Filed: January 26, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`GRÜNENTHAL GMBH,
`
`Petitioner
`
`v.
`
`ANTECIP BIOVENTURES II LLC,
`
`Patent Owner.
`____________
`
`PGR2017-00008
`U.S. Patent No. 9,283,239
`____________
`
`DECLARATION OF DAVID BRAYDEN, Ph.D.
`
`ANTECIP EXHIBIT 2020
`Grunenthal GmbH v. Antecip Bioventures II LLC
`PGR2017-00022
`
`Page 1
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`GRÜNENTHAL GMBH,
`
`Petitioner
`
`v.
`
`ANTECIP BIOVENTURES II LLC,
`
`Patent Owner.
`____________
`
`PGR2017-00008
`U.S. Patent No. 9,283,239
`____________
`
`DECLARATION OF DAVID BRAYDEN, Ph.D.
`
`ANTECIP EXHIBIT 2020
`Grunenthal GmbH v. Antecip Bioventures II LLC
`PGR2017-00022
`
`Page 1
`
`
`
`Table of Contents
`I. Qualifications .................................................................................................. 1
`
`II.
`
`The Scope of My Work in This Matter ......................................................... 3
`
`III. Scientific Background .................................................................................. 6
`
`A.
`
`B.
`
`Pharmacokinetics and Bioavailability........................................................ 6
`
`Preclinical Development and Animal Studies ............................................ 9
`
`IV. Example 7 Does Not Disclose the Human Dosing
`Regimen of Claim 1.................................................................................... 12
`
`A. A POSA Would Not Find Example 7’s Results Reliable ......................... 14
`
`B. A POSA Would Not Assume Beagle Dog Doses of
`Zoledronic Acid Could Be Directly Scaled to Human Doses................... 14
`
`C. A POSA Would Not Dose Human Beings Based on
`Allometric Scaling Alone ........................................................................ 19
`
`D.
`
`Example 7 Does Not Teach Any Dosing
`Regimen for Treatment of CRPS in Humans ........................................... 22
`
`V.
`
`Example 3 Does Not Disclose the Human Dosing
`Regimen of Claim 1.................................................................................... 26
`
`A. A POSA Would Not Directly Scale Rat
`Doses to Human Doses............................................................................ 27
`
`B. A POSA Would Not Assume That the Purported Bioavailability
`Improvement in Dogs Would Also Apply to Rats.................................... 28
`
`Declaration .......................................................................................................... 31
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`Page 2
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`
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`I, Prof. David Brayden, declare as follows:
`
`1.
`
`I have been retained by the law firm Fitzpatrick, Cella, Harper &
`
`Scinto on behalf of Grünenthal GmbH as an independent expert to provide my
`
`opinions on certain matters related to U.S. Patent No. 9,283,239, which I refer to in
`
`this declaration as the ’239 patent (Exhibit (Ex.) 1003).
`
`2.
`
`I understand that Grünenthal GmbH petitioned the Patent Trial and
`
`Appeal Board, or PTAB, to institute a post-grant review of the ’239 patent and
`
`requested that the PTAB cancel all claims of the ’239 patent.
`
`3.
`
`I understand that the PTAB instituted a post-grant review of the ’239
`
`patent on the ground of insufficient written description in the specification to
`
`support the dosing regimen recited in claim 1.
`
`I.
`
`Qualifications
`
`4.
`
`I am an expert in the pharmacology and pharmacokinetics of human
`
`and veterinary medicines. I have extensive education, experience, and expertise in
`
`conducting and analyzing the results of preclinical animal studies in both industry
`
`and academic settings.
`
`5.
`
`A copy of my CV, which describes all of my qualifications as an
`
`expert in this matter, can be found at Exhibit 1054. The following paragraphs
`
`present selected education and experience that I believe are particularly relevant to
`
`this matter.
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`Page 3
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`
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`6.
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`I am currently a Full Professor of Advanced Drug Delivery at the
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`School of Veterinary Medicine, University College Dublin (UCD). I am also a
`
`Fellow of the UCD Conway Institute of Biotechnology.
`
`7.
