Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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]