DECISION
of the Court of First Instance of the Unified Patent Court
Central Division (Section Munich)
delivered on 17 October 2024
concerning EP 2 794 928 B1

HEADNOTES:
1. The Court must examine its international jurisdiction of its own motion when this
is required under Union law.
2. 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. In view of the
circumstances of the case the Central Division does not exercise its discretionary
power to stay the proceedings.
3. The assessment of novelty within the meaning of Art. 54(1) EPC requires the
determination of the whole content of the prior publication. It is decisive whether
the subject-matter of the claim with all its features is directly and unambiguously
disclosed in the prior art citation.
4. Under the front-loaded system of UPC proceedings, parties are under an
obligation to set out their full case as early as possible. Permission for subsequent
request to amend under Rule 50.2 RoP in connection with Rule 30.2 RoP is not given
as the auxiliary request could and should have been filed earlier.

KEYWORDS:
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.
Action n°: UPC 252/2023
Revocation action
ACT_551180/2023 (UPC_CFI_252/2023)

CLAIMANT:
NanoString Technologies Europe Limited, Suite 2, First Floor, 10 Temple Back - BS1
6FL - Bristol - GB
represented by Daniela Kinkeldey of Bird & Bird.

DEFENDANT:
President and Fellows of Harvard College, 17 Quincy Street - 02138 - Cambridge,
MA - US
represented by Axel Berger of Bardehle Pagenberg.

PATENT AT ISSUE
European patent EP 2 794 928 B1, hereafter referred to as ´the Patent´.

PANEL/DIVISION
Panel 1 of the Central Division (Section Munich).

DECIDING JUDGES
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.

DATE OF THE ORAL HEARING
18 September 2024.

SUMMARY OF FACTS AND REQUESTS
1 Procedural background and the proceedings before the Central Division
1.1 On 27 July 2023, NanoString Technologies Europe Limited (the ‘Claimant’)
brought the present Revocation action in the Central Division (Section
Munich) (´Central Division´) against President and Fellows of Harvard College
(the ‘Defendant’).
1.2 On 29 July 2022 NanoString Technologies Germany GmbH brought a
revocation action against the German national part of EP 2 794 928 to the
German Federal Patent Court (´BPatG´, the action is referred to as ´the
German Revocation action´). The Claimant and NanoString Technologies
Germany GmbH have the same parent company: NanoString Technologies,
Inc. (USA). After the hearing in the German Revocation action, which was held
on 7 May 2024, the BPatG held that the Patent was invalid and revoked the
(German part of the) Patent in its entirety. The written grounds for the
decision have been submitted in these proceedings as document D60.
1.3 A request for provisional measures by the Defendant and 10x Genomics, Inc.
against NanoString Technologies, Inc. and NanoString Technologies Germany
GmbH based on the Patent was rejected by the Munich Local Division by
order dated 10 October 2023 in case UPC_CFI_17/2023 (ACT_459996/2023)
amongst others on the ground that the validity of the Patent was
insufficiently certain (D49, p. 35-36).
1.4 The Defendant is also the owner of EP 4 108 782 B1 (EP ´782), which is a
(second generation) divisional patent of the Patent. The Local Division
Munich in case UPC_CFI_2/2023 (ACT_459746/2023) granted a request for
provisional measures based on EP ´782 by order dated 19 September 2023
(submitted in these proceedings as BP4). By order dated 26 February 2024,
the Court of Appeal (‘CoA’) set aside the order of the Local Division on the
grounds that, in sum, the CoA on the balance of probabilities, considered it
to be more likely than not that the subject matter of EP ´782 will prove to be
unpatentable for lack of inventive step over Göransson, document D10 in
these proceedings (also referred to as the ´CoA Order in NanoString/10x
Genomics´). EP ´782 is under opposition at the EPO.
1.5 In the present Revocation action, the Defendant lodged a Preliminary
Objection relating to lis pendens in view of the German Revocation Action
(´PO´). The judge-rapporteur informed the parties by order dated 4 October
4
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.
1.6 The Defendant filed a subsequent application to amend the patent in
response to the CoA order in NanoString/10x Genomics. By order dated 8
March 2024, the judge-rapporteur informed the parties that the panel would
decide at the oral hearing whether permission will be granted, should the
new auxiliary request and its admissibility become relevant. The Claimant
was allowed to submit arguments on the validity of the new auxiliary request
so that this could be discussed in case necessary.
1.7 The oral hearing in the present proceedings was originally scheduled for 17
April 2024. After the Claimant´s parent company filed for relief under Chapter
11 of title 11 of the US Bankruptcy Code in February 2024, the hearing in this
revocation action was, upon suggestion by the Claimant (with the consent of
the Defendant), rescheduled to 18 September 2024. The Claimant informed
the Court that the assets of the NanoString group of entities (which includes
certain subsidiaries such as the Claimant) have been purchased and that this
change in ownership does not affect the present proceedings.
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2 The Patent
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:
1. A method for detecting a plurality of analytes in a sample, comprising:
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 pre-
determined 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 pre-
determined 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;
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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
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.
2. The method of claim 1, wherein:
(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.
3. The method of claim 1 or claim 2, further comprising processing said
sample before said contacting with said plurality of detection reagents.
4. The method of any previous claim, further comprising measuring the
intensity of the optical signal signatures generated from each subpopulation
of the detection reagents, preferably wherein the intensity of the optical
signal signatures generated from each subpopulation of the detection
reagents indicates an amount of the analyte, and/or preferably wherein the
intensity of the optical signal signatures generated from each subpopulation
of the detection reagents is used in identification of the subpopulation of the
detection reagents.
5. The method of any previous claim, wherein:
(i) said each subpopulation of the decoder probes comprises a
different optical detectable label, each different optical detectable
label producing a different optical signal signature; and/or
(ii) said each subpopulation of the decoder probes is at least partially
or completely complementary to said subsequence of the detection
reagents; and/or
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(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.
6. The method of any previous claim, wherein said removing of the optical
signal signature is performed by washing, heating, photobleaching,
displacement, cleavage, enzymatic digestion, quenching, chemical
degradation, bleaching, oxidation or any combinations thereof.
7. The method of any previous claim, wherein:
(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.
