Janssen-Ortho Inc. v. Canada (Health)

Janssen-Ortho Inc. v. Canada (Health)
Court (s) Database
Federal Court Decisions
Date
2010-05-12
Neutral citation
2010 FC 42
File numbers
T-780-08
Notes
Digest
Decision Content
Federal Court
Cour fédérale
Date: 20100512
Docket: T-780-08
Citation: 2010 FC 42
Ottawa, Ontario, May 12, 2010
PRESENT: The Honourable Mr. Justice Zinn
BETWEEN:
JANSSEN-ORTHO INC. and
ALZA CORPORATION
Applicants
and
THE MINISTER OF HEALTH
and NOVOPHARM LIMITED
Respondents
AMENDED PUBLIC REASONS FOR JUDGMENT AND JUDGMENT
(Confidential Reasons for Judgment and Judgment released January 18, 2010)
[1] This application is brought by Janssen-Ortho Inc. (Janssen-Ortho) and Alza Corporation under section 6 of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133, as amended (NOC Regulations), for an order prohibiting the Minister of Health from issuing a Notice of Compliance (NOC) to Novopharm Limited (Novopharm) with respect to its methylphenidate product (the Novopharm Product) until after the expiration of Canadian Patent No. 2,264,852 (the '852 patent).
[2] In its Notice of Allegation (NOA) dated April 1, 2008, Novopharm alleged non-infringement and improper listing against the '852 patent. No motion was brought pursuant to subsection 6(5) of the NOC Regulations to dismiss this application on the ground that the ‘852 patent was improperly listed on the Drug Registry of Health Canada. The sole issue in this proceeding is Novopharm’s allegation of non-infringement.
[3] This case turns on the proper interpretation of the phrase “in a sustained-ascending dose” as found in each of claims 1, 41 and 78 of the ‘852 patent - the three independent claims at issue. Janssen-Ortho submits that these words refer to the pharmacokinetic properties of the formulation taught by the ‘852 patent, and specifically to the ascending methylphenidate concentration in the patient’s blood plasma over the relevant time period. Novopharm submits that these words do not refer to a plasma profile at all; rather, they refer to the specific amount of methylphenidate that is released from the dosage form in a given period of time following administration of the formulation, and more particularly, to the ascending trend of this release over the relevant time period. Novopharm submits that its product cannot infringe the ‘852 patent as its product does not release methylphenidate from its dosage form in an ascending amount over time.
[4] Novopharm further submits that there is no infringement because claims 1 to 40 and 78 to 119 of the ‘852 patent require the dosage form to be used to “regulate tolerance to methylphenidate” or to “compensate for acquired tolerance to methylphenidate” and, it submits, tolerance to methylphenidate has not been proven to exist. Therefore, it is argued, this aspect of the claims in the ‘852 patent cannot be infringed.
[5] For the reasons that follow the application is dismissed.
THE PARTIES
[6] The Applicant, Alza Corporation, is the owner of the ‘852 patent. Janssen-Ortho is an innovative pharmaceutical company that distributes and sells pharmaceutical products. One such product is its methylphenidate product which it markets in Canada and elsewhere in a formulation under the brand name Concerta. The Applicants are known as the “first person” under the NOC Regulations.
[7] The Respondent Novopharm is a generic drug company, known as the “second person” under the NOC Regulations. Novopharm has filed with the Minister an abbreviated new drug submission (ANDS) for the Novopharm Product. As part of its ANDS, Novopharm compared the Novopharm Product with Janssen-Ortho’s Concerta. Under the NOC Regulations Novopharm was obliged to provide an NOA to Janssen-Ortho, which had the ‘852 patent listed on the patent register in respect of Concerta, and to Alza Corporation, the patent owner.
[8] The Minister, following receipt of a drug submission, and after following the required procedures, has the responsibility to issue an NOC to permit the sale and distribution of certain drugs in Canada. The Minister was not represented in these proceedings although she was served with the necessary documents.
THE DRUG
[9] Methylphenidate is a drug used to treat Attention Deficit Hyperactivity Disorder (ADHD). ADHD is a neurobehavioural disorder that affects both children and adults. Those who suffer from ADHD experience symptoms of inattention, hyperactivity and impulsiveness. Attention Deficit Disorder (ADD) is a related neurobehavioural disorder that is characterized by the same symptoms as ADHD with the exception of hyperactivity. The ‘852 patent speaks of methylphenidate having become the standard drug for the management of ADD and makes no reference to ADHD. The parties are in agreement that nothing turns on this and that for the purposes of this application both disorders should be treated as being disorders commonly treated by methylphenidate. As a consequence, reference herein to ADHD should be understood to also encompass ADD.
