Biogen Canada Inc. v. Taro Pharmaceuticals Inc.

Biogen Canada Inc. v. Taro Pharmaceuticals Inc.
Court (s) Database
Federal Court Decisions
Date
2020-05-15
Neutral citation
2020 FC 621
File numbers
T-1163-18, T-220-19
Decision Content
Date: 20200515
Dockets: T-1163-18
T-220-19
Citation: 2020 FC 621
Ottawa, Ontario, May 15, 2020
PRESENT: The Honourable Mr. Justice Manson
Docket: T-1163-18
BETWEEN:
BIOGEN CANADA INC.,
BIOGEN INTERNATIONAL GMBH AND
ACORDA THERAPEUTICS, INC.
Plaintiffs
and
TARO PHARMACEUTICALS INC.
Defendant
Docket: T-220-19
AND BETWEEN:
BIOGEN CANADA INC.,
BIOGEN INTERNATIONAL GMBH AND
ACORDA THERAPEUTICS, INC.
Plaintiffs
and
PHARMASCIENCE INC.
Defendant
JUDGMENT AND REASONS
I. Introduction
[1] These proceedings involve two patent infringement actions pursuant to subsection 6(1) of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 [the Regulations]. The Plaintiffs [collectively Biogen] allege infringement of Canadian Patent No. 2,562,277 [the 277 Patent]. The Defendants, Taro Pharmaceuticals Inc [Taro] and Pharmascience Inc [Pharmascience], deny infringement and allege the patent is invalid for lack of patentable subject matter, anticipation, and obviousness.
[2] The 277 Patent pertains to various uses of fampridine sustained release [SR] formulations and is listed on the Patent Register under the brand name FAMPYRA®. On May 3, 2018, Taro sent Biogen a Notice of Allegation [NOA] pursuant to subsection 5(3) of the Regulations. In response, Biogen commenced the action in Court file T-1163-18 on June 15, 2018. Similarly, Pharmascience sent Biogen a NOA pursuant to subsection 5(3) of the Regulations on December 20, 2018, and Biogen started the action in Court file T-220-19 on February 1, 2019.
[3] Issues of validity were heard concurrently for both actions, based on the same allegations of invalidity and evidence, along with infringement with respect to Taro. If necessary, the infringement portion of the Pharmascience action is scheduled to take place later this year. This decision and reasons relate to validity of the 277 Patent, and Taro’s alleged infringement of the 277 Patent in Court file T-1163-18.
II. Background
A. The Parties
[4] Biogen Canada Inc is an Ontario corporation, and Biogen International GMBH is a Swiss corporation. Biogen Canada is a first person within the meaning of subsections 4(1) and 6(1) of the Regulations.
[5] Acorda Therapeutics Inc [Acorda], a Delaware corporation, is a small biotechnology company and the registered owner of the 277 Patent. Acorda is joined to this proceeding pursuant to subsection 6(2) of the Regulations.
[6] Acorda licenses the 277 Patent to Biogen International, who in turn authorizes Biogen Canada, a related company, to use and sell the invention claimed in the 277 Patent. Biogen Canada markets and sells FAMPYRA in Canada.
[7] Taro and Pharmascience are generic pharmaceutical companies incorporated under the laws of Ontario. Each of these corporations seeks to come to market with its own fampridine SR product in Canada.
B. Multiple Sclerosis
[8] Multiple Sclerosis [MS] is a chronic, progressive and unpredictable disease that affects the central nervous system. Damage to the central nervous system interferes with nerve signal transmission between the brain and spinal cord and the rest of the body.
[9] MS is at least in part a demyelinating disease. The myelin sheath acts as an insulating substance that surrounds nerve fibers, which allows electrical impulses from the brain to reach different parts of the body quickly. In its absence, there is a disruption in the transmission of the electrical signals. The insulation myelin provides is akin to insulation for an electrical wire. If the insulation is defective, current in the nerve fiber loses strength.
[10] Part of the known physiology of the disease is leakage of potassium ions in the nerve fiber. Accordingly, blocking potassium ion leakage was a rational target for treatment. Potassium channel blockers such as fampridine were known to restore conduction of action potentials in demyelinated nerve fibers, and as such fampridine had been tested as a potential symptomatic treatment for some MS patients.