8. The method of any previous claim, wherein said optical signal signatures
comprise signatures of fluorescent colour, visible light, no-colour, Raman
label, or any combinations thereof, or wherein said optical signal signatures
comprise signatures of one or more fluorescent colours, one or more visible
lights, one or more no-colours, one or more Raman labels, or any
combinations thereof.
9. The method of any previous claim, wherein said analytes are selected from
the group consisting of antigens, receptors, proteins, peptides, sugars,
glycoproteins, peptidoglycans, lipids, nucleic acids, oligonucleotides, cells,
viruses, and any combinations thereof, preferably wherein said nucleic acids
are selected from the group consisting of cellular DNA or RNA, messenger
RNA, microRNA, ribosomal RNA, and any combinations thereof.
10. The method of any previous claim, wherein:
(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
8
(iii) said sample comprises an environmental sample, food, food
byproduct, soil, an archaeological sample, an extraterrestrial
sample, or any combinations thereof.
11. The method of any previous claim, wherein said at least one probe
reagent and said at least one nucleic acid label are conjugated together by
at least one linker, preferably wherein:
(i) said linker is a bond; and/or
(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.
12. The method of claim 11, wherein said linker is a particle, preferably
wherein:
(i) said particle is selected from a group consisting of a gold
nanoparticle, a magnetic bead or nanoparticle, a polystyrene bead,
a nanotube, a nanowire, a microparticle, and any combinations
thereof, preferably wherein said particle is a nanoparticle; and/or
(ii) said particle is modified; and/or
(iii) said particle is coated with streptavidin or a derivative thereof;
and/or
(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.
13. The method of any previous claim, wherein:
(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
(ii) said at least one probe reagent is modified; and/or
(iii) said at least one probe reagent is biotinylated.
14. The method of any previous claim, wherein:
9
(i) said at least one nucleic acid label is single-stranded, double-
stranded, 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 cross-
hybridization 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.
15. The method of any previous claim, wherein said plurality of pre-
determined subsequences are conjugated together by at least one sequence
linker, preferably wherein (a) said sequence linker is a bond, and/or (b) said
sequence linker is a nucleotidic linker, preferably wherein said nucleotidic
linker is single-stranded, double-stranded, partially double-stranded, a
hairpin or any combinations thereof, and/or preferably wherein said
nucleotidic linker is at least one nucleotide long.
16. The method of any previous claim, wherein:
(i) said detection reagent comprises one probe reagent and a
plurality of nucleic acid labels; or
(ii) said detection reagent comprises a plurality of probe reagents
and a nucleic acid label; or
(iii) said detection reagent comprises a plurality of probe reagents
and a plurality of nucleic acid labels.
17. The method of any previous claim, wherein:
(i) the method is used in immunofluorescence; and/or
(ii) the method is used in immunohistochemistry; and/or
(iii) the method is used in fluorescence in situ hybridization; and/or
(iv) the method is used in western blot.
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3 Requests of the Parties
3.1 The Claimant argues that the Patent is invalid based on the grounds that its
subject matter is not patentable within the terms of Arts. 52 to 57 EPC (Art.
65(1),(2) UPCA in combination with Art. 138(1)(a) EPC), since it lacks novelty
(Art. 54 EPC) and is not based on an inventive step (Art. 56 EPC); the Patent
does not disclose the invention in a manner sufficiently clear and complete
for it to be carried out by a person skilled in the art (Art. 65(1), (2) UPCA in
combination with Art. 138(1)(b) EPC); and that subject matter of the Patent
extends beyond the content of the earlier applications as filed (Art. 65(1), (2)
UPCA in combination with Art. 138(1)(c) EPC).
3.2 On these grounds, the Claimant requests in the main proceedings (to the
extent still relevant):
- to revoke the patent in its entirety for the territory of the UPC member
states Germany, France and the Netherlands; and
- to dismiss Proprietor's application to amend the patent in suit and thus
reject all Auxiliary Requests 1 to 8
- that the new Auxiliary request 2 is not admitted into the proceedings and
should it be admitted to reject it as invalid
- to order the proprietor to pay the costs of the proceedings (Art. 69(1)
UPCA).
3.3 The Defendant has put forward various defences including a (conditional)
application to amend the Patent which was lodged together with the Defence
to Revocation. By submission dated 1 March 2024, the Defendant requested
permission from the Court for a subsequent application to amend the Patent
in accordance with a new Auxiliary request 2 maintaining the previous main
and auxiliary requests.
3.4 The Defendant requests in the main proceedings (to the extent still relevant):
- that the revocation action be rejected
- in the alternative, that the German, the French and the Dutch parts of EP
2 794 928 be upheld to the extent of one of auxiliary requests 1 to 8
(alternatively 9)
- the Claimant be ordered to pay the costs of the proceedings.
3.5 The grounds and defences as brought forward by the parties will, to the
extent relevant for this decision, be discussed in detail below.
11
GROUNDS FOR THE DECISION
4 Summary of the Outcome
4.1 The Central Division comes to the conclusion that claim 1 of the Patent as
granted lacks novelty because the claimed subject matter is disclosed directly
and unambiguously in the prior art document Göransson. The first Auxiliary
request lacks inventive step over Göransson. The skilled person would,
starting from Göransson, have had an incentive to transfer the method of
Göransson from an in vitro to an in situ context and would thereby have
arrived at the claimed subject matter without inventive skill. Auxiliary
requests 2-8 can also not serve as a basis for revoking the Patent only in part.
Accordingly, the Patent is revoked in its entirety.
5 Admissibility and International Jurisdiction of the UPC
5.1 The Central Division has no concerns as to the admissibility of this revocation
action. The Central Division furthermore establishes that it has (international)
jurisdiction and will not stay the proceedings in view of the German
Revocation action.
The relevant facts and arguments brought forward by the parties in the
withdrawn PO
5.2 In the PO, the Defendant argued that the Central Division (Section Munich)
of the Unified Patent Court is not competent to decide on the validity of the
German part of the Patent, since there is already a revocation action pending
against the Patent at the (competent) BPatG. The Defendant brought forward
that the claimant in the German Revocation action, NanoString Technologies
Germany GmbH, belongs to the same group of companies and has the same
parent company as the Claimant. The Defendant further argued that their
interests in the Revocation action are identical to and indissociable from each
other. Defendant relied in the PO on Article 29 and, in the alternative, Article
30 of Regulation (EU) No 1215/20121 (herein also referred to as “Brussels I
recast Regulation”), dealing with lis pendens and related actions,
respectively, to request a dismissal or alternatively a stay of the action as far
as it concerns the German part of the Patent.
