Myriad, Metabolite, Bilski, and Prometheus: The Four Horsemen of the Biotech Apocalypse?

1. Myriad, Metabolite, Bilski, andPrometheus:The Four Horsemen of the Biotech Apocalypse? Kevin E. Noonan, Ph.D. McDonnell Boehnen Hulbert & Berghoff LLP Professor Christopher Holman

2. Outline of the Talk • Introduction • How did we get here? • AMP v. Myriad Genetics • Parties and interests • The claims: DNA and methods • The arguments • The court’s decision • Constitutional issues?

3. Outline of the Talk • Labcorp v. Metabolite • The claims • The Supreme Court argument • The dissent from dismissal of cert • In re Bilski • The Claims and Federal Circuit decision • How does this relate to biotech?

4. Outline of the Talk Prometheus v. Mayo Labs Claims and issue The Federal Circuit decision: Diagnostic method claims can be patent-eligible Relevance to Myriad decision Recommendations To patent or not to patent 4

5. Introduction 5

6. How did we get here? Tremendous success of a technological age Biotechnology the beneficiary of strong patent protection Biotechnology developed in university setting – 1980 Bayh-Dole Act promotes patenting But success breeds criticism – from variety of sources These include political criticism from those opposed to university patenting 6

7. Where is here? Politically-motivated groups in the arena: ACLU and PubPat PubPat challenges variety of patents (not just biotech); notable the WARF human ESC patents General attitude that patents have become too powerful and retard innovation (little empirical support) Time ripe for Myriad challenge: in addition, the “right” defendant, due to aggressive patent enforcement tactics 7

8. AMP v. Myriad 8

9. Myriad: The parties Suit brought in May 2009, SDNY (Judge Sweet) Plaintiffs: several breast cancer victims, variety of physicians’ groups, certain researchers who claimed research impeded by BRCA patents Defendants: University of Utah (patent assignee), Myriad Genetics, U.S. PTO Supporters: ACLU, PubPat, academics Seven patents/ 15 claims at issue Invalid under patent statute and Constitution 9

10. Patent eligibility versus patentability Patent-ineligible means that the subject matter is not eligible for a patent for public policy reasons notwithstanding the fact that it may be patentable (i.e., useful, novel, and not obvious). Patentable subject matter means the invention as claimed is useful, novel, and not obvious. Myriad: The issue 10

11. Myriad: The claims Two broad types of claims at issue: claims to isolated DNA molecules, and diagnostic method claims DNA claims recite “isolated” DNA encoding specific amino acid sequences (cDNA) Also claims to oligonucleotide probes Method claims: methods of detecting mutation or providing a diagnosis/risk assessment Method claims involve “comparing” mutant sequence to normal sequence 11

12. Myriad: The claims Composition of matter claims covering “isolated DNA” covering the BRCA 1 and BRCA 2 genes. Claim 1 of US Patent 5,747,282 is representative of this class of claims: An isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO:2. 12

13. Myriad: The claims Composition of matter claims covering “isolated DNA” covering the mutations of BRCA 1 and BRCA 2 genes. Claim 1 of US Patent 5,693,473 is representative of this class of claims: An isolated DNA comprising an altered BRCA1 DNA having at least one of the alterations set forth in Tables 12A, 14, 18 or 19 with the proviso that the alteration is not a deletion of four nucleotides corresponding to base numbers 4184-4187 in SEQ. ID. NO:1. 13

14. Myriad: The claims Methods of detecting mutations in the BRCA genes. Claim 1 of US Patent 5,709,999 is the only claim in this class: A method for detecting a germline alteration in a BRCA1 gene, said alteration selected from the group consisting of the alterations set forth in Tables 12A, 14, 18 or 19 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 4184-4187 of SEQ ID NO:1 14

15. Myriad: The claims Methods that “compare” and “correlate” mutations in the BRCA genes with an increased risk of breast or ovarian cancer. Claim 2 of US Patent 6,033,857 is representative of this class of claims: A method for diagnosing a predisposition for breast cancer in a human subject which comprises comparing the germline sequence of the BRCA2 gene or the sequence of its mRNA in a tissue sample from said subject with the germline sequence of the wild-type BRCA2 gene or the sequence of its mRNA, wherein an alteration in the germline sequence of the BRCA2 gene or the sequence of its mRNA of the subject indicates a predisposition to said cancer. 15

16. Myriad: The arguments Regarding the DNA claims, plaintiffs argue that they are “products of nature” and hence not “inventions” No Supreme Court case that DNA patent-eligible Precedent (19th century, subject to interpretation) that “supports” their view Method claim arguments based on Bilski Constitutional argument: violation of 1st Amendment right to biological information and 14th Amendment due process 16

