Header graphic for print
Dangerous Drugs & Medical Devices News & Commentary on Prescription Drug & Medical Device Lawsuits

Lawsuit Over Robert Gale’s Duragesic Patent

Posted in Duragesic / Fentanyl

Here’s some expert testimony that touches on Robert Gale’s patent for the Duragesic fentanyl patch.  This lawsuit dates back to 2000.

This is also actual trial testimony, not just deposition testimony.

Technorati Tags: ,

BY MR. FIGG:

Q Dr. Weiner, where do you currently reside?

A I almost said Burlington, Vermont, but it's – it's Ann Arbor, Michigan.

THE COURT: Are you going to be able to go home for the holiday coming up?

THE WITNESS: No.

THE COURT: Quite the task master, aren't you, Mr. Figg?

MR. FIGG: I'm not sure if I am the master or the slave on that, your Honor.

Q Dr. Weiner, explain to the Court, please, a little bit of your background, what your current position is and what are you doing.

A Yes, I'm emeritus professor at the University of Michigan, College of Pharmacy. I have been teaching and doing research since about 1965. That's – that's almost 40 years. And the field, in the broad sense, my field is physical pharmacy. And physical pharmacy essentially is an area of physical chemistry that relates to pharmaceutical systems. Physical pharmacy rather than say physical chemistry, rather than say synthetic chemistry. I don't particularly deal with the chemical synthesis of drugs but the physical property of materials.

Q And you have been involved in teaching and research throughout your career?

A I have been involved in teaching and research from the very beginning, from when I received my Ph.D. degree in 1965.

Q And what has been the major focus of your teaching and research?

A Yes. From the very beginning, even for my Ph.D. work, my focus has been on biological membranes of various sorts, how things – molecules, drugs, nutrients get in and out of membranes. What membranes are made out of. And in the last 20 years or so, my field of interest has essentially narrowed to one particular membrane, which is the skin.

Q Summarize, if you would, your educational background.

A Yes. I had a Bachelor's degree in Long Island University, Brooklyn College of Pharmacy. I believe that was in 1959, I received my degree. I went to Columbia University for my Ph.D. degree, and received my degree in 1965.

Q And what were the – what was the subject matter of your degree, your degrees, your research that led to your degrees?

A Sure. This was classical types of courses toward Ph.D. degrees in pharmacy schools. Essentially they were advanced courses in various aspects of chemistry, and various aspects of biology, and then more advanced courses blending these together, so that we had subject matters in these – in these advanced areas, as they would apply to pharmaceutical systems.

Q What was the first position you took after obtaining your Ph.D. at Columbia?

A Yeah. I was asked to stay on in a faculty position as an assistant professor at Columbia, and then rose to the rank of associate professor.

Q And did you teach at Columbia? Obviously you did.

A Yes, I did. I taught at Columbia, a series of courses, both to undergraduate students, that is students getting a degree that would go into community and hospital pharmacy, as well as to graduate students, who would be getting their Ph.D. degrees and going on to academia or, for the most part, the pharmaceutical industry.

The types, of courses I taught were essentially courses in various aspects of physical pharmacy, in the chemistry and biology, as they applied to pharmaceutical systems.

Q And were you involved in teaching and research involving drug dosage forms at that stage of your career?

A Oh, yes. That's always been the case where we have worked with – with pharmaceutical systems, and that's what separated us as a pharmacy school from – from biology schools and chemistry schools.

Q Where did you go from Columbia?

A In 1972, I was invited to join the faculty at the University of Michigan, and I stayed there for the rest of my career, rose to the rank of full professor, and stayed there for the remainder of my career, and retired, I think it was three years ago.

Q Did you teach at University of Michigan as well as do research?

A Yes, I did. I taught at the University of Michigan similar types of courses. Advanced courses in physical pharmacy, dosage form design, and – and pursued my research career at the University of Michigan.

Q Now, you have used the term formulations, I believe, drug formulations?

A That's correct.

Q What is meant in the pharmaceutical science area by that term?

A Right. When we are dealing with a drug molecule, a molecule that's going to exert its therapeutic effect, it's never given to an individual as that – as that chemical moiety in itself. It's always combined with something. If it's in a tablet, it will be combined with ingredients that will allow you to form a tablet that will allow the tablet to disintegrate when you swallow it. If it's going to be as a parenteral or something you inject, it must be in a vehicle of some sort. And if it's going to be applied to the skin, there are a number of – numerous considerations of how you would present that molecule. And the molecule, together with all the other ingredients, is the formulation, or the dosage form.

Q Now, you mentioned that you have spent the last 20 years or so involved in the permeation of drugs through the skin; is that correct?

A That's correct.

Q And have you conducted research in this area while at the University of Michigan?

A Yes. I have conducted research in various areas, but for the last 20 or so years, the vast majority of my research has been involved with – with drugs, potential drugs, and formulations that are going to be applied to the skin for the purpose of best allowing the material to go through the skin.

Q And does that research involve understanding the characteristics of a drug that affect its ability to go through the skin?

A Yes. I think, probably it's best to sort of divide this up into two parts because eventually what you want to do is make a formulation. So before you begin to decide, well, what should I put in this formulation, you have to have as clear an understanding as you can of the drug molecule. So the chemist will first look at stability. Is it a stable molecule. And the physical chemist will begin to explore the various properties of the molecule. What's the size of the molecule is. Is it a big molecule or is it a little molecule. Does the molecule have a charge on it, or doesn't it have a charge on it. If it – is it what we could call a weak base or a weak acid. If you know from the chemistry that it's a weak acid or a weak base, then you will know that pH will affect the charge, or the percent of the molecules that will have a charge. So you will explore – you will explore those sorts of things.