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.
12
5.3 In its response to the PO, the Claimant submitted that the Claimant and the
plaintiff in the German Revocation action are not to be considered as the
“same parties” within the meaning of Article 29 and that there should be no
stay pursuant to Article 30 Brussels I recast Regulation.
5.4 At the oral hearing, the Defendant withdrew the PO. Both parties requested
the Central Division to accept international jurisdiction, also where it
concerns the German part of the Patent, and not to stay the proceedings
pending the outcome of the German Proceedings on various grounds, as
further discussed below.
Jurisdiction – examination of its own motion
5.5 The Defendant has (unconditionally) withdrawn its PO. The Court
furthermore understands the parties´ agreement at the oral hearing as a
unanimous wish to submit to the jurisdiction of the UPC (in particular the CD).
5.6 The Court must, however, examine its international jurisdiction of its own
motion when this is required under Union law. The rules of Union law on
jurisdiction contained in the Brussels I recast Regulation, in accordance with
which the Court´s international jurisdiction shall be established (made explicit
in Article 34 UPCA), prevail over the UCPA and the RoP (also see Article 20,
24 UPCA) to the extent these rules of Union law are compulsory and require
the Court to examine its jurisdiction of its own motion. This is regardless of
the possible applicability of Rule 19.7 RoP, in accordance with which the
failure to lodge a preliminary objection (which could arguably be equated
with the withdrawal of a PO) shall be treated as a submission to the
jurisdiction and competence of the Court and regardless of the apparent
agreement between the parties to that effect.
International Jurisdiction of the Court for the present Revocation action
5.7 The present action is a patent revocation action. According to Article 24(4) of
the Brussels I recast Regulation, the courts of each Member State shall have
exclusive jurisdiction in proceedings concerned with the registration or
validity of any European patent granted for that Member State. This exclusive
jurisdiction is to be examined by the Court of its own motion (Article 27
Brussels I recast Regulation).
5.8 In accordance with Article 71a of Regulation Brussels I recast, a “common
court” shall be deemed to be a court of a Member State when such a common
13
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.
5.9 Pursuant to Article 32(1) (d) UPCA, the UPC shall have exclusive competence
for actions for revocation of (European) patents. In view of this exclusive
competence, and since no opt-out from the exclusive competence of the
Court in relation to the Patent is in effect (cf. Article 83(3) UPCA), the UPC –
as a common court of the Member States to the UPCA – in principle has
international jurisdiction based on article 24(4) of Regulation Brussels I recast
and is competent in respect of the present Revocation action. This jurisdiction
extends to the French, Dutch and German parts of the Patent.
Parallel revocation action in relation to the Patent in Germany
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).
14
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).
Article 29 (and 31) Brussels I recast Regulation
5.13 In accordance with Article 29 of the Brussels I recast Regulation, where
proceedings involving the same cause of action and between the same
parties are brought in the courts of different Member States any court other
than the court first seised shall decline jurisdiction in favour of that court.
5.14 It is clear that the German Federal Patent Court was seised before the UPC in
relation to a revocation action in respect of the (German part of) the same
European patent which is the subject of the present Revocation action. The
parties to both actions are, however, not the same.
5.15 The CoA in Mala Technologies/Nokia Technologies, applying the case law of
the (then) ECJ (hereinafter referred to as ´CJEU´) in Tatry (CJEU 6 December
1994, C-406/92, ECLI:EU:C:1994:400) and Drouot (CJEU 19 May 1998, C351,
ECLI:EU:C:1998:242), interpreted and applied Article 29 of the Brussels I
recast Regulation such that despite two parties to a UPC and a national
revocation action in relation to the same national part of the same European
patent being closely related (being part of the same group of companies and
having the same parent company) and therefore being in a position to
coordinate the initiation of proceedings and their submissions in the
proceedings, and notwithstanding the grounds for revocation, arguments
and auxiliary requests raised by both parties being largely the same, the
parties could not be considered the same party for the purposes of Article 29
Brussels I recast Regulation. They were separate legal entities and there was
not such a degree of identity between their interests that a judgment
delivered against one of them would have the force of res judicata as against
15
the other. See the CoA in Mala Technologies/Nokia Technologies, par. 17-19
of the Order.
5.16 Following the above case law of the CJEU and the UPC CoA and applying this
to the present case, the parties are not the same for the purposes of Article
29 Brussels I recast Regulation. NanoString Technologies Germany GmbH
(claimant in the German Revocation action) and the Claimant are not the
same legal entities. The fact that both parties belong to the same group of
companies and have the same parent company is insufficient to conclude
that their interests are, even though they may be to a large extent aligned,
identical and indissociable. No additional facts have been submitted by the
parties to the Court on the basis of which it can be established that there is
such a degree of identity between the interests of the parties to both
proceedings that a judgment delivered against one of them would have the
force of res judicata as against the other. Therefore, Article 29 Brussels I
recast Regulation is not applicable in the present case.
5.17 It follows from the conclusion reached in relation to Article 29 that Article 31
of the Brussels I recast Regulation also does not apply in this case, since the
parties to the proceedings in the German Revocation action are not the same
as the parties to the proceedings before the UPC (cf. CoA in Mala
Technologies/Nokia Technologies, 20-22 of the Order).
Article 30 Brussels I recast Regulation
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.
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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.
17
- 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.
6 Technical Background
6.1 Before discussing the grounds for invalidity raised by the Claimant in detail,
the Central Division finds it useful to provide a brief technical background as
follows from the Patent description.
6.2 According to the background section in the description 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
18
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.
6.3 According to the Summary section of the description of the Patent:
[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 temporally-
sequential 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.
19
6.4 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.
6.5 From the background section above, it follows that in order to obtain as much
information as possible on a variety of analytes (e.g. specific disease-relevant
proteins, RNA or DNA) from one sample, e.g. a biopsy sample, it is
advantageous to be able to test as many analytes as possible on one sample
in so-called “multiplexing” techniques (cf. par. [0003] of the Patent above).
