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NanoString Technologies Europe Limited v. President and Fellows of Harvard College
ACT_551180/2023
Munich (DE) Central Division - Section
Revocation Action
EN
EP2794928B1
Action n°: UPC 252/2023
Revocation action
International jurisdiction. Lis pendens . Related actions. Parallel national revocation action. Articles 29-32 Regulation Brussels I recast. Novelty. Inventive step. Subsequent application to amend. Rule 30.2 RoP. Auxiliary requests.
NanoString Technologies Europe Limited, Suite 2, First Floor, 10 Temple Back - BS1 6FL - Bristol - GB
represented by Daniela Kinkeldey of Bird & Bird.
President and Fellows of Harvard College, MA - US
17 Quincy Street - 02138 - Cambridge, represented by Axel Berger of Bardehle Pagenberg.
European patent EP 2 794 928 B1, hereafter referred to as ´the Patent´.
Panel 1 of the Central Division (Section Munich).
This decision has been delivered by the presiding judge Ulrike Voß, the legally qualified judge András Kupecz as judge-rapporteur and the technically qualified judge Eric Enderlin.
18 September 2024.
2023 that the PO is to be dealt with in the main proceedings (Rule 20.2 RoP). The PO was withdrawn at the oral hearing.
2.1 EP 2 794 928 B1 entitled " Compositions and methods for detecting analytes " was filed on 21 December 2012 (the application as filed was submitted as document D2 in these proceedings). The Patent claims priority to US 201161579265 P of 22 December 2011. The validity of the priority date was not challenged by the Claimant.
2.2 The Patent was granted on 20 February 2019. No opposition was filed. The registered owner of the Patent is the Defendant.
2.3 The Patent is in force in the UPC Contracting Member States Germany (DE), the Netherlands (NL) and France (FR).
2.4 The Claims of the Patent as granted read:
a. contacting the sample with a composition comprising a plurality of detection reagents, wherein each subpopulation of the detection reagents targets at least one different analyte, wherein the analyte is fixed on a solid substrate or support and wherein the solid substrate or support is a chip, a microarray, a blotting membrane or a microscopic slide, and wherein each detection reagent comprises:
at least one probe reagent targeting an analyte and at least one nucleic acid label comprising a plurality of predetermined subsequences, wherein said at least one probe reagent and said at least one nucleic acid label are conjugated together; and wherein at least a portion of said plurality of predetermined subsequences form an identifier of said at least one probe
reagent;
b. removing any unbound detection reagents;
c. detecting in a temporally-sequential manner said plurality of predetermined subsequences of said detection reagent, wherein said detection of the subsequences comprises:
i) hybridizing a set of decoder probes with a subsequence of the detection reagents, wherein each subpopulation of said decoder probes comprises an optical detectable label, each optical detectable label generating an optical signal signature corresponding to each subsequence;
ii) detecting said optical signal signature produced upon the hybridization of said set of decoder probes and obtaining an image;
iii) removing said optical signal signature produced by the hybridization of said set of decoder probes;
iv) repeating steps (i) through (iii) for other subsequences of said detection reagents, thereby producing a temporal order of optical signal signatures corresponding to the plurality of pre-determined subsequences,
wherein the temporal order of the optical signal signatures corresponding to said plurality of pre-determined subsequences of said detection reagent identifies a subpopulation of the detection reagents and is unique for each subpopulation of the detection reagents; and
(i) said each subpopulation of the detection reagents targets a set of analytes; and/or
(ii) said detection reagents are present in a soluble phase.
(iii) at least two or more subpopulations of the decoder probes are at least partially or completely complementary to the same subsequence of the detection reagents.
(i) said optical detectable label comprises or is an optical label selected from the group consisting of a small molecule dye, a fluorescent molecule, a fluorescent protein, a quantum dot, Raman label, a chromophore, and any combinations thereof; and/or (ii) said optical detectable label comprises or is a colourimetric reagent; and/or (iii) said optical detectable label comprises or is a Raman label.
(i) said sample is a protein sample immobilized on a solid support, preferably wherein the solid support is a blotting membrane; or (ii) said sample is a biological sample, preferably wherein said biological sample comprises one or more cells, one or more tissues, one or more fluids or any combinations thereof, and/or preferably (a) wherein said biological sample comprises blood, sputum, cerebrospinal fluid, urine, saliva, sperm, sweat, mucus, nasal discharge, vaginal fluids or any combinations thereof, or (b) wherein said biological sample comprises a biopsy, a surgically removed tissue, a swap or any combinations thereof; or
(iii) said sample comprises an environmental sample, food, food byproduct, soil, an archaeological sample, an extraterrestrial sample, or any combinations thereof.
(ii) said linker is a linker molecule, preferably wherein said linker molecule is a polymer, sugar, nucleic acid, peptide, protein, hydrocarbon, lipid, polyethylene glycol, crosslinker, or any combinations thereof; and/or
(iii) said linker is multivalent, preferably wherein when the multivalent linker is an avidin-like molecule, both the probe reagent and the nucleic acid label are biotinylated.
(iv) said particle is modified with at least one functional group, preferably wherein said at least one functional group is selected from the group consisting of amine, carboxyl, hydroxyl, aldehyde, ketone, tosyl, silanol, chlorine, hydrazine, hydrazide, photoreactive groups, and any combinations thereof.
(i) said at least one probe reagent is selected from the group consisting of a nucleic acid, an antibody or a portion thereof, an antibody-like molecule, an enzyme, a cell, an antigen, a small molecule, a protein, a peptide, a peptidomimetic, a sugar, a carbohydrate, a lipid, a glycan, a glycoprotein, an aptamer, and any combinations thereof; and/or
(iii) said at least one probe reagent is biotinylated.
(i) said at least one nucleic acid label is single-stranded, doublestranded, partially double-stranded, a hairpin, linear, circular, branched, a concatemer, or any combinations thereof; and/or (ii) said at least one nucleic acid label is modified; and/or (iii) said at least one nucleic acid label is designed for minimal crosshybridization of bases with each other; and/or (iv) said at least one nucleic acid label is conjugated to at least one detectable molecule, preferably wherein said at least one detectable molecule is an optical molecule selected from the group consisting of a small molecule dye, a fluorescent protein, a quantum dot, a Raman label, a chromophore, and any combinations thereof.
1 Regulation (EU) No 1215/2012 of the European Parliament and of the Council of 12 December 2012 on jurisdiction and the recognition and enforcement of judgments in civil and commercial matters (recast), ELI: http://data.europa.eu/eli/reg/2012/1215/2015-02-26.
court exercises jurisdiction in matters falling within the scope of the Regulation. Article 71b(1) adds that a common court shall have jurisdiction where, under this Regulation, the courts of a Member State party to the instrument establishing the common court would have jurisdiction in a matter governed by that instrument. The UPC is a ' common court ' within the meaning of Article 71a et seq. of Regulation Brussels I recast, see Article 71a(2) sub a Regulation Brussels I recast and Article 1 UPCA, second part.