[11] MS generally involves two phases. Phase 1 involves attacks of focal neurological dysfunction such as loss of vision, weakness in a limb, and numbness. Phase 2 is commonly called secondary-progressive MS and is amenable to potassium channel blocker treatments. Patients with secondary-progressive MS typically struggle to walk and need assistance to do so, relying on canes, walkers, or part-time wheelchair use.
[12] Impaired walking or walking disability is one of the most commonly reported MS symptoms. Walking impairment can have detrimental effects on patients, and is one sign of the progression of the disease in terms of the practical effect MS has on a patient’s daily life.
[13] The Kurtzke Expanded Disability Status Scale [EDSS] is commonly used to express the level of a MS patient’s disability. Patients are given a score on a scale from 0 to 10 as summarized below. Scores five through eight are specifically tied to a patient’s ability to walk, illustrating the prevalence of this symptom in MS patients:
[14] FAMPYRA and Taro-Fampridine are both indicated for use in adult MS patients with walking disability, defined by an EDSS score of 3.5-7.
[15] MS symptoms are highly unpredictable and vary greatly in type and severity from person to person, and even in the same person over time. Symptoms may come and go or may persist, and often worsen over time. Given the high level of variability, clinical trials in MS patients are challenging. The nature of the disease makes it very difficult to determine whether a potential treatment is having a clinically meaningful effect, or whether any observed change is simply due to the inherent variability of the disease.
[16] To determine whether a given outcome is actually caused by the tested treatment, clinical trials must be placebo-controlled and adequately powered to measure a meaningful response. Due to the inherent variability in MS symptoms, significant variation in the placebo and treatment groups is often seen, which makes it more difficult to detect whether the intervention provides a clinically relevant benefit.
[17] There is no cure for MS. Many approved treatments are aimed at attempting to curb disease progression and manage symptoms. There is no MS treatment that is effective in all patients, so therapies must be tailored to individual patients. In addition to approved treatments, various alternative treatments have been used in the hopes they will provide some relief from MS. Historically, certain alternative treatments have been purported to be “the next best thing” but ultimately have not passed clinical muster. In light of these repeated “false dawns”, MS researchers are highly skeptical of alternative treatments that are not supported by double-blind, placebo-controlled trials.
C. The 277 Patent
[18] The 277 Patent is titled “Methods of Using Sustained Release Aminopyridine Compositions.” The named inventors are Andrew Blight, Lawrence Marinucci, and Ron Cohen. The 277 Patent issued from an application filed in Canada on April 11, 2005, claiming priority from United States Patent Application No. 60/560,894, filed on April 9, 2004. It was laid open on October 27, 2005, and issued on January 27, 2015.
[19] The invention claimed in the 277 Patent relates to using SR compositions of potassium channel blockers, specifically aminopyridines, in the effective treatment of various diseases, including MS. The SR composition provides efficacious and safe plasma levels of aminopyridine for a period of up to 12 hours, allowing for twice daily administration while avoiding excessive peaks and troughs in plasma concentration.
[20] In the “Summary of the Invention” section, the patent states that one embodiment of the invention relates to twice daily use of less than 15 mg of aminopyridine for increasing walking speed or improving lower extremity muscle strength in a subject with MS.
[21] The patent further states that one embodiment of the invention relates to a method of selecting individuals based on responsiveness to a treatment. This “responder” or “post hoc” analysis was the subject of much discussion during the trial. While the disclosure refers to a method for selecting individuals, this method is not a part of the invention as claimed in the 277 Patent.
[22] The asserted claims relate to the twice daily (also known as “bid”) use of 10 mg of a fampridine SR composition for improving walking (or increasing walking speed) in a subject with MS in need thereof for a period of at least two weeks. Dependent claims add certain pharmacokinetic limitations. Asserted claims 17 to 19, and 21 are exemplary:
17. Use of a sustained release 4-aminopyridine composition for improving walking in a subject with multiple sclerosis in need thereof for a time period of at least two weeks at a unit dose of 10 milligrams of the 4-aminopyridine twice daily.
18. Use of a sustained release 4-aminopyridine composition in the manufacture of a medicament for improving walking in a subject with multiple sclerosis in need thereof for a time period of at least two weeks at a unit dose of 10 milligrams of the 4-aminopyridine twice daily.
19. The use of claim 15 or 17, wherein the 4-aminopyridine composition exhibits a CavSS of 15 ng/ml to 35 ng/ml.
[…]
21. The use of claim 15 or 17, wherein the 4-aminopyridine composition provides a mean Tmax in a range of 2 to 5 hours after administration of the 4-aminopyridine composition to the subject.
