Decision
of the Court of First Instance of the Unified Patent Court
Local Division Munich
issued on 12 December 2025
concerning European Patent 2 493 466
CLAIMANTS
1) Sanofi SA as successor of Sanofi Mature IP
2) Sanofi Winthrop Industrie
3) Sanofi Aventis France
4) Sanofi-Aventis GmbH
5) Sanofi Belgium
6) Sanofi-Aventis Deutschland GmbH
7) Sanofi S.r.l.
8) Sanofi B.V.
9) Sanofi - Produtos Farmaceuticos Lda
10) Sanofi AB
11) Sanofi A/S
represented by: Frédéric Chevallier (McDermott Will & Schulte).
DEFENDANTS – UPC_CFI_146/2024 - UPC_CFI_496/2024
1) STADAPHARM GmbH 2) STADA Arzneimittel AG 3) STADA Nordic ApS
represented by: Daniel Hoppe (Bonabry).
Local Division Munich
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DEFENDANTS – UPC_CFI_147/2024 - UPC_CFI_374/2024
1) Reddy Pharma SAS
2) betapharm Arzneimittel GmbH
3) Dr Reddy's Srl
represented by: Dr. Christian Meyer (Maiwald Intellectual Property).
DEFENDANTS – UPC_CFI_148/2024 - UPC_CFI_503/2024
1) Zentiva France
2) Zentiva Pharma GmbH
3) Zentiva, k.s.
represented by: Dr. Anja Lunze (PENTARC Rechtsanwälte).
PATENT AT ISSUE
European patent n° 2 493 466
PANEL/DIVISION
Panel 1 of the Local Division Munich
DECIDING JUDGES
This decision has been issued by Presiding Judge Dr. Matthias Zigann acting as
judge-rapporteur, the legally qualified judges Alima Zana and Tobias Pichlmaier
and the technically qualified judge Carola Wagner.
LANGUAGE OF THE PROCEEDINGS
English.
SUBJECT-MATTER OF THE PROCEEDINGS
Patent infringement with counterclaims for revocation.
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DATES OF THE ORAL HEARING
14 and 15 October 2025.
ANNOUNCEMENT DATE
12 December 2025.
SUMMARY OF FACTS
Sanofi SA is the legal successor of Sanofi Mature IP and the registered proprietor
of European Patent 2,493,466 (the 'patent at issue'). This patent relates to a
novel anti-tumoral use of cabazitaxel and was filed on 27 October 2010, claiming
seven priority dates, with the earliest being 29 October 2009 (US 256160 P). The
publication and grant date is 10 March 2021. The patent is currently valid in
several states, including Austria, Belgium, Germany, Denmark, France, Italy, the
Netherlands, Portugal and Sweden.
The patent at issue comprises one independent and 8 dependant claims:
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The claimants are entities belonging to the Sanofi Group, a French company that
is one of the world's leading pharmaceutical companies.
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Sanofi manufactures and sells the pharmaceutical product JEVTANA as a second-
line treatment for prostate cancer patients.
JEVTANA was authorised by the European Medicines Agency (EMA) on 17 March
2011 under the name 'JEVTANA 60 mg concentrate and solvent for solution for
infusion' (see Exhibits No. C1, page 5, and C.1.2, page 2, first paragraph). The
medicinal product is marketed as a cabazitaxel concentrate in 1.5 ml vials
containing 60 mg of cabazitaxel. Therefore, 1 ml of the concentrate contains 40
mg of cabazitaxel (see Exhibit C.1.2, second paragraph). The recommended
cabazitaxel dose is 25 mg/m², administered via intravenous infusion every three
weeks in combination with 10 mg of prednisone or prednisolone administered
orally daily throughout treatment (Exhibit No. C.1.2, page 3, first paragraph).
The Stada, Dr. Reddy and Zentiva defendants are entities of pharmaceutical
companies who produce and sell generic versions of JEVTANA, namely
CABAZITAXEL STADA, CABAZITAXEL REDDY PHARMA, CABAZITAXEL BETA, and
CABAZITAXEL DR. REDDY and CABAZITAXEL ZENTIVA, respectively:
STADAPHARMA GmbH and STADA Arzneimittel AG hold the marketing
authorisation for the generic product Cabazitaxel STADA 20 mg/ml concentrate
for solution for infusion. The authorisation applications were filed under
decentralised procedures in Germany, Sweden and Denmark. Marketing
authorisations were granted in Germany on 10 November 2020 and in Denmark
on 9 March 2021 (see Exhibit No. D1.1, pages 1 and 3; D1.2, page 1). CABZITAXEL
STADA contains the active substance cabazitaxel. It is sold as a 20 mg/ml
concentrate for solution for infusion. The concentrate is supplied in a 3 ml vial
containing 60 mg of cabazitaxel (see Exhibit No. D1.2, section 'Summary of
Product Characteristics', pages 1–2, items 1 and 2).
Betapharm Arzneimittel GmbH is the marketing authorisation holder for the
generic marketing authorisation filed under the decentralised procedure
DE/H6219/001 (D.1.1 page 1, first entry), and the other Dr Reddy defendants
are the marketing authorisation holders and local representatives respectively
in France and Italy. Since the present action was launched, the defendants have
ceased marketing the infringing product in France as of 31 December 2023. Sales
have continued in Italy and Germany. All of these entities belong to the same
group of companies headquartered in India as Dr Reddy's Laboratories Ltd. They
market the medicinal products “Cabazitaxel beta 60 mg Konzentrat und
Lösungsmittel zur Herstellung einer Infusionslösung” (DE), “CABAZITAXEL
REDDY PHARMA 60 mg, solution for dilution and solvent for solution for
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infusion” (FR), and “CABAZITAXEL DR. REDDY´S 40 mg/ml SOLUZIONE PER
INFUSIONE ENDOVENOSA” (IT) (D.1.1–D.1.5, page 1, entry 'product name').
Marketing authorisations were granted in Germany on 20 July 2020, in France
on 18 June 2020, and in Italy on 13 May 2021 (see Exhibits D1.1 to D1.5, page
1). Each product contains the active substance cabazitaxel. The products are sold
as a 60 mg/ml concentrate for solution for infusion. The concentrate is in a 1.5
ml vial containing 60 mg of cabazitaxel (Exhibit No. D1.2 to D1.5, Section
'Summary of Product Characteristics', Page 1, Items 1 and 2).
Zentiva Pharma GmbH and Zentiva k.s. hold the marketing authorisations for the
generic products filed under decentralised procedures DE/H/6784/001 and
DK/H/3187/001, for Germany and France, among others (see D.1.1, page 1 and
page 3, first entries). According to Zentiva, no products are sold in Italy or
Denmark. Zentiva Pharma GmbH and Zentiva France market the medicinal
products 'Cabazitaxel Zentiva 20 mg/ml concentrate for solution for infusion'
(DE) and 'Cabazitaxel Zentiva solution for dilution for infusion' (FR) (D.1.1, page
1 , entry 'product name', D.1.4, page 1, entry ‘product name’). Marketing
authorisations were granted in Germany on 12 February 2021 and in France on
6 July 2021 (see Exhibits D1.3 and D1.4, page 1; and D4, page 2). According to
D1.2, the marketing authorisation was granted for Germany on 9 February 2021
(D1.3, page 55, no. 9). Each product contains the active substance cabazitaxel.
The products are sold as a 20 mg/ml concentrate for a solution for infusion. The
concentrate is supplied in a 3 ml vial containing 60 mg of cabazitaxel (see
Exhibits D1.3 and D1.4, page 2, section 2. Qualitative and quantitative
composition). The infringing products in question were first placed on the
market in 2021.
On 6 September 2024, the Tribunal Judiciaire de Paris invalidated the French
designation of the patent in question in proceedings involving Sanofi and
Accord. Sanofi appealed (RG No. 21/06416, Portalis No. 352J-W-B7F-CUMKO).
The court held that the patent in question was obvious in light of documents
describing a Phase III clinical trial with cabazitaxel. A skilled person at the priority
date would have had a reasonable expectation of success. On 25 October 2025,
Accord Healthcare and Sanofi submitted appeal briefs to the Paris Court of
Appeal, requesting the reversal of the French first-instance decision of 6
September 2024, in accordance with the Confidential Patent Settlement and
Licence Agreement executed by these entities.
On 15 December 2023, the Opposition Division of the European Patent Office
rejected the oppositions filed against the patent in suit by Accord, Zentiva, Dr
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Reddy, Stada and others. On 3 June 2025, the Boards of Appeal dismissed the
appeals (T 0136/2024 – 3.3.04). Both the OD and the BoA held that the patent
in question was not obvious based on documents describing a clinical Phase III
trial with cabazitaxel. The skilled person at the priority date would not have had
a reasonable expectation of success.
On 13 May 2024, several Sanofi entities filed infringement actions against
several Accord entities (UPC_CFI_145/2024), as well as against Stada
(UPC_CFI_146/2024), Dr. Reddy (UPC_CFI_147/2024) and Zentiva
(UPC_CFI_148/2024) with the Local Division Munich. Each of the defendant
groups filed counterclaims for revocation (Accord: UPC_CFI_463/2024; Stada:
UPC_CFI_496/2024; Dr. Reddy: UPC_CFI_374/2024; Zentiva:
UPC_CFI_503/2024).
Following the Confidential Patent Settlement and Licence Agreement executed
between Sanofi and Accord, the infringement action (UPC_CFI_145/2024) and
the revocation counterclaim (UPC_CFI_463/2024) were withdrawn prior to the
oral hearing.
The Local Division of Munich decided to hear the remaining three counterclaims
for revocation together, and the three infringement actions separately,
following the joint hearing on validity. On the afternoon of the first day of the
oral hearing, scheduled for 14–17 October 2025, the expert witnesses from
Stada (Dr Denmeade), Dr Reddy's and Zentiva (Dr Nelson) were questioned on
the following: 'What information would a person working in the industry at the
priority date have derived from the Phase III TROPIC study and the time that has
passed since it started? Was there a reasonable expectation of a positive
outcome?' The panel asked the expert witnesses ten more detailed questions
on this topic, which had been communicated in advance (see order dated 15
September 2025). Several ad hoc questions from the panel and the UPC
representatives of the parties followed. Both experts confirmed their written
expert reports: Dr Nelson (Exhibit B26 (Sanofi)), Dr Denmeade (Exhibits D54 and
PBP1 (Stada), DFMP D116 (Zentiva) and MWCC 22 (Dr Reddy's)).