[10] Methylphenidate is a mild central nervous system stimulant. It was first approved for use in the 1950s under the brand name Ritalin. By the mid-1990s, Ritalin had become the standard treatment for ADHD. Ritalin was found to effectively control ADHD symptoms for three to five hours, with the greatest effectiveness occurring over the first one to two hours after administration of the drug. As a result, Ritalin was commonly prescribed to be administered two to three times per day.
[11] Ritalin remains in use today as an effective treatment for ADHD; however, its initial formulation posed a number of practical complications, particularly when treating children suffering from ADHD.
[12] Ritalin was introduced in an immediate-release formulation, which means that once ingested, its full contents are released into the body immediately. Effective treatment of ADHD required that the patient ingest multiple doses of Ritalin throughout the day in order to ensure an effective amount of methylphenidate was always in the patient’s system. The desired therapeutic effect required this topping up of the methylphenidate levels. Some patients experienced peaks of effectiveness in ADHD symptom control followed by troughs of lesser effectiveness, until a subsequent dose was ingested. Given that methylphenidate is a controlled substance, its administration in this manner to children during the day in a school setting posed practical complications. Peer stigma of taking this drug was also an issue among children and adolescents.
[13] More than twenty years after the introduction of Ritalin, its makers introduced Ritalin SR, a sustained release, once-a-day formulation of methylphenidate that releases methylphenidate into the patient over an extended period of time, rather than immediately, as is the case with the first Ritalin formulation. The idea behind a sustained-release formulation is that once the tablet is ingested, its contents release over a period of time such that the active pharmaceutical ingredient has a longer lasting effect, and multiple doses are not required.
[14] Ritalin SR was never widely accepted. Ritalin SR was found to be less effective than a multiple dose regime of immediate release Ritalin. Janssen-Ortho submits that acute tolerance, or tachyphylaxis, was created by Ritalin SR and this was the reason why it was found to be less effective in the treatment of ADHD.
[15] Janssen-Ortho submits that the invention expressed in the ‘852 patent was the ascending blood profile its product creates in a patient. A blood plasma profile indicates the amount of the drug that is contained in a specific volume of blood at a given time. The original immediate release Ritalin tablet produced a blood plasma profile of peaks and valleys; the concentration of the drug in the blood would increase from the point when the tablet was ingested, but after a few hours would decrease as the drug was expelled from the body becoming less effective. Ritalin SR created a relatively flat methylphenidate plasma concentration that maintained a concentration of the drug in the blood over a period of several hours without the peaks and valleys of the immediate release formulation.
[16] The phenomenon of acute tolerance or tolerance occurs when a patient experiences a diminished therapeutic response to a drug during the day or during the course of a dose. When tolerance occurs, an increased dose is necessary to achieve the same therapeutic effect. This can result in a never ending cycle that renders a drug ineffective. There is a dispute between the parties and the experts as to whether tolerance to methylphenidate actually exists.
[17] The Applicants submit that tolerance to Ritalin SR was caused by a flat methylphenidate plasma concentration profile. After taking Ritalin SR, the concentration of methylphenidate in the blood increases to a maximum point, and then stays at this level for a period of time, creating a relatively flat profile. It is asserted that Alza Corporation’s discovery was that an ascending methylphenidate plasma concentration profile overcame the acute tolerance issues of Ritalin SR while providing a treatment of ADHD symptoms that was at least as effective as a multiple dose regime of Ritalin. Allegedly, Alza Corporation also discovered that by using an ascending methylphenidate plasma profile, comparable effectiveness could be achieved using lower methylphenidate concentrations.
[18] These discoveries, it is said, form the basis for the ‘852 patent, which is the subject of this proceeding. Janssen-Ortho submits that its Concerta product is governed by the ‘852 patent; Novopharm submits that there is no evidence in the record that Concerta reflects the teachings of the ‘852 patent. In any event, Concerta has become a standard treatment for ADHD with annual sales in the United States in excess of $900 million per year.