Such methods can be performed, for example, by visualising (on the same
sample) different analytes with different optical detection probes. With such
multiplex approaches, however, there are problems if more analytes than
available dyes (also: “colours”) are to be detected, for example if only 4 to 5
different dyes are available for multiplex detection, but 6 or more different
analytes are to be detected.
6.6 According to the Patent in suit, a known possibility to circumvent the problem
of the limited number of available colours was to repeat the test using the
same colours for the detection of different analytes with one and the same
sample (par. [0006]). By way of example par. [0006] mentions an assay
involving 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. A drawback of this is that some target analytes in the
sample can degrade during successive probings resulting in the need to
prioritise the order of detecting different target analytes in a single sample.
6.7 Against this background, the Patent furthermore states in par. [0006] that
there is a need for accurate and sensitive methods with a high throughput for
detection, identification, and/or quantification of target molecules in a
20
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).
6.8 In order to achieve this aim, the Patent claims a method for detecting a
plurality of analytes in a sample having the features as set out below.
7 Claim Features (Main Request, claim 1 as granted)
7.1 The parties agree on the following claim feature breakdown/analysis (see
par. 25 statement of Revocation, p. 10 of the Defence to Revocation,
submitted in these proceedings as BP5) which is largely adopted by the
Central Division (underline added by the CD to highlight particular method
steps):
F1 A method for detecting a plurality of analytes in a sample
F2 a. contacting the sample with a composition comprising a plurality
of detection reagents,
F2.1 each subpopulation of the detection reagents targets at
least one different analyte,
F2.2 the analyte is fixed on a solid substrate or support,
F2.3 the solid substrate or support is a chip, a microarray, a
blotting membrane or a microscopic slide,
F2.4 each detection reagent comprises:
F2.4.1 at least one probe reagent targeting an analyte,
F2.4.2 and at least one nucleic acid label comprising a
plurality of predetermined subsequences,
F2.4.3 said at least one probe reagent and said at least
one nucleic acid label are conjugated together;
21
F2.4.4 at least a portion of said plurality of pre-
determined subsequences form an identifier of said at
least one probe reagent;
F3 b. removing any unbound detection reagents;
F4 c. detecting in a temporally sequential manner said plurality of
predetermined subsequences of said detection reagent,
F4.1 said detection of the subsequences comprises:
F4.1.1 i) hybridizing a set of decoder probes with a
subsequence of the detection reagents
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;
F4.1.2 ii) detecting said optical signal signature
produced upon the hybridization of said set of decoder
probes and obtaining an image;
F4.1.3 iii) removing said optical signal signature
produced by the hybridization of said set of decoder
probes;
F4.1.4 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,
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;
22
F4.1.4.2 is unique for each subpopulation of the
detection reagents;
F5 d. comparing said temporal order of the optical signal signatures
with different identifiers of said at least one probe reagent,
F5.1 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.
8 Claim Interpretation
8.1 In view of the debate between the parties, several features of claim 1 of the
Patent require interpretation.
8.2 As held by this Court in its decisions of 16 July 2024 in cases UPC_CFI_1/2023
and UPC_CFI_14/2023 (par. 6.3-6.8), with reference to the CoA (Order dated
26 February 2024 in UPC_CoA_335/2023, NanoString/10x Genomics, p. 26-
27 of the original German language version, CoA UPC 13 May 2024,
VusionGroup/Hanshow), in accordance with Art. 69 EPC and the Protocol on
its interpretation, a patent claim is not only the starting point, but the
decisive basis for determining the scope of protection of a European patent.
The interpretation of a patent claim does not depend solely on the strict,
literal meaning of the wording used. Rather, the description and the drawings
must always be used as explanatory aids for the interpretation of the patent
claim and not only to resolve any ambiguities in the patent claim. However,
this does not mean that the patent claim merely serves as a guideline and
that its subject-matter also extends to what, after examination of the
description and drawings, appears to be the subject-matter for which the
patent proprietor seeks protection.
8.3 The patent claim is to be interpreted from the point of view of a person skilled
in the art.
8.4 When interpreting a patent claim, the person skilled in the art does not apply
a philological understanding, but determines the technical meaning of the
terms used with the aid of the description and the drawings. A feature in a
patent claim is always to be interpreted in light of the claim as a whole (CoA
UPC 13 May 2024, VusionGroup/Hanshow, point 29). From the function of
the individual features in the context of the patent claim as a whole, it must
be deduced which technical function these features actually have individually
23
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.
8.5 In applying these principles, the aim is to combine adequate protection for
the patent proprietor with sufficient legal certainty for third parties.
8.6 These principles apply also to the assessment of validity. Accordingly, these
principles will also be applied by the Central Division to claim construction in
the context of the present Revocation action. The relevant point in time for
interpreting a patent claim for the assessment of validity is the filing (or
priority) date of the application that led to the patent in suit.
The skilled person
8.7 In the opinion of the Central Division, the skilled person is someone having a
degree in biological sciences (or biochemistry) and several years of
experience in the field of detection of biomolecules in biological samples. A
skilled person having this background will be familiar with both “in vitro” and
“in situ” techniques for the detection of biomolecules.
8.8 The above definition largely corresponds to the definition of the skilled
person adopted by the parties. Different from the Defendant, however, the
Court does not see the skilled person as having several years of experience
only with in situ techniques and not with in vitro methods. The Patent (see
par. [0003]) is generally directed at “those analyzing” test samples in biology
(the term sample being broadly defined in the Patent, see below) who have
a “need for multiplexing techniques”. In the same sense, still in the same
introductory paragraph, the Patent refers to “clinicians and researcher[s]” (in
general) for whom it is desirable to subject each sample to a large set of
probes. No fundamental distinction is made between in vitro and in situ
multiplexing techniques in the Patent. The skilled person must therefore be
defined accordingly.
24
Claim interpretation from the point of view of the above person skilled in the
art applying the above principles
General remarks
8.9 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 “read-
out” and decoded in a temporally sequential manner. To this end, the nucleic
acid label comprises a plurality of “predetermined subsequences” to which
“decoder probes” 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):
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´).