[23] The claims generally break down into two sets: (1) use of fampridine SR for improving walking (or increasing walking speed) in subjects with MS; and (2) use of fampridine SR in the manufacture of a medicament for improving walking (or increasing walking speed) in subjects with MS.
III. Issues
[24] The parties narrowed the issues leading up to trial. The remaining issues are:
Does the Acorda S-1 reference anticipate any of claims 17, 18, 23, 28, 31, 32, 37, or 42 of the 277 Patent?
Are any of claims 17-19, 21, 23, 24, 26, 28, 31-33, 35, 37, 38, 40, or 42 [the Asserted Claims] of the 277 Patent invalid for obviousness?
Are any of the Asserted Claims of the 277 Patent directed to unpatentable methods of medical treatment?
Would the making, constructing, using, or selling of Taro-Fampridine by Taro in accordance with its ANDS infringe any of the Asserted Claims of the 277 Patent?
[25] For the reasons that follow, the Acorda S-1 reference anticipates claims 17, 18, 31, and 32, and all of the Asserted Claims of the 277 Patent are invalid for obviousness. None of the Asserted Claims are directed to unpatentable methods of medical treatment.
IV. Fact Witnesses
[26] As a preliminary note, Biogen submitted affidavit evidence from Ms. Preeti Singh and Mr. H. Samuel Frost, but these witnesses were not put forward or cross-examined at trial and their evidence was of no consequence to the determinative issues. The Court notes that their evidence was in the record.
A. Ron Cohen, MD
[27] Dr. Cohen is the President and CEO of Acorda and a named inventor on the 277 Patent. He gave evidence of the invention story that led to the 277 Patent.
[28] Acorda initially studied fampridine as a potential spinal cord injury [SCI] therapy using immediate release formulations. Dr. Cohen became aware that Elan, an Irish pharmaceutical company, had developed a SR formulation of fampridine, and in 1998, Acorda took over development of fampridine SR as a treatment for MS from Elan.
[29] Elan had received negative results in a large phase 2 study using fampridine SR in MS patients. The Elan study involved 161 patients with MS receiving escalating doses of fampridine SR from 12.5 mg bid up to 22.5 mg bid.
(1) MS-F200
[30] MS-F200 was a phase 1 study that looked at the safety and efficacy of 5, 15, and 25 mg doses of fampridine SR on oculomotor function in MS patients with internuclear ophthalmoplegia. Acorda hoped to differentiate itself from the Elan study which had failed to show statistical improvement in EDSS and most of its secondary measures. The MS-F200 results were negative. Acorda was forced to consider other endpoints for future fampridine SR studies.
(2) MS-F201
[31] Next, Acorda performed a small phase 2 clinical trial that focused on safety and tolerability at escalating doses of fampridine SR. This study included various secondary outcome measures. MS-F201 was a “hypothesis-generating study.”
[32] Doses started at 10 mg bid and escalated to 40 mg bid at a rate of 5 mg each week. Given the small sample size of 36 subjects, this study was insufficiently powered to allow an evaluation of the efficacy of any individual dose compared with placebo. Rather than evaluate efficacy on a dose-by-dose basis, Acorda examined the efficacy endpoints by comparing the pooled data from the fampridine group (all doses combined) with the placebo group, and directly comparing the last measurement during dose escalation.
[33] With the exception of lower extremity manual muscle testing, each of the pre-established endpoints identified in MS-F201 failed, that is, they did not show any statistically significant difference over baseline as compared to placebo. These endpoints included the Timed 25 Foot Walk, a quantitative mobility test based on the time it takes for a patient to walk 25 feet. The results showed large variability, as would be expected, and supported a large placebo effect. Acorda looked to other means of analyzing the data from the study in the hope of finding some other hypothesis from which it could rationalize further studies of fampridine SR.
[34] Acorda reanalyzed the data from MS-F201 and found that scores from two patients were disproportionately influencing the walking times. Looking at walking speed instead of walking time showed a nominally significant difference from baseline was observed in the pooled fampridine SR treated group compared to the placebo group. These results were reported in the Goodman and Acorda S-1 references, discussed below. Based on these results, Acorda planned a further phase 2 study, MS-F202, to evaluate walking speed.