On the second day, the panel announced that they were inclined to declare the
patent in question invalid. The presiding judge then closed the hearing,
announcing 12 December 2025 as the date on which the decision would be
announced.
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The values of the infringement actions and the counterclaims were set by the
judge-rapporteur in an order dated 22 January 2025.
In view of the outcome of the counterclaims, the Local Division Munich decided
to issue a joint decision on the three infringement actions. Any confidential
information forming part of the infringement proceedings has been omitted.
Instead, reference is made to the respective briefs.
Further reference is made to the recordings of the oral hearing and the two
interim conferences, as well as to the parties' submissions and the court's
orders, respectively.
REQUESTS OF THE PARTIES
Counterclaims for revocation:
Stada, Dr Reddy's and Zentiva request the revocation of EP 2 493 466 B1 in its
entirety (claims 1–9) in all Contracting Member States in which it is in force:
Austria, Belgium, Germany, Denmark, France, Italy, the Netherlands, Portugal
and Sweden. They also request that Sanofi bear the costs of the counterclaims
for revocation.
Sanofi requests that the revocation counterclaim lodged by the defendants be
dismissed, that European patent No. 2 493 466 be ruled valid in all UPC
Contracting Member States in which the patent is in force, and that the
defendants be ordered to bear the costs of the counterclaims for revocation.
Infringement actions:
Sanofi requests that it be declared that at least claims 1, 2, 5, 6, 7, 8 and 9 of
European patent No. 2 493 466 have been directly infringed by the defendants
(Stada in Denmark, Germany and Sweden; Dr. Reddy in France, Germany and
Italy; and Zentiva in France and Germany), and that an injunction be ordered, as
well as the payment of damages subject to further assessment, the publication
on websites, the recall and removal of products from the channel of commerce,
the destruction of products, the provision of information for the final calculation
of damages, and the payment of the costs of the infringement proceedings.
The defendants request that the action be dismissed and that the claimants pay
the costs of the proceedings.
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At the request of the defendants, the judge rapporteur urged Sanofi to provide
more detail on who is asking what from whom in which territory during the
written procedure.
Sanofi subsequently filed amended requests to specify more clearly which
claimant is asking for what, from whom, and in which territory. Some of the
claimants no longer formally request any kind of relief. Furthermore, the request
for damages has changed to one for provisional damages and a declaration of
liability for damages. Additionally, a claim for indirect infringement has been
introduced. Finally, a request for an interim award of costs has been introduced.
The parties are arguing about the admissibility of these amendments and their
consequences.
Furthermore, the defendants filed preliminary objections. The judge-rapporteur
informed the parties that these preliminary objections would be dealt with in
the main proceedings (Rule 20.2 of the Rules of Procedure).
POINTS AT ISSUE
Preliminary objections:
Stada, Dr. Reddy and Zentiva argue that the Unified Patent Court lacked
jurisdiction for countries which are not yet Contracting Member States to the
Agreement on a Unified Patent Court (Ireland, Poland, Czech Republic, Slovakia,
Hungary, Romania, Spain, Croatia, Greece and Cyprus). Further, they argued that
the Unified Patent Court lacked jurisdiction over claims arising before the entry
into force of the Agreement on a Unified Patent Court. Zentiva additionally
argues that it is inadmissible to offer evidence in support of Claimants’ standing
to sue in French, a language other than the language of the proceedings
(English).
Counterclaims for revocation:
In the respective counterclaims all defendants request that the patent in
question be revoked. All three argue – already in the counterclaim - a lack of
novelty and inventive step. Stada and Dr Reddy addition argue – already in the
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counterclaim - added matter. Zentiva additionally argues – already in the
counterclaim - a lack of sufficient disclosure (Art. 65(2) UPCA in connection with
Art. 138(1)(b) and 83 EPC). Later amendments to the counterclaims do not play
a role with view to the outcome of the decision. Reference is made to the
respective briefs.
All three counterclaimants argue from the very beginning that the patent lacks
an inventive step in relation to documents describing a Phase III clinical trial with
cabazitaxel. They endorse the reasoning of the Tribunal Judiciaire de Paris in this
regard. Based on the available information and the fact that the trial was shortly
to conclude and had not been stopped prematurely, the counterclaimants argue
that a skilled person at the priority date would have had a reasonable
expectation of success.
Sanofi, who did not file a request to amend the patent, argues that the
counterclaims for revocation should be dismissed. They claim that the Tribunal
Judiciaire de Paris erred in revoking the French designation of the patent in
question due to obviousness considering documents describing a clinical Phase
III trial with cabazitaxel. Sanofi endorses the views of the Boards of Appeal,
which upheld the patent despite those documents. In particular, Sanofi argues
that a skilled person would not have had a reasonable expectation of success,
but rather a mere hope that it could work.
Infringement actions:
The defendants argue that not all claimants have standing to sue, as the sub-
conditions of Art. 47(2-3) UPCA have not been met.
According to Sanofi all claimants have standing to sue, because Articles 47(2)
and (3) UPCA are not applicable when a patent proprietor brings an
infringement action along with its own subsidiaries acting as licensees. The
clause 5.1 of the licence agreement of 1st December 2018 was amended on 18th
March 2025 in view that the “LICENCEE thus has the express right to institute,
bring or join any infringement action instituted, brought or joined by LICENSOR
as from the date on which the Agreement has been effective, in order to seek
relief for the infringement of the Patents” (B1.1.b). Similarly, the sublicense
agreement has been amended on 18th March 2025 (B1.1.2.b). The amendment
is drawn up to retroactively establish the licensees’ rights to sue.
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Defendants further argue that they do not directly infringe the patent in suit as
their respective products do not contain prednisone or prednisolone. The later
introduction of claims relating to indirect infringement is too late and should not
be permitted.
In any case, the infringement actions must be dismissed as the patent is invalid.
GROUNDS FOR THE DECISION
The preliminary objections are dismissed. The patent in question is invalid and
shall be revoked in its entirety. Therefore, the infringement actions shall be
dismissed. Any other outstanding applications and requests relating to the
infringement actions shall be dismissed, as there is no longer any need to
adjudicate them.
A. Preliminary objections:
Sanofi has limited the infringement actions to the aforementioned territories.
Therefore, preliminary objections relating to other territories can be dismissed
(Rule 334 of the Rules of Procedure).
The same applies to the preliminary objections relating to the Unified Patent
Court's competence to deal with infringing acts committed prior to the entry
into force of the Agreement on a Unified Patent Court. However, it should be
noted that the Unified Patent Court does have jurisdiction in this regard, as
detailed in the Court of Appeal's decision on 2 June 2025 (UPC_CoA_156/2025,
APL_8790/2025 – XSYS v. ESKO).
Finally, Zentiva's preliminary objection regarding the language of the evidence
presented to support standing to sue is no longer relevant.
B. Counterclaims for revocation:
I. The Patent in suit EP 2 493 466
The patent describes the use of cabazitaxel in the treatment of prostate cancer,
and in particular, castration resistant metastatic prostate cancer in patients who
have already received docetaxel treatment, which it states is a previously unmet
need.
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Prostate cancer affects a large proportion of the male population worldwide. It
is treated at the start by depriving the androgenic hormones, through excision
of the testicles, or by radiotherapy treatment, while chemotherapy, despite its
effect on the relief of symptoms, is not a routine treatment, due to its toxicity,
especially in elderly patients, and until recently had only mediocre effects. In
particular, mitoxantrone, in combination with prednisone or hydrocortisone,
was used with palliative effects. More recently, treatments with docetaxel, part
of the taxane family, in combination with estramustine or prednisone have
increased patient survival by 2.4 months.
However, it points out that cancer can become resistant to medicines and in
particular to taxanes, as several resistance mechanisms have been described,
such as the expression of P-glycoprotein (or P-gp), the mdr-1 gene, the
modification of the metabolism of taxane and the mutation of the tubulin gene.
The patent states that responses to treatments in this cancer are difficult to
evaluate due to the heterogeneity of the disease and the lack of consensus
regarding the treatment response criteria, but specifies that the level of
prostate-specific antigen (PSA) has proven to be a means for evaluating novel
candidates, with measurement of tumour and bone metastases (where
possible), quality of life and pain.
In order to provide the missing treatment to the patients concerned, the
invention discloses the use of cabazitaxel, a taxane, in combination with
prednisone or prednisolone.
It indicates that one aspect of the invention includes increasing patient survival,
describes the methods of administration, consideration, and prevention of the
risk of various adverse effects, and contraindications to the administration of
cabazitaxel, then describes, through several examples, the results of a clinical
trial, otherwise known as the ‘Tropic study’, which concerned 755 patients and
the purpose of which was to compare cabazitaxel (with prednisone) with
mitoxantrone (with prednisone).
These results indicate in particular that the median overall survival of patients
receiving cabazitaxel was improved by 2.4 months compared to patients
receiving mitoxantrone (15.1 months versus 12.7 months).
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The patent states that this prolongation of survival had been observed even in
the third of patients not responding to docetaxel, in whom the disease had
progressed during docetaxel treatment.
It also mentions the other criteria cited above, such as the PSA response rate,
the tumour response rate, the pain response rate, as well as the duration
without progression of the tumour, without progression of the PSA and without
progression of the pain, all of which are favourable for cabazitaxel (Table 1).
The technical problem that the patent in suit intends to solve, is therefore to
provide a therapeutic option for treating patients suffering of castration
resistant metastatic prostate cancer who have been previously treated with
docetaxel-based regimen and have prostate cancer that progressed during or
after that treatment (EP 466 [0008]). This includes both, increased overall
survival and palliative treatment only.
The proposed solution introduces an antitumoral pharmaceutical therapeutic
use comprising cabazitaxel according to claim 1 (feature breakdown):
A1 Compound of formula
which may be in base form or in the form of a hydrate or a solvate,
A2 in combination with prednisone or prednisolone,
B for use in treating prostate cancer,
B1 in patients with castration resistant metastatic prostate cancer
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B2 who have been previously treated with docetaxel-based regimen and
B3 have prostate cancer that progressed during or after said treatment.
The patent in suit contains further eight dependent claims (claims 2 to 9):
2. Compound for use according to claim 1, where the prostate cancer is an
advanced metastatic disease.
3. Compound for use according to any one of claims 1 to 2, in the form of an
acetone solvate.
4. Compound for use according to claim 3, in which the acetone solvate contains
between 5% and 8% and preferably between 5% and 7% by weight of acetone.
