- translation -
IN THE NAME OF THE QUEEN
DISTRICT COURT THE HAGUE Civil law section Judgment of July 2, 2008 in the case having case number / cause-list number 293668/ HA ZA 07-2628 of NOVARTIS AG, a legal entity under foreign law, having its registered seat and principal place of business at Basel, Switzerland, plaintiff in the main action, defendant in (partly conditional) counterclaim proceedings, procurator litis: previously mr W. Heemskerk, presently mr P.J.M. von Schmidt
auf Altenstadt, attorneys-at-law: mr S. de Wit and mr F.I.S.A.L. van Velsen at Rotterdam,
versus 1. ACTAVIS GROUP HF, a legal entity under foreign law, having its registered seat and principal place of business at Hafnarfirdi, Iceland, 2. ACTAVIS B.V., a private company with limited liability, having its registered seat and principal place of business at Baarn, defendants in the main action, plaintiffs in (partly conditional) counterclaim proceedings, procurator litis: mr A. Killan,
and in the case having case number / cause-list number: 293670 / HA ZA 07- 2629 of NOVARTIS AG, a legal entity under foreign law, having its registered seat and principal place of business at Basel, Switzerland, plaintiff in the main action, defendant in conditional counterclaim proceedings, procurator litis: previously mr W. Heemskerk, presently mr P.J.M. von Schmidt
auf Altenstadt, attorneys-at-law: mr S. de Wit and mr F.I.S.A.L. van Velsen at Rotterdam,
versus PHARMACHEMIE B.V., a private company with limited liability, having its registered seat at Haarlem, defendant in the main action, plaintiff in conditional counterclaim proceedings procurator litis: mr M.A.A. van Wijngaarden.
Parties are hereinafter (also in the operative part) referred to as Novartis on the one hand and Actavis Group, Actavis and Pharmachemie. 1. The
1.1. The course of the proceedings appears from:
- the decisions of this court of July 6 and 27, 2007, respectively, whereby
leave was granted to Novartis to summon Actavis Group and Actavis and Pharmachemie, respectively, according to the regime for accelerated proceedings on the merits in patent cases
- the summons of July 17, 2007 served upon Actavis Group and Actavis - the summons of August 3, 2007 served upon Pharmachemie - the deed of submission of exhibits on the part of Novartis of August 22,
2007 with Exhibits 1 to 7 (in the case versus Actavis Group and Actavis)
- the deed of submission of exhibits on the part of Novartis of August 22,
2007 with Exhibits 1 to 7 (in the case versus Pharmachemie)
- the statement of defense in the main action, also statement of
counterclaim in counterclaim proceedings, also deed of submission of exhibits on the part of Actavis Group and Actavis of November 7, 2007 with Exhibits 1 to 32
- the statement of defense in the main action, also statement of
counterclaim in conditional counterclaim proceedings, also deed of submission of exhibits on the part of Pharmachemie of November 7, 2007 with Exhibits 1 to 30
- the deed of submission of exhibits on the part of Novartis of November 7,
2007, with Exhibits 8 and 9 (in the case versus Actavis Group and Actavis)
- the deed of submission of exhibits on the part of Novartis of November 7,
2007 with Exhibits 8 and 9 (in the case versus Pharmachemie)
- the statement of reply in counterclaim proceedings, also deed of
submission of exhibits on the part of Novartis of January 2, 2008 with Exhibits 10 to 17 (in the case versus Actavis Group and Actavis)
- the deed of change of claim on the part of Novartis of November 7, 2007
(in the case versus Pharmachemie)
- the statement of reply in counterclaim proceedings, also deed of
submission of exhibits on the part of Novartis of January 2, 2008 with Exhibits 10 to 17 (in the case versus Pharmachemie)
- the deed of submission of exhibits on the part of Novartis of March 14,
2008 with Exhibits 18 to 25 (in the case versus Actavis Group and Actavis)
- the deed of submission of exhibits on the part of Novartis of March 14,
2008 with Exhibits 18 to 25 (in the case versus Pharmachemie)
- the deed of submission of exhibits on the part of Actavis Group and
Actavis of March 14, 2008 with Exhibits 33 to 37
- the deed of submission of exhibits on the part of Pharmachemie of
March 14, 2008 with Exhibits 31 to 42
- the letter of mr Van Wijngaarden, also on behalf of mr Killan, to the
court of February 19, 2008, received at the registry on February 20, 2008
- the reaction to this letter, from mr De Wit by fax of February 20, 2008
- the email from the president of the court to mr Van Wijngaarden,
mr Killan and mr De Wit of February 22, 2008
- the email from mr Van Velsen of February 28, 2008 (statement of
reasonable and proportionate judicial and other costs agreed upon between parties)
- the email from the president of the court in response, of March 4, 2008 - the pleadings of mr Van Velsen for the hearing of March 14, 2008, with
text corrected, at the request of mr Van Velsen, in part I in paragraph 24:
"(of paragraph 17)" changed to "(of paragraph 15)" and in part 3, paragraphs 39 and 40, which have not been pleaded, deleted, and the pleadings of mr Killan and mr Van Wijngaarden for this hearing, in
which in part 2 of the pleading of mr Killan paragraph 173, which has
not been pleaded, has been deleted, and in part 3 of the pleading of
mr Van Wijngaarden paragraphs 15 and 16, which have not been
pleaded either, have been deleted; also present at the hearing were the patent attorneys of Novartis, drs J. Renes and Dr. R. Jorritsma, as well
as the patent attorneys of Actavis Group, Actavis and Pharmachemie, Ms ir D.E. Hesselink, Dr. T. Beetz and Dr. T. Wittop Koning
- the email from the court to the counsels of parties of March 20, 2008 - the individual reactions thereto from mr Van Velsen and mr Killan of the
- the email from the court to the counsels of Novartis and Pharmachemie
of April 14, 2008
- the individual reactions thereto from mr Van Velsen and mr Van
Wijngaarden of April 15, 2008, in which they declare they have not reached an amicable arrangement and ask for judgment to be passed.
Initially, oral pleading in the above cases was scheduled on the same day, but on different parts of the day. Prior to oral pleading, mr Van
Wijngaarden, mentioned above, requested the court, also on behalf of
mr Killan, mentioned above, by letter of February 19, 2008, received at the
registry on February 20, 2008, to deal with the two cases simultaneously and to that end proposed a pleading schedule. Mr De Wit thereupon reacted
by fax of February 20, 2008 and submitted an alternative proposal for a pleading schedule. The president of this court informed parties by email of February 22, 2008 that the cases would be dealt with simultaneously and would be divided up into three equal parts, viz. part 1 regarding the validity, part 2 regarding the infringement by Actavis Group and Actavis (with ancillary claims) and part 3 regarding infringement by Pharmachemie (with ancillary claims), and presented a pleading schedule. At the hearing, mr Van Velsen, mr Killan and mr Van Wijngaarden
informed the court that they have shortened the pleading part 3 regarding infringement by Pharmachemie (with ancillary claims) in mutual consultation, in the sense that they will argue only specific points relating to the case, so as to avoid repetition of what has been argued regarding the infringement by Actavis Group and Actavis. Parties further indicated that the written pleadings will be submitted in the pleading part 3, with attached thereto the written pleadings in pleading part 2 regarding the infringement by Actavis Group and Actavis, as well as of the statement of reply in counterclaim proceedings on the part of Novartis, the contents of which are to be deemed repeated and inserted into the respective written pleadings.
Mr Van Velsen, on being asked, informed the court that Novartis
withdraws its primary claim in respect of Pharmachemie, while maintaining what it has claimed in the alternative.
Mr Killan, on being asked, informed the court that Actavis Group and
Actavis are prepared still to make their counterclaim partly conditional, in the sense that the claim for nullification of the patent is filed only in case the court were to be of the opinion that Actavis Group and/or Actavis infringe the Novartis patent, which upon instruction was entered in the records.
1.2. Finally, the date of judgment was set for today. 2. The
2.1 Novartis is holder of the substantively examined Dutch patent having
number 194781 (hereinafter: the patent or NL 781), which relates to a "Pharmaceutical composition for oral administration comprising a
cyclosporin". The patent was granted on March 4, 2003 upon an application
of September 15, 1989 (application number 8902315), invoking priority of two British applications of September 16, 1998 (GB 0008821754) and February 9, 1989 (GB 0008902900). The publication of the grant took place on May 1, 2003. The patent expires on September 14, 2009.
2.2. The Application Department of what was then still called Industrial
Property Office (Patent Office), took different documents from the prior art, among which EP 211258, NL 8802657, EP 32728, EP 100448, JP 61-249918 and US 4,388,307, into consideration and rejected the application by decision of August 11, 1999. Novartis appealed that decision.
2.3. By decision of May 17, 2002, the Appeal Department set aside the decision
of the Application Department of August 11, 1999 and decided to publish the application. To that effect, the Department considered, as far as relevant, as follows:
From United States Patent 4,388,307, to an employee of applicant, a pharmaceutical composition is known which comprises a cyclosporin as
active ingredient and is suitable inter alia for oral administration. In a
preferred embodiment according to the U.S. patent specification, the pharmaceutical composition comprises a carrier consisting of three
ingredients and it is self-emulsifying in the presence of water. This self-emulsifying character, as appears from column 6, lines 13-20 of the U.S.
patent specification, is of relevance with regard to the bioavailability of the
active ingredient, because precipitation in gastric fluid or upon intramuscular injection leads to a strongly reduced resorption. The three
respective ingredients in U.S. Patent 4,388,307 are designated as '(a)', '(i)',
and '(iii)', where: '(a)' represents a transesterification product of a natural or hydrogenated
vegetable oil triglyceride and a polyalkylene polyol, such as the esterification
products known under the trade name of Labrafil; '(i)' is ethanol, and
'(iii)' represents a vegetable oil, such as olive oil or maize oil.
The Appeal Department establishes that '(a)' corresponds to the lipophilic
[underlining added – Court] surfactants with the code number 3.2.1, that
'(i)' is a hydrophilic phase and that '(iii)' as a fatty acid triglyceride belongs to
the lipophilic phases described by applicant with code number 2. Example I
from U.S. Patent 4,388,307 accordingly describes, in the opinion of the Appeal Department, a pharmaceutical composition for oral administration
which comprises a cyclosporin as active ingredient and which comprises a
hydrophilic phase, a lipophilic phase and a surfactant. (.) The only distinction between the pharmaceutical compositions according to
the pretended invention and the compositions known from U.S. Patent 4,388,307 must therefore be seen to reside, apparently, in the circumstance
that the present compositions on contact with water are capable of
spontaneously or virtually spontaneously forming a microemulsion having a particle size of less than 200 nm. U.S. Patent 4,388,307 is silent on the
possible formation of microemulsions and applicant has alleged that U.S.
Patent 4,388,307 describes a macroemulsion, since, according to applicant, Example 1c upon repeat leads to an emulsion having a particle size of more
However, in the opinion of the Appeal Department, it has not become clear in any way why the skilled person, when using the same hydrophilic phase, the
same lipophilic phase and the same surfactant, according to U.S. Patent
4,388,307 would always obtain a pharmaceutical composition which on contact with water forms a macroemulsion.
Applicant, it is true, has stated that the chosen hydrophilic phase and the chosen lipophilic phase are not miscible, but in Example 1.3 adds ethanol as
a co-solvent for the hydrophilic phase while ethanol, as appears from
Examples 3 and 5 of U.S. Patent 4,388,307, is also a solvent for the Miglyol 812 used as lipophilic phase in Example 1.3. Moreover, according to the
original specification of the application, p. 26, line 18 to p. 27, line 4, the
lipophilic phase designated with code number 2 [Miglyol 812 - Court] is a suitable co-solvent for the hydrophilic phase designated with code number
1.1 [Glycofurol 75 - Court].
