Download Patentability of Diagnostic Methods and Biomarkers

Patentability of Diagnostic Methods
and Biomarkers:
A European Perspective
Ana Suarez-Miles
Russell Thom
Oliver Kingsbury
Overview
1) Patentability of inventions under the EPC
– Overarching principles, “Not inventions” and “Excluded” inventions
– Exclusions of particular relevance for biomarkers and diagnostics
2) Claiming personalised medicine inventions in Europe:
– How do the exclusions operate in practice
– How have (or haven’t) they been overcome
3) Claiming diagnostic methods in Europe:
– How do the exclusions operate in practice
– How can we consider these during drafting and prosecution
4) Questions
Patentable inventions under the EPC
Overarching Principle
Article 52(1)
European patents shall be granted for any inventions, in all fields
of technology, provided that they are new, involve an inventive step
and are susceptible of industrial application.
Section 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.
“Not Inventions”
Article 52(2)
The following in particular shall not be regarded as inventions
(a) discoveries, scientific theories and mathematical methods;
(b) aesthetic creations;
(c) methods for performing mental acts, playing games or doing
business, and programs for computers;
(d) presentations of information.
Article 52(3)
Paragraph 2 shall exclude patentability only to the extent to which a
patent application or patent relates to such subject-matter or
activities as such.
“Excluded” Inventions
Article 53
European patents shall not be granted in respect of:
(a) inventions the commercial exploitation of which would be contrary
to "ordre public" or morality; such exploitation shall not be
deemed to be so contrary merely because it is prohibited by law or
regulation in some or all of the Contracting States;
(b) plant or animal varieties or essentially biological processes for
the production of plants or animals; this provision shall not apply
to microbiological processes or the products thereof;
(c) methods for treatment of the human or animal body by surgery or
therapy and diagnostic methods practised on the human or
animal body; this provision shall not apply to products, in particular
substances or compositions, for use in any of these methods.
Article 53(c) – Excluded Method Claims
Enlarged Board of Appeal in G1/07 – 15 February 2010
“The three alternative exclusions in Art 53(c) are thus cumulative
requirements. In order to be patentable a claimed method must
neither be a therapeutic nor a surgical nor a diagnostic one.”
Art 53(c) – The Bermuda Triangle
Therapeutic
Method
Human or
Animal Body
Surgical
Method
Diagnostic
Method
Therapeutic Method
A method suitable or potentially suitable for maintaining or restoring the
health, the physical integrity and the physical well being of a human
being and to prevent diseases
Any method claim which includes or encompasses a therapeutic step
falls within the exclusion
Method must be practiced on the (living) human or animal body
Historically circumvented by “Swiss-style” claim format. Now avoided
by “Product X for use in the treatment of disease Y” claims.
Surgical Method
A method is surgical if it includes:
An invasive step representing a substantial physical intervention on the
body which requires professional medical expertise to be carried out
and which entails a substantial health risk even when carried out with
the required professional care and expertise
Any method claim which includes or encompasses a surgical step falls
within the exclusion
Method must be practiced on the (living) human or animal body
Diagnostic Method
A method is only diagnostic if it includes all of the following steps:
(a)
(b)
(c)
(d)
Examination phase involving the collection of data
Comparison of these data with standard values
Identification of a deviation from the normal or desired state
Attribution of the observed deviation to a particular clinical picture
Furthermore,
Any steps of a technical (rather than mental) nature must satisfy the
criterion “practised on the human or animal body”
Diagnostic Method
Does not depend upon the participation of a medical or veterinary
practitioner (i.e. exclusion applies to patient-operated methods)
Does not require a specific type or intensity of interaction with the
human or animal body; merely necessitates the presence of the latter
The steps of a technical nature which must be practised on the human
or animal body will generally be within the examination phase
Narrow exclusion
CLAIMING PERSONALIZED MEDICINE
INVENTIONS IN EUROPE
ANA SUAREZ-MILES
Use of Biomarkers for patient selection
In a drug development program presence or absence of specific biomarkers can be
useful in the selection of patient population :
•
for better definition of the disease and/or its prognosis: Identification of patients
with a particular disease sub-type or disease severity as a target (e.g., Her-2 and
breast cancer, or Philadelphia chromosome in chronic myeloid leukaemia).