THE PATENT
[19] The ‘852 patent entitled “Use of Methylphenidate or a Pharmaceutically Acceptable Salt Thereof” was filed in Canada on September 16, 1997 and published on April 9, 1998. The relevant date for construing the ‘852 patent is April 9, 1998. The ‘852 patent has 119 claims; however, only three of those claims are independent claims. The following three independent claims of the ‘852 patent are at issue in this application:
1. Use of composition comprising 100 ng to 500 mg methylphenidate or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, the composition releasing methylphenidate or a pharmaceutically acceptable salt thereof in a sustained-ascending dose over time, for regulation of tolerance to methylphenidate or a pharmaceutically acceptable salt.
41. Use of composition comprising 100 ng to 500 mg methylphenidate or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, the composition releasing methylphenidate or a pharmaceutically acceptable salt thereof in a sustained-ascending dose over a period greater than 6 hours and up to 12 hours, for the treatment of Attention-Deficit Disorder.
78. Use of composition comprising 100 ng to 500 mg methylphenidate or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, the composition releasing methylphenidate or a pharmaceutically acceptable salt thereof in a sustained-ascending dose over time, for treatment of Attention-Deficit Disorder and compensation of acquired tolerance to methylphenidate or a pharmaceutically acceptable salt thereof.
THE EVIDENCE
[20] Each party filed evidence from five expert witnesses. The Applicants filed affidavits in support of their application from Dr. Martin S. Angst, Dr. Martyn C. Davies, Dr. Kennerly S. Patrick, Dr. Mario A. González and Dr. Declan Quinn. Novopharm submitted affidavits from Dr. Christopher Rhodes, Dr. Mark Riddle, Dr. Arthur Straughn, Dr. Stanley Kutcher, and Dr. James McCracken.
The Applicants’ Experts
A. Dr. Martin S. Angst
[21] Dr. Angst is a medical doctor and an Associate Professor of Anesthesia at Stanford University School of Medicine. He works as an anesthesiologist and clinical scientist in the field of clinical pharmacology. Dr. Angst’s expertise is in the description of plasma concentration profiles and the relationship between these profiles and clinical effects.
[22] Dr. Angst was asked by Janssen-Ortho to comment on the relevant person skilled in the art (PSIA), the teachings of the ‘852 patent, the meaning of the claims within the ‘852 patent, and the allegations of non-infringement in Novopharm’s NOA. In making these comments, Dr. Angst reviewed Novopharm’s NOA, the documents list in Appendix A to the NOA, the ‘852 patent, and Novopharm’s initial and subsequent productions. Dr. Angst, like all of the Applicants’ experts, was provided with a summary of the legal principles relating to claim construction. More will be said of these instructions later.
[23] Dr. Angst states that the PSIA would possess three qualification sets: (1) a medical degree with at least two years of clinical experience treating ADHD, (2) a medical degree with at least two years of experience in clinical pharmacology, and (3) a doctorate degree with at least three years of experience in pharmaceutical formulations. Dr. Angst admits that he does not have the first and third skill sets, but submits that that he has the second skill set.
[24] Dr. Angst reviews and reiterates much of the content of the ‘852 patent description. Dr. Angst states that a PSIA would read the ‘852 patent description as describing the usefulness of a particular ascending blood plasma profile without the occurrence of clinically significant drops during the period of ascension.
[25] In reviewing the claims of the ‘852 patent, Dr. Angst focuses on claims 1, 10, 41, 47, 78 and 87 and, in particular, on the compositional aspects of the claims. Dr. Angst notes that the language of the phrase “in a sustained-ascending dose” is “somewhat imprecise”, and thus relies on the disclosure to interpret the claims. Dr. Angst concludes that a PSIA would read and understand the words “the composition releasing methylphenidate … in a sustained-ascending dose over time” to mean “in a sustained manner so as to achieve an ascending plasma profile over time”.
[26] Dr. Angst also concludes that a PSIA would understand that the plasma profiles provided in the examples given in the ‘852 patent are not generated from clinical data and that in a clinical setting “a sustained-ascending dose” would allow for intermittent concentration drops of 10 to 15 percent. Dr. Angst then goes on to review and reject statements made in Novopharm’s NOA.
[27] Dr. Angst reviews some of the clinical data provided in support of Novopharm’s product. Dr. Angst does not review the data submitted from an unfed study because even though Concerta can be given with no food, Dr. Angst is of the opinion that the normal administration of the drug in children would be at breakfast time, and thus with food. Dr. Angst reviews the fed study data provided by Novopharm and concludes that [omitted] of the subjects had ascending plasma profiles, and that for [omitted] of the subjects (allowing for intermittent 10 to 15 percent drops in concentration) the plasma profiles ascended for periods greater than [omitted] hours.