The practical examples of the present application do not give any useful indications in this regard, because in none of these examples is a
microemulsion described and/or the particle size mentioned, nor does the
comparative experimentation described in any way devote attention to - what is presently defended by applicant as the essence of the invention - the in
vivo achieved particle size upon administration of the present
pharmaceutical composition and the comparative composition, respectively.
For this reason, the Appeal Department comes to the conclusion that there is
no distinction between the subject matter of claim 1 of the present application and what is known from U.S. Patent 4,388,307 and that this claim, if based on
novel subject matter at all, is not enabling for a skilled person.
Applicant has indicated in a first auxiliary request filed by letter of April 12, 2001, that it was prepared, if necessary, to restrict the hydrophilic phase to
be used according to claim 1, to 1,2-propylene glycol, and subsequently,
during the hearing of April 18, 2001, further indicated by way of alternative that it was prepared, if necessary, to restrict the surfactant to be used
according to claim 1, to the reaction products of natural or hydrogenated
vegetable oils and ethylene glycol, designated by code number 3.1.1. Having regard to the original specification of the present application, the
Appeal Department is of the opinion that the comparative experimentation described gives an indication that the use of hydrophilic [underlining added –
Court] surfactant with code number 3.1.1 yields an unexpectedly favorable
effect over the use of lipophilic [underlining added – Court] surfactant with code number 3.2.1.
The Appeal Department is therefore prepared to cooperate towards
publication of the present application if it is indicated in claim 1 that the surfactant to be used is a reaction product of natural or hydrogenated
vegetable oils and ethylene glycol.
The decision to publish the application for opposition purposes was published on November 1, 2002. No opposition was filed against the grant of NL 781.
2.4. The claims of the patent read as follows
1. A pharmaceutical composition for oral administration comprising a
cyclosporin as active ingredient, and comprising 1) a hydrophilic phase, 2) a lipophilic phase and 3) a surfactant, characterised in that the surfactant comprises a reaction product of natural or hydrogenated vegetable oils and ethylene glycol, and that the composition is an oil-in-water microemulsion preconcentrate which, upon contact with water, is capable of spontaneously or virtually spontaneously forming a microemulsion with a particle size of less than 2,000 Å.
2. A composition according to claim 1, characterised in that the
surfactant comprises a reaction product of a natural or hydrogenated castor oil or fractions thereof with ethylene oxide.
3. A composition according to claim 1 or 2, characterised in that the
hydrophilic phase comprises 1.1) a pharmaceutically acceptable C1-5 alkyl or tetrahydrofurfuryl di- or partial-ether of a mono- or poly-oxy-alkanediol having 2 to 12 carbon atoms or 1.2) 1,2-propylene glycol.
4. A composition according to claim 3, characterised in that the
hydrophilic phase comprises Transcutol or Glycofurol.
5. A composition according to claim 1, 2, 3 or 4, characterised in that
the lipophilic phase comprises a triglyceride of fatty acids having a chain length of 6-12 carbon atoms.
6. A pharmaceutical composition for oral administration comprising a
cyclosporin as active ingredient, characterised in that the composition is a microemulsion with a particle size of less than 2,000 Å, obtained on contact of a microemulsion preconcentrate according to claim 1, 2, 3, 4 or 5 and water.
2.5. Claim 1 of NL 781 as granted consists of the following subfeatures:
(A) A pharmaceutical composition for oral administration which
(B) comprises a cyclosporin as active ingredient and which
(C) is an oil-in-water microemulsion preconcentrate and
(D) comprises a hydrophilic phase,
(E) comprises a lipophilic phase
(F) and comprises a surfactant comprising a reaction product of
natural or hydrogenated vegetable oils and ethylene glycol, wherein
(G) the preconcentrate according to (C) on contact with water is
capable of spontaneously or virtually spontaneously forming a microemulsion with a particle size of less than 2000 Å.
2.6. To the patent belong the following figures:
2.7. Novartis is one of the largest pharmaceutical groups in the world. Novartis
AG has come about through a merger in 1996 between Ciba Geigy AG and Sandoz AG. Novartis is primarily concerned with researching and developing medicines. Novartis has a large number of patents to protect the inventions resulting from R&D, among which NL '781.
2.8. Actavis Group is one of the larger international pharmaceutical enterprises
worldwide and produces and distributes generic and innovative medicines. The head office of Actavis Group is seated in Iceland. Actavis is a Dutch partnership which belongs to the Actavis group.
2.9. On April 5, 2007, Actavis Group obtained marketing authorizations under
RVG numbers 34432, 34433, and 34434 from the Dutch Medicine Evaluation Board (hereinafter: CBG) to market (or cause to be marketed) the product Ciclosporin Actavis in the Netherlands in the dosages 25 mg, 50 mg and 100 mg.
2.10. Pharmachemie is part of the worldwide Teva concern which is engaged in
the development, production and sale of inter alia generic medicines.
2.11. On April 5, 2007 Pharmachemie obtained marketing authorizations under
RVG numbers 34435, 34436, and 34437 from the CBG to (cause) the
product Ciclosporine PCH to be placed on the market in the Netherlands in the dosages 25 mg, 50 mg and 100 mg.
2.12. By letter of June 1, 2007, Novartis' attorney-at-law demanded both Actavis
Group and Pharmachemie to confirm that they will not trade the products according to the obtained marketing authorizations prior to the expiration of NL 781.
2.13. By letter of July 14, 2007, (the attorney-at-law of) Actavis Group informed
Novartis that it intended to bring Ciclosporin Actavis on the Dutch market as of July 10, 2007.
2.14. By letter of June 13, 2007, the attorney-at-law of Pharmachemie informed
the attorney-at-law of Novartis, as far as relevant, as follows:
2.15. At the time of the oral pleading in this case, neither Novartis Group [sic]
nor Pharmachemie was on the Dutch market with their products according to the obtained marketing authorizations.
2.16. Dexcel Ltd (hereinafter: Dexcel) on December 30, 1999 filed a PCT
application WO 00/40219 (hereinafter: WO 219) for a 'dispersible
concentrate for the delivery of cyclosporin'. The PCT application claims
priority based on a United States patent from December 30, 1998. Dexcel produces and trades ciclosporin compositions according to WO 219 and is
inter alia supplier of Actavis Group.
2.17. Actavis Group has instituted – as far as has become known from the
records – nullity actions against the foreign parallel patent of NL 781 in two countries, viz. Denmark and England. GB 770 was maintained for England and Wales by Pumfrey J in his judgment of October 16, 2006. The England and Wales Court of Appeal upheld that decision by judgment of October 18, 2007. On May 21, 2007, the District Court of Lyngby maintained the NL 781-parallel, Danish patent DK 171.433 B1. That decision was upheld by the High Court of Eastern Denmark on October 29, 2007.
in the main action 3.1. In the proceedings against Actavis Group and Actavis, Novartis claims –
summarized – that Actavis Group and Actavis be enjoined from infringing NL 781, on pain of a penalty, with various ancillary claims, and that Actavis Group and Actavis be ordered to pay to Novartis the profits obtained with the patent infringement, in accordance with the certified specified statement of an independent certified accountant, or – this at the option of Novartis - to compensate the damage suffered, to be assessed by the court, with an order for Actavis Group and Actavis to pay the reasonable and proportional costs of the proceedings according to Article 1019h Code of Civil Procedure, assessed by parties in mutual consultation to be 75,000.00, increased by the statutory interest on this amount, starting from the fifteenth day after service of the judgment to be delivered in this case, and with a declaration that the order be provisionally enforceable. The basis for the claims relied upon by Novartis is that Actavis Group and Actavis infringe, at least threaten to infringe, claims 1, 2 and 5 of NL 781 through the announced intention of trading the product Ciclosporin Actavis in the Netherlands.
3.2. Against this, Actavis Group and Actavis put up a reasoned defense,
contending – briefly summarized – that its product Ciclosporin Actavis does not infringe NL 781, and that Actavis does not commit any relevant acts in terms of patent law, respectively, and move in conclusion that the claims be dismissed, with an order for Novartis, by judgment provisionally enforceable at any time before execution has been issued, to pay the reasonable and proportional costs of the proceedings under Article 1019h Code of Civil Procedure, assessed by parties in mutual consultation to be
90,000.00, with a stipulation that statutory interest on these costs will be
due from the moment when the court has delivered judgment.
3.3. After an increase of the claim by deed of November 7, 2007 and after a
decrease of the claim at oral pleading, whereby it withdrew its primary claim (infringement injunction), Novartis presently claims in the proceedings against Pharmachemie only a declaratory judgment to the effect that the product Ciclosporine PCH falls within the scope of protection of NL 781, with an order for Pharmachemie to pay the reasonable and proportional costs of the proceedings under Article 1019h Code of Civil Procedure, assessed by parties in mutual consultation to be 75,000.00, increased by the statutory interest on this amount, starting from the fifteenth day after service of the judgment to be delivered in this case.
3.4. Pharmachemie also puts up a reasoned defense. It primarily puts forward –
briefly summarized – that Novartis' claim is not allowable, at least it should be dismissed, now that Novartis lacks any interest in it, at least that involving Pharmachemie and keeping Pharmachemie involved in these proceedings constitutes abuse of law. In the alternative, Pharmachemie has put forward that the product Ciclosporine PCH, as described in the market authorizations, does not fall within the scope of protection of NL 781, so that the declaratory judgment claimed should be denied for that reason as well, with an order for Novartis to pay the reasonable and proportional costs of the proceedings under Article 1019h Code of Civil Procedure, assessed by parties in mutual consultation to be 100,000.00, this being provisionally enforceable at any time before the execution has issued.
3.5. The submissions of parties, as far as of relevance, will be addressed in more
detail hereinafter.
in (partly conditional) counterclaim proceedings 3.6. After change of their claim, Actavis Group and Actavis claim in conditional
counterclaim proceedings, viz. in case the court were to be of the opinion that they infringe the patent, that NL 781 be declared null and void [nullification is what is presumably meant – Court] by judgment provisionally enforceable. They claim furthermore, insofar as NL 781 were to be wholly or partly maintained, a declaratory judgment that the product Ciclosporin Actavis does not fall within the scope of protection of NL 781. In addition, Actavis Group and Actavis claim that Novartis be ordered to compensate the damage suffered by them as a result of the action instituted and the unlawful enforcement of the patent, this to be further assessed by the court and to be settled according to the law. Pharmachemie, in conditional counterclaim proceedings, viz. in case the court were to be of the opinion that Pharmachemie infringes the patent, also claims nullification of NL 781. Actavis Group, Actavis and Pharmachemie claim, finally, an order for Novartis to pay the reasonable and proportional costs of the proceedings under Article 1019h Code of Civil Procedure, assessed by parties in mutual consultation to be 60,000.00 on the part of Actavis Group and Actavis and 70,000.00 on the part of Pharmachemie.
3.7. The basis on which Actavis Group, Actavis and Pharmachemie rely for
their claims is that the patent is null and void because it is not new, lacks an inventive step and is not enabling. Actavis Group and Actavis base their claim of a declaratory judgment on the contention that the product
Ciclosporin Actavis does not fall within the scope of protection of NL 781. The basis for the claim for damages that Actavis Group and Actavis rely upon is that, at least that is how the court understands it, Novartis acts unlawfully towards them so that they suffer damage, consisting in missed turnover and profit.
3.8. Novartis, in turn, puts up a reasoned defense against this and moves that
the counterclaims be dismissed, with an order for Actavis Group, Actavis and Pharmachemie to pay the reasonable and proportional costs of the proceedings under Article 1019h Code of Civil Procedure, assessed by parties in mutual consultation to be 50,000.00 in the Actavis Group and Actavis case and also 50,000.00. in the Pharmachemie case.