17. Myriad: The decision Judge Sweet agrees that DNA an unpatentable “product of nature” DNA is “the physical embodiment of genetic information” Distinguishes other types of “natural products” (antibiotics, vitamins) on this basis Method claim invalid on Bilski Constitutional arguments avoided, Patent Office dismissed from the lawsuit 17

18. Myriad: The Constitution Although the judge avoided, still important Quickest way to get the Supreme Court’s attention Depends on a failure to appreciate that the information isn’t what is patented in claims to isolated DNA However, information is implicated in method claims, because that is what a diagnostic method claim produces – diagnostic information Should it matter? 18

19. Myriad: Remaining claims A vector comprising isolated DNA operative in a host cell. A host cell containing isolated DNA and control sequences Methods for producing BRCA1 polypeptide comprising culturing cells and harvesting the BRCA1 polypeptide A kit for detecting mutations in the BRCA1 gene A nucleic acid probe specifically hybridizable to BRCA1 DNA The method that amplifies all or part of a BRCA1 gene and sequences the amplified BRCA1 nucleic acids. 19

20. Patentability of Diagnostic Methods

21. Labcorp v. Metabolite

22. Labcorp Claim Claim 13. A method for detecting a deficiency of cobalamin or folate in warm-blooded animals comprising the steps of:  assaying a body fluid for an elevated level of total homocysteine; [a “detecting” step] and correlating an elevated level of total homocysteine in said body fluid with a deficiency of cobalamin or folate [an “inferring” step].

23. General problem of “determine and infer” claims (Prof. Kevin Emerson Collins): Characterized by one or more “determining” steps that involve assays, etc. = transformative Include “mental step” of reaching a conclusion or arriving at an inference based on outcome of determining steps Claim preamble directs method to activity (e.g., diagnosing) based on inference Labcorp dissent - context 23

24. Supreme Court argument • Defendant argued that the claim was not patent-eligible, because it was merely mental activity directed at making a diagnosis • Raised the issue of patents interfering with medicine (surgical techniques earlier lost patent infringement liability) • Methods that occur wholly in the mind, by “correlating” or “comparing” should not be patented

25. Supreme Court argument • Justices heard the arguments, then decided (for procedural reasons) that the Court should not have heard the case • Justices Breyer, Souter and Stevens dissented from this decision • Justice Breyer’s dissent based on his acceptance and agreement with defendants’ argument that the claims not eligible for patenting

26. Labcorp dissent • “As construed by the Federal Circuit, claim 13 provides those researchers with control over doctors' efforts to use that correlation to diagnose vitamin deficiencies in a patient.  Does the law permit such protection or does claim 13, in the circumstances, amount to an invalid effort to patent a ‘phenomenon of nature’"?  • “At most, respondents have simply described the natural law at issue in the abstract patent language of a ‘process.’  But they cannot avoid the fact that the process is no more than an instruction to read some numbers in light of medical knowledge.”  • “[H]ere, aside from the unpatented test, they embody only the correlation between homocysteine and vitamin deficiency that the researchers uncovered.  In my view, that correlation is an unpatentable ‘natural phenomenon,’ and I can find nothing in claim 13 that adds anything more of significance.

27. Labcorp dissent • Justice Breyer misses a few points of well-established patent law: • Whether a claim recites patent-eligible subject matter does not depend on whether the claim is itself patentable • Applications of “phenomena of nature” are patentable; the phenomenon itself is not • Patent eligibility of a claim must be determined from the claim “as a whole”

28. In re Bilski 28

29. In re Bilski: The claims Claims directed to a method for hedging risk in commodities trading Rejected by the patent examiner, affirmed by the patent board of appeals Federal Circuit (appellate court that hears these appeals) agrees, announcing a new test A method to be patentable has to either Be tied to a particular machine or Transform a particular article into a different state or thing 29

30. Supreme Court weighs in Does not reject Federal Circuit test, but says it is not the only test Goes back to first principles, relating to whether what is claimed is an abstract idea that pre-empts every use thereof Benson/Flook/Diehr precedent, wherein applications of abstract ideas are patent-eligible but not if the idea is completely pre-empted But MOT test “should be satisfied” is most cases 30

31. How does Bilski apply to biotech? MOT test not limited to “business methods” Test required for any method, including diagnostic methods Typical diagnostic method is not tied to a particular machine Many diagnostic methods (like in Metabolite) involve using data to make a diagnosis, so don’t “transform” Also based on medical knowledge – is this an “abstract idea”? 31

32. Prometheus Labs v. Mayo 32

33. Consequences of Bilski Decision Prometheus Labs v. Mayo (decided September 16, 2009) Claims a method for optimizing treatment of an immune-mediated gastrointestinal disorder with 6-thioguanine Recited steps of administering the drug to a patient and detecting 6-thioguanine or 6-methyl-mercaptopurine (metabolite) in blood Recites inferring step of therapeutic efficacy when 6-thioguanine levels in red blood cells are between 230 pmol-400 pmol per 8 x 108 red blood cells Levels outside these ranges “indicates a need” to adjust administration amounts accordingly – but does not recite affirmative steps of adjusting 33

