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You are here: BAILII >> Databases >> England and Wales Court of Appeal (Civil Division) Decisions >> Novartis Ag & Ors v Focus Pharmaceuticals UK Ltd & Ors [2016] EWCA Civ 1295 (21 December 2016) URL: https://www.bailii.org/ew/cases/EWCA/Civ/2016/1295.html Cite as: [2016] EWCA Civ 1295 |
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CIVIL
DIVISION)
ON APPEAL FROM THE HIGH COURT OF JUSTICE
CHANCERY DIVISION (PATENTS COURT)
THE HON MR JUSTICE ARNOLD
Strand, London, WC2A 2LL |
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B e f o r e :
LORD JUSTICE FLOYD
and
LORD JUSTICE HAMBLEN
____________________
(1) Novartis AG (2) LTS Lohmann Therapie-Systeme AG (3) Novartis Pharmaceuticals UK Ltd |
Claimants/Appellants |
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- and - |
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(1) Focus Pharmaceuticals UK Ltd (2) Actavis Group PTC EHF (3) Actavis UK Ltd |
Defendants/Respondents |
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And Between: |
Claimants/Appellants |
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(1) Novartis AG (2) LTS Lohmann Therapie-Systeme AG (2) Novartis Pharmaceuticals UK Ltd |
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- and - |
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TEVA UK Ltd |
Defendant/Respondent |
____________________
Daniel Alexander QC and Henry Ward (instructed by Olswang LLP) appeared for
Focus Pharmaceuticals Ltd
Daniel Alexander QC and Henry Ward (instructed by Pinsent Masons LLP) appeared
for Actavis
Daniel Alexander QC and Mark Chacksfield (instructed by Bird & Bird LLP)
appeared for TEVA UK Ltd
Hearing dates : 1st and 2nd November 2016
____________________
Crown Copyright ©
Lord Justice Kitchin:
Introduction
The technical background
i) "Cmax" which is a measure of the peak plasma concentration of the API;
ii) "tmax" which is the time at which Cmax is reached; and
iii) "AUC" or "area under the curve" which, as its name suggests, is the area under the concentration-time curve and reflects the exposure of the body to an API after administration. AUC24h is the AUC over a 24 hour period.
i) only a limited number of APIs are suitable for administration in this way;
ii) TTSs are generally more expensive and time consuming to develop than oral formulations;
iii) the onset of treatment tends to be slower than with oral formulations; and
iv) there is the potential for local skin irritation.
"31. Once an API is identified as being suitable for delivery by a patch, a target dose would be given to the formulator by the clinician and would generally be quantified in terms of a target AUC, typically the AUC24h. The target AUC24h will normally correspond to the AUC24h for the oral dosage form.
32. Once the target dosage is selected, prototypes will be produced and tested in short term accelerated and real time stability tests and their performance will then be assessed based upon the amount of API released from the patch. This is tested in vitro in a test system such as a Franz diffusion cell and, ultimately, in vivo, usually in humans. The Franz diffusion cell test involves measuring diffusion of the test substance across a membrane. This may be a piece of human skin or an artificial membrane such as an EVA membrane.
33. In developing a generic patch formulation (i.e. a generic version of an existing patch), a key step is to ensure that the generic patch will release the same dose as the originator patch. This would be tested in the same way as described above – in vitro by Franz diffusion cell and ultimately in human volunteers."
"92. Taking all of the evidence into account, my conclusions are follows:
i) It was generally accepted that rivastigmine should be administered with food.
ii) As Prof Ballard pointed out, and Prof Francis accepted, this is common practice for many drugs, and there are a number of different potential reasons for doing it.
iii) In the case of rivastigmine, the skilled person would be aware that it was a reasonable hypothesis that administration with food increased the tolerability of rivastigmine and that this was because it increased tmax and reduced Cmax which contributed to cholinergic side effects. The skilled person would also be aware, however, that there was no firm evidence to support this hypothesis.
93. I would add that, even if point (iii) was not common general knowledge, I consider that it would have been an obvious step for the skilled team, at the outset of a project to develop a new formulation of rivastigmine one of whose objects was to improve its tolerability, to undertake a short and focussed literature search into factors affecting the tolerability of rivastigmine. This would have thrown up some, if not all, of the papers considered above, from which the skilled clinician would draw the same conclusions."
The application for the Patent
"The present invention relates to Transdermal Therapeutic Systems comprising a backing layer, a reservoir layer and an adhesive layer, to Transdermal Therapeutic Systems having specific release profiles, to their manufacture and use."
"It is a further objective of the present invention to provide a method of treatment and controlled-release formulation(s) that substantially improves the efficacy and tolerability of rivastigmine.
