2020 FC, 2020 FC 1158

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 J urisdictional 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 me dications 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: a . RRMS is characterized by intermittent and clearly defined relapses with at least partial recovery or remission of some symptoms over weeks to months; b . 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; c .

Primary progressive MS [PPMS] is characterized by a steady decline in neurological function without distinct relapses or remissions; and, d . 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 evaluation is either MS, “possible MS” (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or “not MS.” [ 105 ] The McDonald criteria permitted a diagnosis of MS based on one clinical attack as long as additional evidence was available. Two scenarios were described: 1 . One attack with objective evidence of two or more lesions, which required: dissemination in time demonstrated by MRI or a second clinical attack 2 .

One attack with objective clinical evidence of one lesion (monosymptomatic or CIS), which required: dissemination in space demonstrated by MRI, or two or more MRI detected lesions consistent with MS plus positive cerebral spinal fluid, and

dissemination in time demonstrated by MRI. [ 106 ] The experts agreed that the McDonald criteria result in a diagnosis of either " “MS” " , " “possible MS” " (where the diagnostic evaluation is equivocal) or " “not MS” " . [ 107 ] All the experts noted how the criteria for diagnosis have evolved and agreed that the McDonald criteria gained general acceptance. The experts agreed that the term CDMS has given way to simply MS. Dr. Morrow explained, however, that the McDonald criteria did not immediately replace the Poser criteria and that practicing neurologists remain familiar with the terms CDMS and CIS.

All the experts noted that the POSITA would still be familiar with the terms under the Poser criteria and the McDonald criteria. [ 108 ] The McDonald criteria were refined in 2005, 2010 and 2017. [ 109 ] Dr. Green explained that under the McDonald criteria (Polman et al, " “Diagnostic criteria for multiple sclerosis: 2005 Revisions to the “McDonald Criteria”, 2005 Ann Neurol 58: 840-846” " ), in addition to characteristic symptoms and signs on neurological examination, patients could be diagnosed based on characteristic findings on MRI of the brain and spinal cord.

For example, where a patient presented with a history of two episodes or attacks characteristic of MS but only one lesion was confirmed by objective clinical evidence, the McDonald criteria permitted MRI findings to be relied upon to establish that the disease had affected more than one area of the CNS and to support a diagnosis of MS.

Alternatively, where neurological examination revealed objective clinical evidence of two or more lesions in the CNS, but the patient history suggested only one attack, the McDonald criteria permitted MRI findings to be relied upon to establish that the disease was sufficiently disseminated in time to make a diagnosis of MS. [ 110 ] The experts noted that with the introduction of the 2005 McDonald criteria, relatively more CIS patients were diagnosed as having MS (typically RRMS) on the sole basis of appearance of new MRI lesions, regardless of whether new clinical symptoms developed or whether the lesions were " “clinically silent” " .

F. The Difference between the Poser and McDonald Criteria vis-à-vis a CIS patient [ 111 ] A point of contention in this Action is whether the claims of the ‘437 Patent are directed to a single attack (or CIS) patient, i.e., a patient who has had a single attack without more, or are also directed to a single attack patient who meets the McDonald criteria for a diagnosis of MS, but has not yet had a second clinical attack.

Teva submits that the claims are clearly directed to administering glatiramer acetate to a CIS patient who has not yet had a second clinical attack and, as a result, has not been diagnosed with CDMS.

Teva submits that the claims are not directed at patients who have been or could be diagnosed with MS pursuant to the McDonald criteria. [ 112 ] Pharmascience argues that the McDonald criteria were the applicable diagnostic criteria in 2007 and that some single attack (or CIS) patients that are diagnosed pursuant to the McDonald criteria with MS and who have not yet had a second attack would also fall within the claims of the ‘437 Patent. [ 113 ] This issue is addressed below in the context of the construction of the claims. V.

Overall Position of the Plaintiff Teva on the ‘437 Patent [ 114 ] Teva notes that its glatiramer acetate product, Copaxone, is a therapy effective for the treatment of patients in the relapsing- remitting phase of MS (i.e., RRMS) to reduce the frequency of clinical relapses. [ 115 ] Teva explains that after the initial approval of Copaxone in the 1990s, it spent over 10 years engaged in research and development to improve its product.