5.10 From the facts as brought forward by the parties in the PO, the Court is aware that the German Revocation action is still pending. The BPatG decided in first instance on 7 May 2024 revoking the German part of the Patent in its entirety. By the time of the oral hearing in the present proceedings, the written grounds had been issued by the BPatG and an appeal had been lodged with the Bundesgerichtshof (´BGH´). A (final) decision from the BGH is not to be expected within the next year. As is apparent from the written decision of the BPatG (document D60), the grounds, facts and arguments relied upon by the parties to those proceedings are largely similar to those relied on in the present proceedings.
5.11 In its Order of 17 September 2024 (CoA_227/2024, Mala Technologies/Nokia Technologies) , the CoA confirmed that in the light of the objective and purpose of Art. 29 to 32 of the Brussels I recast Regulation which deal with parallel proceedings (i.e. to offer a clear and effective mechanism for resolving cases of lis pendens and related actions, see par. 12 of the Order), Article 71c(2) of the Brussels I recast Regulation must be interpreted as meaning that these provisions apply where during the transitional period of Article 83 UPCA, proceedings are pending before the UPC and a national court, also where, as is the case in the present proceedings, the proceedings before the national court were initiated prior to the transitional period (par. 12, 13 of the grounds of the Order).
5.12 The concrete facts and circumstances of the present case as known to the Court based on the submissions from the parties - in essence the existence of parallel proceedings in relation to the Patent in the UPC and in another court of a Member State (Germany) - prompt the Central Division to examine its international jurisdiction in view of Articles 29-32 Regulation Brussels I recast which rules, like Article 24 of Regulation Brussels I recast, are compulsory and have to be applied by the Court of its own motion. The compulsory and ex officio nature of these provisions follows from their wording (cf. ' of its own motion ', Article 29) and the object and purpose of these provisions (i.e. to offer a clear and effective mechanism for resolving cases of lis pendens and related actions, see CoA above and references to Union law in the CoA Order).
the other. See the CoA in Mala Technologies/Nokia Technologies, par. 17-19 of the Order.
5.18 Pursuant to Art. 30 of the Brussels I recast Regulation, the UPC may stay proceedings where a related action is pending in a national court. As held by the CoA in Mala Technologies/Nokia Technologies , par. 24 of the Order, the objective of this provision is to minimise the possibility of parallel proceedings before different courts and to improve coordination of the exercise of judicial functions within the European Union and to avoid conflicting and contradictory decisions, even where the separate enforcement of each of them is not precluded.
5.19 As was the case in Mala Technologies/Nokia Technologies , the present UPC proceedings and the proceedings at the (now) BGH are to be considered as related proceedings for the purposes of Art. 30 of the Brussels I recast Regulation. The parties are (closely) related, both proceedings concern the same national part of the same European patent and the proceedings are largely similar in terms of facts, grounds, arguments and (auxiliary) requests brought forward by the parties.
5.20 However, having regard to the objective of Article 30 Brussels I recast Regulation, in view of the following combination of circumstances, which in important aspects deviates from the circumstances of the case before the CoA in Mala Technologies/Nokia Technologies , the Central Division decides not to exercise its discretionary power to stay the proceedings.
-The parties to the present proceedings have unanimously requested the Court to issue a decision, also for the German part of the Patent.
-The parties have explained at the oral hearing that for resolving their dispute, it is important to obtain a decision from the Central Division. This is in particular so because an infringement action is pending in relation to the Patent, also for the German part of the Patent, including a claim for damages. Parties have expressed the wish to have legal certainty as soon as possible.
-The first instance proceedings before the Central Division are already in an advanced stage. The oral hearing has been concluded and the case is ready to be decided. The procedural economical benefits for the Central Division to stay its proceedings at this stage are therefore limited.
-The proceedings at the BGH are still in an early stage. No decision can be expected within the next year.
-If an appeal is filed against the present decision, which is not certain at this point in time, the UPC CoA can be expected to deal with the appeal in approximately one year.
-In the present case, two other national parts of the Patent (the Dutch and the French part) are still in force and are subject of the present Revocation action. The German Revocation action does not affect these parts. The grounds, facts and arguments that the parties have brought forward for these national parts are identical to those brought forward for the German part and thus will have to be considered by this Court at some point in time.
-Staying the action in its entirety risks preventing the parties from obtaining a decision on the (unaffected) national parts within a reasonable time (a fundamental right guaranteed by Article 6 of the European Convention for the Protection of Human Rights and Fundamental Freedoms and Article 47 of the Charter, see in this sense CoA 28 May 2024, UPC_CoA_22/2024 Carrier/Bitzer , Headnote 1).
-Staying the action only for the German part of the Patent would have little benefits in terms of procedural economy as the grounds, facts and arguments brought forward by the parties would then have to be considered in any event for the other national parts of the Patent.
-Going forward with the present case may avoid the costs of conducting the proceedings at the BGH and the UPC CoA if the parties settle the case on the basis of this decision by the Central Division.
-There is no risk of a contradictory or conflicting decision with at least the BPatG as the result is the same in both cases (see below).
5.21 For the above reasons, the interests of the parties and procedural economy outweigh the risk that UPC CoA and BGH proceedings may become pending in parallel (and the related risk of contradictory decisions). Accordingly, the Central Division will not stay the present revocation action.
5.22 The Court notes that it would come to the same conclusion if it were to exercise its discretionary power to stay proceedings on the basis of Rule 295(m) RoP (cf. CoA in Mala Technologies/Nokia Technologies , 32 of the Order). In view of the facts and circumstances discussed above, also in light of the principles of efficiency and expeditious decisions set out in points 4 and 7 of the Preamble of the RoP and Recital 6 of the UPCA, the Court considers that, in the present situation, it is not in the interest of the proper administration of justice to stay proceedings awaiting the outcome of the appeal proceedings at the BGH.
5.23 In sum, the Court has international jurisdiction and has competence to hear the present Revocation action. The action will not be stayed pending the outcome of the proceedings before the BGH relating to the German part of the Patent.
[0003] The need for multiplexing techniques in biology is often driven by the fact that test samples are precious and those analyzing them either do not know in advance precisely what to look for or must extract the most information from any single sample. Hence, it is desirable for clinicians and researcher [sic] to subject each sample to a large set of probes.
