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You are here: BAILII >> Databases >> England and Wales High Court (Patents Court) Decisions >> Novartis AG & Ors v Focus Pharmaceuticals Ltd & Ors [2015] EWHC 1068 (Pat) (27 April 2015) URL: https://www.bailii.org/ew/cases/EWHC/Patents/2015/1068.html Cite as: [2015] EWHC 1068 (Pat) |
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CHANCERY DIVISION
PATENTS COURT
Fetter Lane, London, EC4A 1NLL |
||
B e f o r e :
____________________
NOVARTIS AG LTS LOHMANN THERAPIE-SYSTEME AG NOVARTIS PHARMACEUTICALS UK LIMITED |
Claimants |
|
- and - |
||
FOCUS PHARMACEUTICALS LIMITED ACTAVIS GROUP PTC EHF ACTAVIS UK LIMITED |
Defendants |
____________________
Daniel Alexander QC and Henry Ward (instructed by Olswang LLP) for Focus
Daniel Alexander QC and Tom Moody-Stuart (instructed by Pinsent Masons LLP) for Actavis
Daniel Alexander QC and Mark Chacksfield (instructed by Bird & Bird LLP) for Teva
Hearing dates: 18-20, 24 March 2015
____________________
Crown Copyright ©
MR JUSTICE ARNOLD :
Topic | Para |
Introduction | 1-3 |
Witnesses | 4-10 |
Novartis' experts | 5-7 |
The Defendants' experts | 8-10 |
Technical background | 11-33 |
Alzheimer's disease (AD) | 11-12 |
Acetylcholine (ACh) | 13-15 |
Treatment of AD with AChE inhibitors | 16-19 |
Rivastigmine | 20-21 |
The Exelon SmPC | 22 |
Pharmacokinetic parameters | 23-24 |
Transdermal therapeutic systems (TTS) | 25-30 |
Development of a patch formulation | 31-33 |
The Application | 34-61 |
The Patent | 62-68 |
The claim | 69 |
The skilled team | 70-71 |
Common general knowledge | 72-93 |
Construction | 94-102 |
Added matter | 103-114 |
Obviousness | 115-134 |
US031 | 116-122 |
The difference | 123 |
Was it obvious? | 124-134 |
Insufficiency | 135-142 |
Infringement | 143-149 |
Summary of conclusions | 150 |
Introduction
Witnesses
Novartis' experts
The Defendants' experts
Technical background
Alzheimer's disease (AD)
Acetylcholine (ACh)
Treatment of AD with AChE inhibitors
i) Donepezil (brand name Aricept). Donepezil was started at 5 mg (tablets) once daily, and after one month the dose was increased to 10 mg once daily. 5 mg once daily was the minimum effective dose.ii) Galantamine (brand name Reminyl). Galantamine was started at 4 mg (tablets) twice daily. At four week intervals, each dose was increased by 4 mg, up to a dosage of 12 mg twice daily. 8 mg twice daily was the minimum effective dose.
iii) Rivastigmine (brand name Exelon). Rivastigmine was started at 1.5 mg (capsules or oral solution) twice daily. At intervals of a minimum of two weeks (although in practice four week intervals were commonly used), each dose was increased by 1.5 mg up to a dosage of 6 mg twice daily. 3 mg twice daily was the minimum effective dose.
i) donepezil only required a single daily dose, rather than twice daily doses, which resulted in higher patient compliance and carer convenience;ii) administration of donepezil started with a clinically therapeutic dose, whereas the initial dose of rivastigmine was sub-therapeutic, which both delayed the therapy and meant that patients might experience side-effects without efficacy in the early stages of treatment;
iii) rivastigmine had a more complicated titration regime; and
iv) rivastigmine was perceived to have worse side effects.
Rivastigmine
The Exelon SmPC
"4. CLINICAL PARTICULARS
…
4.2 Posology and method of administration
…
Rivastigmine should be administered twice a day, with morning and evening meals. The capsules should be swallowed whole.
Initial dose: 1.5 mg twice a day.