Teva notes that it had failures but also successes, notably the invention of the ‘437 and ‘802 Patents. [ 116 ] Teva submits that Pharmascience seeks to benefit from Teva’s hard work, investment and inventiveness. [ 117 ] Teva disputes Pharmascience’s allegation or suggestion that it is seeking to extend the life of its patents, referred to as " “evergreening” " . Teva acknowledges that its 20 mg Copaxone product has been available for many years. The 40 mg Copaxone product was approved for sale in Canada in 2016.

Teva also acknowledges that Pharmascience already obtained a NOC to market its 20 mg glatiramer acetate, Glatect. [ 118 ] Teva explains that it designed and conducted a Phase III clinical trial in the early 2000s (the PreCISe trial) to study the effect of glatiramer acetate in patients who had experienced a single attack suggestive of MS and prior to development of CDMS. [ 119 ] Teva characterizes patients who have experienced a single attack suggestive of MS, but who have not yet been diagnosed with MS, as CIS patients. [ 120 ] Teva filed and obtained the ‘437 Patent based on the results of the PreCISe trial.

Teva received regulatory approval for the new indication of CIS in its Product Monograph in 2009. [ 121 ] Teva submits that the claims of the ‘437 Patent are directed to the use of glatiramer acetate to treat CIS patients, including a claim specifying a reduction of at least 50% in new T2 lesions. [ 122 ] Teva submits that Copaxone and Glatect will be used in the same manner if approved in accordance with Pharmascience’s SNDS and draft combined Product Monograph.

Teva also submits that Glatect 40 mg would be marketed in accordance with a Product Monograph that is substantially identical to Teva’s Copaxone Product Monograph. [ 123 ] Teva notes that Pharmascience has not provided any evidence to establish non-infringement.

[ 124 ] Teva submits that Pharmascience cannot rely on the Gillette defence to infringement. Teva submits that Pharmascience is splitting its case and has taken Teva by surprise by seeking to introduce new evidence in Dr. Green’s responding report to the report of Dr. Morrow, Teva’s infringement expert. Teva further submits that the law and the facts do not support the Gillette defence. [ 125 ] Teva disputes that the ‘437 Patent is anticipated by the art cited by Pharmascience, Karussis 2006, discussed more fully below. [ 126 ] Teva also disputes that the ‘437 Patent is obvious.

Teva submits that there are material differences between the state of the art in 2007 – which, among other things, did not establish with any evidence that glatiramer acetate would be effective for CIS patients – and the subject matter of the claims. Teva argues that arriving at the invention required inventiveness. [ 127 ] More generally, Teva alleges that the evidence of Pharmascience’s expert on validity, Dr. Green, was inconsistent and should be approached with caution. Teva goes further in challenging Dr. Green’s evidence suggesting that Dr.

Green went beyond the role of an expert witness and strayed into an advocate for Pharmascience’s position. VI.

Overall Position of the Defendant Pharmascience on the ‘437 Patent [ 128 ] Pharmascience notes that Teva’s Copaxone products have benefited from a 20-year monopoly in the Canadian market. [ 129 ] Pharmascience submits that Teva has attempted to extend its monopoly and " “evergreen” " its invention of glatiramer acetate (Copaxone) through successive patents, which purport to add old uninventive features. [ 130 ] Pharmascience argues that its manufacture, marketing, sale and the overall use of its Glatect products will not infringe the ‘437 Patent. [ 131 ] Pharmascience raises the Gillette defence against Teva’s allegations of infringement of the ‘437 Patent.

Pharmascience submits that it is merely practising the teachings of the prior art which recognized that glatiramer acetate was effective for RRMS and, as a result, Teva’s patent is invalid. Alternatively, if Teva’s patent is valid it cannot be infringed by Pharmascience. [ 132 ] Pharmascience also argues that the ‘437 Patent is invalid due to anticipation and obviousness. [ 133 ] Pharmascience submits that, as drafted, the claims of the ‘437 Patent would encompass patients diagnosed pursuant to the modern and prevailing McDonald criteria.

More specifically, patients who have had a single attack but have not yet had a second clinical attack would be included where they meet the criteria for MS pursuant to the McDonald criteria. [ 134 ] Pharmascience notes that, by November 2007, glatiramer acetate was a first-line treatment for patients with RRMS, which would include patients who had experienced a single attack and met the McDonald criteria for MS. [ 135 ] Pharmascience also argues that if the claims are interpreted narrowly, as advanced by Teva, the claims are still anticipated and are obvious. [ 136 ] Pharmascience disputes what it characterizes as Teva’s " “extreme” " position – i.e., that until a Phase III clinical trial had been completed to demonstrate that early treatment of single attack or CIS patients with glatiramer acetate was successful, the use of glatiramer acetate to treat such patients remained novel and inventive. [ 137 ] In support of its position that the ‘437 Patent is anticipated, Pharmascience points to Karussis 2006.