[0004] Optical readout is common in biology and can be very effective. However, it is typically limited to a relatively small number of available
fluorophores or chromophores (which are referred to collectively as colours). In practice, multiplexing by fluorescence is often limited to 4 or 5 colours, which by traditional methods implies that at most 4 or 5 probes can be detected in a single sample.
[0005] The common approach to improving multiplexing in optical methods is to increase the number of available colours. To this end, quantum dots have been developed to provide a larger range of colours. However, in reality, it is difficult to use more than 6 quantum dot colours simultaneously. Another approach is to use mixtures or ratio of fluorophores as new colours. Such methods have extended multiplexing to hundreds of analytes, but due to the size of the labels (e.g., microbeads), the technology has thus far been limited to flow-cytometry based analyses. Yet another approach involves nanostrings, which are essentially short strings of strung-up fluorophores creating visible colourful barcodes. Unfortunately, nanostring readout requires very high-resolution imaging and a special flow apparatus. Further, the nanostrings can only be used in a sample where the probes' targets are sparse, or the barcodes will overlap and create a blur.
[0006] A simple workaround for the limited number of colours (e.g., 4 or 5 colours) in optical readouts is to repeat the probing of the same sample with multiple small sets of different probes. For example, the assay can involve probing the sample with 4 different antibodies at a time and imaging after every assay. If the test requires probing the sample with a total of 64 antibodies, the 4-probe procedure would have to be repeated 16 times using the sample. As such, the order of detecting different target analytes in a single sample may need to be prioritized, because some target analytes in the sample can degrade during successive probings. Accordingly, there is still a strong need for accurate and sensitive methods with a high throughput for detection, identification, and/or quantification of target molecules in a sample, e.g., complex mixtures.
[0007] Embodiments provided herein are based on, at least in part, the development of a multiplexed biological assay and readout, in which a multitude of detection reagents comprising one or more probes and/or probe types are applied to a sample, allowing the detection reagents to bind target molecules or analytes, which can then be optically identified in a temporallysequential manner. In some embodiments, the multitude of detection reagents comprising one or more probes and/or probe types can be applied to a sample simultanesouly [sic]. Accordingly, provided herein are methods for detecting multiple analytes in a sample.
In relation to the prior art, the description furthermore notes:
[0037] To clarify, the compositions and methods described herein are different from the ones described in the US Patent Application No.: US 2007/0231824. The '824 application discusses methods of decoding a sensor array containing immobilized microspheres, wherein the microspheres are immobilized on a solid support (e.g., an array substrate), rather than designed to be in a solution phase. As such, a sample fluid is flowed over the sensor array containing immobilized microspheres. The analytes in the sample fluid then bind to the immobilized microspheres. After binding, the sample fluid is then discarded and the immobilized microspheres are analyzed. Accordingly, the compositions and the methods described in the '824 application cannot be used and detected directly on a sample (e.g., on a tissue sample) or in situ as described herein, e.g., immunofluorescence, immunohistochemistry, fluorescence in situ hybridization, or western blot.
sample, e.g., complex mixtures. Accordingly, the problem underlying the invention is to develop high-throughput optical multiplexing methods for detecting target molecules in a sample. This definition of the underlying problem corresponds to the problem as defined by the CoA in the appeal proceedings relating to EP ´782 (CoA Order in NanoString/10x Genomics , 4.b) and in essence to the problem as defined by the BPatG in its decision in the German Revocation action (D60, I.2).
F2.4 each detection reagent comprises:
F2.4.4 at least a portion of said plurality of predetermined subsequences form an identifier of said at least one probe reagent;
F3 b. removing any unbound detection reagents;
F4.1 said detection of the subsequences comprises:
F4.1.1.1 each subpopulation of said decoder probes comprises an optical detectable label, each optical detectable label generating an optical signal signature corresponding to each subsequence;
F4.1.4.1 the temporal order of the optical signal signatures corresponding to said plurality of pre-determined subsequences of said detection reagent identifies a subpopulation of the detection reagents;
F4.1.4.2 is unique for each subpopulation of the detection reagents;
and as a whole. The description and the drawings may show that the patent specification defines terms independently and, in this respect, may represent a patent´s own lexicon. Even if terms used in the patent deviate from general usage, it may therefore be that ultimately the meaning of the terms resulting from the patent specification is authoritative.
8.9
Claim interpretation from the point of view of the above person skilled in the art applying the above principles
In the claimed method, a ' nucleic acid label ' is attached (directly or indirectly) to a probe reagent (together these are called a ' detection reagent ') which are used to detect analytes. The nucleic acid label is 'readout' and decoded in a temporally sequential manner. To this end, the nucleic acid label comprises a plurality of ' predetermined subsequences ' to which ' decoder probe s' can hybridize. 'Hybridization' is the formation of a 'hybrid' between two separate (but complementary) single-stranded molecules into one single double-stranded molecule. Two hybridized nucleic acid strands can look as follows (Statement of Revocation, par. 73):
Desoxyribose
The binding between the two strands is based on base-pairing as shown above. Adenin (´A´) binds to Thymin (´T´), Guanin (´G´) to Cytosin (´C´).
8.11 In essence, the method according to the invention results in a particular temporal 'barcode' for each analyte. The approach according to the Patent
is summarized graphically in the following figure (p. 12, Defence to Revocation, not (expressly) contested by the Claimant):
The terms ' sample ' and ' analyte ' as used in claim 1 are to be interpreted together.
8.12 The claimed method pertains to detecting a plurality of analytes in a sample ( F1 ). The parties are divided over the interpretation of the terms ' sample ' and ' analyte '. The claimed method is a method for detecting a plurality of analytes in a sample. Ultimately, in the last step of the method (cf. F5 ) the analyte in the sample is identified. Even though the Central Division agrees with the Defendant that the ' analyte ' and the ' sample ' are not 'identical', the skilled person will not interpret these terms in isolation, but rather together in their mutual context within the claim.
