL page on Medium in English. All the in-depth information that needs to be relayed wil l be published here. You can expect al l the relevant news on project development and upcoming events, where you could meet the team in person, discuss new problems and ways to solve them, new team members or partnerships. Find out more here. You will find the link on our landing page.

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Cryptocurrencyexchanges

We know how impor tant i t i s fo r token ho lders to be ab le to t rade tokens on exchanges as well as prof it from its use inside the system. Therefore, we will deal with the matter of placing our token on large cryptocurrency exchanges after the ICO ends. Our official resources will post updates on t h e p a r t n e r s h i p s c o n c l u d e d w i t h t h e exchanges.

Blockchain projects development

We understand how many di f f icul t ies a star t-up faces on its way to success. And we want to be useful to projects that need to manage large amounts of bio data. They can get access to a working network for medical data at a reasonable price. It will solve many technical problems and a l low them to focus on resarching and fighting towards diseases.Our team is sure that through our combined efforts we can facilitate blockchain adoption in a var ie t y o f med ic a l f i e lds tha t a re undoubtedly set to profit the most from it, where it is really needed.

Besides, our suppor t ser v ice is always ready to help your team in developing a smart contract for integration with BIOHAL. We will f ind the optimal solution for your medical realated DApp.

Appendix :

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BackgroundAging is considered unavoidable for human beings. However, progression of aging varies among individuals due to differences in lifestyle, genes and other various factors. Human DNA is designed for body to function properly for a long period of time by nature.A living cell dies in few days. However, it creates a copy before dying to maintain the same state.Of the 60 tr i l l ion cel ls that make up the human body, about 300 bi l l ion cel ls die everyday. Therefore, all cells in the body are replaced in about 3 months by simple calculation.

If this mechanism works properly, we would not age and should be able to sustain life forever with new cells. However, as cells repeat dividing to make their copies, small errors accumulate in DNA. When the accumulated error becomes too large, the body becomes unable to repa i r damages resu l t ing in becoming cancer cells or causing aging.

In addit ion, as people age, the immune system weakens and resistance to infection decreases in the elderly.

In Japan where the elderly population is high, it is known that many elderly people constantly die of inf luenza, and terminal cancer/stroke patients die of pneumonia.

Background and Today’s Medical and Healthcare　

If we assume a patient receives treatment for a life-threatening disease to increase the maximum lifespan, the patient will die of another cause later in life. As a result, death is postponed, and life is prolonged.

Japan has the longest life expectancy in the world. In Japan, three leading causes of death a re 1. ma l ignant neop lasms, 2 . cardiac diseases, and 3. cerebral vascular diseases in both sexes. By excluding these three leading causes of death, the average life expectancy increases by 9.05 years for male and 8.34 years for female.

Human longevity has consistently increased after 19th century.

In the 20th century, the mortality caused by infection, parasites, nutritional deficiency and complication of pregnancy and delivery decreased significantly in infants and young adu l t s t h rough vac c ine deve lopment , i m p r ove m e n t i n m e d i c a l sy s t e m a n d enhanced safety for childbirth. Also, in the la te 20 th c entu r y, s inc e the mor ta l i t y c aused by c ard iac d iseases, cerebra l vascular diseases, some types of cancers, and chronic hepatic/nephritis/respiratory conditions decreased in middle-aged and senior adults, the average life expectancy has solidly increased.

Personalized MedicineDue to the recent advances in Genome Science, treatment of disease has entered a new phase of personalized medicine.

Fo r ex a m p l e , i n c a n c e r t r e a t m e n t , a stereotypical approach has been commonly used, where adapta t ion and t reatment methods are determined based on the site and stage of cancer. Focusing on the cancer itself rather than constitutional characteristics o f p a t i e n t s , t r e a t m e n t m e t h o d s a r e determined based on the size and state of t h e c a n c e r. I n r e a l i t y, c o n s t i t u t i o n a l characteristics of each patient dif fer from each other. Therefore, it’ s been found that it is extremely effective in cancer treatment to choose treatment methods which fit for that p a r t i c u l a r p a t i e n t a n d p r o v i d e i t a s personalized treatment. This new way of thinking is becoming to be seen as important in cancer treatment.

The merit of personalized medicine is to maximize treatment ef fect and minimize side-effect for each patient.

In conventional medicine, when a disease is d i a g n o s e d b a s e d o n g e n e r a l m e d i c a l information such as information obtained in a medical interview, physical examination, biochemical examination, etc., standard drug for the disease is prescribed.

In this way, since the patient’ s constitutional characteristics are not taken into account, the drug could be ef fect ive but could be ineffective, and sometimes adverse effects could appear. A lso, because the disease state var ies widely among pat ients, i t ’ s been known since old times that even if it’s for the same disease, using the standard drug for al l patients is not entirely correct.

According to Spear, et al. [Spear,B.B., Heath-Chiozzi , M . and Huff, J. (2001)], the highest drug efficacy rate by disease is 80% for COX-2 inhibitor drug and the lowest is 25% for cancer chemotherapeutic agent. Most drugs for other types of diseases have an efficacy rate of 50-75%. I t i s ha rd to te l l t he d i f fe renc e among individuals in drug ef f icacy without actual t reatment and monitor ing and has been thought in order to provide best treatment, heuristic approach is necessary.Personalized medicine aims to individually determines the best treatment method for each patient by understanding patient ’ s genetic background, physiological conditions and disease status using bio markers in addition to general medical information.