Dose titration: The starting dose is 1.5 mg twice a day. If this dose is well tolerated after a minimum of two weeks of treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg twice a day should also be based on good tolerability of the current dose and may be considered after a minimum of two weeks of treatment at that dose level.
If adverse effects (e.g. nausea, vomiting, abdominal pain or loss of appetite) or weight decrease are observed during treatment, these may respond to omitting one or more doses. If adverse effects persist, the daily dose should be temporarily reduced to the previous well-tolerated dose.
Maintenance dose: The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg twice a day.
Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for patients treated at doses less than 3 mg twice a day. Discontinuation should be considered when evidence of a therapeutic effect is no longer present. Individual response to rivastigmine cannot be predicted.
….
Re-initiation of therapy: If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily. Dose titration should then be carried out as described above.
…
4.4 Special warnings and special precautions for use
The incidence and severity of adverse events generally increase with higher doses. If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the possibility of adverse reactions (e.g. vomiting).
Dose titration: Adverse effects (e.g. hypertension, hallucinations) have been observed shortly after dose increase. They may respond to a dose reduction. In other cases, Exelon has been discontinued (see 4.8 Undesirable effects).
Gastrointestinal disorders such as nausea and vomiting may occur particularly when initiating treatment and/or increasing the dose. These adverse events occur more commonly in women. Patients with Alzheimer's disease may lose weight. Cholinesterase inhibitors, including rivastigmine, have been associated with weight loss in these patients. During therapy patient's weight should be monitored.
…
As with other cholinergic substances, rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients with active gastric or duodenal ulcers or patients predisposed to these conditions.
...
4.8 Undesirable effects
The most commonly reported adverse drug reactions are gastrointestinal, including nausea (38 %) and vomiting (23 %), especially during titration. ...
….
4.9 Overdose
…
Treatment: As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. ...
…
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
…
Rivastigmine interacts with its target enzymes by forming a covalently bound complex that temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases acetylcholinesterase (AChE) activity in CSF by approximately 40% within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum inhibitory effect has been achieved. In patients with Alzheimer's disease, inhibition of AChE in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. …
…
Absorption: Rivastigmine is rapidly and completely absorbed, Peak plasma concentrations are reached in approximately 1 hour. As a consequence of the drug's interaction with its target enzyme, the increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose. Absolute bioavailability after a 3 mg dose is about 36%±13%. Administration of rivastigmine with food delays absorption (tmax) by 90 min and lowers Cmax and increases AUC by approximately 30%.
…
Metabolism: Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour), primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (<10%). …
Excretion: Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of elimination. Following administration of 14C-rivastigmine, renal elimination was rapid and essentially complete (> 90 %) within 24 hours. … There is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer's disease."
Pharmacokinetic parameters
i) Cmax is a measure of the peak plasma concentration of the drug;ii) tmax is the time at which Cmax is reached;
iii) AUC or "area under the curve" is the area under the concentration-time curve. This reflects the actual body exposure to a drug after administration. AUC24h is the AUC over a 24 hour period.
Transdermal therapeutic systems (TTS)
i) it bypasses the gastro-intestinal (GI) system, thereby avoiding issues related to metabolism, degradation or absorption, and locally-mediated side effects, in the GI tract;ii) it avoids the first-pass hepatic metabolism;
iii) it provides a means of once daily dosing when that may be impossible with an oral formulation;
iv) it provides a smoother delivery curve, avoiding the rapid fluctuation and peak levels of drug plasma concentrations that are seen with rapidly-absorbed drugs provided by oral administration, and will therefore improve tolerability if there are side effects associated with sharp/high peaks. This is illustrated by the following diagram in Professor Williams' first report:
v) a patch can readily be removed from a patient if required.
i) only a limited number of active pharmaceutical ingredients (APIs) are suitable for administration by transdermal patch;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.
i) An outer backing layer. This is the layer that is most remote from the skin. It holds the patch together, protects it from rubbing off on clothes and prevents cross-contamination when handling the patch. The backing layer should be impermeable to the API and typically be impermeable to water.ii) A preparation containing the API. This contains the API along with excipients.
iii) A release liner. The release liner is a detachable film that is impermeable to the API which is removed before the patch is applied to the skin.