3.9. The contentions of the parties, as far as relevant, will be addressed in more
detail hereinafter,.
4.1. Actavis Group, Actavis and Pharmachemie have expressly filed their
counterclaim for nullification of NL 781 only on the condition that the court were to judge that they infringe the patent. In the main action they have moreover not put forward by way of defense that NL 781 is null and void. Considered thus, it is not obvious first to assess the alleged nullity of the patent for lack of novelty, lack of inventive step or non-enablement. Nonetheless, the court will yet proceed to do so, now that – as will appear hereinafter – in the opinion of the court the product Ciclosporin Actavis falls within the scope of protection of NL 781 and infringement of a null-and-void patent is not possible.
in conditional counterclaim proceedings Introduction to the technique
4.2. The court will give a short introduction to the technique under
consideration here, which has been derived from an elucidation by parties.
4.3. The immune system in the human body tries to reject a transplanted organ
as being foreign to the body. Rejection phenomena can be reduced, for instance by suppressing the immune system using an immunosuppressive substance.
4.4. Around the eighties of the last century, it was discovered that cyclosporin
possesses immunosuppressive activity. Cyclosporin is a naturally occurring cyclic peptide. It has the chemical formula C62H111N11O12 and looks as follows (simplified without taking stereochemical properties into account):
4.5. Cyclosporin is strongly hydrophobic, that is, it dissolves poorly in water.
The solubility decreases at higher temperatures and at body temperature it is practically insoluble (around 10 μg/ml). Conversely, cyclosporin is strongly lipophilic, that is, it dissolves well in lipids (i.e. fats and fatty substances).
4.6. The strongly hydrophobic character of cyclosporin has been one of the
factors that made it difficult to develop a suitable pharmaceutical preparation from it. Poor intrinsic bioavailability, that is, that portion of the active ingredient that is eventually assimilated in the blood, was the result. That drawback could not be removed by (strongly) increasing the dose. For cyclosporin proved to be inter alia nephrotoxic, that is, noxious to
the kidneys. Cyclosporin therefore has a limited therapeutic range, from 100 ng/ml to about 300 ng/ml.
4.7. The first commercial application of cyclosporin was Sandimmune®, a
pharmaceutical preparation originally developed by Sandoz, which became available ten years after the discovery and isolation of cyclosporin and the identification of the immunosuppressive activity thereof. It contains a solution of cyclosporin in ethanol, olive or maize oil, glycerol and Labrafil M-2125 CS.
4.8. In the use of Sandimmune capsules, the capsule is mixed with water to be
used for ingestion thereof and thereupon with gastric fluids in the gastrointestinal tract, so that an emulsion is formed, whereby (cyclosporin containing) oily drops are divided over the aqueous environment. Assimilation of the oil solution depends on the breakdown of the oil, which takes place in the gastrointestinal tract under the influence of gastric bile and enzymes. Here, it appeared that an insufficient presence of gastric bile leads to an extremely low assimilation (by the blood) of cyclosporin. Since the secretion of bile is stimulated by fats present in food, the assimilation of cyclosporin proved strongly dependent on the food eaten by the patient prior to the ingestion of Sandimmune.
4.9. The formulation of Sandimmune was hence not very satisfactory since:
- the bioavailability was relatively low; - the stability of the preparations was limited, which led to further
possible problems in case of uniform dosaging;
- the above problems led to a considerable inter- and intrapatient
variation; this was all the more problematic given the limited therapeutic range of cyclosporin; and
- these problems necessitated a permanent monitoring of patients,
which entailed regular hospitalization of patients.
4.10. Summarized, Sandimmune had unpredictable pharmokinetics and hence a
considerable risk of rejection phenomena remained present.
4.11. In the introduction to the specification of NL 781, the invention is delimited
from US 4,388,307 (hereinafter: US '307), filed by Sandoz and connected with the development of Sandimmune.
4.12. With regard to the pharmacokinetic properties according to the prior art,
the introduction to the specification states (p. 1, line 32 ff)
Secondly, the bioavailability levels achieved using existing oral cyclosporin dosage systems are low and exhibit wide variation between individuals, individual
patient types and even for single individuals at different times during the course of therapy. Thus, reports in the literature indicate that currently available
therapy employing the commercially available Ciclosporin drink solution provides
an average absolute bioavailability of ca. 30% only, with marked variation between individual groups, e.g. between liver (relatively low bioavailability) and
bone-marrow (relatively high bioavailability) transplant recipients. Reported
variation in bioavailability between subjects has varied from anything between one or a few percent for some patients to as much as 90% or more for others. As
already noted, marked change in bioavailability for individuals with time is
frequently observed. (…)
Because of the wide variations in bioavailability levels achieved with conventional
dosage forms, daily dosages needed to achieve required blood serum levels will also vary considerably from individual to individual and even for a single
individual. For this reason it is necessary to monitor blood/blood-serum levels of patients receiving cyclosporin therapy at regular and frequent intervals. (…) This
is inevitably time consuming and inconvenient and adds substantially to the
overall cost of therapy. Beyond all these very evident practical difficulties lies the occurrence of
undesirable side reactions, in particular nephrotoxic reactions, observed
employing available oral dosage forms. In the prior art, many proposals to meet these various problems have been
suggested, including both solid and liquid oral dosage forms. However, an
overriding difficulty which has remained is the inherent insolubility of the cyclosporins, e.g. Ciclosporin, in aqueous media, and hence provision of a dosage
form which can contain cyclosporins in sufficiently high concentration to permit convenient use and yet meet the required criteria in terms of bioavailability, e.g.
enabling effective resorption from the stomach or gut lumen and achievement of
consistent and appropriate high blood/blood-serum levels.
1 The bioavailability varied in different patients upon equal and simultaneous
administration of the medicine (interpatient variation) and the bioavailability varied in one and the same patient upon equal administration with regular intervals (intrapatient
4.13. The object of the invention according to the patent is to provide a
pharmaceutical composition which exhibits a high bioavailability of cyclosporin (p. 2, ll. 21-22). The description mentions:
It has been found that the above-mentioned object is achieved with a
pharmaceutical composition as described in the preamble, characterised in that the surfactant comprises a reaction product of natural or hydrogenated
vegetable oils and ethylene glycol, and that the composition is an oil-in-
water microemulsion pre-concentrate which, upon contact with water, is capable of spontaneously or virtually spontaneously forming a
microemulsion with a particle size of less than 2,000 Å.
4.14. The solution to the above-described problems given in the patent is the use
of a preconcentrate which, upon administration and concomitant contact with water and the (aqueous) gastric fluids, forms a microemulsion.
4.15. In an emulsion, one of the components or 'phases' is present as the so-called
continuous phase. The other 'phase' is present in the form of discrete particles ('drops') and is called the dispersed phase. An emulsion in which water is the continuous phase is called an oil-in-water emulsion. An example is milk, in which milk fat is divided in the form of small droplets. The 'drops' of the dispersed phase of an emulsion normally have dimensions in the order of magnitude of micrometers. Emulsions are thermodynamically unstable, which will result in a gradual separation of the original components. To prevent phase separation, stabilizing surfactants are used. A surfactant is a molecule with a hydrophilic side (the 'head') and a lipophilic side (the 'tail'). The tail attracts the oil phase (likewise lipophilic) while the head attracts the aqueous phase (likewise hydrophilic), with the result that the two phases are kept together and separation is prevented.
4.16. Just like emulsions, microemulsions are intimate mixtures of two phases
which are not miscible with each other, often water and oil. An important difference with emulsions consists in the drop size of the dispersed phase. While the drop size in emulsions is in the order of magnitude of micrometers, the drop size in microemulsions is in the order of magnitude of nanometers, typically 0.2 μm (200 nm) or less. As a result of the small drop size, there is little interference with visible light and due to this a (pure) microemulsion is transparent or opalescent. In contrast to emulsions, microemulsions form (virtually) spontaneously, that is, without supply of a considerable amount of energy.
4.17. The term 'microemulsion preconcentrate' in the patent relates to a
formulation which upon inclusion in or dilution with water or an aqueous liquid such as gastrointestinal fluids, spontaneously forms a microemulsion which consists of an oil phase divided in the aqueous medium. To this end, the preconcentrate should contain an oil phase component in which the active ingredient is dissolved, one or more surfactants as well as a hydrophilic component which supports the formation of the microemulsion upon mixing with water or an aqueous liquid. The stability of the particles to be formed is an important aspect and hence also the choice of the surfactant is important. In the patent, in contrast to the prior art where a
lipophilic (and hence hydrophobic) agent was used, a (relatively) hydrophilic surfactant of the Cremophor type has been chosen.
4.18. By the use of a microemulsion, a great improvement of the bioavailability of
cyclosporin has been achieved.
The average skilled person
4.19. Both Actavis Group and Novartis have extensively devoted attention to
the qualities of the relevant skilled person at the earliest priority date, being September 16, 1988.
4.20. The court will start from the following qualities. The average skilled person
is a formulation expert with a firm pharmaceutical background and knowledge of synthesis of microemulsions, possible working as a team with doctors who are familiar with transplant rejection mechanisms.
Nullity grounds
a. lack of novelty (Article 75 paragraph 1 (a) Dutch Patents Act 1995)
4.21. In substantiation of the nullity of NL 781, Actavis Group has contended
that the invention is not novel because all features are already disclosed in Swiss patent application CH 013, not taken into account by the Patent Office.
4.22. In the assessment, it is stated at the outset that a measure is not new if all
relevant features thereof are disclosed explicitly or implicitly in a direct and unambiguous manner to an average skilled person, making use of his general technical knowledge, in a single reference belonging to the prior art.
4.23. Applying that criterion, the court is of the opinion that CH 013 is not
prejudicial to the novelty of NL 781. CH 013 relates to compositions with an improved uptake of the antibiotic S7481/F-1,a substance that belongs to the group of cyclosporins. The compositions described in CH 013 can be prepared in different forms, viz. Trinklösungen [drink solutions],
Trinkemulsionen [drink emulsions] or Parenterale Injektionslösungen
[parenteral injection solutions] (p. 4, ll. 27-31). Eight examples are described. Novartis has rightly put forward that Actavis Group, to demonstrate the presence of the lipophilic phase, the hydrophilic phase and the surfactant, refer to the general 'multiple choice' concept in respect of
Trinklösungen. CH 013 reads, as far as relevant:
[translated from German]
The compositions according to the invention can be administered in the
following galenic forms:
A) drink solutions
2 For the sake of readability, Actavis Group, Actavis and Pharmachemie will be jointly
referred to as Actavis Group in the discussion of the nullity arguments. In the discussion of the infringement claims filed by Novartis, parties will then be designated separately
B) drink emulsions
C) parenteral injection solutions As drink solutions, preferably the following compositions are administered:
1) antibiotic S 74481/F-1 with benni oil, optionally together with the additions described in b)-d),
2) antibiotic S 74481/F-1 and ethyl oleate and a surfactant indicated in b). These drink solutions optionally contain ethanol in a proportion of 1%
4.24. It is stated at the outset that this disclosure must be regarded as a "generic
disclosure" in the sense that it does not disclose any specific examples of the general concept. While Actavis Group has contended that a "drink solution" of the cyclosporin-like substance with ethyl oleate as lipophilic phase and ethanol as hydrophilic phase is disclosed, that composition is only specifically described in Example 2, in which – contrary to what Actavis Group suggests – not the surfactant Cremophor claimed in NL 781 is mentioned. Cremophor is mentioned in CH 013 exclusively in Example 5, but that Example relates to a parenteral form of administration, i.e. an injection or infusion, where the object of NL 781, viz. increasing the bioavailability, does not play a role since the bioavailability in those forms of administration is already 100%. Thus, the requirement of a direct and unambiguous disclosure is not satisfied.
