Claves de la patentabilidad de arrays y SNPs Enrique Molina Galán Director Biotecnología EPO La Haya Visita a Galicia, Julio 2010

Fase de búsqueda La defininción en si de polymorphismos individuales no suele causar problemas para la búsqueda siempre que el polymorphismo esté definido en una secuencia o en referencia a una secuencia conocida. El mayor problema es la cantidad de (combinaciones de) polymorphismos que se reivindican. En caso de arrays la situacion se complica cuando se reivindica cualquier combinación de al menos n sondas de un array conteniendo m sondas en total. Barcelona, November 2007 15/11/2018

Objecciones posibles No-Unidad (Art. 82 R. 64 EPC) 15/11/2018 Objecciones posibles No-Unidad (Art. 82 R. 64 EPC) Búsqueda incompleta (R. 63 EPC) NU en caso de SNP bien definindos pero sin ninguna característica técnica "especial" en comun. La característica en común puede ser estructural o funcional ligada a una estructura. BI en caso de numero elevado de combinaciones posibles. El solicitante será invitado a proponer cuales se buscan. Conviene elegir los SNP que tienen una verdadera función y no solo "proféticos". Barcelona, November 2007 15/11/2018 Barcelona, November 2007

Partial searches: expression profiles 15/11/2018 Partial searches: expression profiles CLAIMS Method to diagnose disease X consisting of measuring the level of expression of at least one gene selected from Table 1 and comparing it to a reference level, wherein an increased or decreased level of expression of said gene is indicative of the disease. Microarray comprising a probe suitable to detect anyone of the genes of Table 1 (SEQ ID Nos). Typical example of expression profiling application. Hundreds of them during 2004-2005, still coming. CLICK METHOD: Search implies checking whether any of the 2000 genes has ever been used as a diagnostic marker for disease X (novelty) or for a related phenotype/disease (inventive step). ARRAY: Search implies finding mention to support bound probes for each one of the 2000 genes (novelty) or methods where such product is suggested or obvious (inventive step). In summary, a sequence search and a gene search for each one of the 2000 genes, under one fee (1-2 days). Not possible. Table 1 2000 genes !!! Barcelona, November 2007 15/11/2018 Barcelona, November 2007

Partial searches: expression profiles 15/11/2018 Partial searches: expression profiles Method to diagnose disease X consisting of measuring the level of expression of at least one gene selected from Table 1 and comparing it to a reference level, wherein an increased or decreased level of expression of said gene is indicative of the disease. Explain cases. CLICK Consequences follow (CLICK) PRIOR ART REASONING Diagnosis of disease X by expression levels Common concept is not novel Lack of unity Diagnosis of disease X by other methods Common concept is not inventive because the use of expression markers in diagnosis of disease is well known in the field Diagnosis of disease Y by expression levels Barcelona, November 2007 15/11/2018 Barcelona, November 2007

Partial searches: expression profiles 15/11/2018 Partial searches: expression profiles CONSEQUENCES: Each gene expression marker in Table 1 gives place to a separate invention (Art. 82 EPC) Search will be restricted to Invention 1, namely methods and products derived from gene 1 in Table 1 (Rule 64 EPC) Invitation to pay 1999 search fees !! (Rule 64 EPC) Objection maintained at examination stage, invitation to (choose and) restrict (Art. 82 EPC) Most of these applications still under examination. Some already refused under Art. 82 EPC. Some withdrawn. Applicants have tried to circumvent this restriction by… NEXT Barcelona, November 2007 15/11/2018 Barcelona, November 2007

Incomplete searches: expression profiles 15/11/2018 Incomplete searches: expression profiles Method to diagnose disease X consisting of measuring the level of expression of any combination of 5 or more genes selected from Table 1 and comparing them to a reference level, wherein an increased or decreased level of expression of said gene is indicative of the disease. …specific combination of genes 5, 66, 98, 158, 231 and 357. Back to our example: now, let’s focus on “combinations”. METHOD: Search implies checking whether any possible combination of 5, 6, 7, 8,… of the 2000 genes has ever been used as a diagnostic marker for disease X (novelty) or for a related phenotype/disease (inventive step). ARRAY: Search implies finding mention to microarrays comprising any possible combination of 5, 6, 7, 8,… of the 2000 genes (novelty) or methods where such product is suggested or obvious (inventive step). In summary, a sequence search and a gene search for each one of the 2000 genes, under one fee (1-2 days), plus checking if any 5 have been disclosed as a closed set. Not possible. 5 genes: 2x1014 comb. 6 genes: 9x1016 comb. 7 genes: 3x1019 comb. … 2000 genes: 1 comb. Microarray comprising a set of probes suitable to detect at least five of the genes of Table 1 …probes 5, 66, 98, 158, 231 and 357. Barcelona, November 2007 15/11/2018 Barcelona, November 2007

Incomplete searches: expression profiles 15/11/2018 Incomplete searches: expression profiles Method… any combination of 5 or more genes. Microarray… comprising at least 5 probes selected from Table 1. Claim example How to deal with this? CLICK Consequences follow (CLICK) Excessive number of products and methods claimed Technical effect shown only for a few of them Lack of conciseness, support and disclosure, thus no meaningful search possible over the whole scope Incomplete search (restriction to examples or preferred combinations) Barcelona, November 2007 15/11/2018 Barcelona, November 2007