(3) Acorda’s Attempt to Go Public
[35] Following the MS-F201 study, Acorda decided to go public to raise additional funds. Dr. Cohen and Dr. Andy Blight were involved in preparing the business section of the registration statement to be submitted to the US Securities and Exchange Commission [SEC]. This registration statement, now referred to as the “Acorda S-1” is a key document in this litigation.
[36] The Acorda S-1 discloses results from the MS-F201 trial, and the MS-F202 trial design, discussed further below, but states that data for MS-F202 is not expected to be available until March 2004. The signatures on the Acorda S-1 are dated September 23, 2003.
[37] The SEC submission did not garner the desired investment response, and Acorda withdrew the filing in January 2004.
(4) MS-F202
[38] MS-F202 was a phase 2 trial of fampridine SR in the treatment of MS. It was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 206 patients with MS. MS-F202 was initiated in February 2003, and completed in December 2003. The study was designed and powered to compare the efficacy of the three individual doses tested—10, 15, and 20 mg bid—on pre-defined endpoints, including walking speed. Assessments were conducted at five off-treatment visits and four on-treatment visits during the 12-week stable dose period, as shown in the figure below:
Exhibit 5 to the Affidavit of Dr. Ron Cohen, Figure 1, page 28
[39] MS-F202, as a parallel group study, allowed for statistical comparison between the doses tested. The primary efficacy variable was the percent change in average walking speed during a stable 12-week dose period relative to baseline, using the Timed 25 Foot Walk.
[40] Based on certain pre-defined endpoints, the MS-F202 study failed. There were no statistically significant differences observed in the primary efficacy variable, walking speed, at any of the doses tested. Further, there was no significant difference observed in the protocol specified responder analysis (average change of a magnitude of at least 20%) between any of the fampridine SR doses and placebo.
[41] Unsatisfied with the apparent failure, Dr. Cohen re-evaluated the data. He collected blinded printouts of the walking speed results of all 206 patients for each of the weeks of the study where Timed 25 Foot Walk was assessed and looked at them himself.
[42] Dr. Cohen created a scale, which identified patients as either 0, 1+, 2+, 3+ or 4+, depending on how many on-drug visits were faster than the same patient’s fastest off-treatment visit. For this unplanned, post hoc analysis, the patients who were faster during 3 of 4 or 4 of 4 on-treatment visits were labelled as “responders,” and the others as “non-responders.” Dr. Cohen’s impromptu post hoc analysis looked at consistency of response rather than magnitude of response. Approximately 36.7% of patients receiving the drug were responders, as compared to approximately 8.5% of patients receiving placebo.
[43] The MS-F202 results showed no meaningful difference in walking speed between the 10 mg, 15 mg and 20 mg bid doses, and showed a slightly increased prevalence of adverse events in the two higher-dose groups. Therefore, Acorda opted to focus on 10 mg bid dosing for phase 3 trials, which took place after the claim date.
V. Expert Witnesses
[44] As a preliminary point, the parties’ key witnesses’ evidence was uniformly weakened on cross-examination. Given the inconsistencies of evidence, advocacy, and unreasonable positions taken by Drs. Oh and Leist for Biogen, and Drs. Ebers and Bailey for the Defendants, unless otherwise specified, the Court gives limited weight to their expert opinion evidence.
[45] Generally speaking, Drs. Kealey and Williams were credible and helpful witnesses, but their evidence was limited in scope. Dr. Kealey, for the Defendants, gave evidence that the Acorda S-1 document was available to the public as of April 2004. Dr. Williams, for Biogen, opined on whether steady state concentrations of prolonged release drugs can be inferred from single dose bioequivalence studies.
A. Biogen’s Witnesses
(1) Jiwan Oh, MD, PhD
[46] Dr. Oh is a staff neurologist at St. Michael’s Hospital and a scientist at the Keenan Research Center for Biomedical Science in Toronto. Her clinical practice focuses on the treatment of patients with MS, while her research focuses on the use of advanced magnetic resonance imagining techniques in the MS research program at St. Michael’s Hospital.
[47] Dr. Oh was qualified to give expert opinion evidence in respect of: neurology; MS; the treatment of MS; drug products used in the treatment of MS (including the pharmacology, formulations and pharmacokinetics of drug products); fampridine; and the design, conduct and analysis (including statistical analysis) of clinical trials (including clinical trials in patients with MS).
