Patenting Human Genes and Genetic Tests: Recent Developments

1. Patenting Human Genes and Genetic Tests:Recent Developments National Advisory Council on Human Genome Research May 17, 2010 Jorge L. Contreras Washington University in St. Louis School of Law Pilar N. Ossorio University of Wisconsin

2. Requirements for Patentability • Patentable subject matter (§101) • Utility (§101, 112) • Novelty (§102) • Non-obviousness (§103)

3. Topics • Patentable subject matter • Association for Molecular Pathology v. USPTO(a/k/a ACLU v. Myriad) (S.D.N.Y. Mar. 2010) • Utility • Eli Lilly v. Human Genome Sciences (UK Ct. Appeal, Feb. 2010) • Non-obviousness • KSR v. Teleflex, US Supreme Ct. (2007) • In re Kubin, Fed. Cir. (2009) • SACGHS Report on Gene Patents (Feb. 2010)

4. Patent Law • The intellectual property right is defined by a claim. Claims come at the end of a narrative description of the invention and the problem the invention is intended to solve. E.g., • I claim an isolated nucleic acid molecule comprising a polypeptide at least 80% identical to amino acids 22 - 221 of SEQ ID No. 2, wherein the polypeptide binds CD48.

5. Patent Litigation

6. Patentable Subject Matter

7. Patentable Subject Matter • 35 USC §101: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.

8. Association for Molecular Pathology v. USPTO(S.D.N.Y. Mar. 2010)

9. BRCA1 and Myriad Background • Early 1980s: various groups (incl. Collins) begin to seek DNA sequences associated with breast cancer • 1988/89: Intl. Breast Cancer Linkage Consortium established • 1990: Mary-Claire King (Berkeley) linkage analysis paper locating BRCA1 on long arm of chromosome 17 • 1991: Mark Skolnick (w/ W. Gilbert and P. Meldrum) founds Myriad to search for breast cancer genes • Funding: VC, Lilly, NIH ($5M to Univ. UT) • Aug. 1994: Myriad (w/ NIEHS, Univ. UT, McGill & Lilly) clones BRCA1 • Myriad files patent application on BRCA1

10. BRCA2 and Myriad • Sept. 1994: BRCA2 localized through linkage analysis to chromosome 13 • 1995: BRCA2 race between Myriad and UK team (Michael Stratton at ICR and Sanger) • Dec. 18, 1995: Myriad files US patent on BRCA2 • Dec. 22, 1995: Stratton announces sequencing of BRCA2 and files UK patent • Dec. 23, 1995: Stratton BRCA2 paper appears in Nature; Myriad releases sequence to GenBank

11. Myriad Patent Timeline • Oct 1991: Univ. UT grants Myriad exclusive license to BRCA1 • Aug. 1994: Myriad files BRCA1 application • Nov. 1994: Univ. UT grants Myriad exclusive license to BRCA2 • Dec. 1995: Myriad files BRCA2 application • Dec. 1997: first BRCA1 patent issues • Nov. 1998: first BRCA2 patent issues

12. Competing Rights • NIH • Initial Myriad BRCA1 application omitted NIH inventors Wiseman, Futreal • 1994: NIH settles dispute with Myriad/Utah and grants Utah exclusive license under BRCA1 rights • Oncormed • 1997: Oncormed sues Myriad • infringement of 1996 consensus wild-type BRCA1 sequence (NIH) • incorrect inventorship of 2 Myriad patents • 1998: Myriad settles with Oncormed and obtains Oncormed patents

13. BRCA1/2 Testing/Enforcement • 1996: Myriad begins to offer BRCA1/2 screening; U. Penn screens 500 patients/year • 1998: Myriad sues U. Penn for patent infringement; Penn ceases testing • 1999: Myriad requests Georgetown to stop testing for NCI’s Cancer Genetics Network Project (CGNP) • 2000: Myriad cease and desist to Yale • Today: Myriad is the only U.S. provider of commercial BRCA1/2 screening • Myriad permits research, but without provision of results to patients