5. Compound for use according to any one of claims 1 to 4, administered at a
dose of between 15 and 25 mg/m², with prednisone or prednisolone
administered at a dose of 10 mg/day.
6. Compound for use according to claim 5, administered at a dose of 25 mg/m².
7. Compound for use according to any one of claims 1 to 6, comprising repeating
the administration of such compound as a new cycle every 3 weeks.
8. Compound for use according to any one of claims 1 to 7, in combination with
prednisone.
9. Compound for use according to any one of claims 1 to 8, wherein said patients
have been previously treated with at least 225 mg/m² cumulative dose of
docetaxel.
2. On Interpretation
According to Art. 69 EPC in conjunction with the Protocol on its interpretation,
the patent claim is not only the starting point but also the decisive basis for
determining the scope of protection of a European patent. The interpretation of
a patent claim does not depend solely on its literal wording. Rather, the
description and the drawings must always be consulted as aid to the
interpretation of the claim and not only to clarify any ambiguities in the claim.
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This does not mean, however, that the patent claim only serves as a guideline
and that its subject matter also extends to what is presented as the applicant’s
claim after examination of the description and drawings (UPC_CoA_335/2023,
decision of 26 February 2023 in conjunction with decision of 11 March 2024,
GRUR-RS 2024, 2829, headnote 2 and margin no. 73 - 77 - Nachweisverfahren;
UPC_CFI_452/2023 (LD Düsseldorf), Order of 9 April 2024, p. 13, GRUR-RS 2024,
7207, margin no. 49).
a) Claim 1 as granted is directed to a further medical use and has been
drafted as a purpose-limited product claim in the format according to Article
54(5) EPC. In accordance with the established practice, for claims directed to a
further medical use, attaining the claimed therapeutic effect is regarded as a
functional technical feature of the claim (see e.g. T 609/02, Reasons 9). While
the pertinent comments in T 609/02 relate to claims drafted in the so-called
Swiss-type format established by the Enlarged Board in G 5/83, they apply
equally to claims drafted in the newer format according to Article 54(5) EPC).
In the present case, this therapeutic effect is the treatment of prostate cancer
in the specified patient group. Claim 1 as granted specifies in this regard "for use
in treating prostate cancer, in patients with castration resistant metastatic
prostate cancer who have been previously treated with docetaxel-based
regimen and have prostate cancer that progressed during or after said
treatment."
b) Feature A1
The compound cabazitaxel belongs to the taxoid family and has the formula
indicated in feature A1. The chemical name of cabazitaxel is 4α-acetoxy-2α-
benzoyl oxy-5β, 20-epoxy-1β-hydroxy-7β,10β-dimethoxy-9-oxo-11-taxen-13α-
yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.
Cabazitaxel is synonymously known as (2α, 5β, 7β, 10β, 13α)- 4-acetoxy- 13-
({(2R, 3S)- 3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-
1-hydroxy-7,10-dimethoxy-9-oxo-5, 20-epoxytax-11-en-2-yl benzoate (EP 466
para [0023]). It is also known by its study name XRP6258 (RPR 116258A) (EP 466
para [0010]).
Cabazitaxel may be in form of an anhydrous base (cf. formula above), a hydrate
or a solvate, in particular an acetone solvate (EP 466, claim 3, para. [0014],
[0024]).
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c) Feature A2
According to feature A2 cabazitaxel is administered in combination with
prednisone or prednisolone. As to claim 8 and paragraph [0026] prednisone and
prednisolone are alternative corticoids. In the dependent claim 8 the
combination is restricted to cabazitaxel and prednisone. Thus, feature A2 is not
directed to a triple combination of cabazitaxel with both prednisone and
prednisolone.
As per the description of EP 466 cabazitaxel and the corticoid are administered
as two distinct pharmaceutical preparations (EP 466 para. [0026]). The
combination is administered repeatedly according to a protocol that depends
on the patient to be treated. Cabazitaxel is administered by perfusion to the
patient according to an intermittent program with an interval between each
administration of 3 weeks. Prednisone or prednisolone may be administered
daily, for example in the form of one dosage intake per day, throughout the
duration of the treatment. According to claim 5 cabazitaxel is administered at a
dose of between 15 to 25 mg/m2 and prednisone or prednisolone being
administered at a dose of 10 mg/day. The recommended dose of 25 mg/m2 for
cabazitaxel is administered as one-hour infusion, while prednisone or
prednisolone is administered orally in a dose of 10 mg per day (EP 466 claim 5
to 7, para. [0027]).
c) Feature group B
aa) The treatment according to feature B must be understood as a non-
curative therapy, because metastatic castration resistant prostate cancer is an
incurable condition. A therapeutic effect according to the patent is the absence
of progression or death when the progression is either an increase of the PSA,
or of the tumour, or of the pain (EP 466, para. [0074]). Therefore, the treatment
is a life extending therapy, delaying tumour recurrence and progression, or a
palliative therapy focused on maintaining the quality of life (EP 466, para [0017];
B0.7.1, para 35, 87).
bb) According to features B1 to B3 the patients to be treated are men who
suffer from castration resistant metastatic prostate cancer who have been
previously treated with docetaxel-based regimen and who have prostate cancer
that progressed during or after said treatment (EP 466 claim 1, para. [0013]).
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Cancer which has spread beyond the prostate is called metastatic. At the start
prostate cancer is treated with hormone-based therapy to lower or block the
hormones that promote prostate cancer growth. Typically, the hormonal
therapy is surgical or medical castration to drastically reduce the levels of
testosterone. When the patient’s cancer worsens despite castrate levels of
testosterone, the cancer is referred to as castration resistant prostate cancer
(CRPC) or hormone-refractory prostate cancer (EP 466 para. [0003], [0021], third
bullet point; Dr. B0.7.1, para 32 to 34). Metastatic prostate cancer which
has progressed to castration resistant prostate cancer, is commonly referred to
as “mCRPC” (Dr. B.07.1, page 10, para 0035).
According to features B2 und B3 the prostate cancer of these patients has
progressed during or after a previous docetaxel treatment. These features
therefore include both patients who responded to a docetaxel therapy but
progressed afterwards and patients who developed resistance to docetaxel (EP
466 para. [0028]; expert witness statements).
3. On inventive step of Claim 1
The following documents will be discussed:
D-Number Catchword Full data Sanofi exhibit number
D1 TROPIC 2009 Tropic 2009, idem, ibidem, as at
11 September 2009
B.17
D2 NHSC 2009 NHSC, Cabazitaxel (XRP-6258)
for hormone refractory,
metastatic prostate cancer -
second line after docetaxel,
National Horizon Scanning
Centre, April 2009
B.20
D4 ‘Phase I and
Pharmacokinetic Study of
XRP6258 (RPR 116258A), a
Novel Taxane, Administered as
a 1-Hour Infusion Every 3
Weeks in Patients with
Advanced Solid Tumours,
Clinical Cancer Research, 15(2),
723-730, 15 January 2009
B.18
D6 TROPIC 2008 Tropic 2008, XRP6258 Plus
Prednisone Compared to
Mitoxantrone Plus Prednisone
in Hormone Refractory
Metastatic Prostate Cancer
(Tropic), taken from the
website ClinicalTrials.gov,
saved at archive.org, on 23
October 2008
B.17.1
D7 and
Systemic therapy after first-line
B.6
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docetaxel in metastatic
castration – resistant prostate
cancer, Current Opinion in
Supportive and Palliative Care,
2:161-166, 2008
D9 and others, Paclitaxel
And Docetaxel Resistance:
Molecular Mechanisms and
Development of New
Generation Taxanes,
ChemMedChem, 2007, 2, 920-
242, 2007
B.13
D12 Dr. Declaration by Dr. of 23
December 2020
B.7.6
D13 Pivot X. Pivot, and others, A
multicenter phase II study of
XRP6258 administered as a 1-h
i.v. infusion every 3 weeks in
taxane-resistant metastatic
breast cancer patients, Annals
of Oncology 19: 1547-1552,
B.19
D18 Guideline on the Evaluation of
Anti-Cancer Medicinal Products
in Man
EMA Guidelines on the
Evaluation of Anticancer
Medicinal Products in Man
(June 2006)
B.33
D20 Annual Report 2008 Sanofi 2008 (Annual Report),
Accord Exhibit No. 5.12
B.22.2
D21 EMA Assessment Report for
Jevtana (cabazitaxel), January
20, 2011
EMA/CHMP/66633/2011
Assessment Report for Jevtana
(cabazitaxel), procedure no.:
EMEA/H/C/002018,
footnote on 2-66:
EMA/CHMP/782336/2010
-
(Stada D21; Zentiva DFMP D21)
D26 and others, Update
on tubulin-binding agents,
Pathology Biology, 54:72-8 4,
2006
B12
D35 Leaflet Leaflet “XRP6258 and XRP9881
Novel Taxoids” by Aventis
Pharmaceuticals Inc., 2003
B.37
D58 Declaration by (23
April 2022)
B.25
D59 and
New drugs in prostate
cancer, Current Opinion in
Urology, 6:138-145, 2006
B.9
D91 et al. 2000 B.36
- Expert report of Dr. of 22
December 2016
B.07.1
- and Can the
pharmaceutical industry
reduce attrition rates?, Nature
Reviews Drug Discovery, Vol. 3,
p. 711, August 2004
B.14
- and and
Estimation of clinical trial
success rates and related
parameters,
Biostatistics, 20, 2, pp. 273-286,
2019
B.16
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a. The defendants‘ position
The defendants maintain that, according to settled case-law in France, Germany
and at the European Patent Office, the disclosure of phase III clinical trials
relating to the claimed application gives rise to a reasonable expectation of
success for the person skilled in the art, unless there is evidence to the contrary
since these trials, which constitute routine tests for the person skilled in the art,
are selected on the basis of experimental data suggesting their success, and that
this is particularly true when they are supported by previous studies.
In this particular case, in order to demonstrate the obvious use of cabazitaxel to
treat castration-resistant metastatic prostate cancer which progressed during or
after a previous treatment with docetaxel, they argue that the disclosure of the
Tropic study (Tropic documents or NHSC), a Phase III clinical trial specifically
relating to that therapeutic application, corroborated by various pre-clinical and
clinical data, created a reasonable expectation in the person skilled in the art
that that application would be successful.