It is a further objective of the present invention to provide a method of treatment and controlled-release formulation(s) that substantially reduces the time and resources needed to administer rivastigmine for therapeutic benefit.
It is a further objective of the present invention to provide a method of treatment and controlled-release formulation(s) that substantially improves compliance with rivastigmine therapy.
"Tests with active ingredients for the treatment of Alzheimer's disease have surprisingly shown that a line of silicone adhesive can be applied to a poorly adhesive reservoir matrix, thus significantly increasing the adhesive properties of the preparation without affecting the thermodynamic properties of the TTS, i.e. without reducing the release of active ingredient from the matrix and its permeation through the skin."
"The present invention provides TTS comprising a backing layer, a reservoir layer containing at least one active ingredient and a polymer, an adhesive layer comprising a silicone polymer and a tackifier.
A TTS according to the invention shows improved adhesive properties. Further, and very surprisingly, the so obtained TTS has essentially the same release profile when compared with a standard TTS."
"The present invention is further related to a method for substantially improving the efficacy and tolerability of rivastigmine, comprising application of a TTS in the range of 2 to 50 cm2, said formulation providing a mean maximum plasma concentration of about 1 to 30 ng/mL from a mean of about 2 to 16 hours after application and an AUC24h of about 25 to 450 ng.h/mL after repeated "QD" (i.e., once daily) administration.
A TTS according to the invention quite surprisingly shows improved tolerability, particularly gastrointestinal adverse events such as nausea and vomiting, relative to equivalent levels of exposure (AUC24h) of Exelon® capsule."
As the judge noted, these pharmacokinetic data are not said to relate to the starting dose prescribed to a patient.
"In a preferred embodiment, the TTS provides a mean maximum plasma concentration of rivastigmine of 1 to 30 ng/ml from a mean of 2 to 16 hours after application with an AUC24h of 25 to 450 ng.h/ml, particularly preferred, the TTS provides a mean maximum plasma concentration of rivastigmine of 2.5 to 20 ng/ml from a mean of 4 to 12 hours after application with an AUC24h of 45 to 340 ng.h/ml."
"In a further aspect, the invention provides a TTS which incorporates as active agent a cholinesterase inhibitor in free or pharmaceutically acceptable salt form, for use in the prevention, treatment or delay of progression of dementia."
"In a further aspect, the invention provides a method for the prevention, treatment or delay of progression of Alzheimer's disease in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of a TTS which incorporates as active agent a cholinesterase inhibitor in free or pharmaceutically acceptable salt form."
"Little has been published in detail on rivastigmine's biopharmaceutical properties in humans. It is rapidly and completely absorbed. We have found that it is metabolised mainly through hydrolysis by esterases, e.g., acetyl and butyryl cholinesterase and has a plasma half life of 1 hour. It is subject to pre-systemic and systemic metabolism. We now have found that a TTS containing rivastigmine may be produced with advantageous properties, e.g., better tolerability."
"The TTS of the invention allows, e.g., the manufacture of once a day pharmaceutical forms for patients who have to take more than one dose of an active agent per day, e.g., at specific times, so that their treatment is simplified. With such compositions tolerability of rivastigmine may be improved, and this may allow a higher starting dose and a reduced number of dose titration steps.
A [sic] increased tolerability of rivastigmine provided by the compositions may be observed in standard animal tests and in clinical trials."
Capsule | AUC24h | Patch | AUC24h |
1.5 mg bid (3 mg) | 12.3 + 7.41 | 5 cm2 (9 mg loaded dose) | 45.6 + 16.6 |
3 mg bid (6 mg) | 52.7 + 20.2 | 10 cm2 (18 mg loaded dose) | 123 + 41.0 |
4.5 mg bid (9 mg) | 90.4 + 45.1 | 15 cm2 (27 mg loaded dose) | 226 + 85.5 |
6 mg bid (12 mg) | 150 + 58.8 | 20 cm2 (36 mg loaded dose) | 339 + 138 |
The Patent
"The present invention relates to rivastigmine, in free base or pharmaceutically acceptable salt form, for use in a method of preventing, treating or delaying progression of dementia or Alzheimer's disease, wherein the rivastigmine is administered in a Transdermal Therapeutic System and the starting dose is as defined in claim 1."
"In one aspect, the present invention provides rivastigmine, in free base or pharmaceutically acceptable salt form, for use in a method of preventing, treating or delaying progression of dementia or Alzheimer's disease, wherein the rivastigmine is administered in a TTS and the starting dose is as defined in claim 1."