14. Alleged Effects of Myriad’s Gene Patents • Pricing ($3200/test) places testing beyond financial means of many patients • Inability for patients to get confirmatory testing from second lab • Myriad testing is not state-of-the-art • Researchers cannot tell patients results of testing, conflicting with ethical obligations • General chilling effect on research into genetic tests • Interference with ability to investigate complex multi-gene diseases

15. The Litigation On May 12, 2009, a group of plaintiffs represented by the American Civil Liberties Union (ACLU) sued Myriad, the Univ. of Utah and the USPTO to invalidate 15 claims of 7 Myriad BRCA1/2 patents

16. The Litigation: Plaintiffs • Counsel: ACLU and Public Patent Foundation at Cardozo School of Law • Plaintiffs: • Associations – Assn. for Molecular Pathology (AMP), Am. Coll. Of Medical Genetics (AMCG), Am. Soc. For Clin. Pathology (ASCP), Coll. Of Am. Pathologists (CAP) • Researchers – Kazazian, Ganguly (Penn), Chung (Columbia), Ostrer, Reich (NYU), Ledbetter, Warren (Emory), Matloff (Yale) • Advocacy Groups – Breast Cancer Action (BCA), Our Bodies Ourselves • Patients – Ceriani, Limary, Girard, Fortune, Thomason, Raker

17. The Patents • 7 patents (5 BRCA1, 2 BRCA2) • 15 claims • Composition of Matter claims • Method/Process claims • Terms extend from 2015-2018 • Myriad holds 16 other BRCA1/2 patents not in suit (expiring 2023)

18. Composition of Matter Claims • “An isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO:2” (‘282, cl.1) • “[Cl. 1]… wherein said DNA has the nucleotide sequence set forth in SEQ ID NO:1” (‘282, cl. 2) • “An isolated DNA having at least 15 of the nucleotides of the DNA of claim 1/2” (‘282, cl. 5/6)

19. Patentable Subject Matter:Laws of Nature • “The qualities of these bacteria, like the heat of the sun, electricity, or the qualities of metals, are part of the storehouse of knowledge of all men. They are manifestations of laws of nature, free to all men and reserved exclusively to none. He who discovers a hitherto unknown phenomenon of nature has no claim to a monopoly of it which the law recognizes” (Funk Bros. Seed Co. V .Kalo Inoculant Co. (US 1948) • “Phenomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson (US 1972)

20. Do Myriad’s Composition Patents Cover “Products of Nature”? • Myriad’s arguments • USPTO Utility Examination Guidelines expressly allow patenting of isolated genetic material • Patents claim isolated DNA, which does not occur in nature

21. What is not a Product of Nature? • To be patentable, a composition must have “markedly different characteristics” from any occurring in nature. (Diamond v. Chakrabarty (US 1980)) • Mere “purification” of a natural compound does not render it patentable. (Am Wood-Paper Co. v. Fibre Disintegrating Co. (US 1874) • Discredits Learned Hand’s 1911 holding in Parke-Davis v. Mulford, that isolated and purified adrenaline is patentable

22. Myriad’s Product of Nature Arguments • M: Isolated DNA has different structural and chemical properties (chromatin, introns, methylation) than native DNA • Court: “In light of DNA’s unique qualities as a physical embodiment of information, none of the structural and functional differences cited by Myriad … render the claimed DNA ‘markedly different’.” • M: Isolated DNA has functional utility in probes and primers that native DNA does not. • Court: usefulness of isolated DNA in probes/primers exists only because of the identity of nucleotide sequence between isolated and native DNA.

23. Myriad’s Product of Nature Arguments, cont. • M: Invention required identification of genes plus isolation of sequences away from other DNA and cellular material • Court: Discovery is of the “handiwork of nature” and not patentable; Isolation was “simply the application of techniques well-known to those skilled in the art”

24. Holding: Myriad’s BRCA Composition of Matter Claims Invalid • “Because the claimed isolated DNA is not markedly different from native DNA as it exists in nature, it constitutes unpatentable subject matter …” • Claims are thus invalid.

