Gene patents and genetic testing for inherited risk of

cancer: state of play

9 January 2014Advisory Committee on Breast Cancer in Young Women

Robert Cook-Deegan, MDInstitute for Genome Sciences & Policy

Sanford School of Public PolicyDuke University

Source: Mark Hakkarinen and Bob Cook-Deegan, DNA Patent Database, 12 March 2013Creative Commons "free use with attribution" license, with the attribution to Genomics Policy Resource.

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DNA Patents by year through 2012

Year

Sample claims

US Patent 5,747,282 (BRCA1, breast CA)

1. An isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO:2.2. The isolated DNA of claim 1, wherein said DNA has the nucleotide sequence set forth in SEQ ID NO:1.6. An isolated DNA having at least 15 nucleotides of the DNA of claim 2.

US Patent 5,753,441 (BRCA1)1. A method for screening germline of a human subject for an alteration of a BRCA1 gene which comprises comparing germline sequence of a BRCA1 gene or BRCA1 RNA from a tissue sample from said subject or a sequence of BRCA1 cDNA made from mRNA from said sample with germline sequences of wild-type BRCA1 gene, wild-type BRCA1 RNA or wild-type BRCA1 cDNA, wherein a difference in the sequence of the BRCA1 gene, BRCA1 RNA or BRCA1 cDNA of the subject from wild-type indicates an alteration in the BRCA1 gene in said subject.

AMP v Myriad: conspicuous case, wrong lessons

• Suit happened not because advocates worry about monopoly, but because they were concerned about who makes medical decisions

• Price an issue, but not the main issue

• Dislike of business practices, not of patents per se

• Line of attack = patents

AMP v Myriad• May 2009, suit filed

• March 2010, Federal District Court Judge Robert Sweet rules claims are invalid: “Pigs Fly”

• 2011 and 2012: Court of Appeals for the Federal Circuit upholds invalidation of method claims, reverses on one method claim and DNA molecule claims (allows them as patentable subject matter)

• June 2013: Supreme Court invalidates genomic DNA, upholds cDNA claims

Myriad Cases: the story goes on

• Myriad sues Ambry, Gene by Gene, Quest, GeneDx, Labcorp and InVitae

• Based on claims in ten BRCA patents and some cases also mut-Yh gene

• Myriad has pledged not to sue for academic nonprofit research use or verification testing

• Quest, Counsyl counter-sue for declaratory judgement of non-infringement in Calif

• Ambry, Gene by Gene raise antitrust issues; InVitae raises jurisdiction issue

Heroic stories of Genentech

Insulin and growth hormone

Herceptin

Contrast with BRCA1/2, Canavan controversies

Commercial BRCA testing, early history

Oncormed

• Mary-Claire King and Mike Stratton patents licensed

• IRB protocol

• Test through physicians only

• Stringent high-risk criteria

• Research phase first

• Counseling required

• Sublicensing provisions for BRCA2; NHS testing in UK

• Mutation-truncation-sequencing tiered testing

Myriad

• “Startup” sole-provider business model

• Blockbuster diagnostic patents

• Accept tests outside research and professional guidelines

• Some DTC advertising

• Counseling not required

• No sublicensing except common mutations

• PCR-exon sequencing of both genes

Timeline

Caulfield, Cook-Deegan, Kieff & Walsh: Nat Biotech 2006 Sep;24(9):1091-4.

Cases in policy reports 2002-6

Caulfield, Cook-Deegan, Kieff & Walsh: Nat Biotech 2006 Sep;24(9):1091-4.

Tone of Newspaper Coverage by Country

Source

: Cau

lfield

T, B

ub

ela

T &

Mu

rdoch

CJ, "M

yria

d a

nd

th

e M

ass M

ed

ia: T

he C

overin

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f a G

en

e Pa

ten

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on

troversy

,“ Gen

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20

07

Dec;9

(12

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0-5

.

Mark SkolnickUniv Utah and Myriad

Andrew FutrealUNC, NIEHS, Duke, MDAnderson,

and Sanger Institute

Mary-Claire KingUCBerkeley & Univ

Washington

Joanna Rudnick“In the Family”

BRCA previvor and survivor

Michael StrattonCancer Research Campaign (UK)Sanger Institute

Things Myriad does well• Turnaround time

• Accuracy of testing

• Clarity of reporting

• Third-party reimbursement

• Marketing

• Free family testing for Variants of Unknown Significance

• Data-pooling

• Generating revenue

BRACAnalysis® Revenue

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012$0

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$460M 2012-2013 BRACAnalysis® (BRCA1/2 sequence)$60M BART (rearrangements) [Revenues 2012-3]

Why so much ill will?• Carry-over from a hotly contested race to the genes

• Overt noncompliance with testing guidelines in late 1990s

• Enforcement letters to universities and competitors

• Stopped contributing to BIC and other databases Nov 2004

• Never announced decision to withhold data

• Left impression it was “open” by continuing claim to be “main contributor of data in BIC”

• Proprietary database and algorithms

• Direct marketing to primary care physicians; direct-to-consumer marketing

The other issue: trade secrets• Myriad’s proprietary database

drawing on ~1 million tests

• Leveraged on sole-provider status in US

• Database exclusivity does not expire with patents

• Myriad claims 2% variants of unknown significance (VUS) compared to 30% for Euro competitors (this figure is inflated, but the underlying point is valid)

The long tail of mutation• Most common mutations are usually

discovered first

• Patents and IP established on first discovery

• Two decades and >1 million tests later, we are still finding mutations in BRCA genes

• BRCA1/2 have been joined by ~20 other genes in conferring risk for breast/ovarian cancer

Restatements of independent verification in genomics• Cech report (Sharing Publication-Related Data and Materials) 2002, National Research Council

• Omics report (Evolution of Translational Omics) 2012, Institute of Medicine

• Precision Medicine report (Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease) 2012, Institute of Medicine

Crucial issues looming• Incentives to share data v capture it in

proprietary databases (Myriad, Foundation Medicine, OncoType Dx)

• Infrastructure to pool data (ClinVar, Global Alliance, Internal Consortium for Clinical Genomics, etc.)

• Linkages among databases on genotype, phenotype, clinical outcomes

• Algorithms for interpreting the clinical significance of variants