[28] Consequently, Dr. Angst concludes that the Novopharm Product infringes the ‘852 patent.
B. Dr. Martyn C. Davies
[29] Dr. Davies received his Ph.D. in pharmacy from the University of London. He is a Professor at the University of Nottingham, School of Pharmacy. Dr. Davies’s expertise is in the area of biomaterials, polymer therapeutics, and drug delivery (including controlled release technologies).
[30] Dr. Davies reviewed the same documents as Dr. Angst, and was given a similar mandate with the addition of the following question: “Whether at the publication date of April 9, 1998 of the '852 patent, and having that patent in hand, a skilled formulator, knowing the pharmacokinetics of methylphenidate, could devise without undue experimentation, a formulation that released in humans methylphenidate in increasing amounts over time that was less than 6 hours that also effected a sustained-ascending methylphenidate plasma concentration of greater than 6 hours.”
[31] Dr. Davies states that the PSIA would have multiple skill sets. First, the PSIA would be a medical doctor. The PSIA would also be a formulator, with a Ph.D. in pharmacy, chemistry or chemical engineering and at least three years of experience in the field of controlled release dosage forms.
[32] Dr. Davies notes that the term “sustained ascending dose” is “not the chosen language of a skilled formulator” because it usually refers to a singular dose at a given time. Nonetheless, Dr. Davies concludes that “sustained ascending dose” would be understood by the PSIA to mean “that the drug is presented in a controlled release formulation such that in the bloodstream its concentration ascends in a sustained manner over time.” Dr. Davies states that the ‘852 patent does not require the release rate of the drug to be ascending in the same manner as the plasma profile, and that any ambiguity in the claims is overcome by considering the disclosure of the patent.
C. Dr. Kennerly S. Patrick
[33] Dr. Patrick received his Ph.D. in medicinal chemistry from the University of Iowa. His expertise is in the pharmacokinetics and pharmacodynamics of methylphenidate. Dr. Patrick has worked specifically on formulations of methylphenidate, including Ritalin.
[34] Dr. Patrick was given a mandate similar to that of Dr. Angst and Dr. Davies, with the addition of a request to provide a review of the history of methylphenidate. In reaching his conclusions, Dr. Patrick reviewed the ‘852 patent, a series of journal articles, two US patents, the product monographs for Ritalin, Ritalin SR and Concerta, an FDA report relating to new drug applications, and Novopharm’s draft product monograph.
[35] After reviewing the history of methylphenidate and the practical problems posed by Ritalin, and the relative ineffectiveness of Ritalin SR, Dr. Patrick addresses the ‘852 patent. Dr. Patrick describes the studies conducted by Dr. Swanson for Alza that led to the discovery that an ascending plasma profile could provide effective therapy for ADHD in an extended-release formulation. Dr. Patrick explains that for ethical reasons the studies conducted by Dr. Swanson did not draw actual blood samples from the child subjects, but rather relied on a “sipping” methodology to simulate certain plasma profiles.
[36] Dr. Patrick explains that some experts, including him, consider acute tolerance to methylphenidate to be only theoretical on the grounds that scientific data does not exist to prove acute tolerance. Dr. Patrick goes on to opine that this data does not exist because the studies needed to obtain the data would require multiple blood samples from children – an approach that would be difficult to justify to an ethics committee. Nonetheless, he is of the view that acute tolerance is observed clinically, for example in the studies of Dr. Swanson.
[37] Dr. Patrick concludes that the PSIA would have three skill sets: (1) “a physician with experience in treating patients with ADHD and possessing a good understanding of clinical pharmacology”, (2) “a physician with experience in pharmacodynamics and pharmacokinetics,” and (3) a formulator.
[38] Dr. Patrick states that the PSIA would understand the words “releasing methylphenidate” to mean releasing methylphenidate in vivo, i.e. inside the body. Dr. Patrick also states that there is ambiguity in the words “sustained releasing dose”. He says that the phrase “is not precisely the language a clinical pharmacologist or physician would use since, strictly speaking, an oral dose (singular) is the specific formulation given at an indicated time.” He concludes that a PSIA would understand these words, in the context of the ‘852 patent, to mean a sustained increasing concentration in the bloodstream. Dr. Patrick goes on to state that the PSIA would interpret “sustained ascending” to permit intermittent drops in methylphenidate concentration of between 10 to 15 percent.