Personal ized medic ine wi l l s igni f icant ly change the medical treatment. It will allow us not only to prevent disease onset, but also

receive best treatment af ter onset without hospitalization. No hosp i ta l izat ion means pat ients can receive treatment while living everyday life with family or working normally, which could lead to maintain the QOL (Quality of Life). However, on the other hand, patients need to handle the burden of managing self-information including genetic data and physiological conditions. In other words, patients need to understand one’ s body well, and prepare a mechanism to safely manage self-data. In order to live a long life, the patient needs to self-monitor various physical states (or be monitored by family members) to prevent, detect early and deal with initial symptoms of illnesses and diseases.

Data AggregationThere are mul t ip le technical and soc ia l challenges for sharing and using physical state monitoring results and past medical records of individuals.

Examples of technical challenges include standardization (i.e. which data format to use for standardization,) linking method (i.e. how to link disaggregated data to individuals,) management method (i.e. how to store and manage distr ibuted information,) shar ing method (i.e. how to share the data in what format,）and security (i.e. how to prevent information leakage.) Examples of social challenges include economic efficiency (i.e. what return is expected on investment for using medical information,) privacy (i.e. how to ba lanc e t he p ro tec t i on o f pe r sona l i n f o r m a t i o n a n d b e n e f i t o f u s i n g t h e information,) incentive (i.e. what motivation is necessary to promote data sharing,) legal systems（ i .e. what guidel ines and legal

systems are needed in order to accomplish this,） and difference among nations (i.e. how to set the sharing rules among countries with different systems and opinions.)

Medical treatment consists of data processing and patient treatment. Doctors collect various data from patients in off ice visits and examinations, analyze the data and assume what ’ s going on in the patient. When doctors become conf ident ab ou t t he as sumpt i o n , t he d i sease i s diagnosed. Once a patient is diagnosed with a disease, doctor deals with the patient conditions and attempt to bring the patient to the original healthy state as much as possible. The numbers of ways to collect patient data a n d a m o u n t o f c o l l e c t a b l e d a t a ke e p increasing significantly due to advancement of medical technology. However, the informat ion obtained f rom patients is often times too fragmentary for doctors to accurately diagnose patients. In estimation, there are 60 trillion cells in a human body. Speaking of extremes, each of all these cells release different information in di f ferent locat ion. I t can easi ly infer l i fe informat ion that can be obtained f rom a single patient is enormous. If there is an observation method to analyze information of each cell, we will be able to find out what’s changing where in patients in real time. Obviously, such testing equipment and method don’ t exist at this time. However, t he amount o f in fo r mat ion tha t c an be obtained from human beings will explosively increase in the future. When it becomes possible to identify changes between normal a n d a b n o r m a l c o n d i t i o n s f r o m s u c h enormous data, we can expect dramatical

advances in medicine by analyzing such data. Even now, the data collected from patients has wide-var iety and could be enormous over long period of time. By collecting and analyzing data from many patients who have b e e n d i a g n o s e d a s h av i n g t h e s a m e disease, we may be able to f ind previously unknown body conditions (generally called clinical conditions.) However, although wide-variety of data can be obta ined f rom a s ing le pat ient , i t i s d i f f i cu l t to ana ly ze da ta f rom mu l t ip le patients diagnosed for the same disease. This is because for a particular disease, the number of patients that can be treated at a medical institution is few thousand at the most, and few if it is a rare disease.

By analyz ing pat ient data for the same disease all over the world at a large scale, it may become possible to discover unknown knowledge, or by matching the data with the conditions of current patient, it may become possible to accurately diagnose the patient with rare conditions.

Patients’ condit ion dif fers slightly among patients. Even many patients are diagnosed as hav i n g a pa r t i c u l a r d i s e as e o u t o f thousands of diseases, transition in disease condit ion is dif ferent for each patient. Of course, there are many diseases and injuries such as common cold and cuts which can eas i l y be t r ea te d w i t hou t t ak i ng suc h individual differences into account.

However, if a patient has unique background condit ions; for example, when an elder ly patient with impaired renal function gets influenza, unlike a healthy individual, there is

a chance that the patient can develop severe p n e u m o n i a o r r e n a l f u n c t i o n f u r t h e r deter iorates and becomes into another

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It is thought the following 6 items contributed to rise longevity in the 20th century: (a）Medical development and breakthrough in medical technology(b） Imp r ove m ent i n m e d i c a l se r v i c e s (including increase in the number of medical facilities such as hospitals and clinics, and medical staf f such as doctors and nurses, and expansion and penetration of medical insurance system）(c）Improvement in diet and nutrition(d）Slackening of somatasthenia due to improvement in l i fe s tandard and work conditions(e）Decrease in infectious disease morbidity (f）Improvement in academic standards

Even now, the average life expectancy is increasing 3 months per year wor ldwide. More than 500 thousand centenarians are l i v ing in t he wor ld , and the number o f centenarians is increasing 7% annually.

According to World Health Statistics 2015, Japan had the longest life expectancy in the world and the average life expectancy was 84 years. In comparison, the average life expec tancy for the ent i re wor ld was 71 years. There are still obvious differences in the average life expectancy among countries and area.

The di f ference in the l i fe expectancy is becoming smaller but still obvious between Japan and other advanced countries where the aforementioned 6 requirements for rising longevi ty are met. For example, the l i fe expectancy is 80 years in Germany and 72 years in China.

~How to live a long life~Although wide variety of data that can be used as reference for l iving a long l i fe is available, it’ s not easy to actually apply it to individual’ s life. No one has yet attempted to collect life and medical information as big data to be compared and referred to and be analyzed for practical use.

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systems are needed in order to accomplish this,） and difference among nations (i.e. how to set the sharing rules among countries with diff

wp biohal v1.4.5(20181113) fix - biohal open networkc ontents 1 message from the ceo and founder ......

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