Pharmascience describes Karussis 2006 as the consensus of an international group of 13 MS specialists [the Karussis Working Group] that indicates that glatiramer acetate should be used to treat single-attack patients who meet the McDonald criteria and also those who fall short of meeting the McDonald criteria. [ 138 ] Pharmascience submits that Karussis 2006 indicated that glatiramer acetate " “should work” " in the treatment of single-attack patients (including those who fell short of the McDonald criteria for MS) and that it would be reasonable to use it to treat such patients. [ 139 ] With respect to anticipation, Pharmascience submits that Karussis 2006 meets the requirements of disclosure and enablement. [ 140 ] Pharmascience further submits that claim 16 of the ‘437 Patent is anticipated by Pinchasi 2007 as it disclosed the use of 40 mg glatiramer acetate for the treatment of RRMS. [ 141 ] Pharmascience also argues that there are no differences between the state of the art in November 2007, which includes Karussis 2006, and the claims of the ‘437 Patent.

As a result, the ‘437 Patent was obvious. Pharmascience submits that, to the extent that there were any differences, these would easily be bridged by the POSITA using the common general knowledge and information found by conducting a reasonably diligent search. [ 142 ] Pharmascience challenges Teva’s reliance on the Regulations to obtain declarations of patent infringement in respect of both of Pharmascience’s products – Glatect 20 mg administered daily and Glatect 40 mg administered three times per week – given that Pharmascience obtained a NOC for Glatect 20 mg in 2017 and has been marketing it since that time.

VII. Overall Position of the Plaintiff Teva on the ‘802 Patent [ 143 ] Teva reiterates that it worked over the years to improve its products, including to develop an oral formulation, which proved

unsuccessful in a Phase III clinical trial (CORAL), and to develop a 40 mg daily dose of glatiramer acetate, which did not prove to be more effective than the 20 mg dose in the Phase III clinical trial (FORTE). [ 144 ] Teva notes that the ‘802 Patent was the result of a successful Phase III clinical trial (GALA) that showed that 40 mg glatiramer acetate administered three times weekly was effective for the treatment of RRMS. [ 145 ] Teva argues that Pharmascience’s Glatect product will infringe the ‘802 Patent as Pharmascience’s product will be used in exactly the same manner as Copaxone 40 mg if it is approved in accordance with Pharmascience’s SNDS and proposed draft Product Monograph.

Teva notes that Pharmascience has not provided any evidence that it will not infringe, rather it alleges only that the ‘802 Patent is invalid. [ 146 ] Teva disputes that the ‘802 Patent is invalid due to obviousness or lack of sound prediction of utility. [ 147 ] Teva submits that Pharmascience has adopted a hindsight approach to obviousness and has " “cherry-picked” " the prior art, some of which is obscure, to carve a path to show that the state of the art was such that an every other day dose of 40 mg glatiramer acetate was known and that it would be self-evident to simply change the administration to three times a week. [ 148 ] Teva submits that the evidence of its experts should be preferred as it was more balanced.

Teva submits that without knowledge of the invention as claimed it would not have been obvious to a POSITA to administer 40 mg glatiramer acetate three times per week to RRMS patients. [ 149 ] Teva notes that Pharmascience has led no evidence to support its argument that the ‘802 Patent lacks utility.

Teva notes that all that is required is a scintilla of utility and there is no doubt that Copaxone 40 mg is useful. [ 150 ] With respect to the allegations regarding lack of sound prediction of utility, Teva notes, among other things, that the ‘802 Patent includes a detailed description of the GALA study, a Phase III clinical trial, including efficacy and safety results of 40 mg glatiramer acetate three times per week, and includes at least 18 references to support the invention. VIII.

Overall Position of the Defendant Pharmascience on the ‘802 Patent [ 151 ] Pharmascience submits that the ‘802 Patent is invalid due to obviousness. Alternatively, it is invalid due to inutility or lack of sound prediction of utility. [ 152 ] Pharmascience submits that Teva had already publicly disclosed an every-other-day dosing regimen for 40 mg glatiramer acetate. Pharmascience relies on a mosaic of the prior art to argue that the state of the art was that 40 mg glatiramer acetate was known to be effective (as was 20 mg) on an alternate day basis.