They consider that the closest prior art document is the NHSC document, in that
it discloses, in addition to the protocol of the Tropic study, the existence of
promising results and the dosage of 25 mg/m² every 3 weeks claimed in the
patent, whereas the Tropic documents do not disclose the existence of a
technical effect or this dosage; that the objective technical problem is the
provision of alternative treatment for castration-resistant metastatic prostate
cancer in patients previously treated with a docetaxel-based regime and whose
cancer has progressed during or after such treatment. They state that this
problem should not be limited to improving overall survival but includes several
other criteria that were also evaluated in the Tropic study (progression-free
survival, percentage of objective or biological responses, progression of PSA
level, progression of pain and so on), adding that in practice, it is not possible to
confine oneself to survival because one cannot wait for the patient's death to
evaluate the treatment given to him. In any case, they believe, even if limited to
overall survival, the technical problem is an improvement that only needs to be
compared with patients treated with mitoxantrone, because this is the only
comparative effect that the study (and the patent that includes the results)
demonstrates.
According to them, the person skilled in the art is a team of scientists composed
in particular of a pharmacologist with experience in the treatment of cancer by
means of taxanes, a person with experience in the regulation of oncological
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medicinal products and the approval of clinical studies by the regulatory
authorities.
In this context, they claim that pre-clinical data showed that cabazitaxel was
effective on taxane-resistant cancer cell lines, in particular docetaxel, and
indicated that it had a lower affinity than docetaxel with the P-glycoprotein
efflux pump or P-gp, which is responsible for docetaxel resistance
documents); whereas a Phase I study of different types of cancer, including
castration-resistant metastatic prostate cancer, showed a promising safety
profile of cabazitaxel and an effectiveness in PSA levels in two patients with this
cancer (Mita document); lastly, a Phase II study, conducted on breast cancer and
not prostate cancer, showed an encouraging response to cabazitaxel in patients
previously treated with docetaxel and having developed resistance to this
molecule (Pivot, Beardsley documents). The difference in cancer at issue is not
decisive, in their view, because they are tumours with common properties, for
which the same molecule, docetaxel, is an approved standard treatment, a
molecule which, moreover, had itself initially been studied for the prostate
cancer because it had been shown to be effective on the breast cancer, and the
lesson from this trial is also the promising activity of cabazitaxel against a tumour
which has become resistant to docetaxel, as in the indication which is the subject
of the patent.
They add that the prior art also suggested further treatment with docetaxel
itself, despite the resistance acquired by the tumour, after an interruption of a
few months, in patients who initially responded well to the first-line treatment
(Beardsley document), which is also confirmed by a subsequent opinion of the
French National Authority for Health (after the priority date). They conclude that
cabazitaxel, which is of the same taxane class but has less affinity with one of
the resistance factors to docetaxel, was even more likely to be effective. They
point out in that regard that the Tropic study concerned only patients with an
‘ECOG PS’ of 0 to 2 (NHSC document), that is to say, patients who were either
asymptomatic, completely ambulatory or bedridden for less than half a day, and
therefore patients in a good situation, which implies, they consider, that they
have tolerated the first docetaxel treatment, and therefore that further
treatment with docetaxel could be envisaged for them.
They also rely on Sanofi's financial report for 2008 (Sanofi 2008 document), in
which the company states that it has refocused its research efforts on the ‘most
promising projects’ and that, as a result, while research on cabazitaxel in breast
cancer, which is the subject of the abovementioned Phase II study, has been
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abandoned, the development of cabazitaxel continues. They infer from this that
the person skilled in the art was aware of the significant potential of cabazitaxel
in the treatment of metastatic prostate cancer and that this development was
maintained in the light of intermediate results showing that the chances of
success were great.
As regards the toxicity of cabazitaxel, the defendants state that the
abovementioned phase I and II tests showed relatively encouraging toxicity
data, taking into account the fact that the serious adverse effects encountered
(in particular neutropenia) were known and considered acceptable, the patent
itself indicating a high toxicity which did not prevent the approval of the
medicinal product, so that these data would not have deterred the person
skilled in the art.
They consider that the chances of success of the Tropic trial were all the greater
because its ambition was low, comparing cabazitaxel with mitoxantrone, which
is known to be ineffective while being toxic (and which itself had never been
authorised for second-line treatment as in this particular case), to the extent
that no clinical trial comparing mitoxantrone with another molecule had ever
shown greater efficacy of that molecule, whereas the Tropic trial, representing
a very high cost, probably greater than 100 million dollars, had, by definition,
required prior convergent analyses in order to justify it, and having been in
progress for 3 years at the priority date, without having been interrupted (which
would have been the case if the patients were put in danger), finally close to its
originally announced end date, gave in itself reasonable expectation of success
as regards its object, without any element of the prior art contradicting this
expectation. In this respect, they also dispute the relevance of the statistics
invoked by the Sanofi companies on the failure rate of the phase III trials, due to
the parameters specific to each study and argue that the same statistics show a
success rate of more than 50% when the study relates to the main indication of
the medicinal product, as in this particular case.
Lastly, they argue that the decisions of the United States are irrelevant because
the claims of the patent have been substantially modified in comparison with
those of this patent.
In the alternative, the defendants rely on what is known as a ‘test to see’
approach, according to which, when the implementation or testing of an
approach suggested by the prior art does not present any particular technical
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difficulty, the person skilled in the art would have been required to test it, even
if there was no reasonable prospect of success.
b. Sanofi`s position
In response, Sanofi argues that the effect of the disclosure of a Phase III clinical
trial on the inventive step must be analysed according to the specifics of each
case, that the European Patent Office's decision T0239/16 opens the possibility
that the prior art deters the person skilled in the art, that the previous decisions
which rejected the inventive step because of the disclosure of a clinical trial
concerned very different situations, in particular dosage patents. They point out
that drug patents are often revoked on the grounds that they are filed too early,
before possession of the invention (in the case of finasteride, raloxifene), and
that this would have been the case here before the results of the Tropic trial
were obtained. They rely on the decisions of the Opposition Division of the
European Patent Office in the patent at issue and of the US courts in the parent
patent (whose claims differ little according to them) which had concluded that
the patent was valid.
They explain that the closest prior art consists of the Tropic 2009 document,
because it is more recent than the NHSC document, which is moreover
speculative and removes the person skilled in the art from the invention by
confirming the unsatisfied need for the treatment which is the subject of the
invention. According to them, this Tropic document differs from the invention
in that it is merely a description of a clinical trial which does not disclose any
effect of the treatment, whereas the invention consists in providing a treatment
which prolongs the life of patients, constituting the first effective second-line
treatment in the indication in question. They infer from this that the objective
technical problem is to increase the survival of the patient concerned, and not
only to provide an alternative treatment, which would only be the case if the
invention did not provide a therapeutic advantage (and in particular, here, a
prolongation of survival). Nor, in their view, is it a question of confirming
effective treatment in the broad sense, but of overall survival alone, which is the
reference for evaluating new treatments, and moreover the condition without
which the treatment would not have been authorised.
The person skilled in the art is, according to Sanofi, a team comprising a medical
oncologist with clinical experience in the treatment of castration-resistant
metastatic prostate cancer and chemical and biochemical researchers working
in the field of research and development of such treatments, and therefore
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familiar with the mechanisms of action of the taxanes and of resistance to this
agent.
In this context, they argue that castration-resistant metastatic prostate cancer
is a disease that is particularly difficult to treat, especially in the second line after
the reference treatment with docetaxel, which is heterogeneous (results vary
greatly between patients), and with treatment that is difficult to measure (the
measurement of overall survival involves controlled trials with a large number
of patients), for which finally, more than 200 candidate medicines
document) have proved to be failures, only cabazitaxel having finally proved to
be effective; cabazitaxel is still the only successful new taxane, out of 9
molecules studied document), including larotaxel, which has been the
subject of three phase III trials (including one on breast cancer), all of which were
failures. They point out that, more generally, the success rate of candidate
medicines in oncology is 3.4% (and only 1.6% when, as here, they are not
associated with biomarkers, as indicated in the 2019 document), that this
is 70% in phase II and still 59% in phase III document), that is to say, 12.3%
when combining phases II and III; this makes the pre-clinical data even less
relevant, especially for metastatic prostate cancer, for which there is no relevant
preclinical model.
They claim, in particular that the other parameters, in particular the PSA level,
are unreliable, as they may be influenced by causes other than the course of the
disease, in addition to the fact that the PSA response in itself has no benefit for
the patient; whereas resistance to taxanes involves several mechanisms and not
only affinity with P-gp, so that efficacy could not be expected on that basis alone;
that the response rate (of only 14%) obtained in phase II in another indication
(breast cancer) is also not predictive of a future outcome and in any event not
relevant for prostate cancer.
They explain that the indication subject of the patent had been directly tested
in a Phase III clinical trial, without a Phase II trial, which is rare but justified here,
they continue, because of the ‘compelling need’ for treatment to extend the life
of patients who previously died of their disease (they do not claim, however,
that the patent treatment cures patients but only show a median survival of 2.4
months longer than the mitoxantrone treatment), and was made possible by the
acceptable toxicity of cabazitaxel, studied in the Phase I trial which was only
intended to do so (not the evaluation of effectiveness), so the expectation of
success of the Tropic trial was ‘dreadful’ and a reluctance to launch the study
had been encountered.
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Against the document, they claim that this involves old data (2001 trial),
already criticised document), showing an effect on a single patient
concerned by the indication in question (patient already treated with docetaxel),
measured only by the PSA level (moreover in a single measurement) without
any effect being inferred on his lifetime, and after administration of a dose of 25
mg/m², to which the other patients have shown serious adverse effects, in
particular neutropenia, to the extent that the document subsequently
recommends a dose of only 20 mg/m², from which the person skilled in the art
would have deduced that the dose likely to be effective might well be too high
to be tolerable, with potentially counterproductive effects (myelosuppression
which may limit the extent of tumour destruction). For example, the
document argues that it is unlikely that the new taxanes, including cabazitaxel,
will ‘have a significant impact on patients’ or that ‘major improvements to
currently approved drugs will be achieved.’
They add that these toxicity data, which gave rise to the fear of failure at the
dose covered by the patent (25 mg/m²), could not be attenuated by the lesson
learnt from the Phase II trial on breast cancer (the Pivot document) since
patients with two different cancers may react differently, especially here, since
they are women in one case and men in the other, since men with prostate
cancer often undergo radiation therapy on the pelvis which weakens a
significant part of the bone marrow where blood cells are produced, which
would have led to the fear of greater sensitivity to cabazitaxel toxicity, and that
in any case, the same doubts result (only 28% of the patients were able to
increase the dose up to 25 mg/m²).