You will want to know something about the solubility of the drug because eventually you have to use solvents, so you want to know what the solubility of the drug is in various solvents. You will want to know something like, something called the partition coefficient, because where it might be important to know the solubility of a drug, say in water, and the solubility of a drug, say in an oil, what's even more important is to know the relative solubility between the two.

So these are the sorts of things you will want to know about the drug molecule before you do even a single test about putting it in a formulation, because those kind of things will give you guidance as to what you should put in the formulation.

And once you have those things down, then you will begin to want to do some experiments with changing things in the formulation, and the simplest thing might be if you want to put something through the skin, you will want some base, some guidance and some base lines, and the first thing that's almost always done is to put this in water, and if you put it in water, you will get some – the most general kind of guidance you can get, and if you know it's a weak acid or a weak base, you will change the pH. You might change the solvents. Those are the things you would do.

Q I just interrupt because I don't want to get into the substantive issues at this point of your examination because the Court has to agree that –

A Oh, I'm sorry.

Q – you're here as an expert.

A You are doing a professor's thing.

Q A properly qualified expert.

A Professor's thing in speaking too much.

Q Plus I feel as if I should do something here.

THE COURT: Well, assuming that you are speaking so much, that means you are a professor, which means you are qualified to speak, so –

THE WITNESS: At least qualified to speak.

THE COURT: That's right.

Q During your career at the University of Michigan, have you received grants to conduct research in the field of drug permeation?

A Yes. Because in an institution like the University of Michigan or any research incentive institution, you can do anything you want in research as long as someone pays for it, and we are required to get the money to pay for all the research that we do, and I have been fortunate enough to have been supported throughout my career with grants from – from predominately the National Institutes of Health, and other government agencies, and grants from the private sector.

Q Have you served as a consultant in the pharmaceutical industry?

A Yes, I have. I have been a consultant and have consulted for somewhere between 75 and a hundred companies.

Q What are some of the companies for which you have consulted?

A Well, I think just about every major company like Merck, Novartis, Abbott, and Johnson & Johnson, to name a few.

Q And what is the nature of these consultancies that you have been involved in?

A Well, it varies greatly, but generally what happens is I am invited to give a talk. The talk is usually about something related to drugs in the skin. I will give a talk for an hour and a half, then I am moved into a room and various groups of people come and visit me in that room for various periods of time, talking to me about their problems, and how, if I may be able to help them.

And this can vary all over the place, but almost always it's about the molecules of interest to the company, or the formulations of interest to the company, and asking for my advice and sometimes guidance on how to formulate these particular molecules or if it's even worthwhile trying to formulate.

Q And have you been involved in consulting on drugs that became commercial products?

A Yes, I have. Yes, I have, during my consultantships, and some have been rather long term, and I have been involved in projects as they progressed that eventually have – have ended up as commercial – rather successful commercial products.

THE COURT: Are you still actively involved in consulting, Doctor? Or are you fully retired?

THE WITNESS: No, what I have done is essentially given up my laboratory, but I still maintain an office there, and I am still on students committee, and I have a wonderful deal that I can do a lot of work for the university and not get paid.

Q Dr. Weiner, I have provided you with a copy of defendant's trial exhibit 1198. Is that your curriculum vitae?

A Yes, it is.

Q And when did you prepare this?

A I believe it was sometime late last year.

Q Does this identify scientific publications that you have authored?

A Yes, it does.

Q How many, publications have you authored in the area of your research and specialty?

A It's about 175 publications.

Q What are the areas in which you have published?

A Well, they are referenced in the publications, and they vary quite a bit. The vast, vast majority have to do with membranes and molecules going through them, and over the last, if you trace this over the last 20 years or so, in the last 20 years, the vast majority have been on – on projects involving molecules applied to the skin.

Q Does your CV identify lectures and seminars that you have been involved with?

A Yes. And I have only put down, what are called invited seminars, when someone, company or – asks me to come down. Not when I have asked to come down to a company.

Q Sort of like this seminar you are giving?

A This would be an invited talk.

Q And how many lectures or seminars have you been involved with dealing with the subject of drug permeation through the skin?

A Yeah, I think there's been a total of about 200, and to be on the conservative side, I would say probably about only 150 of those have been specifically related to – to skin.work.

Q And you have been named as an inventor on patents?

A Yes, two.

Q Two. Have you received any honors or awards for your scientific work?

A Yes. I have received a few. The main one is I am a fellow of the American Association of Pharmaceutical Scientists, and also of the Society of Cosmetic Chemists. I am a reviewer for a number of journals, been on committees evaluating grants for federal agencies, and I have been given a special grant a few years ago by Johns Hopkins University because of my work on membranes to work on model systems for – to reduce animal testing.

Q Now, you have been retained to testify as an expert witness in this case by the defendant, Mylan, correct?

A Yes, I have.

Q Have you been retained as a consultant or an expert for Mylan before this?

A No, I haven't.

Q Have you ever worked for Mylan?

A No, I haven't.

Q Has any of your research been funded by Mylan?

A No, it hasn't.

Q And you are receiving compensation for the time that you are putting into the work on this case, right?

A Yes, I am.

Q Or you hope you are?

A Yes, I – I hope I am, yes.

Q And that's at the rate of $350 per hour?

A That's correct.

Q And this compensation-is not related in any way to the outcome of the litigation, correct?

A Certainly not.

Q Have you testified as an expert witness before in this kind of litigation?

A In patent litigation?

Q Yes.

A Yes, I have.

Q On how many occasions?

A I think it's about three or four. I have listed them in my expert report.

Q And on how many occasions have you been retained as an expert witness?

