ratiopharm (UK) Ltd v Alza Corp

These are two actions for infringement and revocation of European Patent (UK) No 1 381 352 (“the Patent”). Alza Corporation is proprietor of the Patent and JanssenCilag Limited is its exclusive licensee. In this judgment I refer to them collectively as “Alza”. The Patent has a priority date of 16 March 2001 and is directed to transdermal patches for administering fentanyl, a potent opioid analgesic, through the skin. Alza sells patches made in accordance with the invention under the name Durogesic DTrans.

Alza complains that ratiopharm and Sandoz (collectively “the defendants”) have infringed the Patent by selling fentanyl transdermal patches under the names Osmach and Mezolar Matrix respectively. They dispute infringement and contend the Patent is invalid on the following grounds:

Anticipation by:

International Patent Application WO 01/26705 A2 (“Samyang”);

a 1996 article by Roy et al. (“Roy”).

Obviousness in the light of common general knowledge, Roy and the following further publications:

a 2000 conference poster by Yu et al. (“the Yu Poster”).

a 2000 conference abstract by Yu et al. (“the Yu Abstract”);

European Patent Application 0 913 158 A1 (“Permatec”);

United States Patent 5 006 342 (“Cygnus”);

European Patent Application 0 622 075 A1 (“Hercon”).

Insufficiency. The defendants contend the claims of the Patent are so uncertain it is not possible to determine their scope and they are therefore uninfringeable or insufficient. They also contend it requires undue experimentation to determine whether a product infringes. Both allegations depend upon the proper interpretation of the claims.

Finally, I should mention that Alza has made a conditional application to amend the Patent in the event I find it anticipated by Samyang. This application is not resisted.

Each side relied on the evidence of a single expert. Alza called Dr David Enscore. He graduated from North Carolina State University with a BSc in Chemical Engineering in 1973 and was awarded a PhD in Chemical Engineering in 1977. He was then awarded a post-doctoral fellowship at the Centre National de la Recherche Scientifique, the largest governmental research organization in France. Between 1979 and 1995, Dr Enscore worked at Alza. He began as a senior chemical engineer researching bio-erodible polymers and formulation development for transdermal dosage forms. During the course of his employment, he held directorship posts in a number of different areas of the business including Physical Sciences and New Product Discovery. In 1994, he became the Executive Director of Transdermal Product Development where he was responsible for development of specific drug delivery technologies. In his time at Alza, Dr Enscore was involved in 15 to 20 product development activities and led the development of three commercially successful transdermal patches for controlled release pharmaceuticals, namely nicotine, clonidine and testosterone. He also led the initial development of the liquid reservoir Durogesic patches, but, due to commitments on other projects, transferred responsibility for the later stages of this project to one of his colleagues. In 1995, Dr Enscore left Alza and spent the next eight years working on the application of polymer technology to other modes of drug delivery. He returned to transdermal drug delivery in 2003 before becoming an independent consultant in 2007.

The defendants make no criticism of the way Dr Enscore gave his evidence under cross examination but suggest that aspects of his written reports were overstated or wrong and that overall they were argumentative documents which presented a view which Dr Enscore did not support in person. In my judgment these criticisms are overstated. I accept that he qualified some of his written evidence in the course of his cross examination, but not in such a way as to cast doubt on his objectivity. The defendants also submit that Dr Enscore was hampered because he left the transdermal delivery field in 1995 and was not particularly aware of events which happened thereafter until the priority date including, most importantly, the introduction of six drug in adhesive products. There is, I think, more force in this criticism. Dr Enscore accepted that he did not work actively in the transdermal field over this period but suggested he did, to some extent, look at new products and market trends out of personal interest. Nevertheless, overall, I have no doubt Dr Enscore was trying to assist me throughout and I have found his evidence of great assistance.

Dr Walters gained a Membership of the Institute of Biology in 1974 and was awarded his PhD in 1979 based upon his work on the effects of nonionic surfaceactive agents on epithelial membranes. From 1978 until 1980 he was a postdoctoral fellow in the laboratories of Dr Gordon Flynn at the University of Michigan, College of Pharmacy where he gained experience of drug delivery through the skin. Following a further post-doctoral period at the University of Bath, School of Pharmacy, Dr Walters was employed first, by Fisons Pharmaceuticals to establish a section concerned with skin drug delivery and then, from 1986, by Eastman Kodak in Rochester, New York to work in their emerging Pharmaceutical Division as a transdermal delivery scientist. In about 1992, Dr Walters joined An-eX Analytical Services Ltd (“An-ex”), an independent contract research and development laboratory that offers a range of specialist services to the pharmaceutical, cosmetic, chemical and agrochemical industries. The research and development activities of An-eX are focused primarily in the dermal and transdermal field and include prediction of dermal permeation, formulation development, formulation evaluation, assessment of bioequivalence, skin penetration enhancement or retardation, demonstration of efficacy and risk assessment. During his time at An-eX, Dr Walters has managed over 100 projects in the dermal and transdermal drug delivery fields. Between 1992 and 2001, he contributed to the development of dermatological and transdermal systems containing a wide range of pharmaceuticals, including hydrocortisone, hydromorphone, hydroxytamoxifen, ketoprofen, ibuprofen, methotrexate, niacinamide, nicotine, norethisterone, oestradiol, oxybutynin, piroxicam and testosterone. The transdermal systems he investigated included sprays, powders, semi-solids, membrane-controlled and drugin-adhesive systems. By 2001, he had considerable experience working with academics and industry formulating and evaluating transdermal drug delivery systems and had hands on experience of patch formulation.

Alza suggest that Dr Walters was at times somewhat argumentative and unwilling to answer the questions he was asked. I reject this submission. I found Dr Waters to be well informed, clear and objective and I believe he too was doing his best to assist me throughout his cross examination. A more substantive criticism was that his reports were inevitably tainted by hindsight because it was apparent to him from the way he was presented with the prior art that the focus of the case was subsaturated drug in adhesive fentanyl patches. I believe Dr Walters accepted this was so, and it is a matter which I have had well in mind in assessing the weight to be attached to his evidence.

For many years before the priority date, Alza had sold a transdermal fentanyl patch under the name Durogesic for the treatment of chronic pain. This patch was sold in a range of sizes and was designed to be used in a three day treatment regimen, in that each patch provided an amount of fentanyl sufficient to induce and maintain analgesia over three days, after which the patient would remove the patch and apply a new one.

Durogesic was a liquid reservoir system and had the structure depicted below:

It had two important features: first, a liquid reservoir (3) containing fentanyl above the saturation concentration, with the result that the reservoir contained undissolved crystals of fentanyl; and second, a rate controlling membrane (4). This latter feature is essential when the drug is present as a liquid and it has a number of important properties. It decreases the in vitro release rate of the drug from the patch and increases the system rate control, and so reduces the variability in transdermal drug flux due to the inherent variability in the permeability of the skin. The reduced system release rate also means that the flux profile will decay more slowly than a corresponding system without a rate controlling membrane. Importantly, the membrane acts as an “artificial skin barrier” to ensure that the drug flux onto the skin will not exceed a certain level determined by the membrane. This is a useful safety feature in any case where there is a concern as to the effect that a large uncontrolled dose of the drug might have. In addition, the Durogesic patch had a backing layer (2) and the external surface of the rate controlling membrane was coated with an adhesive (5). The adhesive was covered by a protective release liner (not depicted). In use, the release liner was removed and the adhesive layer pressed against the skin of the patient. It was, however, recognised that liquid reservoir systems did suffer from certain disadvantages. In particular, it was perceived the presence of undissolved drug could cause stability problems during storage, although these were not known with Durogesic. Moreover, the patches were relatively complicated to fabricate.

There were two other well known patches in 2001, namely multi-laminate and monolithic patches. A typical multi-laminate patch is depicted below:

In this patch, a solid state (polymer) reservoir (16) is sandwiched between a backing layer (12) and a rate controlling membrane (13). The external surface of the rate controlling membrane is coated with an adhesive layer (14). A peelable release liner (15) is then applied to the adhesive layer. Sometimes the rate controlling membrane is omitted.