8.10 The decoder probes contain an “optically detectable label”, e.g. a fluorescent
dye (or “colour”). This allows the decoder probes to produce a signal that can
be detected (“signal signature”). After one “round of detection”, the signal
signature is removed and another set of decoder probes (having different
nucleic acid sequences than the first set of decoder probes) is added. These
decoder probes in turn hybridize with the detection reagents on
complementary subsequences (but at a different location on the nucleic acid
label than during the first “round”), producing new decoder probe signals.
The order of the signals produced by multiple runs with different decoder
probes makes it possible to identify the corresponding analytes.
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
25
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.
26
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, single-
stranded 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
27
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.”
8.15 In the claimed method, the analytes are detected using “detection reagents”
that “target” the analytes (F2 and F2.1) by means of a “probe reagent”
targeting an analyte (F2.4.1). These features do not further define or narrow
the skilled person´s understanding of “analyte”, also not when seen in their
technical functional context. The skilled person understands that the part of
the detection reagent that interacts with the target molecule (the “analyte”)
is the so-called “probe reagent” (F2.4.1) which is defined in par. [0024] of the
description as “any targeting molecule of interest”. Par. [0024] adds:
“Examples of the probe reagent can include, but are not limited to, a nucleic
acid, an antibody or a portion thereof, an antibody-like molecule, an enzyme,
a cell, a virus, an antigen, a small molecule, a protein, a peptide, a
peptidomimetic, a sugar, a lipid, a glycoprotein, a peptidoglycan, an aptamer,
and any combinations thereof. In some embodiments, the probe reagent can
be modified by any means known to one of ordinary skill in the art. By way of
example, the probe reagent can be genetically modified, or it can be
biotinylated.” Therefore, the broad definition of “probe reagent” provided in
the Patent description is congruent with the broad interpretation of
“analyte”.
At least one nucleic acid label comprising a “plurality” of predetermined
subsequences (F2.4.2)
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).
28
8.17 According to the Claimant, the skilled person would interpret the claim such
that a detection reagent comprising one pre-determined subsequence is also
covered by the claim. In support, the Claimant has referred to par. [0112] of
the description which states: “According to the invention, the nucleic acid
label comprises a plurality of predetermined nucleic acid subsequences. In
some embodiments, the nucleic acid label or nucleic acid tag can comprise
any number of the pre-determined nucleic acid subsequences, e.g., ranging
from about 1…” together with the use of “Two or more” pre-determined
subsequences in par. [0119].
8.18 According to the Central Division, the skilled person interprets the term
“plurality” as used in F2.4.2 in accordance with its plain meaning in common
language use, i.e. as “more than one” (or: “two or more”). This interpretation
is further supported and confirmed by the technical functional context of the
claimed method in light of the description.
8.19 The claimed method pertains to the detection of a plurality of analytes (F1,
the Central Division notes that it is not in dispute between the parties that
“plurality” in F1 means “more than one”), by inter alia the step of hybridizing
a set of decoder probes with a subsequence of the detection reagents which
step is repeated for other subsequences of the detection reagents).
Accordingly, the claim requires a plurality of, i.e. more than one
predetermined subsequence per detection reagent to function. A skilled
person will thus appreciate that detection reagents having a nucleic acid label
with only one pre-determined subsequence are not covered by the claimed
method.
8.20 In the view of the Central Division, an interpretation as advocated by the
Claimant would be at odds not only with the wording and context of the
claimed method as set out above, but also with the description as a whole,
especially the background section, par. [0003]-[0006], wherein the Patent
describes the prior art. Therein, it is made clear that optical readout is
common in biology but typically limited to a relatively small number of
colours. The common approach to improving multiplexing in optical methods
is to increase the number of available colours. However, using more than 6
colours simultaneously is difficult in reality. A “simple workaround” is,
according to the description, to repeat the probing of the same sample with
multiple small sets of different probes. As an example, the description
mentions probing a 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
29
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.
8.21 In conclusion, the skilled person would understand from the use of the word
“plurality” in the claim, in the context of the claimed method and the
description as a whole that only embodiments with detection reagents
having more than one pre-determined subsequence fall within the scope of
the claim.
Does the claimed method require that a detection reagent stays bound to an
analyte throughout the method?
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.
30
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
31
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).
8.28 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.
32
8.29 The Central Division finds, contrary to the Defendant, that the use of the
reference words “said” (and “the”) in feature group F4, in particular F4.1.4,
does not imply that the claimed method is limited to using the identical
detection reagent throughout the entire method. First, “said detection
reagent” in F4.1.4 refers back to the general definition of detection reagent
provided in F2.4 rather than to the “plurality of detection reagents” with
which the sample is contacted. Moreover, and more importantly, it follows
from an interpretation of these features in the context of the claim in the
light of the description and their technical function, as explained above, that
the claim is not limited to adding a detection reagent only once and/or that
the (same) detection reagent must remain bound throughout the entire
method. For the same reason, the circumstance that the claim defines a
number of sequential steps does not exclude that before step c, (more of the
same) detection reagents are added.
8.30 The use of the wording “comprising”, which generally has a non-exclusive
meaning (as confirmed in par. [0278] of the description of the Patent),
confirms for the skilled person that the claim does not exclude a step of
(removal and) addition of (the same) detection reagents before the detection
of other subsequences of the detection reagents in accordance with step c as
set out above.
8.31 Nothing in par. [0052] of the description, which was referred to by the
Defendant, excludes the removal and re-adding of the same detection
reagents. This paragraph merely describes detecting or decoding in a time
series a plurality of the pre-determined subsequences within the nucleic acid
labels of any detection reagents that are bound to target analytes in a sample.
Par. [0052] further describes that the time period between any two detection
steps can be “of any length”, including hours and longer than 1 day. The
skilled person will rather take this as an indication that the time that it might
require to add “fresh” detection reagents before another detection step is
not an impediment.
8.32 The further argument brought forward by the Defendant that the long
incubation time required with a complex biological sample would make the
skilled person realise that it would be unpractical to re-add detection
reagents cannot be followed (even leaving aside that the claim is not limited
to “complex biological samples”). The Central Division notes that the wording
of the claim does not contain any limitation as to the incubation time of the
sample (referred to as “contacting” in the claim, F2, step a). The description
of the Patent, in par. [0046], discloses a very wide range of incubation times
33
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.