"65. The remainder of the description of the Patent is broadly similar to that of the Application, but there are a number of differences. The principal differences are as follows. First, whereas the Application said that "[t]he present invention provides" a TTS comprising a backing layer, a reservoir layer and an adhesive layer, and so on, the Patent instead refers to "one embodiment [of] the present disclosure" of the Patent doing so, to "a TTS according to the disclosure" or to "a TTS as used in the invention" etc (see, for example, [0019], [0020] and [0022]). Similarly, whereas in the Application there was reference to preferred embodiments having particular characteristics in relation to e.g. the reservoir or silicone adhesive layer, in the Patent the corresponding passages now refer to preferred embodiments in which the TTS comprises such a reservoir or silicone adhesive layer (see, for example, [0032] to [0043]).
66. Secondly, the extensive definition of "active ingredient" contained in the Application has been deleted from the Patent.
67. Thirdly, the passage concerning better tolerability (at [0049] corresponding to page 9 of the Application [quoted at [31] above] is no longer followed by the consistory clauses concerning the specified pharmacokinetic profiles.
68. Fourthly, the passage referring to the starting dose (at [0057] corresponding to page 11 of the Application [quoted at [32] above] now refers to the TTS "used in", rather than "of", the invention."
[1] Rivastigmine for use in a method of preventing, treating or delaying progression of dementia or Alzheimer's disease,
[2] wherein the rivastigmine is administered in a TTS and
[3] the starting dose is that of a bilayer TTS of 5 cm2 with a loaded dose of 9 mg rivastigmine,
[4] wherein one layer: has a weight per unit area of 60 g/m2 and the following composition:
- rivastigmine free base 30.0 wt %
- Durotak® 387-2353 (polyacrylate adhesive) 49.9 wt %
- Plastoid® B (acrylate copolymer) 20.0 wt %
- Vitamin E 0.1 wt %
[5] and wherein said layer is provided with a silicone adhesive layer having a weight per unit area of 30 g/m2 according to the following composition:
- Bio-PSA® Q7-4302 (silicone adhesive) 98.9 wt %
- Silicone oil 1.0 wt %
- Vitamin E 0.1 wt %
Construction
"Novartis' construction of the claim is that it has three components. First, it is a claim to rivastigmine for use in treating dementia or AD. Secondly, the rivastigmine is administered via a TTS. Thirdly, the "starting dose" of rivastigmine administered by the TTS is the dose released by a reference TTS which is specified in integers [3], [4] and [5] of the claim. Thus the TTS may have any structure or composition providing it can be used to deliver the same starting dose. "
"In my judgment Novartis' construction is the correct one. Although counsel for the Defendants advanced a number of arguments in support of the Defendants' construction, none of them really engaged with the language of the claim, and in particular the words "the starting dose is that of" in integer [3]. The natural meaning of those words is that the method of administration involves a starting dose which is the same as that of a TTS having the specified characteristics. If the patentee had intended to claim administration of rivastigmine via a TTS having the structure of TTS #2, then those words would be redundant…"
Added matter
i) first, the skilled team is informed for the first time that the invention lies in the selection of a particular starting dose for rivastigmine administered via a TTS for the treatment of dementia or AD;
ii) secondly, the skilled team is informed for the first time that the dose delivered by the 5 cm2 TTS#2 should be used as the starting dose; and
iii) thirdly, the skilled team is informed for the first time that this starting dose may be obtained using a TTS which does not have the structural and compositional features disclosed in the Application.
"I have set out the disclosure of the Application in some detail above. In summary, it discloses an invention which has two main aspects. The first aspect concerns a three-layer TTS. The second aspect concerns a TTS providing Cmax and AUC24h values of rivastigmine within the broad ranges disclosed and claimed in the Application. I have also set out the disclosure of the Patent above. In summary, it discloses an invention in which rivastigmine is administered via a TTS with a starting dose which is the same as that of a reference patch, namely a 5 cm2 TTS #2 patch."
"… in my judgment that does not meet the Defendants' point. What the Patent tells the skilled team for the first time is that it is the starting dose delivered by the TTS that matters, not the structure or composition of the TTS, whereas previously the structure and composition of the TTS was presented as the core of the invention."
"… the claim in the Patent is an intermediate generalisation because it takes the feature of the starting dose delivered by a 5 cm2 TTS #2 stripped of its context in the example when it would not be clear to the skilled team that that feature was generally applicable or that the other features of the example were inessential to the invention."
"Turning to the Defendants' first point, counsel for Novartis really had no answer to this. In my judgment it encapsulates the fundamental objection to the Patent when compared with the Application."
" Q. Now, if the skilled team looked at this document in 2005, they would be aware that the patch being described, the TTS2 patch, and indeed the TTS1 patch, delivered a certain dose to the skin at a certain rate.
