The Alchemy of Personalized Medicine: Turning Biomarkers into Gold Debra (Deb) Gordon, Ph.D., J.D. San Diego, CA 19-MAY-2011
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The Alchemy of Personalized Medicine:Turning Biomarkers into Gold
Debra (Deb) Gordon, Ph.D., J.D.San Diego, CA19-MAY-2011
Footnote text
Personalised Healthcare at RocheStrong 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
Early ForesightDirected Acquisitions Dating Back Years
*majority ownership
1990 1995 2000 2005 2010
Syntex
Boehringer M.
Chugai*
Ventana
Boehringer M. #1in Biotech
#1 in IVD
Genentech
PCR
SyntexGenentech*
Rich History One Company
Today1990 1995 2000 2005 2010
Syntex
Boehringer M.
Chugai*
Ventana
Boehringer M. #1in Biotech
#1 in IVD
Genentech
PCR
SyntexGenentech*
Rich History One Company
Today
Pharma Diagnostics
The Roche GroupStructured to Facilitate PHC
ChugaiGenentech RocheDiabetes
Care
RocheAppliedScience
RocheProfessionalDiagnostics
RocheMolecular
Diagnostics
RocheTissue
Diagnostics
RochePharma
Ventana End to End Biomarker Development
Uniquely Positioned to Partner with Pharma to Develop Companion Dx
BiomarkerDiscovery
IVDDevelopment
ClinicalValidation
PMA Dx ClinicalTrial
PrototypeAssays
Translational Diagnostics – TDx Life Cycle Management
Drug Development
Pre-Clinical Phase I Phase II Phase III Commercialization
Example Drug Candidates Developed as Personalized Therapies
T-DM1 Metastatic breast cancer
(HER-2 expression level)
PertuzumabMetastatic breast
cancer(HER-2/3 expression
level)RG71281
Hepatitis C(HCV viral load,
genotype)
MetMAb1
Non-small cell lung cancer
(MET status)
Lebrikizumab1
Asthma(periostin level)
RG7204Metastatic melanoma
(BRAF V600E mutation)
1 Phase III start pending
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.
Diversity Global Scale / Reach
Phar
ma
Dia
gnos
tics
Cohesion
Gro
up
Finance, IT, Legal, HR, Communications
PartneringPharma MedicinespRED
gRED
Chugai
Global Functions
DiagnosticsRegions
Diabetes Care
Business Areas
Roche Group OrganizationFocus on & Facilitate PHC
**
**Worldwide Sales Affiliates
The Alchemy of Personalized Medicine: Turning Biomarkers into Gold
Terry Mahn, Fish & RichardsonTeresa Lavoie, PhD, Fish & Richardson
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 righttime to right patient
10
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
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
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 well‐established 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
Biomarkers
• Probable Valid biomarker (FDA) – scientific framework is not yet established
• Known Valid biomarker (FDA) – widespread agreement in the medical or scientific community
14
Examples of Biomarkers:
Genetic ‐ e.g., SNP, insertion, deletion, amplificationNon‐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
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
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
Examples of Known Valid Biomarkers onApproved 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
Examples of Biomarker Tests on ApprovedLabels
• 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
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
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
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
Patents
Compositions (e.g., probes/primers, antibodies, arrays)
Assay Methods (e.g., risk, diagnosis, prognosis, drug response)
23
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
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
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
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 exclusivetest 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
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
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
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
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
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, data‐gathering steps”
32
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
Patent‐Eligible Subject Matter: Claim Strategies
Claims to primers, probes, antibodies, and arrays for detecting the marker(s) Issue:
‐ Patent‐eligible subject matter: Myriad• how does DNA differ from polypeptides etc. that also occur naturally in
the body?
‐ Possible fixes:• 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
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
Issue: Multiple party infringement- MuniAuction – Fed. Cir. 2008; SIRF Technology ‐ Fed. Cir. 2010
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 outcometo:
(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
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
Issue: Patent‐eligible subject matter Possible fixes:
- Claim uses of multiple markers- Consider that certain limitations:
• May not “limit” the claimso 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
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
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
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
Composition claims
Utility
Can be problematic for SNP claims
This SNP has been linked to specific treatment, so should be OK
42
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
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
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
Method claims
Can also claim methods that link the SNP to treatment with Drug X, as illustrated in the next hypothetical
46
Hypothetical #2
Known in the art: 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
Method claims (Hypo #2)
5. A method comprising
(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
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
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
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
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
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
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
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
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
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
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
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
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