Finally, there is the monolithic, otherwise known as the drug in adhesive or matrix patch:

This, the most simple design, comprises a self-adhesive reservoir (3), commonly made of polyacrylate, sandwiched between a peelable release liner (5) and a backing layer (2). It may, in addition, comprise a further thin adhesive layer (4) where the adhesive reservoir does not itself provide sufficient adhesion over the working life of the patch.

An important difference between the depicted monolithic systems on the one hand and liquid reservoir and typical multi-laminate systems on the other is the absence of the rate controlling membrane. They therefore lack this element of system rate control, as I shall explain. However, they were recognised to have other advantages, notably they might be thinner and hence more cosmetically appealing and with better adherence characteristics than the other systems. It was also well known they could be used to deliver extended release of certain drugs, such as estradiol, over a three day period. They were also more simple to make, more robust and less open to abuse than liquid reservoir patches.

It was well known that in a transdermal drug delivery system, both the skin and the patch provide resistance (respectively, R_skin and R_sys) to drug permeation. The total or net resistance is a function of both and may be represented by the fomula: R_net = Rskin + Rsys

The rate at which the drug is delivered (the flux) is determined by the resistance it experiences. The reciprocal of the flux equals the resistance. Hence: 1/J_net = 1/J_skin + 1/J_sys

In this formula J_sys is the flux from the patch. It represents the drug release rate from the patch into an infinite sink, that is to say the rate of drug release from the patch without considering the effect of the skin.

J_skin represents the flux across the skin. For a drug to enter the systemic circulation it has to partition into the upper layers of the skin and then diffuse through the lower layers until it reaches the capillaries. These layers present a tortuous path for drug migration and limit the rate of transdermal drug permeation.

Importantly, the flux across the skin (J_skin) is not affected by the concentration of the drug in the reservoir of the patch, but instead by the degree of saturation of the drug in the reservoir. This is what provides the chemical potential. It follows that J_skin is not a fixed parameter. If the drug in the reservoir is at a high concentration relative to its saturation concentration, the flux across the skin will be higher.

The system release rate (J_sys) is affected by a number of factors, most importantly the physical properties of the system and the chemical potential of the drug in the reservoir. If a rate control membrane is included between the drug reservoir and the

As Dr Enscore says in his first report, these formulae are not immediately intuitive. But they show that even if the skin provides more resistance to drug transport than the transdermal patch, the patch will nevertheless still have an effect on the total resistance and will reduce the total net flux of the drug.

It was also known that the permeability of skin varies greatly both between and within individuals. If the resistance of the skin (R_skin) is low, the flux may be correspondingly high. But what effect this will have on the net flux (J_net) will depend on the resistance of the patch (R_sys). Even if R_skin becomes very small, R_net can never be less than R_sys, and so the rate of drug release from the patch into the bloodstream (J_net) can never be higher than the intrinsic rate of release of drug from the patch itself (J_sys). Hence the patch can be used to produce a rate controlling effect because it provides an effective upper limit on the rate of systemic drug absorption.

This is, in practice, one of the uses of a rate control membrane. It ensures an upper limit for J_sys which cannot be exceeded. It also increases the proportion of the overall rate control provided by the patch. Hence a patch with a rate control membrane will release drug at a lower and less variable rate than an otherwise equivalent patch with no rate control membrane.

There is one other important aspect of patch design which follows from the foregoing. In the case of subsaturated patch reservoirs, the chemical potential begins to decrease as soon as the drug is released from the patch. By contrast, in the case of saturation plus excess patch reservoirs, the chemical potential remains constant until all the undissolved drug is exhausted, at which point it begins to decline. This property of saturation plus excess patches will tend to ensure that the delivery rate of the drug remains relatively constant – a characteristic referred to as ‘zero order kinetics’. It also follows that a subsaturated monolith patch will release drug at a lower rate than an equivalent saturation plus excess monolith patch due to the lower chemical potential of the drug. But that is not to say the skilled person had no means of controlling delivery from a subsaturated monolith patch. To the contrary, he knew sustained delivery could be improved by, for example, using a thicker slab or selecting an adhesive with a higher solubility for the drug to be delivered.

The Patent is entitled “Transdermal Patch for Administering Fentanyl”. Paragraph [0001] of the specification explains that the invention relates to a method and patch for the transdermal administration of fentanyl and its analogues for analgetic purposes. In particular, it is said the invention relates to a subsaturated patch for administering fentanyl to a subject through skin over an extended period of time.

The background of the invention is elaborated in paragraphs [0002] through [0013]. At the outset the specification explains that fentanyl and its analogues are powerful synthetic opioids used in both human and veterinary medicine.

Paragraph [0003] states that the transdermal administration of fentanyl has been suggested in numerous patents including US Patent 4, 558, 580, which discloses the reservoir system of the Durogesic patch.

Paragraph [0004] explains that a transdermal patch is typically a small adhesive bandage that contains the drug to be delivered and which can take several forms. The simplest type is identified as an adhesive monolith comprising a drugcontaining reservoir disposed on a backing. The reservoir is typically formed from a pharmaceutically acceptable pressure sensitive adhesive but, in some cases, can be formed from a non-adhesive material, in which case the skin-contacting surface is provided with a thin layer of a suitable adhesive. The rate at which the drug is administered to a patient from these patches can vary due to normal person-toperson and skin site-to-skin site variations in the permeability of skin to the drug.

The specification continues in paragraph [0005] by describing the more complex multilaminate or liquid reservoir types of patch in which a drug release-rate controlling membrane is disposed between the drug reservoir and the skincontacting adhesive. It says that this membrane reduces the effects of variations in skin permeability by decreasing the in vitro release rate of drug from the patch. The specification suggests this type of patch is generally preferred when a highly potent drug is being administered but recognises that it has the disadvantage of usually having to cover a larger area of skin than a monolithic patch to achieve the same drug administration rate.

Paragraphs [0006] and [0007] elaborate the difference between subsaturated and depot (saturation plus excess) patches. In subsaturated patches the drug is completely dissolved in the reservoir. By contrast, depot patches contain an excess

The specification then turns to a consideration of fentanyl and its characteristics. Paragraph [0008] suggests that fentanyl has a narrow therapeutic index, with the therapeutic effect obtained only over a narrow range of concentrations; concentrations below the range being ineffective and concentrations above the range being associated with serious and potentially lethal side effects. Paragraph [0009] continues that because of the wide variations in individual drug clearance rates and the subjective nature of pain and the dangers associated with overdose, patients typically need to be titrated upwards to determine the appropriate dose. Treatment begins with a dose that is expected to be safe and it is then gradually increased until adequate analgesia is obtained. Over time, both tolerance to opioids and an increase in the severity of pain may occur and so doses may subsequently be increased or supplemented with other analgesics. In addition, some patients require the rescue use of other opioids for the treatment of breakthrough pain alongside their baseline treatment.

Paragraph [0010] explains that Durogesic is a patch that administers fentanyl for three days and is indicated for the treatment of chronic pain. At the end of each three day period the patch is removed and replaced with a fresh patch. It is contemplated that doses may be increased over time and that other analgesics may be needed to deal with breakthrough pain. Paragraph [0011] relates that because of fentanyl’s high potency and narrow therapeutic index, Durogesic was designed as a rate controlled liquid reservoir depot patch.

Paragraphs [0012] and [0013] then explain that the inventors claim to have discovered that fentanyl can be safely and analgetically effectively delivered over periods of at least three days from non-rate controlled, monolithic, subsaturated patches with the advantage of simple fabrication and improved stability and comfort. Paragraph [0013] says that the patch of the invention is bioequivalent or pharmacologically equivalent to Durogesic.