Against the document, Sanofi companies argue that it only refers to
the Phase II trial described in the Pivot document and the Tropic trial by offering
an explanation for the initiation of this trial (the activity of cabazitaxel in the
docetaxel refractory framework) without allowing a positive outcome to be
predicted. Against the NHSC document, they argue that this is not a scientific
publication but a prospective and speculative document from a public health
centre, that the person skilled in the art did not consult it and did not attach
importance to it, and that it merely describes the objective of the Tropic trial by
indicating the speculative aspect of the situation and confirming that the
lifetime is the objective of the treatment. The Sanofi 2008 document does not
create any expectation of success, according to them, despite the heading ‘the
most promising projects’, in that it indicates that the development of larotaxel
has been stopped for breast cancer and that the Tropic trial is continuing while
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cabazitaxel has also been stopped for breast cancer. Moreover, they consider
that what this document reveals is only the opinion of the inventor, which is not
the opinion of the person skilled in the art.
As for the ‘test to see’ approach, the Sanofi companies, who consider this
approach inapplicable here, argue that its underlying idea is to test whether a
potential solution would work with routine testing when the reasonable
expectation of success test cannot be applied; whereas the Boards of Appeal of
the European Patent Office have already considered that tests on humans were
not known routine tests; that exceptions are only allowed on a case-by-case
basis, e.g., for tests concerning the maximum duration of application of a device
already in use with known properties (T 293/07).
c. Findings of the Court
The panel finds that the invention of the patent in suit is obvious over the Phase
III TROPIC trial (NHSC) document. All other invalidity attacks therefore do not
need to be considered.
aa. Test on inventive step
Among the conditions for patentability referred to in Article 138(1)(a) EPC,
Articles 52 and 56 require that an invention must involve an inventive step, that
is to say, if, having regard to the state of the art, it is not obvious to a person
skilled in the art. The elements of the prior art are destructive of an inventive
step only if, taken in isolation or placed together in a combination reasonably
accessible to the person skilled in the art, they clearly enabled the latter to
provide the same solution to the problem solved by the invention as the latter.
In order to assess inventive step, the European Patent Office and some national
courts usually proceed according to what is known as the problem-solution
approach, which consists in determining the closest prior art, establishing, by
comparison with the claimed invention, the objective technical problem to be
solved, and then considering whether the solution proposed by the invention to
this problem would have been obvious to the person skilled in the art. In
particular, the Office defines the objective technical problem as ‘the aim and
task of modifying or adapting the closest prior art to provide the technical
effects that the invention provides over the closest prior art’ (EPO Guidelines for
Examination, G, VII, 5.2).
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The Court of Appeal of the Unified Patent Court has in its decision dated 25
November 2025 (UPC_CoA_528-2024, 529/2024 – Amgen v. Sanofi-Aventis):
applied the following test to determine inventive step of a second medical use
claim:
“123. A European patent is only validly granted for an invention if – apart
from other requirements – it involves an inventive step. 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 (Art. 56 EPC).
124. National courts of the various EPC countries have different
approaches and use different guidelines when assessing whether an
invention involves an inventive step. One of those approaches is the so-
called ’problem-solution-approach’ used by the European Patent Office
(EPO) and the Technical Boards of Appeal (TBA) of the EPO. In some
jurisdictions, such as France, Italy, The Netherlands and Sweden, this
approach is applied as well, but not necessarily as the only possible
approach. In other jurisdictions, such as Germany and the UK, other
approaches – sometimes referred to as more ’holistic’ – are used. Despite
the differences in approach, all of these are just guidelines to assist in the
establishment of inventive step as required by Art. 56 EPC, that, when
properly applied, should and generally do lead to the same conclusion. 21
125. The burden and presentation of 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, R. 44(e)-(g), 25.1(b)-(d) RoP).
Even though proof of certain facts, if contested, may be required, the
assessment of whether the legal consequence for which the facts and
circumstances have been submitted is justified, is a question of law.
126. The approach taken by the Unified Patent Court when establishing
inventive step, which can already be derived from the Order of the Court
of Appeal in Nanostring/10X Genomics (supra), is as follows.
127. It first has to be established what the object of the invention is, i.e.
the objective problem. This must be assessed from the perspective of the
skilled person (m/f – hereinafter referred to as ’it’), with its common
general knowledge, as at the application or priority date (also referred to
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as the relevant date) of the patent. This must be done by establishing
what the invention adds to the state of the art, not by looking at the
individual features of the claim, but by comparing the claim as a whole in
context of the description and the drawings, thus also considering the
inventive concept underlying the invention (the technical teaching),
which must be based on the technical effect(s) that the skilled person on
the basis of the application understands is (are) achieved with the claimed
invention.
128. In order to avoid hindsight, the objective problem should not contain
pointers to the claimed solution.
129. The claimed solution is obvious when at the relevant date the skilled
person, starting from a realistic starting point in the state of the art in the
relevant field of technology, wishing to solve the objective problem,
would (and not only: could) have arrived at the claimed solution.
130. The relevant field of technology is the field relevant to the objective
problem to be solved as well as any field in which the same or similar
problem arises and of which the person skilled in the art of the specific
field must be expected to be aware.
131. A starting point is realistic if the teaching thereof would have been
of interest to a skilled person who, at the relevant date, wishes to solve
the objective problem. This may for instance be the case if the relevant
piece of prior art already discloses several features similar to those
relevant to the invention as claimed and/or addresses the same or a
similar underlying problem as that of the claimed invention. There can be
more than one realistic starting point and the claimed invention must be
inventive starting from each of them.
132. The skilled person has no inventive skills and no imagination and
requires a pointer or motivation that, starting from a realistic starting
point, directs it to implement a next step in the direction of the claimed
invention. As a general rule, a claimed solution must be considered not
inventive / obvious when the skilled person would take the next step
prompted by the pointer or as a matter of routine, and arrive at the
claimed invention.
133. A claimed solution is obvious if the skilled person would have taken
the next step in expectation of finding an envisaged solution of his
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technical problem. This is generally the case when results of the next step
were clearly predictable, or where there was a reasonable expectation of
success.
134. The burden of proof that the results were clearly predictable or the
skilled person would have reasonably expected success, i.e. that the
solution he envisages by taking the next step would solve the objective
problem, lies on the party asserting invalidity of the patent.
135. A reasonable expectation of success implies the ability of the skilled
person to predict rationally, on the basis of scientific appraisal of the
known facts before a research project was started, the successful
conclusion of that project within acceptable time limits.
136. Whether there is a reasonable expectation of success depends on
the circumstances of the case. The more unexplored a technical field of
research, the more difficult it was to make predictions about its successful
conclusion and the lower the expectation of success. Envisaged practical
or technical difficulties as well as costs involved in testing whether the
desired result will be obtained when taking a next step may also withhold
the skilled person from taking that step. On the other hand, the stronger
a pointer towards the claimed solution, the lower the threshold for a
reasonable expectation of success.
137. When the patentee brings forward and sufficiently substantiates
uncertainties and / or practical or technical difficulties, the burden of
proof that these would not prevent a skilled person from having a
reasonable expectation of success, falls on the party alleging obviousness.
138. The fact that other persons or teams were working
contemporaneously on the same project does not necessarily imply that
there was a reasonable expectation of success. It may also indicate that it
was an interesting area to explore with a mere hope to succeed.”
The second decision from the same date (UPC_CoA_464/2024, 457/2024,
458/2024, 530/2024, 532/2024, 533/2024, 21/2025, 27/2025 – Meril v.
Edwards) applies the same test on inventive step.
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Both decisions were delivered after the oral hearing had closed. The approach
adopted by the Court of Appeal is similar to that taken by the Tribunal Judiciaire
de Paris when deciding the revocation action against the French part of the
patent in suit. The parties presented extensive arguments. These included
arguments both for and against this approach. Neither the oral hearing nor the
hearing of the two experts focused on a specific legal test to be applied. In fact,
the legal test to be applied was also discussed at the oral hearing. Therefore,
this panel holds that it is not necessary to reopen the oral hearing. The case can
be decided on the basis of the arguments and facts provided to date.
Therefore, the test set out by the Court of Appeal will be used.
bb. Skilled person
The person skilled in the art is the person in the technical field in which there
emerges the problem which the invention, which is the subject of the patent, is
intended to solve. In this particular case, while the parties define this differently,
they do not explicitly draw any conclusion from it on the inventive step.
Since the patent concerns a medicinal product for treating a castration-resistant
metastatic prostate cancer after first-line treatment with docetaxel, which is a
taxane, the person skilled in the art is a team comprising an oncologist who is
familiar with the treatment of this type of cancer, and a chemist plus a
pharmacologist, who are familiar with pharmacokinetic and the formulation of
chemotherapeutic drugs including taxanes.
cc. Objective technical problem
Adopting the problem-solution approach, the EPO BoA in T 0136/24-3.3.04
defined the technical problem in face of the NHSC document in “to put into
practice the effective treatment of prostate cancer with cabazitaxel in co-
administration with prednisone in patients with mCRPC who have previously
been treated with a docetaxel-based regimen and who have prostate cancer
that progressed during or after that treatment” (EPO BoA paragraph 7.8).
This deviates from the approach formulated by the Court of Appeal as the
formulation of the objective technical problem contains parts of the solution
and thus does not avoid hindsight.
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The objective technical problem to be solved by the invention is therefore to
provide a therapeutic option for treating patients suffering of castration
resistant metastatic prostate cancer who have been previously treated with
docetaxel-based regimen and have prostate cancer that progressed during or
after that treatment. This includes both, increased overall survival and palliative
treatment only.
dd. NHSC (D2) as starting point
D2 discloses the protocol of the clinical phase III trial with Cabazitaxel (XRP-
6258) in combination with prednisone (features A1 and A2) for hormone
refractory, metastatic prostate cancer, a second line treatment after a docetaxel
treatment (features B, B1, B2 and B3) (D2, page 2, title, first to third and fifth
para., page 3, table, sixth entry, page 4, second para.). D2, like the Tropic 2009
document (D1) proposed by the Sanofi, therefore discloses all features of claim
1, but feature group B), comprising features B-B3, is only disclosed in the form
of a hypothesis that is currently being verified.
(1) Background information
By way of background information, the party experts, Dr Nelson and Dr
Denmeade, have unanimously testified that new pharmaceuticals are generally
discovered and approved through pre-clinical and clinical trials. Clinical trials
have three phases. In the pre-clinical phase, a molecule is tested in vitro for
activity related to the disease to be cured. Clinical Phase I involves testing on a
relatively small number of healthy volunteers to obtain information on dosage
and tolerance. Clinical Phase II is dedicated to obtaining information on
symptoms from tests with a small number of patients. Phase III involves testing
the new drug on a larger number of patients to determine its performance
compared to a placebo or standard treatment.