A Probably another three or four times, over – over my career.

MR. FIGG: Your Honor, at this time I would ask that Dr. Weiner be qualified as an expert in physical chemistry and pharmaceutics related to transdermal drug delivery.

MR. LEWIS: No objection.

THE COURT: All right, so qualified.

Q Dr. Weiner, I would like to address some of the concepts that we have heard about throughout the trial up to now.

Have you had experience in evaluating the permeability of drugs through the skin using in vitro flux experiments?

A Oh, yes, quite a bit.

Q And we have a graphic, I believe, showing how those kinds of – showing the apparatus that's used for conducting those experiments?

A Yes.

Q With the assistance of this graphic, can you explain to the Court how in vitro flux experiment is conducted?

A Yes. It's – this is a classic type of diffusion cell, and it's fairly simple in design. There's really three parts to it. There's this top part here, which is called – I have it on the screen. If I point here that's not going to help.

Q No, you have to use that pointer –

THE COURT: Well, I can be looking in that direction. I was just looking at the screen.

A This part here, this top part is called the donor area. In other words, this is the part that you put the dosage on. It could be anything from a simple solution to a final dosage form.

And then there's the second part, is – now it's writing – which is the membrane, and that can be any membrane. It could be a polymer film. But the membrane we are interested in is human skin. So human skin would be here.

And the third part looks a little complicated but a lot of this is bells and whistles. This is called the receiver compartment, and that's where the drug will go from this donor compartment, through the skin, and into the receiver compartment.

The other things in here are things to keep the temperature constant, so we know what the temperature is. Someplace where you can take a measurement. That's why this is called a sampling port. We put a pipette or something in and draw out a sample.

So what you do with this thing is you – you have the composition of interest, which as I said could be something as simple as a solution of the drug in water, and you will put it in there, start it going, make sure the temperature's okay. You have a stirring thing in there. So as it goes into the receiver compartment, it's uniform. And then you will take a sample every – at some periods of time. Typically it might be after one hour or after two hours, and various time periods, maybe every hour. And you will keep the experiment going on, usually for 12 hours or for 24 hours.

So you have a set of data. And the set of data is how much you got out of this receiver compartment or receptor compartment versus time, and you can plot it. And now you have your flux data.

But there's one other little thing. The size of this can vary. It can be pretty big or pretty small. So.if it varies, the area of the skin will vary. So people will know what you are doing, will understand your data, you will normalize it. In other words, if you use a five square centimeter piece of skin and somebody else uses a three square centimeter piece of skin, they are going to get different flux data. So to keep it normalized so everybody's talking about the same thing, you will normalize it, so instead of the amount per unit time, you will say the amount per square centimeter per unit time.

So almost in all cases, when people talk about flux, unless they say otherwise, they are talking about the amount per time per square centimeter.

Q Now, this is just one example of these types of devices take different forms, correct? And as you say, different sizes?

A Some are. You pull by hand; some you make, they are automated, it pulls it by itself. But that's right, there will be different sizes.

Q What's that spring-like looking thing in it?

A That is probably a mixing device. To make sure it's uniform.

Q To keep the solution circulating?

A That's right. You will want to know when you take a sample that it's uniformly dissolved.

Q Now you have referred to putting liquids in the donor area. Can you test patches on this as well, or transdermal systems?

A You can test finished products, and that's what's usually done at the end.

Q In the 1983-84 time frame, were in vitro flux experiments commonly used, uncommonly used in assessing the permeability of materials through the skin?

A Yes. That's the first thing that's done. It's – numerous things you do in the final development of a – of a dosage form, but I think it's totally common practice that that's number one. That's the first thing that you do. The first piece of information you are going to – you are going to get. And in fact, this type of experiment often creates a go/no-go situation. Do you carry on with this or don't you carry on with this.

If I was going to take some bizarre molecule of a million molecular weight and I put this in and I try in a number of ways and I can't get a single molecule through, that's going to tell me, forget the project. But – so this will give me enormous amount of information about possibilities. It will give me an enormous amount of information about what pH is going to do. And it will give me an enormous amount of information about the effects of solvent on this particular system.

Q Are flux results involved in any way in submissions to the Food and Drug Administration in connection with drugs?

A In my recollection, they expect that. They expect to see your flux data in submitting papers to the FDA.

Q Are in vitro flux results – withdrawn.

In the 1983-1984 time frame, were in vitro flux results considered to be predictive of the permeation of drugs in vivo?

A Yes. They're predictive. In no way does an in vitro experiment give you the answer with a hundred percent certainty that you are going to get a final product. But it's predictive of permeation through the skin.

THE COURT: Was this device that you have got, I don't know what the number is, but on the screen, was this in place in 1984?

THE WITNESS: You know, your Honor, I am not really certain. We people in the field of transdermals kind of steal slides from other people all the way through in giving demonstrations. And I am not really sure if this is the one that was – but if it wasn't, it was a very similar device.

THE COURT: Well, I just wonder if there's any development in the art, that is improvement in the ability to predict the flux rates between 1984 and presently?

THE WITNESS: I understand your question. I think there's been a lot of advances in making life easier for the formulator. In other words, to instead of pulling samples, there are even devices now that will automatically pull them, and put them – and actually put them into testing devices, in other words, to analyze them, that will actually take the samples and place them in a device, that may be HPLC or it might be some other analytical test, and do it.

But as far as the type of results you get, in other words, will the results be any better, the answer's no, because it's a very simple principle. You put – you put the material in, it goes through the membrane, or the skin. You take what's in the receiver compartment and you measure it.