25. Method Claims A method for detecting a germline alteration in a BRCA1 gene, said alteration selected from a group consisting of the alterations set forth in Tables … in a human which comprises analyzing a sequence of a BRCA1 gene or BRCA1 RNA from a human sample or analyzing a sequence of BRCA1 cDNA made from mRNA from said human sample with the proviso that said germline alteration is not a deletion of 4 nucleotides corresponding to base numbers … (‘999, cl. 1)

26. Method Claims: Unpatentable Subject Matter • “Phenomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson (US 1972) • A claimed process may be patentable if it “transforms a particular article into a different state or thing” (In re. Bilski (Fed. Cir. en banc 2008, cert. granted 2009)

27. Myriad’s Methods Not Transformative • Simply “analyzing” and “comparing” DNA sequences is an abstract mental process • The preparatory isolation/purification steps are not part of these claims • Any “transformations” associated with isolating and sequencing DNA are mere data gathering steps that are not central to patentability. • Holding: method claims are invalid

28. Outcome • All 15 of Myriad’s claims-in-suit are invalid • Myriad has announced plans to appeal to the Federal Circuit • At least some justices of the Supreme Court (Breyer) have indicated an interested in patentability issues • 2-4 more years before a final resolution

29. Myriad’s European Patents • 1998: EPO allows patenting of genes (Council Dir. 98/44) • 2001: Myriad’s European patents on BRCA1 granted • 2002: Institut Curie and other oppose Myriad patents • Feb. 2004: Cancer Res. UK gets patent on BRCA2 • May 2004: EPO revokes first Myriad BRCA1 patent • Jan. 2005: EPO limits claims of 2 remaining Myriad BRCA1 patents • Jan. 2005: Myriad gets European patent covering BRCA2 test for Ashkenazi-Jewish women • Nov. 2008: EPO limits BRCA1 patent to BRCA1 frameshift mutations only (not full BRCA1 gene)

30. Utility

31. Utility in the U.S. • 35 USC §101: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor... • 35 USC §112: The specification shall contain a written description of the invention, and of the manner and process of making and using it…

32. Eli Lilly v. Human Genome Sciences (UK Ct. Appeal, Feb. 2010)

33. HGS’s neutrokine-a Patent • 1996: HGS patents sequence for neutrokine-a, a protein identified using bioinformatics techniques • Function is unknown, so a list of potential uses including therapies for solid tumors, schistosomiasis, and other parasitic diseases is listed • Eli Lilly, also developing neotrokine-a antibodies, challenges patent

34. Industrial Application Test • Comparable to U.S. specific and substantial utility test • Patent description must disclose a practical way of exploiting the invention in at least one field of industrial activity • Requirement is not satisfied by claiming an interesting research result without specified application • Speculative indication of possible objectives not sufficient

35. Challenges to Patent • Jul 2008: UK Patent Court strikes down patent • 2009: EPO Technical Board of Appeals upholds patent • Feb. 2010: UK Court of Appeal strikes down patent • Possible appeal to UK Supreme Court • NOTE: UK decisions not binding in other EU states

36. Non-obviousness

37. Non-obviousness • A patent may not be obtained… if the differences between the subject matter sought to be patented and the prior artare such that the subject matter as a whole would have been obvious at the time the invention was madeto a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.

38. Biotech Non-obviousness • 1990s to 2007: • Many scholars and firms believed that the court of national jurisdiction for patent appeals (CAFC) had developed the law in such a way that the non-obviousness requirement was too lenient. • Other requirements of the patent law are being applied so as only to uphold relatively narrow claims to DNA or protein sequences (§ 112 requirements). • The upshot: many DNA patents, none of which are worth much. Patent thicket?

39. Biotech Non-obviousness • In re. Bell, 991 F. 2d 781 (CAFC 1993) • DNA seq and cDNA seq for Insulin-like Growth Factor 1 and 2 (IGF1 & 2) are not obvious in light of the completeprotein sequences for each and a well-known method for cloning the DNA. • CAFC: Not obvious!