4.25. In addition, Novartis is also right in contending that CH 013 also lacks the
features C) and G) (see ground 2.5). Indeed, as Actavis Group has acknowledged (cf. paragraph 145 of its statement of defense in the main action, also counterclaim; paragraph 28 written pleading mr Killan),
CH 013 does not disclose the features that the composition is an oil-in-water microemulsion preconcentrate and that that preconcentrate upon
contact with water forms a microemulsion with a particle size of less than 2,000 Å. Actavis Group, however, contends, referring to the assessment of the Patent Office regarding US '307 (see ground 2.3), that it cannot be said of CH 013 that the invention described therein would not form a microemulsion. That line of argument is disregarded. In the first place, US '307 is a "continuation in part" of CH 013, which means that the first-mentioned document by definition contains added and omitted subject matter. US '307 described for instance a self-emulsifying system, something that is not disclosed in CH 013, while US '307 describes that in the use of self-emulsifying system, Cremophor 40 is not the surfactant of choice. Accordingly, the one-on-one application of the argument of the Patent Office does not hold. In the second place, the court is of the opinion, like Novartis, that the line of reasoning of Actavis Group is not compatible with the relevant TBA case law. As appears from T 943/93, a 'hypothetical
possibility of operating within the claimed region per se (…) legally not
sufficient to deprive this region of novelty, particularly if the skilled person
had no technical motive and thus no practical necessity to work within this
region'. As will appear hereinafter, those last-mentioned situations do not
occur here either.
4.26. CH 013 therefore does not anticipate the invention described in claim 1 of
b. lack of inventive step (Article 75, paragraph 1 (a) Dutch Patents Act 1995)
4.27. Actavis Group has taken the position that, as for as they are concerned,
there are two most promising springboards, viz. CH 013 and US '307.
CH013 is successively combined by Actavis Group with what it calls general technical knowledge, EP 0 211 258 (Abbott) and Ritschel. US '307 is combined by Actavis Group with general technical knowledge, CH 013 and EP 0 249 587 (Hässle), respectively.
CH 013 and general technical knowledge
4.28. Actavis Group has contended that the skilled person, starting from CH 013
as closest prior art and combined with his general technical knowledge, would come to the invention according to NL 781 without inventive activity. For such general technical knowledge, Actavis Group has referred inter alia
to publications of Kahan (Exhibit 24 Actavis Group), Bhargava (Exhibit 25 Actavis Group) and Tarr & Yalkowski (Exhibit 26 Actavis Group). The publication of Kahan was published in November 1988, that of Tarr & Yalkowski in January 1989. This means these two documents are not timely, now that NL 781 claims priority of September 16, 1988 based on GB 0008821754 (GB 754).
4.29. Actavis Group has argued, however, that NL 781 unjustly claims priority of
September 16, 1988. To that end, Actavis Group has submitted that in claim 1 of NL 781 a composition is claimed with a hydrophilic phase, whereas that hydrophilic phase is not mentioned anywhere in GB 754 as such, that is, in generic terms. While, so argues Actavis Group, GB 754 discloses in Example 3 the species Glycofurol 75 and this element anticipates the generically claimed element hydrophilic phase, this is not relevant because the specific element should be given a limited interpretation and may not be broadened to the generic class of hydrophilic phases. That argumentation is rejected.
4.30. For valid reliance on priority for 'the same invention' as referred to in
Article 87 EPC in conjunction with Article 9 Dutch Patents Act 1995, it is required that the subject matter of a claim can be derived directly and unambiguously from the disclosure of the invention in the priority document as a whole, also taking into account all features that are disclosed implicitly to the skilled person, using his general technical knowledge (G2/98, OJ 2001, 413; see also Guidelines for Examination in the European Patent Office, 2007, part C, chapter V, paragraph 2.2). Starting from this standard, the skilled person will understand from GB 754, in particular pages 9 and 10 and the Glycofurol mentioned in Example 3, that in addition to the active ingredient, a lipophilic phase and a surfactant, also a hydrophilic phase is needed to achieve the result contemplated with the invention, viz. a higher bioavailability of the active ingredient. This means that a valid reliance on priority of September 16, 1988 based on GB 754 accrues to claim 1 of NL 781, and, in the wake of claim 1, also claim 2 and, insofar as that claim refers back to claim 1, also claim 5, so that the non-timely publications of Kahan and Tarr & Yalkowski may not be regarded as part of the general technical knowledge of the average skilled person,
leaving aside, for that matter, whether these publications can actually qualify as indications of general technical knowledge in the first place, having regard to the requirements to be imposed on them according to established case law.
4.31. What is described in the Bhargava publication, also mentioned by Actavis
Group, is, starting from CH 013, insufficient to urge the skilled person to the use of a microemulsion, let alone a microemulsion preconcentrate. The problem solved by NL 781, viz. providing a pharmaceutical composition for oral administration that exhibits a high bioavailability of cyclosporin, is not mentioned in CH 013. It does not disclose any microemulsion preconcentrate nor any self-emulsifying system. Novartis rightly points out in this connection that reading the problem solved by NL 781 into CH 013 whereas that problem is neither mentioned nor suggested in CH 013 boils down to a forbidden ex post facto analysis. Here, it is furthermore of relevance that Bhargava, not relating to cyclosporin nor disclosing the specific surfactant Cremophor, speaks only in general terms about the use of microemulsions for medicine delivery. Accordingly, CH 013 combined with Bhargava would not have led the skilled person to the invention.
4.32. As for the other publications mentioned by Actavis Group (Exhibits 18-20
Actavis Group), what holds is that Novartis has submitted, unchallenged, that they say hardly anything about microemulsions, much less do they disclose the advantages that can be obtained with microemulsions.
CH 013 and EP 258 (Abbott)
4.33. Nor does the combination of CH 013 and Abbott bring the skilled person to
the invention according to the patent. Abbott relates to a parenteral administration, that is, intravenously (through an injection or infusion), of especially food, and hence not – as the patent discloses – a (primary) pharmaceutical composition suitable for oral administration. A bioavailability problem such as it manifests itself in oral forms of administration does not present itself in the case of such compositions, since the active ingredient then isn't assimilated in the blood via the gastrointestinal tract but enters the bloodstream directly. The reference to the passage on page 4, lines 1-4, as Novartis has rightly noted, must be considered within the wider context of the problem that is solved by Abbott, viz. obtaining a sterile parenteral solution, and hence relates to a different problem than the problem for which NL 781 offers a solution. Also, obtaining the Abbott solution requires addition of considerable energy, for instance homogenization, which is precisely something that is not required for obtaining a microemulsion according to NL 781 since that is formed (virtually) spontaneously.
CH 013 and Ritschel
4.34. Ritschel was published, as Actavis Group has stated, in January 1989, so
that it is not part of the prior art at the first priority date of NL 781, so that this document is disregarded.
US 307 and general technical knowledge
4.35. US 307 relates to galenic compositions, in particular several formulations
which contain pharmacologically active monocyclic peptides. US 307 discloses many kinds of preparations, drink solutions, drink emulsions, injection solutions, troches, etc. One of these preparations can be a self-emulsifying system for oral administration. NL 781 is delimited from US 307 and has been judged to be new and inventive over it by the Patent Office and the Appeal Department. NL 781 is distinguished by the following features:
- US 307 concerns a (macro)emulsion and does not disclose a
microemulsion, as NL 781 does;
- US 307 does not contain any reference to particle size, whereas the
claims of NL 781 claim that the particle size in the microemulsion formed should be less than 200 nm;
- US 307 does not disclose the specifically claimed surfactant of NL 781
4.36. The other features mentioned in the patent, viz. cyclosporin as active
ingredient of the pharmaceutical composition, a hydrophilic ingredient and a lipophilic ingredient are disclosed in US 307. As regards the
bioavailability problem, it is said that this is solved by the preparations of US 307. The description of US 307 reads, as far as relevant:
4.37. Accordingly, it may be conceded to Novartis that for the skilled person,
starting from US 307, there will be no incentive to consider other
improvements, for instance the use of a microemulsion and the use of a specific hydrophilic surfactant as in NL 781.
4.38. The Natterman publication (EP 0 100 448) cited by Actavis Group in this
connection does not contribute to this. Natterman does not relate to cyclosporin and does not relate to pharmaceutical compositions for oral administration, but relates to compositions for injectable application. Natterman does not mention the specific surfactant of the Cremophor-type. The disclosed polyethoxylated caprylic acid/capric acid glyceride is at best one of the possible and optional co-surfactants as enumerated in 3.2.2. of the patent. If there were any reason at all for the skilled person to improve the composition of US 307, Natterman would not lead the skilled person to the invention according to NL 781.
4.39. The Denis article, which Actavis Group also lists under the heading of
general technical knowledge, was not published timely, so that it is disregarded.
US 307 and CH 103
4.40. In US 307, let it be repeated, it is stated that the invention described
therein solves the bioavailability problem. Having regard to the fact that CH 103 is completely silent on the bioavailability problem, a skilled person would not have any reason to combine the two documents with each other. If he were do so at all, what holds is that CH 013, unlike US 307 (cf. column 6, ll. 13-16), does not disclose any self-emulsifying properties and mentions Cremophor merely as one of the many possible surfactants. When the US 307 systems that are self-emulsifying are used, the skilled person is
taught to use a lipophilic surfactant of the Labrafil type, which, accordingly, teaches the skilled person away from the combination of a self-emulsifying system and a hydrophilic surfactant of the Cremophor type.
US 307 and EP 587
4.41. US 307 with Hässle will lead the skilled person still further away from the
use of microemulsions, since the latter document teaches the skilled person to make a solid pharmaceutical composition with slowed-release dosaging.
Conclusion inventive step
4.42. On the ground of the foregoing, the assessment is that claim 1 of NL 781
must be deemed to be inventive over the prior art.
4.43. As regards claim 2, what holds is that it is dependent on the new and
inventive claim 1, so that the novelty and inventive step of claim 2 is given. The same applies to the inventive step of claims 3, 4 and 5 depending from claim 1. As regards claim 6, finally, the following holds. This claim refers to each of the pharmaceutical compositions according to claims 1-5, with the proviso that the preconcentrate of each of the preceding claims has already been brought into contact with water. Actavis Group has challenged the
inventive step, referring to CH 013. That challenge is disregarded, now that it has been established hereinabove that CH 013 does not disclose all features of claim 1 or any one of the subclaims, while this publication moreover does not contain any indication that would lead the skilled person to the invention according to NL 781.
c. insufficient disclosure (Article 75 paragraph 1 (b) Dutch Patents Act 1995)
4.44. Actavis Group has also relied on the contention that the patent is not
enabling for the skilled person.
4.45. Actavis Group has submitted in the first place that the description on the
aspect of the microemulsion is so vague that it is not clear to the skilled person what exactly is being disclosed. In particular, Actavis Group argues that the definition of a microemulsion given by the patent, viz. 'one or more
of the following characteristics', is not correct so that the skilled person is
set on the wrong track and will not be straightforwardly able to establish what exactly is meant in the description. That contention is rejected. Although, as will also be discussed hereinafter, a (pure) microemulsion should in principle possess all characteristics mentioned in the description, the skilled person reading the claims would understand in the light of the description what is meant by microemulsion, in particular having regard to the passage indicating that the microemulsion is meant in its
'conventionally accepted sense' and to the literature reference to Müller
(see ground 4.67 below). That the definition given in the description speaks of 'one or more of the following characteristics' does not alter this, now that
he will see that at least the features of spontaneous formation,
thermodynamic stability and particle size of less than 200 nm must be met.