•
for excluding patients at increased risk: Identification of patients at increased risk
of experiencing a serious adverse drug reactions for the purpose of excluding them
from further clinical trials or treatment with that specific agent.(e.g., HLA B* 5701 and
abacavir use or carbamazepine and HLA-B*1502)
•
for prediction of drug response: Identification of patients with high likelihood of
experiencing benefit with a particular medicinal product with few or no safety
issues/adverse events (trastuzumab in Breast cancer with Her-2 overexpression).
1. A compound X for use in treating disease Y in a patient with BIOMARKER A
Company Confidential
Copyright © 2009 Eli Lilly and Company
14
EPO Case Law - New therapeutic application based
on the group of subjects to be treated
•
G5/ 83 Headnote:
II. A European patent may be granted with claims directed to the use of a substance
or composition for the manufacture of a medicament for a specified new and
inventive therapeutic application.
•
T19/86: (sero-positive vs. Seronegative piglets)
The therapeutic application of a vaccine, which is known for treatment of a particular
class of animal to a new and different class of the same animal is a second
medical use within the principle set out in Decision G 05/83, and is therefore
patentable if such new use is inventive.
•
T 893/90 (haemophilic patient vs. normal, non-haemophilic subject).
A method of producing a pharmaceutical composition for controlling bleeding in nonhemophilic mammals characterized by forming a mixture of phospholipid vesicles and mammalian blood
Factor Xa in a form suitable for administration, the phospholipid and Factor Xa being present in amounts and in
proportions just sufficient to arrest bleeding, said mixture excluding other physiologically-active materials.
•
T 233/96 vs. T1399/04 Company Confidential
Copyright © 2009 Eli Lilly and Company
15
T 233/96 :
"a human who is unable to exercise adequately"
Claim:
1. The use of adenosine as a pharmacological stressor in the preparation of a diagnostic agent to be
given to "a human who is unable to exercise adequately"...
If the use of a compound was known in the treatment or diagnosis of a disease of a
particular group of subjects, the treatment or diagnosis of the same disease with the
same compound could nevertheless represent a novel therapeutic or diagnostic
application, provided that
i.
it is carried out on a new group of subjects which is clearly distinguishable with respect
to its physiological or pathological status
ii.
and does not overlap with the group previously treated
iii. the choice of the new group must not be arbitrary, which means that there must exist a
functional relationship between the particular physiological or pathological status
of this new group and the therapeutic effect obtained.
•
"a human who is unable to exercise adequately" cannot be regarded as a feature capable
of distinguishing the subject-matter of claim 1 from the closest prior art.
Company Confidential
Copyright © 2012 Eli Lilly and Company
16
T 1399/04 physiological and pathological status
“the patient is an antiviral treatment naive patient, and the patient is one having a
HCV genotype type 1 infection and a viral load of greater than 2 million copies per ml of
serum as measured by HCV-RNA quantitative PCR."
•
at least more than 50% overlapped with the patient group disclosed in the prior art.
•
The Patentee argued that the patient group according to present claims 1 to 3 is defined
as being infected by a specific genotype of HCV, genotype 1, which is a pathological
characteristic allowing to differentiate members of this group from all other HCV patients,
and it is further defined by a viral load of greater than 2 million copies per ml of serum,
which is a physiologically characterising feature. Both features are not disclosed in
document (OD8).
•
The Boards of appeal, considered that the invention represents a new therapeutic
application as the patient group concerned is distinguishable from the patient group of
document (OD8) by its physiological and pathological status.
•
The patent in suit contains studies which convincingly show that it is exactly the patient
group according to claims 1 to 3 which profits most from an extension of the combination
therapy from 24 weeks to 48 weeks.
•
Novel over the prior art.