`
`I received a Ph.D. in Pharmacology from the University of
`
`Cambridge, UK in 1989. Prior to that, I received a 1st Class B.Sc. Hons. Degree in
`
`Pharmacology and Toxicology, from UCD in 1984, a M.Sc. in Pharmacology from
`
`UCD in 1985, and a M. Phil. in Pharmacology from the University of Cambridge,
`
`UK in 1986.
`
`8.
`
`I was also Postdoctoral Research Fellow in the Cystic Fibrosis
`
`Research Laboratory at Stanford University from 1989 to 1991.
`
`9.
`
`After my postdoc, I helped set up Elan Biotechnology Research’s in
`
`vitro pharmacology laboratory in Dublin in 1991. At Elan, I became a senior
`
`scientist and project manager of several of Elan’s joint-venture drug delivery
`
`research collaborations with U.S. biotech companies. I worked for Elan for 10
`
`years and my work concerned various issues related to drug delivery and oral
`
`dosage forms.
`
`10.
`
`I am the author or co-author of more than 200 research publications
`
`and patents. I serve on the editorial advisory boards of Drug Discovery Today,
`
`European Journal of Pharmaceutical Sciences, Advanced Drug Delivery Reviews
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`2
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`Page 4
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`
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`and the Journal of Veterinary Pharmacology and Therapeutics. I am a Senior
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`Associate Editor of Therapeutic Delivery.
`
`11.
`
`I am a Fellow of the American Association of Pharmaceutical
`
`Sciences. I was also the Director of the Science Foundation Ireland (SFI) Research
`
`Cluster (The Irish Drug Delivery Research Network) from 2007-2013.
`
`12.
`
`I also work as an independent consultant for various pharmaceutical
`
`companies. As a part of my consultancy activities, I advise pharmaceutical
`
`companies on issues related to the design of animal studies and scaling up to
`
`human doses for clinical trials.
`
`13. Over the course of my career in industry and academia, I have worked
`
`on preclinical animal studies and on the process of going from animal to human
`
`dosing for at least 20 different drugs.
`
`II.
`
`The Scope of My Work in This Matter
`14.
`I understand that I must conduct my analysis from the perspective of a
`
`person of ordinary skill in the art, which I refer to in this declaration as a “POSA.”
`
`15.
`
`The ’239 patent claims concern methods of treating complex regional
`
`pain syndrome (CRPS) by administering about 80 mg to about 500 mg of
`
`zoledronic acid to a human being within a period of six months. Ex. 1003, ’239
`
`patent, claims 1-17.
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`3
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`Page 5
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`16.
`
`I understand that another expert has opined that, for the ’239 patent, a
`
`POSA would have an M.D. or a Ph.D. in a pain medicine relevant discipline, such
`
`as clinical health psychology or neuroscience, and 3 to 5 years of experience in the
`
`treatment or study of chronic pain management. I have applied this definition
`
`throughout this declaration.
`
`17.
`
`I understand that a patent’s specification must contain a written
`
`description of the invention. I understand that this means the specification must
`
`describe the claimed invention in sufficient detail such that a POSA could
`
`reasonably conclude that the inventor was in possession of, and actually invented,
`
`the claimed subject matter.
`
`18.
`
`I understand that when a range of values is given in a claim, the full
`
`scope of the range must be supported by a written description in the specification.
`
`19.
`
`I was asked to review the ’239 patent and offer my opinions regarding
`
`what, if anything, the animal studies reported in Examples 3 and 7, in light of the
`
`specification as a whole, teach a POSA regarding the dosing regimen of zoledronic
`
`acid for treatment of CRPS in human beings.
`
`20.
`
`In particular, I was asked to offer my opinion as to whether a POSA
`
`would have understood, based on Examples 3 and/or 7 of the ’239 patent, that the
`
`inventor of the ’239 patent was in possession of and actually invented a method of
`
`treating CRPS by orally administering from about 80 mg to about 500 mg of
`
`4
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`
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`zoledronic acid to a human being within a six-month period, as recited in claim 1
`
`of the ’239 patent.
`
`21. As part of my analysis I was also asked to review and provide my
`
`opinions regarding the declaration of the Patent Owner’s expert, Dr. Papapoulos
`
`(Ex. 2015), and the opinions he expressed in his declaration regarding the animal
`
`studies discussed in the ’239 patent.
`
`22.