So I don't believe that advances from the very – from reasonably near the very beginning – I mean, first ones may have had stuff leaking, I don't know, but from the times when they were used till the present day, while there are advances in the ease of use, I believe that there's absolutely nothing in there that will – that will change the results.

THE COURT: Yeah, you just described a couple of variables. The reason I asked the question is you described a variable, number one, heat, and second, circulation.

THE WITNESS: Right.

THE COURT: And I wondered if that was – if that was true in the 80s, or whether that's a relatively new addition to the science?

THE WITNESS: Well, that's a good question, because I remember the first time we were sticking thermometers in to measure, but that was always a concern. We always wanted to know what was – what was the temperature. I mean, and normally the studies were done, were done at temperatures ranging from 32 to 37 degrees. And that remains a constant, all the way through.

So – and the stirring was sometimes done by stirring rods, with magnets in there, to keep them stirring, so those –

THE COURT: Manually, you would just go in there and stir?

THE WITNESS: No, it's with a motor. It's with a motor. So you have this on a magnetized sort of thing with a magnet in there and it goes around and this little stirring bar goes around.

The question you asked was always asked by the investigator, because they are very important, and people in the field understood this, and people would take care. It's just that today, it's automatic. You don't have to worry about it.

THE COURT: Okay.

BY MR. FIGG:

Q Dr. Weiner, I would like to turn now to some questions about the Gale '580 patent that's the subject matter of this litigation, and you will find that in our binder at – as PTX 1, and PTX 2 is the January – s the January 3rd, 1989 reexamination certificate. some of the claims are in there.

A I see, yes.

Q And have you familiarized yourself with this patent?

A Yes, I have.

Q Just in general terms, could you explain to the court your understanding of what the Gale patent discloses?

A Yes. It discloses a process for inducing and maintain analgesia for the transdermal administration of fentanyl.

Q Have you focused on any claims of the Gale patent?

A Well, I may have read all the claims, but I haven't focused on all the claims, and what I did focus on was claim one of the patent, and I focused as well on certain of the specifications in the Gale patent.

What I was really interested in was parts of the Gale patent that dealt with analgetically effective rates, so I focused on parts of the patent that talked about analgetically effective rates, and I am pretty sure I also searched for claims that dealt with analgetically effective rates. So – but I didn't really fully study all of the claims of the patent.

Q All right. You did indicate you had looked at claim one and I would like to ask you some questions about that. And I think we have a graphic showing claim one?

In general, Dr. Weiner, can you explain to the Court your understanding of claim one of the Gale patent?

A Yeah. I think what I said a moment ago, it's a process for, as I said, for inducing and maintaining analgesia, and it tells you that it's in a human being, and it tells you that it's for a particular type of administration. It tells you it's transdermal administration. And it also tells you the drug, which is fentanyl. That's – that's the part that's highlighted here.

And the next part of the claim tells you that it must be at analgetically – I'm sorry, it says analgetically effective derivatives. And it also tells you it's for continuous administrationto humans for an extended period of time, at least sufficient to induce analgesia.

Q Does the claim describe details of how to deliver fentanyl transdermally?

A No, as I said it's a very broad claim. It justtells you that you use fentanyl, and you use enough to induce and maintain analgesia, and for some period of time, an extended period of time. So it doesn't tell you how much fentanyl, and it doesn't tell you for how long. It's a broad claim.

Q Have you studied the prosecution history of the '580 patent?

A Yes, I have.

Q Have you studied the reexamination file histories of the '580 patent?

A Well, I actually just skimmed through the first reexamination of it, and I didn't study that in detail but I looked at it. But I paid particular attention to the second reexamination of the – of the '580 patent.

Q And generally speaking, what is your understanding of what was involved with the second reexaminationproceeding?

A Well, another patent was discovered, and that was the Keith patent, and this was the – this was the focus of the second reexamination, was the Keith patent. Michaels was the first reexamination, and the Keith patent was the second, was the patent of the second reexamination.

Q Okay. And referring to the Keith patent, we have a graphic but everybody has seen this already anyway. The patent you are referring to is what we have been calling the Keith patent or the '962 patent, correct?

A Yes, that's correct.

Q And I take it you have familiarized yourself with that patent?

A Yes, I have.

Q Have you read the prosecution history of the Keith patent?

A Yes, I have.

Q In general terms at this point, Dr. Weiner, would you describe what your understanding is of the disclosure of the Keith patent?

A Yeah. It's – it discloses a polymeric gel matrix that includes at least one therapeutic agent or one drug for administration to the skin that will give you either transdermal – I'm sorry, for transdermal or for topical application.

Q I believe we have some graphics to assist as we go through the Keith patent, Dr. Weiner, but you have indicated that the Keith patent describes a polymeric diffusion matrix. What do you mean by that?

A It's a gel. It's what happens when you take one or more polymers, which are solids, and then dissolve them in water and heat them and let them cool down, and when that happens, you get a gel, a semi-solid instead of a liquid, and that's a diffusion matrix.

And saying it's a diffusion matrix means, matrix essentially tells you you are going to put something in there, and that thing is going to – whatever you put in, which will be a drug molecule, will diffuse or move in this matrix.

Q And is the drug dispersed uniformly throughout the diffusion matrix? Is that the way you read the Keith patent?

A Yes, it is. In pharmaceutical systems, when someone says disperse something, you assume it to mean disperse it uniformly. That's an absolute assumption.

Q Now, the Keith patent also refers to the inclusion of drugs in the matrix, right?

A That's correct.

Q And what does it say about that? We have another graphic to –

A Yes, it tells you that the matrix may further contain a therapeutically effective, amount of one or more drugs for transdermal application to a patient, and so if you take the drug in the matrix, you have a drug delivery device.

