“The practice of the present invention will employ, unless otherwise indicated, conventional methods used by those in pharmaceutical product development within those of skill of the art. Such techniques are explained fully in the literature. See, e.g., Patini, G.A. and Chein, Y.W., Swarbrick, J. and Boylan, J.C., eds, Encyclopedia of Pharmaceutical Technology, New York: Marcel Dekker, Inc., 1999 and Gale, R., Hunt, J. and Prevo, M., Mathiowitz, E., ed, Encyclopedia of Controlled Drug Delivery Patches, Passive, New York: J Wiley & Sons, Inc, 1999.”
“Thus, as evidenced from the results tabulated above and illustrated in Figures 3-8, the monolithic, subsaturated, transdermal patch of the present invention comprising a drug reservoir comprising a single phase polymeric composition comprising a subsaturation concentration of the drug, are bioequivalent products to the rate-controlled, saturated DURAGESIC fentanyl system. In particular, the monolithic subsaturated patches according to the invention display pharmacokinetic parameters comparable to the transdermal DURAGESIC fentanyl system.”
“When the prior inventor’s publication and the patentee’s claim have respectively been construed by the court in the light of all properly admissible evidence as to technical matters, the meaning of words and expressions used in the art and so forth, the question of whether the patentee’s claim is new … falls to be decided as a question of fact. If the prior inventor’s publication contains a clear description of, or clear instructions to do or make, something that would infringe the patentee’s claim if carried out after the grant of the patentee’s patent, the patentee’s claim will have been shown to lack the necessary novelty, that is to say, it will have been anticipated… If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee’s claim, but would be at least as likely to be carried out in a way which would not do so, the patentee’s claim will not have been anticipated, although it may fail on the ground of obviousness. To anticipate the patentee’s claim the prior publication must contain clear and unmistakeable directions to do what the patentee claims to have invented… A signpost, however clear, upon the road to the patentee’s invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee.”
“In recent years, various pressure-sensitive adhesives were considered for fabricating transdermal delivery systems. To fabricate such a transdermal device, the drug was either dissolved or dispersed in a polymeric solution, and a thin film of desired thickness was then prepared by the solvent-cast method. The rate of release of drug from such an adhesive matrix is governed by drug solubility and diffusion coefficients in polymer. Usually, these parameters were greatly influenced by the physicochemical properties of the polymer or adhesive. Therefore, it is important to evaluate the physicochemical parameters of an adhesive to design a suitable transdermal system that would eventually deliver a drug at a desired rate through skin for an extended period. …”
“In summary, the diffusion coefficient of fentanyl in silicone2920 adhesive was the highest among the four pressuresensitive adhesives examined. The silicone-2920 with 2% drug loading provided the highest skin flux. Because of low drug solubility, a high diffusion coefficient, and a low Kp/w, the silicone-2920 adhesive appears to be a very promising adhesive candidate for designing a transdermal device with minimum drug loading to sustain the delivery of fentanyl at a desired rate to induce analgesia in humans for the relief of acute and chronic pain.”
“Q. If you want to make an acrylate patch with fentanyl in, Roy does not specify a thickness to use that acrylate layer, does he? A. No. Q. Mr. Watson put to Dr. Enscore, the day before yesterday, a paragraph in the Permatec patent -- I don't know if you remember that -- where there was a suggested preferable range for the adhesive layer of 50 to 150 microns. A. Yes. Q. And Dr. Enscore agreed with Mr. Watson that those were reasonable thicknesses traditionally used in transdermal devices. You would agree with that? A. Yes. Q. If you wanted to make an acrylate patch with fentanyl in having read Roy, one could choose a thickness in the range of 100 to 150 microns. A. One could, but 150 microns is getting a bit on the thick side and would take a long time to dry.”
“Q. As I understand it, you agree that while Roy does not tell you what thickness his two Gelva patches are to be rolled at, I think you agree that 70 microns would be a reasonable place - not inevitable but would be a reasonable thickness to make. A. 70 microns is within the range of reason, yes.”
“In the Court of Appeal, Jacob LJ dealt comprehensively with the question of when an invention could be considered obvious on the ground that it was obvious to try. He correctly summarised the authorities, starting with the judgment of Diplock LJ in Johns-Manville Corporation's Patent[1967] RPC 479 , by saying that the notion of something being obvious to try was useful only in a case in which there was a fair expectation of success. How much of an expectation would be needed depended upon the particular facts of the case. As Kitchin J said in Generics (UK) Ltd v H Lundbeck A/S[2007] RPC 32 , para 72: “The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success.”” “The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success.””