The Patent then provides some definitions. Paragraph [0026] explains that the term bioavailabilty refers to the rate and extent to which the active ingredient is absorbed from a drug product and becomes available at the site of action. The rate and extent are established by pharmacokinetic-parameters, such as the area under the blood or plasma drug concentration-time curve (AUC) and the peak blood or plasma concentration (C_max) of the drug. Paragraph [0027] continues that two different products are considered to be bioequivalent if they produce substantially the same pharmacokinetic effects when studied under similar experimental conditions.

Paragraph [0028] explains that two different products are considered to be pharmacologically equivalent if they produce substantially the same therapeutic effects when studied under similar experimental conditions.

The detailed description of the invention begins in paragraph [0043], where it is stated:

This paragraph is of some importance. It reveals the patentee thought the process of formulation of the patch to be conventional. Rather, the invention lies in the idea of providing a non-rate controlled, monolithic, subsaturated patch for the transdermal delivery of fentanyl and analogues at a rate and in an amount sufficient to induce and maintain analgesia over a period of at least three days. Paragraph [0046] explains that if the reservoir is made from a material that does not have adequate adhesive properties then the skin contacting surface may be formulated with a thin adhesive coating.

Various ingredients are listed in the following paragraphs. At paragraph [0050] is a list of pharmaceutically acceptable polyacrylate adhesives, all of which were well known at the priority date. At paragraph [0052] various preferred concentrations of fentanyl are given. Paragraphs [0053] to [0060] then describe the materials which can be used for fabricating the various layers of the patches of the invention, none of which are said to be other than standard.

There then follows a section on the drug administration. Paragraph [0061] explains that upon application to the skin, the drug in the reservoir of the patch diffuses into the skin where it is absorbed into the blood stream to produce a systemic analgesic effect. The onset of analgesia depends upon various factors, such as potency of the drug, the solubility and diffusivity of the drug in the skin, the thickness of the skin, the concentration of the drug within the skin application site and the concentration of the drug in the drug reservoir, amongst other factors.

In a similar vein, paragraph [0063] elaborates that when continuous analgesia is required a depleted patch should be removed and a fresh patch applied. Since absorption of the drug from the fresh patch into the new application area usually occurs at substantially the same rate as absorption by the body of the residual drug within the application site of the depleted patch, blood levels will remain substantially constant. But it is clear that analgesia may not be complete. The specification teaches that doses may be increased over time and that other analgesics may be used to deal with breakthrough pain.

Paragraphs [0064] and [0065] then explain that preferred embodiments of the invention exhibit a normalised C_max (peak plasma concentration normalised for the rate of drug delivered) and a standardised C_max (peak plasma concentration standardised per unit area of the drug delivery system) within wide ranges. More helpfully, paragraph [0065] also explains that steady-state administration rates obtainable for a fentanyl patch according to the invention range from 1 to 300 µg/h; preferably 2 to 250 µg/h; and more preferably 5 to 200 µg/h.

The Patent then describes various illustrative examples. Examples 1 to 7 describe the preparation of monolithic transdermal patches using polyacrylate adhesive. Example 8 describes in vitro tests carried out on the patches of the invention and Durogesic patches using a diffusion-cell apparatus to obtain in vitro drug flux. The results are displayed in Figure 3 of the Patent. Examples 10 and 11 then describe in vivo tests, and the results appear in Tables 1 to 4 and are illustrated in Figures 7 and 8. The results of these various tests are summarised at paragraph [0096]:

Two claims are alleged to have independent validity, claims 1 and 21.

Claim 1 reads:

a backing layer;

a reservoir disposed on the backing layer, at least the skin contacting surface of said reservoir being adhesive; said reservoir comprising a single phase polymeric composition free of undissolved components containing an amount of a drug selected from the group consisting of fentanyl, alfentanil, carfentanil, lofentanil, remifentanil, sufentanil and trefentanil sufficient to induce and maintain analgesia in a human for at least three days;

Claim 21 reads:

In the end the parties agreed there is no difference between them and that I should decide the case on the basis that claim 1 already includes the limitation of claim 21, namely the patch does not have a rate controlling membrane. It follows that if claim 1 is invalid then claim 21 must also fall.

The correct approach to the interpretation of a patent was explained by the House of Lords in Kirin Amgen v Hoechst Marion Roussel [2004] UKHL 46; [2005] RPC

Moreover, as Aldous J explained in Rediffusion Simulation v Link-Miles [1993] FSR

In the end only two issues of construction fall to be determined. I address them in turn.

This is relevant to the allegation of lack of novelty. The defendants say that although the term “monolithic” might normally be understood to refer to just a single slab of material, in the context of the Patent it clearly goes wider. In particular, the Patent expressly covers patches including a backing layer and patches where an additional layer of adhesive is added on the skin side to provide extra adhesion, and explains such patches should be understood to be monolithic. Accordingly, contend the defendants, the claim covers patches containing two adhesive slabs which each contain an analgesic drug and which lie on top of one another to form a multilaminate (as in Cygnus) or side by side to form a binary patch (as in some of the examples of Samyang).

I am unable to accept that the claim is this broad. The Patent uses the term monolithic to describe a patch containing a drug containing adhesive reservoir in the form of a single slab disposed on a backing. It explains that if the reservoir material is insufficiently adhesive then a thin adhesive coating may be added, but such that the reservoir may still be considered to be in contact with the skin. This is entirely consistent with the evidence of Dr Enscore that the key feature of a monolithic patch is that a single entity within the patch controls the release rate of the drug. There can be no doubt that forming a multilaminate will significantly affect drug delivery, as will placing two slabs side by side to form a binary system. In my judgment the skilled person would understand monolithic in the context of the Patent to mean a patch which has one functional layer as far as drug delivery is concerned. It excludes multilaminates and binary systems.

This is an important integer and it has a bearing on the allegations of anticipation, obviousness, insufficiency and infringement.

The defendants’ primary position is that the integer is completely unclear and accordingly the claim cannot be infringed and is insufficient. The Patent itself recognises that patients vary widely in their individual pharmacokinetic and pharmacodynamic response to opioids. They have different drug clearance rates and pain itself is highly subjective. Over time, tolerance to opioids may increase and the severity of the pain may change. Moreover, there is up to a five fold variation in skin permeability between individuals and a three fold variation in permeability across the body of any one individual.

The defendants also say that the difficult issues which arise are exemplified by a consideration of the allegedly infringing products, the Osmach and Mezolar Matrix patches. The product literature for these makes clear that any particular patch may:

In these circumstances, the defendants contend it is impossible to determine conclusively whether any particular patch contains an amount of fentanyl sufficient to induce and maintain analgesia in a human for at least three days. A patch may induce analgesia for three days in one patient but not in another. A patch which induces analgesia in a particular patient when first administered may fail to do so at a later date. The defendants say all of this produces a hopeless degree of uncertainty.

Alza has taken different positions during the course of the action. Dr Enscore explained in his first report, and I accept, that the skilled person would be very familiar with the three day treatment regimen of Durogesic. The patches are applied and replaced in sequence, such that a sufficient level of drug is maintained in the blood to ensure that the induced analgesia is sufficient to treat the level of pain experienced by the particular patient. He also explained, and again I accept, it was well understood that there is an initial period during the first three day application when the blood concentration is rising but is below the minimum level required for analgesia; and further, it was well understood that it might be necessary to try different patch sizes and to titrate upwards to find the correct dosage level for any individual.

Dr Enscore concluded the skilled person would understand the patch of the invention had to be capable of use in a multi-day regimen like that used for Durogesic. Dr Enscore also explained that in vivo tests are necessary to show whether the three day requirement was satisfied, a view supported by Alza in opening because, it said, in vitro tests can only ever be predictive of in vivo performance. In particular, a patch that exhibits a particular in vitro flux profile may give an unexpected in vivo profile. Further, the amount of time that any particular patch remains stuck to a person will play a large part in determining how much drug that person will receive. Overall, Alza argued, the patches of the invention must be comparable to Durogesic.

During the course of its opening submissions and again in closing, Alza accepted that the claim is broader than patches which are bioequivalent to Durogesic, and submitted it is enough that a patch causes analgesia in some humans in a three day cycle of applications.