Q And does the Keith patent – again we should go through this quickly because I know the Court's heard it, but it identifies particular drugs for inclusion inthe matrix, right?

A That's correct.

Q Does the Keith patent say anything about how the drugs are delivered from this matrix?

A Yes. They say they're delivered by administration to the skin.

Q Okay. And we have just highlighted the part of the Keith patent here on this graphic that identifies the reference to fentanyl, right?

A Yes. It's a chemical name that I think no one here wants to pronounce but everyone agrees that that's the chemical name for fentanyl, and it also tells you what fentanyl is used for. That it's a narcotic analgesic.

Q What does the Keith patent tell you about the manner in which the diffusion matrix delivers the drug?

A Well, it tells you that it's for sustained release for a prolonged period, and gives you a typical time period, which is 24 hours, and it tells you that over this time period, whatever it is, but typically 24 hours, you will get a steady application of the drug.

Q I think we have the list of drugs oh the next graphic, which we can't read. Are all of the drugs listed in the Keith patent for transdermal administration?

A No, no, no. Some of the drugs are for transdermal administration and some of them are for topical administration.

Maybe I could spend a moment explaining what the difference is, if that's all right, your Honor?

THE COURT: Is that all right?

MR. FIGG: You and the witness may talk about whatever you would like, your Honor.

THE COURT: He is a professor. You are not going to control –

MR. FIGG: That's true.

THE COURT: – what he has to say here, so go ahead.

THE WITNESS: But you are the judge.

THE COURT: That's right.

THE WITNESS: When you say transdermal, the expectation is it's going to go through the skin and eventually end up in the blood circulation, so it's going to – if you apply it here, it's going to be used somewhere else in the body.

And when you say local application, what you are really saying is, I am applying it here, on my forearm, and I want this to do something connected with my forearm.

So, for example, if I have psoriasis over here on my forearm, I am going to apply it to my forearm, and that's where I expect it to work. And that is called a local application.

Q Is it also called topical application?

A That's right. And it's, called topical application.

THE COURT: And topical applications wouldn't go into the bloodstream. They are basically limited to the skin, are they not? Or am I wrong?

THE WITNESS: Well, you are more right than you think you are, your Honor, because you don't want it to go into the circulation, but the drug molecule doesn't know that, so what happens, your Honor, is once the drug goes through the skin, it – we say it doesn't have a memory anymore, and it doesn't know where it's supposed to go. So we – so that's why, in a sense, topical applications are more difficult to formulate because you really want to try to prevent too many of the molecules from going into the circulation. So it's really more of an intent than what really happens.

Q So, Dr. Keith identified – withdrawn.

Dr. Keith explained that the matrix that he was describing could be used either for transdermal or topical delivery?

A That's correct.

Q Dr. Weiner, is it clear from Keith whether fentanyl was intended for transdermal as opposed to topical use?

A Yes. He tells you what it is. It's a narcotic analgesic, and anyone skilled in the art, most not skilled in the art, would know that works systemically and not topically.

Q So that's a drug you have to get into the bloodstream to do what it's supposed to do?

A That's correct.

Q Doctor, we are going to be using some chemical terms during your examination and I am going to take you through a few of them and just ask you to explain. We have heard a great deal of testimony and discussion of the term fentanyl base.

A Right.

Q And can you explain to the Court your understanding of what that term means?

A Okay. First of all, we define it as a base, and when you say you have a base, that essentially tells you – you have a molecule that's what you call a hydrogen ion acceptor. In other words, this molecule is going to look for hydrogenions. And when it finds it, it will essentially take it into its molecule. And so the base is the molecule before it accepts a hydrogenion.

And so when you start adding hydrogen ions to the – to the system, and you do that by adding an acid, and the more acid you add, the more hydrogen ions you create, and the more of the molecule will go from the base form to the ionized form.

Q What is it in fentanyl that makes it a base?

A It's an amine group, and a molecule having an amine group is called a weak base because amine groups are quite willing to accept these hydrogen ions.

Q And amine group just means it has a nitrogen atom?

A It has a specific type of nitrogen that's connected to specific things. Not all nitrogens are amine groups, but fentanyl has an amine group which will accept hydrogen ions.

Q And if we can see the next graphic, I would like you to explain how the acid or base characteristic of a compound is expressed or measured.

I think we have gotten out of order here a little bit.

Why don't you go ahead and explain what is in this graph.

A Yes. This is what's called an equilibrium. It means there's arrows going both ways, and things can move in either direction of these arrows. So what we have here in the green part is the fentanyl base. That's the, what's called un-ionized or not charged part of the fentanyl.

Now, as you begin to add more hydrogen ions, now, you can actually know exactly how many hydrogen ions you have, and that's – those are very, very, very small numbers in terms of how they are – how they are measured, so we create a system that makes the numbers reasonable, and that's – that's called pH. So the lower the pH value because it's an inverse number, the lower the pH values – the lower the pH values, the more hydrogen ions you have. So, at a pH of one, you have an enormous amount of hydrogen ions. At a pH of 14, you have very few hydrogen ions, and people say, well, that's base.

So what happens is as you add more hydrogen ions, as the pH goes down, there's more hydrogen ions available, and this equation shifts to the right. In other words, the more hydrogen ions you have, the more pH plus, which is the ionized form – I apologize, I am going to use terms interchangeable: ionized form, salt, citrate. They all mean the same thing in a sense.

So there's the base or the uncharged form, and there's the ionized form. So the more H plus you have, the more this is going to shift towards the – towards the ionized form. And this H plus has to come from somewhere, and it comes from an acid.

So in this particular demonstrative, I picked citric acid because it could be any acid, but I picked citric acid because that's discussed in the patent.

