Teva Canada Innovation v. Pharmascience Inc.

Teva Canada Innovation v. Pharmascience Inc.
Court (s) Database
Federal Court Decisions
Date
2021-01-06
Neutral citation
2020 FC 1158
File numbers
T-2182-18, T-2183-18
Decision Content
Date: 20210106
Dockets: T-2182-18
T-2183-18
Citation: 2020 FC 1158
Ottawa, Ontario, January 6, 2021
PRESENT: The Honourable Madam Justice Kane
BETWEEN:
TEVA CANADA INNOVATION AND
TEVA CANADA LIMITED
Plaintiffs
and
PHARMASCIENCE INC
Defendant
and
YEDA RESEARCH AND DEVELOPMENT CO., LTD.
Patentee added pursuant to ss 6(2)
of the PM (NOC) Regulations and
ss 55(3) of the Patent Act
PUBLIC JUDGMENT AND REASONS
(The Confidential Judgment and Reasons were issued on December 16, 2020 and no redactions are necessary)
Table of Contents
I. Overview.. 4
II. The Patents at Issue. 12
A. The ‘437 Patent 12
B. The ‘802 Patent 14
III. The Witnesses and the Nature of their Evidence. 16
A. The ‘437 Patent 16
(1) Fact Witnesses for Teva. 16
(2) Expert Witnesses for Teva. 17
(3) Fact Witnesses for Pharmascience. 18
(4) Expert Witnesses for Pharmascience. 18
B. The ‘802 Patent 19
(1) Fact Witnesses for Teva. 19
(2) Fact Witnesses for Pharmascience. 19
(3) Expert Witnesses for Teva. 20
(4) Expert Witness for Pharmascience. 20
IV. MS and its Diagnosis / Criteria. 21
A. Types of MS. 22
B. Clinically Isolated Syndrome. 23
C. Diagnosis of MS. 24
D. Use of MRI. 27
E. The McDonald Criteria. 28
F. The Difference between the Poser and McDonald Criteria vis-à-vis a CIS patient 31
V. Overall Position of the Plaintiff Teva on the ‘437 Patent 32
VI. Overall Position of the Defendant Pharmascience on the ‘437 Patent 34
VII. Overall Position of the Plaintiff Teva on the ‘802 Patent 37
VIII. Overall Position of the Defendant Pharmascience on the ‘802 Patent 39
IX. Onus and Burden of Proof. 40
X. The ‘437 Patent – Description and Disclosure. 40
XI. The ‘802 Patent – Description and Disclosure. 45
XII. The Structure of this Judgment 47
XIII. Overview of the Experts’ Evidence re the ‘437 Patent 48
A. Pharmascience’s Expert, Dr. Green. 48
B. Teva’s Expert, Dr. Morrow.. 52
C. Teva’s Expert, Dr. Selchen. 54
D. Teva’s Expert, Dr. Kreitman. 56
XIV. The POSITA for the ‘437 Patent 57
A. The Principles from the Jurisprudence. 57
B. Who is the POSITA for the ‘437 Patent?. 58
XV. The Construction of the Claims. 60
A. The Principles from the Jurisprudence. 60
B. The Claims of the ‘437 Patent 61
C. The Dispute regarding the Patients Included in the Claims. 64
(1) Pharmascience’s Submissions. 64
(2) Teva’s Submissions. 66
D. What do the Experts Say regarding the Patients Included in the Claims?. 69
(1) Dr. Green. 69
(2) Dr. Morrow.. 71
(3) Dr. Selchen. 73
E. The Patients Included in Claim 1 and Subsequent Claims. 76
XVI. Prior Art related to the ‘437 Patent 84
A. Prior art on the use of glatiramer acetate in MS. 85
B. Prior art on CIS progressing to MS. 85
C. Prior art on the use of interferons in CIS. 86
D. Prior art cited by Pharmascience as anticipatory references. 89
XVII. Common General Knowledge. 90
A. Principles from the Jurisprudence. 90
B. What Do the Experts Say?. 91
(1) Dr. Green. 91
(2) Dr. Selchen. 95
C. The Common General Knowledge regarding the ‘437 Patent 98
XVIII. Can Pharmascience rely on the Gillette Defence to the Allegations of Infringement of the ‘437 Patent? 101
A. Principles from the Jurisprudence. 101
B. Pharmascience’s Submissions. 102
C. Teva’s Submissions. 103
D. The Gillette Defence Cannot Succeed. 104
XIX. Is the ‘437 Patent Anticipated?. 105
A. Principles from the Jurisprudence. 105
B. Pharmascience’s Submissions. 108
C. Teva’s Submissions. 111
D. What do the Experts Say?. 114
(1) Dr. Green. 114
(2) Dr. Selchen. 116
E. Karussis 2006 does Not Anticipate the Claims of the ‘437 Patent 118
XX. Is the ‘437 Patent Obvious?. 129
A. Principles from the Jurisprudence. 129
B. Pharmascience’s Submissions. 134
C. Teva’s Submissions. 139
D. What do the Experts Say?. 143