In my judgment this modified construction contended for by Alza is correct. The skilled person would not understand the claim to be limited to patches which are bioequivalent to Durogesic, nor to patches which induce analgesia over three days in all humans. The range of humans and their inherent variability means that no patch could ever satisfy this requirement. The specification would be understood to mean that the patches of the invention must contain sufficient analgesic to induce and maintain analgesia in some patients for three days. It matters not that other patients may suffer breakthrough pain or that analgesia in such other patients may not last for the whole three days.

The next question is how the skilled person is to determine whether this requirement is satisfied. I accept that the specification envisages this may be determined by in vivo tests on healthy volunteers and determining the plasma levels generated. In this regard the specification provides various normalised and standardised ranges in paragraphs [0063] and [0064] and, more importantly, the skilled person would know that the Physicians Desk Reference (also known as the PDR) specifies that minimum effective plasma concentrations of fentanyl in opioid naïve patients range from 0.2 to 1.2 ng/ml. So long as the plasma levels remain above this level in at least some humans then the skilled person knows that analgesia will be induced in at least some humans.

In closing, Alza made a further concession. It accepted for the purposes of these proceeding only and on the basis of the evidence at trial, that in vitro skin permeation studies on monolithic patches provide an alternative method for the skilled person to assess whether such patches satisfy the three day requirement. In my judgment this concession was rightly made. The expert evidence was clear that the measurement of flux in properly conducted and validated in vitro skin permeation studies provides a sufficiently accurate indicator of the in vivo flux, and hence of the plasma levels. As to the lower limit on the flux that will cause analgesia in some humans, Dr Enscore thought it to be about 1 µg/hr, as described in paragraph [0065] of the Patent. I am satisfied that this is the extreme edge of the

There is only one issue on infringement, namely whether the three day requirement of the claim is (or can be) satisfied. The defendants say Alza has not established that the Osmach and Mezolar Matrix patches contain sufficient fentanyl to induce and maintain analgesia in a human for at least three days.

Both the Osmach and Mezolar Matrix patches have obtained marketing approval on the basis of their bioequivalence to the Durogesic patch. I have no doubt that any patch which meets the requirements of European marketing approval on the basis of bioequivalence to Durogesic will induce and maintain analgesia in some humans for at least three days and this was confirmed by both experts. These products fall right in the centre of the claim. Infringement is therefore established.

In the light of my conclusion on construction, I can deal with the allegation of insufficiency quite shortly. There can be no doubt that in certain circumstances ambiguity in the claims can render a patent insufficient. As Lord Hoffmann explained in the Kirin Amgen case at [121] to [131], ambiguity may not simply throw up the possibility of doubtful cases but make it very difficult, if not impossible, to carry out the invention at all.

The defendants contend that this is not a case where there are puzzles at the edge of the claim. Rather, they say, the requirement that the patch must contain an amount of fentanyl sufficient to induce and maintain analgesia in a human for at least three days is so unclear as to be insufficient. I am unable to accept this submission. The Patent contemplates in vivo tests on healthy volunteers and observing the plasma levels generated. If they are above 0.2 ng/ml then, as I have indicated, the skilled person knows that analgesia will be induced in some patients. Likewise the Patent contemplates in vitro tests to determine the level of flux a patch will generate. If it is above the lower limit of 1 µg/hr then, once again, the skilled person knows that the patch will induce analgesia in some patients. I would also emphasise that these are the extreme edges of the claim and that those seeking to practise the invention are likely to work substantially above them, as the alleged infringements in this case demonstrate.

In my judgment the claims are broad but not ambiguous and no undue burden is imposed on the skilled person in determining whether a patch falls within their scope.

The decision of the House of Lords in Synthon v SKB [2006] RPC 10 makes clear there are two requirements for a patent claim to be anticipated by an earlier published document: it must disclose the invention claimed in the patent, and the

The disclosure requirement is a strict one. The earlier document must give clear and unmistakeable directions to do what is claimed. As the Court of Appeal explained in General Tire v Firestone [1972] RPC 457 at 485-486:

In the present case there are two novelty citations, Samyang and Roy.

Samyang was filed on 6 October 2000 but not published until April 2001, shortly after the priority date of the Patent. It is therefore a novelty only citation under section 2(3) of the Patents Act 1977.

The invention of Samyang is a transdermal patch comprising two adjacent drug containing adhesive layers which have different solubilities for the drug in question. This difference affects the rate of drug release from each. By selecting appropriate polymers for each reservoir, patches can be made so as to provide an initial rapid dose of drug from the first, low solubility, reservoir and a delayed but more sustained drug release from the second, high solubility, reservoir.

Samyang describes a number of examples of patches in accordance with its invention (Examples 1-5) and two comparative examples of patches not made in accordance with its invention (Comparative Examples 1 and 2).

The defendants contend the Patent is anticipated by Examples 1 and 4 and by Comparative Example 2, but particular attention was focused on Example 4 and Comparative Example 2. The first of these, Example 4, discloses a fentanyl patch made up of two adhesive slabs side by side. One is a silicone adhesive slab which will release drug at a rapid rate. The other is an acrylate adhesive slab which releases the drug more slowly. Comparative Example 2 discloses a patch containing a single acrylate adhesive slab.

The defendants have carried out experiments based on Example 4 and Comparative Example 2 to support their argument that they each release enough fentanyl to induce and maintain analgesia for three days and, in the case of Example 4, the defendants made up a patch comprising only the acrylate slab of the example. In the light of these experiments I do not understand it to be seriously disputed that the patches tested in the experiments do indeed release enough fentanyl to satisfy the three day requirement. Accordingly, the issues which remain to be determined have been helpfully identified by Alza as follows:

whether Examples 1 and 4 disclose monolithic transdermal patches;

whether polyacrylate patches made in accordance with Examples 1 and 4 satisfy the three day requirement. It is to be noted that this is not the same question as whether the patches of the experiments satisfied the three day requirement - the reason being that the patches of the experiments contained a polyacrylate slab but not the silicone slab of the Example 4;

whether a polyacrylate patch made according to Example 1 would have a reservoir which was a single phase polymeric composition free of undissolved components.

As for point (i), the defendants contend that the fact that Examples 1 and 4 describe a binary system does not prevent a finding of anticipation because it is trite law that the addition of an additional element (here a silicone slab) does not take something out of the claims; and in any event the claim uses the word “comprising”.

It follows from my conclusion on construction that the defendants’ submission must be rejected. The claim is directed to a monolithic patch. It is a characteristic of such patches that a single entity within the patch controls the release rate of the drug. The binary systems of Examples 1 and 4 have two adhesive slabs, not one. This is not a case where the prior art discloses a patch which falls in the claim and which has another feature as well. The presence of two adhesive slabs in the binary system means it does not fall in the claim at all.

Turning to point (ii), the three day requirement, Alza submits that there is insufficient evidence for the court to decide whether this requirement is satisfied in relation to Examples 1 and 4. The experiments conducted in relation to Example 4 showed that a patch containing the polyacrylate part of the example would deliver a flux of at least 10 µg/hr over 72 hours, which is plainly sufficient. However, says Alza, the amount of drug in the polyacrylate slab may have decreased had it been placed next to the silicone slab due to its partitioning sideways between the two polymers. This contention was supported by the evidence of Dr Walters who accepted under cross examination that fentanyl would partition between the two polymers until they were at equilibrium.

The defendants respond that the point taken by Alza is a bad one because if the polyacrylate slab anticipated the claim when it was cast, it is no defence to argue that on storage the position may have become different.

I have some concern about the way this point was advanced by Alza because it was not foreshadowed in the reports of Dr Enscore. Nevertheless and not without some hesitation, I have come to the conclusion it is a good one. The experiment was not adequate to determine whether the three day requirement would have been met had the acrylate and silicone slabs been placed side by side. It is simply not possible for me to determine on the evidence whether it would or not. Moreover the defendants’ response does not meet the point. The patch must be such that it will deliver sufficient fentanyl to induce analgesia over three days. The fact that it may deliver enough fentanyl to induce analgesia at the moment it is cast is not sufficient. It must do so over the whole three days and so after the reservoirs have become partially depleted.

