diagnostic methods biomarkers ep

8/11/2019 Diagnostic Methods Biomarkers EP

1/34

Patentability of Diagnostic Methods

and Biomarkers:A European Perspective

Oliver KingsburyRussell ThomAna Suarez-Miles


2/34

Overview

1) Patentability of inventions under the EPC

Overarching principles, Notinventionsand Excludedinventions

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 havent)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


3/34

Patentable inventions under the EPC


4/34

Overarching Principle

Article 52(1)

European patents shallbe granted for anyinventions, 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 anynew and useful process,machine, manufacture, or composition of matter, or anynew and

useful improvement thereof, mayobtain a patent therefor, subject to

the conditions and requirements of this title.


5/34

Not Inventions

Article 52(2)

The following in particular shall notbe regarded as inventions

(a) discoveries, scientific theories and mathematical methods;

(b) aesthetic creations;

(c) methods for performing mental acts, playing games or doingbusiness, 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.


6/34

Excluded Inventions

Article 53

European patents shall notbe 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 orregulation 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 bysurgery ortherapy 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.


7/34

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 cumulativerequirements. In order to be patentable a claimed method must

neither be a therapeutic nor a surgical nor a diagnostic one.


8/34

Art 53(c)The Bermuda Triangle

Human or

Animal Body

TherapeuticMethod

Surgical

Method

Diagnostic

Method


9/34

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.


10/34

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 withthe 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


11/34

Diagnostic Method

A method is only diagnostic 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

Furthermore,

Any steps of a technical (rather than mental) nature must satisfy the

criterion practised on the human or animal body


12/34

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 thehuman 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


13/34

CLAIMING PERSONALIZED MEDICINE

INVENTIONS IN EUROPE

ANA SUAREZ-MILES


14/34

Use of Biomarkers for patient selection

Company Confidential

Copyright 2009 Eli Lilly and Company

14

In a drug development program presence or absence of specific biomarkers can beuseful in the selection of patient population :

for better definition of the disease and/or its prognosis: Identification of patientswith a particular disease sub-type or disease severity as a target (e.g., Her-2 andbreast cancer, or Philadelphia chromosome in chronic myeloid leukaemia).

for excluding patients at increased risk: Identification of patients at increased riskof experiencing a serious adverse drug reactions for the purpose of excluding themfrom further clinical trials or treatment with that specific agent.(e.g., HLA B* 5701 andabacavir use or carbamazepine and HLA-B*1502)

for prediction of drug response: Identification of patients with high likelihood ofexperiencing benefit with a particular medicinal product with few or no safetyissues/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


15/34

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 substanceor composition for the manufacture of a medicament for a speci f ied n ew andinvent ive therapeut ic appl icat ion.

T19/86: (sero-positive vs. Seronegative piglets)

The therapeutic application of a vaccine, which is known for treatment of a particularclass of animal to a new and different class of the same animalis a secondmedical use within the principle set out in Decision G 05/83, and is thereforepatentable 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 non-hemophilic mammals characterized by forming a mixture of phospholipid vesicles and mammalian bloodFactor 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 -



15


16/34

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 begiven 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 aparticular group of subjects, the treatment or diagnosis of the same disease with thesame compound could nevertheless represent a novel therapeutic or diagnosticapplication, provided that

i. it is carried out on a new group of subjects which is clearly distinguishable with respectto 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 afunctional relationship between the particular physiological or pathological statusof this new group and the therapeutic effect obtained.

"a human who is unable to exercise adequately" cannot be regarded as a feature capableof distinguishing the subject-matter of claim 1 from the closest prior art.



16


17/34

T 1399/04 -

physiological and pathological status

the patient is an antiviral treatment naive patient, and the patient is one having aHCV genotype type 1 infection and a viral load of greater than 2 million copies per ml ofserum 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 definedas 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 indocument (OD8).

The Boards of appeal, considered that the invention represents a new therapeuticapplication 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 patientgroup according to claims 1 to 3 which profits most from an extension of the combinationtherapy from 24 weeks to 48 weeks.

Novel over the prior art.



17


18/34

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 effectfrom the one disclosed in document (1). Document (1) discloses indeed the use ofinterferon-2 for the purpose of activating mature lymphoid cells exerting cytolytic Tcell 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 casediscloses the use of sigma ligands to inhibit tumour cell survival, which would treatcancer. The overlap in the therapeutic application of the use of the prior art andthe use of the claim is irrelevant,because the technical effect stated in the claimidentifies a new clinical situation and remains different from that of the prior art.



