The Alchemy of Personalized Medicine: Turning Biomarkers into Gold. Debra (Deb) Gordon, Ph.D., J.D. San Diego, CA 19-MAY-2011

Transcription

1 The Alchemy of Personalized Medicine: Turning Biomarkers into Gold Debra (Deb) Gordon, Ph.D., J.D. San Diego, CA 19-MAY-2011

2 Personalised Healthcare at Roche Strong Commitment It is an unfortunate fact that medicines are currently not as effective as they could be, with a substantial proportion of patients not receiving adequate benefit from their medication. This is why Roche is systematically pursuing Personalised Healthcare it is an approach that has the potential of increasing the efficacy, safety and cost-effectiveness of treatment. Severin Schwan, May 2008 Footnote text

3 Early Foresight Directed Acquisitions Dating Back Years Rich History One Company PCR Genentech * Syntex Syntex #1 in IVD Boehringer M. Ventana Genentech Chugai * Boehringer M. #1 in Biotech Today * majority ownership

4 The Roche Group Structured to Facilitate PHC Pharma Diagnostics Roche Pharma Genentech Chugai Roche Applied Science Roche Molecular Roche Professional Roche Tissue Diagnostics Diagnostics Diagnostics Roche Diabetes Care

5 Uniquely Positioned to Partner with Pharma to Develop Companion Dx Drug Development Pre-Clinical Phase I Phase II Phase III Commercialization Ventana End to End Biomarker Development Translational Diagnostics TDx Life Cycle Management Biomarker Discovery Prototype Assays Clinical Validation IVD Development PMA Dx Clinical Trial

6 Example Drug Candidates Developed as Personalized Therapies T-DM1 Metastatic breast cancer (HER-2 expression level) Pertuzumab Metastatic breast cancer (HER-2/3 expression level) RG Hepatitis C (HCV viral load, genotype) MetMAb 1 Non-small cell lung cancer (MET status) Lebrikizumab 1 Asthma (periostin level) RG7204 Metastatic melanoma (BRAF V600E mutation) 1 Phase III start pending

7 Disclaimer: Any opinions expressed herein are the views of the speaker and do not necessarily reflect the views and opinions of Ventana Medical Systems, Inc. or any other member of The Roche Group of companies.

8 Roche Group Organization Focus on & Facilitate PHC Pharma Diversity gred pred Partnering Global Scale / Reach Chugai Pharma Medicines Diagnostics Business Areas Global Functions Diabetes Care Diagnostics Regions ** Group Finance, IT, Legal, HR, Communications Cohesion **Worldwide Sales Affiliates

9 The Alchemy of Personalized Medicine: Turning Biomarkers into Gold Terry Mahn, Fish & Richardson Teresa Lavoie, PhD, Fish & Richardson

10 Why Personalized Medicine? Traditional epidemiological studies of large cohorts do not account for genetic variability of individuals within a population Result drugs are not effective due to heterogeneity of diseases and variability in drug response 2009 PWC study found only 20 75% of patients respond to drugs they are taking; 2009 HHS report said <60% Goal of PM ensuing the right drug at the right dose is prescribed at right time to right patient 10

11 How is PM Achieved? Determining how genes, proteins and metabolic pathways impact human physiology Molecular profiling technologies ( translational research ) genomics proteomics metabolomics Development of companion diagnostics Stratification of diseases selection of proper medication and tailoring dosages to patient needs Assessment of particular risk factors Identification of relevant biomarkers 11

12 Elements of PM Simplified Reliance on relevant biomarkers Availability of diagnostic tests Clinical expertise to interpret test data Selection of best drug or dosage for the individual patient 12

13 Biomarkers Definition (FDA) characteristic that is objectively measured and evaluated as an indication of normal biologic processes, pathogenic processes or pharmacologic response to a therapeutic intervention Valid biomarker (FDA) measured in an analytical test system with wellestablished performance characteristics and for which there is an established scientific framework or body of evidence that elucidates the physiologic, toxicologic, pharmacologic or clinical significance of the test results 13

14 Biomarkers Probable Valid biomarker (FDA) scientific framework is not yet established Known Valid biomarker (FDA) widespread agreement in the medical or scientific community 14