Company Confidential
Copyright © 2009 Eli Lilly and Company
17
T 836/01, T1642/06
T 836/01
•
In spite of the above overlap in composition and disease treatment aimed at,
the board observes that the claimed invention relies upon a different technical effect
from the one disclosed in document (1). Document (1) discloses indeed the use of
interferon-ß2 for the purpose of activating mature lymphoid cells exerting cytolytic T
cell activity on cancer cells (see document (D1), page 11, lines 2 to 12) or to stimulate
the immune system of patients undergoing (cancer) radio- or chemotherapy (page 9,
end of first full paragraph).
T1642/06
•
The prior art in T 290/86 disclosed the use of lanthanum salts to reduce the solubility
of tooth enamel, which would inhibit tooth decay. The prior art in the present case
discloses the use of sigma ligands to inhibit tumour cell survival, which would treat
cancer. The overlap in the therapeutic application of the use of the prior art and
the use of the claim is irrelevant, because the technical effect stated in the claim
identifies a new clinical situation and remains different from that of the prior art.
Company Confidential
Copyright © 2009 Eli Lilly and Company
18
So, where does the case law leave us?
•
The June 2012 issue of epi Information provides a report of a meeting between the EPO
and the biotech committee of the epi:
8. Inventions in the area of pharmacogenomics:
This concerns cases which are based on a genetic marker to treat a disease, for example
methylation profiles. It can involve a new patient group defined by an SNP. The EPO said that
often the claims can lack novelty, as one patient will have inevitably been treated with the SNP,
even if the art does not explicitly say so.
•
This has been seen by some commentators* as an indication that the EPO is taking a
much stricter view in the assessment of novelty when looking at medical use claims that
refer to treatment of a specific patient group
•
so we asked the EPO.....
* http://ipkitten.blogspot.co.uk/2012/08/taking-it-personally-patents-medicines.html
Company Confidential Copyright © 2012 Eli Lilly and Company
19
Claims: Presence/absence of a biomarker (1)
•
1.
A compound X for use in treating disease Y in a patient with BIOMARKER A.
Situation 1: BIOMARKER A is not known
Situation 2: BIOMARKER A is known but correlation between presence of the biomarker
and therapeutic efficacy of compound X is not known
•
In both situations, novelty is largely dependent on compound X.
•
If compound X is a known, approved drug for the treatment of disease Y, and it is
established that BIOMARKER A occurs in a significant proportion of
patients/population, the EPO considers that it is beyond reasonable doubt that at
least one patient has been treated and therefore the above claim is anticipated.
•
There is still an argument that this type of claim is a selection invention however for the
time being, the EPO will reject such claims and any arguments that the above type of
claim constitutes a selection invention will have to be submitted to a Technical Board of
Appeal.
Company Confidential Copyright © 2012 Eli Lilly and Company
20
Claims: Presence/absence of a biomarker (2)
A compound X for use in treating disease Y in a patient, comprising
–
assaying a blood sample from a patient to determine if a patient has BIOMARKER A and
–
administering a therapeutically effective amount of compound X to the patient if
BIOMARKER A is present.
Novelty objection for the same reasons as for the previous claim...
...BUT the EPO has indicated that, on principle, Examining Divisions will accept that the
following claim is novel:
A compound X for use in treating disease Y in a patient, comprising
–
assaying a blood sample from a patient,
–
determining if a patient has BIOMARKER A, and
–
administering a therapeutically effective amount of compound X to the patient if
BIOMARKER A is present.
Company Confidential Copyright © 2012 Eli Lilly and Company
21
Required Data
•
The novelty of this type of claim hinges on whether the Applicant can provide evidence
that there is a link between the presence or absence of biomarker (physiological or
pathological status) and the improvement in the treatment.
•
In general, the type of evidence that the EPO is looking for :
i) safety: there are fewer side-effects of compound X in one patient sub-population
than the other(s); or
ii) efficacy: Compound X is more efficacious in one patient sub-population than the
other(s)
•
The EPO did not indicate how many patients would be required in order for the
evidence to be convincing, noting only that 2-3 patients would not be enough but 510+ patients may suffice
•
Evidence should ideally be from patients rather than animal models
Company Confidential Copyright © 2012 Eli Lilly and Company
22
RECOMMENDATIONS
•
INCLUDE BOTH TYPE of CLAIMS:
1)
A compound X for use in treating disease Y in a patient with BIOMARKER A.
2)
A compound X for use in treating disease Y in a patient, comprising assaying
a blood sample from a patient, determining if a patient has BIOMARKER A, and
administering a therapeutically effective amount of compound X to the patient if
BIOMARKER A is present.
•
Include data in your application as filed to show that:
– there is a link between the presence or absence of biomarker and the
improvement in the treatment (efficacy or safety) and
– the presence/absence of biomarker distinguishes the patient population
from the point of view of a physiological or pathological status.
Company Confidential Copyright © 2012 Eli Lilly and Company
23
Diagnostic tests
– selecting the individual –
personalised medicine from the
other side
Russell Thom
© Murgitroyd & Company 2012
Diagnostic Claims
©
(G1/04 – five essential characteristics of an excluded diagnostic method claim)
Only diagnostic methods performed on the human or animal body are excluded
– i.e. if it includes all of the following steps
©
©
©
©
a) Examination phase involving the collection of data
b) Comparison of these data with standard values
c) Identification of a deviation from the normal or desired state
d) Attribution of the observed deviation to a particular clinical picture
©
And any steps of a technical nature (typically step a) must satisfy the criterion “practised on the
human or animal body”
©
Claims to diagnostic methods in Europe are patentable!
© Murgitroyd & Company 2012
Mayo vs Prometheus / US : EP
©
Claim 1 of the Prometheus U.S. Patent No.
6,355,623.
©
Claim 1 of corresponding European Patent No.
EP1115403
A method of optimizing therapeutic efficacy for treatment
of an immune-mediated gastrointestinal
disorder, comprising:
(a) administering a drug providing 6-thioguanine to a
subject having said immune-mediated gastrointestinal disorder; and
An in vitro method for determining efficacy of treatment
of a subject having an immune-mediated gastrointestinal
disorder or a non-inflammatory bowel disease (non-IBD)
autoimmune disease by administration of a 6mercaptopurine drug, comprising
(b) determining the level of 6-thioguanine in said subject
having said immune-mediated gastrointestinal
disorder,
determining in vitro a level of 6-thobuanine in a sample
from said subject having said immune-mediated
gastrointestinal disorder or said non-inflammatory bowel
disease (non-IBD) autoimmune disease,
wherein the level of 6-thioguanine less than about 230
pmol per 8×108 red blood cells indicates a need to
increase the amount of said drug subsequently
administered to said subject and
wherein said treatment is considered efficient if the level
of 6-thoguanine is in the range of about 230 pmol per
8x108 red blood cells.
wherein the level of 6-thioguanine greater than about 400
pmol per 8×108 red blood cells indicates a need to
decrease the amount of said drug subsequently ad
ministered to said subject.
© Murgitroyd & Company 2012
Mayo vs Prometheus / US : EP
©
Claim 1 of the Prometheus U.S. Patent No.
6,355,623.
©
Claim 1 of corresponding European Patent No.
EP1115403
A method of optimizing therapeutic efficacy for treatment
of an immune-mediated gastrointestinal
disorder, comprising:
(a) administering a drug providing 6-thioguanine to a
subject having said immune-mediated
gastrointestinal disorder; and
An in vitro method for determining efficacy of treatment
of a subject having an immune-mediated gastrointestinal
disorder or a non-inflammatory bowel disease (non-IBD)
autoimmune disease by administration of a 6mercaptopurine drug, comprising
(b) determining the level of 6-thioguanine in said subject
having said immune-mediated gastrointestinal
disorder,
determining in vitro a level of 6-thobuanine in a sample
from said subject having said immune-mediated
gastrointestinal disorder or said non-inflammatory bowel
disease (non-IBD) autoimmune disease,
wherein the level of 6-thioguanine less than about 230
pmol per 8×108 red blood cells indicates a need to
increase the amount of said drug subsequently
administered to said subject and
wherein said treatment is considered efficient if the level
of 6-thoguanine is in the range of about 230 pmol per
8x108 red blood cells.
wherein the level of 6-thioguanine greater than about 400
pmol per 8×108 red blood cells indicates a need to
decrease the amount of said drug subsequently ad
ministered to said subject.
© Murgitroyd & Company 2012
AMP vs Myriad / US:EP
©
Claim 1 of the U.S. Patent No. US 5709999.
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
©
Claim 1 of European Patent No. 0699754B2
A method for diagnosing a predisposition for breast and
ovarian cancer in a human subject which comprises
determining in a tissue sample of said subject whether
there is a germline alteration that is a frameshift mutation
in the sequence of the BRCA1 polypeptide altering the
open reading frame for SEQ ID NO: 2, said alteration
being indicative of a predisposition to said cancer.
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.
© Murgitroyd & Company 2012
What is a surgical step?
©
G 1/07 – consider what constitutes a surgical intervention on case by case basis
©
T663/02 –
A method of imaging an artery in a region of interest in a patient using magnetic resonance
imaging and a magnetic resonance contrast agent, the method comprising the steps
-
Injecting the magnetic resonance contrast agent into a vein remote from the artery,
-
Monitoring the region of interest by using a series of magnetic resonance radio frequency pulses and
measuring the response of the region of interest to the series of magnetic resonance radio frequency
pulses;
Detecting the arrival of the contrast agent in the region of interest by comparing the response of the
region of interest to the series of magnetic resonance radio frequency pulses before injecting the contrast
agent to the patient to the response of the region of interest to the series of magnetic resonance radio
frequency pulses during or after injecting the contrast agent to the patient;
Generating an imaging initiation signal after detecting the arrival of the contrast agent in the region of
interest;
Collecting magnetic resonance image data in a magnetic resonance imaging sequence in response to the
imaging initiation signal, wherein the magnetic resonance image data which is representative of the
central portion of k-space is collected at the beginning of the imaging sequence and the data which is
representative of the periphery of k-space is collected thereafter; and
-
-
Constructing an image of said artery, using the magnetic resonance image data, wherein the artery
appears distinct from the adjacent veins and background tissue.
© Murgitroyd & Company 2012
Drafting considerations (1)
© Include language in specification when drafting to provide:
© Methods that don’t require all the steps required for diagnosis
© Methods that don’t require surgical or therapeutic method steps
–
e.g. “providing a catheterised patient” rather than “catheterising a patient”
© An in vitro method of examination….
–
–
Discussion of tissue sample may not be sufficient as may not be “in vitro”
e.g. analysing a blood sample from a patient rather than analysing a patient’s blood.
© Murgitroyd & Company 2012
Drafting considerations (2)
© To minimise possible objections under Art 53(c), avoid wording claims such that they
•
•
•
include an actual diagnostic step
– Methods of data gathering provide only intermediate results
include an interventional step on the body
– Start or stop the method after or before the surgical steps
claim the invention as a method of treatment
© Murgitroyd & Company 2012
Drafting considerations (3)
© In prosecution consider
There will likely be a strict application of prohibition of added matter (Art 123(2) EPC)
•
This may prevent you from deleting a diagnostic step / surgical step / therapeutic step from your claims.
There will likely be requirements for support in the description (Art 84 EPC)
•
This may prevent deletion of steps presented in the description as being essential.
© In opposition proceedings, there is a prohibition against extending the scope of protection (Art
123(3)
•
This will prevent deletion of diagnostic step / surgical step / therapeutic step from a granted claim
© Murgitroyd & Company 2012
Thank you!
www.murgitroyd.com
© Murgitroyd & Company 2012
Questions?
Ana Suarez-Miles
Russell Thom
Oliver Kingsbury
[email protected]
[email protected]
[email protected]