“A patentee who contributes something new by showing that, contrary to the mistaken prejudice, the idea will work or is practical has shown something new. He has shown that an apparent lion in the path is merely a paper tiger. Then his contribution is novel and non obvious and he deserves his patent.”
“It is also particularly important to be wary of hindsight when considering an obviousness attack based upon the common general knowledge. The reason is straightforward. In attacking a patent, attention is focussed upon the particular development which is said to constitute the inventive step. With this development in mind it may be possible to mount an attack which is unencumbered by any detail which might point to non obviousness: Coflexip v. Stolt Connex Seaway (CA) [2000] IP&T 1332 at [45]. It is all too easy after the event to identify aspects of the common general knowledge which can be combined together in such a way as to lead to the claimed invention. But once again this has the potential to lead the court astray. The question is whether it would have been obvious to the skilled but uninventive person to take those features, extract them from the context in which they appear and combine them together to produce the invention.”
“I am unable to accept either of these submissions. In my judgment the first is a wholly artificial approach and it is not one which the law requires. I accept that the skilled person must be deemed to consider any piece of prior art properly and in that sense with interest. This emerges clearly from the decision of the Court of Appeal in Asahi Medical Co Ltd. v. Macopharma (UK) Limited[2002] EWCA Civ 466 and is necessary to prevent a patent from depriving the public of their right to make or do anything which is merely an obvious modification of what has been done or published before. But the law does not deem the skilled person to assume the prior art has any relevance to the problem he is addressing or require him to take it forward. Having considered it, he may conclude that it is simply not a worthwhile starting point and so put it to one side.”
“…there is nothing to single out Chakrabarti’s work from all the other work being conducted contemporaneously to solve that problem. An approach which focuses unduly on Chakrabarti and examines what the skilled person could or might do with that document, to the exclusion of the prior art as a whole, is therefore tainted to some degree with hindsight.”
“Q. Now, Dr. Walters I would suggest to you very fairly pointed out that whereas he would favour a subsaturated patch, there may have been those that would have favoured a suspension patch. Now, would you agree that it is one of those things where reasonable men can differ? A. Oh, absolutely. Q. So you are not suggesting that Dr. Walters' attitude was atypical of a significant part of those in this field in 2001 that you would aim for sub-saturation if you could achieve it? A. 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. Q. As everything in this art, it is all a trade off, is it not, in the sense that if you go subsaturated you are probably going to need a thicker patch for a given adhesive? A. To avoid fall off, yes. Q. Again, how much thicker? Can we live with it? It is a matter of judgment and trial and error that the skilled formulator -- that is what he does. A. Correct.”
“Q. Now, there are a number of points arising. First, you agree, I assume, that when you have produced a particular adhesive drug matrix, you can easily test it to see what its release characteristics are and then by adding enhancers, perhaps less drug, perhaps a different adhesive, you can adjust the release rates up or down. That is all basic skill, is it not? A. Yes.”
“Q. Nevertheless, if your instinct is to go for a drug-inadhesive, you would trial various adhesives, various concentrations, carry out in vitro tests, vary the thickness, until you arrived at the profile you wanted. The Duragesic generic would be designed in exactly the same way as all the other drugs that have been drug-in-adhesives. A. That would be the way you would design a drug-in-adhesive patch, yes. Q. And the designer would be doing nothing untoward. He would be carrying out using his normal abilities and knowledge to formulate a suitable patch A. To formulate a patch he hopes eventually is suitable, yes.”
“Q. Now, I read those two paragraphs as you telling my Lord that in your view nobody would think of putting fentanyl into a drug-in-adhesive because of the concern about not having the rate-controlling membrane. Now, that just is not accurate, is it, doctor? A. It is my opinion that clearly people have thought about doing it, as evidenced by the passages we have been reading. Q. So it is not the case that the skilled man would have been put off putting fentanyl into a drug-in-adhesive by concerns that there was not the safety of the rate-controlling membrane. It was not a concern. The absence of a rate-controlling membrane would not have been a concern to the skilled man in 2001? A. It might have been a concern, but it didn't dissuade them from doing it. Q. It is just one of the evaluation points that you have to look at? A. (Nodding). …. The answer was yes.”