8.13 The Patent description gives a broad definition of the term ' sample '. A sample can be derived ' from any sources ' (par. [0008] and [0213] of the description) and ' …is not limited to biological samples, e.g., collected from organisms, animals or subjects, environmental samples, food, food byproduct, soil, archaeological samples, extraterrestrial samples, or any combinations thereof. For example, a sample can be a protein sample immobilized on a solid support including, e.g., a blotting membrane. In alternative embodiments, a sample can comprise one or more cells, one or more tissues, one or more fluids, or any combinations thereof. In some embodiments, the sample can comprise a tissue sample. ' Accordingly, the term ' sample ' will be interpreted by the skilled person as relating to its origin (' source ') and/or to its nature (e.g. immobilised proteins, cells or tissue). The description furthermore indicates that the sample can be processed or treated before it is contacted with the plurality of detection reagents (see par. [0011] and [0214] of the description). Such (pre)treatment may involve ' releas[ing] or expos[ing] target analytes from other components of the sample ' (par. [0219]). Numerous ways of processing the sample are mentioned in the description (par. [0049], [0050]), including the ' addition of DNA extraction agents ' and ' isolation of proteins or nucleic acids '. It is therefore clear for the skilled person that a sample which has been processed in a variety of ways before starting the method to detect analytes is also covered by the term ' sample '. It also follows that the term ' sample ' is not limited to a ' (biological) sample comprising one or more cells and/or one or more tissues ' (to the extent the Defendant is arguing this on p. 3 of the Rejoinder, par. 2). The Patent claims nor the description provide any basis for such a narrow interpretation. Also from a technical functional perspective, the skilled person will understand that any sample can qualify as a sample for the purposes of the claimed method, as long as it contains analytes that can be detected/identified using the claimed method.
8.14 The term ' analyte ' is also broadly defined in the Patent (see par. [0008] and [0210] of the description as ' the molecule detected, identified or measured '. Par. [0210] specifies that the analyte ' …can be, but is not limited to, any of the following or any combinations of the following: nucleic acid, peptide, a polypeptide/protein (e.g., a bacterial or viral protein or an antibody), a lipid, a carbohydrate, a glycoprotein, a glycolipid, a small molecule, an organic monomer, sugar, peptidoglycan, a cell, a virus or a drug. Nucleic acids that can be analyzed by the methods herein include: double-stranded DNA, singlestranded DNA, single-stranded DNA hairpins, DNA/RNA hybrids, RNA (e.g. mRNA or miRNA) and RNA hairpins. Generally, a target molecule can be a naturally occurring molecule or a cDNA of a naturally occurring molecule or
the complement of said cDNA. In other embodiments, a target molecule can be modified, e.g., by mutation or chemical reaction. In some embodiments, a target molecule can be synthetic or recombinant. '). Par. [0212] of the Patent adds that: ' A target molecule or an analyte can be part of a sample that contains other components or can be the sole or major component of the sample. A target molecule or an analyte can be a component of a whole cell, tissue or body fluid, a cell or tissue extract, a fractionated lysate thereof or a substantially purified molecule. The target molecule can be present in solution or attached to a solid substrate, including, for example, to a solid surface such as a chip, microarray, bead or a blotting membrane. According to the invention, the analyte is fixed on a solid substrate or support, wherein the solid substrate or support is a chip, a microarray, a blotting membrane or a microscopic slide. Also the target molecule or analyte can have either a known or unknown structure or sequence. '
8.16 In addition to a ' probe reagent ' ( F2.4.1 , discussed above), a detection reagent in accordance with the claimed method comprises ' at least one nucleic acid label comprising a plurality of predetermined subsequences ' ( F2.4.2 , underline CD).
antibodies, the 4-probe procedure would have to be repeated 16 times using the sample. The methods provided in the Patent overcome the need for such successive probings by optically identifying the detection reagents in a temporally-sequential manner by their predetermined subsequences. If only one predetermined subsequence would be available per detection reagent, the method would in essence be identical to the prior art which the Patent tries to distance itself from wherein the sample would have to be probed repeatedly with (sets of) different probes.
8.22 Parties are divided as to whether or not one-and-the-same ('identical') detection reagent with which the sample is contacted in step a ( F2 ) of the claimed method has to remain bound throughout the entire detection sequence of feature F4.1.3 (this is the interpretation according to the Defendant) or whether the claim allows the detection reagents to be removed and replaced with the same detection reagents after the step of removing the optical signal signature (this is the interpretation of the Claimant).
8.23 The Central Division is of the opinion that the skilled person interprets the claimed method such that it does not require that the detection reagent with which the sample is contacted in step a remains bound throughout the detection in accordance with step c and also does not exclude that the same detection reagent is added (or replaced) before another round of detection is carried out in accordance with step c. Nothing in the claim wording, the description, also when read in their technical functional context, excludes this.
8.24 First of all, the wording of the claim does not say that detection reagents may only be added once and/or that the identical detection reagent must remain bound throughout the entire method. Nothing in the Patent description explicitly states that it is necessary that the detection reagent must remain bound.
8.25 Such a requirement also does not follow from F3 of claim 1. F3 requires the removal of any unbound detection reagents (step b of the method). This removal can for example be done by washing (see par. [0051], Example 1, par. [0300], line 34. The Patent description does not provide an explicit technical reason for this step of removing the unbound detection reagents. The skilled person, using their common general knowledge to interpret the claim, will understand that the unbound detection reagents are removed because they are of no use in the subsequent detection step c which is carried out to ultimately identify an analyte in the sample ( F5.1 ). Detection reagents which are not bound to an analyte cannot contribute to this function (and could possibly create background signal) and therefore these are removed. From these considerations it does not, however, follow that the identical detection reagents which are bound upon starting step c must remain bound throughout each repetition of detection of the subsequences. F3 is silent where it concerns the possible removal and addition of (the same) detection reagents during the course of step c, in particular before another round of detection (repeating steps (i) through (iii)) in accordance with F4 F4.1.4 ( ).
8.26 The claimed method does not preclude that the detection reagents, after contacting the sample in step a and after a round of detection in accordance with step c are removed, for example together with the removal of the signal signatures. The step of removal of the ' optical signal signature ' in F4.1.3 is so broadly worded (as opposed to for example specifically and exclusively removing only the decoder probes) that the skilled person would not exclude that the claim (also) covers the situation in which (some of) the detection reagent is removed together with the signal signature. This understanding is confirmed by par. [0074] of the description according to which the ' removal of the signal signatures can be done by any methods known in the art, including, but not limited to, washing, heating, photo-bleaching, displacement, cleavage, enzymatic digestion, quenching, chemical degradation, bleaching, oxidation, and any combinations thereof. ' The skilled person would realise that these methods may include conditions which result in the removal of (bound) detection reagents and would therefore not rule out the possibility of having to add (more of the same, identical) detection reagent when repeating steps i)-iii) in accordance with F4.1.4 .
8.27 A technical functional perspective confirms the above interpretation. The description states that the methods described can significantly increase the number of different probes (and corresponding analytes) that can be simultaneously detected in a multiplex assay as compared to a traditional
8.28
assay wherein each probe is labelled with only one fluorescent label and thus multiplexing is limited by the number of available and practically usable colours. Because the detection reagents are detected and/or imaged in a temporal series of steps, the number of probes (and corresponding analytes) that can be detected in a multiplex assay grows multiplicatively with the number of detection steps in a time series and the number of optical labels being used. By way of example, the description mentions that 3 set of images in which 4 distinct optical labels are used can encode 4 x 4 x 4 = 64 distinct probe reagents (see par. [0040] of the Patent).