15 Examples of Biomarkers: Genetic e.g., SNP, insertion, deletion, amplification Non Genetic e.g., Polypeptide/carbohydrate/lipid levels Cells Cell surface molecule alterations Immunoglobulin/antibody levels Enzyme activities/drug metabolism Hormones/levels Changes to CBC, other hematologic changes Pathogen responses Neurotransmitter levels/types Medical imaging changes 15

16 FDA Regulation of Biomarkers Disease related vs. drug related individualize/personalize therapies maximize drug effectiveness minimize drug risk Different biomarker submission algorithms required for INDs, NDAs/BLAs and Supplements 16

17 Biomarkers on Drug Labels Information purposes 10% of all labels include some biomarker information Dose adjustments based on metabolism genotype Side effects in individuals with certain genotype or gene expression profiles Therapeutic purposes testing required or recommended Choosing dose or dosing schedule Identifying patients at risk Identifying patient responders 17

18 Examples of Known Valid Biomarkers on Approved Drug Labels Maraviroc (first approved biomarker test 2007) genetic test to determine mutation of HIV virus Gleevec test to identify patients that over express a particular protein, to treat GIST Revlimid test for cytogenetic abnormality, to treat transfusion dependent anemia Warfarin genotype test to identify SNPs, for accurate dosing of coumadin Ziagen test for alleles to calibrate dosing Plavix genotype test to identify patients who may not respond to drug Elitek test for enzyme deficiency to determine patient monitoring Herceptin test for over expression of protein to identify cancer patients eligible to take the drug 18

19 Examples of Biomarker Tests on Approved Labels EGFR Pharma DX test tests for presence of cell receptors for certain cancer treatments Invader UGT1A1 Molecular Assay detects gene variations to determine dosing for certain drugs >2000 off label genetic tests in NIH data base 19

20 Why PM is the Future of Healthcare Biomarker testing is becoming less complex, more standardized and cheaper More valid biomarkers are being identified Point of care testing is being made more available Smart dosing algorithms are being developed Future standards of care will incorporate testing for disease stratification dosing selection monitoring of outcome 20

21 Biomarker Patents and Drug Labels Biomarker patents for information purposes only Not a condition of use No OB listing Will not block generic entry Biomarker patents for therapeutic purposes May be a method of using drug (screening, dosing, monitoring, etc.) OB listable Can extend product life cycle (block generic entry) Screening test may also qualify to be on label 21

22 Patents Newly discovered marker that correlates with risk, diagnosis, prognosis, and/or drug response Previously known marker newly discovered correlation(s) Multiple markers and correlations 22

23 Patents Compositions (e.g., probes/primers, antibodies, arrays) Assay Methods (e.g., risk, diagnosis, prognosis, drug response) 23

24 Claims to primers, probes, antibodies, and arrays for detecting the marker(s) Greater Perceived Value? Issues: Prior art/scope Utility Near future irrelevance (personal genome sequencing) Enablement (antibodies?) Patent eligible subject matter 24

25 PATENT ELIGIBLE SUBJECT MATTER The U.S. patent statute sets out four categories of patent eligible subject matter: processes, machines, manufactures, and compositions of matter. The Supreme Court has called out three exceptions to these categories: abstract ideas, laws of nature, and physical phenomena. These judicially recognized exceptions have been described using various other terms, e.g., mental processes, natural phenomena, products of nature, scientific principles, disembodied concepts, mathematical algorithms and formulas. 25

26 A specific application of a judicially recognized exception can constitute patent eligible subject matter, provided the application does not wholly preempt the use of the exception such that it would amount to a patent on the exception itself. 26

27 EVOLVING CASE LAW: A. Bilski Claims to methods of hedging risk in commodity trading Federal Circuit (en banc) held the claims invalid as failing to meet the machine or transformation test, which it held to be the exclusive test for patent eligible subject matter Supreme Court affirmed invalidity, but determined that the machine or transformation test is not the exclusive test The Supreme Court also recognized only three exceptions: laws of nature, physical phenomena, and abstract ideas (the Bilski case dealt with the abstract idea exception) Diagnostic and PM claims more likely will face the law of nature analysis 27

28 B. Labcorp v. Metabolite (Supreme Court, Pre Bilski) Claim: Method for detecting a deficiency of cobalamin or folate, comprising assaying for an elevated level of total homocysteine; and correlating an elevated level with the deficiency The Court held the writ of certiorari to have been improvidently granted, and dismissed the case Three dissenters, Breyer, Stevens, and Souter, stated: There can be little doubt that the correlation between homocysteine and vitamin deficiency set forth in claim 13 is a "natural phenomenon."... [The claimed] process instructs the user to (1)obtain test results and (2) think about them.... At most, respondents have simply described the natural law at issue in the abstract patent language of a process. 28