No elaborated examples
4.46. Actavis Group has further argued – briefly summarized – that the skilled
person on the basis of the data described in the patent specification is not able to make a preconcentrate falling within the patent, at least not in all cases. To that end, Actavis Group has contended inter alia that the relative
amounts of the various components in the composition are of relevance. While, so argues Actavis Group, these amounts are shown in Figs. I and II of the patent (see ground 2.7), where lines a and b indicate the areas of the relative amounts where microemulsions are formed, these areas depend on the properties of the various components and their interaction, which means that the areas can change considerably if other components are used. In those cases, it is necessary for the skilled person to do extensive experimentation. On this point, the court considers as follows.
4.47. Actavis Group rightly contends that in the formation of a microemulsion
the relative amounts of the various ingredients are of relevance. As has also been acknowledged by Actavis Group, this belongs to the general technical knowledge of the average skilled person. Therefore the skilled person will be well able to adapt these amounts according to need. The description in this regard contains sufficient guidance on how to vary the
various ingredients with cyclosporin (p. 10, ll. 15-20), the lipophilic phase (p.10, ll.33-40), the hydrophilic phase (p.10, ll. 21-32) and the surfactant (p.10,ll.41-53), while also the plots of Figs. I and II are explained (p.10, l.54-p.11,l.30). That the skilled person in some cases is supposed to experiment does not lead straightforwardly to non-enablement. A fair amount of trial and error may then be expected from one who carries out the patent (cf. T 226/85, OJ 1988, 336), as long as there is no undue burden involved.
That this is supposed to be involved in the present case has been alleged in an insufficiently reasoned manner.
4.48. Referring to the experiments it has performed ('droplet size measurements'-
Exhibit 32 Actavis Group), Actavis Group has, in the wake of the foregoing, further contended that upon repeat of the Examples of the patent not all dilutions fall within the range of the particle size according to the claim, so that no microemulsions are formed. The results submitted by Actavis Group in this connection are not in agreement with the experiments performed by the expert of Novartis, Prof. Fahr. The results of the repeats by Prof. Fahr of the Examples mentioned in the patent are summarized as follows:
This shows that the object of the invention is achieved, i.e. a microemulsion is formed with a higher bioavailability, with particle sizes well within the claims. These results have not been challenged by Actavis Group at the oral pleading. Nor has Actavis Group addressed Novartis' criticism of the experiment performed by Actavis Group, viz. that that experiment does not contain any factual description of the tests performed. Given that state of affairs, the contention of Actavis Group that the Examples of the patent are not (all) enabling, will be dismissed by the court as having been contested with reasons and thereupon not having been substantiated further. It would have been up to Actavis Group to allege serious doubts in that regard, substantiated by verifiable facts (cf. TBA October 3, 1990, T 19/90, OJ 1990, 476).
4.49. Actavis Group has alleged that the patent is also not enabling because it
does not meet the requirement of clarity and completeness in respect of the feature that the microemulsion has a particle size that is less than 2,000 Å. That contention is dismissed as being unbased now that the claim is clear
on this point. Apparently, by this argument, Actavis Group seeks to allege that a product of which the particle size is not completely below the limit of 2,000 Å cannot be regarded as a microemulsion in the sense of NL 781 That argument does not relate to an enablement (sufficiency) problem but qualifies as a non-infringement defense , which will be dealt with hereinafter.
4.50. Actavis Group has furthermore taken the position, with reliance on the
priority document GB 8902900, in particular the table on page 23 thereof, that the patent is not enabling because the particle size depends on the dilution that is used. It is stated at the outset here that, as Novartis has rightly argued, the priority document in question is, strictly speaking, not relevant to the enablement of NL 781 because the patent itself must be enabling. Leaving this aside, what holds is that the particle size, as Actavis Group has argued, indeed depends on the chosen dilution. For that reason, the description teaches (p. 5, ll. 19-20):
It will of course be understood that, to obtain a microemulsion, adequate water will be required. While the upper limit of dilution is not critical, a
dilution of 1:1 or more, e.g. 1:5 wt. parts ("microemulsion pre-concentrate": H20) will generally be appropriate.
From this, the skilled person will understand that the object of the invention can be achieved starting from 1:1 dilutions as a lower limit to an upper limit that is not critical, for instance a normal amount of aqueous solution that is necessary to be able to swallow a capsule. The skilled person will then realize, prompted by the above passage where the example of 1:5 wt. parts is mentioned, that the results in the middle range will be better than at the extremes thereof. An indication of a suitable dilution is further to be found by the skilled person in the description (p.15, ll.15-18). Regarding the experiment concerning the bioavailability of the compositions according to the patent in dogs, it is mentioned there that they were administered to the animals with 20 ml 0.9% NaCl aqueous solution, being a ratio of 1:40.
Measuring method
4.51. That the patent does not give any method for determining the particle size
has as a consequence, in the view of Actavis Group, that the patent is not enabling for the skilled person for lack of clarity. This argument is disregarded, if only because the skilled person was capable at the priority date of performing such a measurement. This appears for instance from Bhargava, which publication mentions for instance light-scattering as a suitable measuring method (p.50, Table III). That is the method that was also used by both Dr. Müllertz and Prof. Fahr and in that context is designated as the Zetasizer method.
Choice for hydrophilic or lipophilic phase too broad
4.52. In the context of its non-enablement argumentation, Actavis Group has
further alleged that the patent claims too broadly as far as the choice of the
hydrophilic or lipophilic phase is concerned. Any composition with a hydrophilic or lipophilic phase is protected, whereas, so argues Actavis Group, it is unlikely that for every hydrophilic and lipophilic phase a microemulsion can be obtained.
4.53. In this connection, too, Actavis Group has relied on the report already
mentioned in ground 4.48. Leaving aside Novartis' criticism thereof, already mentioned, and not contradicted by Actavis Group, what holds is that Novartis, in respect of variation with regard to the hydrophilic and lipophilic phase to be used, has further put forward in supplementation that the experiment performed wrongly fails to take the relative amount of the selected phases into account. Here, Novartis has referred to the phase diagram of Figs. I and II (see ground 2.7) and submitted that replacing one component, for instance Glycofurol by Ethyl Lactate, without taking account of the properties of the component in question, almost logically does not straightforwardly yield the desired result. That criticism, which appears plausible to the court, has not been contradicted by Actavis Group at the oral pleadings, so that the criticism is held to be valid. For that reason, the test will be left out of consideration in this regard too and the argument of Actavis Group derived therefrom is rejected.
4.54. Finally, Actavis Group submits that the patent is non-enabling because it
is supposed to be unclear what is to be understood by a hydrophilic and lipophilic phase. This same submission was also used by Actavis Group in contesting the infringement alleged by Novartis. The court dismisses the submission of Actavis Group with reference to what will be considered about it hereinafter, in nos. 4.70-4.75.
4.55. Actavis Group has not separately elucidated its non-enablement arguments
in respect of claim 2 to 6, so that in respect of those claims too, what holds is that non-enablement has not been established.
4.56. In the context of these proceedings, it is to be assumed that NL 871 is valid,
so that the claimed nullification of the patent will be denied.
in the main action 4.57. This leads us to the assessment of the claims of Novartis in the main action. Actavis
4.58. The claims against Actavis are to be dismissed, already because Actavis is
not holder of the market authorization and any involvement of this company in the alleged infringement by Actavis Group has not been established. This is not altered by the fact that Novartis, as it has argued at the oral pleading, in reply to the reaction of Actavis Group further to Novartis' demand of June 1, 2007, has communicated that it assumed that Actavis could be regarded as a co-defendant, which assumption, according
to Novartis, was not subsequently refuted by Actavis. Being the party awarded against, Novartis will be ordered to pay reasonable and proportional costs of the proceedings incurred on the part of Actavis, under Article 1019h Code of Civil Procedure. Novartis' argument at the oral pleading that an order to pay costs can be withheld since Actavis cannot be deemed to have incurred any costs of its own in the defense, is not shared by the court. By email of February 28, 2008, mr Van Velsen informed the
court, also on behalf of mr Killan and mr Van Wijngaarden, that they had
reached an agreement in respect of the reasonable and proportional costs under Article 1019h Code of Civil Procedure. Since the estimate on the part of Actavis Group as given therein makes no distinction between costs of Actavis Group and Actavis, the court asked Actavis Group and Actavis for that by email of March 20, 2008, whereupon mr Killan indicated that the
costs have been incurred equally by Actavis Group and Actavis because they have both put up a defense with non-infringement argumentation and with a counterclaim for nullification, and he proposed a 50%-50% distribution code. On the part of Novartis, there was no reaction to that email, so that the court holds that said defense was no longer maintained. Having regard to the above, the court will order Novartis to pay Actavis the costs it has incurred in the main action, being an amount of (50% x
90,000- =) 45,000.-. Insofar as Actavis has also claimed extrajudicial
costs, these are denied since they have been contested by Novartis and have not subsequently been substantiated further by Actavis. The claimed statutory interest on the costs is allowable with the proviso that it will not be due until Novartis is in default of payment. The claimed declaration of the order being provisionally enforceable will also be awarded, albeit not at any time before execution has issued, now that on the one hand the necessity of enforcing the judgment also during evening hours, weekends and holidays is not seen and on the other hand Actavis has no interest in the order being declared provisionally enforceable at any time, since Actavis will have an enforceable executory copy at its disposal.
4.59. After withdrawal at the hearing of its primary claim, Novartis presently
claims only a declaratory judgment that the product Ciclosporin PCH falls within the scope of protection of NL 781. That claim is dismissed. Novartis has only alleged that it has an interest in it because, if it were not to dispose of it, it will suffer irreparable damage since it has no instruments available to be able to act adequately if Pharmachemie were to launch its product early, i.e. before the expiration. With the declaratory judgment, thus Novartis has argued, it has all means at hand to prevent this in (ex parte) summary proceedings. Pharmachemie, however, has expressly promised "that it will not commence any marketing sale and distribution in
the Netherlands of 'Deximmune' or any product identical thereto" before
the expiration date of the patent barring the circumstances mentioned in ground 2.14, which, however, do not as yet occur. Now that Pharmachemie at the oral pleading moreover acknowledged that the product Ciclosporin PCH is identical to Deximmune and no evidence has appeared of facts and/or circumstances to the effect that the promise has been or will be violated, Novartis has no interest in its alternative claim.
4.60. Being the party awarded against, Novartis will be ordered to pay the costs
incurred on the part of Pharmachemie under Article 1019h Code of Civil Procedure, assessed by parties in mutual consultation to be 100,000.00. Insofar as Pharmachemie has also claimed extrajudicial costs, these are denied since they have been contested by Novartis and subsequently have not been substantiated further by Pharmachemie. The claimed statutory interest on the costs is allowable with the proviso that it will not be due until Novartis is in default of payment. The claimed declaration of the order being provisionally enforceable will also be awarded, albeit not at any time before execution has issued, for the same reason as considered in ground 4.58.
4.61. In assessing the question whether Ciclosporin Actavis infringes NL 781, it
is stated at the outset that the scope of protection of a patent valid in the Netherlands, in accordance with Article 69 of the European Patent Convention and the corresponding Article 53, paragraph 2, Dutch Patents Act 1995, is determined by the content of the claims, with the description and the drawings serving to interpret the claims. In applying this criterion, the Interpretation Protocol to Art. 69 is to be taken into account. According to the protocol, a position is to be taken between a literal, non context-bound interpretation of the claims and an interpretation where the claims serve only as a guideline for the determination of the scope of protection and it is considered what the inventor in the eyes of the average skilled person has sought to protect. With such an interpretation, according to HR January 13, 1995, LJN ZC 1609, Ciba Geigy/Oté Optics as interpreted in HR September 7, 2007, LJN BA3522, Lely/Delaval, the viewpoint (and no longer: the starting point) is what is essential to the invention whose protection is claimed – stated differently: what is the inventive idea behind the words of the claims – as opposed to the literal text of the claims. In doing so, the judge will also have to assess whether the result of his examination does sufficient justice to the legal certainty for third parties - with a lack of clarity for the average skilled person wishing to determine the boundaries of the protection conferred by the patent in principle working to the disadvantage of the patentee, while the judge should equally look out for a reasonable protection of the patentee. In such consideration, according to the protocol, also equivalents are to be involved.