Pharmascience submits that the difference between the state of the art and the claims of the ‘802 Patent is only the difference of one less 40 mg dose in a two-week period. Pharmascience argues that it is easier for a patient to remember to take their medication three times a week on fixed days rather than every other day.

Pharmascience argues that the difference between the state of the art and the claims would be easily bridged by the POSITA who would move to the fixed day regime. [ 153 ] Pharmascience also suggests that the Court’s determination of the validity of the ‘802 Patent should be informed by related proceedings.

Pharmascience notes that the ‘802 Patent is being examined by the Canadian Intellectual Property Office [CIPO], and that equivalent patents have been found to be obvious in the U.K. and U.S. [ 154 ] Pharmascience argues that if the ‘802 Patent is not obvious due to the state of the prior art, then Teva cannot resort to the prior art that it discounts or rejects to support the utility or sound prediction of utility of the ‘802 Patent. [ 155 ] Pharmascience argues that the evidence of its experts should be preferred.

Pharmascience submits that Teva’s experts were misinstructed regarding the test for obviousness and, more generally, are not of the same caliber as its expert Dr. Green who, among other expertise, is experienced in clinical trial design. IX. Onus and Burden of Proof [ 156 ] The burden is on the Defendant, Pharmascience, to prove each ground of invalidity on a balance of probabilities. The burden is on the Plaintiff, Teva, to prove infringement on a balance of probabilities. Where the validity of a patent is at issue, the starting point is that the patent is presumed to be valid. X.

The ‘437 Patent – Description and Disclosure [ 157 ] The ‘437 Patent is titled, " “Method of Delaying the Onset of Clinically Definite Multiple Sclerosis” " . [ 158 ] The ‘437 Patent acknowledges that it cites various publications and that these publications are incorporated by reference into the patent application " “to more fully describe the state of the art to which this invention pertains” " .

These references include: the Poser criteria; Brex PA et al, " “A longitudinal study of abnormalities on MRI and disability from multiple sclerosis” " , 2002 N Engl J Med 346(3): 158-164 [Brex 2002]; Frohman EM et al, " “The utility of MRI in suspected MS: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology” " , 2003 Neurology 61(5): 602-611 [Frohman 2003]; Johnson KP et al, " “Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III

multicenter, double-blind, placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group” " , 1995 Neurology 45: 1268-1276 [Johnson 1995]; Cohen JA et al., Rovaris, " “9006 Study Group.

Randomized, double-blind, dose-comparison study of glatiramer acetate in relapsing–remitting MS” " , Neurology, 2007, 68(12): 939-944 [Cohen 2007 or FORTE Phase II]; and, Comi G et al, " “European/Canadian Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of the Effects of Glatiramer Acetate on Magnetic Resonance Imaging-Measured Disease Activity and Burden in Patients with Relapsing Multiple Sclerosis” " , 2001 Ann Neurol 49: 290-297 [Comi 2001]. [ 159 ] In the Background of the Invention, the authors state that MS is " “one of the more common chronic neurological diseases in human adults” " and that it is a " “chronic, inflammatory [CNS] disease characterized pathologically by demyelination” " and " “classified as an autoimmune disease” " . [ 160 ] The ‘437 Patent states that " “MS disease activity can be monitored by cranial scans, including [MRI] of the brain, accumulation of disability, as well as rate and severity of relapses” " . [ 161 ] The ‘437 Patent further states that that the diagnosis of CDMS as determined by the Poser criteria " “requires at least two neurological events suggesting demyelination in the CNS separated in time and in location” " . [ 162 ] The ‘437 Patent notes that a CIS is a single monosymptomatic attack suggestive of MS such as optic neuritis, brain stem symptoms, and partial myelitis.

