Gene patents and genetic testing for inherited risk of cancer: state of play 9 January 2014 Advisory Committee on Breast Cancer in Young Women Robert Cook-Deegan, MD Institute for Genome Sciences & Policy Sanford School of Public Policy Duke University

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

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):

Cases in policy reports Caulfield, Cook-Deegan, Kieff & Walsh: Nat Biotech 2006 Sep;24(9):

Tone of Newspaper Coverage by Country Source : Caulfield T, Bubela T & Murdoch CJ, "Myriad and the Mass Media: The Covering of a Gene Patent Controversy, “ Genet Med 2007 Dec;9(12):850-5.

Mark Skolnick Univ Utah and Myriad Andrew Futreal UNC, NIEHS, Duke, MDAnderson, and Sanger Institute Mary-Claire King UCBerkeley & Univ Washington Joanna Rudnick “In the Family” BRCA previvor and survivor Michael Stratton Cancer 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 $460M BRACAnalysis® (BRCA1/2 sequence) $60M BART (rearrangements) [Revenues ]

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