4.62. The invention as laid down in the patent – briefly stated – relates to a
pharmaceutical composition for oral administration comprising cyclosporin as an active ingredient, which composition has the pharmaceutical shape of an oil-in-water microemulsion preconcentrate, which on contact with water forms a microemulsion. The composition according to the invention has as an object to provide a high bioavailability of cyclosporin. That object is achieved with a composition which comprises 1) a hydrophilic phase, 2) a lipophilic phase and 3) a surfactant, wherein the surfactant is hydrophilic, and the composition as mentioned is an oil-in-water microemulsion preconcentrate which on contact with water spontaneously or substantially spontaneously form a microemulsion having a particle size of less than 2,000 Angstrom.
4.63. Between parties it is not at issue that the product of Actavis Group,
Ciclosporin Actavis, meets the features A), B) and F) of NL 781 (see ground 2.5). Actavis Group has argued, however, that its product does not infringe because it does not meet the features D) and E) of the patent, viz. that the composition comprises a D) hydrophilic phase and E) lipophilic phase. Further, its product, thus Actavis Group, does not meet the feature C) and – in the wake thereof G) – since it does not give a microemulsion, at least not a microemulsion preconcentrate that meets all "features" of the definition thereof, which according to Actavis Group is necessary to be able to assume infringement. In this regard, the court considers as follows.
Hydrophilic phase and lipophilic phase
4.64. Actavis Group has adduced that claim 1 of NL 781 requires that the
preconcentrate comprises two phases: a hydrophilic phase and a lipophilic phase. In this connection, it referred to page 6, lines 33 ff of the description,
where it is mentioned:
The pharmaceutical composition for oral administration according to the
invention comprises not only a hydrophilic phase (1) but also a lipophilic phase (2).
Suitable components for use as lipophilic phase include any pharmaceutically acceptable solvent which is non-miscible with the
selected hydrophilic phase (…)
According to Actavis Group, the average skilled person will read the
non-miscibility as an essential feature of the hydrophilic and lipophilic
phase. In that connection, Actavis Group has had a number of experiments performed, by which it tries to demonstrate that the ingredients chosen in Ciclosporin Actavis, i.e. ethyl lactate and Tricaprin, by contrast, mix completely with each other and that the preconcentrate hence involves a single phase. Now that both the claim and the description of NL 781 make clear that the preconcentrate according to NL 78 needs to involve two phases not miscible with each other, Ciclosporin Actavis does not infringe, so argues Actavis Group.
4.65. It may be conceded to Actavis Group that claim 1 of NL 781 does not make
it immediately clear what is meant by the requirement that the composition comprises a hydrophilic and a lipophilic phase. The literal text of the claim seems to say that the preconcentrate should comprise the phases mentioned. That text, however, with the standard mentioned in ground 4.61 in mind, should be interpreted contextually, in the light of the description and the drawings. It is true that, as Actavis Group has put forward as a further argument, the description on page 6, lines 33 ff
discloses that the hydrophilic and lipophilic phases may not be miscible. Novartis has adduced, however, that the average skilled person will not read the claim in that way, but will understand that the term 'phase' in the claim must be understood thus that the composition, more precisely the microemulsion preconcentrate, must contain ingredients or components intended to form the different phases in the microemulsion stage, viz. the dispersed, lipophilic phase and the continuous, hydrophilic phase. For this, Novartis has referred to a number of passages in the description, for instance to the passage where it is described that the composition can be
prepared in the form of a microemulsion preconcentrate 'by intimately mixing the individual components thereof (p.9, ll. 32-40) and to the passage
where it is described that it is the microemulsion that contains a dispersed or particulate (drop) phase (p.3,ll. 46-47) and hence not, so argues Novartis, the microemulsion preconcentrate. The condition that is set, thus Novartis, is that the preconcentrate upon being contacted with water, which according to Novartis also means upon coming into contact with the juices of a patient's gastrointestinal tract, forms a microemulsion. In that connection, Novartis points to page 5 of the description where in line 19 it is described that "it will of course be understood that, to obtain a
microemulsion, adequate water will be required".
4.66. Further, Novartis has adduced that the average skilled person will
understand also from the examples mentioned in the description that the stated requirement of non-miscibility of the lipophilic and hydrophilic phase plays a role exclusively in the phase where a microemulsion is formed. In Examples 1a, 1b and 1c, the lipophilic phase designated by code number 2, viz. Miglycol, is a suitable solvent for the hydrophilic phase designated by code number 1.1., viz. Glycofurol. Moreover, in Example 1c ethanol is added as co-solvent for the hydrophilic phase, while ethanol, as the skilled person knows from Unites States Patent US 388,307, acknowledged in the description as the closes prior art, is also a suitable solvent for the lipophilic phase designated by code number 2, viz. Miglycol. Stated differently, the hydrophilic and lipophilic ingredients according to these Examples are miscible.
4.67. The court considers as follows. Faced with the apparent contradiction
between the literal reading of the claim (where the term 'phase' is given the meaning of non-miscible component) on the one hand and the passages in the description (where the terms 'phase' and 'ingredient' are used as synonyms) and the Examples (where the different ingredients in the preconcentrate are miscible) on the other, the skilled person will ask himself which interpretation seems to make most sense. In the literature, the skilled person only finds indications that the requirement of being non-miscible applies to the stage where a microemulsion is formed. Müller (annex to Exhibit 4 Novartis) defines a microemulsion as follows:
A microemulsion contains at least one surfactant or surfactant mixture and
two liquids miscible with each other only to a limited extent, in a ratio such
that without the surfactant addition at the temperature considered, at least two phases would form
From this, the skilled person will understand that the prescribed non-miscibility of the ingredients that are used as lipophilic phase with the chosen hydrophilic phase must be understood thus that the hydrophilic and lipophilic ingredients upon contact with suitable water, without the presence of a surfactant, would form two phases. Nor has the patent attorney of Actavis Group, on being asked, been able to explain why, as Actavis Group contends, it would be self-evident for the skilled person that the lipophilic phase in the preconcentrate is immiscible with the
hydrophilic phase. In particular, it has been neglected to indicate what the technically meaningful interpretation or the technical advantage of such a requirement would be.
4.68. In addition, there are also secondary indicia that lead to the conclusion that
the average skilled person will read the claim of the patent thus that the preconcentrate does not involve phases in the strict sense, but involves ingredients that form non-miscible phases only in the microemulsion stage. Actavis Group has submitted a statement of its expert Dr. Müllertz dated February 28, 2008 (Exhibit 35 Actavis Group). In that statement, Dr. Müllertz gives a further explanation of the passage included in her report (Exhibit 11 Actavis Group) 'Ciclosporin Actavis contains tricaprin as
the lipophilic phase and ethyl lactate as the hydrophilic phase'. She
believes that this passage has been taken out of context, whereas Novartis contends that this shows that there are two phases also in the Ciclosporin Actavis product, as in NL 781. The further explanation of Dr. Müllertz reads as follows:
It is clear to any skilled person reading my report that the term 'phase' in
this sentence has the meaning 'component'.
This shows that the expert of Actavis Group considers the term 'phase' to be interchangeable with 'component' or 'ingredient'. In this, the court finds confirmation that the average skilled person will attach more value to a meaningful interpretation of the claim, in the light of the description, than to the strict literal meaning of the term 'phase'.
4.69. Under these circumstances, in the opinion of the court, what is involved is
not such a lack of clarity for the average skilled person wishing to determine the boundaries of the protection conferred by the patent, that the certainty of third parties would justify a restrictive interpretation more in line with the wording of the claims. Indeed, the literal interpretation of the claims as advocated by Actavis Group would be in conflict with Article 69 EPC. In such a case, there is no justification for an interpretation in line with the literal wording of the claims, precisely because the average skilled person, as explained hereinabove, will not start out from that interpretation and so the legal certainty is not at stake. In addition, what is also to be taken into consideration is the extent to which the patented invention has been innovative. It is undisputed that the invention has brought with it an important improvement over the prior art, viz. forming a microemulsion which especially in the inter- and intrapatient relations has yielded a substantial improvement of the bioavailability of the active ingredient.
4.70. On the ground of the above, it is therefore held that the requirement of a
separate hydrophilic and lipophilic phase has any meaning only in the microemulsion stage when it has come into contact with water.
4.71. In this connection Novartis has performed tests twice with the Tricaprin
chosen as lipophilic phase in Ciclosporin Actavis and the ethyl lactate chosen as hydrophilic phase. The last tests were performed with the ratio
3 The court has noticed, for that matter, that the application as laid-open to public
inspection (Exhibit 36 Actavis Group) refers to an ingredient and then without apparent
discussion switched to the terminology phase, without this having had any meaning in
occurring in the product of Actavis Group of 2:1 with water in the ratio of 2:1:5 and 2:1:50, prepared at 25 ºC and 37 ºC (Exhibits 4 and 16 Novartis). These tests show that when the surfactant is left out in the microemulsion stage, the Tricaprin and the ethyl lactate form two phases, in agreement with the definition of Müller. Actavis Group has not contested the result of these tests. The tests performed by Actavis Group showing that Tricaprin and ethyl lactate mix in the preconcentrate, do not alter this and, having regard to the fact that the non-miscibility requirement has any meaning only in the microemulsion stage, are not conclusive, for that matter. The contention of Actavis Group, finally, that ethyl lactate is not a hydrophilic phase, is rejected now that this is factually incorrect. In that connection, Novartis has rightly pointed to WO 219 where on page 9 ethyl lactate is mentioned as a 'hydrophilic solvent'.
4.72. All this leads to the Actavis Group product meeting the subfeatures D) and
4.73. Actavis Group has furthermore argued that its product does not involve a
microemulsion preconcentrate and that its product does not give a microemulsion either, so that the subfeatures C) and G) are not met.
4.74. In answering the question whether the Actavis Group product satisfies the
subfeature that a microemulsion preconcentrate is involved which, on contact with water, is capable of spontaneously or virtually spontaneously forming a microemulsion with a particle size of less than 2,000 Å, it should first be determined what properties are characteristic of a microemulsion.
4.75. The relevant passage in the description (p.3, ll.31-47) says the following
The pharmaceutical composition for oral administration according to the
invention is an oil-in-water microemulsion pre-concentrate which, upon
contact with water, is capable of spontaneously or virtually spontaneously forming a microemulsion with a particle size of less than 2,000 Å.
By the term "microemulsion pre-concentrate" as used herein is meant a
system which on contact with, e.g. addition to, water, is capable of providing a microemulsion. The term "microemulsion" as used herein is
used in its conventionally accepted sense as a non-opaque or substantially
non-opaque colloidal dispersion comprising water and organic components, including hydrophobic (lipophilic) organic components. Microemulsions are
identifiable because they have one or more of the following characteristics. They are formed spontaneously or substantially spontaneously when their
components are brought into mutual contact, that is without any
substantial energy supply, e.g. without heating or the use of high shear equipment or other substantial agitation. They exhibit thermodynamic
stability. Further, they are monophasic. They are substantially non-
opaque, i.e. are transparent or opalescent when viewed by optical microscopic means. In their undisturbed state they are optically isotropic,
though an anisotropic structure, for instance when using x-ray technique,
may be observed.
Microemulsions comprise a dispersed or particulate (droplet) phase, the
particles of which are of a size less than 2,000 Å, hence their optical transparency (…)
4.76. So, starting from the description, the following characteristics of a
microemulsion are mentioned:
a) they are formed spontaneously or virtually spontaneously if
the ingredients are contacted with each other,
b) they exhibit a thermodynamic stability c) they form one phase d) they are substantially non-opaque, that is, transparent or
e) they are optically isotropic f)
they have a particle size of less than 2,000 Å.