`
`I am qualified to opine on what a POSA would have known regarding
`
`preclinical animal studies, and how a POSA would have interpreted the animal
`
`studies described in the ’239 patent. In my current academic post, I lecture future
`
`M.D.s and veterinarians on the drug discovery and development process and
`
`specifically teach in the area of oral absorption of drugs in human and veterinary
`
`species. Specifically, in the courses I teach to medical and veterinary medicine
`
`students, we cover the subjects of allometric scaling and the process of going from
`
`an animal dose to a human dose and vice versa.
`
`23.
`
`In addition, as a consultant to the pharmaceutical industry, I regularly
`
`work with M.D.s on designing animal studies with the intention of scaling up to
`
`human doses.
`
`5
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`Page 7
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`III.
`
`Scientific Background
`
`A.
`24.
`
`Pharmacokinetics and Bioavailability
`Pharmacokinetics (PK) is the science that describes the time course of
`
`drug disposition by the body. Even more simply, it can be summarized as a study
`
`of what the body does to a drug. It involves mathematical characterization of drug
`
`absorption, distribution, metabolism, and excretion (ADME).
`
`25.
`
`The pharmacokinetic properties of a drug can be assessed both by in
`
`vitro or in vivo methods. In vitro refers to those that are conducted in an
`
`environment outside of the body of an animal. Studies conducted in live humans
`
`or animals are referred to as in vivo studies.
`
`26. An in vivo pharmacokinetic study typically involves measuring the
`
`concentration of a drug in plasma samples taken at various time intervals after a
`
`drug is administered. Once plasma samples are collected and analyzed, one can
`
`use the data points to create a curve of plasma concentration on one axis versus
`
`time on the other axis. Ex. 1056, Shargel & Yu, Applied Biopharmaceutics and
`
`Pharmacokinetics 26-27 (2nd ed.1985). These measurements can then be used to
`
`describe bioavailability differences among drugs. Id. at 25.
`
`27.
`
`Three parameters are frequently used to describe the concentration
`
`versus time profile:
`
` Cmax is the maximum concentration of drug in the plasma;
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`6
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`Page 8
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` Tmax is the time required for the maximum plasma concentration to be
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`reached;
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` AUC is the area under the plasma concentration curve versus time.
`
`Ex. 1057, Welling, Pharmacokinetics: Processes and Mathematics 171 (Am.
`
`Chem. Soc. 1986).
`
`28.
`
`The figure below depicts a plasma concentration versus time curve
`
`following administration of an oral dose wherein Cmax, Tmax, and AUC are
`
`identified. These parameters are used to determine the rate and extent of drug
`
`absorption.
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`29. Bioavailability is defined as the fraction or percentage of the
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`administered dose of the active pharmaceutical ingredient (API) reaching the
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`7
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`Page 9
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`
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`bloodstream intact. In other words, bioavailability reflects the extent of drug
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`absorption and is measured using AUC.
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`30.
`
`The bioavailability of an API from a test formulation is determined by
`
`comparing the AUC of the test formulation with the AUC of a reference
`
`formulation typically administered by a parenteral route. When the reference
`
`formulation is an intravenous dose, the absolute bioavailability of the test
`
`formulation is determined. Otherwise, when the reference product is a non-IV
`
`dose, the bioavailability measurement is called relative bioavailability.
`
`31.
`
`In order for a drug to reach the bloodstream and become bioavailable,
`
`it must first absorb from the gut lumen across the intestinal wall. Both in the
`
`lumen and in the intestinal wall, the drug is susceptible to metabolism before
`
`entering the bloodstream. Finally, the fraction of the dose absorbed into the
`
`bloodstream must first pass through the liver and escape hepatic metabolism
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`(termed the “first-pass effect”) before becoming systemically available.
`
`32.
`
`The rate and extent of drug absorption from the intestines can be
`
`influenced by a number of factors including the physicochemical properties of the
`
`drug, such as its solubility in the gastrointestinal (GI) fluids, its degree of
`
`ionization, and its intestinal wall permeability, the nature of the drug delivery
`
`system, anatomical and physiologic characteristics of the GI tract, the presence or
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`absence of food, environmental factors, and the presence of underlying disease.