It states that " “[p]atients with CIS that experience a second clinical attack are generally considered to have [CDMS]” " and that " “[o]ver 80 percent of patients with a CIS and MRI lesions go on to develop MS, while approximately 20 percent have a self-limited process” " . [ 163 ] The ‘437 Patent describes five types of MS: benign, RRMS, secondary progressive MS, progressive relapsing MS and primary progressive MS. [ 164 ] The ‘437 Patent describes glatiramer acetate and notes that it is marketed as Copaxone which had been approved as a 20 mg glatiramer acetate injection for patients with RRMS. [ 165 ] The ‘437 Patent also notes that the synthesis of Copaxone had been disclosed in several U.S. patents and that the formulation of 40 mg Copaxone has been disclosed in a U.S. patent. [ 166 ] The ‘437 Patent further states that the " “efficacy of Copaxone® in reducing the frequency of relapses in patients with RRMS is well established” " and that both the 20 and 40 mg daily subcutaneous dose have been shown to reduce the total number of enhancing lesions in MS patients as measured by MRI (citing Cohen 2007). [ 167 ] The ‘437 Patent notes that it was an open question whether Copaxone would be effective in patients suffering from earlier stages of MS and that there was a debate in the medical and scientific community as to the benefits of commencing MS therapy at the early stage.

It states: " “[s]pecifically, questions exist regarding whether the benefits of early treatment outweigh the inconvenience, cost, potential adverse effects of treatment, and the risk of submitting patients that independently of treatment would not experience further events to unnecessary long-term therapy” " . [ 168 ] The

Summary of the Invention states that the invention " “provides a method for delaying the onset of [CDMS] in a patient at risk of developing [CDMS], the method comprising periodically administering a pharmaceutical composition comprising a therapeutically effective amount of glatiramer acetate to the patient, thereby delaying onset of [CDMS] in the patient” " . [ 169 ] The

Summary adds, among other things, that the invention also provides a method to reduce progression of MRI-monitored disease activity in a patient at risk of developing CDMS, a method for reducing the progression of symptoms, and a method of delaying the progression to CDMS. The

Summary adds that the invention of the medicament of glatiramer acetate is for the treatment of a patient who: " “experienced a single demyelinating event and an active inflammatory process, which are indicative of the patient being at high risk of developing CDMS” " ; and, who " “experienced a first clinical event suggestive of [MS] and is at risk of developing [CDMS]” " . [ 170 ] The ‘437 Patent sets out

definitions of the terms used therein. These

definitions are noted in the discussion in

Part XV, Construction of the Claims. [ 171 ] The ‘437 Patent includes five examples to illustrate the invention and to " “aid in an understanding of the invention” " but not to " “limit in any way the invention as set forth in the claims” " . The examples describe a clinical trial to assess the effect of treatment with daily subcutaneous injections of 20 mg of glatiramer acetate compared to placebo on the time to conversion to CDMS as determined by the Poser criteria.

Examples 1, 2 and 5 specifically refer to evaluating the effect of glatiramer acetate on patients presenting with CIS. [ 172 ] The ‘437 Patent states that the results of the examples " “show that early, pre-diagnosis i.e., pre-CDMS, [glatiramer acetate] treatment confers long-term benefits on MS symptoms and on the progression of disability” " . [ 173 ] The ‘437 Patent further states that the results show that glatiramer acetate " “delays the development of [CDMS] when administered to patients presenting a single, clinically isolated syndrome (CIS) suggestive of MS” " . XI.

The ‘802 Patent – Description and Disclosure [ 174 ] The 802 Patent is entitled, " “Low Frequency Glatiramer Acetate Therapy” " . [ 175 ] The ‘802 Patent acknowledges that " “[t]hroughout this application various publications are referenced by their full citations. The disclosures of these publications are referenced in this application in order to more fully describe the state of the art” " . [ 176 ] In the Background of the Invention, MS is described, as are the various types of MS and methods to monitor the disease.

Glatiramer acetate is also described. [ 177 ] The ‘802 Patent explains that patients suffering from RRMS " “experience sporadic exacerbations or relapses, as well as periods of remission” " and that " “[l]esions and evidence of axonal loss may or may not be visible on MRI for patients with RRMS” " . [ 178 ] The ‘802 Patent notes that glatiramer acetate " “is marketed under the tradename Copaxone®” " and that Copaxone as a 20 mg daily injection " “is an approved therapy for patients with [RRMS], including patients who have experienced a first clinical episode” " . [ 179 ] The ‘802 Patent also notes that " “[t]he 20mg/day subcutaneous (s.c.) dose has been shown to reduce the total number of enhancing lesions in MS patients as measured by MRI” " and that " “[s]afety data accumulated for [glatiramer acetate] in clinical trials shows that the drug product is safe and well tolerated” " . [ 180 ] The