However, in the field of oncology, Dr Nelson and Dr Denmeade both agreed that
all phases are conducted with patients who have the disease under
investigation, as the drugs to be tested are essentially poisonous and it would
be unethical to administer them to healthy volunteers. Further phase I is
basically dedicated to initially understand whether and to what extend the drug
shows some anti-tumour activity in humans and which dose is safe and
tolerated. In phase II the focus lies in further defining the anti-tumoral activity
with the dose tested in phase I. In phase III the anti-tumoral drug is tested
against the standard of care.
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Both experts explained that to get a phase III trial started an expert review of
the data on safety, toxicity management, dosing schedule and anti-tumoral
activity derived from phases I and II must be passed. To this end an expectation
that the trial will meet the defined endpoint, or in other words, will be
successful, must be established. Further a monitoring plan and a statistical plan
must be developed and approved.
According to Dr Denmeade, in oncology, it is not mandatory for a phase III trial
to receive DSMB (Data Safety Monitoring Board) approval based on patients
with the same tumour type as in phase II. Information on the safety, toxicity and
management of the drug derived from a phase II trial involving patients with a
different tumour can be transferred if the tumours are comparable. This
happens in about 1/3 of the oncological phase III trials. Nowadays, it is even
possible to skip phase II completely. Dr Nelson agreed, but pointed out that such
an approach carries more risks, and that the tumours discussed (breast and
prostate cancer) are, in his view, not comparable, which renders the results of
the phase II trial irrelevant to the approval of the phase III trial. He explained
that, in his view, younger women tolerate taxanes better than older men.
The DSMB will closely monitor the data on toxicity, chances of success, evidence
of superiority compared to the control arm and data integrity. The results of
these activities will be reported to the sponsor. A phase III trial will not be
stopped but will continue in the absence of relevant negative or positive
triggers. A negative trigger might be higher toxicity than previously anticipated.
A positive trigger might be clear superiority of the tested drug over the control
arm, in which case it would be unethical to withhold the superior treatment
from patients in the control arm. An early intervention is an unusual event.
Both experts explained that the failure rate of phase III trial in general is between
40 to 50 percent. Dr. Denmeade additionally pointed out that the percentage
goes down with the progress of the trial. Dr. Nelson did not object.
Dr Denmeade explained that the combination of mitoxantrone and prednisone
is the standard comparator used in phase III oncology trials, as this is the
standard treatment available. However, as this standard treatment has no anti-
tumoral effect, but only a palliative effect, any promising anti-tumoral drug will
show a 100 percent success rate. Dr Nelson added that the same drug might fail
with other comparators.
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Cabazitaxel (XRP-6258) is a taxane anti-neoplastic agent. It works by disrupting
the microtubular network that is essential for mitotic and interphase cellular
functions and causes inhibition of cell division and cell death. Cabazitaxel in
combination with prednisone is intended to provide a further treatment option
for patients with progressive disease following or during docetaxel-based
treatment (feature B3). Cabazitaxel is administered by intravenous (IV) infusion
at 25 mg/m2 every 3 weeks (D2 page 2, second para.).
(2) Details of the disclosure of D2
At the publication date of D2, April 2009, the TROPIC study was still ongoing (D2
page 3, table, line 3). The expected reporting date (ending) of the study was May
2010 (D2, page 3, table, last entry). D2 mentions also, that cabazitaxel has shown
a promising safety profile and activity in patients progressing after docetaxel
therapy (D2 page 1, third para.). This is in accordance with the Guideline on the
Evaluation of Anti-Cancer Medicinal Products in Men (D18), which demands that
a clinical phase III trial must be based on results that had been obtained in earlier
studies, which prove the anti-tumour efficacy and safety of the active ingredient
(D18, page 16, para. 3). These earlier studies are documented in D9-Galetti 2007,
D4-Mita 2009, D13-Pivot 2008 and D7-Beardsley.
However, D2, like the Tropic 2009 document (D1) proposed by the Sanofi, only
discloses feature group B), comprising features B-B3, in the form of a hypothesis
that is currently being verified.
D6 is an earlier publication (14.11.2008) of the TROPIC trial than D2. The
information in D6 is the same as in D2.
The Tropic trial (D2) is thus not novelty destroying but constitutes a relevant
starting point for the thought processes of the person skilled in the art and
obviousness can be assessed with regard to it.
(3) Reasonable expectation of success based on the disclosure of D2
The invention is obvious if the hypothesis on which it is based — which is fully
disclosed by the TROPIC trial — was followed by the person skilled in the art,
checking this, if necessary, by routine operations, with a reasonable expectation
of success.
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However, it is important to note that the question of reasonable expectation of
success of the approach disclosed in the TROPIC trial documents, in terms of
assessing an inventive step, is not the same as the question of whether the
TROPIC trial will meet its primary endpoint. This is because the technical
problem that the patent in suit intends to solve is to provide a therapeutic
option for treating patients with castration-resistant metastatic prostate cancer
who have previously been treated with a docetaxel-based regimen and whose
cancer has progressed during or after that treatment. This includes both
increased overall survival and palliative treatment. The primary endpoint of the
TROPIC trial, however, is defined as overall survival in patients in the cabazitaxel
group compared to the control group.
The Panel notes that the EPO BoA adopted a similar approach in paragraph 7.10,
stating that the invention would be obvious if the person skilled in the art had
had a reasonable expectation of success with regard to the experimental arm of
the TROPIC trial.
(4) Positive and negative pointers as indicators
Thus, faced with the disclosure of a therapeutic avenue which has been
considered sufficiently promising to initiate a phase III clinical trial (the Tropic
trial), the person skilled in the art is encouraged to seek in the prior art what is
likely to support or refute this hypothesis.
In the words of the Technical Board 3.3.04 positive and negative pointers must
be evaluated and weighed against each other.
In more neutral terms, this panel must evaluate various indicators in the prior
art and provide an overall assessment.
ee. Indicators
(1) (D7)
The (D7) document is meant to review ongoing developments in the
search for a treatment for castration-resistant prostate cancer that has
progressed after docetaxel-based first-line chemotherapy. This is the
therapeutic indication for the Tropic trial and the patent.
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Beardsley talks about several options, including cabazitaxel. She says that this
has been tested in a trial on patients with metastatic breast cancer who don't
respond to docetaxel. The trial found that 14 percent of patients had a positive
response (p.163, right column, fourth para.). She says that cabazitaxel could be
tested in a Phase III trial for prostate cancer (the Tropic phase III trial) without
first being tested in a Phase II trial for this type of cancer because of how well it
worked in a trial for breast cancer that did not respond to docetaxel:
“A phase II trial with XRP6258 has not been performed in patients with CRPC;
however, given its activity in the docetaxel refractory setting described above,
this agent in currently being investigated on a phase III multi-center, randomized
superiority trial comparing 3-weekly XRP6258 with prednisone to mitoxantrone
with prednisone in patients with castrate resistant metastatic prostate cancer
previously treated with docetaxel-containing treatment." (p.163, right column,
fifth para.)
It is important to remember that the survival of a patient depends on the type
of cancer and how far the disease has spread. Because of this, the skilled person
generally must have more information before he can use the results of a phase
II clinical study on breast cancer to predict how it might work with prostate
cancer. But this document makes it clear how the treatments of these two
illnesses (breast cancer and prostate cancer) are connected, which would have
been hard to predict otherwise: “given its activity in the docetaxel refractory
setting described above". The document explains that, in both types of cancer,
the problem of resistance to taxanes in general, and to docetaxel in particular,
can be overcome by administering cabazitaxel along with prednisone.
In this context, the fact that cabazitaxel is in the same class as docetaxel — which
would generally dissuade the skilled person from expecting an alternative
treatment for patients who have progressed during or after docetaxel treatment
— and the fact that both experts testified that the mechanism of resistance to a
particular taxane in humans is still to be fully understood and requires further
research, are not particularly relevant, as this document suggests otherwise.
This is supported by the fact that the skilled person will appreciate that
cabazitaxel was specifically developed to treat tumour diseases such as prostate
cancer, and to overcome docetaxel resistance in these treatments (D4, page
727, left column, paragraph 2; page 729, right column, paragraph 2; D9, page
922, right column, paragraph 1; page 933, right column, final paragraph; page
938, left column, paragraph 1; D26, page 75, left column, paragraph 2, table 3).
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Further its efficacy in cases of docetaxel resistance has already been described
in Pivot (D13, page 1551, left column, paragraph 3).
(2) Pivot (D13)
In 2008, the pivot (D13) study revealed favourable outcomes for cabazitaxel in
patients with taxane-resistant metastatic breast cancer. Cabazitaxel was
described as active and tolerable in selected patients at doses of up to 25
mg/m². Despite neutropenia being an adverse effect, Pivot concluded that the
results supported further clinical trials (D13, page 1547, title and abstract). The
two experts explained that, given cabazitaxel's similar chemical structure to
docetaxel, it was expected to have some anti-tumour activity, but also to be
more toxic to the bone marrow. Given the positive conclusion in the Pivot
document, this side effect would not have prevented the skilled person from
continuing the trials.
The Pivot (D13) document also explains that the breast cancer patients in this
Phase II trial had all previously been treated with a taxane, with most having
received docetaxel (65 per cent received docetaxel alone and 10 per cent
received more than one taxane), as specified in the patent. Although breast
cancer is a different type of cancer, and the patient groups differ in terms of sex
and age, as Dr Nelson testified, this study sheds light on an interesting property
of cabazitaxel with regard to the problem addressed by the patent (the
treatment of patients who are resistant to a first taxane, namely docetaxel).
While the results of this study are limited, they are also encouraging. According
to the Pivot document, the results justified the continuation of the clinical
development of this agent and demonstrated activity even when the strictest
resistance criterion was used.
(3) (D9)
(D9) shows as does Pivot (D13) that this potential property is supported
metabolically by the lower affinity of cabazitaxel to the P-glycoprotein (or P-gp),
which is a known cause of tumour resistance to taxanes, as well as by preclinical
studies showing a cytotoxic effect of cabazitaxel on cell lines having acquired
resistance, in particular, to docetaxel.