[48] Dr. Oh gave evidence on the person of ordinary skill in the art [POSITA], the common general knowledge, and infringement of the 277 Patent by Taro. Dr. Oh took some inconsistent positions between her expert report and cross-examination. For example, on cross-examination she stated that the product monograph informs her understanding of the claims. She further stated that the post hoc responder analysis described in the disclosure is part of the claims. On a plain reading of the claim language, this approach is both incorrect and not credible.
[49] Further, when asked whether anything in the Taro product monograph discusses a type of “responder” analysis, Dr. Oh answered that because the Taro product monograph refers to the FAMPYRA product monograph, the skilled person would import the FAMPYRA product monograph discussion of clinical trials using a post hoc responder analysis into the Taro product monograph. Again, this position demonstrates an unreasonable approach in viewing the Taro product monograph in purposive manner.
(2) Roger Williams, MD
[50] Dr. Williams is a consultant in the area of clinical pharmacology, and is board certified in clinical pharmacology and internal medicine. His work experience includes employment at the FDA as the Director in the Office of Generic Drugs from 1990-1993, the Associate Director in Science and Medical Affairs from 1993-1994, the Acting Director in the Office of New Drug Chemistry from 1995-1996, and Deputy Centre Director from 1995-2000.
[51] Biogen submitted Dr. Williams’ affidavit in reply to new issues raised by Dr. Bailey. Dr. Williams’ only mandate was to respond to paragraphs 17-23 of the Bailey Report, relating to the issue of whether steady state concentrations of prolonged release drugs can be inferred from single dose bioequivalence studies, and indicate points of agreement and disagreement.
[52] Dr. Williams was qualified to give expert opinion evidence in respect of: pharmacokinetics, including steady-state pharmacokinetics of SR products; and bioequivalence and bioequivalence testing, including regulatory standards and approaches in respect thereof.
[53] Dr. Williams was a credible witness.
(3) Thomas Leist, MD, PhD
[54] Dr. Leist is the Chief of the Clinical Neuroimmunology Division and Director of the Comprehensive MS Center at Thomas Jefferson University in Philadelphia, Pennsylvania. He has held these positions since 2000, and has taught neurology as a professor at Thomas Jefferson University since 2014.
[55] Dr. Leist obtained his PhD in Biochemistry from the University of Zurich, Switzerland in 1985, and obtained his MD from the University of Miami in 1993.
[56] Dr. Leist gave evidence on the scientific background of MS, claim construction, the state of the art and POSITA’s common general knowledge as of April 2004, anticipation, and obviousness. He also responded to Dr. Ebers’ opinions on anticipation and obviousness.
[57] Dr. Leist was qualified to give expert opinion evidence in respect of: neurology; MS; the treatment of MS; drug products used in the treatment of MS (including the pharmacology, formulations and pharmacokinetics of drug products); fampridine; and the design, conduct and analysis (including statistical analysis) of clinical trials (including clinical trials in patients with MS).
[58] On cross-examination, Dr. Leist stood by the opinions expressed in his report. However, he approached much of the prior art with an apparent mind unwilling to understand. Dr. Leist was evasive in answering simple questions about the prior art cited in his report, particularly with respect to the Goodman Abstracts and Poster. His approach seemed focused on disparaging the cited art that was unfavourable to Biogen to the point that, in his opinion the POSITA would not have learned anything from any of these prior art references.
B. Defendants’ Witnesses
(1) Burch Kealey, PhD
[59] Dr. Kealey is an associate professor of accounting at the University of Nebraska at Omaha. His opinion evidence relates solely to the date on which Acorda S-1 would have been available to the public through the SEC EDGAR database, and how many times this document was accessed between its release date and April 11, 2004.
[60] Dr. Kealey was qualified to give expert opinion evidence on the public availability of financial documents provided to the SEC EDGAR electronic database and the extent to which such documents were publicly disseminated through EDGAR.
[61] Dr. Kealey was a credible witness.
(2) George Ebers, MD
[62] Dr. Ebers is an Emeritus Professor at the Nuffield Department of Clinical Neurology at the University of Oxford. He gave evidence on the scientific background regarding MS, the POSITA and their common general knowledge, claim construction, the state of the art as of April 2004, anticipation, and obviousness.
[63] Dr. Ebers is trained as a consultant neurologist and medical doctor. He practiced as a neurologist and taught as a Professor at Western University from 1977 to 1999, treating patients with MS and general neurology patients during that period. His research at Western focussed on epidemiology, genetics, natural history and clinical trials in MS. He has been head of the Department of Clinical Neurology at Oxford since 1999, and has continued practicing medicine.