Having this explanation in mind, the skilled person understands that the technical function of step c is to detect the detection reagents (and corresponding analytes) in a temporal series of steps thereby allowing the detection of more detection reagents than there are available colours. To this end, the claimed method requires a plurality of pre-determined subsequences that form an identifier of at least one probe reagent ( F2.4.4 ). By in step c repeatedly hybridizing a set of decoder probes having an optical detectable label, a signal signature is generated corresponding to each subsequence. This is repeated in step c.iv for other subsequences whereby a temporal order of optical signature signatures is produced which identifies a subpopulation of the detection reagents ( F4.1.4.1 ). Since the temporal order of signal signatures is unique for each subpopulation of the detection reagents ( F4.1.4.2 ) it can be used to identify the analyte in the sample which corresponds to the subpopulation of detection reagents ( F5.1 ). In other words, the claimed method is based on the detection of a subpopulation of detection reagents that targets an analyte by 'reading out' the temporal barcode that is unique for that subpopulation (and thereby the analyte). For the method to function, it is not necessary that one-and-the-same detection reagent remains bound all throughout the method, in particular in the detection step c. The only requirement is that a specific subpopulation of detection reagents that are capable of (via the decoder probes) generating the signal signature(s) corresponding to each subsequence are bound to the analytes in step c, in other words that the same barcodes are read out in each 'detection round' of step c. It is therefore not excluded that 'fresh' detection reagents (but still the same ones in the sense of having the same barcode, i.e. belonging to the same subpopulation) are added or replaced before starting another round of detection. Regardless of whether the 'original' or 'fresh' detection reagents are used, the result is that more analytes can be detected than there are colours with less detection rounds.
from ' at least about 30 seconds ' to ' 48 hours or longer '. No technical reason is provided nor is it apparent why a limitation as argued by the Defendant would nevertheless be assumed by the skilled person. Therefore, the argument that in practice the skilled person would understand re-incubating with the same detection reagents as excluded from the claim fails.
D10 - Göransson et al. (´Göransson´)
B
tag 2
tag
9.7
9.8
9.9
the labelled ASMs after the different hybridization reactions along with an image showing the identified ASMs. The ASM arrays were decoded in four cycles of hybridization and dehybridization (Göransson, p. 4, left-hand column/p.5, right-hand column).
'C' shows the decoding scheme used for multiplex decoding of genomic fragments. The names of the gene loci and their corresponding number are listed vertically and the labels from the two tags are illustrated horizontally. Green labels are for the fluorescent dye Cy3, red labels represent Texas Red and blue correspond to Cy5 labelling. Black means no labelling, i.e. absence of a detectable signal (tag probe).
According to Göransson, ASMs (corresponding to the ' plurality of analytes ' in claim 1 of the Patent) are prepared from a genomic DNA sample. The ASMs are mounted (' fixed ') on a microscopic glass slide (a ' solid substrate or support ' as required by F2.3) and contacted with a plurality of sandwich probes which target different ASMs (these correspond to the ' detection reagents ' in claim 1) in order to bind each to the other. The sandwich probes contain a part that targets a specific ASM (corresponding to ' a probe reagent targeting an analyte ') which is linked (' conjugated ') to another part that can hybridize to a ' nucleic acid label comprising a plurality of predetermined subsequences ' (in Göransson referred to as decoding tag 1 and tag 2) to a set of 'tag probes' (which are the ' decoder probes ' as defined in claim 1 of the Patent). Each subpopulation of tag probes comprises a detectable tag that produces an ' optical signal signature ' (one of the fluorescent dyes Cy3, Texas Red or Cy5). The signal signatures generated by the hybridization are obtained (see the 20 x 20 pixel image sections in Figure 3) and thus ' detected '. After a first round of detection, the signal signatures are removed by dehybridization (F3), and a new hybridization cycle begins with different sets of decoder probes (corresponding to the detection steps in F4). The resulting ' temporal order of the optical signal signatures ' are compared to a predetermined ' order ' for a particular analyte to ' identify the analyte' (see 'C', the decoding scheme of Göransson).
There is no dispute between the parties in relation to the disclosure of Göransson so far. Accordingly, there is no dispute between the parties that Göransson discloses all of the features of claim 1, except that - according to the Defendant - Göransson does not disclose the detection of analytes in a sample (F1 and F5.1) and that Göransson also does not disclose that the
detection reagents remain bound to the analyte throughout the detection method.
9.10 The dispute between the parties thus essentially focusses on the interpretation of claim 1 of the Patent rather than on what Göransson actually discloses to the skilled person. According to the Defendant, Göransson does not disclose the detection of analytes ' in a sample ' because the sample is genomic DNA and in Göransson it is not this genomic DNA that is fixed on the slides, but only the ASMs derived from the genomic DNA. The process described in Göransson furthermore, according to the Defendant, makes it impossible to perform in situ detection or analysis. Finally, the Defendant argues that claim 1 requires that the detection reagents remain bound to the analyte and that Göransson does not disclose this directly and unambiguously (Göransson rather discloses the dehybridization of the analytes).
9.11 The Central Division does not follow the Defendant´s interpretation of the claimed subject matter and thus comes to the conclusion that Göransson is novelty destroying for claim 1 of the Patent as granted.
9.12 As held above under ' Claim Interpretation ', the terms ' analyte ' and ' sample ' are broadly interpreted. According to the Central Division, these terms include ASMs prepared from genomic DNA and fixed on a microscopic slide as disclosed by Göransson. In Göransson, a genomic DNA sample is (pre)treated such that a collection of ASMs is formed on a microscopic slide (p. 8 left-hand col. under ' Discussion ', ' a random array of all molecules in a sample is created that can be targeted by a series of hybridization reactions to decode the identity of the molecules. '). As set out above (see par. 8.13), according to the description of the Patent a sample may be pre-treated or processed. This includes pre-treatment by e.g. DNA extraction reagents (par. [0049] of the Patent description). 'Extracting' DNA by generating ASMs from a genomic DNA sample, is therefore a way of processing the sample resulting in a processed sample, but there is still a sample 'in' which the individual target analytes (in this case the ASMs) can be detected. Such a sample is covered by claim 1.
9.13 Claim 1 of the Patent - in the form as granted - is also not limited to in situ detection or analysis, not based on its wording, the context of the claim itself or the description. As follows from the interpretation as provided above, the requirement that the plurality of analytes has to be detected in a sample does not constitute such a limitation.