Development of a patch formulation
The Application
"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 and their manufacture and use."
"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 to 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 about 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."
"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."
"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."
"A person skilled in the art is familiar how to produce a TTS having the above defined plasma profiles. A person skilled in the art will appreciate that such plasma profiles may be obtained by varying, e.g.:
- the composition of the first and/or second components, e.g., the nature and amount of excipients and/or active agent(s)
- the type of the adhesive layer
- the dimension of the patch
A TTS may be formulated with the following aspects in mind:
- the time until the release of active agent (lag time or delay time)
- the rate of release of the active agent (fast or slow)
- the duration of release of active agent (long or short)
- Reducing first-pass metabolism
- Improve [sic] compliance of the patients
- Reduce [sic] application intervals
Such aspects may be observed in standard in vitro dissolution tests, e.g., in water or if desired in body fluids, e.g., artificial gastric juices."
"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."
Rivastigmine (free base) | 30 wt-% |
Durotak® 387-2353 (polyacrylate adhesive) | 49.85 wt-% |
Plastoid® B (acrylate copolymer) | 20.0 wt-% |
Vitamine [sic] E | 0.1 wt-% |
Bio-PSA Q7-4302 (silicone adhesive) | 98.9 wt-% |
Silicone oil | 1.0 wt-% |
Vitamine [sic] E | 0.1 wt-% |
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."
"[0015] Embodiments of the present invention are set out in the enclosed independent claim.
[0016] 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."
The claim
"[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 %."
The skilled team
Common general knowledge
i) the side effects of rivastigmine were caused by sharp peaks in drug levels, indicated by short tmax and high Cmax; andii) the recommendation to administer with food was given in order to improve tolerability.
Novartis dispute this.
"However, a major difference between this study and a third study reported by Sramek at el [16] discussed here in the following pages is that, in the former case, the drug was given before food, whereas in the Sramek et al study, it was given after food. Data from other studies (Sandoz Pharma Ltd Basel, data on file) indicate that food has an appreciable effect on the plasma levels of ENA-713. Giving the drug after food reduces the Cmax by approximately 30%, with a concurrent increase in AUC of approximately 30%. This could well point to a mechanism influencing intolerance to the drug, and in phase III studies currently underway patients are instructed to take the drug with food."
"Coadminstration of rivastigmine with food slows absorption (tmax increased by 1.4 to 1.6 hours, maximum concentration [Cmax] reduced) but increases bioavailability by 30% compared with the fasting state. Although this is only a moderate food effect, it is recommended that rivastigmine be administered in conjunction with food, since the propensity for gastrointestinal side effects may be related to high peak plasma concentrations.13"
Reference 13 is "Data on file. Novartis … 1996". Again, on its face, this is a speculative statement, but it does suggest that there may be a link between administering rivastigmine after food, increasing tmax and reducing Cmax and increasing tolerability of the drug.
"Concomitant food slows the absorption of rivastigmine and results in a decrease in Cmax values of approximately 30% and an increase in AUC values of about 30%.23 Thus rivastigmine should be administered with food, which improves tolerability (Sections 5 and 6)."
"The tolerability of higher doses of rivastigmine was improved by administration of the drug after food and addition of antiemetics to the treatment regimen32 (administration with food decreases the Cmax and increases the AUC of rivastigmine (Section 3))."
Reference 23 is "Anand R. Clinical expert report … 1997 (Data on file)". Reference 32 is Anand et al. This time the link is firmly stated, but pursuing the reference would reveal that it was speculative.
"Ingestion of food with medication can ease the gastrointestinal distress associated with the AChEIs. Administration with meals is highly recommended to improve tolerability of high doses of donepezil19 or rivastigmine.10 … "
Reference 10 is the paper by Sramek et al discussed in Anand et al. Although this links improved tolerability with administration with food, it does not refer to tmax or Cmax.
"The incidence and intensity of the cholinergic adverse effects was greater with drugs such as physostigmine, tacrine and rivastigmine that reach the CNS relatively quickly than metrifonate, eptastigmine and donepezil and could be significantly reduced by a slow dose titration99 or sustained release preparations.10"
Reference 99 is Cutler and Sramek. Again, on its face, this is a speculative statement, but it does suggest that there may be a link between smoothing out the peaks in the curve and increasing tolerability of the drug.