The case on Example 1 relied upon the experiment conducted in relation to Comparative Example 2. Dr Enscore considered it was possible to extrapolate from 12 %wt fentanyl (Comparative Example 2) to 10 wt% (Example 1) and likewise from 10 cm² to 7 cm². Hence the resultant steady state flux from the polyacrylate patch would be about 17 µg/hr and the final flux would be expected to be about 7 µg/hr. Dr Walters broadly agreed. Alza sought to put to Dr Walters that it was not possible to make a quantitative prediction because the patches were of different thickness, the patch of Comparative Example 2 having a thickness of 50 µm and that of Example 1 having a thickness of 40 µm. Dr Walters accepted that it would make a difference but believed it would not be a very big one. I agree and do not think there is anything in this particular point. Nevertheless, the partitioning point referred to above in relation to Example 4 is an equally valid objection in relation to Example 1.

It follows that the defendants have not established that polyacrylate patches made in accordance with Examples 1 and 4 satisfy the three day requirement.

Finally, I must deal with point (iii). Alza has never been asked to agree and has never agreed that anything made in accordance with Example 1 would have a reservoir which was a single phase polymeric composition free of undissolved components. The defendants led no evidence on this and asked no questions about it. It has not been established this element of the claim is satisfied.

That leaves Comparative Example 2. This is a patch comprising a single slab of acrylate material containing fentanyl and so the side by side objection does not arise. I am satisfied in the light of the evidence that this patch would provide a flux at least as high as that of the commercial 12 µg/hr patches and it therefore falls right in the heart of the claim.

In conclusion, the allegation that the Patent lacks novelty over Comparative Example 2 of Samyang succeeds. However, it is accepted by the defendants this invalidity can be cured by amendment.

Roy was published in 1996 and describes work done on various forms of drug in adhesive fentanyl patches, using polyisobutylene (PIB), polyacrylate (GELVA 737) and silicone adhesives and the production of a number of patches and tests done on them.

The purpose of the work was explained by Roy in the following passage upon which Alza places particular reliance:

I think it is fair to say that the reader would therefore understand Roy to be describing the results of an investigation into the properties of various polymers and adhesives rather than the production of finished patches.

As Dr Walters explained, Roy reports that skin fluxes from 2% fentanyl in PIB, polyacrylate and various silicones were all in the region 0.9 – 6.3 µg/cm²/h, with steady state fluxes achieved over at least 24 hours. More specifically in relation to polyacrylates, Roy made patches from GELVA 737 containing 2% and 4% fentanyl by weight. The in vitro skin permeation tests were performed with 1.3 cm² patches. Alza accepts that these patches were single phase patches free of undissolved components.

In the light of all his results, Roy concludes:

The defendants contend that Roy anticipates the Patent because it teaches the production of acrylate patches made of GELVA 737 which satisfy all the elements of the claim. Alza says there are two respects in which the attack must fail:

Roy does not specify the thickness of the acrylate adhesive so it cannot be assumed it fell within the claim limits of 0.0125mm to 0.1mm.

The experimental data based upon the Roy patches show that they do not satisfy the three day requirement.

It is correct that Roy does not give the thickness of the acrylate adhesive which he used in his skin permeation tests. However, he also carried out a membrane permeation test and for that he used an acrylate reservoir thickness of 70µm.

Dr Walters explained in his report that, unless stated otherwise, the skilled person would presume the same thickness had been used in both experiments. Thus, he said, the value of 70 µm would seem to him to be the correct one to use and he believed the skilled formulator would have done likewise. However, in cross examination he accepted the skilled person could choose a different thickness, and one outside the limits of the claim (Day 4 at 439):

In my judgment it is plain that Dr Walters did not consider it inevitable that the skilled person would make a patch falling in the claim by following the teaching of Roy. This was confirmed by the way the case was put to Dr Enscore in cross examination (Day 2 at 248):

Turning to the three day requirement, the defendants relied upon an experiment to show the flux achieved by a 4 wt% patch. I am satisfied that the skilled person would not take a single result to determine the flux and that the approach taken by the defendants in their experiments was appropriate. This gave a flux of 0.9334 µg/hr from 48-60 hrs and 0.91 µg/hr from 60-72 hrs. It was therefore below the lower limit of 1 µg/hr described in paragraph [0065] of the Patent and once again outside the scope of the claim. It is clear that the Roy 4 wt% patch does not satisfy the three day requirement as the flux is below 1 µg/hr for the final period of 24 hours.

I conclude Roy does not contain clear and unmistakeable directions to make a patch falling within the claim. The allegation of lack of novelty over Roy therefore fails. Invalidity - Obviousness

It is convenient to address the question of obviousness by using the structured approach explained by the Court of Appeal in Pozzoli v BDMO [2007] EWCA Civ 588; [2007] FSR 37. This involves the following steps:

(a) Identify the notional "person skilled in the art".

Identify the inventive concept of the claim in question or, if that cannot readily be done, construe it.

Identify what, if any, differences exist between the matter cited as forming part of the "state of the art" and the inventive concept of the claim or the claim as construed.

Ask whether, when viewed without any knowledge of the alleged invention as claimed: do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?

The last question requires the court to take into account all the relevant circumstances. It is also helpful to consider the nature of the obviousness case. Here the defendants say that there were three obvious routes for a designer of a fentanyl transdermal patch to consider, one of which was drug in adhesive without a rate controlling membrane. I think it is fair to characterise this as being an ‘obvious to try’ case, and so it is one of the kind considered by the House of Lords in Conor v Angiotech [2008] UKHL 49. There Lord Hoffmann said at [42]:

As part of its response to the allegation of obviousness, Alza submits that invention may lie in overcoming the preconceptions and prejudices of the skilled workers in the field and showing that which was thought would not work, in fact would work. I accept that is so. As Jacob LJ said in Pozzoli at [27]:

Alza also properly warns me of the danger of allowing ‘obvious to try’ arguments to invalidate commercially valuable patents in research-intensive fields.

I must also avoid hindsight. This is particularly important where, as here, there is an allegation of obviousness based upon the common general knowledge. I put it this way in Abbott v Evysio [2008] EWHC 800 at [180]:

The allegation of obviousness is also founded on a number of prior publications. Each of these must be deemed to be read properly and with interest and the public has a right to make anything which is an obvious development of what is disclosed. But I accept Alza’s submission that the fact that a document is published does not mean it necessarily forms a realistic starting point for an obviousness attack. As I said in Eli Lilly v Human Genome Sciences [2008] RPC 29 at [295]:

More recently, in Dr Reddy’s v Eli Lilly [2008] EWHC 2345 Floyd J emphasised the danger of focussing on one prior publication to the exclusion of the prior art as a whole at [170]:

In my judgment all these principles are relevant to the allegations of obviousness advanced in this case and I have them well in mind.

It is common ground that in 2001 it was obvious to seek to develop a fentanyl patch which was bioequivalent to Durogesic. The case of obviousness over the common general knowledge then runs as follows. A monolithic drug in adhesive patch was one option available to the skilled person and, due to its simplicity, probably the preferred option. Such a patch would inevitably have a backing layer with a reservoir disposed on it. A subsaturated patch would be one of the two options available to the skilled person and, due to the manufacturing and stability issues of saturation plus excess patches, probably the preferred option. It would be necessary

Alza’s answer is equally straightforward and comprises two elements. First, it contends that the prevailing attitude of the skilled person was that a rate controlling membrane was required in order to produce a fentanyl patch that displayed acceptable safety characteristics similar to those of Durogesic. The skilled person was well aware that fentanyl posed significant risks due to its narrow therapeutic window, and therefore the primary objective in developing a patch was to ensure that the maximum dose it could deliver would not put the patient at risk. Moreover, it was also well known that in some people the skin at the site of application would absorb fentanyl at an unusually high rate, and that in order to minimise the risk to these people it was believed that a patch must have a rate controlling membrane so as to provide an upper limit on the rate of drug flux.