9.14 As furthermore follows from the claim interpretation as set out above, the Central Division does not adopt Defendant´s view that the claim requires that the identical detection reagents must stay bound to the analytes throughout the entire detection method claimed. Regardless of whether or not Göransson discloses directly and unambiguously that all the sandwich probes are dehybridized between two consecutive hybridization and read-out steps (see ' Dehybridization of ASMs ', p. 3, right-hand col. Göransson in combination with Fig. 3 depicted above, washed in a dehybridization buffer containing 50% formamide and 2x SSC buffer at 50 ᵒC for 1 min.), the dehybridization of the analytes and the subsequent addition of 'fresh' detection reagents before a new round of detection, as is undisputedly disclosed by Göransson, is not excluded by the claims of the Patent as granted (see par. 8.22 - 8.33 above, also see par. [0075] of the Patent which mentions the use of denaturants such as formamide, used by Göransson, as a way of modifying the decoder probes, i.e. removing the signal signature).
9.15 In conclusion, all features of claim 1 of the Patent as granted are disclosed directly and unambiguously in Göransson. The claimed subject matter therefore lacks novelty.
9.16 Since the Patent cannot be maintained as granted, the condition under which the Defendant has made an application to amend is fulfilled (Defence, p. 39, top). The Court will therefore proceed to consider the admissibility of the application to amend and to assess whether the grounds for revocation brought forward affect the Patent in part or entirely.
10.1 The application to amend lodged with the Defence to Revocation ('DtR'), Auxiliary requests AR1-AR8, is admissible. New AR2, lodged on 6 March 2024, is not admitted into the proceedings.
10.2 The application to amend was made in the Defence to Revocation (Rule 30 RoP which applies mutatis mutandis in a revocation action based on Rule 50 RoP). Various amendments were proposed by way of multiple alternative sets of claims (Auxiliary requests 1-8, ' AR1-AR8 '). The Claimant has not argued that the Defendant´s application to amend does not meet the requirements of Rule 30.1 RoP. The Central Division sees no reason to find otherwise. The application to amend is therefore admissible.
10.3 The Court does not give permission for the subsequent application to amend as lodged by the Defendant on 6 March 2024, comprising a new auxiliary request 2, maintaining all the auxiliary requests already proposed in the application to amend that was made in the Statement of Defence. The reason for filing the subsequent application to amend that was provided by the Defendant was the CoA order in NanoString/10x Genomics . The reasoning of the CoA in relation to claim construction prompted the Defendant to file ' a further AR emphasizing even more expressly the required persistent binding of the detection reagents to the analytes during the readout of the predetermined subsequences of the detection reagents. '
10.4 Under the front-loaded system of UPC proceedings parties are under an obligation to set out their full case as early as possible (Preamble RoP 7, last sentence). The subsequent application to amend was filed late in the proceedings, after closure of the written proceedings and after the interim conference, less than 1.5 months before the (at the time scheduled) oral hearing. The explanation provided by the Defendant as to why it was not possible to set out their full case (by filing the auxiliary request) earlier, i.e. the fact that a CoA order was issued on 26 February 2024 and in particular the claim construction adopted by the CoA, does not justify allowing the new auxiliary request into these proceedings at this stage of the proceedings. Although the Defendant indeed acted swiftly in submitting the application within one week after the CoA order becoming available, the substantive part of the CoA order that triggered the filing of new AR2, i.e. the claim construction issue in relation to the ´persisted binding´, albeit in relation to a different patent (EP ´782), could not have come as a surprise to the Defendant. That the CoA followed the interpretation as argued by the Claimant is not a valid reason. Already in the Statement of Revocation (´SoR´) in the present Revocation action, the Claimant provided its interpretation of the relevant features (par. 91 and footnote 8 and par. 97 footnote 9). In the DtR, the Defendant acknowledged and responded to the issue (DtR p. 16, under b). The Claimant then reiterated and further explained its position in the Reply to the Defence to Revocation (´RtD´, see par. 34-51). Under these circumstances, the Central Division is of the opinion that the Defendant could and should have filed the auxiliary request earlier. New AR2 is filed in response to an issue that was known to the Defendant at the very least since 27 November 2023, the date of the RtD. No satisfactory explanation has been provided why the Defendant waited until 2 March 2024 to file new AR2. This is in violation of the Defendant´s obligation to set out its case as early as possible thereby making it unnecessarily difficult for the Claimant and the
Court to properly deal with the new request. Permission under Rule 50.2 RoP in connection with Rule 30.2 RoP is therefore not given.
11.1 Auxiliary request 1 cannot serve as a basis to revoke the Patent in part as the subject matter claimed lacks inventive step.
11.2 Claim 1 of Auxiliary request 1 is amended vis-à-vis claim 1 of the Patent as granted in the following way (annotations by the Defendant):
A method used in (i)immunohistochemistry and/or (ii) fluorescence in situ hubridization_for detecting a plurality of analytes in a sample , comprising:
contacting the sample with a composition comprising a plurality of detection reagents, wherein each subpopulation of the detection reagents targets at least one different analyte, wherein analyte is fixed on a solid substrate or support and wherein the solid substrate or support is a chip; a detection reagent comprises: the
at least one probe reagent targeting an analyte and at least one nucleic acid label comprising a plurality of pre-determined subsequences; wherein at least one probe reagent and said at least one nucleic acid label are conjugated together; and wherein at least a portion of said plurality of predetermined subsequences form an identifier of said at least one probe reagent; said b. removing any unbound detection reagents;
iii) removing said optical signal signature produced by the hybridization of set of decoder probes; said iv) repeating steps (i) through (iii) for other subsequences of said detection reagents, thereby producing a temporal order of optical signal signatures corresponding to the plurality of pre-determined subsequences; wherein the temporal order of the optical signal signatures corresponding to said plurality of pre-determined subsequences of said detection reagent identifies a subpopulation of the
detection reagents and is unique for each subpopulation of the detection reagents; and d. comparing said temporal order of the optical signal signatures with different identifiers of said at least one probe reagent, wherein an agreement between the temporal order of the optical signal signatures and a particular identifier of said at least one probe reagent identifies the analyte in the sample; wherein
said sample is a biologicalsample comprising one or more_cells and/or one ormore_tissues; and wherein saidanalutes are selected_from the group consisting ofproteins_peptides and nucleic acids_wherein said nucleic acids areselected fromn the group any combinations thereof
11.3 The features of AR1 that have been introduced into claim 1 of the Patent as granted are:
-the method is used in in situ fluorescence hybridization and/or immunohistochemistry
-the sample is a biological sample comprising one or more cells and/or one or more tissues
-analytes are selected from the group consisting of proteins, peptides and nucleic acids, wherein said nucleic acids are selected from the group consisting of cellular RNA, messenger RNA, microRNA, ribosomal RNA, and any combinations thereof.