(1) Dr. Green. 143
(2) Dr. Selchen. 146
E. The Claims of the ‘437 Patent are Obvious. 150
(1) The State of the Art 151
(2) The Differences between the State of the Art and the Subject Matter of the Claims. 155
XXI. The ‘802 Patent 159
A. The POSITA for the ‘802 Patent 160
B. The Construction of the Claims of the ‘802 Patent 161
XXII. Prior Art and Common General Knowledge related to the ‘802 Patent 161
A. Prior art on glatiramer acetate 20 mg daily vs. every-other-day (alternate-day) 162
B. Prior art on glatiramer acetate 20 mg vs. 40 mg administered daily. 165
C. Prior art on glatiramer acetate 40 mg every-other-day. 167
D. Prior art on injection site reaction and immediate post injection reaction. 167
XXIII. Overview of the Experts’ Evidence on the ‘802 Patent 168
A. Pharmascience’s Expert, Dr. Green. 168
B. Teva’s Expert, Dr. Prat 169
C. Teva’s Expert, Dr. Day. 171
XXIV. Is the ‘802 Patent Invalid due to Obviousness?. 172
A. Teva’s Submissions. 172
B. Pharmascience’s Submissions. 180
C. What do the Experts Say?. 186
(1) Dr. Green. 186
(2) Dr. Prat 194
D. The ‘802 Patent is Not Obvious. 206
(1) The State of the Art 216
(2) Differences between the State of the Art and the Subject Matter of the Claims. 218
(3) Not Obvious to Try. 219
XXV. Is the ‘802 Patent Invalid due to Lack of Utility or Sound Prediction of Utility?. 224
A. Teva’s Submissions. 224
B. Pharmascience’s Submissions. 228
C. Principles from the Jurisprudence. 230
D. The ‘802 Patent is not Invalid due to Lack of Sound Prediction of Utility. 235
XXVI. The Jurisdictional Issue – Can Teva rely on the Regulations to assert infringement by Pharmascience of 20 mg Glatect?. 241
XXVII. Infringement by Pharmascience. 245
XXVIII. Costs. 249
I. Overview
[1] These proceedings involve two patent infringement actions [the Action] pursuant to subsection 6(1) of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 [the Regulations].
[2] At issue are medications that treat multiple sclerosis [MS]. The Teva Canada Innovation and Teva Canada Limited [collectively, Teva] product is Copaxone® [Copaxone]. Copaxone 20 milligram [mg] has been on the market since the mid-90s. Copaxone 40 mg is a more recent product.
[3] The Pharmascience Inc. [Pharmascience] generic product is Glatect® [Glatect]. Pharmascience obtained a Notice of Compliance [NOC] from the Minister of Health [Minister] for Glatect 20 mg, which is administered daily, in 2017 and has been marketing Glatect 20 mg since that time. The Glatect Product Monograph, which, among other things, describes what Glatect 20 mg is intended to treat, is described in more detail later in these Reasons. Teva has confirmed that regardless of the outcome of this Action, the NOC issued to Pharmascience for Glatect 20 mg daily will not be affected.
[4] Pharmascience now seeks to expand its Glatect product to include a 40 mg strength to be administered three times per week. Pharmascience submitted a Supplementary New Drug Submission [SNDS] to do so and, in that context, identified Copaxone 40 mg as the reference product. Pharmascience describes its SNDS as a line extension to its 20 mg product.
[5] This Action arises from Pharmascience’s filing of the SNDS. Teva submits that Glatect 40 mg would be marketed in accordance with Pharmascience’s proposed Glatect Product Monograph that is substantially identical to Teva’s Copaxone Product Monograph.
[6] Teva argues that Pharmascience’s Glatect products will infringe the two patents at issue – Canadian Patent Nos. 2,702,437 [the ‘437 Patent] and 2,760,802 [the ‘802 Patent]. Teva submits that Pharmascience will manufacture, sell and induce the use of its products, which will be for exactly the same patient population, in the same dosage strength, and with the same dosage regimen to achieve the same outcomes. Teva submits that Pharmascience has not led any evidence to demonstrate that it will not infringe. Pharmascience argues that the patents are invalid.