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`8
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`33. Although some similarities exist, the anatomy and physiology of the
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`GI tract differs greatly across different species. Different species may have
`
`significant differences in the overall length of the GI tract, the length/proportions
`
`of different GI tract regions (such as length of the small intestine or colon), pH
`
`values in the lumen of the different GI regions, the quantity and species of bacteria,
`
`the secretion of bile, the gastric retention times for drug formulations, as well as
`
`transit times for drug formulations along the GI tract, among other differences.
`
`Any one or more of these differences could have a significant impact on the oral
`
`bioavailability of a particular drug in different animal species.
`
`Preclinical Development and Animal Studies
`B.
`34. Broadly speaking, preclinical research encompasses the stages of drug
`
`development prior to the drug being tested in human clinical trials. The
`
`components of the process leading to clinical trials incorporate several aspects,
`
`including:
`
` Chemical development of the compound: stability, optimisation and
`
`scale-up, purification, batches for testing
`
` Pharmaceutical Development: formulations, dosage forms, delivery
`
`systems for biological testing of safety and efficacy in animals
`
` Drug Metabolism (DM) and PK: analytical techniques, metabolite
`
`detection, PK parameters in several species
`
`9
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`Page 11
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`
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` Safety Assessment: pharmacology, in vitro and in vivo toxicology in
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`several species
`
`See Ex. 1058, Hill & Rang, Drug Discovery and Development 205 (2nd ed. 2013).
`
`35.
`
`In the preclinical development of a drug, extensive animal studies are
`
`conducted to get information on the drug’s likely PK, safety, and efficacy in man.
`
`36. Data from these preclinical animal studies provide information and
`
`arguments that the drug maker can put forward to justify a “First-In-Man” Phase I
`
`safety trial, which is typically carried out in healthy male subjects.
`
`37. One of the purposes of a Phase I clinical trial is to determine the dose
`
`of the drug to administer to humans. Phase I trials are small, typically enrolling
`
`30-50 healthy human subjects. The study design is a dose escalation beginning at
`
`dose levels at a safety margin well below the No Observed Adverse Effect Level
`
`(NOAEL) observed in animals administered the same formulation by the same
`
`route of delivery. The NOAEL is the highest dose level that does not produce a
`
`significant increase in adverse effects in comparison to the untreated control group.
`
`An advanced trial design may also contain crossover dosing, and subsequent Phase
`
`I trial designs typically include dosing at the highest safe dose seen in human
`
`subjects for extended periods. See generally, Ex. 2020, 2005 FDA Guidance for
`
`Industry.
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`10
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`38.
`
`Importantly, the data generated from preclinical animal PK studies
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`does not establish a safe dose of a drug to administer to humans for treatment of a
`
`particular disease. Animal PK study data, in conjunction with other information
`
`gleaned during preclinical development, can be used to estimate the maximum safe
`
`starting dose or maximum recommended starting dose (MRSD) for a Phase I
`
`clinical trial in healthy human volunteers. See id. at 2.
`
`39.
`
`Estimating the dose levels and frequency to start with in a Phase I
`
`clinical trial requires an extensive preclinical programme of animal studies that
`
`provides an understanding of the PK profile, the relationship between
`
`pharmacological effect of the drug and PK, how it can be scaled from animals to
`
`man, and the link between the pharmacological effect of the drug and the clinical
`
`outcome. Ex. 1058, Hill & Rang at 152-53. A battery of safety and toxicity
`
`studies in different animal species is also required. Id. at 211-12.
`
`40. Guidelines and calculations for estimating an MRSD for Phase I trials
`
`are given, for example, in a 2005 FDA Guidance for Industry. Ex. 2020. The
`
`process outlined in the FDA Guidance includes (1) determining the NOAELs for
`
`multiple animal species, (2) scaling up the NOAELs to human doses based on
`
`body surface area ratios, also known as “allometric scaling,” (3) selecting the most
`
`appropriate animal species, (4) applying a safety factor, and (5) considering the
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`pharmacologically active dose. Id. at 5-12.
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`11
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`41. Determining a dose that will be safe to administer to human
`
`volunteers, let alone effective, is no small task. “[T]he extrapolation from animal
`
`toxicology to safety in man is difficult because of the differences between species
`
`in terms of physiology, pathology, and drug metabolism.” Ex. 1058, Hill & Rang
`
`at 223.