Summary of the Invention describes a " “method of alleviating a symptom of [RRMS] in a human patient suffering from [RRMS] or a patient who has experienced a first clinical episode and is determined to be at high risk of developing [CDMS] comprising administering to the human patient three subcutaneous injections of a therapeutically effective dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection so as to thereby alleviate the symptom of the patient” " . [ 181 ] The ‘802 Patent describes several embodiments including " “the therapeutically effective dose of glatiramer acetate is 40mg/ml” " . [ 182 ] Under the Detailed Description of the Invention, the ‘802 Patent again describes its goal and sets out the several potential embodiments, including several different schedules of three injections per week.

Other embodiments describe means of alleviating the symptoms of RRMS, for example, reducing the level of disability and reducing the number of different types of lesions. [ 183 ] The ‘802 Patent includes the following

definitions: Immediate post injection reaction (IRPR)” refers to “a reaction such as, palpitations, feeling hot, flushing, hot flushes, tachycardia, dyspnoea, chest discomfort, chest pain, and non-cardiac chest pain that occurs immediately following injection. Injection site reaction (ISR)” refers to “a reaction such as erythema, hemorrhage, induration, inflammation, mass, pain, pruritus, urticaria, and welt that occurs immediately around the site of injection.

Tolerability” relates to “the level of discomfort associated with [glatiramer acetate] treatment” and “is associated with the frequency and severity of post injection reactions and injection site reactions” and “influences the period that a patient can follow [glatiramer acetate] treatment. [ 184 ] Other

definitions include, " “clinically isolated syndrome” " , " “Gd-enhancing lesions” " , " “single clinical attack” " , and reference is made to the Poser criteria for a diagnosis of CDMS. [ 185 ] The ‘802 Patent notes that the example

section is set out to aid in understanding of the invention but is not intended to " “limit in any way the invention as set forth in the claims” " . [ 186 ] Experimental Details are set out over 16 pages. [ 187 ] The Discussion notes that a " “significant drawback to [glatiramer acetate] therapy is the requirement of daily injections, which can be inconvenient” " .

It adds that " “in all clinical trials, injection-site reactions were seen to be the most frequent adverse reactions and were reported by the majority of patients receiving [glatiramer acetate]” " (as compared to placebo). [ 188 ] The ‘802 Patent has 66 claims. The asserted claims are set out in Annex 2. Note that the asserted claims all address the use of 40 mg glatiramer acetate for RRMS patients. XII. The Structure of this Judgment [ 189 ] As noted, Teva alleges infringement by Pharmascience of both the ‘437 and the ‘802 Patents.

Pharmascience disputes that it will infringe and alleges that the ‘437 and ‘802 Patents are invalid. The principles from the jurisprudence, set out below, apply to the determination of the issues with respect to both patents. There is some evidence that applies to both patents, including about the treatment of MS. However, other evidence is specific to the patent at issue. The allegations regarding the ‘437 Patent are addressed first, followed by the allegations regarding the ‘802 Patent. XIII. Overview of the Experts’ Evidence re the ‘437 Patent A. Pharmascience’s Expert, Dr. Green [ 190 ] Dr.

Green described the POSITA as a medical professional (e.g., a neurologist), with experience evaluating and diagnosing patients with MS and administering therapeutic agents for the treatment of MS, who would also be a member of a drug development team. [ 191 ] With respect to the common general knowledge as of November 28, 2007, Dr.

Green stated that the POSITA would be knowledgeable about MS and its characteristics, the classification of MS, brain imaging (including the use of MRI), the evolution of diagnostic criteria for MS, CIS, MS therapies (including glatiramer acetate) and CIS therapies (including ongoing clinical studies of glatiramer acetate) and, more generally, the treatment of MS. Dr. Green set out the sources of knowledge, including conferences, journals, online resources such as PubMed and EMBASE (a subscription literature database) and the articles found therein. Dr. Green

referred to several reports of studies, suggesting that these were part of the common general knowledge. [ 192 ] Dr. Green stated that generally, the ‘437 Patent relates to the treatment of patients who do not yet have CDMS to delay the onset of CDMS (and the progression of MS-related symptoms). He stated that, more particularly, the ‘437 Patent relates to the use of glatiramer acetate, which was a known treatment for patients suffering CDMS (in particular RRMS), to treat patients who had not yet developed CDMS. [ 193 ] In his written opinion, Dr.