[7] The criteria for a diagnosis of MS is a point of contention between Teva and Pharmascience as this has an impact on the scope of the claims of the ‘437 Patent and in turn the allegations of infringement and invalidity. As described below, in the 1980s and 1990s, the diagnosis of MS was based on criteria developed by Poser (Poser CM et al, “New Diagnostic Criteria for Multiple Sclerosis: Guidelines for Research Protocols”, 1983 Ann Neurol 13(3): 227-230 [the Poser criteria]) which required the demonstration of two clinical attacks. In 2001, new criteria were developed by McDonald (McDonald et al, “Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis”, 2001 Ann Neurol 50: 121-127 [the McDonald criteria]) which relied more extensively on magnetic resonance imaging [MRI] evidence to demonstrate the disease and its progression. The McDonald criteria were updated in 2005, 2010 and 2017. The experts noted that while the McDonald criteria gained wide acceptance, the Poser criteria and terminology remain within their knowledge and some physicians continue to refer to the Poser criteria.
[8] Teva submits that the claims of the ‘437 Patent are directed only to patients who have had one clinical attack and have not yet been diagnosed with MS.
[9] Teva does not dispute that Copaxone 20 mg was known as an effective therapy for patients diagnosed with relapsing-remitting multiple sclerosis [RRMS], a type of MS. Teva argues that the ‘437 Patent was novel and inventive in identifying 20 mg of glatiramer acetate daily for the early treatment of patients after their first clinical attack and before the onset of MS. Teva argues that the prior art relied on by Pharmascience was obscure and only speculated that glatiramer acetate administered daily would be effective for the early treatment of patients.
[10] Pharmascience argues that it will not infringe the ‘437 Patent because the patent is invalid and because its Glatect 40 mg product is not intended for the single-attack patient but for patients who meet the criteria for a diagnosis of MS or RRMS.
[11] Pharmascience asserts the Gillette defence in response to Teva’s allegations of infringement. Pharmascience argues that it does not infringe the ‘437 Patent because its Glatect product merely practices the teachings of the prior art. Pharmascience submits that the claims of the ‘437 Patent include RRMS patients, and the prior art includes that glatiramer acetate was well known to be an effective treatment for RRMS.
[12] Pharmascience also argues that the ‘437 Patent is neither novel nor inventive and, as a result, is invalid due to anticipation and obviousness.
[13] Pharmascience submits that, although the claims of the ‘437 Patent reflect the Poser criteria, the claims include some patients who meet the McDonald criteria for MS. If Pharmascience’s interpretation prevails, then those patients who have had only one clinical attack but who meet the criteria for a diagnosis of MS (i.e., based on MRI evidence) would fall within the claims of the ‘437 Patent. Argueably, these MS patients are no different from the RRMS patients for which Copaxone 20 mg was a well-known treatment.
[14] Pharmascience also submits that if the claims of the ‘437 Patent are interpreted narrowly, to single-attack patients (as Teva proposes), the claims are still anticipated by the prior art, which recommended that glatiramer acetate should be considered for the early treatment of such patients.
[15] Pharmascience argues that the claims are obvious because there was no difference between the state of the art in November 2007 and the subject matter of the claims.
[16] Jurisdictional issues have been raised by Pharmascience regarding whether the scope of the Regulations permits Teva to assert infringement of the ‘437 Patent with respect to Glatect 20 mg on a go-forward basis in these circumstances, given that Pharmascience has already obtained a NOC. This issue is addressed later in these Reasons in Part XXVI.
[17] With respect to the ‘802 Patent, Teva argues that Pharmascience will infringe the patent because Pharmascience’s Glatect product is indicated for the very same patient population, primarily patients with RRMS, with the same dosing schedule of 40 mg three times weekly. Teva disputes that the ‘802 Patent is invalid for obviousness or lack of sound prediction of utility.
[18] Teva argues that there were material differences between the state of the art in August 2009 and the subject matter of the claims of the patent. Teva disputes that the prior art relied on by Pharmascience was authoritative or known by the person skilled in the art [POSITA or skilled person] or would be considered as a “mosaic” by the POSITA. Teva argues that the POSITA would not reach the invention using their common general knowledge and routine work. Rather inventiveness was required. Teva submits that there is no question that the 40 mg three times per week invention is inventive and useful.
[19] Pharmascience submits that it will not infringe Teva’s ‘802 Patent because the ‘802 Patent is invalid due to obviousness.
[20] Pharmascience alternatively submits that if the ‘802 Patent is not obvious based on the prior art, then Teva has neither demonstrated utility nor soundly predicted utility. Teva notes that there are no results set out in the ‘802 Patent, but only a proposal for a study of the expected results.
[21] Generally, the parties have mapped out different paths to lead to the findings they seek and have pointed to excerpts in the evidence in support of their particular directional paths. However, the role of the Court is to take the “high road” and to consider all the relevant evidence in its proper context.