34. Prometheus Labs v. Mayo Steps for administering a drug and determining metabolites can be transformative and satisfy Bilski Such steps can be “method of treatment” steps that are “always transformative” Involving “natural processes” not determinative, since “every transformation of physical matter . . . occurs as the result of natural processes” A process for chemical or physical transformation of a physical object or substance are “virtually self-evidently” patent-eligible subject matter Inclusion of a mental step does not negate patent-eligibility 34

35. Prometheus Labs v. Mayo In the wake of Bilski, the Supreme Court granted cert, vacated the Federal Circuit decision and remanded Mayo has asked the court for en banc review No matter what the Federal Circuit decides, expect appeal to Supreme Court 35

36. Consequences and the Future

37. Recommendations: Isolated DNA claims • If “isolated” is insufficient, many DNA claims invalid • Consequences depend on what the claims are protecting • For making therapeutic proteins, recombinant cell claims should survive • Vector claims should also be patentable (man-made) • Kit claims should also be patentable, as manufactures

38. Recommendations: Diagnostic Method claims Fate of diagnostic method claims may be language-dependent Insofar as claim can be cast as “merely mental step” then at greater risk “Correlating”/“comparing” language problematical Claims containing more active steps (like “sequencing”) may be at lower risk 38

39. Recommendations: Diagnostic Method claims Bigger problem for these claims (even if they survive Bilski /Prometheus decisions) Potential for a patent “thicket” Some efforts around this (patent pooling, SNP consortium, Navigenics “ASCAP” solution) Will get worse before it gets better, particularly regarding personalized medicine 39

40. Recommendations: Ways forward Patented technology Licensing Litigation New technology To patent or not to patent 40

41. Recommendations: Patented technology “Narrowing” reissue a possibility For DNA claims, can limit to “manufactured” DNA – claim scope expressly outside chromosomal DNA by structure Can also narrow vector claims to these embodiments Diagnostic method claims to include “active” steps like sequencing 41

42. Recommendations: Patented technology In litigation, DNA claims not usefully asserted But then, what damage (usually) from DNA claim alone? Recombinant cells should survive Myriad even at Supreme Court Pharmaceutical infringement should involve at least use of recombinant cells 42

43. Recommendations: New technology Patenting may not be an option (or at least be unattractive) For industry, when you cannot patent, trade secret becomes attractive Not easy, but attractive But may be worth the risk and investment Broad (and negative) implications for academic research 43

44. “Old” technology BRCA1 and BRCA2 the anomalous – many common diseases (diabetes, most cancers, cardiovascular disease) multigenic Requires detection of more than one dominant mutant gene Not difficult to identify “disease” genes But may be difficult to obtain sufficient correlations between several genes to be useful 44

45. Recommendations: New technology Academia versus industry: what industry does better Focused investigation to determine which genes in combination are diagnostic Wealth of genetic data (thanks, Human Genome Project) + large reservoirs of frozen tumor and other tissue Capacity to use both for to develop assays for making diagnostic decisions 45

46. Recommendations: Diagnostic methods/ trade secrets With existing technology, can analyze tens of thousands of frozen normal and disease-specific tissue samples Identify the differences between normal and disease that are common in disease Perform prospective study on normal/ diseased cohorts to show predictive power Assemble roster of disease-specific genes for a particular disease 46

47. Recommendations: Diagnostic methods/ trade secrets Diagnostic test is “gene chip” containing >10,000 sequences Some of these are specific for the disease (multiple sequences from different genes) Some are positive controls Some are negative controls All are assembled on the chip “randomly” – positions encrypted for each chip 47

48. Recommendations: Diagnostic methods/ trade secrets Encryption informs reader which sequences are determinative for disease Billions of permutations, (almost) impossible to decipher/reverse engineer Showing of reliability may be required, but identity of genes should not be FDA issues regarding extent of disclosure required, but alternative may be no test at all 48

49. Recommendations: Diagnostic methods/ trade secrets Consequences: Academia/industry collaborations over Research-intensive efforts preclude global approaches Pace of genetic research on diseases slows Disclosure disappears No disclosure = no need to reduce prices ever Fundamentally shifts progress (negatively) and incentives to innovate 49

50. Recommendations: Possible alternative Industry abandons the space entirely Diagnostic genetic testing done in university or hospital settings exclusively Concentrated in large medical centers, with advantages and disadvantages: Test consistency and reliability concerns Relationship to university mission Best use of resources Availability/cost of genetic counseling 50