Secondly, the prevailing attitude of those skilled in the art was that in order to achieve a sustained fentanyl release rate that achieved the same therapeutic effect in humans as Durogesic, the patch would have to contain fentanyl at saturation plus excess. The skilled person would have been aware of the importance of chemical potential in determining the flux of drug through the skin. He would also have been aware that in a subsaturated patch, the chemical potential in the reservoir and hence the flux begins to drop off as soon as the patch starts to deliver drug. By contrast, in a saturation plus excess design, the excess drug continually tops up the reservoir and thereby maintains the chemical potential and hence a relatively steady drug delivery rate. The skilled person knew that Durogesic achieved this by using a saturation plus excess design, in combination with a rate controlling membrane.

Accordingly, says Alza, it was not obvious to the skilled person that an effective generic version of Durogesic could be made by developing a subsaturated patch that did not use a rate controlling membrane.

In assessing these rival submissions, it is convenient to begin by summarising some of the main aspects of the common general knowledge.

At a general level I am satisfied the skilled person would have known there were essentially three transdermal systems, namely liquid reservoir with a rate controlling membrane, polymer laminates with a rate controlling membrane and drug in adhesive without a rate controlling membrane.

The liquid reservoir system has two principal design features which were known to bring advantages. Saturation plus excess tends to ensure that the chemical potential remains constant throughout the period of administration and this is plainly a desirable feature in a system for the delivery of a drug such as fentanyl with a relatively narrow therapeutic index and potentially serious side effects. The rate controlling membrane sets an upper limit to the system flux and so provides safety, acts to increase the resistance of the system relative to the skin, so reducing the

Nevertheless, by 2001, the drug in adhesive systems, commonly comprising polyacrylate adhesives, were undoubtedly very popular and were perceived to have the advantages of being thinner, cosmetically more appealing, more robust, less open to abuse, having better skin adherence and avoiding instability problems sometimes associated with saturation plus excess designs. I am also satisfied that it was known that drug in adhesive patches could deliver drugs over a period of a day and, indeed, that the available estradiol patch (a drug with a similar permeation coefficient to that of fentanyl) was effective for seven days. The skilled person was well aware of techniques to address a fall off in drug delivery, such as by making the patch thicker or selecting an adhesive with a higher solubility for the drug to be delivered, and so permitting an increase in the drug loading. He would also have known that the composition of the reservoir affects the release rate.

More specifically, the experts agreed the skilled person would have known that fentanyl is a potent opioid with potentially serious side effects of respiratory depression and that it was therefore only used to treat chronic pain. He would also have known that for any given individual, fentanyl had a relatively narrow therapeutic index. As for patients, he would have known that there are significant variations both between and within individuals in terms of skin permeability, even disregarding damaged skin. He would have known of Durogesic and its component elements, that it was a saturation plus solid excess design with a rate controlling membrane and that it was the only transdermal fentanyl patch available at the priority date. He would have appreciated that the rate controlling membrane was a safety feature which mitigated uncontrolled drug release, reduced the effect of skin variability and limited flux drop off over time.

Against this background I come to the heart of the issue, namely whether it was obvious to develop a fentanyl drug in adhesive patch. Here I found the evidence of the experts particularly helpful. In his reports, Dr Enscore suggested that in 2001 the skilled person would not have thought that a drug in adhesive system could be made safely and effectively in a patch required to be used for the same indication and broadly in the same way as Durogesic. However, under cross examination, Dr Enscore frankly accepted that there were advantages associated with both approaches, namely liquid reservoir and drug in adhesive systems, and that it was perfectly reasonable to favour either, as shown by this interchange on Day 2 at 161:

There are advantages associated with both approaches. A skilled formulator would examine both approaches, examine the advantages and disadvantages offered by each and make a decision.

Moreover, testing a drug in adhesive matrix and then adjusting the formulation to modify its drug release characteristics was a basic skill, as Dr Enscore accepted on Day 2 at 165:

Yes.”

He gave similar evidence to like effect a little later on the same day at 238:

That would be the way you would design a drug-in-adhesive patch, yes.

As for the rate control membrane, Dr Enscore accepted this was just one of the matters to be evaluated, on Day 2 at 193-4:

It is my opinion that clearly people have thought about doing it, as evidenced by the passages we have been reading.

In the end, Dr Enscore accepted that the skilled person would consider drug in adhesive and he would experiment with the known adhesives like the acrylates, on Day 2 at 240-241:

Once he had made a patch and actually conducted a bioequivalence study against Duragesic, had he made a patch that was bioequivalent, it would have been shown to be bioequivalent.

If he did so, he would make a patch within the claim, and he would find it worked.

Dr Walters expressed the opinion in his reports that it was well known at the priority date that formulators knew how to exercise control over drug release profiles through the choice of adhesive used and that a rate controlling membrane was not necessary for sustained release or for safety. Moreover he would always start with a preference for a subsaturated patch so as to avoid long term problems with stability. The subsaturated patches also had advantages in that they were less susceptible to misuse and risk of rupture and were the simplest to make. He believed the skilled person would try a drug in adhesive system and he would find that it worked.

Under cross examination Dr Walters recognised the importance of rate control and that a rate control membrane had always been used for fentanyl and there was no general understanding it could be dispensed with. He also accepted that zero order kinetics was the ideal for sustained delivery and accepted that this could not be achieved with a subsaturated patch. He also accepted that one would not have expected to be able to match the Durogesic in vitro flux profile using a subsaturated drug in adhesive patch. Nevertheless, he maintained that he would still conduct in vitro tests on a drug in adhesive design because of the advantages of such systems and because he thought what was important was to deliver drug in the therapeutic window and he considered that could be achieved. In re-examination he elaborated his reasoning by explaining that an increase in drug concentration or patch thickness would alleviate any tail off in the rate of flux. In considering this evidence I think it important to have in mind that Durogesic does not itself provide a consistent flux over the whole three day period, as Figure 3 of the Patent demonstrates. Moreover, and importantly, bioequivalence does not demand an exact match of the profiles but only a reasonable one. Indeed, as the Patent explains, bioequivalence is concerned with substantially the same pharmacokinetic effects as demonstrated by the AUC and C_max. The fact that the skilled person would expect a greater fall off in flux over time with a drug in adhesive patch, again as shown in Figure 3 of the Patent, is therefore by no means inconsistent with bioequivalence.

I have come to the conclusion in the light of the evidence as a whole that it was obvious at the priority date to try to develop a patch which was bioequivalent to Durogesic and for that purpose to make and carry out in vitro tests on a drug in adhesive subsaturated fentanyl patch. In so doing it was obvious to make a patch falling within the scope of the claims. The skilled person would have recognised the advantages and disadvantages associated with both liquid reservoir and drug in adhesive patches and he would have considered them both well worth trying. He would not have regarded the presence of a rate controlling membrane and an excess of drug to be essential features of any design for the transdermal delivery of fentanyl.

The attack of obviousness over the common general knowledge therefore succeeds.

I have discussed the general disclosure of Roy earlier in this judgment. I concluded it does not give clear and unmistakeable directions to make a patch having a thickness of 0.0125 mm to 0.1 mm, nor to make a patch which satisfies the three day requirement. I must therefore consider whether these differences constitute steps which would have been obvious to the person skilled in the art or whether they involved any degree of invention.

The defendants contend it would have been perfectly apparent to the skilled person that he could take the idea of a polyacrylate fentanyl patch forwards and that he would be encouraged by the data in relation to a subsaturated PIB matrix which shows little tail off over 72 hours. If he had done so he would not have encountered any difficulty in producing something in accordance with the claims. In particular, the 1.3 cm² patches used by Roy were obviously only for the purposes of the reported experimental investigation and could be increased in size to give the rate of administration required. Roy evaluated, inter alia, 4 wt% and 2 wt% fentanyl patches made of the acrylate GELVA 737. Increasing the 4 wt% experimental patch to 20 cm² (still a small patch) would give an administration rate of 26 μg/h (equivalent to the smallest commercial Durogesic patch). Likewise, increasing the 2 wt% patch to 40 cm² (still well within the typical range of up to 100 cm²) would give the same flux. Alternatively, or in addition, the skilled person could increase the concentration of fentanyl in the patch, to produce yet higher fluxes. Moreover, the thickness requirement of the claim is entirely standard.

