Lessons in university intellectual property management: The secret to survivin’ or a

train bound for nowhere? Tania Bubela

Professor

With apologies to Kenny Rogers

Disclaimer

The secret to survivin’: Seven things that matter. • Goals

• Metrics

• Size

• Timelines

• Strengths

• Relationships

• Value

Goals Matter Reassess roles of university technology transfer offices. One size does not fit all.

Incentives & Metrics Matter

You get what you measure. Measure the wrong thing and you get the wrong behaviors.“

John H. Lingle

Publications Associated with Top 100 Patented vs Unpatented Mouse Genes

An example of poor intellectual property management driven by metrics

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STATUS AND FILING DATE OF 816 MOUSE GENE PATENTS (US)

http://www.viewsoftheworld.net/wp-content/uploads/2014/11/THErankings2014-15.jpg

SIZE MATTERS: The World University Rankings 2014-2015 By Population By GDP

1-25 25-50 51-75 76-100 101-150 151-200

Canada

Canada

Strengths Matter Infrastructure, research & human capacity

Timelines Matter

Realistic assessment of contribution, transaction costs, & patent life

Adapted from Carl June:

2012 Chabner Colloquium – Collaboration in Cancer Drug Trials

https://www.youtube.com/watch?v=jQfFCC6i5_o

Translational Research

from

Basic through Clinical

1989

• Redirected T cell concept in vitro • Gross et al., PNAS

1998

• First HIV CAR patients treated (CD4 Zeta)

• Persistence of CAR T cells up to 11 years post infusion (STM, 2012)

2008

• First Cancer Clinical Trials –poor T cell engraftment

• Kershaw et al Clin Cancer Res; Lamers et al., J Clin Oncol

2004-2010

• T Cell Translational Research and First Clinical Trials: CD19 target in B cell malignancies

2014

1987 • Discovery role of CD28 in T

cell proliferation

1993 • CD3/CD28 beads produced

(culture system)

1998 • Bead removal - passage

over magnetic field

2010 • In-hospital production for

T-cell infusion

2014- • Scale-Out: Development of

robotic systems (QC)

Development of

Clinical Scale T Cell

Manufacturing Process

Relationships Matter

• New funding calls for collaborative, multi-national, multi-disciplinary, and increasingly multi-sectorial research

• Access to precompetitive research outputs raises the level of knowledge for all R&D actors.

• Precompetitive research does not limit appropriation of innovation that is closer to practical application.

• Avoids duplicative research.

• Reduces negotiating costs associated with an abundance of intellectual property rights.

• Promotes use of standard research tools and methods

Relationships Matter Supporting precompetitive research

Value Matters

Look for opportunities. Be flexible. You've got to know when to hold 'em Know when to fold 'em

Novartis-Penn Center for Advanced Cellular Therapeutics

Build on respective strengths: Example 1 – Cellular Onco-Immunotherapy

Clinical translation is global

Sponsors of 1554 cellular immunotherapy clinical trials

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Start Year

industry

NIH

NIH & industry & other public sector funder

NIH & other public sector funder

other public sector funder

Plug knowledge/technology gaps

Gap • Lack of cancer cell specific antigens

causes off-target toxicity

• Need fully humanized CAR T-cell constructs

• Need more efficient genetic engineering methods

• Need robotic cell processing systems

• Need to control duration of immune response to limit adverse side-effects

Plug • Target discovery is an academic

strength • Vector development is an academic

strength • CRISPR/Cas systems developed in

academia and spun out to biotechnology companies

• Academic/industry co-development in bio-engineering

• Academic/industry co-development of suicide switch

Play a more effective role in assessing value. Know when to walk away And know when to run

More Medicine Goes Off Limits in Drug-Price Showdown

By Robert Langreth - Nov 25, 2014

Steve Miller is waging war on high-priced medicine, guiding decisions to ban drugs from the health plans of millions of Americans and sending companies reeling in a $270 billion market. He and his colleagues at Express Scripts Holding Co. (ESRX) say they are just getting started.