“Q That the skilled man is trying to make a three day patch for fentanyl, you agree he would consider a drug-inadhesive patch. You agree he would experiment with the known adhesives like the acrylates. Yes? A. Yes. Q. And he would find out that he could do it. All the patent says is, "We have done it," but the skilled man, without seeing the patent, would have arrived at that conclusion simply through routine trials, would he not? A. 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. Q. Yes, but if he is trying to make a patch that is bioequivalent, that is going to be his design goal. He wants to make a drug-inadhesive. He will experiment with different acrylates until he finds the right combination of thickness. It is just all routine, is it not? A. It depends on how you define routine. I mean, it is --- Q. Nobody arrives at a drug, sorry - I didn't mean to cut across. Did you finish? A. That is OK. Q. Nobody designs a drug-in-adhesive just "there it is". For all the different drugs, you run trials with different adhesives, different concentrations, different thicknesses. That is what the doctors and the Walters and people working at Alza are paid to do [sic]. That is routine. A. You apply a design method to the patch and you develop a patch. I can't argue against that.”
“Q. Now, this is published in 1995. Six years later, Dr. Walters and other workers in the field have a wide variety of adhesives which they can experiment with, including increasingly acrylics. Now, you are not suggesting to my Lord that there is anything other than a routine investigation to compare acrylics to PIB for potential use in a three day patch. A. It appears to be what Roy and Cleary did in this paper. Q. But you would want to try it. He only tried Gelva 737. Six years later, you would want to try it with Durotak 4098 and 2287. There are whole new kids on the block in terms of acrylics. A. I have no idea when those adhesives were introduced. I don't know if they were available in 1995 or not. Q. Doctor, you are a skilled man. You are using your experience, the knowledge that you have to test a variety of formulations to get the best combination. Are you suggesting to my Lord that it would require anything other than mere routine investigation to try dissolving fentanyl in some of the known popular polyacrylates existing in 2001 and to test them for their in vitro flux? A. No, that would be a common thing to do. Q. And if you did that, you would find that 4098, for example, would give you a flux of the type that we see in the experiments. A. That is likely. Q. That would be something that you could then test in vitro against Duragesic. If the comparison was close enough, you could go forward into in vivo tests. A. Yes. Q. So what does the patent tell you that the skilled man would not have arrived at by routine investigation in the light of Roy? A. My answer would be that it worked. Q. The skilled man would anticipate from his in vitro investigations that it would work, would he not? A. If he matched Duragesic flux and managed to do that with a reasonable mass loading of fentanyl at a reasonable thickness and did not see much greater variability in the permeability across the skin dermas he was using compared to Duragesic, that would give him great hope that it would work in vivo. Q. Granted the task of "make me a generic Duragesic and I would like it to be drug-in-adhesive if you can", if the skilled man had not thought of a way to do it from his common general knowledge, Roy clearly points the way - don't need a ratecontrolling membrane, choose the right adhesive and you will be there. A. Given that you don't care what the thickness is going to be, and fentanyl content, yes, absolutely. Q. You would experiment to see whether the thickness was acceptable or not. A. Yes. Q. But it would certainly be worth trying. A. Sure.”
“To fabricate such a matrix transdermal device, several pressure sensitive adhesive polymers (acrylate and silicone) were characterised with respect to fentanyl’s solubility, diffusion coefficient and permeability coefficient. In addition, the skin flux of several combinations of these adhesives were evaluated to optimize the matrix formulation adequate for inducing sufficient analgesia in a human.”
“Q. If you were tasked to produce a generic Duragesic and you were wanting to make it bioequivalent to get the shortcut regulatory approval, you would know that the initial hit aspect would have to be avoided because you wouldn't have bioequivalence, would you? A. Correct. Q. 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. That would be one approach. You could dispense with the acrylate and use silicone and adjust the loading and pick one with the solubility you wanted and possibly achieve the same result. Q. So if you were tasked with making a bioequivalent Duragesic, and you had the Samyang abstract, it would suggest to you two ways forward. Both would be drug-in-adhesive. Yes? A. Yes. Q. No rate-controlling membrane? A. They do not use a rate-controlling membrane. Q. And it would then be a matter of design choice whether you experimented to get the flux as close to Duragesic as you wished with the polysilicone or with the acrylic. A. Yes.”
“Q. The point is, how do I make a bioequivalent patch to Duragesic? In the Samyang poster, and particularly in figure 6, there is your answer, is it not? It is demonstrated that acrylic will give you a reasonable in vitro match. You are going to have to fine tune it and ---- A. Clearly you have to fine tune it because there is more of a difference between the two curves. There is more difference between the two curves than can be accounted for with the amount of drug in the silicone layer. Q. 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. A. A way forward, yes. Q. And as to whether you would make it saturated or subsaturated, you would wish to make it subsaturated if you could accommodate that in an acceptable thickness. A. I wouldn't, but ---- Q. Others would. A. Others might.”
“In vitro drug permeation through skin from adhesive matrices was highly dependent on the kind of adhesives. In the case of silicone matrix, fentanyl permeated the skin fast, resulting in the high permeation rate and short time lag. On the other hand, acrylate matrices showed a relatively lower and sustained skin flux over 72 hours.”