[64] Dr. Ebers estimates that he has seen between six and seven thousand MS patients over the past four decades. He was responsible for the MS Clinic in London, Ontario, which became the largest in the world under his direction, and co-founded and developed the Canadian MS Clinic Network. In these roles, he actively participated in clinical trials and the evolution of knowledge about this disease and its treatments.
[65] Dr. Ebers was qualified to give expert opinion evidence about MS; the etiology of MS; the progression of MS; the treatment of MS and its symptoms; the role of potassium channel blockers in the treatment of MS; the use of drugs, including fampridine, in the treatment of the symptoms of MS; the design, conduct and analysis of clinical trials related to MS; and the use and pharmacokinetics of SR drug products used to treat MS.
[66] While the parties agreed on his qualifications, Dr. Ebers admitted on cross-examination that he does not consider himself an expert in the role of potassium channel blockers in the treatment of MS, or the pharmacokinetics of SR drug products used to treat MS.
[67] Dr. Ebers’ testimony on the history of MS and treatments for MS was believable and detailed. He has clearly dedicated much of his life to studying and documenting MS and treatments for the disease.
[68] However, Dr. Ebers testimony related to the state of the art and obviousness was weakened on cross-examination. When taken to the prior art he cited in his report, he disparaged virtually every study put forward as prior art, labelling them as speculative, poorly designed, and limited by the small number of patients tested.
[69] Given his long history in treating MS and the repeated occurrence of “false dawns,” Dr. Ebers was understandably skeptical of purported new treatments. That said, his unbridled skepticism weakened his opinion, as he appeared to see no value in many of the studies put to him, including those cited in his own report, and the studies conducted in the development of the 277 Patent.
[70] Dr. Ebers’ report was also far from impartial. Biogen highlighted approximately one hundred paragraphs of his report that were copied nearly verbatim from Taro’s NOA, which Dr. Ebers acknowledged he had never reviewed.
[71] It is certainly permissible for counsel to help an expert prepare his or her report (Moore v Getahun, 2015 ONCA 55 at paras 55, 64). Counsel may even point the expert to relevant prior art, as long as the expert reviews and confirms the content of his or her report, as the choice of prior art is entirely in the hands of the party alleging obviousness (Ciba Specialty Chemicals Water Treatments Limited’s v SNF Inc, 2017 FCA 225 at para 60). It is quite another story for an expert to do little or no independent research and accept, verbatim, large portions of a NOA prepared by legal counsel which the expert has never seen, let alone reviewed. This crosses the line of propriety and puts into real doubt the impartiality and independence of the expert; key aspects of the expert’s duty to the Court (White Burgess Langille Inman v Abbott and Haliburton Co, 2015 SCC 23 at paras 26-32).
(3) David Bailey, PhD
[72] Dr. Bailey is a clinical pharmacologist at the Lawson Health Research Institute and a Professor Emeritus in the Department of Medicine, Clinical Pharmacology at Western University in London, Ontario.
[73] Dr. Bailey’s area of research includes pharmacokinetic drug interaction investigations, specifically looking at pharmacokinetic parameters such as those measured in bioequivalence studies.
[74] Dr. Bailey was qualified to give expert opinion evidence on the pharmacokinetics of SR drug products, including steady-state pharmacokinetics of SR products. He responded to Dr. Oh’s infringement opinion on whether steady state concentrations of SR drug products can be established from single dose bioequivalence studies.
[75] Dr. Bailey was, in his own words, passionate. However, at times on cross-examination he was obstructionist, answering counsel’s questions with further questions. On multiple occasions he avoided answering straightforward questions by talking about his own research and numerous publications.
VI. Claim Construction
[76] Claim construction is a matter of law for the judge, and claim construction is antecedent to consideration of both infringement and validity issues (Whirlpool Corp v Camco Inc, 2000 SCC 67 at paras 43, 61 [Whirlpool]). The same construction of the claims applies to issues of infringement and validity (Whirlpool, above, at para 49).
[77] Where the judge can construe the patent as it would be understood by a skilled person, expert evidence is not required (Pfizer Canada Inc v Canada (Minister of Health), 2007 FC 446 at paras 25, 35-36; Excalibre Oil Tools Ltd v Advantage Products Inc, 2016 FC 1279 at para 119).