[22] Both Teva and Pharmascience raised objections to particular evidence of the other party.
[23] For example, Teva submits that Pharmascience has engaged in case splitting by introducing new evidence, in particular, the international patent application WO 2007/081975 [Pinchasi 2007], noted in Dr. Ari Green’s responding report on non-infringement. Pharmascience disputes this allegation and argues that it clearly pleaded the Gillette defence as an infringement issue. Pharmascience explains that Dr. Green was given and asked to review the prior art product monographs for Copaxone and Pinchasi 2007 and to describe how a skilled person would understand them. He was also asked to review the Glatect Product Monograph and to provide his opinion as to whether it followed the teachings of the prior art.
[24] Pharmascience explains that it does not rely on Dr. Green’s opinion on Pinchasi 2007 in his responding non-infringement report for its anticipation arguments; rather it relies on this evidence for the Gillette defence. Pharmascience notes that Teva did not provide any reply to Dr. Green’s non-infringement report.
[25] Pharmascience also notes that it clearly cited Pinchasi 2007 as an anticipatory reference and it can, therefore, be relied on to show anticipation.
[26] Teva also submits that Pharmascience sought to introduce additional evidence in its closing arguments. Pharmascience responds that the additional 21-page compendium contains only excerpts of documents already in evidence to more clearly point to the references Dr. Green relied on in his validity opinion.
[27] More generally, each party seeks to diminish the expertise and evidence of their opponents’ experts by, among other things: questioning their understanding of the legal tests and instructions provided; suggesting that they are in the pockets of big pharmaceutical companies due to past research grants and consulting fees; suggesting that they have exceeded their mandates; suggesting that they have not published in certain top scientific journals; suggesting that they have cited other experts in the field in their publications who they now seem to differ with on specific points; and, challenging their specific expertise, such as not being part of a drug development team.
[28] In my view, all the experts have established their particular expertise and all have offered evidence that is helpful to the Court on the issues at play. All the experts are clearly committed to improving the experience of persons with MS. I have considered the submissions of both parties who seek to discount the evidence of the other party’s witnesses. I have considered all of the evidence in its proper context and have weighed it. I have not discounted the evidence of any expert because they have been paid by the parties in this or other litigation or in their research, or because they have published more or less extensively than other experts. Clearly, they are all experts in the diagnosis and treatment of MS and have been so qualified for the purpose of this Action. However, the experts have provided different opinions on key issues that are not possible to reconcile. Cross-examination has identified some inconsistencies and frailties in some of the evidence. However, some of the questions posed to the experts on cross-examination were detailed and specific and understandably sought to elicit support for particular arguments. In some instances, the questions and answers were confusing and contrived and have required me to very carefully consider the totality of the expert’s extensive evidence. The assessment of the evidence is addressed in the context of the relevant issues.
[29] For the reasons that follow, I find that the ‘437 Patent is not anticipated by Karussis D et al, “A recommended treatment algorithm in relapsing multiple sclerosis: report of an international consensus meeting”, 2006 Eur J Neurol 13: 61-71 [Karussis 2006]. However, I find that the ‘437 Patent is obvious.
[30] The jurisdictional issue regarding Teva’s reliance on the Regulations to allege infringement with respect to the 20 mg Glatect product need not be addressed given my conclusion that the ‘437 Patent is not valid.
[31] I find that the ‘802 Patent is valid; it is not obvious and it soundly predicted its utility.
[32] With respect to infringement, if Pharmascience proceeds to market Glatect 40 mg in accordance with its proposed SNDS, it will infringe the ‘802 Patent.
II. The Patents at Issue
A. The ‘437 Patent
[33] Yeda Research and Development Co., Ltd. [Yeda] is the owner of the ‘437 Patent.
[34] Pursuant to section 42 of the Patent Act, RSC 1985, c P-4 [Patent Act], Yeda has the exclusive right, privilege and liberty of making, constructing, using and selling to others to be used, the invention claimed in the ‘437 Patent.
[35] Yeda is a corporation with a head office in Rehovot, Israel.
[36] Teva Canada Innovation is a corporation with a head office in Montreal Quebec, and an office in Toronto, Ontario. Teva Canada Limited is a corporation with a head office in Toronto, Ontario.
[37] The ‘437 Patent is listed on the Patent Register maintained by the Minister pursuant to the Regulations in respect of Teva's 40 mg glatiramer acetate product marketed under the brand name Copaxone in 40 mg/1 mL pre-filled syringes for subcutaneous injection. Teva’s 20 mg strength glatiramer acetate is not listed on the Patent Register.