So the hydrogen ion comes from – from citric acid, and that – that ionizes into citrate and hydrogen ion. And that's where we get the hydrogen ion. But it could come from another acid. It could come from a buffer. It could come from anywhere. It doesn't, essentially doesn't know where it came from.

THE COURT: Well, is there a particular pH level which is universally determined to be the balance between base and acidic? For instance, at one particular point, 6.5 to 7.0 was described – well, I am not so sure it's linked to it, but it was called slightly acidic.

THE WITNESS: Yes.

THE COURT: Is there a balance between the two when base becomes acidic?

THE WITNESS: Yes. What we have essentially is how acidic something is, is in terms of something – of how many hydrogen ions there are. But there's another balance somewhere in which – in which – in which there's another kind of ion called a hydroxide ion. That's really a base ion. And at a pH of seven, everything is equal. In other words, you have an equal amount of – and people call that neutral. Neither too basic or too acidic. And that's sort of a standard because actually it's right in the middle of this pH graph because the pH goes from zero to 14. So if you are 14, you are extraordinarily basic. Something very close to 14 – oh, we have –

MR. FIGG: We put a graphic up, might help you, with common examples.

THE WITNESS: Something extraordinarily basic would be lye. Something extraordinarily acid would be something like stomach acid or hydrochloric acid or Pepsi-Cola.

THE COURT: So when Keith says slightly acidic, 6.35 to 7.0, basically what he is saying is 6.5 is slightly acidic, 7.0 is not slightly acidic; is that right?

THE WITNESS: Right. I think Keith is talking about this very scale. It's – when – if you were to go to a scientist and say, with no other information whatsoever, and say, I have a neutral solution, that scientist would mean that the pH is seven Or if you go to a scientist with no other information whatsoever, and say, here's something that's slightly acidic, to that scientist it would mean it's a little below seven.

THE COURT: Okay, so then how does this translate to the testimony that the Court's already-received, the Court's already heard, that fentanyl citrate is approximately – well, when the pH is 6.5 to 7.0 – 7.0, the – it is the product, is in fact 96 percent fentanyl citrate and four percent fentanyl base, when in fact you are suggesting that it is somewhat in the middle; how does that work?

THE WITNESS: I think you have given me a segue into my next demonstrative.

MR. FIGG: Yes, please put that on.

THE WITNESS: Okay.

THE COURT: Oh, all right.

MR. FIGG: Good time, your Honor.

THE COURT: Okay.

MR. FIGG: That's okay.

THE WITNESS: Now, I said, in the absence of anything else, it's – we talk about neutral solutions, et cetera, but now we are not talking about, without, in the absence sense of anything. We are putting a molecule in. We are putting a drug in. And, as I said, this drug has an amino group that's capable of taking a hydrogen ion.

Now, different molecules will have amino groups in different places. They will have different groups associated with this group. So depending upon where the – where that amino group is, and what's near it in the organic chemistry, will decide how easily this will take a hydrogen ion. And that determines this thing you have heard about called the PKa.

And because of the structure of this molecule, and the relative propensity of it to accept hydrogen ions or give up hydrogen ions if it's going the other way, it's been experimentally determined, in fact we know it's experimentally when two different people give you two different values, determined that at this certain pH, which happens to be – and let's use 8.3, because I think everyone is accepting that value. Doesn't matter what it is, but let's take 8.3. If we have that value of 8.3, it's at that exact value for this exact molecule that you will get 50/50. Half of it will be in the base form and half of it will be in the – in the ionized form.

Now, what that also means, if anything has a PKa, it means by changing the pH, I am going to change this equilibrium because the arrows are going both ways. So now if I go up one unit, in other words, if I take away more hydrogen ions, right, because it's making more basic so there's less hydrogen ions, so if you look at this, at pH of 9.3, which is only one pH unit, but as was pointed out it's a large scale, it's very powerful, I have gone from 50/50 to 90/10.

Now 90 percent is going to be in the base form and only ten percent in the salt form. I don't have it on this demonstrative, but if I go up one more, say ten points, it's going to be 99 percent and one percent. I think you can see how powerful it is.

Now if I, go down one unit, from 8.3 to 7.3, now 90 percent of it is in the salt form or the ionized form, and only ten percent is in the – is in the base form. And if the two that I think are of most interest to everybody is pH of seven and 6.5, and at pH seven, I did a calculation of about 4.6, so I made it five percent in the – in the base form and 95 percent in the salt form. There were other numbers of four percent or three point something. That's fine. Nothing's going to change based on that. The theory isn't going to change whatsoever.

And at 6.5, I calculated only two percent is going to be in a base form. And I think there was another calculation, that said only one percent, and I will accept that. It doesn't matter, the number. So that's where essentially the – these numbers iome from. That's what's in solution. That's what's in solution only.

THE COURT: So you have to know what the pK rate is to start the analysis. So – I mean I assume. So was there something, was there something in the Keith patent which indicated that he had an understanding of the pK rate of fentanyl to begin the analysis so that he would understand necessarily that reducing the pH level to 6.5 to 7.0 would mean that 95 percent of the product was fentanyl citrate?

THE WITNESS: Yes. Well –

THE COURT: This is probably way ahead of what you –

MR. FIGG: I am perfectly happy for Dr. Weiner to respond to your question.

THE WITNESS: Yeah, I think it's fine, and I will try to give you a complete answer. Please tell me if I don't.

But he would understand because it was generally well-known that that's a weak base. Fentanyl is a weak base. And anyone with any experience in pharmaceutical systems – and this is not just pharmacists. These are – you first learn about PKa not in pharmacy but in chemistry courses. That's how important that is.