29 C. Prometheus v. Mayo Claims: Methods of optimizing therapeutic efficacy, comprising administering a drug [in the prior art] determining the level of a metabolite of the drug [in the prior art] wherein a level less than X indicates a need to increase the amount of drug administered and wherein a level greater than Y indicates a need to decrease the amount of drug administered Other claims omitted the administering step Federal Circuit held the claims valid as meeting the machine or transformation test The Supreme Court granted cert., vacated the Federal Circuit panel decision, and remanded for reconsideration in light of Bilski 29

30 C. Prometheus v. Mayo (cont.) On Remand: The Fed. Cir. reaffirmed its previous decision: claims are patent eligible Acknowledged the last step was a mental step; but claims must be viewed in their entirety Found both types of claims (with or without administering step) patent eligible under the machine or transformation test Treatment steps are always transformative when defined drugs are administered to a body to treat an undesired condition Determining step is also transformative, not mere data gathering, since it works a chemical and physical transformation on physical substances, which sufficiently confines the patent monopoly as required by the machine or transformation test Court emphasized the claims are directed to treatment protocols, which may limit the decision s implications for many diagnostic claims Also, does not address situation where personal genome sequence is known, and no wet lab test is necessary 30

31 D. AMP et al. v. USPTO et al. ( Myriad ) Claims: Isolated, non mutated nucleic acids encoding BRCA1/2; also fragments; also isolated DNA with a BRCA1/2 mutation Methods of diagnosis, e.g.: A method for identifying a mutant BRCA by comparing the suspected mutant BRCA allele sequence with the wild type sequence, wherein a difference identifies a mutant. Methods of screening for new cancer therapeutic drugs using host cells transformed with mutant BRCA nucleic acids, and comparing growth in presence/absence of drug candidate 31

32 D. Myriad (cont.) SDNY (Judge Sweet) decision: Composition claims are directed to unpatentable products of nature; isolation of the DNA from its native environment does not render the claimed DNA markedly different Diagnostic method claims rejected under the machine or transformation test Claims directed only to abstract mental processes of comparing or analyzing gene sequences, not molecules Do not require isolating or sequencing; and, isolating and sequencing would be mere data gathering steps that would not save the claims in any case Screening claims rejected as claiming a basic scientific principle; transformative steps are nothing more than preparatory, datagathering steps 32

33 D. Myriad (cont.) On appeal to the Federal Circuit: Myriad s principal brief on appeal: products of nature not an exception to 101 Court ignores longstanding USPTO practice Court misread Supreme Court precedent Markedly different standard is wrong Court was wrong in rigidly applying the MOT test (post Bilski), and ignored transformation of human samples and BRCA molecules in samples U.S. Dept. of Justice Amicus Brief 101 requires more than identifying and isolating what exists in nature Isolated genomic DNA is unpatentable; cdna, vectors etc. are patent eligible 33

34 Patent Eligible Subject Matter: Claim Strategies Claims to primers, probes, antibodies, and arrays for detecting the marker(s) Issue: Patent eligible subject matter: Myriad Possible fixes: how does DNA differ from polypeptides etc. that also occur naturally in the body? hope that Myriad is modified or goes away claim substrates or other specific assay components claim kits/combinations with multiple markers claim N.A. s that differ from the sequences found in nature 34

35 Claims to Assay/Correlation Methods Issue: Prior Art (known variants) - inherent anticipation Possible fixes: - claim substrates or other specific assay components - claim kits/combinations with multiple markers BUT!! might simplify design around, so choose combinations that provide synergistic effect or unexpected additional statistical power strengthen non obviousness argument and less readily designed around by deletion of one factor 35

36 Issue: Multiple party infringement - MuniAuction Fed. Cir. 2008; SIRF Technology Fed. Cir Possible fixes to multiple party issue: - Construct claims that are infringed by a single party, e.g., change (1) isolate DNA from a patient s tumor sample, (2) test the DNA for presence [absence] of biomarker, and (3) modify the patient s medical record to reflect the test outcome to: (1) test a patient s tumor DNA for presence [absence] of biomarker; and (2) communicate the test results to the patient s health care provider (of course, the revised claims may present other problems) 36