“MR. TAPPIN: So, doctor, this abstract would not persuade you that you could make something equivalent to Duragesic just using an acrylate drug-in-adhesive patch, would it? A. 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. Q. Doctor, would it be fair to say that if you were given this abstract, before taking any decisions on it, you would really want to see the poster or the presentation of which it was an abstract? A. Well, that is what one normally does, if you go to a conference and you have read the abstracts beforehand and decided which posters you are going to go to. Q. I mean, you would want to see the actual data, would you not, before making any decisions? A. I would like to see the human data, yes. Q. Would it be fair to say really, doctor, there is not enough data in this abstract on which to make any decision? A. I think there is enough data there to convince me to consider using the acrylates to do some further experiments with. Q. But, doctor, you would not think, on the basis of this, that you could make something bioequivalent to Duragesic using acrylate drug-in-adhesive. A. To the experiment - and find out. Q. But if you were asked, doctor, would you, on the basis of this, expect to succeed, you would have to say that really you would have no idea. A. Of course I would have no idea. I would want to try it myself and find out.”
“Q. Again, if you are trying to make a generic Duragesic, this document is also telling you polyacrylates will deliver fentanyl at acceptable rates for up to 72 hours. A. OK, they deliver 1 to approximately 4 for up to 72 hours. Q. That is in the Duragesic ballpark, is it not? 4 mcg per centimetre squared means that you can get to 100 mcg an hour with a 25 square centimetre -- it is all right for everybody else, they are just standing listening, but Dr. Enscore and I have been humming away. A. Yes, they don't speak about system sizes, but one presume they could select a system size. Q. If you were dithering, "How on earth do I make a generic Duragesic?", here is the answer on a plate for you. A. Stick your acrylate adhesive and hope that you get lucky relative to matching the Duragesic transdermal flux profile with acceptable error with acceptable residual drug at the end of 72 hours. Q. But remember the claim is not limited to Duragesic. We are simply showing that it would be obvious to make a patch containing fentanyl which will deliver sufficient fentanyl over 72 hours to give analgesia and here it is reported that a polyacrylate adhesive will give up to 72 hours in the range of, let us say, 3 mcg per hour centimetre squared. That is clearly in any sensible size patch, 10, 20 cm squared, going to be giving you the flux of fentanyl that you would need for analgesia for chronic cancer pain. A. In some patients. Q. Yes. So what has the patent given you that you could not readily work out for yourself from the abstract? A. Again, I can only say that all the things came together and that the patch of the patent worked.”
“When layer 17 is the primary reservoir for drug, its thickness will depend on the intended lifetime of the device. Thicker layers (and hence more drug and, when present, enhancer) will be used to increase the lifetime. In the case of estradiol …; whereas with fentanyl the effective lifetime will be about 1 to 7 days. In estradiol …; whereas in fentanyl embodiments [the reservoir layer] will normally be about 25 to 150 microns thick.”
“Device 11 does not include means for controlling the rate at which either drug or enhancer is administered to the skin. Instead, in the case of an estradiol or fentanyl device employing PGML as enhancer, estradiol/fentanyl is presented to the skin at rates in excess of that which the treated area of the skin is able to absorb, while PGML is presented to the skin in quantities sufficient to allow necessary skin interaction. The system does not control either the rate of administration of estradiol/fentanyl or GML. Unlike ethanol, increasing the concentrations and thermodynamic activities of the PGML in the system does not increase estradiol/fentanyl flux appreciably beyond a limiting PGML concentration in the range of 6% to 10% in the adhesive layer. At PGML concentrations equal to or above this level, estradiol/fentanyl skin permeation becomes essentially constant and independent of PGML driving force in the system or estradiol loading above the limiting level necessary to provide equilibrium saturation in all layers and components of the composite.”
“Fentanyl skin flux from the occlusive system was 2.96 µg/cm2/hr, whereas the nonocclusive system gave 0.37 µg/cm2/hr. The lower flux of fentanyl from the nonocclusive system is due to the dehydration of the skin. Although the fentanyl flux decreased significantly from the nonocclusive system, a steady-state flux of 0.37 µg/cm2/hr was maintained up to 72 hours.”
“Q. But if somebody came to you and said, we have had a brilliant idea, everything is good about this patch, but we have found that the adhesive that we have been recommended from 3M, in fact it is sticky enough on its own, we are going to do away with that extra adhesive layer and compensate by putting a little bit more fentanyl into the polyacrylate layer, you would say, mmm, that is a pretty straightforward modification. Try it. A. One could try it. Q. It is something that would occur to one of ordinary skill. A. Yes.”