11.4 There is no real dispute between the parties about the interpretation of the individual features that have been added to claim 1 of the Patent as granted. The description of the Patent characterises (fluorescence) in situ hybridization (FISH) in par. [0236] as a ' technique for detecting (and/or quantifying) the presence of certain cellular DNA or RNA (often ribosomal RNA ' Immunohistochemistry is defined as ' ). antibody-based staining of cell or tissues for microscopic evaluation ' in par. [0235] of the Patent (also see the dictionary definition in D53). The skilled person is familiar with these methods from their common general knowledge and generally knows how these should be performed. The Patent contains no specific teaching in relation to these methods per se .
11.5 In the opinion of the Central Division, the method as claimed in claim 1 of the first Auxiliary Request, by specifying that the method 'is used ' in the context of in situ hybridization and/or immunohistochemistry, is limited vis-à-vis the claims as granted in that the method must actually be used in an in situ context, i.e. for that purpose. In other words, methods that are not used in the context of either of these (well known) in situ methods are excluded from the claimed subject matter. This understanding is in line with and further confirmed by the second amendment in Auxiliary request 1 which specifies that the sample is a biological sample comprising one or more cells and/or one or more tissues and the limitation of the analytes.
11.6 The Defendant further argued that the skilled person, in the context of an in situ method, to which the claims of AR1 are undisputedly limited, would on the basis of their common general knowledge be aware that significantly longer detection probes (also referred to as ' probe reagents ', the part of the detection reagent that interacts with the analyte of interest), had to be used compared to an in vitro method. The ' decoder probes ' (the probes hybridizing the predetermined subsequences) would be much shorter than the detection probes. The likelihood of the detection reagents being 'washed away' together with the removal of the signal signature when using such long
detection probes would be next to nil. This knowledge, as the Court understands the argument, would lead to a claim interpretation whereby the skilled person would understand that - in any event in an in situ context (all) the detection reagents with which the sample is contacted in step a of the method would remain bound to 'their' analytes throughout the entire detection method.
11.10 The Central Division adopts the principles for assessing inventive step as set out by the CoA in CoA NanoString/10x Genomics Order and in the Central Division´s decisions of 16 July 2024 in cases UPC_CFI_1/2023 and UPC_CFI_14/2023 (par. 8-2-8.10), also see LD Munich Order dated 27 August 2024 in case UPC_CFI_201/2024, C.4.b).
11.11 According to Article 56 EPC, an invention shall be considered as involving an inventive step if, having regard to the state of the art, it is not obvious to a person skilled in the art.
11.12 Whether inventive step is acknowledged is always to be assessed in each individual case and requires a legal evaluation of all relevant facts and circumstances. As held by the Court of Appeal in NanoString/10x Genomics (p. 30, fourth par.) the burden of presentation and proof with regard to the facts from which the lack of validity of the patent is derived and other circumstances favourable to the invalidity or revocation lies with the claimant in a revocation action (Art. 54 and 65(1) UPCA, Rules 44(e)-(g), 25.1(b)-(d) RoP). Even though proof of certain facts, if contested, may thus be required, the ultimate assessment of the relevant facts circumstances is a question of law which does not lend itself to the taking of evidence.
11.13 An objective approach must be taken to the assessment of inventive step. The subjective ideas of the applicant or inventor are irrelevant. In principle, it is also irrelevant whether the invention is the result of serendipity or of systematic work involving (potentially costly and laborious) experimentation. It is only relevant what the claimed invention actually contributes to the prior art.
11.14 Inventive step is to be assessed from the point of view of the skilled person on the basis of the state of the art as a whole, including the skilled person´s common general knowledge. The skilled person is assumed to have had access to the entire publicly available art on the relevant date. The decisive factor is whether the claimed subject matter follows from the prior art in such a way that the skilled person would have found it on the basis of their knowledge and skills, for example by obvious modifications of what was already known.
11.15 In order to assess whether or not a claimed invention was obvious to a skilled person, it is first necessary to determine a starting point in the state of the art. There has to be a justification as to why the skilled person would consider a particular part of the state of the art as a realistic starting point. A starting point is realistic if its teaching would have been of interest to a skilled person who, at the priority date of the patent at issue, was seeking to develop a similar product or method to that disclosed in the prior art which thus has a similar underlying problem as the claimed invention (cf. Court of Appeal NanoString/10x Genomics , p. 34 under 'cc' in the German original version, ' Für eine Fachperson, die sich zum Prioritätszeitpunkt des Verfügungspatents vor die Aufgabe gestellt sah war […] D6 von Interesse' . ) There can be several realistic starting points. It is not necessary to identify the 'most promising' starting point.
11.16 Comparing the claimed subject matter, after interpretation following the guidelines provided above under 'claim interpretation', and the prior art, the subsequent question is whether it would be obvious for the skilled person to, starting from a realistic prior art disclosure, in view of the underlying problem, arrive at the claimed solution. If it was not obvious to arrive there, the claimed subject matter meets the requirements of Article 56 EPC.
11.17 In general, a claimed solution is obvious if, starting from the prior art, the skilled person would be motivated (i.e. have an incentive or in German: ' Veranlassung ', see the CoA in NanoString/10x Genomics, p. 34) to consider the claimed solution and to implement it as a next step (' nächster Schritt ', CoA in NanoString/10x Genomics, p. 35, second par.) in developing the prior art. On the other hand, it may be relevant whether the skilled person would have expected any particular difficulties in taking any next step(s). Depending on the facts and circumstances of the case, it may be allowed to combine prior art disclosures.
11.18 A technical effect or advantage achieved by the claimed subject matter compared to the prior art may be an indication for inventive step. A feature that is selected in an arbitrary way out of several possibilities cannot generally contribute to inventive step.