8.33 In sum, the claim wording, considering the features of the claim the context
of the claim as a whole in light of the description and their technical function,
does not exclude that before another round of detection (repeating steps (i)
through (iii)) in accordance with F4 (F4.1.4), the sample is contacted (again)
with the (more of the same) detection reagents. The skilled person would,
moreover, not interpret the claim such that the same detection reagent
necessarily stays bound to the analyte throughout all the steps of F4.1.3.
9 Novelty of the Main Request (Claim 1 as granted)
9.1 For the purposes of Article 54 EPC, an invention shall be considered to be new
if it does not form part of the state of the art. The state of the art, in
accordance with Article 54(2) EPC shall be held to comprise everything made
available to the public by means of a written or oral description, by use, or in
any other way, before the date of filing of the European patent application
(or when applicable the priority date).
9.2 The assessment of novelty within the meaning of Art. 54 (1) EPC requires the
determination of the whole content of the prior publication. It is decisive
whether the subject-matter of the claim with all its features is directly and
unambiguously disclosed in the prior art citation (see UPC CoA, Order of 25
September 2024, UPC_CoA_182/2024, App 21143/2024, Mammut/Ortovox,
par. 123).
9.3 Applying the above standard to the case at hand, the Central Division comes
to the conclusion that the subject matter of claim 1 of the Patent as granted
lacks novelty over document D10, Göransson et al.
D10 - Göransson et al. (´Göransson´)
9.4 Göransson is a prior art scientific publication relating to a new random array
format together with a decoding scheme for targeted multiplex digital
molecular analyses (Abstract, first sentence). Figure 3, which is shown below,
depicts the method disclosed in Göransson involving the multiplex encoding
and decoding of genomic loci.
34
9.5 As shown under “A”, a genomic sample is prepared by restriction digestion of
the sample genome with an appropriate restriction enzyme. (i) probes
designed to target specific genomic sequences are added and genomic DNA
circles are formed. The DNA circles are either (ii) directly amplified by RCA
(rolling-circle amplification), or (iii) enriched for by a process which includes
restriction digestion of the RCA products into monomers that can be ligated
into new circles to generate amplified single molecules (ASMs). An array is
created by random immobilization of the ASMs to a microscopic glass slide.
9.6 As shown under “B” the ASMs that have been immobilized on the array are
decoded by sequential hybridizations of sandwich probes (grey), tag probes
(red or blue) and a general tag probe (orange). The sandwich probes contain
two regions, one complementary to a specific ASM and one region containing
the two decoding tags. These decoding tags, denoted tag 1 and tag 2,
hybridize with corresponding tag probes. A small 20 x 20 pixel image shows
35
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).
9.7 “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).
Göransson discloses all features of claim 1 directly and unambiguously
9.8 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).
9.9 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
36
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.
37
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 Application(s) to Amend: Admissibility
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.
38
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 pre-
determined 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
39
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.
10.5 The Claimants have raised several objections against Auxiliary request 1 in
relation to the requirements of Articles 84 and 123(2) EPC. It is not necessary
for the Central Division to decide on these objections since the proposed
claim amendments cannot in any event save the Patent from revocation in its
entirety (see below).
11 Auxiliary request 1: Inventive Step
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):
40
Interpretation of claim 1 of AR1
11.3 The features of AR1 that have been introduced into claim 1 of the Patent as
granted are:
41
- 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
42
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.
11.7 The Central Division does not follow the Defendant´s interpretation. Neither
the claim nor the description of the Patent contain any information that
points in the direction of a limitation for the absolute and/or relative length
of probe reagents and decoder probes, specifically for an in situ method such
as FISH. On the one hand, it is stated in par. [0060] of the description that the
decoder probe “can have a sequence of any length”, whereby 100
nucleotides is mentioned concretely as (the larger end of a) preferred
sequence length. Probe reagents, on the other hand, are even much broader
defined in the description par. [0087] et seq. including “an entity (e.g., but
not limited to, a molecule, a particle, a composite entity, or a multi-molecular
entity) that interacts with or binds to a target molecule”. The probe reagent
is thus not even necessarily a nucleic acid, but can for example be a protein
(like an antibody in immunohistochemistry). Probe reagents are furthermore
not specified by their length, let alone the number of nucleotides, let alone
the number of nucleotides relative to the number of nucleotides of a decoder
probe.
11.8 In view of the foregoing, even if the Defendant´s contention that the skilled
person would, on the basis of their common general knowledge, have used
longer probe reagents in situ than they would have used in vitro, is followed,
it cannot be seen that it is required by the claim that the same detection
reagent stays bound to “its” analyte throughout the method, also if the
method is carried out in situ. This analysis does not change when taking into
account the article of He et al. (Exhibit BP9). It may be so that in an in situ
method published by employees belonging to the Claimant´s group of
companies in October 2022 certain probes and (de)hybridization conditions
are used, this does not affect the skilled person´s interpretation of the claims
of AR1 at the priority date in accordance with the general principles for claim
interpretation as set out above.
11.9 Against the background of this interpretation, the Central Division now will
turn to inventive step of Auxiliary Request 1 (“AR1”) first as there is no
dispute between the parties that the subject matter of Auxiliary Request 1 is
novel over Göransson.
43
Legal framework inventive step
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.
44
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.
45
Inventive step over Göransson
11.20 Several prior art disclosures have been relied upon by the Claimant for lack
of inventive step of AR1. One of these is Göransson. As discussed above under
“novelty” in relation to the Main Request, Göransson discloses all the
features of claim 1 of the Patent as granted.
11.21 The finding that Göransson discloses all the features of claim 1 as granted
(and hence has many features in common also with claim 1 of AR1) is an
indication that Göransson is a realistic starting point for the assessment of
inventive step of the subject matter claimed. Furthermore, both the Patent
and Göransson relate to (high-throughput) optical methods for the multiplex
detection of target molecules in a sample. Therefore, they have the same
underlying problem.
11.22 Both Göransson and the Patent address the need to increase the number of
analytes that can be identified with a limited number of available “colours”.
See for the Patent e.g. DtR, p. 10-11 under “Gist of the Invention”: “to
significantly increase the number of analytes that can be assessed with a
limited number of fluorophores”. Cf. Göransson Fig. 3, above, and p. 4, left-
hand column under “Results”: “Any multiplex molecular analysis utilizing
fluorescence for readout is limited by the number of fluorescence spectra that
can be resolved. […] By combining the information from several tags, more
identities than there is tag probes can be decoded.” Also see p. 8, right-hand
col.: “Regardless of how the tags are introduced, three variables affect the
number of identities that can be decoded using the proposed strategy: the
number of fluorophores that can be resolved in individual decoding reactions,
the numbers of tags used and the number of serial hybridization reactions to
the ASMs.”