Green noted that while all the claims use slightly different language to describe the patient groups, the POSITA would understand that the claimed patient population for all claims is a CIS patient at risk of developing CDMS (and who has not yet developed CDMS) and who presents with at least one lesion consistent with MS. [ 194 ] In his written report in response to Dr. Morrow’s report on validity, and in his oral evidence, Dr. Green opined that the claims also covered patients with MS in accordance with the McDonald criteria. [ 195 ] Dr.

Green stated that the inventive concept of the claims of the ‘437 Patent is the same as the subject matter defined by the claims. Other experts agreed. [ 196 ] In Dr. Green’s opinion, the claims of the ‘437 Patent were anticipated. Dr. Green stated that Karussis 2006 both disclosed and enabled the subject matter of all the claims of the ‘437 Patent. [ 197 ] In Dr. Green’s opinion, the subject matter of the claims was also obvious. Dr. Green stated that there was no difference between the state of the art in 2007 and the subject matter of the claims disclosed in the ‘437 Patent. [ 198 ] Dr.

Green stated that, by November 2007, a large Phase III clinical study using glatiramer acetate to treat CIS patients was underway (i.e., the PreCISe trial). He also stated that the consensus of leaders in the field was that using glatiramer acetate to treat CIS patients was reasonable and " “should work” " , and that the ongoing clinical study (i.e. the PreCISe trial) was likely to show that early treatment at the time of the initial CIS would have enhanced efficacy compared to later treatment of RRMS. [ 199 ] Dr.

Green added that, to the extent that there was any difference between the state of the art and the inventive concept, it would have been easily bridged by the POSITA using the common general knowledge. No inventive ingenuity was required. [ 200 ] Dr. Green explained that the POSITA was aware of the concept of CIS. He added that disease-modifying drugs or therapies [DMDs or DMTs] (e.g., interferons) used to treat MS including RRMS had been shown to be effective in treating CIS patients by reducing the likelihood of progression to CDMS and/or delaying the progression to CDMS. Dr.

Green added that the POSITA would be motivated to find new treatments, and glatiramer acetate was the obvious choice. [ 201 ] Dr. Green provided a second written opinion in response to the report on infringement by Teva’s expert, Dr. Morrow. Dr. Green’s second report addresses several mandates. [ 202 ] Dr. Green indicated that he generally agreed with Dr. Morrow’s opinions regarding the scientific and clinical overview of RRMS, description of the POSITA and construction of the claims. [ 203 ] Dr. Green criticised Dr.

Morrow’s use of the terms " “CDMS” " and " “probable MS” " given her acknowledgement that these terms were not used after the McDonald criteria were adopted. In Dr. Green’s opinion, the McDonald criteria had replaced the Poser criteria by 2005, at the latest. However, Dr. Green agreed that practicing neurologists remain familiar with the terms CDMS and CIS. [ 204 ] Dr. Green acknowledged that in 2007 a CIS diagnosis would have been for patients who had a single clinical event suggestive of MS. [ 205 ] Dr. Green offered a revised opinion regarding the patients addressed by the claims.

In his responding report he stated that " “by June 4, 2009, … at least some patients presenting with a single clinical attack and at least one lesion would have been categorized as having MS pursuant to the 2005 McDonald Criteria” " and would be included within the claims. [ 206 ] Dr. Green’s evidence on this issue is elaborated on in the discussion on the construction of the claims in

Part XV. [ 207 ] In his second report, Dr. Green referred to Pinchasi 2007 (a patent application). Dr. Green stated that, as read and understood shortly before November 28, 2007, Pinchasi 2007 directed physicians to use glatiramer acetate to treat patients with RRMS, which would include some patients who had only experienced a single clinical attack. On cross-examination, Dr. Green agreed that a physician would not read Pinchasi 2007 to guide their prescribing practices in 2007 or now. [ 208 ] Dr.

Green also provided his opinion on product monographs in general and, more specifically, on the Copaxone 2001 and 2006 product monographs. [ 209 ] Dr. Green stated that, prior to November 2007, he and other physicians prescribed Copaxone to treat CIS patients (i.e., patients who had only experienced a single clinical attack but did not meet the 2005 McDonald criteria to confirm a diagnosis of MS). He acknowledged that this was " “off-label” " use, meaning uses not approved and not indicated in the product monograph. [ 210 ] Dr.