40. Biotech Non-obviousness • In re Deuel, 51 F. 3d 1552 (Fed. Cir. 1995) • Claim for DNA seq and cDNA seq for heparin binding growth factor (HBGF) not obvious over method of cloning, and a partial protein seq (amino terminus. • PTO argued that when a protein sequence or part of it was put into the public domain, then so was the DNA sequence because a person of ordinary skill in the art would be motivated to clone the gene and would know how to do it. CAFC disagreed!

41. Biotech Non-obviousness • Protein seq plus a method of cloning the gene does not make DNA seq obvious because: • The relationship between DNA seq and protein seq through the genetic code does not establish a prima facie case of obviousness. • Redundancy of the genetic code precludes a scientist from formulating an idea of the exact DNA sequence just by knowing a protein sequence. • No structural similarity between nucleotides and amino acids  there is no structurally similar compound in the prior art for somebody to modify to create the specific, structurally defined DNA molecule. • It is not enough that the general idea of the claimed molecule exists in scientists minds.

42. Biotech Non-obviousness • From Deuel and Bell: • The existence of a method of cloning is “essentially irrelevant” in the absence of information in the field suggesting the exact structure of the DNA molecule (including every base in each codon). • “A general incentive does not make obvious a particular result” and “obvious to try has long been held not to constitute obviousness.” Deuel at 1559.

43. Biotech non-obviousness • Biology as an unpredictable art • Analogy to small molecule chemistry in which a very small change in the molecule can substantially alter its properties. • Contrast to the “predictable arts,” e.g. mechanical and electrical arts • DNA is just another chemical, and we have a chemistry jurisprudence already.

44. KSR International Co. v. Teleflex Inc., 127 S.Ct. 1727 (2007)

45. Facts and Case History • Teleflex holds an exclusive license to pt for an adjustable pedal assembly. • Teleflex sues KSR for infringing claim 4 of its patent. • Claim for combining an electronic sensor with an adjustable automobile pedal so that the pedal’s position could be transmitted to a computer that controls the automobile’s throttle. • Supreme Ct. held that the trial court correctly applied the law when it found this invention obvious.

46. Predictability & Non-obviousness • After KSR, role of predictability in assessing obviousness: • An invention is obvious if… • It is a combination of familiar elements • According to known methods • That does no more than yield predictable results. • An invention is obvious if… • It claims a structure already known in the field and does no more than • Substitute one material or element for another known in the field • And produces a predictable result.

47. Biotech Non-obviousness • Obvious to try test after KSR? • Obvious to try + • Motivation to try from design need or market pressure (or regulatory pressure, or ???) + • Finite number of identified, predictable solutions + • Likelihood of success. • If all of the above apply, then the invention was obvious. Repudiates Deuel’s formulation of the obvious-to-try doctrine.

48. In re Kubin,561 F. 3rd 1561 (Fed Cir 2009)

49. Kubin • Claim for isolated DNA encoding a protein at least 80% identical to 199 amino acids of the NAIL protein (natural killer cell activation inducing ligand, aka P38), “wherein the polypeptide binds CD48.” • Protein had previously been reported, there was a commercially available MAb to NAIL/p38, a mouse ortholog had been cloned and had bound to human DNA. • Previous patent disclosed p38 receptor/NAIL protein and gave explicit instructions on how to clone the cDNA.

50. Kubin • The CAFC upheld the Patent Office’s finding that the Kubin’s NAIL gene sequences were obvious. • Here, the prior patent and lab manual taught the existence of the protein, provided motivation to clone the gene, and provided a step-by-step method for cloning this particular gene  • The prior art provided explicit motivation for somebody to try cloning the NAIL gene, and a “person of ordinary skill in the art” would have had a reasonable expectation of success in doing so given what was disclosed in the prior art. • A person of “skill in this advanced art would find these claimed ‘results’ profoundly ‘predictable.’” p. 1360. • Granting patent protection to advances that would have occurred in the ordinary course of activities in the field retards innovation rather than advancing it.