[38] Teva notes that it has obtained Yeda’s consent for the inclusion of the ‘437 Patent on the Patent Register maintained by the Minister pursuant to the Regulations. Teva is authorized by Yeda to sell, and sells, the drug Copaxone (glatiramer acetate) in Canada.
[39] The ‘437 Patent is titled, “Methods of Delaying the Onset of Clinically Definite Multiple Sclerosis”. The ‘437 Patent issued on June 25, 2013 and has not expired.
[40] The parties agree that the relevant date for claims construction is the date of the publication of the patent, June 4, 2009. For anticipation and obviousness, the relevant date is the claim date, November 28, 2007.
[41] The ‘437 Patent contains 50 claims. The claims relate to glatiramer acetate, or medicaments comprising glatiramer acetate, for use in treating human patients at risk of developing MS. The claims at issue (Claims 1, 2, 3, 4, 13, 14, 15, 16, 19, 24, 33, 47 and 50) are set out at Annex 1.
[42] On November 13, 2018, Teva was served with a Notice of Allegation [NOA] from Pharmascience, a generic pharmaceutical company, in respect of Glatect 40 mg regarding the ‘437 Patent. The NOA alleges that the ‘437 Patent would not be infringed by Pharmascience making, constructing, using or selling Glatect and that the ‘437 Patent is invalid.
B. The ‘802 Patent
[43] Yeda is also the registered owner of the ‘802 Patent and is a party to this Action pursuant to subsection 6(2) of the Regulations.
[44] Pursuant to section 42 of the Patent Act, Yeda has the exclusive right, privilege and liberty of making, constructing, using and selling to others to be used, the invention claimed in the ‘802 Patent.
[45] The ‘802 Patent is listed on the Patent Register maintained by the Minister pursuant to the Regulations in respect of Teva’s glatiramer acetate product marketed under the brand name Copaxone in 40 mg /1 mL pre-filled syringes for subcutaneous injection.
[46] Teva notes that it has obtained Yeda's consent for the inclusion of the ‘802 Patent on the Patent Register maintained by the Minister pursuant to the Regulations. Teva asserts that it is authorized by Yeda to sell, and sells, the drug Copaxone (glatiramer acetate) in Canada.
[47] The ‘802 Patent is titled, “Low Frequency Glatiramer Acetate Therapy”.
[48] The parties agree that the relevant date for construing the claims is the publication date of the patent application, February 24, 2011. The relevant date for the allegations of obviousness is the claim date, August 20, 2009. The relevant date to assess utility is the filing date, August 19, 2010.
[49] The ‘802 Patent contains 66 claims. All claims relate to glatiramer acetate, or medicaments comprising glatiramer acetate, for use in treating human patients with, or at risk of developing, MS. The claims at issue are Claims 1, 2, 3, 4, 22, 24, 25, 36-39, 47-57, 59, 60, 63-66 and are set out at Annex 2.
[50] On November 13, 2018, Teva was served with a NOA from Pharmascience in respect of Glatect regarding the ‘802 Patent. The NOA alleges that the ‘802 Patent would not be infringed by Pharmascience making, constructing, using or selling Glatect and the ‘802 Patent is invalid.
III. The Witnesses and the Nature of their Evidence
[51] The parties presented their evidence in both written reports from fact and expert witnesses and oral testimony from many of the witnesses. The witnesses and a brief synopsis of the nature of their evidence is set out below.
A. The ‘437 Patent
(1) Fact Witnesses for Teva
[52] Ms. Sigalit Zecharia Daniel is the Senior Director, Head of Global Clinical Quality at Teva Pharmaceutical Industries Ltd. Ms. Daniel attached to her affidavit documents related to clinical studies that Teva had conducted, including the clinical study protocols and reports.
[53] Dr. Rivka Kreitman holds a Ph.D. in biochemistry and completed a post-doctoral fellowship in molecular biology and genetics. She joined Teva in 1993 and left in 2018. During her time at Teva, among other things, she and her team were responsible for the research, development, regulatory filings and clinical studies of Copaxone. Dr. Kreitman provided documents related to the development of Copaxone. Dr. Kreitman has also provided evidence in proceedings in other jurisdictions regarding the patents at issue.
(2) Expert Witnesses for Teva
[54] Dr. Sarah Morrow is a neurologist with expertise in neurological disorders, including the diagnosis and treatment of MS. Dr. Morrow described the POSITA, the disclosure of the ‘437 Patent and the construction of the claims. Dr. Morrow’s evidence focussed on whether the using or selling of Pharmascience’s Glatect products, as described in the Glatect Product Monograph, would infringe the claims of the ‘437 Patent.