Green was challenged on his inconsistent testimony in proceedings in the U.K. where he suggested that off-label use should only be done in the context of a research study. B. Teva’s Expert, Dr. Morrow [ 211 ] Dr. Morrow provided an overview of the scientific and clinical history of MS, including the criteria for its diagnosis, as it relates to the ‘437 Patent. Dr. Morrow explained that the Poser criteria for diagnosing MS, which were introduced in the 1980s, used the term CIS

for patients who had experienced only a single clinical attack, and CDMS for patients who had experienced at least two clinical attacks. [ 212 ] Dr. Morrow noted that the Poser criteria were gradually replaced by the McDonald criteria, which do not use the terms CIS or CDMS, and do not draw a clear distinction based solely on the number of clinical attacks to make a diagnosis of MS. [ 213 ] Dr. Morrow explained how MRI demonstrates DIT and DIS and that the increasing use of MRI permits the diagnosis of MS without the demonstration of clinical attacks. [ 214 ] Dr.

Morrow stated that the POSITA would understand that the language in the claims refers to terms that were used in relation to the Poser criteria (i.e., CDMS), which required the confirmation of a second clinical attack. Dr. Morrow stated that the POSITA would understand that the ‘437 Patent is directed to using glatiramer acetate to treat patients who have had one clinical attack suggestive of MS but have not yet experienced a second clinical attack. [ 215 ] With respect to infringement, Dr.

Morrow stated that in her opinion, if Pharmascience’s Glatect product is made, sold, used or constructed in accordance with the Glatect Product Monograph she had reviewed, Glatect 20 mg and 40 mg will be used in the manner set out in the asserted claims of the ‘437 Patent. Dr. Morrow noted the specific wording of the 20 mg product and 40 mg product and the distinctions between them. C. Teva’s Expert, Dr. Selchen [ 216 ] Dr. Selchen agreed with Dr. Morrow and with Dr. Green’s initial opinion regarding the construction of the claims of the ‘437 Patent as focussed on the CIS patient. [ 217 ] Dr.

Selchen stated that in 2007, a patient presenting with the profile described in claim 1 was typically diagnosed as a patient with CIS. He explained that CIS was treated as distinct from CDMS, which required the confirmation of a second clinical attack (and ruling out other possible non-MS causes for the first attack). [ 218 ] Dr. Selchen emphasized that the claims of the ’437 Patent are directed to the CIS patient and not to a patient who could be diagnosed pursuant to the 2001 or 2005 McDonald criteria with MS, including RRMS. [ 219 ] Dr.

Selchen noted that the claims of the ‘437 Patent sets out various modes of efficacy, including: delaying the onset of CDMS; reducing progression of MRI-monitored disease activity (including a reduction in the rate of accumulating new T2-weighted lesions, a measure of active inflammatory process); reducing the progression of symptoms of MS; and, reducing the frequency of relapse. [ 220 ] Dr. Selchen also agreed that the inventive concept of the claims is the subject matter of the claims asserted. [ 221 ] Dr. Selchen did not fully agree with Dr.

Green regarding the extent of the common general knowledge, particularly articles from less known journals and those that reported on pilot studies or case reports. [ 222 ] With respect to the allegation of anticipation, Dr. Selchen opined that Karussis 2006 neither disclosed nor enabled a skilled person to practice the subject matter of the claims at issue. [ 223 ] Dr. Selchen noted that the Karussis Working Group was tasked with developing evidence-based recommendations.

Karussis 2006 clearly stated that their proposed recommendation for using glatiramer acetate (among other therapies) to treat patients with CIS was not evidence-based. Dr. Selchen stated that the suggestion in Karussis 2006 that the approved therapies " “should” " work did not single out glatiramer acetate. He stated that the suggestions and opinions would not enable a skilled person to achieve the claimed outcomes of the ‘437 Patent. [ 224 ] Dr. Selchen acknowledged that in November 2007 the POSITA would have known only that a clinical study had been commenced (i.e., the PreCISe trial). Dr.

Selchen also noted that several other clinical trials studying drugs for use in treating MS had failed to meet their objectives and the POSITA would not have assumed the successful outcome of the PreCISe trial simply because the trial had been started. [ 225 ] Dr. Selchen stated that, in 2007, the POSITA would not and could not have treated CIS patients with glatiramer acetate, noting that it was not approved for t

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