11.23 The argument from the Defendant that Göransson is not a suitable starting
point for the assessment of inventive step because the fields of cell biology
and array technology were not integrated cannot be followed. In the view of
the skilled person, who has knowledge of in vitro and in situ methods, both
the Patent and Göransson relate to biological optical multiplexing detection
methods. The lack of available fluorophores is moreover a generic issue for
all biological multiplex detection methods that make use of such
fluorophores. Even though there are differences in relation to the samples
and methods used where it concerns ASMs on an array and RNA or proteins
in a sample comprising cells or tissues fixed on a slide, the skilled person who
46
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.
11.24 In sum, Göransson and the claimed subject matter have a significant number
of technical features in common and relate to a similar underlying problem.
Therefore, Göransson is a realistic starting point for the assessment of
inventive step.
11.25 Göransson and claim 1 of AR1 differ in that 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
and the analytes are selected from proteins, peptides and certain RNAs. In
sum, the claimed method is an in situ method for the detection of analytes
as specified in the claim whereby more analytes than available colours can be
detected.
11.26 Starting from Göransson, it was in the view of the Central Division obvious for
the skilled person at the priority date to transfer the method of Göransson to
an in situ context, for instance in FISH, to detect e.g. RNA or proteins, thereby
arriving at the claimed subject matter. The following reasons support this
conclusion.
11.27 Göransson explicitly discloses to the skilled person a generic decoding
scheme for biomolecules that can be encoded into a DNA circle (cf. Abstract,
last sentence, “The decoding strategy is generic…”) as a solution to a general
problem in “Any multiplex molecular analysis utilizing fluorescence” (cited
above). Göransson furthermore discloses to the skilled person: “analysis of
biomolecules based on a combination of molecular probing and decoding
reactions. The biomolecules are first probed with techniques that generate
DNA circles upon recognition. ASMs are generated through RCA, and then
attached to glass slides in a random pattern. The rolling-circle ASMs include
sets of tags that are used for identification following a combinatorial
decoding scheme, similar to that used to identify hundreds of thousand bead
species in random bead arrays (37). Our approach is generic and can be
47
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).
11.28 Therefore, taken as a whole, the teaching of Göransson provides a motivation
for the skilled person to consider whether the method of Göransson can also
be applied to other assays than the random ASM array format that was used
to demonstrate the approach for quantitative multiplex analysis.
11.29 Having established this general motivation, the subsequent question is
whether the skilled person, without having the benefit of hindsight, would
indeed as a next step have applied the Göransson method in situ (as per the
claimed subject matter).
11.30 In this respect, the disclosure of Göransson itself already points the skilled
person concretely towards in situ application of the methods disclosed
therein, see page 2, left-hand col. in the middle: “The proximity ligation assay
has been used to detect proteins, protein modifications and interactions in
serum samples and in situ (32–35). Rolling-circle ASMs have been used for
readout in several genotyping assays (20,21,36), for detection of protein and
protein complexes in situ using proximity ligation (33), and for detecting
microbes with padlock probes followed by counting individual rollingcircle
ASMs pumped through a microfluidic channel (19)” (underline CD).
11.31 Reference 33 is the publication of Söderberg et al., submitted in these
proceedings as D30. Söderberg et al., discloses combining “proximity ligation
with RCA for localized readout in fixed cells or tissues.” (Title, p. 995 left-hand
col.). It is not in dispute between the parties that in the procedure described
by Söderberg et al., proximity ligation rolling circle amplification (RCA) is
performed to detect protein analytes in situ. According to the Defendant,
however, D30 does not teach an in situ procedure in which repeated de/re
hybridizations would be performed (DtR, p. 46, penultimate paragraph) and
therefore the skilled person would not transfer the method of Göransson to
an in situ context. In the view of the Central Division, this interpretation of
the teaching of Göransson ignores the generic character of the coding and
decoding method in the context of the multiplexing problem explicitly taught
by Göransson. In other words, the skilled person will not see the pointer in
Göransson to in situ methods separately from the other clear message
conveyed by the Göransson publication being that the decoding strategy is
48
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.
11.32 The Central Division finds further support for the conclusion that the skilled
person would indeed as a next step apply the method from Göransson in situ
in the PhD thesis of Ida Grundberg, submitted in these proceedings as exhibit
D50, which was published in April 2011 and (undisputedly) forms part of the
state of the art.
11.33 Grundberg developed a technique involving the use of padlock probes and a
proximity ligation assay (“PLA”) for detecting and determining (“genotyping”)
point mutations and SNPs (“single nucleotide polymorphisms”) in genes in
situ, see title, abstract, and page 27 under the heading “Padlock probes”.
Padlock probes were also used by Grundberg’s colleagues Göransson et al. –
working in the same laboratory at the time – in the development of their
array assay (p. 23, Rejoinder to the reply to the Defence to Revocation).
11.34 On p. 46 of D50, penultimate par., cited by the Claimant in par. 353 of the
Reply to the Defence to revocation, markings by Claimant, Grundberg notes
that a limitation to the current method design when it comes to multiplexing
is the restricted number of fluorophores that can be used. In order to solve
that multiplexing problem, Grundberg suggests using the decoding scheme
consisting of consecutive hybridization steps as taught by Göransson as a next
step (NB reference 133 is to Göransson):
49
11.35 In the thesis from Grundberg, the skilled person thus finds a further incentive
to use the decoding scheme of Göransson in situ. The Defendant´s reading of
this disclosure in the Grundberg thesis, namely that Grundberg considered
the use of a decoding scheme of D10 for detecting the padlock probes in her
genotyping and mutation detection assay (and not transferring the sandwich
probe setup for detecting analytes in situ), Rejoinder p. 23 bottom, is not
supported by the disclosure of Grundberg as depicted above in the light of
the thesis as a whole. As the title of D50 suggests, Grundberg investigates
Genotyping and Mutation Detection In Situ. The part of the thesis cited
above, relates to the in situ use of primary (padlock) probes to detect and
discriminate multiple targets using the consecutive hybridization scheme as
taught in Göransson, i.e. in a multiplexing method which is to be carried out
in situ. From this disclosure it rather follows that in a real-world scenario
(devoid of any hindsight), the skilled person would have realised that the
generic decoding scheme as taught by Göransson would indeed be applicable
to in situ methods to solve the very problem of having a restricted number of
fluorophores that can be used in multiplexing methods.