[55] Dr. Selchen is a neurologist with expertise in neurological disorders, including the diagnosis and treatment of MS. Dr. Selchen responded to Dr. Green’s invalidity opinion. Dr. Selchen addressed the POSITA, common general knowledge, construction of the claims and the state of the art in relation to the ‘437 Patent.
[56] Mr. Neil Palmer is an expert on the Canadian pharmaceutical marketplace. He is the Founder, Senior Adviser, and President Emeritus of PDCI Market Access Inc., an Ottawa-based pricing and reimbursement consultancy. Mr. Palmer’s evidence addressed, among other things, the public and private reimbursement regimes relevant to glatiramer acetate including Copaxone and Glatect. The parties agreed that Mr. Palmer’s report be accepted without oral testimony.
[57] Dr. Gregory Grant is a biochemist and professor of developmental biology and biochemistry in medicine. Dr. Grant’s evidence addressed a biochemist’s understanding of “glatiramer acetate” relative to the ‘437 and ‘802 Patents and assessed whether Glatect contains glatiramer acetate. The parties agreed that Dr. Grant’s evidence be accepted without oral testimony.
(3) Fact Witnesses for Pharmascience
[58] Mr. Graham McKinnon is a registered patent agent in Canada and the United States. Mr. McKinnon attached to his affidavit documents related to the filing history of the U.S. Patent Application No. 11/651,212 and Canadian Patent No. 2,191,088 [the ‘088 Patent].
[59] Mr. Deirdre Cozier is the Director of Global Regulatory Affairs at Pharmascience, responsible for compiling information and data and making submissions related to Pharmascience’s pharmaceutical products to regulatory authorities worldwide, including Health Canada. Mr. Cozier attached to his affidavit documents related to the regulatory filings of Glatect, including the product monograph and SNDS.
(4) Expert Witnesses for Pharmascience
[60] Dr. Ari Green is a neurologist with expertise in neurological disorders, including the diagnosis and treatment of MS. He provided two reports with respect to the ‘437 Patent. Dr. Green first set out his opinion on the validity of the ‘437 Patent and addressed anticipation, citing Karussis 2006, and obviousness with reference to the prior art and common general knowledge. Dr. Green also provided a second report in response to Dr. Morrow’s infringement report. In the second report, Dr. Green addressed product monographs, elaborated on the target patient population and cited additional prior art. Dr. Green has also provided expert evidence in proceedings in other jurisdictions regarding the patents at issue or their equivalents.
[61] Ms. Susanne Picard is a pharmacist and regulatory affairs consultant with expertise in the regulatory approval of pharmaceutical products. Ms. Picard’s evidence addressed, among other things, the requirements for New Drug Submissions [NDS] and SNDS, the use of product monographs and, more particularly, the Glatect SNDS and Product Monograph.
B. The ‘802 Patent
(1) Fact Witnesses for Teva
[62] Ms. Sigalit Zecharia Daniel and Dr. Rivka Kreitman, described above, also provided evidence for the ‘802 Patent.
(2) Fact Witnesses for Pharmascience
[63] Mr. Graham McKinnon and Mr. Deirdre Cozier, described above, also provided evidence for the ‘802 Patent.
(3) Expert Witnesses for Teva
[64] Dr. Reza Vosoughi is a neurologist with expertise in neurological disorders, including the diagnosis and treatment of multiple sclerosis. Dr.Vosoughi’s evidence addressed the POSITA, construction of the claims and infringement of the claims of the 802 Patent.
[65] Dr. Alexandre Prat is a neurologist with expertise in neurological disorders, including the diagnosis and treatment of multiple sclerosis. Dr. Prat responded to Dr. Green’s opinion on the invalidity of the ‘802 Patent.
[66] Dr. Simon Day is a biostatistician with expertise in clinical trial design and interpretation. Among other things, Dr. Day addressed how the POSITA would have regardedthe results of clinincal studies and other abstracts relating to glatiramer acetate.
[67] Mr. Neil Palmer and Dr. Gregory Grant, described above, also provided evidence for the ‘802 Patent.
(4) Expert Witness for Pharmascience
[68] Dr. Ari Green, described above, also provided his opinion on the validity of the ‘802 Patent.
IV. MS and its Diagnosis/Criteria
[69] MS is a disease of the central nervous system [CNS], which includes the brain, optic nerve and spinal cord. MS is considered to be an inflammatory or autoimmune disease in which the patient’s own immune system attacks the myelin of the CNS.
[70] As explained by Teva’s witness Dr. Morrow, and reiterated by the other experts, the CNS is composed of grey matter and white matter. Grey matter contains neuron cell bodies, while white matter contains axons, which are the projecting portions of neurons. The axons of the CNS white matter are wrapped in a fatty substance known as myelin. The myelin forms a sheath (analogous to insulation) that enables rapid transmission of electrical signals generated in neuron cell bodies that are propagated along the length of axons.