`
`IV. Example 7 Does Not Disclose the Human Dosing Regimen of Claim 1
`42.
`In Example 7 of the ’239 patent, beagle dogs were orally administered
`
`150 mg zoledronic acid equivalent either in the disodium salt form or the free acid
`
`form. There were three dogs in the disodium salt group and three dogs in the free
`
`acid group. Ex. 1003, ’239 patent col. 19, ll. 18-34.
`
`43.
`
`Each animal was given a one-time 150 mg dose, administered as
`
`three 50 mg tablets taken together. Id. The concentration of zoledronic acid in
`
`plasma was then measured for 48 hours. Id. col. 19, ll. 41-42.
`
`44. According to Example 7, the disodium salt of zoledronic acid
`
`produced significantly higher plasma levels of zoledronic acid than the free acid
`
`form in these dogs, suggesting improved oral absorption in that species. Id. col.
`
`20, ll. 17-19. According to Example 7, the 150 mg dose of the free acid form
`
`resulted in an average AUC0-∞ of 2217 ng·h/mL, while the average AUC0-∞ of the
`
`disodium salt form was 4073 ng·h/mL. Id. col. 20, ll. 26-29.
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`12
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`45.
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`Example 7 states that a hypothetical dose of about 3 mg to about 4 mg
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`of the disodium salt would be expected to result in an AUC0-∞ of about 100
`
`ng·h/mL, whereas a hypothetical dose of about 7 mg to about 8 mg would be
`
`expected to result in an AUC0-∞ of about 200 ng·h/mL. Id. col. 20, ll. 29-33.
`
`46. Dr. Papapoulos selects the hypothetical dog dose of “about 3 mg to
`
`about 4 mg” of the disodium salt of zoledronic acid mentioned in Example 7, uses
`
`allometric scaling to calculate a human dose of 9.72, and then rounds this dose up
`
`to about 10 mg. Ex. 2015, Papapoulos Decl. ¶¶9-13. Similarly, he also selects the
`
`hypothetical dog dose of “about 7 mg to about 8 mg,” uses allometric scaling to
`
`calculate a human dose of 25.92, and then rounds this dose down to about 20 mg.
`
`Id.
`
`47. Without providing supporting data, Dr. Papapoulos next states that a
`
`POSA would recognize 10 mg as the “lowest oral unit dose of disodium zoledronic
`
`acid that could be given weekly to a human patient.” Id. ¶14. He then picks a
`
`weekly dosing regimen for 1 or 2 months from among many options listed in
`
`another part of the specification and applies it to the hypothetical doses in Example
`
`7 to obtain an 80 mg dose over a two-month period. Id. ¶¶15-17. The patent does
`
`not discuss rounding or calculations of the type Dr. Papapoulos describes.
`
`48.
`
`I disagree with Dr. Papapoulos’s conclusions regarding Example 7 for
`
`a number of reasons, which I discuss below.
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`13
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`A.
`49.
`
`A POSA Would Not Find Example 7’s Results Reliable
`It is well-known that oral bioavailability may be quite variable in
`
`beagle dogs. For example, wide intra- and inter-individual variations in gastric pH,
`
`particularly in the fasting state, have been reported. Ex. 1059, Yamada et al.,
`
`Gastric pH Profile and Its Control in Fasting Beagle Dogs, 37(9) Chem. Pharm.
`
`Bull. 2539-41 (1989).
`
`50.
`
`Example 7 only used only three dogs in each group. Due to the
`
`potential for significant variation in oral bioavailability between dogs—or even in
`
`the same dog at different times—data from only three animals is not enough
`
`information to draw reliable conclusions on bioavailability. The doubling of
`
`bioavailability observed for the disodium salt may simply have been based on
`
`chance.
`
`51.
`
`Thus, in order to confirm the alleged increase in bioavailability
`
`observed for the disodium salt, a POSA would have to conduct further testing in a
`
`larger number of animals.
`
`B.