Alza submits Roy does not claim to be teaching the skilled reader how to make a finished patch at all. Rather its teaching is limited to one element (the reservoir) in a transdermal patch and does not extend to any of the other functional elements that may be needed. It therefore does nothing to lead the skilled person away from his belief that a rate control membrane was necessary for safety reasons and a saturation plus excess design was necessary to achieve sustained release. Further, the teaching of Roy is clear as to the adhesive which should be used to fulfil the aim of sustained delivery of fentanyl transdermally; and that is silicone-2920.

Dr Walters explained in his reports why he considered it was obvious to take the steps necessary to make a patch in the claims. In particular, he said that the skilled formulator would typically aim for a patch of up to 100µm thickness and if the level of analgesia was not enough the skilled person could easily change the size or drug content of the patch to produce something with a higher flux. Moreover, the data in Roy show that silicone-2920 has a high flux rate and a low solubility for fentanyl which would raise a concern that a silicone-2920 patch might run too low on fentanyl to function properly over a three day period. By contrast, the other adhesives would not run the risk of being exhausted in this way.

Under cross examination he maintained this position. It was suggested to him that Roy’s teaching is entirely sound and that the conclusions are justified on the basis the authors are proposing silicone-2920 on the basis of its low solubility for fentanyl which means that a high chemical potential can be generated with little drug. Flux can then be maintained over an extended period by using a saturation plus excess design with a rate control membrane. Dr Walters did not agree. As he understood the paper, the authors had in mind sustained delivery from silicone for only about one day. If, on the other hand, the skilled person had a preference for sustained delivery over three days with a subsaturated patch, so avoiding long term instability and adhesion problems, then it would be plain to the skilled person that silicone2920 was not suitable and he would investigate the polyacrylates.

Dr Enscore expressed the opinion in his first report that the skilled reader would have assumed the conclusions in Roy were justified on the data presented and the skilled person would have moved forward with silicones as the preferred adhesive, with PIBs as a possible back up. He would have had no incentive to investigate polyacrylates further, and indeed would have had a positive disincentive to do so.

Under cross examination, Dr Enscore adopted a rather different position, as is apparent from the following revealing, if rather lengthy, exchange on Day 2 at 244246:

I understood Dr Enscore to accept that the skilled person interested in making a three day fentanyl patch would not simply focus on the silicones and that in the light of Roy it would have been routine and, indeed, a common thing to do, to investigate the available polyacrylates and test their in vitro flux. They could then be tested against Durogesic. If the comparison was close enough the skilled person would proceed to in vivo tests. Moreover, the Patent teaches no more than that patches made in the course of this routine investigation would work.

In my judgment the arguments advanced by Alza are artificial and involve an unduly narrow and blinkered approach by the skilled person which was not reflected in the evidence of the experts. I believe Roy is encouraging and that the skilled person would have considered the available polyacrylates for a sustained release subsaturated fentanyl in adhesive patch without a rate control membrane. It was obvious to investigate the polyacrylates for this purpose and to make a patch falling within the claims. The allegation of obviousness over Roy therefore succeeds.

There was a further argument on Roy which I can dispose of shortly. The defendants say the skilled person is entitled to repeat Roy and cast a large patch of 4% drug in GELVA 737 at any sensible thickness. From that patch he can then cut subpatches for further experiment. Even if the 1.3 cm² patches Roy describes do not fall in the claims because the flux is too low, the skilled person could cut out from his large patch subpatches to whatever size he needed for his particular experiment and such patches would fall in the claims.

I am not satisfied this argument adds anything to the general attack of obviousness. It assumes the skilled person thinks it worth repeating Roy and, more importantly, making a patch as opposed to a polyacrylate membrane. Had I rejected the general attack, I do not believe this attack could have succeeded.

The Yu Poster reports studies done by employees of Samyang into a binary system in which a patch is made up of two different adhesive blocks side by side.

On page 2, the poster refers to the use of fentanyl as an analgesic and to its transdermal delivery by the known Durogesic patch.

On page 4, the poster sets out its “Objective”. It recites that transdermal fentanyl could be administered easily without the aid of a physician, is very useful for chronic pain treatment, has a long duration of action and can be applied twice per week. It continues that, in contrast to Durogesic, the solid matrix system composed of “monolayer adhesive gives good touches and comfort to patients due to its thin and compact size”. It then states:

Experimental methods are described on page 5. Six adhesives were tested: three silicones and three polyacrylates, namely Durotak 87-2196, 87-2287 and 87-4098. The defendants fairly emphasise that all of these are listed as suitable adhesives in paragraph [0050] of the Patent, and that Durotak 87-2287 is the specific acrylate used in the examples of the Patent.

Importantly, hairless mouse skin was used for the in vitro permeation tests, and it was agreed this is a poor model for human skin.

The results appear from page 7. In vitro skin permeation studies are reported for two of the polyacrylates (Durotak 87-2287 and 87-4098) and two of the silicones. It is apparent from page 10 that the silicones gave rapid drug release over the first 24 hours, but very little thereafter. By contrast, the polyacrylates gave sustained release over 50 hours, the period of the studies.

Figure 6 on page 14 is a graphical representation of the results of a comparative study between Durogesic and a binary patch of silicone and polyacrylate. This shows that the binary patch delivers significantly more fentanyl over the first 24 hours and that delivery from the two patches then gradually converges over the next 48 hours.

It is apparent that the difference between what is disclosed and the alleged invention is the use of a single polyacrylate matrix and a direction to make a subsaturated patch without a rate control membrane.

The defendants accept that the binary patch described in the poster would not be ideal for a Durogesic equivalent due to the initial spike given from the silicone element of the patch. They contend, however, that the obvious step to take would be to remove that element and just use the acrylate layer, which is shown in the poster to give sustained release matching that of Durogesic over 72 hours, and to incorporate it in a subsaturated patch.

Alza says this approach involves hindsight and, most importantly, relying on results obtained from hairless mouse skin, a notoriously poor model for human skin. It then requires the skilled person to reject the teaching of the document itself (using silicone and acrylate polymers side by side) and perceive that he might be able to use acrylate polymers alone to produce a three day patch.

Further, it requires the skilled person to decide to avoid a saturation plus excess design and a rate control membrane despite the well known Durogesic design and the fact there is nothing in the poster to demonstrate to him that subsaturated and non rate controlled patches could be made to work effectively and safely in humans.

Dr Walters recognised in his reports that the in vitro data is obtained in hairless mouse skin but explained that historically this had been used for permeation studies even though it was known to be a poor model for human skin. He thought the skilled person would treat the results with circumspection but nonetheless read the document with interest. He also believed the data in the poster suggest that the silicones released fentanyl quickly but that the polyacrylate gave steady release over a much longer period. He also found Figure 6 of interest in teaching that the dual patch initially released more fentanyl than Durogesic, but over time the profiles of the two tended to converge. This would have suggested to the skilled person interested in a patch which was bioequivalent to Durogesic that the initial burst was not a good thing and that the constant release provided by the polyacrylate would be likely to produce a profile closer to that of Durogesic.

In cross examination Dr Walters again readily accepted that hairless mouse skin is a poor model, indeed he would not trust it at all. He also accepted that it was not possible to say the difference in profiles in Figure 6 was entirely attributable to the silicone and he was not clear as to whether the drug was present at saturation plus excess. Nevertheless he maintained the poster does teach that the solubility of fentanyl in silicone is lower than in acrylate and that if long term delivery was required then an acrylate would probably be more suitable.