Partial and incomplete searches 15/11/2018 Partial and incomplete searches Method to diagnose disease X consisting of measuring the level of expression of at least one gene selected from Table 1 and comparing it to a reference level, wherein an increased or decreased level of expression of said gene is indicative of the disease. …any combination of 5 or more genes. …specific combination of genes 1, 66, 98, 158, 231 and 357. Microarray comprising a probe suitable to detect anyone of the genes of Table 1 (SEQ ID Nos). …comprising at least 5 probes... …comprising probes 1, 66, 98, 158, 231 and 357. gene 1 Both problems together. Search is severely restricted: COMPLEX: CLICK UNITY: CLICK Example with expression profiling, but the same occurs when multiple SNPs or other markers are claimed: CLICK gene 1 Barcelona, November 2007 15/11/2018 Barcelona, November 2007

Fase de examen Barcelona, November 2007 15/11/2018

Novelty - general vs. specific 15/11/2018 Novelty - general vs. specific Claim: Method for predicting drug response to "Y" by detecting a SNP in gene "X" Prior Art: method in which drug response to "Y" is predicted by detecting SNP xxx which is located in gene "X". Examination: Not novel One of the most important principles in the novelty examination is that the general disclosure does not take the novelty away of a specific embodiment Barcelona, November 2007 15/11/2018 Barcelona, November 2007 30

Novelty - general vs. specific (cont.) 15/11/2018 Novelty - general vs. specific (cont.) Claim: Method for diagnosing disease "Y" by detecting SNP "Z" in the promoter region of protein "X" Prior Art (patent): silencing of gene "X". Examination: Novel. No direct link between silencing and the SNP (i.e. silencing can be caused by other factors) Relevant to Inventive Step. Barcelona, November 2007 15/11/2018 Barcelona, November 2007 31

Novelty - general vs. specific (cont.) 15/11/2018 Novelty - general vs. specific (cont.) Claim: Method for predicting response to drug "Y" in which both SNP "X" and SNP "Z" are analysed. Prior Art : Method for predicting response to drug "Y" by analysing SNP "X" Prior Art: SNP "Z" Examination: Novel. None of the prior art documents show a method employing expression of both gene "X" and gene "Z". Relevant to Inventive Step. Before we continue it is perhaps a good idea to look at a few examples of patent applications as they are filed with the EPO. They put into perspective the number of genes and the scope of diagnosis which the applicant intends to cover with their claims. Barcelona, November 2007 15/11/2018 Barcelona, November 2007 32

Prior art document : Method for predicting 15/11/2018 Novelty - selection Prior art document : Method for predicting response to a drug selected from Y1-Y50 by identifying a SNP selected from X1-X50. EP-application: Method for predicting response to Y2 by identifying X13. No example of Y2 and X13 in combination. Novel If a prior art document, eg a patent document relating to pharmacogenomics, mentions a number of uses and a number of SNPs which may be used in the method (THE SOCALLEDS WASHING LISTS), then the selection of a limited number of uses combined with a limited number of genes will normally be considered novel . . Barcelona, November 2007 15/11/2018 Barcelona, November 2007 33

Actividad Inventiva (Art. 56 EPC): Un SNP debe de estar caracterizado funcionalmente, e.g. Correlación con (predisposicion a) una enfermedad particular Correlación con un diagnóstico Correlación con respuesta a tratamiento La correlación debe ser estadísticamente relevante! Barcelona, November 2007 15/11/2018

Actividad Inventiva (Art. 56 EPC): En caso de que el SNP esté correctamente caracterizado (y sea nuevo): Estado del arte mas cercano: Idealmente documentos mostrando marcadores correlacionados con la misma funcionalidad Problema a resolver: Proveer marcadores alternativos o, en caso de presentar un efecto mejorado, proveer marcadores "mejorados" Conclusión: Si el estado del arte sugieriese los nuevos SNP o, en caso de que sean mejores, si la mejoría era de esperar: Obvio! Barcelona, November 2007 15/11/2018

Actividad Inventiva (Art. 56 EPC): ...y si un SNP no estuviese caracterizado funcionalmente ? - se sabe que la densidad de SNP en el genoma es alta y hoy en dia encontrarlos es técnicamente rutinario. Encontrar un SNP sin saber su función es una mera selección al azar entre todos los SNP que se podrían encontrar de forma rutinaria Conclusión: no cumple con las exigencias del Art. 56 EPC! Barcelona, November 2007 15/11/2018

Inventive Step - Example 15/11/2018 Inventive Step - Example Claim: Method for predicting response to drug X in a patient suffering from disease Y by analysing the SNP at position xxx in gene Z Prior Art (different options) : If gene locus Z is known to play a role in disease Y If gene is known to play a role in disease Y If SNP is known in disease prognosis If SNP is known in response to drug X Combinations of these prior art documents In all instances the prior art contains an indication to investigate further the SNP . In many cases the outcome of the inventive step analysis will depend on the technical problem solved. In other words if the application contains data showing that an unexpectedly reliable prediction is achieved using the said SNP, then this is an indicator which points in the direction of acknowledgment of inventive step. Thus, the evaluation of inventive step depends very strongly on the data shown in the application. Barcelona, November 2007 15/11/2018 Barcelona, November 2007 40