He would absolutely know that different pHs would give you different percentages of that. Now, Keith would not necessarily know at this point this exact amount. He would not know this exact amount. So –

THE COURT: What do you mean by this exact amount? He would not know that it's 95/5?

THE WITNESS: Right.

THE COURT: Would he not know that because he would not know necessarily the pK of 8.3?

THE WITNESS: That's right, he may not necessarily kn;(C)w the PKa when he – when he did the patent, he might not know the exact PKa, but he would know there was a PKa because there was a weak base. Every weak base has a-PKa, and I feel he would know that you have a PKa and that PKa would determine – would determine the relative amount at any given pH. So that would be known by anyone. But the exact values, I'm not sure he would know that.

BY MR. FIGG:

Q Dr. Weiner, there's been a lot of testimony that the, chemical name that we saw in the Keith patent is the name for the base, and you agree with that?

A Yes.

Q I would like to turn now to Dr. Keith's description of how to make his polymeric diffusion matrices. Do you understand how these polymeric diffusion matrices are prepared in the Keith patent?

A Yes, I do.

Q And can you explain that to the Court?

A Yes. The directions for the preparation of the matrices are given in various places in the – in the body or the specifications of the patent. In fact, he gives two different methods of making it at different pressures. And the most precise one is in the example that he gives, in example one of his patent.

Q I believe we have a graphic that helps with this. And we have heard some of this, but I would like for you to take the Court through your understanding of what's going on in example one.

A Yes. I kind of call this a cookbook recipe because it's – it's precise in terms of what you need to do.

So he first tells you to take 45 mils of glycerol. And by the way, your Honor, I think you have heard that term glycerol and glycerin and that's the exact same thing. Of glycerol, and 45 milliliters –

Q Just to stop you, nitroglycerin is something else?

A Nitroglycerin is very different.

Q Okay.

A Together with one percent by weight of sodium citrate are mixed together, and that's precise. And the pH is adjusted to seven through the addition of citric acid. In other words, you are adding sodium citrate, which in terms of all these definitions, is a base. And then they don't tell you how much, exactly how much citric acid you have to add, but they tell you keep adding it until the pH goes down to 7.

So that's – that's – it's pretty cookbook at that point.

The next thing is that you – this high-tech is wonderful – is that you take this mixture and heat it to 90 degrees, centigrade. That's 90 degrees centigrade, which is very close to the boiling point of water. That's quite high. And after reaching at least 70 degrees, you add these polymers. These two polymers. And these – these are two polymers that are – that are non-ionic polymers that don't ionize. And they tell you the exact type of polymer, the molecular weight and things like that. And the mixture is stirred at 90 degrees –

Q Doctor, if I could just stop you. You said these two, polymers are not ionized or nonionized, I think you said?

A Yes.

Q What is the implication of that with respect to their effect on the pH?

A They wouldn't have any effect on the pH because they don't have any hydrogens to donate.

Q Okay. Please proceed.

A Yes. The mixture is stirred at 90 degrees until you get – solution is effected. That really means until everything is dissolved, which may take about ten minutes. And it's telling you if you have larger quantities, it's going to take longer than ten minutes. So at this point, you have glycerin, the water, citric acid – the sodium citrate, and the two polymers in solution, and that's what happens up to this point.

Q Okay.

A The next thing that the – the recipe tells you to do is take – you have 45 mils, and 45, so that's 90. But now it's telling you to take 80 mils – 80 mils of this solution, and then mix it with 20 grams of a lactose triturate. Lactose triturate is ten percent nitroglycerin and 90 percent lactose. They just don't want the nitroglycerin to explode. And it's put in with lactose, and this mixture is then mechanically stirred until homogeneous.

So you have a situation where it says stir until homogeneous. It doesn't say stir until it's in solution, because there may be some solid left over. But you want this uniformly mixed.

And then the next part is directions on how to make the polymer matrix. Gives you exact instructions of how to make the polymer matrix.

Q All right. It tells you then how to – to form that into a film that becomes the matrix patch?

A That's correct. It tells you about the thickness of it, the size, et cetera. And it tells you, gives you an example of a total surface area.

THE COURT: All right. This obviously is example one. The example six is the fentanyl in the Keith patent. Are you suggesting that you just take – because this is obviously a nitroglycerin patch, right?

THE WITNESS: Right.

THE COURT: You just take the same amount of fentanyl and you put it in at the ten percent solution or if adjusted based upon the quantity in some way?

THE WITNESS: Yeah. I mean, I think if we look at example six, it's going to give you some guidance. And no, it doesn't say take that same amount. It says, by substituting an appropriate amount of fentanyl. So it doesn't say the same amount, and it doesn't, by itself, tell you the amount. It says, use an appropriate amount. And if you look and say what is that, you would expect the patent, you would hope that the patent would give you some guidance, because I think the assumption is made that the person Who is reading the patent is going to read the whole thing and not take things out of context and not take just one thing, but I think the idea is that will – will the person who is looking at this thing get some guidance into what is an appropriate amount.

THE COURT: The patent clearly gives guidance in regard to the quantity of the nitroglycerin, the ten percent.

THE WITNESS: I think it gives more than guidance. It gives absolute direction, right. Right. It's the ultimate guidance. It tells you how much. You don't have to look further.

THE COURT: No, it sounds like Betty Crocker, actually. You just follow the directions, but – so what you are suggesting is the appropriate quantity. You would see that, you would determine the appropriate quantity pursuant to example six by looking at the entire patent, I mean, obviously the claims, the specifications, et cetera, and then you determine from that what appears to be, in the patent, an appropriate quantity, and then you'd use that. Is that – is that how you arrive at the figure?