A. Yes.
Q. And in so far as the starting dose produced a certain effect on the body; okay, which was deemed by the clinician to be beneficial, it would be apparent that you could make other patches also delivering the same dose at the same rate that would do the same.
A. Yes.
Q. And reading this document the skilled person would have no doubt that there would be other patches that could produce the same effect with the same starting dose.
A. That is correct.
Q. And they would not think that the effect can only be achieved with that particular design of patch, that particular TTS2 design of patch.
A. This particular composition, no."
Obviousness
"The transdermal devices of the invention in general have, for example, an effective contact area of pharmaceutical composition on the skin of from 1 to about 80 square centimeters, preferably about 10 square centimetres, and are intended to be applied at intervals of about once every 1 to 7 days, preferably 1-3 days. Compound A is well tolerated at a dose of 36 mg in free base form in up to 80 cm2 of patches according to the invention containing 36 mg compound A from which 12 mg was absorbed. Compound A may, for example be administered at a dose of 8 mg in a patch of ca. 10 cm2, once every day. …
… The exact amounts of compound A to be administered may depend on a number of factors, e.g. the drug release characteristics of the compositions, the drug penetration rate observed in vitro and in vivo tests, the duration of action required, the form of compound A, and for transdermal compositions the size of the skin contact area, and the part of the body to which the unit is fixed. The amount of and, e.g. area of the composition etc. may be determined by routine bioavailability tests comparing the blood levels of active agents after administration of compound A in a composition according to the invention to intact skin and blood levels of Compound A observed after oral administration of a therapeutically effective dose of the compound.
Orally, the Compound A is well tolerated at an initial dose of 1.5 mg twice a day orally and the dose may be stepped up to 3 mg twice a day in week 2. Higher doses are possible, for example 4.5 mg twice daily and even 6 mg twice daily. Tolerability is seen to be even better for the transdermal device, wherein 24 mg were absorbed in 24 hours."
i) The skilled team would have been motivated to develop a formulation of rivastigmine which addressed the disadvantages of rivastigmine compared to donepezil. In particular, the skilled team would have been motivated to develop a formulation which enabled once daily administration.
ii) The skilled team would have known that a transdermal patch would be likely to enable once daily administration to be achieved.
iii) The skilled team would have ascertained, if necessary by routine testing, that the properties of rivastigmine made it suitable for administration by a transdermal patch.
iv) In developing a transdermal patch for rivastigmine, the skilled team's starting point would have been to seek to develop a patch which delivered an AUC24h which matched that of an existing oral formulation, namely Exelon capsules.
"133. It is also important to remember that, while the side effects of rivastigmine could be unpleasant for patients, they were generally not severe. The inventors of the Patent were not put off trying the dose released by the 5 cm2 TTS #2 as the starting dose in their study by the potential side effects, and there is nothing to suggest that they were taking a risk that the skilled team would not have been prepared to countenance. On the contrary, a paper by G. Lefevre et al, "Pharmacokinetics and pharmacodynamics of the novel daily rivastigmine transdermal patch compared with twice-daily capsules in Alzheimer's disease patients", Nature, 83, 106-114 (2008), published after the priority date, which describes more fully the trial reported in the Patent, indicates that the inventors followed exactly the reasoning advanced by the Defendants (at 106):
"The incidence of centrally induced cholinergic gastro intestinal side effects with rivastigmine has been associated with the high maximum plasma concentrations (Cmax) and short times to Cmax, (tmax) provided by oral administration. Measures that prolong tmax and reduce Cmax such as the administration of rivastigmine capsules with food, may improve tolerability of cholinesterase inhibitors.8,9 For a given level of exposure, the transdermal administration of rivastigmine, by providing continuous delivery of drug with reduced fluctuations in plasma levels (i.e., lessening the rapid rise and fall of drug concentration), prolonging tmax and achieving a lower Cmax is expected to reduce side effects. This may also offer additional therapeutic advantages over oral administration, such as access to higher doses, with the potential to improve compliance and treatment effects."
(Reference 8 is Jann, Shirley and Small. Reference 9 is a post-priority date paper.)"
"134. In those circumstances, I conclude that it would have been obvious to try the dose released by the 5 cm2 TTS #2 as the starting dose in a small scale clinical trial for both the reasons advanced by the Defendants. So far as the first reason is concerned, while it is true that US301 does not in terms instruct the skilled team to omit the sub-therapeutic dose, it cannot be inventive to do exactly what it does say. So far as the second reason is concerned, I consider that, having regard to the skilled team's motivation and the relative ease with which a small study could be carried out, the skilled team would have had a sufficient expectation of success to warrant trial. Accordingly, I conclude that the Patent is invalid for lack of an inventive step."
Insufficiency
Conclusion
Lord Justice Floyd:
Lord Justice Hamblen: