No toleration for Novartis - rivastigmine patch patent declared invalid

It has been all quiet on the pharma patent front since the beginning of March (when the epic series of first instance decisions on Swiss form claims came to and end: see here, here, here and here), and so this moggy was delighted when there fell into his paws the decision of Mr Justice Arnold in Novartis v Focus, Actavis, Teva [2015] EWHC 1068 (Pat).

The case concerns a transdermal patch for rivastigmine, which is acetylcholinesterase (AChE) inhibitor used in the treatment of Alzheimer's disease.  In the original oral dosage form, problems with side effects such as nausea, vomiting and diarrhoea meant that the drug had to be initially administered at a sub-therapeutic dose (starting dose), and then titrated up to a therapeutically effective dose as the side effects became tolerated in the patient.  The use of a transdermal patch according to the patent allowed the starting dose to be much higher, with tolerable side effects.

The patent concerned was EP 2292219, which was one of a chain of divisionals derived from WO 2007/064407.

The claim is of an interesting form (integers added as in the judgment):

[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 %.

Although the defendants argued to the contrary, the Judge accepted that the claim was not to the use as a starting dose of the specific patch defined in [3], [4] and [5], but any transdermal patch (Transdermal therapeutic system or TTS) that would deliver the same dose, because of the wording "the starting dose is that of".  The claim on this construction interested this Kat, because it effectively claims "the dose obtainable from this specific patch", or "any dose that is the same as the dose from this specific patch".  This echoes considerations of "product-by-process" claims (where the patent claims the product of a specific process, and anything else that is the "same", or "obtainable" by the same process) - about which he wrote here and here.

In this particular case, however, this construction of the claim gave rise to no difficulties for the judge, and the finding of infringement was pretty much inevitable, not least since the defendants' products were generic versions of the Novartis patches.  But validity was much more interesting, and on this Novartis lost on two of the main issues - added matter and obviousness, although they prevailed on insufficiency.

The added matter aspect is the most interesting.  The patent derived from a PCT application that was originally mainly directed to a (presented as inventive) 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.  The only reference to starting dose was as follows:

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.

Therefore, although a TTS as defined in integers [3], [4] and [5] of the patent claim was disclosed in the PCT application, there was no indication that this should be used specifically as the starting dose for treatment of Alzheimer's disease.  Accordingly the Defendants attacked the patent for added matter in three ways, all of which were accepted by Arnold J:

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 AD. 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. 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.

In relation to the third of these points, Arnold J observed:

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.

So the patent was held invalid for added matter.

On obviousness, the attack was based on US 6335031, which the judge found disclosed a patch of the same structure and composition as that claimed, and differed only in unit size (but from which it would have been straightforward to produce the patch needed for the claimed invention by halving the size).  However, US 6335031 did not disclose the starting dose; but it did say that the size of the patch:

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 [emphasis added].

(In US 6335031 rivastigmine is called Compound A)

Novartis contended that this would be interpreted analogously to the practice for oral rivastigmine as nevertheless requiring initial treatment at a sub-therapeutic dose.  The Defendants argued that the skilled person would try what the passage quoted above said and start at the dose lowest therapeutic oral dose of rivastigmine.  They also argued that the skilled team would know that a patch would deliver rivastigmine with a smoothed out plasma profile compared with the oral dosage form and so with less fluctuation of the drug concentration in the patient, which was believed according to a number of prior art reviews to be the cause of the side effects found with oral administration.

The judge accepted that the skilled team, for the reasons put forward by the defendants, would try the claimed dose as the starting dose in a small scale clinical trial and would have had a sufficient expectation of success to warrant trial.  He noted that:

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

And so the patent was found to be obvious.

For a full decision on validity and infringement, this is rather a short judgment at 42 pages and 150 paragraphs.  And the operative part is very concise - much of the length is the explanation of the disclosure of the PCT application, the patent, and the prior art including the Summary of Product Characteristics of rivastigmine.

In the meantime, the patent is under opposition at the EPO by no fewer than 13 opponents (although Merpel notes that Sir Richard wrote "less").  Oral Proceedings are scheduled for 15 to 17 December 2015, and the preliminary opinion of the Opposition Division is that the patent is invalid on grounds of insufficiency and added matter.

Merpel is impressed that Novartis got the added matter issues past the Examining Division of the EPO in the first place.