`
`A POSA Would Not Assume Beagle Dog Doses of Zoledronic Acid
`Could Be Directly Scaled to Human Doses
`52. Although beagle dogs can be “a very useful model” in preclinical
`
`testing during drug development, a POSA would know that “a significant number
`
`of cases exist for which there is a large discrepancy between the oral
`
`bioavailability observed in dogs, and that observed in humans.” Ex. 1064,
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`14
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`Page 16
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`
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`Dressman, Comparison of Canine and Human Gastrointestinal Physiology, 3(3)
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`Pharm. Res. 123-31, 123 (1986).
`
`53.
`
`In fact, oral bioavailability correlations between dogs, rats, and
`
`humans are generally very weak. Ex. 1060, Hatton et al., Animal Farm:
`
`Considerations in Animal Gastrointestinal Physiology and Relevance to Drug
`
`Delivery in Humans, 104 J. Pham. Scis. 2747-76, 2748 (2015). As such,
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`successful allometric scaling between dog and human is not the norm. In fact, in
`
`one particular study, only 11 out of 44 drugs tested, most of which were antibiotics
`
`with simple pharmacokinetics and pharmacology, showed any statistically
`
`significant allometric correlation between dog and human doses. Ex. 1061, Riviere
`
`et al., Interspecies Allometric Analysis of the Comparative Pharmacokinetics of 44
`
`Drugs Across Veterinary and Laboratory Animal Species, 20 J. Vet. Pharmacol.
`
`Therap. 453-63, 456 (1997).
`
`54. Drugs in which the doses between human and dog are correlated at
`
`least to some extent are typically drugs that are well-absorbed, have simple
`
`distribution patterns with high concentrations in blood, and are excreted via the
`
`kidney. Id. at 454-55. Most of these characteristics do not apply to zoledronic
`
`acid. As Dr. Papapoulos has written, bisphosphonates like zoledronic acid have
`
`“pharmacological properties that are unique among medications used in the
`
`treatment of osteoporosis,” including “selective uptake and long-term residence in
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`15
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`Page 17
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`
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`the skeleton.” Ex. 2025, Papapoulos, Bisphosphonates: How Do They Work?,
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`22(5) Best Practice & Res. Clin. Endocrin. & Metabolism 831-47, 832 (2008).
`
`55.
`
`Zoledronic acid is also known to have very low oral bioavailability,
`
`reported in the literature as 1% or less. Ex. 1062, Dalle Carbonare et al., Safety
`
`and Tolerability of Zoledronic Acid and Other Bisphosphonates in Osteoporosis
`
`Management, 2010(2) Drug, Healthcare & Patient Safety 121-137, 124 (2010).
`
`Most of the administered dose is not absorbed and remains in the intestinal lumen.
`
`And much of the portion that is absorbed is then sequestered in bone, resulting in
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`very different pharmacokinetics as compared to drugs wherein doses are
`
`reasonably correlated between dog and human. See id. at 122.
`
`56.
`
`There are many differences between dogs and humans in terms of
`
`anatomy and physiology of the GI tract, which account for discrepancies in
`
`bioavailability and poor allometric correlation between dog and human doses. Ex.
`
`1064, Dressman at 123.
`
`57. Because most drugs are absorbed in the small intestine, the length of
`
`the small intestine and the time the drug remains there can impact bioavailability.
`
`Dogs have a short, simple GI tract. The dog small intestine, for example, is about
`
`half the length of the human small intestine. Dogs also have much shorter
`
`intestinal retention times compared with humans—approximately 2.8 hours in the
`
`fasted state compared with 4.5 hours in human subjects. Ex. 1060, Hatton at 2766;
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`16
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`Ex. 1064, Dressman at 126-27. This means that solid dosage forms can be
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`expected to move down the small intestine quicker in dogs, with therefore less time
`
`available to contact the intestinal wall for absorption.
`
`58.
`
`In addition, weakly acidic and basic drug substances (which comprise
`
`the majority of approved oral medicines) are absorbed better when they are in their
`
`unionized state (i.e., when they do not carry a positive or negative charge).
`
`Whether the compound is in its unionized state depends in part on the pH of the
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`various different portions of the GI tract, which can therefore have an impact on
`
`bioavailability. Ex. 1064, Dressman at 127.
`
`59.