[39] Dr. Patrick concludes that the PSIA would be aware of the difference between acute and chronic tolerance, would know that acute tolerance was proposed as an explanation for the ineffectiveness of Ritalin SR, and would read the ‘852 patent as addressing acute tolerance to methylphenidate.
[40] Dr. Patrick does not provide an opinion on whether Novopharm’s product will induce physicians to use its produce to compensate for acute tolerance. However, Dr. Patrick concludes that Novopharm’s product will result in infringement of claims 1 and 78 because the “product will be a composition of methylphenidate that provides a sustained ascending dose of methylphenidate over time.” With respect to infringement of claim 41, Dr. Patrick reviewed Novopharm’s patient data and concluded that when allowing for intermittent drops of 10 to 15 percent in the concentration of methylphenidate, approximately [omitted] of the patients would have plasma profiles that ascended for a period of greater than [omitted] hours. Therefore, Dr. Patrick concludes that the Novopharm Product will infringe claim 41 of the ‘852 patent.
D. Dr. Mario A. González
[41] Dr. González obtained his Ph.D. in pharmacokinetics from the University of California, San Francisco. He is the President and CEO of P’Kinetics International, which is a consulting company that provides research and development services to the pharmaceutical sector, particularly in the area of extended-release oral or transdermal (skin patch) formulations. Dr. González is also an Adjunct Professor at the University of Florida, College of Pharmacy. He has experience with methylphenidate formulations used for treating ADHD, including extended-release formulations. He has co-authored one academic article with Dr. Patrick.
[42] Dr. González was asked to review and comment on the plasma concentration data reported by Novopharm, and also to provide an opinion as to whether similar data would likely be expected if the same study was conducted using the 54 mg Novopharm Product. Dr. González was also asked to provide an opinion as to how a clinical pharmacologist with two years of pharmacokinetics experience would define a “sustained-ascending” plasma methylphenidate concentration profile and he was asked to respond to certain allegations in Novopharm’s NOA.
[43] Dr. González concludes that a “sustained ascending methylphenidate plasma concentration” would be defined as a plasma profile that ascends to a maximum methylphenidate concentration (Tmax), but which may have periodic concentration drops on the ascension of 10 to 15 percent. Dr. González states that “sustained ascending” should be read as “substantially ascending”.
[44] Dr. González determines that if 10 percent drops are permitted, [omitted] of Novopharm’s subjects exhibit a sustained-ascending plasma methylphenidate concentration profile
for greater than [omitted] hours. If 15 percent drops are permitted, the percentage of infringing patients rises to [omitted].
[45] Dr. González predicts that similar results would be obtained if Novopharm’s study was repeated with their 54 mg product. Dr. González reaches this prediction on the basis that methylphenidate displays linear pharmacokinetics.
[46] Dr. González explains that the relative ineffectiveness of Ritalin SR was initially thought to be the result of formulation issues, but that a paper by Dr. Patrick refuted this hypothesis. Dr. González states that the published work of Dr. Swanson demonstrated clinical acute tolerance in the Ritalin SR formulation. Dr. González states that tolerance is not a condition that is regulated, but rather is a side-effect experienced by some patients. Dr. González explains that the FDA found insufficient evidence to prove acute tolerance, but argues that this does not mean the relative ineffectiveness of Ritalin SR was not the result of acute tolerance. Dr. González also says that it would be unreasonable to conduct a study to obtain acute tolerance data in children because of the ethical and methodological issues of taking multiple blood samples.
E. Dr. Declan Quinn
[47] Dr. Quinn is a psychiatrist specializing in ADHD. He has been involved in pharmacokinetic studies involving psychostimulants (one of which is methylphenidate). Dr. Quinn was involved in the development of Canadian practice guidelines for ADHD and is currently a professor at the Royal University Hospital, University of Saskatchewan.
[48] Dr. Quinn was given the same mandate as Dr. Angst, Dr. Davies and Dr. Patrick, with the addition of a request to comment on “whether Novopharm's product monograph materials would induce the relevant medical community (individuals treating ADHD) in Canada … to use this formulation of methylphenidate because this formulation would be beneficial in the regulation of tolerance to methylphenidate.” In executing this mandate, Dr. Quinn reviewed Novopharm’s NOA, the documents listed in Appendix A of that NOA, the Concerta product monograph, and the ‘852 patent.