[71] With MS, the body’s immune system attacks elements of the CNS and leads to the destruction of the myelin sheath in the brain, optic nerve and spinal cord (referred to as “demyelination”) and axonal loss, which causes CNS damage, or lesions over time.
[72] Demyelination may occur at various sites within the CNS. The symptoms experienced by an MS patient depend upon the site or sites within the CNS that are affected by demyelination and by the size of the lesions.
[73] Pharmascience’s expert, Dr. Green, explained that MS is characterized early on by intermittent but potentially debilitating inflammatory and demyelinating events (also called “attacks”, “relapses”, “exacerbations”, and “episodes”). One of the common presenting clinical attacks is optic neuritis (which manifests itself as a loss of vision and pain behind the eye). Other common clinical attacks include episodes of numbness, tingling, muscle weakness and spasticity, incoordination, loss of control of bowel and bladder, general fatigue, dizziness and depression.
A. Types of MS
[74] The expert witnesses all described the categories of MS in a similar manner noting that the categories are related to the course or progression of the disease.
[75] The experts explained that as of November 2007, with respect to the ‘437 Patent, and as of August 2009, with respect to the ‘802 Patent, four distinct clinical courses or categories of MS had been described:
RRMS is characterized by intermittent and clearly defined relapses with at least partial recovery or remission of some symptoms over weeks to months;
Secondary progressive MS [SPMS], which follows a diagnosis of RRMS is characterized by progressive worsening of symptoms over time with fewer or no intermittent relapses interspersed with periods of partial recovery;
Primary progressive MS [PPMS] is characterized by a steady decline in neurological function without distinct relapses or remissions; and,
Progressive-relapsing MS [PRMS] is characterized by a steady decline in neurological function from onset overlaid with occasional relapses and periods of recovery during which progressive worsening of symptoms continues.
[76] Several experts explained that RRMS remains the most common type of MS.
B. Clinically Isolated Syndrome
[77] Teva’s witness, Dr. Selchen explained that, as of November 2007, patients presenting with a single clinical attack having features typical of MS were diagnosed as having a clinically isolated syndrome [CIS]. Dr. Selchen noted that when examining a patient presenting with a possible CIS, it would be important for the clinician to consider whether the CIS is caused by something other than MS. Dr. Selchen also noted that it was recognized that many, but not all, cases of MS begin as a CIS.
[78] MRI could be used for patients who had a single clinical attack to determine if the attack was suggestive or supportive of an MS diagnosis.
[79] Dr. Green also explained that the term CIS was generally applied to patients who had a single episode of clinical neurological worsening that was suspicious for demyelination with MRI evidence of other lesions (at least one or two). CIS with evidence of MRI lesion(s) was often distinguished from an episode that was suspicious for inflammatory demyelination but did not have MRI lesions by calling it “high risk” CIS. Dr. Green stated that most of these “high risk” CIS patients go on to develop RRMS.
[80] Dr. Green added that the primary means of distinguishing who is at risk of developing future attacks is evidence of prior episodes that preceded the clinical event (the CIS event). As of November 2007, this risk was largely assessed via the identification of suspect lesions on MRI.
C. Diagnosis of MS
[81] All the experts agreed that the diagnosis of MS has evolved over time.
[82] The experts also agreed that there is no single diagnostic test for any type of MS. The diagnosis is based on a combination of findings from a patient’s history, physical exam, ancillary diagnostic tests (such as MRIs of the brain and spinal cord) and examination of cerebrospinal fluid through lumbar puncture.
[83] As Dr. Green elaborated, by November 2007, MS diagnosis depended upon (and still depends upon) numerous objective and subjective analyses. Objective analyses include clinical examination, formalized clinical evaluations scored to measure disability, MRI scans, extended clinical assessments (e.g., neuropsychological assessments and neurovisual assessments) and relapse frequency assessments. Subjective assessments include patient questionnaires targeting measurement of clinical progression.
[84] Although MS was diagnosed long before the 1980s, the criteria of relevance to this Action are the Poser and McDonald criteria.
[85] The “Poser criteria” were developed in the 1980s. The Poser criteria depended to a great extent on clinical observation.
[86] The concepts or pillars of the criteria are “dissemination in space” [DIS], described as evidence of lesions at multiple locations in the CNS, and “dissemination in time” [DIT], described as the occurrence of distinct episodes separated in time.
[87] Dr. Green explained that DIT and DIS continue to be crucial characteristic features of MS.
[88] Dr. Selchen also explained that a diagnosis of MS can be made only after demonstration of both DIT and DIS.