37 Issue: What if the patient s genome/proteome/metabolome is known? - How accurate? Does it require confirmatory sequencing in the marker region(s)? - how to claim when assay is merely inspecting a database? Potential Fixes: - consider active method steps post inspection - not an issue if specific tissue (e.g., tumor etc.) needs to be tested, e.g., for mutations not likely to be present in germ line 37

38 Issue: Patent eligible subject matter Possible fixes: - Claim uses of multiple markers - Consider that certain limitations: May not limit the claims o e.g., wherein or whereby clauses that simply state disembodied facts May encompass mental steps, e.g.: o correlating or determining o classifying or diagnosing (may be better?) - Such limitations may be problematic if they represent the sole basis for patent eligible subject matter 38

39 Possible fixes (cont.): - Consider adding active steps: Communicate results to another (but see, King Pharmaceuticals v. Eon Labs) Modify a patient s medical record Refer the patient to a particular specialty Administer a drug, discontinue a drug, change a dose or dosing schedule, or undertake another treatment, in response to the assay (of course, any/all of these may have other problems ) 39

40 Hypothetical #1 Known in the art: Sequence of all exons of ABC gene, including exon 1 (SEQ ID NO:1) Drug X is sometimes effective for treating pancreatic cancer Newly discovered: Novel G>T SNP at position 212 of SEQ ID NO:1 Drug X is effective only in tumors containing the SNP. 40

41 Composition claims Claim the biomarker: 1. An isolated nucleic acid comprising SEQ ID NO:1 in which the G at position 212 is replaced with a T. 2. An isolated nucleic acid comprising a fragment of SEQ ID NO:1 at least 15 nucleotides in length, the fragment encompassing position 212 of SEQ ID NO:1, wherein the G at position 212 is replaced with a T. Claim probes and primers Patent eligible subject matter (Myriad)? 41

42 Composition claims Utility Can be problematic for SNP claims This SNP has been linked to specific treatment, so should be OK 42

43 Method claims Claim method of detecting the biomarker: 3. A method comprising (a) providing a sample comprising nucleic acid of a human; and (b) determining whether the nucleic acid comprises an ABC gene in which the G at position 212 of SEQ ID NO:1 is replaced with a T. Inherent anticipation Inherently anticipated by prior art sequencing of exon 1 (SEQ ID NO:1) Reword as determining that 43

44 Method claims Patent eligible subject matter (Prometheus)? Determining alone could be broadly read to cover not only assaying, but also just thinking or reading (no transformation) Providing alone can be read as passive (no transformation) Combining the two steps implies that an assay (transformation) is done Better to make transformation explicit in definition or claim, as in claim 4 44

45 Method claims 4. A method comprising (a) providing a sample comprising nucleic acid of a human, the nucleic acid comprising exon 1 of an ABC gene; (b) assaying the sample to identify the nucleotide at position 212 of SEQ ID NO:1; and (c) determining that the nucleotide at position 212 is a T. Step (b) makes transformation explicit Step (c) is necessary to avoid inherent anticipation 45

46 Method claims Can also claim methods that link the SNP to treatment with Drug X, as illustrated in the next hypothetical 46

47 Known in the art: Hypothetical #2 Sequence of all exons of ABC gene, including exon 1 (SEQ ID NO:1) G>T SNP at position 212 of SEQ ID NO:1 is associated with some cases of pancreatic cancer Drug X is sometimes effective in treating pancreatic cancer Newly discovered: Drug X is effective only in tumors containing the SNP. 47

48 5. A method comprising Method claims (Hypo #2) (a) determining that an ABC gene of a pancreatic cancer patient includes a T at position 212 of SEQ ID NO:1; and (b) treating the patient with Drug X. Step (b) provides transformation, so don t need a transformative assay step Can use broad determining language here e.g., just reading a report Use of determining instead of assaying helps avoid possible joint infringement problems Both steps (a) and (b) are necessary to avoid inherent anticipation 48

49 Method claims (Hypo #2) Broader claim 6 is probably inherently anticipated: 6. A method comprising (a) determining whether an ABC gene of a pancreatic cancer patient includes a T at position 212 of SEQ ID NO:1; and (b) if the ABC gene includes a T at position 212, treating the patient with Drug X. Step (a) ( determining whether ) encompasses both outcomes (T and not T). Step (b) applies only if position 212 is a T, so (b) is not limiting if not a T. Claim is anticipated by any instance in the art when position 212 of an ABC gene of a pancreatic cancer patient was found to be G (or C or A). 49