[49] Dr. Quinn states that the PSIA would have three qualifications: (1) a clinician or researcher with experience treating ADHD and knowledge of pharmacokinetics and pharmacodynamics, (2) a formulator with experience in pharmacokinetics, and (3) a formulator with experience in controlled release formulations.
[50] Dr. Quinn explains the types of complications that a child psychiatrist faces when treating children for ADHD.
[51] Dr. Quinn notes that the phrase “ascending dose” in the claims of the ‘852 patent is “somewhat imprecise” but concludes that a PSIA would read the claims, in conjunction with the disclosure, and understand that what is claimed is methylphenidate plasma levels that are ascending in a sustained manner.
[52] Dr. Quinn determines that the words “regulation” and “compensation” with respect to acute tolerance would be understood to mean counteracting the phenomenon even though these would not be the words a PSIA would normally employ. Dr. Quinn states that a PSIA would understand that what is meant is acute tolerance not chronic tolerance. He also reaches the same conclusion as Dr. González with respect to the FDA’s comments on acute tolerance.
[53] Dr. Quinn concludes that the Novopharm Product monograph would induce physicians to use its product in a manner similar to the use of Concerta. Dr. Quinn also states that the PSIA would understand the ‘852 patent claims to mean an ascending concentration in vivo and not in vitro.
NOVOPHARM’S EVIDENCE
A. Dr. Christopher Rhodes
[54] Dr. Rhodes obtained his Ph.D. in pharmacy from the University of London. He has been a professor at a number of universities, and is currently Professor Emeritus at the University of Rhode Island. Dr. Rhodes has worked as an evaluator for the FDA, and has been a consultant to private pharmaceutical companies as well as government.
[55] Dr. Rhodes comments on the relevant PSIA, how this PSIA would interpret the ‘852 patent claims, and whether Novopharm’s product would infringe the ‘852 patent. He was also asked to respond to the affidavits of Dr. Davies, Dr. Patrick and Dr. González, as well as the claim construction aspects of the affidavits by Dr. Angst and Dr. Quinn. Dr. Rhodes also reviewed the disclosure provided by Novopharm on July 11, 2008.
[56] Dr. Rhodes states that the ‘852 patent is primarily directed to a formulator, but that minor aspects are directed to a clinician or researcher in the area of ADHD. Dr. Rhodes asserts that the formulator would be a person with a first degree in pharmacy with at least two years of relevant post-degree experience or a person with a related degree such as chemical engineering with at least four years of post-degree experience. Dr. Rhodes does not comment on the knowledge of the clinician or researcher.
[57] Dr. Rhodes provides an explanation of drug delivery systems and a discussion of the absorption, distribution, metabolism, and elimination processes that pertain to methylphenidate.
[58] Dr. Rhodes concludes that the words “sustained-ascending dose over time” would be interpreted to mean the release of the drug over time at an ascending rate. The word “dose” in this context would be understood to mean a specific quantity of a drug, and “sustained-ascending” would be understood to mean constantly increasing.
[59] Dr. Rhodes determines that the words “for regulation of tolerance to methylphenidate” would be understood to mean that the composition would be therapeutically advantageous relative to compositions that display a constant or diminishing release rate over time. Dr. Rhodes states that where the time period is not expressly specified, the PSIA would understand the period to be not less than four hours.
[60] Dr. Rhodes, notes that some may find the phrase “sustained-ascending dose over time” to be “somewhat obscure” but states that the disclosure reinforces his conclusion as to its meaning. In particular, Dr. Rhodes focuses on the disclosure’s discussion of the problems with the prior art sustained-release formulations and he comments that they “do not provide a continuously increasing release rate per hour throughout the extended dosing period;” This he argues is evidence of the inventors’ intention to claim an increasing release rate.
[61] Dr. Rhodes reviews the mathematical equations in the disclosure that are used to explain the '852 patent's “method of delivery rate in mg per hour that continually compensates for the development of acute tolerance.” Dr. Rhodes argues that these equations would be interpreted by the PSIA to suggest a formulation that delivers increasing concentrations of the drug into the body at a specific time, i.e. that it is the release rate of the drug that is increasing.
[62] Dr. Rhodes comments on the three delivery methods that are described in the disclosure, and explains that they are more complicated than the “one of the simplest and quite common methods of formulating a conventional sustained release drug delivery system.” Dr. Rhodes argues that this complexity would be understood by the PSIA as suggesting an increasing release rate, because otherwise the objective could be achieved through a simpler delivery system.