[89] Under the Poser criteria, a diagnosis of MS (also referred to as “clinically definite MS” or CDMS) required evidence of multiple CNS lesions. This could be demonstrated by neurological examination (referred to as clinical signs of neurological dysfunction) or by tests and procedures that demonstrate the existence of a lesion without the patient having reported or observed a clinical sign (referred to as paraclinical signs of neurological dysfunction, e.g., relying on MRI). Patients had to have evidence that there was more than one lesion separated in space (i.e., DIS) and evidence of more than one prior episode or relapse (i.e., DIT).
[90] Under the Poser criteria, a diagnosis of CDMS required:
Two attacks and clinical evidence of two separate lesions; or
Two attacks and clinical evidence of one lesion and paraclinical evidence (i.e., MRI) of another, separate lesion.
[91] In simpler terms, the diagnosis in accordance with the Poser criteria (and in accordance with the McDonald criteria) requires that the disease is demonstrated to affect different parts of the CNS and at different times.
[92] Dr. Green explained that the Poser criteria initially established that, to make out a diagnosis of CDMS, it was necessary to demonstrate that the disease involved more than one pathway (DIS) and was not “monophasic” (i.e., a single phase) (DIT). This depended on clinical evaluation and typically required that a patient have two identified attacks (i.e., relapses) of more than 24 hours duration separated by more than a one-month interval together with clinical evidence of lesions in at least two different places within the CNS.
[93] Dr. Morrow explained that according to the Poser criteria, a patient that has only experienced one attack and had clinical or paraclinical signs of at least one CNS lesion was referred to as having CIS.
[94] Dr. Morrow stated that the majority of CIS patients progress to being diagnosed with CDMS. Dr. Green agreed. Dr. Selchen also agreed but noted that some patients would need to be followed for a longer period of time.
[95] Dr. Selchen explained that CIS has been called a “clinical event suggestive of MS” because in many patients it precedes a diagnosis of MS.
D. Use of MRI
[96] By the early 2000s, MRI was increasingly relied on in the MS clinical setting. Dr. Morrow explained that MRI is a highly sensitive technique for detection of tissue changes in patients with MS. MRI is used as a paraclinical measure for the diagnosis of MS and to monitor both disease activity and progression in patients.
[97] The experts explained how MRI of the brain to identify lesions that are characteristic of MS depicts the disease and its progression and can guide the management of the disease. The two main types of images are “T1-weighted” and “T2-weighted” images.
[98] Dr. Vosoughi and the other experts noted that inflammation in the brain can be observed with the injection of Gadolinium (referred to as Gd or GAD). This was described as an imaging technique in which the patient is given an “enhancing agent”, like a dye, to increase the contrast between healthy and damaged tissues. Dr. Morrow and Dr. Green similarly explained the visualization using MRI T1-weighted images and T2-weighted images and the use of Gd on post-contrast images.
[99] Dr. Vosoughi explained that in patients with MS, T1 lesions tend to increase in number and volume over time. In addition, when the immune system attacks the brain (or spinal cord) in MS patients, new T2 lesions appear. Over time, the number of T2 lesions and their volume increases. In addition to diagnosis and progression of the disease, the measurement of the number and volume of T1 and T2 lesions is used in clinical trials to monitor the effects of what is being tried.
E. The McDonald Criteria
[100] In 2001, the International Panel on MS Diagnosis published a report proposing revised diagnostic criteria for MS, known as the “McDonald criteria”. The McDonald criteria permitted the diagnosis of “monosymptomatic” disease (i.e., one attack) suggestive of MS, which was not previously treated as MS, but would have been diagnosed under the Poser criteria as CIS (i.e., patients who had only one confirmed attack). The McDonald criteria also relied on the concepts of DIS and DIT and highlighted the use of MRI along with other diagnostic methods.
[101] Dr. Green noted that the McDonald criteria were developed in response to the need for earlier diagnosis of MS and the increasing use of MRI. Dr. Selchen explained that the McDonald criteria responded to the need to diagnose with specificity and sensitivity; in other words, to identify for treatment those patients that had MS and to exclude from treatment those that did not have MS. MRI provided a means to document DIS and to standardize how to document DIT.
[102] The experts agreed that, by November 2007, it was routine to use MRI findings to confirm a diagnosis of MS.
[103] In accordance with the McDonald criteria, a patient could be diagnosed with MS after a single attack where MRI results could be relied upon to show objective evidence of DIT and DIS (i.e., even if there is no clinical evidence of a second attack or no reporting of a second attack by the patient).
[104] An excerpt from the abstract from McDonald 2001 states:
The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including “monosymptomatic” disease suggestive of MS, disease with a typical relapsing-remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as “clinically definite” and “probable MS” are no longer recommended. The outcome of a diagnostic evalua