50 Method claims (Hypo #2) Claim 7 is probably also inherently anticipated: 7. A method comprising (a) assaying a sample comprising nucleic acid of a pancreatic cancer patient to identify the nucleotide at position 212 of SEQ ID NO:1; and (b) determining that the nucleotide at position 212 is a T, wherein a T at position 212 indicates that Drug X will be effective in treating the patient. Wherein clause does not further limit the claimed method. Describes an inherent property that was always present, though not recognized No action (not even thinking) is required by the wherein clause, unlike claim 8 50

51 Method claims (Hypo #2) 8. A method comprising (a) assaying a sample comprising nucleic acid of a pancreatic cancer patient to identify the nucleotide at position 212 of SEQ ID NO:1; and (b) determining that the nucleotide at position 212 is a T; and (c) diagnosing the patient as in need of treatment with Drug X. Positive step of diagnosis (step (c)) provides novelty But joint infringement issue If omit assaying step to cure joint infringement problem, then may not have patent eligible subject matter (no transformation) 51

52 Claims on the label Label language should track claim language Patent people and regulatory people should agree on language useful for both claims and label Pioneer negotiates label with FDA Generic label with patent protected information can be evidence of direct infringement or inducement of infringement Generic generally must copy Pioneer label word for word 52

53 FDA s Label carve out Rules Generic label generally required to be identical to pioneer label Exception for patent protected use for which generic is not seeking approval Patent carve out allowed only if generic drug is no less safe or effective than pioneer for all remaining non protected conditions of use Only patents in OB can be carved out; thus, an FDA required Biomarker test on the label that is not a method of using the drug cannot be carved out 53

54 Biomarker Patents and Generic Carve Outs Grasping the mechanics of the carve out rule: Identify protected language on pioneer label Carve protected language out of label, leaving only non protected conditions of use this is the proposed generic label Compare S&E of generic label with the full pioneer label If generic is less S or E for uses on the generic label, no carve out allowed Biomarker patents that improve safe or effective treatment of patients should survive carve out attempts Biomarker patents that add an indication may be carved out 54

55 Biomarker Patents and Generic Carve Outs Carve out examples: 1) Drug X approved to treat Indication A (not patented) and for patients with [a certain genotype] to treat Indication B (patented). Generic seeks to carve out Indication B. FDA would find Generic as S&E as Pioneer for treating Indication A. 2) Drug X approved for treating Indication A. Warning on label requires patients of a certain genotype to lower dosage due to known adverse effects. OB patent claims method of testing for the genotype and lowering dosage to avoid adverse effects. If Generic seeks to carve out warning, FDA would find it less safe than Pioneer for patients with genotype. 55

56 Biomarker Patents and Generic Carve Outs Orange Book use codes Use code required to describe method of use claimed in the patent and approved by FDA (140 characters) Use means any conditions of use on approved label Pioneer is allowed to select use code language Use code determines scope of generic carve out 56

57 Biomarker Patents and Generic Carve Outs Biomarkers and use codes Carve out example # 1 Drug X approved to treat Indication A (not patented) and for patients with [a certain genotype] to treat Indication B (patented) Indication A liver cancer Indication B non small cell lung cancer Use Code method of treating cancer Result no carve out because use code applies to both indications Is this Kosher? Caraco v. Novo Nordisk (CAFC 2010) 57

58 Biomarker Patent Strategy Develop internal guidelines to coordinate patent, clinical and regulatory functions, focusing on carve out issues Beware of turf battles Legal focus is on maximizing patent protection, minimizing risk Marketing how do new warnings or conditions impact sales? Scientific will want to see scientific or medical rationale for labeling changes Regulatory compliance protective of labeling text; overly deferential to FDA 58

59 Biomarker Patent Strategy Regulatory personnel need to understand the kinds of labeling protections likely to survive generic carve out efforts Clinical trials and PMRs should be designed with carve out rules in mind Patents should be prosecuted with carve out rules in mind Inventorship issues need to anticipated in licenses and contracts Orange Book use codes should be carefully reviewed with carve out rules in mind 59