[63] Dr. Rhodes reviews the examples provided in the '852 patent. Dr. Rhodes concludes that Example 1 describes an ascending release rate. Dr. Rhodes reaches a similar conclusion with respect to Example 2.
[64] Dr. Rhodes is of the view that one can use in vitro dissolution testing to mimic how a formulation will release its drug in vivo. He explains that the Novopharm Product utilizes a much simpler delivery system than described in the '852 patent.
[65] Dr. Rhodes examines the in vitro dissolution profiles of both Concerta and the Novopharm Product. [omitted]
Dr. Rhodes states that that the Novopharm Product data does not disclose that it is a sustained-ascending dose and that therefore is of the view that the Novopharm Product does not infringe the '852 patent.
[66] Dr. Rhodes goes on to comment on the affidavits provided in support of the Applicants' case. There is little agreement between Dr. Rhodes and the Applicants' experts. Notably, Dr. Rhodes critiques the figures included in the '852 patent, and argues that they are limited in what they teach the PSIA. In any event, Dr. Rhodes argues that plasma concentration profiles are not mentioned in the language of the claims. Dr. Rhodes also says that it is an error to ignore the unfed patient data provided by Novopharm on the basis that “patients, and children in particular, often skip breakfast which is the intended time for such a medication to be taken.”
B. Dr. Mark Riddle
[67] Dr. Riddle obtained his medical degree from Indiana University. He also has an M.S. in pharmacy. Dr. Riddle has held a number of positions in child psychiatry. He is currently Director of the Division of Child and Adolescent Psychiatry at The Johns Hopkins University School of Medicine, and he is also Professor in the Department of Psychiatry and Pediatrics at Johns Hopkins. Dr. Riddle has been a member of review groups for the National Institute of Mental Health, and in particular, was part of the Special Review Committee of the Multimodal Treatment Study of ADHD.
[68] Dr. Riddle comments on the relevant PSIA and meaning of the relevant claims in the '852 patent. Dr. Riddle states that the PSIA would have three skill sets: (1) a pharmacist, physician and/or researcher with experience in clinical pharmacology and a reasonable understanding of the design, conduct and evaluation of bioavailability studies, (2) a pharmaceutical formulator with a graduate degree and at least two years of experience in the preparation of pharmaceutical formulations, and (3) a psychiatrist with clinical experience relating to the treatment of ADHD.
[69] Dr. Riddle concludes that the '852 patent teaches: (1) a formulation that releases a particular methylphenidate profile “whereby the amount of methylphenidate released in each time period is greater than that released in the preceding time period,” (2) potential blood plasma profiles that might result from this formulation, (3) methods for making such formulations, and (4) that such formulations are useful for addressing acute tolerance of methylphenidate.
[70] Dr. Riddle provides an interpretation of claims 1, 41 and 78. He determines that “releasing methylphenidate” would be interpreted to mean release of the drug from the dosage form for absorption into the body. Dr. Riddle states that “dose” is normally understood to mean “either (1) the actual dosage form given to a patient, or (2) the portion of a drug released from a particular dosage form.” Dr. Riddle concludes that it is the latter usage that is referred to in the ‘852 patent. Dr. Riddle argues that the use of the word “dose” in the dependent claims is clear, and that this use should be inferred in the independent claims. On this basis, Dr. Riddle concludes that the words “sustained-ascending dose” would be read by the PSIA to mean “the release of constantly increasing portions of methylphenidate from the dosage form over time.” Dr. Riddle states that the PSIA would not read the predicted plasma profiles as part of the claims.
[71] Dr. Riddle states that the PSIA would read the ‘852 patent as directed toward acute tolerance, even though he argues that acute tolerance to methylphenidate was not proven at the relevant date. Dr. Riddle suggests that since there is no acute tolerance to methylphenidate, Novopharm’s product could not be used to treat something that does not exist, and therefore it cannot infringe the ‘852 patent.
[72] Dr. Riddle concludes that claims 1, 41 and 78 would be interpreted by a PSIA as follows:
(a) Claim 1: the use of a dosage form comprising methylphenidate, the dosage form releasing methylphenidate in constantly increasing amounts for at least four hours, for the regulation of acute tolerance to the therapeutic effects of methylphenidate.