"The rate of absorption determines the onset of the pharmacodynamic activity and may influence the occurrence of cholinergic-mediated adverse effects. Drugs that are rapidly absorbed may cause abrupt stimulation of the cholinergic system, with the consequent onset of cholinergic adverse effects. Conversely, cholinesterase inhibitors that are slowly absorbed may allow the organism to adapt to the cholinergic stimulation, with consequent reduced risk of cholinergic toxicity.
… The slow rate of absorption or rate of onset of pharmacodynamic activity of donepezil and eptastigmine agree with their good cholinergic tolerability profile. Other compounds, such as physostigmine and rivastigmine, have a short tmax CHE (0.5 to 1.5 hours) and increased tendency to generate cholinergic adverse effects."
This makes a firm link between short tmax and increased side effects, but no data or reference is provided to substantiate the statement.
"Another factor is the drug absorption rate, since cholinesterase inhibitors that are rapidly absorbed may cause a rapid stimulation of the cholinergic system with adverse effects closely following.10 Administering the drug with food can lower the amount of gastrointestinal effects by delaying the tmax."
Reference 10 is Imbimbo. Again, on its face, this is a speculative statement, but it does suggest that there may be a link between food, increasing tmax and increasing tolerability of the drug.
"Slower titration and administering rivastigmine with food appears to decrease the risk of GI side effects. Galantamine is also best taken with meals. If nausea and vomiting occur with rivastigmine or galantamine, first ensure that they are being taken with food, as this will decrease the Cmax and delay the Tmax of both agents.48, 49"
"Rivastigmine reaches the CNS more rapidly and has a quicker onset of pharmacological effect. This may explain the seemingly greater frequency of GI AEs seen with it.4, 68"
Reference 48 is to what I understand to be the Canadian equivalent to the SmPC. Reference 4 is Weinstock. Reference 68 is Imbimbo. Again, these statements suggest that there may be a link between food, increasing tmax and reducing Cmax and increasing tolerability of the drug.
"Rivastigmine is taken twice-daily with full meals (to reduce cholinergic side effects caused by rapid absorption), starting treatment with a low dose that is escalated slowly."
"Administration with meals is strongly recommended for those ChEIs whose absorption rate is affected by food. This can delay the absorption and lower the peak plasma concentration of ChEIs, which may reduce the likelihood of acute cholinergic events."
Again, these statements suggest that there may be a link between food, increasing tmax and reducing Cmax and increasing tolerability of the drug.
"It is thought that the occurrence of these AEs [adverse events] reflects the rapid increase in central ACh levels after oral intake.37"
"In addition to slow dose escalation, administration of some ChE inhibitors with a full meal also may reduce the incidence of centrally mediated cholinergic AEs.12,41 Administration of these agents with a meal delays drug absorption and lowers the peak plasma and brain concentrations, which reduces the likelihood that the patient will experience acute AEs. For rivastigmine and galantamine, it is recommended that the drug be taken with morning and evening meals.12"
Reference 12 is the Physicians Desk Reference. Again, on their face, these are speculative statement, but they do suggest that there may be a link between food, increasing tmax and reducing Cmax and increasing tolerability of the drug.
"The shorter tmax (time to reach maximum concentration) and half-life of rivastigmine (necessitating more frequent administration) may lead to rapid increases in acetylcholine levels, contributing to the incidence of centrally mediated gastrointestinal adverse events ...118"
"Many of the adverse effects (e.g. nausea, diarrhoea and bradycardia) caused by the use of cholinesterase inhibitors are related to the stimulation of cholingeric neurons in the periphery. … Large fluctuations in cholinesterase inhibitor plasma concentrations and the attendant proportional AChE inhibition may contribute to an increase in the incidence of adverse effects. Cholinesterase inhibitors with shorter half-life require more frequent administration and are, thus, more likely to have large peak trough differences in their plasma concentrations, in particular, before steady state is achieved . … Furthermore, cholinesterase inhibitors that are rapidly absorbed may abruptly stimulate the cholinergic system, thereby causing cholinergic adverse effects.104"
Reference 118 is Weinstock. Reference 104 is Imbimbo. Again, on their face, these are speculative statements, but they do suggest that there may be a link between food, increasing tmax and reducing Cmax and increasing tolerability of the drug.