18


19/34

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 examplemethylation profiles. It can involve a new patient group defined by an SNP. The EPO said thatoften 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 amuch stricter view in the assessment of novelty when looking at medical use claims thatrefer 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


20/34

Claims: Presence/absence of a biomarker (1)

1. A com pou nd X for use in treat ing disease Y in a pat ient with BIOMARKER A.

Situation 1: BIOMARKER A is not known

Situation 2: BIOMARKER Ais known but correlation between presence of the biomarkerand 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 isestablished that BIOMARKER Aoccurs in a significant proportion ofpatients/population, the EPO considers that it is beyond reasonable doubt that atleast one patient has been treatedand therefore the above claim is anticipated.

There is still an argument that this type of claimis a selection invention however for thetime being, the EPO will reject such claims and any arguments that the above type ofclaim constitutes a selection invention will have to be submitted to a Technical Board of

Appeal.



21/34

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 ifBIOMARKER 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 thefollowing claim is novel:

A compound X for use in treating disease Y in a patient, comprising

assayinga blood sample from a patient,

determiningif a patient has BIOMARKER A, and administer inga therapeutically effective amount of compound X to the patient if

BIOMARKER A is present.


Claims: Presence/absence of a biomarker (2)


22/34

Required Data

The novelty of this type of claim hinges on whether the Applicant can provide evidencethat there is a link between the presence or absence of biomarker (physiological orpathological 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-populationthan the other(s); or

ii) efficacy: Compound X is more efficacious in one patient sub-population than theother(s)

The EPO did not indicate how many patients would be required in order for theevidence to be convincing, noting only that 2-3 patients would not be enough but 5-10+ patients may suffice

Evidence should ideally be from patients rather than animal models



23/34

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 assayinga blood sample from a patient, determiningif a patient has BIOMARKER A, and

administering a therapeutically effective amount of compound X to the patient ifBIOMARKER A is present.

Include data in your application as filed to show that:

there is a linkbetween the presence or absence of biomarker and the

improvement in the treatment (efficacy or safety) and

the presence/absence of biomarker distinguishes the patient populationfrom the point of view of a physiological or pathological status.



24/34 Murgitroyd & Company 2012

Diagnostic tests

selecting the individual

personalised medicine from the

other side

Russell Thom



(G1/04five 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 thehuman or animal body

Claims to diagnostic methods in Europe are patentable!

Diagnostic Claims



Mayo vs Prometheus / US : EP

Claim 1 of the Prometheus U.S. Patent No.6,355,623.

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 gastrointesti-

nal disorder; and

(b) determining the level of 6-thioguanine in said subject

having said immune-mediated gastrointestinaldisorder,

wherein the level of 6-thioguanine less than about 230

pmol per 8108red blood cells indicates a need to

increase the amount of said drug subsequently

administered to said subject and

wherein the level of 6-thioguanine greater than about 400pmol per 8108red blood cells indicates a need to

decrease the amount of said drug subsequently ad

ministered to said subject.

Claim 1 of corresponding European Patent No.EP1115403

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 6-

mercaptopurine drug, comprising

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 said treatment is considered efficient if the level

of 6-thoguanine is in the range of about 230 pmol per

8x108red blood cells.


27/34

Murgitroyd & Company 2012

Mayo vs Prometheus / US : EP

Claim 1 of the Prometheus U.S. Patent No.6,355,623.

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

(b) determining the level of 6-thioguanine in said subject

having said immune-mediated gastrointestinaldisorder,

wherein the level of 6-thioguanine less than about 230

pmol per 8108red blood cells indicates a need to

increase the amount of said drug subsequently

administered to said subject and

wherein the level of 6-thioguanine greater than about 400pmol per 8108red blood cells indicates a need to

decrease the amount of said drug subsequently ad

ministered to said subject.

Claim 1 of corresponding European Patent No.EP1115403

Anin 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 6-

mercaptopurine drug, comprising

determiningin 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 said treatment is considered efficient if the level

of 6-thoguanine is in the range of about 230 pmol per

8x108red blood cells.


28/34


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

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.

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.


29/34


What is a surgical step?

G 1/07consider what constitutes a surgical intervention on case by case basis

T663/02A method of imaging an artery in a region of interest in a patient using magnetic resonanceimaging 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 andmeasuring 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 theregion 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 ofinterest;

- Collecting magnetic resonance image data in a magnetic resonance imaging sequence in response to theimaging 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 arteryappears distinct from the adjacent veins and background tissue.


30/34


Drafting considerations (1)

Includelanguage in specification when drafting to provide:

Methods that dont require all the steps required for diagnosis

Methods that dont 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 patients blood.


31/34


To minimise possible objections under Art 53(c), avoidwording 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



32/34



In prosecution considerThere 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 (Art123(3)

This will prevent deletion of diagnostic step / surgical step / therapeutic step from a granted claim


33/34


Thank you!

www.murgitroyd.com


34/34

Oliver [email protected]

Russell [email protected]

Ana [email protected]

Questions?

diagnostic methods biomarkers ep

Documents