Dr Enscore explained in his first report that he did not think the skilled team interested in developing a transdermal patch for use in the same indication as Durogesic would have considered the Yu Poster useful for three reasons. First, it does not address the instability problem with any patch made up of a combination of adhesives, namely that drug will tend to migrate between the reservoirs to achieve equilibrium. Second, the patches are designed to decrease the time required to achieve analgesic plasma concentrations – a consideration relevant for the treatment of acute pain but not chronic pain. Third, the patches are tested on hairless mouse skin. As to the first point, Dr Enscore considered that binary patches suffer from the serious flaw that they are inherently unstable if the chemical potential in the two contiguous polymeric reservoirs is different. As to the second point, he observed that the initial burst of analgesia required by Yu is achieved by using two reservoirs made of different polymers; the silicone to release the initial burst of fentanyl and the polyacrylate to release the fentanyl over a longer time. As to the third point, hairless mouse skin was known to be a poor predictor of flux in humans.

In cross examination Dr Enscore adopted a much more pragmatic attitude. He accepted that one perfectly clear approach to making a generic Durogesic would have been to drop the silicone, as appears from this interchange on Day 2 at 251252:

Would it not be perfectly clear that if you were not trying to make an improved fentanyl patch, if all your task was to match Duragesic, to simply dispense with the silicone layer and just use fentanyl dissolved in Durotak?

A little later he accepted it would be clear that a way forward would be to use fentanyl in polyacrylate without a rate control membrane, at 253-254:

Yes. Following on from that, you have to fine tune, but with the task of the generic Duragesic, the Samyang poster and in particular figure 6, it would be clear that a way forward would be drug-in-adhesive, polyacrylate adhesive, no ratecontrolling membrane.

These are important passages. In the end there was practically nothing between the experts. One of the obvious ways forward in the light of the Yu Poster was to make a polyacrylate subsaturated patch without a rate control membrane. The Patent is obvious in the light of this citation.

The Yu Abstract reports an evaluation of the diffusion characteristics of several adhesives with a view to designing a novel transdermal delivery system for fentanyl, in which two adhesive matrices are positioned in parallel.

Three polyacrylates were tested, namely Durotak 87-2196, 87-2287 and 87-4098, and three polysilicones. In vitro fentanyl flux through human skin from adhesive matrices was conducted using modified Franz diffusion cells at 32ºC. It was found that the solubility of fentanyl in the polyacrylate adhesives was about 10 times higher than those in the silicone adhesives. The section headed results reads:

The defendants say that based upon this teaching the skilled person would have known that he could achieve 72 hour sustained release of fentanyl from a polyacrylate adhesive patch. Alza counters the skilled person is not taught whether the patches were saturated or subsaturated and the Yu Abstract does nothing to dissuade him from adopting that which he would have thought necessary, namely a saturation plus excess design with a rate control membrane.

In his report, Dr Walters accepted that one cannot tell from the abstract the patch thickness, nor the area, nor whether it was saturated or subsaturated but the information that acrylate drug in adhesive patches provide sustained delivery for 72 hours would be encouraging and the skilled person would appreciate that one option would be to make a subsaturated patch.

In the course of his cross examination, Dr Walters maintained there was enough information here to convince him to carry out further experiments on the acrylates to see if success was achievable, as appears from the following exchange on Day 3 at 413-414:

This abstract tells me that I could probably get sustained delivery, maybe not zero order, but I could get sustained delivery, from an acrylate for 72 hours. I would do my own experiments from there to see what kind of levels I would get.

Dr Enscore explained in his third report that the abstract simply does not contain enough information to allow any decisions to be made as to patch design. But under cross examination he again accepted that the abstract teaches that polyacrylates will deliver fentanyl at acceptable rates for up to 72 hours, as appears from these answers on Day 2 at 255-256:

OK, they deliver 1 to approximately 4 for up to 72 hours.

I think it is clear from this that Dr Enscore was contemplating a subsaturated drug in adhesive and without a rate control membrane. The abstract encourages the skilled person to investigate the polyacrylates which have been shown to provide extended release of fentanyl over 72 hours at a level sufficient to induce analgesia in some patients. The skilled person would not have known the investigation would be successful; but it was obvious to try.

In my judgment the Patent is obvious over the Yu Abstract.

Permatec describes an invention relating to a novel composition for sustained and controlled transdermal drug administration comprising a combination of saturated and unsaturated fatty acids or alcohols of different chain lengths as permeation enhancers. It contemplates the use of monolithic patches for multi-day release over a period of up to seven days.

A long list of drugs which can be used in the invention appears in paragraph [0055], of which fentanyl is one, although it is not singled out for particular attention. Similarly, many different adhesives are identified in paragraph [0059], including polyacrylates.

The preferred range of thickness of the reservoirs is described as being between 50150µm and those of the examples have thicknesses varying from 80-100 µm.

In the light of this disclosure, the defendants say the skilled person would understand that a polyacrylate adhesive subsaturated patch may be made for the transdermal delivery of many drugs, including fentanyl, and that sustained delivery can be achieved for up to seven days. This was supported by Dr Walters both in his second report and under cross examination. I have carefully considered that cross examination and do not consider the position taken by Dr Walters persuasive. I believe it is tolerably clear he has simply picked out the parts of Permatec which, together, can be said to point to a patch falling in the scope of the claims of the Patent.

Dr Enscore gave evidence in his first report that a skilled person seeking to design a fentanyl patch would not have been interested in Permatec, a view which was not challenged effectively in cross examination.

In my judgment any obviousness case founded on Permatec must rely heavily on hindsight to identify the aspects of the disclosure which, when pieced together, may be said to teach a patch falling in the claims of the Patent. It adds nothing to the case based upon the common general knowledge.

Cygnus is directed to resilient patches with improved skin adhesion. More specifically it relates to patches that include a number of spaced resilient structural laminates that enable the patches to stretch in concert with the area of skin to which they are adhered and which facilitate their handling prior to application. It also teaches that propylene glycol monolaurate (PGML) can be used as a permeation enhancer to increase the transdermal delivery rate of fentanyl.

The defendants focus particular attention on the paragraph bridging columns 7 and 8 which addresses the lifetime and thickness of typical estradiol and fentanyl patches:

They also rely on the passage in column 8, lines 6 – 25, which refers to the absence of a rate controlling membrane in a fentanyl patch, and states:

The defendants then turn to Examples 20 and 21 which describe polyacrylate patches with different backing layers, one being occlusive and the other non occlusive. These are said to consist of a drug reservoir lamina consisting of 2.5% fentanyl base, 1.5% PGML and 96% acrylate polymer, and a pressure sensitive adhesive consisting of 1.5% fentanyl base, 1.5% PGML, 2.5% silicone oil and 94.5% amine resistant polydimethylsiloxane. In relation to these, Cygnus states:

Based upon this disclosure, the defendants say the skilled person would appreciate that the occlusive patch provides a steady drug release over 72 hours, and at a rate that if made at, say, 72 cm² would be expected to provide the same total drug flux as the 25 µg/hr Durogesic patch then on the market.

Dr Walters supported this conclusion in his third report. However, under cross examination he accepted there was nothing to tell the skilled person how thick the fentanyl containing siloxane layer was. Moreover there was nothing to suggest it was there simply as a thin layer of adhesive to adhere the acrylate to the skin. Indeed, he considered the siloxane layer would have an effect on drug release, that the flux would depend upon the partition coefficient of fentanyl as between the skin and the siloxane and on the chemical potential of the fentanyl in the siloxane, that it would partition between the siloxane and the acrylate and that, in a sense, the acrylate was acting as a reservoir to top up the siloxane.

Dr Enscore was cross examined on these examples and the highlight was this interchange on Day 2 at 266:

It is notable the question was put on the basis that the skilled person had been presented with a different adhesive and told to do away with the siloxane layer.

I think it plain that the allegation of obviousness over Cygnus relies on substantial hindsight to modify the multilaminate systems described so as to produce a patch falling within the claims. This citation therefore adds nothing to the allegation of obviousness over the common general knowledge.