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Sanofi's assertion that resistance to taxanes involves several factors confirms
that this approach is uncertain by definition and that the mechanisms involved
are complex.
(4) (D4)
The (D4) document refers to a Phase I study on cabazitaxel, conducted in
25 patients with different tumours, eight of which were prostate cancer, two of
whom showed a more than half reduction in the prostate specific antigen (PSA),
or PSA-50, as well as a decrease in the size of measurable tumours and, for one
of them, a reduction in pain. One of these two patients had previously been
treated with docetaxel:
“An 80-year-old male with prostate cancer metastatic to liver and bones whose
disease had progressed through surgical castration, bicalutamide, diethyl
stilbestrol, and mitoxantrone and prednisone experienced a reduction in
prostate-specific antigen from 62 to 21 ng/mL, decreased disease-related bone
pain, and reduction in his target lesion, a lymph node metastasis, which qualified
as confirmed partial response after four courses at the 15 mg/m2 dose level. The
patient declined further treatment after his sixth course, at which time his
response persisted. A 50-year-old male with hormone- and docetaxel-refractory
prostate cancer metastatic to bone and iliac lymph nodes also experienced a
partial response after treatment with XRP6258 at the 25 mg/m2 dose level of
XRP6258. His prostate-specific antigen decreased from 415 to 44 ng/mL, and his
measurable disease showed a confirmed partial response. Progressive disease
was noted after eight courses (D4, page 727 left col. second para.).”
Further Cabazitaxel is characterised by convenient administration with less
premedication, linear PKs, and a favourable safety profile for hematologic
toxicity and hypersensitivity reaction. Cabazitaxel is described in D4 as promising
candidate for the treatment of patients with taxane resistance (D4 page 729,
right col., last para.).
Further D4 indicated that 82 percent of patients treated with 25 mg/m2
cabazitaxel experienced as side effect grade 3 or 4 neutropenia. describes
the duration of severe neutropenia as typically brief and rarely associated with
fever, which means to skilled person that it is manageable (D4 page 728 left col.,
second para., first sentence).
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This document concludes that there is encouraging antitumor activity in patients
resistant to taxanes and considers that cabazitaxel is recommended for Phase II.
The person skilled in the art will appreciate that in vitro testing with prostate
cancer cells (D4 Page 724, left col., second para.; D26 page 74, right col., last
para. to page 75 first para, Table 3, first entry), but not with docetaxel-resistant
cancer cells, had been completed as the phase I study started. Further
cabazitaxel was tested on cell lines with docetaxel resistance (D91). An overview
is provided in D35.
Despite the limitations of this data from the preclinical phase the Phase I study
demonstrated a response to treatment with docetaxel alone. This finding
suggests the efficacy of docetaxel in treating this specific tumour type in patients
who had been previously treated with docetaxel. Whilst this assertion is indeed
accurate, it should be noted that the nature of the data did not permit any
observations to be made with regard to a potential increase in overall survival.
This question was left for further trials.
Doubts that cabazitaxel will work in every case of docetaxel-resistance, e.g., in
cases where the resistance is not caused by P-gp-upregulation, like a docetaxel-resistance
based on tubulin-alterations, are overcome by the positive results of
the phase I and II clinical studies.
As laid out in D4 cabazitaxel is characterised by convenient administration with
less premedication, linear PKs and a favourable safety profile for hepatologic
toxicity and hypersensitivity reaction. It is a weak P-gp substrate in preclinical
models (D4 page 729, right col).
Sanofi argues that the skilled clinician would not have viewed the partial
response in this single patient in as sufficient to reasonably expect that
cabazitaxel would provide an improved treatment to patients having progressed
during or after the treatment with docetaxel. This might be true, if there was no
phase III trial. However, in the present case the phase III trial TROPIC was almost
complete, without interruption or discontinuation. This implied for the skilled
person that this was effective in the treatment of patients with mCRPC
previously treated with docetaxel.
In contrary to Sanofis’ view it is not unusual in the field of oncology that a clinical
phase III trial is based on a phase I trial including patients having different types
of cancer besides the cancer type selected for the phase III trial and a phase II
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trial concerning a different type cancer as such of the phase III trial (e.g.
“Larotaxol”, B07.1 para. 59-64).
In conclusion, there was no evidence against cabazitaxel’s efficacy in the
treatment of mCRPC as a second-line treatment after a docetaxel regimen has
been discontinued.
(5) Elements considered collectively
When considered collectively, these elements substantiate the chances of
success of cabazitaxel in cases of docetaxel-resistant prostate cancer, as
envisaged by the launch of the TROPIC trial. Even more so, this is true of the
prospect of success of the patented treatment for patients who have previously
been treated with docetaxel, but that treatment was discontinued. As
mentioned above, the patient group referred to in the patent claim is not limited
to patients who have developed a resistance to docetaxel or do not respond to
docetaxel. The patient group is simply defined as those who have previously
received a docetaxel treatment. As Dr Denmeade explained, it is not uncommon
for patients receiving a docetaxel-based treatment to stop treatment
temporarily, referred to as “treatment holiday”, and then resume it.
When discussing whether the skilled person in the view of the indicators at hand
would have taken the claimed steps to solve the objective technical problem the
probability of success needs to be balanced against the therapeutic options
available for this patient group at the priority date. In this regard it must be
noted that no accepted standard systemic treatment existed for those patients
(D7, page 161, Abstract, Summary, D12 page 5, sect. 26-27). In many cases only
a palliative treatment was possible (D12, page 2, sect. 16). Since cabazitaxel was
determined to be safe and tolerable (results of the phase I and II studies on
prostate cancer and breast cancer), the risks of verifying the actual efficacy of
cabazitaxel were rather low, but the possible results were extremely valuable.
The observation that one of the two patients in the Phase I study exhibited a
response to treatment with docetaxel alone suggests the efficacy of docetaxel
in treating this particular tumour type. This finding is a valuable lesson in itself.
The efficacy of the treatment in combating docetaxel resistance is indicated by
two main factors. Firstly, the results observed in the other patient enrolled in
the Phase I study are indicative of the treatment's effectiveness. Secondly, the
combination of all the data discussed above provides further evidence for the
treatment's efficacy.
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It has been asserted that, in the case under consideration, the conventional
pathway of drug development, which encompasses a phase I study, followed by
a phase II study to evaluate dosage and efficacy, and subsequently a
"confirmatory" phase III study in a substantial population to substantiate the
efficacy (see D18), is only inadequately reflected. No phase II study in mCRPC
was carried out. The phase II study in breast cancer (see D13) was not followed
by a phase III study in breast cancer, as this line of development was
discontinued (see D20). Consequently, the TROPIC study on prostate cancer
cannot be regarded as a standard confirmatory study, as earlier data are lacking
and only a single patient in the population to be treated had been reported in
phase I (see D4). However, it is imperative to emphasise that the evaluation of
each case must be conducted with a meticulous consideration for its unique set
of circumstances. Automatic inference is not possible in this case. As outlined
above, the absence of a phase II trial for prostate cancer in the conduct of a
phase III clinical trial on prostate cancer does not preclude the successful
development of a new drug or drug application, despite deviating from the
conventional approach. As testified by both experts this happens in about a third
of all oncological phase III studies. Anecdotally, D21, which was published after
the priority date, reveals that Sanofi relied on the breast cancer Phase II trial to
support its application to have the Phase III prostate cancer trial approved (see
D21, p. 27, 30, 33-34,52 and 60).
(6) PSA level as indicator
Admittedly, indirect indicators such as the PSA level are not in themselves
evidence of an effect on the patient's survival time; however, as the patent itself
states both in its introduction and in the data it discloses to support its
therapeutic effect, this PSA level, as well as the measurement of tumour, pain
and the duration without progression of the disease, were accepted criteria as
indicators of the potential effectiveness of the treatment, which includes the
prospect of prolongation of survival. It is therefore irrelevant whether or not the
patent is limited to survival alone (certainly its therapeutic effect, in fact, is not
limited to survival alone) because, as the judges in interim proceedings have
pointed out, these different indicators are indissociable and it is not possible
artificially to isolate different aspects of the therapeutic effect. Otherwise
formulated, the technical effect of the invention is a favourable response of the
disease with a prolongation of survival (which is an inseparable whole) but this
effect could reasonably be expected on the basis of the usual criteria such as the
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PSA rate notwithstanding their imperfection. Again, reasonable expectation of
success is not the certainty or even the near certainty of success.
As a result, for the person skilled in the art, the encouraging results of
cabazitaxel on prostate cancer on the one hand, and on resistance to docetaxel
on the other hand, could give him expectation of a favourable effect on survival,
even though these results related only to indicators other than survival alone.
(7) Dosage
More specifically, as regards the dose likely to have a favourable effect, the
Tropic trial was carried out at a dose of 25 mg/m² (although the patent covers a
range of 15 to 25), whereas the document deduces from the Phase I test
that the recommended dose for the Phase II tests should be only 20 mg/m²,
whereas the patient resistant to docetaxel on which cabazitaxel had an effect in
the Phase I test had received a dose greater than 25 mg/m², which the Sanofi
companies infer from the fact that the Tropic trial would have been considered
doomed to failure due to the risk of excessive toxicity.
In D26 the adverse effect of myelosuppression was only mentioned in
relation to maximum tolerated dose up to 30 mg/m2, which would be limited to
some extend by this side effect (D26 page 75, right col. first para.). Due to the
safety results of the Pivot study (D13) this side effect was not a major concern,
when the regulatory authorities approved the clinical trial TROPIC with 25
mg/m2 .
However, the document more generally found that the toxicity data for
cabazitaxel were encouraging compared to other taxanes, while the Pivot
document showed that the Phase II breast cancer study increased the dose to
25 mg/m² in 28 percent of patients. Therefore, the person skilled in the art,
noting that the dose of 25 mg/m² was approved for the conduct of a phase III
trial involving 750 patients, would not have seen it as an indication of probable
failure but as a rational choice of experimentation. Moreover, the patent itself
does not provide any surprising information on the toxicity of cabazitaxel in the
indication at issue, which remains high, concerns a large number of patients and
requires special consideration, which it describes. This is therefore a foreseeable
disadvantage consistent with the reasonable expectation of the person skilled
in the art in the light of the protocol of the Tropic trial.
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(8) (D26)
As for the opinion expressed by the (D26) document and relied on by
Sanofi, according to which it was unlikely that taxanes would have a ‘major
impact on the fate of the patients’, it must be noted that this is not called into
question by the patent, the moderate effect of which on the increase in overall
survival cannot reasonably be described as a ‘major’ impact on the ‘fate’ of the
patients. The fact that the person skilled in the art would not have expected such
an impact is therefore irrelevant.