11.36 Contrary to the Defendant, the Central Division does not find that the skilled
person takes from document D39 (Lagunavicius et al.) that RCA cannot be
used reliably for the in situ detection of RNA due to a too low detection
efficiency. Leaving aside that neither the claims of the Patent nor the
description provide any technical teaching relating to or reporting the (RNA)
detection efficiency of the claimed method, in the passage of D39 cited by
the Defendant in the DtR, p. 50, bottom, it is indeed remarked by the authors
that “the RCA technique is not suitable for single-copy target examination in
a single cell.” This does, however, not mean that the technique is in general
unsuitable for in situ RNA detection. In the same paragraph, it is said “it still
can be used for the detection and analysis of high-copy RNA transcripts”. In
fact, Lagunavicius et al. report under conclusions that “padlock probe
sequence amplification [was, CD] successfully applied in vitro and in situ” and
“individual RNA targets are visualised […] in situ” (also see Fig. 3). D39 thus
provides the skilled person with a further incentive to indeed apply the in
vitro method as taught by Göransson in situ to detect RNA.
11.37 The Central Division also takes the above discussed disclosures as an
indication that the skilled person would not have expected any particular
technical difficulties in transferring the in vitro method as taught by
Göransson to an in situ application. It is moreover undisputed, at least not
sufficiently concretely contested by the Defendant, that at the priority date,
it was routine for the skilled person to set up a (multiplex) FISH method for in
50
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.
51
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
52
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.
11.44 Since the condition that the Patent cannot be maintained in accordance with
AR1 is fulfilled, the Central Division will revert to the other auxiliary requests
on file.
12 Further Auxiliary Requests AR2-8 and Subclaims
12.1 Turning to the originally filed auxiliary requests, which are formally
admissible (see above par. 10.2), Auxiliary request 2 (´AR2´) submitted by the
Defendant is further limited with respect to F4, in that the detection of the
plurality of predetermined subsequences is performed “directly on the
sample.” Furthermore, an additional limitation of F6 (compared to claim 1
according to AR1) is proposed in that the sample is a “biological sample
comprising one or more fixed cells”.
12.2 The Central Division finds that these amendments do not render the subject
matter of AR2 inventive. The skilled person knows from their common
general knowledge that in situ methods are normally performed (directly) on
cell or tissue samples which are typically fixed on a solid support such as a
microscopic slide. There is no inventive (technical) contribution related to
these further limitations with respect to F4 and F6.
12.3 Auxiliary requests 3 and 4, adding “at a special location” to F4.1.2 and F4.1.4
and being further restricted to use in FISH, respectively, are further
alternatives by which the Defendant wishes to emphasize the in situ context
of the claimed subject matter (p. 26 Reply to the Defence to the application
to amend). As follows from the discussion in relation to AR1, the Central
Division finds that performing the method in an in situ context, including the
well known in situ method FISH, was obvious in view of the state of the art
53
(in particular Göransson). Therefore, these auxiliary requests also cannot
render the claimed subject matter inventive for the same reasons as AR1.
12.4 Auxiliary request 5 has compared to claim 1 of AR1 an additional limitation
of F4.1.3 according to which the removing of the optical signal signature,
resulting from hybridization of the decoder probes with the predetermined
subsequences, is performed “by cleavage”. Against the Claimant´s
substantiated assertion (with reference to exhibit D54) that cleaving off a
fluorescent label was part of the common general knowledge, nothing
concrete has been put forward by the Defendant. The subject matter of
Auxiliary request 5 therefore lacks inventive step for the same reasons as for
AR1. The additional feature does not render the subject-matter of claim 1
inventive.
12.5 In submitting Auxiliary requests 6 and 7, specifying in claim 1 the length of
the predetermined subsequences and the decoder probes, respectively, the
Defendant does not provide any other arguments in defence of patentability
compared to the previous Auxiliary Requests. Therefore, these claims lack
inventive step for the same reasons and require no separate discussion.
12.6 Auxiliary request 8 specifies in claim 1 that a plurality of predetermined
subsequences is “at least two”. This request requires no separate discussion
as the Central Division has already interpreted a plurality as “at least two”
(see par. 8.18 above) and has found a lack of novelty/inventive step on the
basis of this interpretation.
13 Conclusion
13.1 In conclusion, the subject matter of claim 1 as granted (Main request) lacks
novelty over Göransson. The subject matter of Auxiliary request 1 lacks
inventive step over Göransson. Auxiliary requests 2-8 can also not serve as a
basis for revoking the Patent only in part. The patent must therefore be
revoked in its entirety.
13.2 Since the Patent is revoked in its entirety on the ground of lack of novelty and
lack of inventive step, the Central Division does not have to decide on the
other grounds for revocation raised by the Claimant.
13.3 The Central Division notes that it comes to the same conclusion as the
German Federal Patent Court on essentially similar grounds. Furthermore,
this decision is substantively in line with the findings of the CoA in the
54
NanoString/10x Genomics appeal where many similar issues were dealt with
by the CoA.
14 Costs
14.1 In accordance with Article 69 UPCA and Rule 118.5 RoP the Defendant, as the
unsuccessful party, the Patent being revoked entirely, has to bear the legal
costs of the Claimant.
55
DECISION
Having heard the parties on all relevant aspects of the case, the Central Division:
1. Revokes European Patent 2 794 928 B1 entirely with effect to the territory of
France (FR), Germany (DE) and The Netherlands (NL).
2. The Defendant as the unsuccessful party shall bear the legal costs incurred
by the Claimant.
3. Dismisses any further request made.
NAMES AND SIGNATURES
Judges
Presiding judge:
Ulrike Voß
Legally qualified judge:
András Kupecz (judge-rapporteur)
Technically qualified judge:
Eric Enderlin
For the Deputy-Registrar
Natalie Gnaß
Information about appeal
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).
Information about enforcement
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.