(b) Claim 41: the use of a dosage form comprising methylphenidate, the dosage form releasing methylphenidate in constantly increasing amounts for a time period between six and twelve hours, for the treatment of ADHD.
(c) Claim 78: the use of a dosage form comprising methylphenidate, the dosage form releasing methylphenidate in constantly increasing amounts for at least four hours, for the treatment of ADHD and the compensation of acquired acute tolerance to the therapeutic effects of methylphenidate.
C. Dr. Arthur Straughn
[73] Dr. Straughn holds a Pharm.D. from the University of Tennessee. He is currently Professor Emeritus, Director of the Drug Research Laboratory at the University of Tennessee. Dr. Straughn’s expertise is on the effect drug formulation dissolution rates have on plasma drug concentration profiles. Dr. Straughn has co-authored papers with Dr. Patrick and Dr. González.
[74] Dr. Straughn was asked to comment on the relevant PSIA, the meaning of the claims in the ‘852 patent, and whether Novopharm infringed these claims. He was also asked to comment on the affidavits of Janssen-Ortho’s experts. In fulfilling this mandate, Dr. Straughn reviewed the ‘852 patent and portions of Novopharm’s ANDS.
[75] Dr. Straughn’s conclusions regarding the relevant PSIA are similar to the views of Dr. Riddle. Dr. Straughn argues that clinical pharmacology and formulation aspects, within the ‘852 patent, are more significant than the treatment of ADHD aspect.
[76] Dr. Straughn provides information on drug delivery systems as well as on methylphenidate. Dr. Straughn notes that the Ritalin SR formulation releases methylphenidate at a decreasing rate over time. Dr. Straughn does not comment on the relative effectiveness of Ritalin SR.
[77] Dr. Straughn reaches the same conclusions as Dr. Riddle with respect to what the ‘852 patent teaches. He emphasizes that the plasma profiles provided in the ‘852 patent were not actually measured, but rather that they were predicted.
[78] Dr. Straughn concludes that the PSIA would interpret the words “sustained-ascending dose” to mean “the release of the drug methylphenidate from the dosage form in amounts that are constantly increasing.” Dr. Straughn reaches the same conclusion as Dr. Riddle on the meaning of the word “dose”, i.e. that it means the portion of the drug that is released at a given time.
[79] Dr. Straughn concludes that claims 1, 41 and 78 have the following essential elements: The use of a dosage form comprising methylphenidate, the composition releasing methylphenidate in a constantly increasing amount for at least four hours for (a) the regulation of tolerance (in the case of claim 1); (b) the treatment of Attention-Deficit Disorder (in the case of claim 41); or (c) the treatment of Attention-Deficit Disorder and compensation of acquired tolerance to methylphenidate (in the case of claim 78).
[80] Dr. Straughn analyzes the dissolution data of Novopharm’s Product and concludes that it exhibits a [omitted] dose over time. On this basis, Dr. Straughn argues that Novopharm
does not infringe the ‘852 patent.
[81] Dr. Straughn disagrees with the statements made by Janssen-Ortho’s experts. Notably, Dr. Straughn argues that their definition of “sustained-ascending dose” is wrong because Ritalin SR also displays a sustained-ascending plasma profile over four hours, and arguably over five hours. Dr. Straughn states that Figure 9 in the disclosure is evidence that the inventors acknowledged there were multiple ways to achieve a sustained-ascending plasma concentration profile, but that they believed an ascending release rate provided a particularly beneficial therapeutic effect.
D. Dr. Stanley Kutcher
[82] Dr. Kutcher holds a medical degree from McMaster University and a diploma in child psychiatry from the University of Toronto. He is a Fellow of the Royal College of Physicians and a professor of psychiatry at Dalhousie University. Dr. Kutcher has extensive experience diagnosing, treating and researching ADHD. He also has experience working with methylphenidate.
[83] Dr. Kutcher was asked to comment on the meaning of “tolerance” in general and in relation to the treatment of ADHD, whether Novopharm’s Product monograph is directed at compensating for acquired tolerance, and whether the Concerta monograph is directed at compensating for acquired tolerance. Dr. Kutcher was also asked to review and comment on Dr. Quinn’s affidavit.
[84] Dr. Kutcher provides background information on tolerance in general and tolerance in the context of methylphenidate. Dr. Kutcher argues that tolerance to methylphenidate has not been fully established:
In my opinion, the evidence for the existence of acute tolerance to methylphenidate, is speculative, and has not been shown to exist in usu