(9) Study was nearing completion
It is true, as the Technical Board 3.3.04 noted (EPO BoA paragraph 7.15.5), that
the fact that a study is nearing completion per se, is in the absence of knowledge
of the parameters selected for monitoring, neither a positive nor a negative
pointer when assessing expectation of success. Further in this case no
information is on file regarding the work of the Data Safety Monitoring Board
(DSMB), the timing of interim reviews and the predetermined criteria on which
such interim reviews would have been based. Further it is true that no specific
information was available at the priority date on why the regulatory authorities
have approved the phase III TROPIC study. While D21 indicates that "non-clinical
and clinical data based on applicants’ own tests and studies" were submitted,
the nature and content of these data are not mentioned (see D21: page 4).
But what can however be derived from the fact that the Tropic trial had been
approved and had been in progress for three years at the priority date without
having been stopped, is that at least the sponsor of this trial had not considered
it disappointing at the start and at no time until the priority date.
This supports the expectation of success, because the Phase III study “TROPIC”
was based on successful previous preclinical and clinical data and was expected
to end very soon in May 2010 after 4 years. Six months before the ending of the
trial the skilled person knowing that in a clinical trial interim results must be
evaluated in view of benefits and risks according to the clinical trial plan
periodically, and noticing that no negative events had occurred or were
published, had a reasonable expectation for success for the use of the
combination of cabazitaxel and prednisone in the treatment of the patient group
in question.
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This view is supported by Dr. Nelson`s and Dr. Denmeade`s testimony who both
said that an untimely termination of the TROPIC trial would have been made
public, and by Dr. testimony (B.25, para. 58: “The fact that a trial had been
ongoing for some time would mean only that there has not been a very severe
adverse safety signal and that in a very stringent statistical analysis, the trials
was not destined to fail unequivocally.”) Contrary to the argument of Sanofi,
that many trails proceed for years and eventually fail, thus a guarantee for a
positive outcome does not exist, the skilled person gains an expectation of
success, because of the late stage of the ongoing clinic trial phase III.
The sponsor of the TROPIC study may have considered the poor prognosis for
patients with metastatic castration-resistant prostate cancer (mCRPC),
particularly those with docetaxel-refractory mCRPC, as a key factor in allowing
the study to proceed, given that the risk/benefit assessment would have
favoured moving forward. The patients had a terminal disease and there were
no approved treatment options available. The de facto standard treatment was
highly toxic chemotherapy with no clear data on a palliative effect. In contrast,
the potential benefits to patients of a positive finding in the study were
significant. Phase I toxicity studies had been completed, suggesting that the risks
were manageable. Even the slightest hope of success would have been sufficient
to tip the balance in favour of proceeding with the study. However, as no details
on these considerations have been made available to the skilled person on the
priority date, these considerations cannot be taken into account when assessing
inventive step.
This assessment is also supported by the differing answers of the two experts to
the question of whether the skilled person would have had reason to expect the
TROPIC study to be successful, given that they knew the study had been
approved and had been ongoing for three years without premature
interruption. Dr Denmeade refuted the notion put forward by Dr Nelson that
the DSMB might have lowered the bar to give the go-ahead for the phase III
study, given that the patients had a lethal disease and no further treatment was
available, only palliative care. In his view, the DSMB would always insist that
safety and some degree of efficiency be demonstrated so that the benefits
outweigh the risks, as there was nothing special about the urgent need in this
case. Treatment for all kinds of cancer is needed. Ultimately, this discussion does
not provide any additional guidance on the question of inventive step, as the
DSMB's considerations were unavailable to the skilled person at the priority
date.
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(10) Other Phase III taxane trials discontinued
The fact that other Phase III taxane trials, in particular the one on cabazitaxel in
breast cancer, had been discontinued (Sanofi 2008 document) cannot generally
call into question the promising elements described above. These
discontinuations could be interpreted in different ways (i.e., by comparison, the
continuation of cabazitaxel research for the prostate revealed that it was more
promising, or conversely, that taxanes were beginning, as a class, to prove a
dead end, with this second interpretation not explaining why, then, the
cabazitaxel trial should be continued if such a general conclusion on taxanes
were to be drawn), without leading the person skilled in the art to unfavourably
modify the teaching of the previous data corroborated by the launch and then
the continuation of the Tropic trial.
In this respect, the statistical data cited by the Sanofi companies and available
at the priority date and UPC Sanofi Exhibit No. B.14 document),
according to which phase III trials are successful in 41 percent of cases in
oncology, only confirm the fact that any trial is uncertain, while indicating that
at this advanced stage of development, the average chances of success are close
to half. In fact, the same document states that the chances of success vary
greatly depending on the case and states in particular that success is more likely
for compounds whose mechanism of action is already implemented by another
compound and document, p. 713, nd column, l. 4-11), which is the
case for the cabazitaxel selected because it belongs to the same taxane class as
docetaxel, with the known effect, while having promising characteristics in the
face of the resistance encountered by taxanes.
Also, the argument that all the mentioned failed Phase III trials show that
authorisation to carry out a Phase III trial does not mean that the trail is
successful, is not sustainable. As mentioned before, the crucial point in the
present case is not the authorisation of the trial, it is the course of the trial
without incident and the near ending of the trial, which leads to an expectation
of success.
ff. Overall assessment
Thus, in the light of these prior art data, the person skilled in the art would have
considered that, compared to mitoxantrone plus prednisone, which he knew
had only a first-line palliative effect and was not even approved for second-line
use, the second-line cabazitaxel plus prednisone experiment in progress in a
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phase III trial for more than three years, had a reasonable chance of showing a
favourable effect including the (moderate) increase in survival.
As a matter of fact, the skilled person does not need to have been certain of
success by any means; for rendering a solution obvious, it is sufficient if the
skilled person would have followed the teaching available in the prior art with a
reasonable expectation of success (case law of the Boards of Appeal, I.D.7.1:
https://www.epo.org/en/legal/case-law/2022/clr_i_d_7_1.html; EPO Board of
Appeal T 2506/12, para. 3.12.2; T 0096/20, para. 8 and 9), which is the case here.
gg. No binding effect of decisions by the EPO or national courts
In light of the differing findings of the Opposition Division and the Boards of
Appeal regarding the opposition to the patent in question, the Unified Patent
Court may, in principle, consider decisions and opinions issued by national
courts and the EPO when interpreting the EPC. However, this does not relieve a
UPC panel of its duty as an independent judicial body to interpret and apply the
EPC, nor does it relieve them of their duty to decide on the counterclaims. Thus,
national decisions and EPO decisions are elements to be considered by UPC
panels, but are not binding on them. In this sense, they may have a persuasive
effect. Within this framework, this panel has carefully considered the findings of
the Opposition Division and the Boards of Appeal. However, in view of the
reasoning set out above, the panel follows the Tribunal Judiciaire de Paris and
cannot agree with the conclusions reached by the Opposition Division and the
Boards of Appeal regarding inventive step.
Therefore, claim 1 does not involve an inventive step.
3. On inventive step of Claims 2-8
Sanofi did not argue that dependent claims 2 to 8 contain subject matter that is
inventive in relation to the prior art, independently of claim 1. The following
discussion is therefore included for the sake of completeness.
As the defendant companies point out, claim 2, by specifying that the use of the
drug is for an advanced metastatic disease, does not bring anything inventive,
the metastatic prostate cancer considered in claim 1 already being an advanced
metastatic disease.
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The features of dependent claims 3 and 4, which relate to cabazitaxel being in
the form of an acetone solvate, are not linked to any technical effect.
Furthermore, it is within the skilled person’s common general knowledge to
provide a specific solvate, such as the acetone solvate, of an active agent such
that these features are not suited to establish an inventive step.
The doses of cabazitaxel and prednisone and the 3-week dosing interval, which
are the subject of claims 5, 6 and 7, are disclosed in the NHSC document and the
evidence of their effect follows from the foregoing considerations on claim 1. A
fortiori, the combination with prednisone per se, which is the subject of claim 8.
Nor is it disputed lastly, that the limitation to patients who have previously
received a minimum dose of 225 mg/m² of docetaxel, which is the subject of
claim 9, does not provide any distinct technical effect, so that, responding to the
same problem or merely providing an arbitrary characteristic, it is not inventive
either.
Consequently, the European Patent 2 493 466 is revoked in its entirety (claims 1
to 9) with effect for the following UPC Contracting Member States:
Austria, Belgium, Germany, Denmark, France, Italy, the Netherlands, Portugal
and Sweden.
4. No auxiliary requests
Sanofi did not file an application pursuant to Rule 30 of the Rules of procedure.
Therefore, no auxiliary requests must be considered.
C. Infringement actions:
As the patent in question is invalid and is revoked in its entirety the infringement
actions shall be dismissed.
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D. Any other outstanding applications and requests:
As the infringement actions are dismissed, any other outstanding applications
and requests relating to them no longer need to be adjudicated (R. 334 RoP).
These requests shall be set aside.
E. Costs
As losing party Sanofi SA must bear the costs of the counterclaims. All Sanofi
claimants must bear the costs of the infringement actions as they have either
withdrawn the infringement claims or lost them, due to the invalidity of the
patent.
DECISION
1. The European Patent 2 493 466 is revoked in its entirety (claims 1 to 9) with
effect for the following UPC Contracting Member States: Austria, Belgium,
Germany, Denmark, France, Italy, the Netherlands, Portugal and Sweden.
2. The infringement actions are dismissed.
3. The costs of the counterclaims for revocation shall be borne by Sanofi SA.
4. The costs of the infringement actions shall be borne by all Sanofi claimants.
5. All other outstanding applications and requests, including the preliminary
objections, do not need consideration and are set aside.
INFORMATION ON 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
An authentic copy of the enforceable decision will be issued by the Deputy-
Registrar upon request of the enforcing party, R. 69 RegR.
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INSTRUCTIONS TO THE REGISTRY
A copy of this decision, once it has become final, is to be sent to the European
Patent Office and the
- Österreichisches Patentamt
- Belgian Office for Intellectual Property
- Deutsches Patent- und Markenamt
- Danish Patent and Trademark Office
- Institut National de la Propriété Industrielle
- Italian Patent and Trademark Office
- Netherlands Patent Office
- Portuguese Institute of Industrial Property
- Swedish Intellectual Property Office.
This decision was issued on 12 December 2025.