4.77. Referring to the description, Novartis has submitted that microemulsions
can be identified because they possess one or more of the characteristics mentioned.
4.78. It may be conceded to Actavis, as such, that one may speak of a (pure)
microemulsion only if it possesses not one but all characteristics mentioned. Support for that view is to be found in the Müller reference (Exhibit 4 Novartis), mentioned in the patent, which defines a microemulsion as follows:
A microemulsion is a thermodynamically stable, monophasic, transparent or opalescent, fluid and in unsheared condition optically isotropic system.
The average skilled person will accordingly understand the (pure) microemulsion in its 'conventionally accepted sense' to be an emulsion in which all features a) through f) are united. This means that in respect of the alleged infringement of NL 781 Novartis should in principle demonstrate that Ciclosporin Actavis possesses all above-mentioned characteristics. However, this does not prejudice that, as Novartis has rightly submitted, the focus is on the subfeatures a) spontaneous formation, b) thermodynamic stability and f) particle size of less than 2,000 Å. Those are the primary characteristics. Like Novartis, the court is of the opinion that the other subfeatures mentioned in the description, in particular the subfeatures that the microemulsion is substantially non-opaque, that is, transparent or opalescent when viewed with an optical microscope, are to be regarded as secondary indicia, in the English proceedings designated as
'first rough and ready test' to establish whether a microemulsion is
involved. Indeed, if for instance the thickeners mentioned as optional in the patent specification are added to the microemulsion or the microemulsion otherwise contains other (often larger) particles, that will have an effect on the composition and hence possibly also on the translucency thereof. What
holds in any case is that the optical appearance of the microemulsion is of less relevance, in the sense that if a particular emulsion is clouded, that does not say anything definitive about the particle size occurring therein. In such a case, the 'first rough and ready test' is not helpful, so that the
skilled person would have to carry out an extensive analysis to determine the particle size. As far as necessary, this will be reverted to hereinafter.
4.79. Thus, it will first be considered if Ciclosporin Actavis possesses the primary
characteristics referred to above.
a) spontaneous formation
4.80. The Actavis Group product satisfies the subfeature that the microemulsion
is formed spontaneously or virtually spontaneously. Actavis Group has adduced that the requirement of spontaneous or virtually spontaneous formation precludes a situation such as that in the gastrointestinal tract, with slight agitation. That defense is rejected. Actavis Group has insufficiently contested Novartis' submission that the expert of Actavis Group, Dr. Müllertz, has acknowledged in the Danish proceedings that slight agitation from the gastrointestinal peristaltics fits within the definition of spontaneous or virtually spontaneous formation. At the hearing, on being asked, Dr. Müllertz did not in so many words acknowledge that she had made that pronouncement – she said that it is difficult to assess what happens to the Ciclosporin Actavis in situ - but she did not deny it either. What is more, the position of Actavis Group is not well in line with its own experiments – performed by Dr. Müllertz – where in the preparation of the dilutions of Neoral and Ciclosporin Actavis also a slight agitation (i.e. shaking) took place ('The mixtures were gently shaken
until they were homogeneous' - Exhibit 10 Actavis Group and 'The
mixtures were gently shaken manually' - Exhibit 12 Actavis Group).
b) thermodynamic stability
4.81. The patent teaches that the microemulsions obtained upon contact of the
microemulsion preconcentrates with water or any other aqueous medium, exhibit thermodynamic stability. The passage relevant to this point in the description of the patent reads as follows:
The microemulsions obtained on contacting the "microemulsion pre-
concentrate" compositions of the invention with water or other aqueous medium exhibit thermodynamic stability, that is they will remain stable
at ambient temperatures, e.g. without clouding or regular emulsion type
droplet formation or precipitation, over prolonged periods of time. (…) Preferably, on contacting with water, the "microemulsion pre-concentrate"
compositions of the invention are capable of providing microemu1sions
which remain stable at ambient temperatures, e.g. as evidenced by absence of any optically observable clouding or precipitation over periods
of at least 2 hours, in particular at least 12 to 24 hours.
4.82. Unlike in the Danish proceedings, Actavis Group has adduced in the
present proceedings that Ciclosporin Actavis is not thermodynamically stable. That defense is rejected. Dr. Müllertz, as appears from the witness
testimony in the Danish proceedings, submitted by Actavis Group (Exhibit 2 Actavis Group, p. 6), has stated:
4.83. This shows that a precipitation occurs only after 24 hours. That statement
is largely in agreement with the tests submitted in these proceedings by Actavis Group. While they show that in the Ciclosporin Actavis some precipitation occurs after 24 hours, this precipitation is limited – except for the 1:5 test of Dr. Müllertz, which, for lack of a correct mixing ratio (Müllertz gave it the interpretation of 1 volume of formulation and four volumes of water), will be disregarded – to at most 3.08% at the 1:20 ratio. Thus, the Actavis Group product accordingly satisfies the requirement set in the description, viz. that the microemulsion remains thermodynamically stable for at least 2 hours, in particular at least 12-24 hours. The interpretation given by Actavis Group to the term thermodynamic stability, viz. that a microemulsion should in theory be infinitely stable, is disregarded in view of the period of time mentioned in the patent specification. In addition, it is to be borne in mind that, as Novartis has rightly submitted, the Figs. III and IV of the patent show that in trials the peak amount of cyclosporin in the blood occurs 1-2 hours after ingestion, while after 6 hours the cyclosporin level in the blood has dropped to 1/10 of C-max, stated differently: if the product is to work effectively, it needs to be present as a microemulsion for at least 2 hours to allow assimilation of the active ingredient into the blood. This is amply satisfied in the case of Ciclosporin Actavis, given Dr. Müllertz's statement.
4.84. The outcome of the above is that thermodynamic stability of the product of
Actavis Group can be assumed.
f) particle size
4.85. Novartis and Actavis Group have both performed so-called Zetasizer tests
to determine the particle size of the cyclosporin in the Ciclosporin Actavis. Novartis has submitted that the reports of these tests, drawn up by Prof. Fahr, the expert of Novartis, and by Dr. Müllertz (Exhibit 7 Novartis and Exhibit 11 Actavis Group, respectively) show that the percentage having a particle size within the range according to the claim, i.e. of less than 200 nm, varies around 94.5-99% (Müllertz's results) and 97.1-98.9% (Fahr's results). Novartis thereby acknowledges that the product of Actavis Group does not completely satisfy the requirement of a particle size of less than 200 nm. This means that Actavis Group does not 'literally' infringe claim 1 of the patent.
The secondary indicia: features c, d and e
4.86. The above would also explain why, as was already established in ground
4.83, after 24 hours some precipitation occurs. However, the conclusion that Actavis Group draws from this, viz. that there is hence no single phase involved, that the product of Actavis Group is not transparent and is not isotropic, is unfounded. Ciclosporin Actavis is substantially
thermodynamically stable, as was already assessed. Contrary to what Actavis Group argues, that assessment implies ipso facto that the subfeatures of forming one phase and being isotropic are also substantially satisfied. The tests performed by Dr. Müllertz which allegedly demonstrate that the Actavis Group product is not transparent or opalescent, should be assessed in this same light. The patent specification moreover does not require a complete transparency, but speaks of substantially non-opaque, a term which, as Novartis has rightly observed, covers a wider range than transparent. Pumfrey J. in his judgment of October 16, 2006 spoke of
'transparent or slightly cloudy, rather than milky'. Looking at Dr. Müllertz'
report (Exhibit 14 Actavis Group) - again leaving the 1:5 ratio aside - it cannot be stated plainly that in respect of the 1:10 and 1:20 ratio, both as regards the situation immediately after mixing and that after 24 hours, that criterion has not been met. The photos in the report are of such a quality that it may very well be that these two ratios still satisfy the criterion of being substantially non-opaque. It is additionally observed here that the description of the patent on page 3 speaks of "substantially non-
opaque, that is (…) transparent or opalescent when viewed by optical
microscopic means [underlining added – court]. Inspection with the naked
eye, let alone inspection of small photographic images, does not seem to satisfy that. Even if the microemulsions obtained with the Actavis Group product were somewhat opalescent, this, let it be repeated, may be a consequence of not literally satisfying the requirement that the particles should be smaller than 200 nm. In the description, this link is also made quite clearly ("hence their optical transparency" – p.3,l.47).
Infringement in the range of equivalence
4.87. With due observance of the standard formulated in ground 4.61, there is, in
the opinion of the court, infringement in the range of equivalence, for which the following is considered.
4.88. The average skilled person who reads the claims of the patent, in
conjunction with the description and the drawings, will understand that the problem for which the patent presents a solution resides in the improvement of the bioavailability of the active ingredient cyclosporin. That improvement is achieved in that the cyclosporin is carried by small(er) particles. Again leaving the 1:5 test of Dr. Müllertz aside, the results mentioned in the reports drawn up by Prof. Fahr and Dr. Müllertz show that circa 94 to 99% of the particle size in Ciclosporin Actavis falls within the claimed range, in a peak of circa 20 to 22 nm. In the test under in situ conditions (1N HCl at 37ºC) as performed by Fahr, moreover, a result was achieved of 100% particles of less than 200 nm. The argumentation of Actavis Group that those test conditions are not correct because the patent speaks of contact with water, is rejected. The patent speaks of water or aqueous media. Having regard to the oral administration form of the composition described in the patent, it will be clear to the skilled person that the microemulsion is formed under in situ conditions. Thus, the dissolution of Ciclosporin Actavis in hydrochloric acid at body temperature cannot be qualified as an unsuitable method.
4.89. Actavis Group has further adduced that the measuring method used by
Fahr is less suitable for measuring larger particles. According to Actavis Group, laser diffraction is a better method for that purpose. That argument is surprising in the sense that it is hard to reconcile with the fact that the test of Dr. Müllertz too (Exhibit 11 Actavis Group) was carried out in the same way. However that may be, it makes no difference for the conclusion that the claimed range is substantially satisfied. The results obtained with the aid of laser diffraction are in agreement with those obtained upon the Zetasizer method. Actavis Group has argued that it follows from the test results (Exhibit 16 Actavis Group) that in a hundred-fold dilution more than 50% of the particles were larger than 1560 nm. That is remarkable because the results obtained by Dr. Müllertz with the aid of the Zetasizer method at the same dilution show a volume percentage of 99.5% with a peak of 22.2 nm. In addition, Novartis has put forward, without this being challenged, that the results in reality demonstrate that circa 99.5% of the particles have a dimension of less than 50 nm (cf. paragraph 6.37-6.42 statement of reply in the counterclaim). For that reason, the argument of Actavis Group is rejected.
4.90. Having regard to the slight percentage by volume of particles in Ciclosporin
Actavis that do not satisfy the range claimed in the claim, it is held that this product exhibits only insubstantial differences with the protected
composition according to the patent.
4.91. The contention of Actavis Group that Novartis, by including an upper limit
of 200 nm in the claim, has expressly waived compositions having a particle size of more than 200 nm, so that Novartis is not entitled to reliance on equivalence, is unfounded. In HR January 27, 1989, NJ 1989, 506, LJN AD0607, repeated in HR December 22, 2006, NJ, LJN AZ1081, the Supreme Court – briefly stated – has ruled that third parties may assume that the applicant of the patent, through the formulation used in the patent specification, has wished to waive a part of the protection which the patent confers, only if, having regard to the content of the patent specification in the light of any other known data, such as the data from the patent examination file that are also accessible to them, there are good grounds for this. The mere assertion of Actavis Group that in the claim an upper limit has been included, viz. 200 nm, which has been added to the original application only during the examination proceedings, is not sufficient for that. This is all the more cogent because the examination file does not show, either, that the upper limit has been included by Novartis to delimit its invention from prior art already known. Nor is the argument successful that in any case it is not clear to the skilled person how the 200 nm limit is to be understood, which lack of clarity, according to Actavis Group, should be for the risk of the patentee. The skilled person reading the claims in the light of the description and the drawings will see that the invention relates to a microemulsion. Thus considered, it will be clear to him that the particle size should be substantially below the upper limit of 200 nm included in the claim in order for the envisaged object to be achieved.
