Redefining the Concept of Standardisation for Pluripotent Stem Cells€¦ · Redefining the Concept of Standardisation for Pluripotent Stem Cells July 31st–August 4th, 2011 PICMET

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Redefining the Concept of Standardisation for

Pluripotent Stem CellsJuly 31st – August 4th, 2011

PICMET '11 Conference

Dr. Shintaro SengokuThe Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University

Dr. Koichi SumikuraNational Graduate Institute for Policy Studies (GRIPS)

Dr. Toshihiko Oki, M.D.The Institute of Medical Science, the University of Tokyo (IMSUT)

© Copyright 2009-11 Innovation Management Group, iCeMS, Kyoto University. All Rights Reserved.

Abstract

In this report we review the concept of standardization and propose an exhaustive framework for the proper management of technology on pluripotent stem cells. There are two fundamental issues: first, these initiatives and attempts tend to be limited to currently existing categories of pluripotent stem cells, although the technological opportunity to enable clinical/commercial application is equally open to all stem cell types. Second, the subject to be examined for standardization is set to a quite narrow range compared to precedent practices in other industrial sectors. To address these issues, we propose a strategic framework for standardization with an emphasis on comprehensiveness covering various technological opportunities and consistency to learning in the management science. By utilizing this framework it is suggested that development of intellectual property rights not only through patents but through taking leadership in standardization be considered as means for improving research and development competence. Of particular concerns is the formation of quality standards for final products/services and core elemental technology, in particular, specific pluripotent stem cell lines. Furthermore, we inferred two stages of the standardization process, individualization where a particular product/service is firstly accepted by the market, then standardization where the elemental technology is subsequently established as standards.

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2011 Proceedings of PICMET '11: Technology Management In The Energy-Smart World (PICMET)


Type of stem cells and potency for differentiation

TotipotencyMulti/uni-potency

Pluripotency No potency

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Summary

• Objective: review the concept of standardization and propose an exhaustive framework for the proper management of technology on pluripotent stem cells

• Two fundamental issues

• Initiatives and attempts tend to be limited to currently existing categories of pluripotent stem cells, although the technological opportunity to enable clinical/commercial application is equally open to all stem cell types

• The subject to be examined for standardization is set to a quite narrow range compared to precedent practices in other industrial sectors

• Proposals

• A strategic framework for standardization with an emphasis on comprehensiveness covering various technological opportunities and consistency to learning in the management science. By utilizing this framework it is suggested that development of intellectual property rights not only through patents but through taking leadership in standardization be considered as means for improving research and development competence

• Of particular concerns is the formation of quality standards for final products/services and core elemental technology, in particular, specific pluripotent stem cell lines

• A two step model of the standardization process: individualization where a particular product/service is firstly accepted by the market, then standardization where the elemental technology is subsequently established as standards. 3

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Research background, aim & purposes and approaches

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Background• Stem cell research has shown a remarkable progress at a basic level• Strategy for technology development has yet to be sufficiently proposed

Research aim and purposes• Identify current issues regarding formation and application of intellectual property

• Elaborate initial thoughts and plans for:–Strategy for technology standardization–Practitioner’s business modeling

Approaches• Technology mapping & patent analysis–Understand comprehensively the state of patent landscape– Investigate selected key patents at a claim level

• Case studies– Identify IP elements which form competitive advantages–Analyze linkages between the IPs and their business model


Hot war for first mover advantage

Source: Proteus Venture Partners; Terrapin’s Stem Cell & Regenerative Medicine Congress on May 13-15 in London, UK

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Current efforts for stem cell standardisation (1/4): International frameworks

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• International Stem Cell Forum (ISCF)

–International Stem Cell Initiative (ISCI)

• Reviews the characteristics or criteria for human embryonic stem cell (hESC) lines

• Considers the infrastructure development for stem cell research

–International Stem Cell Banking Initiative (ICSBI)

• Functions as an hESC lines bank

• Sets the minimum quality standard for hESC lines.

• International Organization for Standardization (ISO)

–ISO-TC150 (surgeon implant) SC7 (regenerative medicines)

–Considering industrial standards for regenerative medicine products and services

Building knowledge infrastructure

Source: Sengoku, S., et al., Stem Cell Reviews and Reports (2011)


Current efforts for stem cell standardisation (2/4): UK

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• UK Stem Cell Bank (UKSCB)

–A subsidiary of National Institute for Biological Standards and Control (NIBSC) responsible for the standardisation of biopharmaceuticals

–Develops quality management technology for stem cells

–Implements tests for applied research in clinical settings

–Shows a strong international presence in terms of hESC lines by providing them free of charge

• SC4SM (Stem Cells for Safer Medicines）

–A public-private consortium that developed toxicity testing technology for new chemical compounds as drug candidates utilizing stem cells

–A consortium of the public, academic and private sector (pharmaceuticals)

UK is developing a forum for standardization


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Current efforts for stem cell standardisation (3/4): USA

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• Wisconsin International Stem Cell Bank

–WiCell /U. Wisconsin: widely distributing hESC lines

–Geron Corp.: start a clinical trial to treat patients with spinal cord injury using the WiCell’s hESC H9 line

–FDA: has approved the clinical trials with certain guidelines

• The Harvard Stem Cell Institute

–Co-development of assay systems using hESC with GlaxoSmithKline

• Pharmaceutical companies

–Pfizer: launched a new center for stem cell research in Cambridge

–VBs e.g. CDI, iPierian, Fate Therapeutics, ModeRNA Therapeutics

The academic and private sector are leading the way in standardisation



Current efforts for stem cell standardisation (4/4): Japan

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• Ministry of Education, Culture, Sports, Science and Technology (MEXT)’s “iPS Cells Research Network"

–A system to efficiently share research information and materials between organizations participating in projects associated with MEXT’s hiPSC research.

• Excess legislation to human ESC research

–Promising discoveries using human induced pluripotent stem cells (hiPSCs)

Efforts towards standardisation are unique, focusing on hiPSCs


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Issues and necessity of strategic framework for the standardisation

• The attempt to limit to currently existing embryonic and pluripotent(reprogrammed) stem cell types

–The goal in clinical practice is effective therapy, not a successful story for a particular stem cell type nor line

–A stem cell type/line is just a technical opportunity

–Provisions for the possibility of a totally new paradigm shift that overcomes the disadvantages of hESCs or hiPSCs.

• Standardisation issues have been narrowly approached

–Centred around evaluation methods for cell line characterisation i.e. the formation of lateral compatibility standard

–Need for discussion on quality and vertical compatibility standards

• Qualification of final products/services

• Conjugation of core and peripheral (or new and commodity) technology areas

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Six categories for classification of stem cell-related technologies

Category Technology Area Material/instrument Method/know-howGeneration Fertilized egg ES and ES-derived cell ES generation

Sperm/unfertilized egg GS cell GS generationFetal tissue iPS and iPS-derived cell, various stem cells iPS generation from fetal tissueAdult tissue iPS and iPS-derived cell iPS generation from adult tissue

Maintenance Medium Medium, serum ES/GS maintenance, iPS maintenanceSupplement Small molecule, protein (growth factor, etc.)Instrument Cell culture instruments / machineries Maintenance the pluripotency

Differentiation Medium Medium, serum ES/GS maintenance, iPS maintenanceSupplement Small molecule, protein (growth factor, etc.)Instrument Cell culture instruments / machineries Differentiation to somatic stem cell / mature cell

Analysis Physical quality analysis

FACS (or alternative tool) Detection of morphology, surface antigen

Functional quality analysis

Detection of morphology, surface antigen

Safety analysis Method to analyze infectivity, genomic stability, tumorgenicity

Modification Cell isolation FACS, MACS (or alternative tool) Germ cell isolation method (gynecological or urological method)Blood cell isolation method (e.g. bone marrow sampling, aphaeresis)Non blood cell isolation method (biopsy, surgery)Other somatic cell isolation method

Transduction Vector, protein, small compound Transduction methodTissue engineering Cell / tissue culture system (for industrial use) Tissue engineering methodCell expansion and safety ensuring tool

Cell / tissue manufacturing system (for industrial use)

Administration Intravenous injection Intravenous injection system Bone marrow transplantation, etc.Non-intravenous injection

Endoscopic device Endoscopic methodSurgical transplantation

Technology mapping

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0 20 40 60 80 100

Others

Administration

Modification

Analysis

Differentiation

Maintenance

Generation

Number of patent applications for pluripotent stem (ES/iPSC) technologies:

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• “Process” patent• Narrow claiming• Less competitive with substitutive technologies

Category of technology No. of patents applied worldwide Other observations

• Non-specific to SC• Know-how oriented, difficulty in describing as a right

Source: Sengoku, S., et al., Stem Cell Reviews and Reports (2011); Japan Patent Office (2009)

Limitation of a simple “pro-patent” approach?


Usage of induced pluripotent (reprogrmmed) stem cells

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Source: Nature Reviews Genetics advance online publication Published online 22 February 2011 doi:10.1038/nrg2937

Variable applications with different skill sets

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Type of standardisation and applicability

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• Lat. compatibility (qualification)

• Lat. compatibility (qualification)

• Vart. compatibility

• Quality • Quality

Generation DifferentiationMaintenance PackagingFinal product/

service

hESC(E=embryonic)

hiPSC(iP=induced pluripotent)

hMSC(M=mesenchymal)

hNSC(N=neural)

hHSC(H=hematopoetic)

Pharmaceutical assay system

Tailor-made diagnostic system

Cell therapysystem

Regenerative medicine system

Approach

Liver cell

Cardiomyocyte

Neuron

Blood cell

Source: the authors


A hypothetical framework for stem sell standardisation strategy

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Objective and approach for standardization

De facto standard:Achieve sufficient (or best-choice) conditions

Consensus standard:Preserve necessary conditions

De jure standard:Defined by regulations/guidelines

Quality standard:Component

• Final product/service• Architecture

• Core component of product/service (e.g. stem cell lines)

• Regulations (e.g. GMP)• Regulatory guidelines for efficacy and safety

Vertical compatibility Standard:Process

• Process technology for guaranteeing maximum quality

• Process technology for ensuring minimum quality

• Process technology for ensuring regulations/regulatory guidelines

Lateral compatibility Standard:Evaluation

• Evaluation technology for guaranteeing maximum quality

• Evaluation technology for ensuring minimum quality

• Evaluation technology for ensuring regulations/regulatory guidelines

Source: Sengoku, S., et al., Stem Cell Reviews and Reports (2011); partially revised.

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Example (1/3): quality standardisation for a specific stem cell line:Frequency of hESC lines used in studies

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Source: Christopher Thomas Scott, Jennifer B McCormick, Mindy C DeRouen, Jason Owen-Smith, Federal policy and the use of pluripotent stem cells, Nature Methods 7, 866–867 (2011)

The H9 line used for the first clinical trial with hESC, forming a de facto also in basic research


Example (2/3): vertical compatibility standardisation for process technology:Establishment of hiPSC from blood cells

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• Potentiality to utilise existing bone marrow donor registry in common for stem cell-based diagnostics and therapies

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Example (3/3): lateral compatibility standardisation for qualification of hES/hiPS cell types and lines: methods and theories

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• Advanced evaluation methods for hES/hiPSC across species and lines

• Proposal of a theoretical framework for quality assessment

Source: Bock C. et al, Cell 144(4), 439-452 (2011); Hanna, J. H., Saha, K., Jaenisch, R, Cell 143(12), p.508-525 (2010)


Key points of discussions for standardisation and intellectual property formation strategies

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Potential areas of international standardisation

• Consensus standard

-Core component of product/service (e.g. stem cell lines)

-Process/evaluation technology for ensuring minimum quality

Potential areas of patenting

• Packaging and key peripheral technologies

-Consolidation/aggregation of key components to a particular product/service

-Key peripheral technologies (e.g. small chemical compounds for efficient and robust differentiation)

Potential areas of “black box” instead of patents

• Process/evaluation technologies enough to achieve the best quality standard

-Design concept of architecture

-Novel biomarkers

-Manufacturing know-howsSource: Sengoku, S., et al., Stem Cell Reviews and Reports (2011); partially revised.

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• Compatible standard

– Complementary product/services

• Quality standard

– Public regulations

– Minimum attributes

– Product characteristics

A proposed model for the uptake and innovation for stem cell technologies

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IndividualizationThrough in-house, integral optimization

GenerationAnalysis

Modification

MaintenanceDifferentia-

tionApplication

StandardizationWith modularity, N/W externality

Related patents, tangible assets,

know-how & external networks

A standardstem cell line

for the purpose

A concluded product / service

Source: Sengoku, S., et al., Stem Cell Reviews and Reports (2011); partially revised.


Summary and discussion

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Limitation of a simple “pro-patent” approach for stem cell technology• Mainly “process” patents• Fragmented ownership• May not always be the first choice for IP formation

Need for “pro-innovative” business modeling• Endorsement of standardisation guidelines and frameworks• Effective IP formation along with the governing thought• In-house and integral optimisation of the target product and service

Implications to practitioners• Qualitative demands: depending on the difference in the purpose of industrialisation

• Quality standard: defined with the final product/service of interest• Compatible standard: derived from components of the product/service

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Appendix

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Importance of “black box” strategy: two representative cases

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Company Name ReproCELL Incorporated Japan Tissue Engineering Co., Ltd.(J-TEC)

Governance Private by the founders, management, strategic investors and VCs

Listed to JASDAQ NEO

Features The first company worldwide which succeeded to commercialize the hiPSCtechnology

The first company to materialize regenerative medicine in Japan, with an authorized medical product by the regulatory

Main business areas

1.Research reagents for ES/iPS cells (Medium, Antibodies, etc)2.Drug screening and toxicity testing using ES/iPSC (“QTempo” for cardio-toxicity testing)3.Primary cell development for drug screening and assay services4.Other diagnostics & services

1.Tissue-engineered medical products(“JACE” for the treatment of severe skin burn)2.Research and development support

Source: the authors

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Maintenance/differentiation into somatic cells

ReproCELL’s business model for “QTempo”, a service of cardio-toxicity testing for pharmaceutical companies

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Chemical compoundlibrary

ADME (TBD)

Toxicity

Hit to Lead

Screeningassay

Drug candidate

Neural cells

G8

0 200 400 600 800

Time [ms]

-20.0

-10.0

0.0

10.0

20.0

FP

[µ

V]

0pM

300pM

1nM

3nM

10nM

30nM

100nM

300nM

1µM

3µM

10µM

30µM

hESC

Hepatocyte

Cardio-myocyte

Generation of pluripotent cell

strains

Measurement and analysis of cardio-

toxicity

Receiving patient tissue

Seed cell for iPSC

hiPSC

Source: ReproCELL, Inc.



Measurement/ differentiation into

cardiomyocyte

Generation of pluripotent cell

strains

Measurement and analysis of cardio-

toxicity

• Composition of culture medium

• Characterization of obtained hES/iPSCs

• Cell strain selection method

• Undifferentiated cell culturing method

• Differentiated cell seeding method

• Supply agreement of hESC strains

• Licensing agreement with two academic institutions

• Standard protocol

• Patient tissue collection and inspection

• Biological product safety management

• Strain-dependent differentiation method

• Standard protocol• Culture reagents

such as medium, detachment solution, and stock solution

• High throughput measurement instrument

• Composition of medium

• Patent / tangible asset licensing agreements from business partners

• Licensing relationship (differentiation method)

• Advisory contract with four experts

• Measurement instrument (generic)

• Analysis software (generic)

Know-how

Externalnetwork

Patent

Tangibleasset

Technology mapping of ReproCELL’s "QTempo"

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Source: the authors

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J-TEC’s business model for “JACE”, a medical product for treatment for severe skin damage

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Healthy skinFrom a patient

Autologous transplantation to the patient

Product

Incominginspection

Culture

Packaging

Shipping inspection

Post-marketing surveillance

& reporting to the authorsity

Delivery and application of JACE

Regulatory complianceReceiving patient tissueManufacturing of cultured

epidermal sheet

Source: the authors


• Skin culture method• Production method• Quality inspection

method (culture)

• Transportation container & packaging method

• In-house distribution network


Delivery and application of JACE

Manufacturing of cultured epidermal

sheet

• Network with medical institutions capable of appropriate treatment of severe burn cases

• Customized made-to-order system

• Production facility and hardware complying to GMP

• Patient tissue validation technology

• Methods for operations of tissue culturing, production and quality inspection

• Consulting contract regarding appropriate tissue differentiation and culturing

• License for a feeder cell

• Transportation device

• Treatment guidelines (for physician and for patient)

• Tissue inspection• Biological product

safety management

Regulatory compliance

• Storage facility of final product (store for at least 30 years)

• Monitoring systems after manufacturing and distribution

• Regulatory correspondence

• Post-marketing surveillance targeting all cases during reexamination period (seven years)

• Quality assurance method

• Treatment method

Technology mapping of J-TEC’s "JACE"

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Know-how

Externalnetwork

Patent

Tangibleasset

Source: the authors

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References

• Asai, Y., Tada, M., Otsuji, G., Nakatsuji, N. (2010). Combination of Functional Cardiomyocytes Derived from Human Stem Cells and a Highly-Efficient Microelectrode Array System: An Ideal Hybrid Model Assay for Drug Development, Current Stem Cell Research and Therapy, 5(3), 227-232.

• Adewumi, O., Aflatoonian, B., Ahrlund-Richter, L., et al. (2007). Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nature Biotechnology, 25, 803-816.

• Bergman, K., Graff, G. D. (2007). The global stem cell patent landscape: implications for efficient technology transfer and commercial development. Nature Biotechnology, 25, 419-424.

• Bock, C., Kiskinis, E., Verstappen, G., Gu, H., Boulting, G., et al. (2011) Reference Maps of Human ES and iPS Cell Variation Enable High-Throughput Characterization of Pluripotent Cell Lines, Cell 144(3) 439-452.

• Hanna, J., Saha, K., Jaenisch R. (2010) Pluripotency and Cellular Reprogramming: Facts, Hypotheses, Unresolved Issues. Cell 143(4) 508-525.

• Hu, K., Yu, J., Suknuntha, K., Tian, S., Montgomery, K., Choi, K. D., Stewart, R., Thomson, J. A., Slukvin, I. I. (2011) Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cell, Blood 117(14), 109-19.

• Kawakami, M., Sipp, D., Kato, K. (2010). Regulatory impacts on stem cell research in Japan. Cell Stem Cell, 6, 415-418.

• Kim, K., Doi, A., Wenet, B., et al. (2010). Epigenetic memory in induced pluripotent stem cells. Nature, 467, 285-290.

• Loring, J. F., Rao, M. S. (2006). Establishing standards for the characterization of human embryonic stem cell lines. Cell Stem Cell, 24, 145-150.

• Maherali, M., Hochedlinger, K. (2008). Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell, 3, 595-605.

• Polo, J. M., Liu, S., Figueroa, M. E. et al. (2010). Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nature Biotechnology, 28, 848–855.

• Scott, C. T., McCormick, J. B., DeRouen, M. C., Owen-Smith, J. (2011). Federal policy and the use of pluripotent stem cells, Nature Methods 7, 866–867.

• Sengoku, S., Sumikura, K., Oki, T., Nakatsuji, N. (2011) Redefining the Concept of Standardization for Pluripotent Stem Cells, Stem Cell Reviews and Reports 7(2) 221-226.

• Swann, G. M. P. (2000). The economics of standardization: final report for standards and technical regulations directorate, Manchester: University of Manchester Press.

• Takahashi, K., Tanabe, K., Narita, M., Ichisaka, T., Tomoda, K., Yamanaka, S. (2008). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131, 861-872.

• Teece, D. J. (1986). Profiting from technological innovation: Implications for integration, collaboration, licensing and public policy. Research Policy, 15, 285-305.

• Vrtovec, K. T., Scott, C. T. (2008). Patenting pluripotence: the next battle for stem cell intellectual property. Nature Biotechnology, 26, 393-395

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Documents

Redefining the Concept of Standardisation for Pluripotent Stem Cells€¦ · Redefining the Concept of Standardisation for Pluripotent Stem Cells July 31st–August 4th, 2011 PICMET