`
`In the fasted state, the dog stomach has a significantly higher pH
`
`(approximately 1.5) than the human stomach (approximately 1.3). Id. at 128. The
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`pH along the length of the dog intestine (approximately 7.3) is also higher than that
`
`in humans (approximately 6.0). Ex. 1063, Lui et al., Comparison of
`
`Gastrointestinal pH in Dogs and Humans: Implications on the Use of the Beagle
`
`Dog as a Model for Oral Absorption in Humans, 75(3) J. Pharm. Scis. 271-74, 271
`
`(1986); Ex. 1060, Hatton at 2754; Ex. 1064, Dressman at 128-29. This difference
`
`in pH can have a dramatic impact on bioavailability for a drug like zoledronic acid,
`
`and therefore “the beagle dog has not been considered to be a suitable animal
`
`species for the pharmaceutical evaluation of weakly basic and weakly acidic
`
`drugs.” Ex. 1059, Yamada at 2540.
`
`17
`
`Page 19
`
`
`
`60.
`
`In particular, zoledronic acid is a weak acid which means that it only
`
`partially dissociates into its ionized form at a pH of 7. As pH of the small intestine
`
`increases above 7, as it is likely to occur in different regions and to a greater extent
`
`in dog small intestine compared to the human small intestine, more of the drug will
`
`be in its unionized form and, thus, will likely be more orally bioavailable from the
`
`dog small intestine than from the human counterpart.
`
`61. Dogs and humans also differ in variability of fasted versus fed
`
`stomach pH, which could also influence bioavailability. Ex. 1060, Hatton at 2754.
`
`62. Dogs and humans also differ in the calcium levels present in the GI
`
`tract. This is significant because the bioavailability of bisphosphonates like
`
`zoledronic acid is known to be affected by the presence of calcium, which is
`
`believed in part to be due to the formation of unabsorbable complexes. Ex. 1065,
`
`Pazianas et al., Eliminating the Need for Fasting with Oral Administration of
`
`Bisphosphonates, 2013(9) Therapeutics & Clin. Risk Management, 395-402, 396-
`
`97 (2013).
`
`63. A POSA would have also understood other important differences
`
`between the dog and human GI tracts where different bile composition,
`
`concentrations, and secretion patterns also impact oral bioavailability of drugs. See
`
`Ex. 1064, Dressman; Ex. 1060, Hatton. The presence of bile can impact the
`
`dissolution of a dosage form and can interact with the released API to increase or
`
`18
`
`Page 20
`
`
`
`decrease its absorption. See Ex. 1066, Holm, Müllertz & Mu, Bile Salts and Their
`
`Importance for Drug Absorption, 453 Int’l J. Pharm. 44-55, 49-52 (Aug. 2013).
`
`64.
`
`In light of the fact that known differences in anatomy and physiology
`
`between the human and dog GI tracts could have a dramatic impact on the
`
`bioavailability of zoledronic acid in each species, a POSA would have understood
`
`that the hypothetical beagle dog doses in Example 7 could not be precisely
`
`estimated, let alone directly scaled, to human doses using allometric surface area
`
`calculations.1 Rather, a POSA would know that it is very likely that the
`
`bioavailability of the scaled-up human dose would be different than the
`
`bioavailability of the dog dose due to the many well-known differences between
`
`the dog and human GI tracts.
`
`C.
`
`A POSA Would Not Dose Human Beings Based on Allometric
`Scaling Alone
`65. Moreover, a POSA would not have used allometric scaling alone to
`
`determine the dose of zoledronic acid to administer to humans.
`
`66.
`
`I understand that Dr. Papapoulos has previously opined in this case
`
`that, based on the state of knowledge at the time of the ’239 patent, a POSA would
`
`never have orally administered zoledronic acid for treatment of CRPS. If this is
`
`true, the information regarding the appropriate dosing regimen would have to be
`
`1 I also note that the inventor of the ’239 patent did not attempt to do allometric scaling in
`Example 7 to convert the hypothetical dog doses to human doses, although he did purport to do
`allometric scaling for other doses reported elsewhere in the ’239 patent.
`19
`
`Page 21
`
`
`
`found in the ’239 patent in order for the POSA to understand that the inventor in
`
`fact invented a oral dosing regimen for treatment of CRPS with zoledronic acid.