[78] The principles of claim construction were laid out by the Supreme Court of Canada in Whirlpool and Free World Trust (Whirlpool at paras 49-55; Free World Trust v Électro Santé Inc, 2000 SCC 66 at paras 44-54 [Free World Trust]). Claims are to be read in an informed and purposive way, with a mind willing to understand and viewed through the eyes of a POSITA having regard to the common general knowledge. The entire patent specification should be considered in order to ascertain the nature of the invention, however adherence to the claim language allows the claims to be read in the way in which the inventor is presumed to have intended, promoting fairness and predictability.
[79] The relevant date for construing the claims is the publication date: October 27, 2005.
A. Person of Ordinary Skill in the Art [POSITA]
[80] The parties generally agreed that the 277 Patent is directed towards a skilled team comprising a clinician with experience treating MS patients, an individual with a basic understanding of pharmacokinetic parameters, a pharmaceutical formulator with experience with SR formulations, and an individual with experience in the design and analysis of clinical trials.
[81] Dr. Ebers opined that the POSITA team would also include support staff who monitor publicly available information, including patent literature, press releases and/or technical documents relating to fampridine and other disease modifying therapies for MS.
[82] Biogen disputes Dr. Ebers’ inclusion of this “searcher” or “support staff” member of the POSITA team. I agree. The POSITA is a worker of ordinary skill “in the art to which the patent relates” (Whirlpool at para 53).
[83] It is well accepted that the notional POSITA may be a team of persons with different skills (Pfizer Canada Inc v Pharmascience Inc, 2013 FC 120 at para 28). However, the notional team must still be made up of workers of ordinary skill in the field to which the patent relates. Regardless of whether a drug development team would practically include support staff whose job it was to search the patent literature and press releases, the patent at issue does not relate to the field of patent searching. The patent relates to the treatment of MS, and the make up of the composite POSITA should reflect as much.
[84] Having considered the expert testimony on the composite POSITA, I find that the 277 Patent is directed to a POSITA team with expertise in the treatment of MS, design and analysis of MS clinical trials, and pharmaceutical formulations. Further, the POSITA understands basic pharmacokinetic parameters and biostatistics. No expert pharmacokineticists or biostatisticians were put forward as witnesses for claim construction, so I accept that the skilled MS clinician/neurologist would have sufficient expertise in these areas to understand and interpret the 277 Patent.
[85] The skilled team does not include support staff who monitor publicly available information such as the patent literature and other technical documents.
B. Common General Knowledge
[86] While acknowledging that the relevant date for claim construction is October 27, 2005, Drs. Ebers and Leist both outlined the common general knowledge as of April 2004, the relevant date for assessing anticipation and obviousness. Neither party advanced evidence that the common general knowledge changed appreciably between April 2004 and October 2005, so for the purpose of claim construction, the common general knowledge will be taken to be the same as of both of these dates.
[87] The common general knowledge includes at least the background on MS discussed at the outset of these reasons, in addition to knowledge of fampridine as it relates to MS treatment, as detailed below.
[88] As part of their common general knowledge, the POSITA would have been aware of fampridine’s postulated mechanism of action, and that this drug had potential utility in various central nervous system disorders, including SCI and MS.
[89] The POSITA would known that MS was not a stereotypical disease, with substantial variability both between individuals (inter-individual variability), and within individual patients (intra-individual variability) on a weekly and sometimes daily basis. Due to this variability, a drug substance may provide significant improvement in one individual and have little to no effect in another.
[90] Studies had shown that stable MS patients can experience day-to-day variability in Timed 25 Foot Walk results of up to 20%. Accordingly, some researchers used a threshold of a 20% improvement at a statistically significant level as a minimum requirement when evaluating whether a given intervention caused a particular effect, as opposed to chance improvement due to variability.
[91] The POSITA would have been aware that MS is a debilitating progressive chronic disease. Where symptomatic treatments like fampridine are used, long-term or continuous administration is required to see continued benefit. Fampridine was thought to have a narrow therapeutic window, and higher doses of fampridine were associated with serious adverse effects, including seizures. When selecting a proper dose of fampridine, the POSITA would have been aware of potential adverse effects, and the “start low, go slow” approach to therapy was commonly used. Many clinical studies using fampridine started patients at a low dose before titrating the patient up to higher levels.