4.92. In addition to the actual test results, there is moreover corroborative
evidence of infringement in the form of WO 219 (see ground 2.16). Novartis has contended that Actavis Group has admitted in the Danish proceedings
that Example 10 of WO 219 discloses a composition which is identical to Ciclosporin Actavis. That contention has only been contested by Actavis Group at the hearing to the extent that it adduces that it has not acknowledged in the Danish proceedings that its product is identical to Example 10 in terms of ingredients, but that is insufficient in the light of the other circumstances. In the first place, Actavis Group has contended (see paragraph 7 statement of defense in the main action, also counterclaim) that its product is equivalent in bioavailability to Sandimmune Neoral of Novartis 'but has a unique formulation of its own, for which, incidentally,
its supplier Dexcel has filed a patent application'. In the second place,
Novartis has pointed to the report of Dr. Müllertz (Exhibit 11), the expert of Actavis Group. The relevant passage on page 3 reads as follows:
Further on in the report, Ciclosporin Actavis is designated by the code "Lot: 05A95/1", hence the lot number assigned to Deximmune. This is done for instance on page 6, stating:
This shows that Ciclosporin Actavis is identical to the product Deximune 50 mg. Now that it is not at issue between parties that Deximune is the product of Dexcel, being the supplier of Actavis Group, the court holds that Ciclosporin Actavis, also having regard to the product information as represented in the instructions insert, which corresponds to the ingredients mentioned in Example 10 of WO 219, is equal to the composition according to Example 10 of WO 219.
4.93. The composition of Example 10 of WO 219 contains
4 But also on pages 8 and 10.
4.94. The relevant passages of WO 219 read as follows:
This shows that the composition according to Example 10 of WO 219 upon dissolution in water or an aqueous medium has an average particle size of 25-50 nm (feature G), while reference is made to an almost clear dispersion.
4.95. WO 219 also satisfies the other features of claim 1 of NL 718. It is a
pharmaceutical composition for oral administration (feature A), it contains, as appears from the table, cyclosporin as active ingredient (feature B) and can be regarded as an oil-in-water microemulsion preconcentrate (feature C), since the description of WO 219 states about this (p. 1, l.30-p.2,l.2):
4.96. Further, the composition has a lipophilic phase (feature E), viz. Tricaprin,
which is a variation on the Captex 355 used in NL 781. Tricaprin is not miscible with the hydrophilic phase. WO 219 describes:
4.97. Also, the composition has a hydrophilic phase (feature D). In WO 219 an
alternative has been chosen with respect to the Glycofurol preferred in NL 781. Table 12B of WO 219 clearly shows the effects on the particle size in relation to the choice of the hydrophilic solvent:
The mere replacement of Glycofurol by the hydrophilic phase Ethyl Lactate chosen in WO 219 has an adverse effect on the particle size (cf. column 3, with Glycofurol 400 a particle size of 25.2 is obtained, whereas when Glycofurol is replaced by ethyl lactate 400 – see column 1 – a particle size of 94.8 nm is obtained). When this happens in combination with an increase of the amount of lecithin (phospholipid in the table), this yields a desired result, viz. a particle size of 30.1 nm (see column 6).
4.98. As a surfactant (feature F), finally, the composition of Example 10 of WO
219 contains, just as in NL 781, Cremophor RH40.
4.99. The upshot is that, also on the basis of WO 219, it can be established that
Ciclosporin Actavis is an oil-in-water microemulsion preconcentrate which, upon contact with water, is capable of spontaneously or virtually spontaneously forming a microemulsion with particles of less than 2,000 Å, so that Ciclosporin Actavis falls within the scope of protection of the patent, if not literally, then in any case still by way of equivalence.
4.100. The conclusion is that the intended product of Actavis Group falls within
the scope of protection of claim 1 of NL 781.
Subclaims 2 and 5
4.101. Claim 2 claims a composition according to claim 1, characterized in that
the surfactant comprises a reaction product of natural or hydrogenated castor oil or fractions thereof and ethylene oxide. Ciclosporin Actavis contains as surfactant Cremophor RH40, which is mentioned in the patent as a preferred embodiment. The intended product of Actavis Group therefore falls within the scope of protection of claim 2 as well.
4.102. Claim 5 claims a composition according to inter alia claims 1 and 2 –
Novartis relies on claim 5 only insofar as it refers back to these two claims – characterized in that the lipophilic phase comprises a triglyceride of fatty acids having a chain length of 6-12 carbon atoms. Ciclcosporin Actavis comprises as a lipophilic phase Tricaprin, a triglyceride of fatty
acids having a chain length of 8-12 carbon atoms. Thus, Ciclosporin Actavis also falls within the scope of protection of claim 5, insofar as it refers back to claims 1 and 2.
Ancillary claims
4.103. Now that hereinabove it has come to be established that Actavis Group, if
it were to trade its product – as announced – on the Dutch market, infringes NL 781 and therefore a threat of infringement is real, the injunction claim, strengthened by a penalty, is allowable as set forth in the operative part.
4.104. Now that Actavis Group has alleged, without this having been
contradicted, that it has not yet entered the Dutch market with its product, there is no reason for allowance of the statement of an independent certified accountant regarding the sale/delivery data , as claimed in 2 of the relief sought, nor for the notification to buyers and recall claimed in 3 of the relief sought. Nor is this the case for the claimed surrender for destruction. This is because a Dutch patent is involved here and, in principle, Actavis Group is free to trade its product in a country where Novartis does not have any patent rights or where those patent rights have come to lapse.
4.105. The claimed specified statement of the profits made will also be denied, for
lack of any trading by Actavis Group in the Netherlands. The same holds for the claimed damages to be assessed by the court. Now that it has become insufficiently plausible that Novartis, as a result of the threat of patent infringement, has suffered any damage other than that resulting from the enforcement of its patent and which will be compensated in the manner to be mentioned hereinafter, this claim too will be dismissed.
4.106. As the party being largely awarded against, Actavis Group will be ordered
to pay the reasonable and proportional costs incurred on the part of Novartis in the main action, under Article 1019h Code of Civil Procedure, assessed by parties in mutual consultation to be 75,000.00. The claimed statutory interest on the legal costs is allowable with the proviso that it will not be due until Actavis Group is in default of payment. The claimed declaration that the order be provisionally enforceable will also be awarded.
in (partly conditional) counterclaim proceedings Actavis
4.107. Now that the condition on which Actavis has filed the claimed
nullification of NL 781 has not been fulfilled, it can be disregarded in these proceedings. This means furthermore that the costs incurred by Actavis in counterclaim proceedings are not eligible for compensation.
4.108. The declaratory judgment claimed (unconditionally) in counterclaim
proceedings is denied. Leaving aside the question whether Actavis itself would have any interest in it at all, what holds is that – as will appear
hereinafter – the product Ciclosporin Actavis falls within the scope of protection of NL 781, so that the declaratory judgment is not allowable.
4.109. The damages claimed (unconditionally) in counterclaim proceedings,
insofar as they are to be deemed to have been filed at all by Actavis as well, are also denied. The basis underlying the claim is – briefly stated – that Novartis has enforced its patent right unlawfully in respect of Actavis, so that Actavis suffers damage, consisting in lost turnover and profits. However, now that Actavis itself does not possess any marketing authorizations and has also contested involvement in any other respect in the trade of Ciclosporin Actavis, it is not seen that Actavis has suffered any damage on that ground.
4.110. The costs incurred by Novartis in counterclaim proceedings relate
virtually exclusively to the nullification of NL 781 claimed by Actavis Group and (conditionally) by Actavis and Pharmachemie. Under those circumstances, the court, although it disallows the claims referred to in grounds 4.108 and 4.109 which Actavis has filed unconditionally in counterclaim proceedings, sees no reason to order Actavis in counterclaim proceedings to pay costs in favor of Novartis.
4.111. As already considered hereinabove in ground 4.56, the claimed
nullification of NL 781 is dismissed.
4.112. The damages claimed by Actavis Group will be denied, if only because
Novartis has enforced its patent in respect of Actavis Group, considering the infringement claims ready to be allowed, on good grounds. Thus, already for that reason alone, there is no unlawful act of Novartis in respect of Actavis Group involved.
4.113. Now that the condition on which it has been filed has been fulfilled, the
claimed declaratory judgment that Ciclosporin Actavis does not infringe NL 781 needs to be assessed. The declaratory judgment is denied, now that infringement is actually involved.
4.114. As the party being largely awarded against, Actavis Group will be ordered
to pay the reasonable and proportional costs incurred on the part of Novartis in counterclaim proceedings, under Article 1019h Code of Civil Procedure, assessed by parties in mutual consultation to be 50,000.00. The claimed statutory interest on the legal costs is allowable with the proviso that it will not be due until Actavis Group is in default of payment. The claimed declaration that the order be provisionally enforceable will also be awarded.
4.115. Now that the condition on which Pharmachemie has filed its claim in
counterclaim proceedings has not been fulfilled, the costs incurred by Pharmachemie in counterclaim proceedings are not eligible for compensation.
The court in the main action 5.1
enjoins Actavis Group immediately after service of this judgment from infringing Dutch patent 194781, in particular by making, using, putting on the market or reselling, delivering or otherwise dealing in Ciclosporin
Actavis (hereinafter: infringing product) in or for its business, or offering,
importing or stocking it for any of those purposes;
orders Actavis Group to pay to Novartis an immediately payable penalty of 50,000.00 per whole or partial violation of the injunction mentioned in ground 5.1 and per day that a violation will have continued or, at the option of Novartis, 5,000.00 for each infringing product by which Actavis Group has violated the injunction;
orders Actavis Group to pay the costs of the proceedings, on the part of Novartis so far assessed to be 75,000.00, to be increased by the statutory interest on this amount from the day that Actavis Group will fail to pay;
declares this judgment so far to be immediately enforceable;
dismisses what has been claimed more or otherwise from Actavis Group;
dismisses the claims against Actavis;
orders Novartis to pay the costs related to these proceedings in the dispute against Actavis, on the part of Actavis up to this judgment assessed to be 45,000.00, to be increased by the statutory interest on this amount from the day that Novartis will fail to pay;
declares this judgment in respect of the order to pay costs in favor of Actavis to be immediately enforceable;
dismisses the claims against Pharmachemie;
5.10. orders Novartis to pay the costs related to these proceedings in the
dispute against Pharmachemie, on the part of Pharmachemie up to this judgment assessed to be 100,000.00, to be increased by the statutory interest on this amount from the day that Novartis will fail to pay;
5.11. declares this judgment in respect of the order to pay costs in favor of
Pharmachemie to be immediately enforceable;
in the (partly conditional) counterclaim 5.12. dismisses the claims;
5.13. orders Actavis Group to pay the costs of the proceedings, on the part of
Actavis up to this judgment assessed to be 50,000.00, to be increased by the statutory interest on this amount from the day that Actavis Group will fail to pay;
5.14. declares this judgment in respect of the order to pay costs in favor of
Novartis to be immediately enforceable.
This judgment has been delivered by mr G.R.B. van Peursen, mr J. Th. van
Walderveen and mr R. Kalden and pronounced in open court on July 2, 2008.
Source: http://www.fisal.nl/wp-content/uploads/2013/07/court-decision-18.pdf
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