`
`67. No such information appears in the patent. At best, a POSA could use
`
`the dog bioavailability data in Example 7 as a starting point from which to conduct
`
`further animal testing and human clinical trials to try to determine the appropriate
`
`oral zoledronic acid dosing regimen for treatment of CRPS in humans. These
`
`further experiments would include bioavailability studies, efficacy studies, and
`
`dose-ranging studies, among others.
`
`68. Dr. Papapoulos’s allometric calculations are not even sufficient to
`
`ensure the safety of healthy human volunteers in such clinical trials, let alone
`
`determine the ultimate dosing regimen that could be used to treat human CRPS.
`
`Dr. Papapoulos referred to the 2005 FDA guidance for estimating the MRSD in
`
`Phase I clinical trials in healthy human volunteers, but he only performed a portion
`
`of one of the five steps outlined in that guidance: Calculating a human equivalent
`
`dose based on the body surface area for just one test species.
`
`69. He skipped all of the other steps of the analysis, which include:
`
` Reviewing and evaluating animal data to determine the NOAELs for
`
`several animal species
`
` Selecting the most appropriate species from which to calculate the human
`
`equivalent dose
`
`20
`
`Page 22
`
`
`
` Applying a safety factor
`
` Considering the pharmacologically-active dose.
`
`Ex. 2020, 2005 FDA Guidance for Industry at 5-12.
`
`70.
`
`The ’239 patent does not contain the information necessary to do the
`
`analysis outlined in the FDA guidance. There is no information about adverse
`
`events and side effects, so a POSA could not determine the NOAEL or apply a
`
`safety factor, and there is virtually no data from which a most appropriate species
`
`analysis could be performed.
`
`71. A POSA would not have gone directly from an animal dose to a
`
`human dose using allometric scaling alone. A POSA would have known that not
`
`only would this fail to ensure adequate bioavailability and efficacy, it would also
`
`risk the safety of the human subjects. Further experimentation, potentially
`
`including further animal studies or human clinical trials, would be required to
`
`determine a safe dose that could be used to initiate clinical trials to ultimately
`
`determine what dose, if any, could be administered to humans for treatment of
`
`CRPS.
`
`72. Moreover, allometric scaling is generally not recommended for use
`
`for therapeutics administered by alternative routes for which the dose might be
`
`limited by local toxicities. Ex. 2020, 2005 FDA Guidance for Industry at 8. As
`
`discussed above, a POSA would have known that an oral form of zoledronic acid is
`
`21
`
`Page 23
`
`
`
`likely to be associated with local GI toxicity. Ex. 1008, McHugh et al., MER101
`
`Tablets: A Pilot Bioavailability Study of a Novel Oral Formulation of Zoledronic
`
`Acid, AACR-NCI-EORTC Int’l Conf.: Mol. Targets and Cancer Ther., B194 (San
`
`Francisco, CA, Oct. 22-26, 2007); Ex. 2005, Conte & Guarneri, Safety of
`
`Intravenous and Oral Bisphosphonates and Compliance with Dosing Regimens,
`
`9(suppl 4) The Oncologist 28-37, 29 (2004).
`
`73. Allometric scaling is also not recommended for drugs wherein
`
`distribution of the dose outside of the compartment it is administered to is very
`
`limited, as is the case for zoledronic acid. Likewise, a POSA would have known
`
`that most of the orally administered dose of bisphosphonates remains in the GI
`
`tract as it is so poorly absorbed due to poor bioavailability. Ex. 1008, McHugh.
`
`D.
`
`74.
`
`Example 7 Does Not Teach Any Dosing Regimen for Treatment of
`CRPS in Humans
`Even if Dr. Papapoulos’s allometric scaling analysis were valid, based
`
`on Example 7, there is no reason why a POSA would choose to administer 10 mg
`
`or 20 mg of zoledronic acid weekly for 4 or 8 weeks to treat CRPS, as Dr.
`
`Papapoulos suggests.
`
`75.
`
`Example 7 contains no information about the efficacy of any
`
`particular zoledronic acid dose for treatment of CRPS. Based on Example 7, a
`
`POSA could not know whether the hypothetical beagle dog doses mentioned could
`
`be used for treatment of CRPS.
`
`22
`
`Page 24
`
`
`
`76.
`
`In addition, Example 7 was a one-time administration of a 150 mg
`
`dose wherein plasma levels were measured and monitored
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