C. Claim Terms Needing Construction
[92] As stated above, the claims generally break down into two sets: (1) use of fampridine SR for improving walking (or increasing walking speed) in subjects with MS at a unit dose of 10 mg bid; and (2) Swiss-type claims for the use of fampridine SR in the manufacture of a medicament for improving walking (or increasing walking speed) in subjects with MS at a unit dose of 10 mg bid. Dependent claims add further limitations, namely specific pharmacokinetic parameters and administration timing.
[93] All relevant claims of the 277 Patent are reproduced in Appendix A. For ease of reference, independent claim 17 reads:
Use of a sustained release 4-aminopyridine composition for improving walking in a subject with multiple sclerosis in need thereof for a time period of at least two weeks at a unit dose of 10 milligrams of the 4-aminopyridine twice daily.
[94] The Asserted Claims use plain, simple terms. The Court generally does not need expert assistance in order to understand the terms “10 mg twice daily,” “improving walking,” “increasing walking speed,” and “subject with MS in need thereof.” The POSITA would have understood these terms at the relevant date as follows:
Improving walking includes improving some aspect of walking, such as endurance, step strength, or walking speed. The improvement must be quantitatively measured, and given the variability of symptoms and the prevalence of placebo effect in MS treatment, the quantitative improvement must be statistically significant.
A subject with MS in need thereof refers to MS patients who experience some form of walking disability. This is necessarily a subset of all MS patients, as patients with little to no disability (e.g. EDSS scores 0 – 2) are not in need of improvement walking, and patients who are immobilized (e.g. EDSS scores 8 – 9) are no longer able to walk, and will not benefit from treatment to improve walking. Therefore, a subject with MS in need of treatment is a subject with an EDSS score of approximately 3.5 to 7.
For a time period of at least two weeks means the fampridine SR is used for at least two weeks, at a fixed dose of 10 mg bid.
Unit dose of 10 milligrams of the 4-aminopyridine twice daily means the dose amount is 10 mg twice daily, or 10 mg bid.
[95] The improvement in walking or increase in walking speed need not be “clinically meaningful,” as argued by Biogen. Although Dr. Leist opined that the POSITA would only consider walking to be improved if a quantitative improvement also had a perceived benefit to the MS patient, on a purposive construction such a subjective element does not form part of the claimed invention.
[96] In arguing for a construction that includes a clinically meaningful improvement in walking, Biogen invites the Court to include a qualitative indicia that engages the skill and judgment required to gauge the subjective perceived benefit to a given patient in the context of the physician-patient relationship, thus treading into the territory of an unpatentable method of medical treatment. Moreover, inclusion of a subjective element would make it nearly impossible to establish infringement, as the patentee would need to show that any given patient would perceive a benefit in their walking or walking speed.
[97] Further, I do not accept Biogen’s argument that the claim limitation “for a time period of at least two weeks” requires that walking be consistently improved. The plain claim language merely requires use of 10 mg bid fampridine SR over the entire two week period.
[98] Independent claim 18 is a Swiss-type claim that is otherwise identical to claim 17. The experts agreed that claim 18 and its dependent claims cover the activities of a pharmaceutical manufacturer.
[99] Independent claims 31 and 32 mirror claims 17 and 18, but claim use of fampridine SR “for increasing walking speed” rather than “improving walking.” The experts agreed that increasing walking speed is narrower than improving walking.
[100] Dependent claims 19, 24, 33, and 38 add the further limitation that the fampridine SR composition exhibits a CavSS of 15 ng/mL to 35 ng/mL. I accept Dr. Ebers’ evidence that CavSS means average plasma concentration at steady state.
[101] Dependent claims 21, 26, 35, and 40 add the further limitation that the fampridine SR composition provides a mean Tmax in a range of 2 to 5 hours after administration. As defined in the disclosure, Tmax is the “time to maximum plasma concentration.”
[102] Dependent claims 23, 28, 37, and 42 state that the fampridine SR composition is in a form for administration every 12 hours, further limiting “twice daily” administration.
[103] Each of the asserted dependent claims also depends from earlier unasserted claims. These unasserted claims are broader in that they do not include the element “for a time period of at least two weeks” (claims 15, 16, 29, and 30), and some of the claims specify a broader mean Tmax range of 1 to 6 hours or 2 to 6 hours after administration (claims 20, 22, 25, 27, 34, 36, 39, and 41).
[104] As a final note on claim construction, to the extent that Biogen’s experts advocated for reading the post hoc responder analysis from the disclosure into the claims, this approach is incorrect. Drs. Oh and Leist both pr