"2 Q. I know you have expressed your reservations about the Anand
3 paper, but it does rather look as though the proposition that
4 Cmax and tmax are implicated in side-effects for rivastigmine
5 was common wisdom at the time. You may say it is misguided,
6 but you would accept that it was the common wisdom?
7 A. No, I do not think I would accept that. I think I would
8 accept that there are a number of review articles that have
9 made statements speculating that food may reduce Cmax and that
10 that may be related to tolerability. So I think based on the
11 available evidence, what reviewers are citing generally is
12 that that is a reasonable hypothesis and in clinical practice
13 it might be sensible to give rivastigmine with food, based on
14 that hypothesis. I do not think they are saying anymore than
15 that.
16 Q. Okay. Perhaps we can put it like this. The common wisdom was
17 that it was a reasonable hypothesis that Cmax and tmax were
18 implicated in side-effects?
19 A. I would agree with that with one word different. Contributed
20 to I would agree with.
21 Q. Right. Of all the papers that we have been looking at, the
22 thing that is particularly singled out as of utility in
23 reducing the side-effects is things to address Cmax and tmax.
24 That is correct, is it not?
25 A. I think it is one specific thing that is mentioned in most of
2 the studies, which is administration with food, which is based
3 on good clinical practice and would be done for a wide variety
4 of agents."
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.
Construction
Added matter
" 12 Q. Now, if the skilled team looked at this document in 2005, they
13 would be aware that the patch being described, the TTS2 patch,
14 and indeed the TTS1 patch, delivered a certain dose to the
15 skin at a certain rate.
16 A. Yes.
17 Q. And in so far as the starting dose produced a certain effect
18 on the body; okay, which was deemed by the clinician to be
19 beneficial, it would be apparent that you could make other
20 patches also delivering the same dose at the same rate that
21 would do the same.
22 A. Yes.
23 Q. And reading this document the skilled person would have no
24 doubt that there would be other patches that could produce the
25 same effect with the same starting dose.
2 A. That is correct.
3 Q. And they would not think that the effect can only be achieved
4 with that particular design of patch, that particular TTS2
5 design of patch.
6 A. This particular composition, no."
Obviousness
US031
"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."
Compound A | 18 mg | 30% |
Polymer | 29.94 mg | 49.85% |
Methacrylate | 12 mg | 20% |
(-tocopherol | 0.06 | 0.1% |
Total | 70 mg | 100% |
Bio-PSA Q7-4302 | 29.67 mg | 98.9% |
Silicone oil | 0.3 mg | 1.0% |
(-tocopherol | 0.03 mg | 0.1% |
Total | 30 mg | 100% |
The difference
Was it obvious?
i) The skilled team would have been motivated to develop a formulation of rivastigmine which addressed the disadvantages of rivastigmine compared to donepezil identified in paragraph 18 above. 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.
"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.)
Insufficiency
Infringement
i) Focus and Actavis are supplying and offering to supply 5 cm2 and 10 cm2 patches branded "Voleze" which release 4.6 mg/24 h and 9.5 mg/24 h of rivastigmine respectively.ii) Teva is supplying and offering to supply 5 cm2 and 10 cm2 patches branded "Rivatev" which release 4.6 mg/24 h and 9.5 mg/24 h of rivastigmine respectively.
"Initial dose
Treatment is started with 4.6 mg/24 h.
After a minimum of four weeks of treatment and if well tolerated according to the treating physician, this dose should be increased to 9.5 mg/24 h, which is the recommended effective dose."
Summary of conclusions
i) the Patent is invalid on the ground of added matter;ii) the Patent is invalid since the claimed invention lacks an inventive step over US031;
iii) the Defendants have not established that the Patent is insufficient;
iv) if the Patent was valid, the Defendants would have infringed it.