INVESTMENT

Animal

and/or

Laboratory

Studies

I About 4.5 Years I About 8.5 Years II 1.5 Years

Health

Technology

Assessment

Clinical

Adoption

Phase IV

Post-market

Phase 1 to

Phase 2

Phase 2 to

Phase 3

Phase 3 to

NDA/BLA

NDA/BLA to

Approval

LOA from

Phase 1

Lead Indication All Indications

67% 64%

39%

32%

68%

60%

86%

10.4%

83%

15.3%

Translational Stage Pre- clinical Phase I Phase II

Step 1: Headroom

Analysis

He

alth Im

pact

Re

sou

rce Imp

act

Social V

alue

Imp

act

Technology & clinical

landscapes

Confidence Adjustments

A framework for value evaluation

Translational Stage Pre- clinical Phase I Phase II

Step 1: Headroom

Analysis

He

alth Im

pact

Re

sou

rce Imp

act

Social V

alue

Imp

act

Technology & clinical

landscapes

Confidence Adjustments

A framework for value evaluation

De-risk

Technology

for Phase III

Investment

STEP 2: Macro Analyses –

Cost-Effectiveness Modeling

• Assumes cost of

goods and

effectiveness

based on similar

bio-therapeutics

Clears

Value

Hurdle

YES NO

STEP 3: Micro Analyses –

Cost-Effectiveness Modeling

• Cost of Goods • Regulatory

compliance • Manufacturing Scale-

up • Structural barriers to implementation

• Effectiveness

• Safety profile

• IP and patent

life

YES NO

Value based reimbursement

-60000

-40000

-20000

0

20000

40000

60000

-3 -2 -1 0 1 2 3

Cost Effectiveness Plane

Incremental Value (QALYs)

Incremental Cost ($s)

Evidence Matrix: Type 1 Diabetes

Intensive Insulin Therapy

Insulin Pumps

Bone Marrow Transplant

Artificial Pancreas

Beta Cell 2

Beta Cell Transplant X X X X X

Insulin

Insulin Pumps

Bone Marrow Transplant

Artificial Pancreas

Beta Cell 2

• Safety • Effectiveness • Cost of Goods

Islet Transplant?

Current

Future

Unstable Type 1 Diabetes

Islet beta cell transplantation – donor harvested

“We” built a model and unpacked the Cost of Goods

Unpacking the problem: cost of beta cells

• Value of information modeling established max cost/dose for therapy in Canada @ $50,000/QALY and 5% discount rate.

• Was $17,344 without immunosuppression but -$36,039 with immunosuppression.

• Business model (scale-up or scale-out) and manufacturing to meet regulatory burden will determine minimum cost/dose.

• Need to factor in profit-margin. • But immunosuppression will be major cost

driver. • Apply effort to immunosuppression-free

technology prior to phase 3 trials.

More to life than money – Destroying relationships. You never count your money When you're sittin' at the table

• Practising/non-practising entities.

• Post-hoc rent seeking behaviour.

• Drives behaviour of risk averse institutions.

• May discourage commercial users.

• But litigation rare.

Are universities patent trolls?

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461 litigations 590 patents Patent Trolls

Decade of University Litigation

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Top 19 Institutions of 118

• MTAs are substantial disincentive to accessing and providing materials for basic and translational research.

• Problematic in context of research and funding timeframes.

• Complexity not proportional to value

• Rarely enforced

• Use simplified agreements.

Material Transfer Agreements

Make deals to enable partnerships There'll be time enough for countin' When the dealin's done

Schofield, Bubela, et al.

• Operations started in June 2004

• Government agencies, Wellcome Trust, charities & leading pharma companies

• +300-strong team in six countries: Oxford, Toronto, Stockholm, Campinas (Brazil), Chapel Hill (US) & Frankfurt

• Open Access Policy:

– Promptly placing results, reagents and know-how in the public domain

– SGC scientists never file patents

Nat Chem Biol. 2010 Mar;6(3):166-169; Nature. 2011 Feb 10;470(7333):163-5.

Addressing herd behaviour

A general model for open access/ open source in early stage drug discovery

Public-Private-Patient Partnership

Public Domain Commercial

Tools & Basic Knowledge NOVEL Proteins only! • Structure • Chemistry • Antibodies • Screening • Cell Assays

Discovery and Exploration • No patent • No restriction on use • Open access to tools and data. • Target identification & validation

Drug Discovery and Development Facilitated by access to increased amount of information in the public domain - (re)Screening - Lead Optimisation - Pharmacology - Metabolism - Pharmacokinetics - Toxicology - Chemical development - Clinical development

PRE-COMPETITIVE – NON PROPRIETARY PROPRIETARY

Weigelt J. EMBO Reports 10:941-5 (2009)

Huntington’s Disease

Concluding thoughts Every gambler knows That the secret to survivin' Is knowin' what to throw away And knowin' what to keep 'Cause every hand's a winner And every hand's a loser And the best that you can hope for….