11.19 The Central Division emphasises that hindsight needs to be avoided. The question of inventive step should not be answered by searching retrospectively, with knowledge of the patented subject matter or solution, for any (combination) prior art disclosures from which that solution could be deduced.
takes note of Göransson would realise that the part of its disclosure relating to the multiplexing problem is not limited to ASMs prepared from genomic DNA randomly spotted on an array. See e.g. Abstract of Göransson, last sentence: ' the target can be any biomolecule which has been encoded into a DNA circle via a molecular probing reaction. ' Likewise, Göransson teaches a ' generic decoding strategy ' (Abstract). So it cannot be said that Göransson´s teaching is confined to ASMs from genomic DNA on an array and will be disregarded by the skilled person who is interested in the detection of biomolecules in other contexts.
applied for multiplex quantification of ASMs created from any assay that results in circular DNA molecules. We demonstrate our approach for quantitative multiplex analysis by using it to measure relative copy numbers of 31 autosomal and sex chromosome loci, targeted by selector probes (28).. ' (p.2, left-hand col., last par., underline CD).
generic and can be applied to any biomolecule and ASMs from any assay (see above). The skilled person will thus realise that the generic decoding strategy as taught by Göransson can be used as well in other contexts, in particular in situ , where the lack of available fluorophores is also an issue.
what will_be_the_next_step to_take_with_this_described technique? Well, the potentials are infinite. What might be the most selfexplanatory and natural application is further mutation detection analysis on tissues. That would especially involve point mutations or other genetic alterations with minor sequence differences; such as deletions or fusion transcripts that other techniques cannot distinguish between. In both paper II and III we explored the multiplex ability of the method and we are convinced that crosshybridization between the padlock_probes_are not_an issue, which opens up the possibility of detecting multiple mutations in a tissue as a general mutation analysis tool A limitation with the current method design, when it comes to multiplexing, is the restricted number_of fluorophores that can be used in order to not get a spectral overlap that may leads to difficulties in discriminating between signals. However, previous_studies_have shown that_by_designing_padlock_probes with many sequences for_detection multiple targets can be_ detected and discriminated with the use of a decoding scheme consisting of many consecutive hybridization_stepsuz (see D5O, page 46, penultimate paragraph, emphasis added) "So, tag
situ RNA detection (273 SoR et seq., with reference to numerous prior art documents).
11.38 The Defendant nevertheless referred to a number of 'problems' that the skilled person would have faced which would have caused the skilled person to not have a reasonable expectation of success even if they would have had an incentive to transfer the method of Göransson from an in vitro to an in situ context (p. 47 DtR, p. 21-22 R). The doubts that the skilled person would have had were according to the Defendant: the destruction of the sample and analytes; sensitivity of native analytes, especially RNA, to degradation; duration of the procedure with repeated hybridization of the primary probes; change in location of ASMs compared to analyte localization across cycles; separability/distinguishability of multiple analytes occurring in close spatial proximity ('molecular crowding'); autofluorescence and heterogeneity in a cell or tissue sample; sample penetration and distribution of reagents).
11.39 The Central Division finds that the Claimant has in par. 362 RtD, credibly argued that most of the problems raised by the Defendant were problems that were common issues with any prior art FISH or IHC application and that those issues were routinely solved by the skilled person. Such problems have no bearing on the expectation of success of transferring the method of Göransson from an in vitro to an in situ context. Moreover, the fact that none of the problems identified by the Defendant are even mentioned in the Patent as ' in situ problems', let alone that the Patent provides any solutions for these alleged problems is a strong indication that these problems would be readily addressed by the skilled person should they occur at all (also see below).
11.40 The above applies equally to what according to the Defendant is the 'main problem' for transferring the method of Göransson into the in situ context which would be the time delay caused by repeatedly hybridizing the primary probe following the teaching of Göransson. As also discussed above in the context of claim interpretation of Auxiliary Request 1, an in situ method would require longer probe lengths that would require proportionally longer incubation times (p. 47 DtR). The Defendant refers to BP9, the CosMx Spatial Molecular Imager which has a probe length of 35-50 nucleotides and an incubation time of 16-18 hours. Göransson´s probes have a maximum length of 23 nucleotides and require only one hour to incubate, the Defendant points out.
11.41 First of all, the Central Division notes that the claims of AR1 require (underline CD) ' contacting the sample with a composition comprising a plurality of detection reagents ' (and removing unbound detection reagents) without any indication or limitation as to how long the contacting step should last. In par. [0046] the description of the Patent discloses a wide range of possible contact times being ' at least about 30 seconds, at least about 1 minute, at least about 5 minutes, at least about 10 minutes, at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 24 hours, at least about 48 hours or longer. ' From this the Central Division concludes that the skilled person will be able to determine an appropriate contact time. This is also confirmed by the specification of the Patent in suit, see the last sentence of par. [0046]: ' One of skill in the art can adjust the contact time accordingly. ' Likewise, as discussed above, in par. 11.7, the probe reagents can be of any length. The description adds in par. [0088] ' An ordinary artisan can readily identify appropriate probe reagents for the target molecules or analytes of interest to be detected in various bioassays. ' In view of this information in the Patent, the Central Division concludes that the skilled person, starting from Göransson, would have been able, based on their common general knowledge, to design appropriate probe reagents and contacting times for use in situ even if the skilled person would have 'stuck' with multiple (re)hybridizations as taught in Göransson (and not excluded by the Patent).
11.42 Based on the foregoing, the Central Division comes to the conclusion that it would have been obvious for the skilled person to, starting from the prior art disclosure of Göransson, arrive at the subject matter of claim 1 of AR1.
11.43 In coming to this conclusion, the Central Division has furthermore taken into account that the claimed subject matter is not limited to nor provides the skilled person with any guidance as to the number of analytes that has to be detected, the time within which this is to be done, the sensitivity of the method that must be reached, the resolution of a spatial location, etc. Such information or guidance is also not to be found in the Patent description. In addition, as stated by the Claimant (in the Statement of Revocation, at par. 191), and not contested by the Defendant, there is not a single experimental example in the Patent of how a FISH method can be carried out with RNA as analyte. Further, there are no experimental examples demonstrating the use of a FFPET (Formalin-Fixed Paraffin-Embedded Tissue used in immunohistochemistry, CD) sample or detection of a particularly high
number of analytes or at least explains under which conditions a particularly high throughput could be realized. The claimed method thus on the one hand includes embodiments wherein the method (arguably) still 'works' (i.e. detects a plurality of analytes, at least two analytes) but provides none of the advantages relied upon by the Defendant in support of inventive step. On the other hand, the description does not provide sufficient technical information that the above-mentioned problems (which are according to the Defendant specific for in situ methods) actually exist, let alone are overcome by the claimed subject matter. In the absence of such a concrete technical teaching or contribution, these 'problems' cannot in the view of the Central Division be used as the basis on which to acknowledge inventive step.
(in particular Göransson). Therefore, these auxiliary requests also cannot render the claimed subject matter inventive for the same reasons as AR1.
NanoString/10x Genomics appeal where many similar issues were dealt with by the CoA.
Having heard the parties on all relevant aspects of the case, the Central Division:
An appeal against the present Decision may be lodged at the Court of Appeal, by any party which has been unsuccessful, in whole or in part, in its submissions, within two months of the date of its notification (Art. 73(1) UPCA, R. 220.1(a), 224.1(a) RoP).
Art. 82 UPCA, Art. Art. 37(2) UPCS, R. 118.8, 158.2, 354, 355.4 RoP.
An authentic copy of the enforceable decision will be issued by the Deputy-Registrar upon request of the enforcing party, R. 69 RegR.