THE WITNESS: Yes. That's absolutely correct. And I think that's what someone would be – would do. Someone who reads a patent would then – wouldn't say appropriate and then throw it away. They would go and look and see, is there really guidance on – if I look at this, and I look at it logically, and plus what I know – you can't do it in a vacuum – would that, would that give me guidance, would it allow me to know what an appropriate amount is. I think that's a fair question.

THE COURT: Okay.

BY MR. FIGG:

Q Dr. Weiner, let's look at that then. Let's look at the parts of the Keith patent that you believe teach how to determine an appropriate amount, and you said you looked to the specification?

A Right.

Q And you have a graphic that refers to that, correct?

A I think I have a series of graphics that refer to that.

It's almost as if I am anticipating your questions, your Honor.

MR. FIGG: You are almost – you are almost on my outline, your Honor.

THE COURT: This is the fifth day of trial, and I don't mean to suggest that I could take Mr. Figg's place here, but there is –

MR. FIGG: I am quite sure you could not only take my place, but frankly, I –

THE WITNESS: I think you are doing better than Mr. Figg is.

THE COURT: There we have it.

Okay, now are we going to go to the ten times section of the patent?

THE WITNESS: Yes.

THE COURT: Oh, we are? Is that it?

THE WITNESS: That's one of the things, yes.

MR. FIGG: We weren't sure what the plaintiffs were going to do, your Honor.

THE COURT: I understand.

MR. FIGG: So I think we – we do have to put that in our case. So why don't we go through this quickly, Dr. Weiner.

THE WITNESS: Yes.

MR. FIGG: Because certainly everyone has heard it before.

BY MR. FIGG:

Q Is this the first part of the patent you were referring to in response to Judge Sessions' questions?

A Yes, I have it as a demonstrative. Where it got it from, first it says therapeutically.effective amount. First thing it tells you is, well, how much do you put in. You put in an amount that works that gives you therapeutic activity. That's the first thing.

Q And does the patent give you an idea for what therapy the fentanyl is intended for?

A Yes. It tells you that it's a – it tells you that it's a narcotic analgesic. And that's in a couple of places. So it tells you, use a therapeutic amount, and now it's telling you what to use it for.

Q And so what would therapeutically effective mean, as connected with a narcotic analgesic?

A That it will induce and maintain analgesia.

Q And can we have the next graphic. Is this the next part of the patent to which you were referring?

A Yes.

It says the amount of drug dispersed in the diffusion matrix can be varied in accordance with the desired dosage and the length of time the matrix is to remain on the skin.

In other words, it's basically telling you that if you want to use it for one amount of time, you are going to have – you are going to have to put some amount in; and if you want to use it, for example, if you want to use it for 12 hours or 24 hours, here's an amount to put in, but if you are going to use it for 72 hours, you are going to have to put a different amount in. So it's broad enough to cover various, various times. And also various doses. There might be situations where you will want to put it on a small child, and another situation where you will want to put it on a 320 pound linebacker, and they would be different – different dosage. They conceivably could be different dosages and different amounts. So it reads to that, that situation.

Q And Dr. Weiner, how would a skilled – so if I understand the approach that you are describing, is you determine what a therapeutically effective amount is and then you use that amount for determining what goes into the matrix itself?

A That's exactly correct. And that's going to be based on the time that you want to use it and the – and might be the severity of pain or the weight of the patient or things of this nature.

Q I think next we come to the tenfold excess language to which Judge Sessions was referring.

A Right. And it's giving you some guidance right here, and basically saying that it's going to be used for a sustained release for a long period of time, and the guidance it's giving you is once you calculate that therapeutically effective dose, then you take that number and multiply it by ten, and, that's the amount for this instance where you would have guidance for 24 hours, in this particular case.

Q So you determine how much your target for therapeutic amount for delivery is, multiply that by ten, and also factor in the length of time it will be applied?

A That's correct. Because this is for 24 hours.

Q And Dr. Weiner, we have heard a lot of testimony. What is your view of how someone would go about determining what the therapeutic amount of fentanyl is?

A Okay, what one would do is what one does in any normal thing that one has to find, is go to the literature. That's what someone would do. They would look in the literature.

Now, I think, you have to sort of remember here that any product that's used, transdermally used on the skin, even for local action, I don't remember a single case where a molecule was – was developed and devised first for application to the skin. It's almost always, this was used in some other form before, like a parenteral product in the blood or an oral product, and then normally the company then says, well, can we use this – can we use this for the skin. It's what's called a secondary use.

So there's always a lot of information out in the literature before – to go to, to see what's available. Is there anything available in the literature that's going to help me determine what this is. And people have spoken to this already at the trial, and there is, I guess some controversy, is this piece of literature good or is this piece of literature not good, and I am not a pharmacokineticist, your Honor, so I don't have the ability to go through this literature and tell you this is a good paper and this is not a good paper.

But I can tell you that you would go through the literature, exhaustively, if you are interested in that, and search for that literature, and then if you can't find it exactly, or you are not sure, there are always experiments that one can do, clinical studies that one can do to get that value.

So, while I am not – I don't have, I think, the expertise to go through line by line on those papers, because I am not a pharmacokineticist, this can be done.

Q Now, Dr. Weiner, is the idea that the person, the reader of the Keith patent, in – of ordinary skill then, would look to the literature to find out what is meant by the term therapeutically effective amount?

A Yes, you never work in an vacuum. You go through the literature and that's the first place you would look to find what a therapeutically effective amount would be.

MR. FIGG: Your Honor, this is an unusual request in terms of our time crunch here, but I am actually about to move into some much more substantive areas, things that we haven't already heard before, and