What does Canadian success look like?

What does Canadian innovation success look like?

Conclusions

• New collaborative, translational research models gaining momentum, building on respective strengths of innovation stakeholders.

• Needs innovation and flexibility in technology transfer management of intellectual property.

• Specifically, attention on IP management best practices, appropriate metrics, and realistic attention to enforcement and evaluation of value.

• Especially important is enabling partnerships, build trust and enhance social capital.

THANK YOU

Funders Collaborators: Christopher McCabe Richard Gold Timothy Caulfield Robert Cook-Deegan Paul Schofield Jean-Sebastien Delisle Katherine Bonter

Research staff/students: Amrita Mishra, Mark Bieber, Jenilee Guebert, Rhiannon Adams, Andreas Strotmann, Zackariah Breckenridge, Monica Wang, John Minkley, Yael Mansour, Jaclyn Hutchinson

Publications 1. Bubela T. How to build a biomedical research commons: lessons from the humble laboratory mouse. In Stranbourg K, Madison M and

Frischmann B (eds) Governing Medical Research Commons. (Cambridge University Press, in press 2016)

2. Bubela T, Vishnubhakat S, Cook-Deegan R (2015) The Mouse that Trolled: The Long and Tortuous History of a Gene Mutation Patent that Became an Expensive Impediment to Alzheimer’s Research. Journal of Law and the Biosciences. April 23, 2015: 1-50. ePUB Ahead of Print: http://jlb.oxfordjournals.org/content/early/2015/04/23/jlb.lsv011.short?rss=1;

3. Bubela T, Cook-Deegan R (2015) Keeping score, strengthening policy and fighting bad actors over access to research tools. Nature Biotechnology 33(2): 143-147. [IF 39.1; PMID 25658278]

4. Bubela T, Guebert J, Mishra A (2015) Use and Misuse of Material Transfer Agreements: Lessons from Research, Repositories, and Litigation. PLoS Biology 13(2): e1002060. [IF 12.690; PMID 25646804]

5. Mishra A, Schofield PN, Bubela T (in press, 2015) Sustaining large-scale infrastructure to promote pre-competitive biomedical research: Lessons from mouse genomics. New Biotechnology.

6. Mishra A, Bubela T (2014) Legal Agreements and the Governance of Research Commons: Lessons from Materials Sharing in Mouse Genomics. Omics A Journal of Integrative Biology 18(4) 254-273. [IF 2.730]

7. Li MD, Atkins, HL, Bubela T (2014) The Global Landscape of Stem Cell Clinical Trials. Regenerative Medicine 9(1), 27-39. 8. Bubela T, McCabe C (2013) Value-Engineered Translation for Regenerative Medicine: Meeting the Needs of Health Systems. Stem Cells and

Development 22, 89-93. 9. Mathews DH, Cook-Deegan R, Bubela T (2013) Patents and Misplaced Angst: Lessons for Translational Stem Cell Research from Genomics.

Cell Stem Cell 12: 508-512. 10. Bubela T, Schofield PN, Ryan C, Adams R, Einhorn D (2012) Managing Intellectual Property to Promote Pre-Competitive Research: The

Mouse as a Model for Constructing a Robust Research Commons. Journal of Law, Information and Science 20(2): 98-121. 11. Bubela T et al. (2012) Recalibrating Intellectual Property Rights to Enhance Translational Research Collaborations. 4 Science Translational

Medicine 122cm3. 12. Bubela T, et al. (2010) Commercialization and Collaboration: Competing Policies in Publicly-Funded Stem Cell Research? 7 Cell Stem Cell

21-30. 13. Bubela T, Caulfield T (2010) Role and Reality: Technology Transfer at Canadian Universities. 28 Trends in Biotechnology 447-451 14. Schofield PN, Bubela T, et al. (2009) Post-publication sharing of data and tools. 461 Nature 171-173 .