TAKEDA CANADA INC. Plaintiff v. APOTEX INC., 2024 FC 106

Date: 20240207 Docket: T-151-22 Citation: 2024 FC 106 Toronto, Ontario, February 7, 2024 PRESENT: The Honourable Madam Justice Furlanetto BETWEEN: TAKEDA CANADA INC. Plaintiff and APOTEX INC. Defendant and TAKEDA PHARMACEUTICAL COMPANY LIMITED AND TAKEDA PHARMACEUTICAL USA, INC. Defendants/Patent Holders PUBLIC JUDGMENT AND REASONS (Confidential Judgment and Reasons issued January 23, 2024) I. Overview [ 1 ] This judgment arises from a patent infringement action brought under subsection 6(1) of the Patented Medicines (Notice of Compliance Regulations) , SOR/93-122 [ PMNOC Regulation s].

The patent at issue is Canadian Patent No. 2,570,916 [916 Patent]. The innovative drug relating to the action is DEXILANT®, which is used to treat heartburn associated with gastroesophageal reflux disease [GERD], as well as to heal damage to the esophagus from stomach acid. [ 2 ] Takeda Canada Inc. [Takeda] is the " “first person” " in accordance with the PMNOC Regulations . Takeda Pharmaceuticals USA, Inc. is the registered owner of the 916 Patent and is a party to the action pursuant to subsection 6(2) of the PMNOC Regulations .

Takeda claims that the making, constructing, using or selling by the Defendant, Apotex, Inc. [Apotex], of its dexlansoprazole oral dose capsules in strengths of 30 mg and 60 mg [Apotex Product] in accordance with Apotex’s Abbreviated New Drug Submission [ANDS] Control Number 256485 will infringe at least one of claims 1, 5-8, 10-11 and 16 [Asserted Claims] of the 916 Patent.

Apotex denies infringement and asserts in defence that the Asserted Claims are invalid for anticipation, obviousness, inutility, insufficiency, overbreadth, ambiguity and/or as unpatentable subject-matter. [ 3 ] For the reasons that follow, I find that the action should be dismissed as the Asserted Claims of the 916 Patent are not infringed and are also invalid for failure to meet the disclosure requirements under subsection 27(3) of the Patent Act and to provide proper disclosure of the factual basis and line of reasoning to support a sound prediction of utility. II.

Background [ 4 ] The 916 Patent is listed on the Patent Register in association with the medicine dexlansoprazole, which is the R -enantiomer of lansoprazole. [ 5 ] Dexlansoprazole is one of a group of compounds known as proton pump inhibitors [PPIs] that function by inhibiting the gastric hydrogen potassium pump, known as the H + /K + ATPase [proton pump] found in cells in the lining of the stomach. Activation of the proton pump results in the formation of gastric acid which decreases the pH in the stomach. PPIs react with acid to form a compound that inhibits the proton pump through covalent bonding.

The result is a decrease in the gastric acid level and a corresponding increase in the pH in the stomach. [ 6 ] Dexlansoprazole is the active ingredient in Takeda’s product DEXILANT®. DEXILANT® is a pulsatile release formulation sold in capsule form that includes two types of delayed-release beads containing dexlansoprazole.

The dexlansoprazole is released from the dosage form in two discrete pulses, with one of the types of delayed release beads designed to release drug after it reaches the proximal small intestine and the second type of delayed release bead designed to release drug in the distal region of the small intestine, several hours later. [ 7 ] Takeda obtained a Notice of Compliance [NOC] and began selling DEXILANT® in Canada in 2010.

At the time DEXILANT® entered the Canadian marketplace it was the sixth PPI available, with the market already including other PPIs, namely omeprazole, esomeprazole, lansoprazole, pantoprazole (and pantoprazole magnesium) and rabeprazole, which were sold as single release formulations for treating GI disorders related to increased and delocalized gastric acid. [ 8 ] This action initially alleged infringement of two patents listed on the Patent Register – the 916 Patent and Canadian Patent No. 2,671,369 [369 Patent].

However, by letter dated June 12, 2023, Takeda advised the Court that it would not be pursuing the allegations in respect of the 369 Patent. At trial, Takeda confirmed that it had abandoned its infringement claim with respect to the 369 Patent and that there were no issues for the Court to determine with respect to the 369 Patent.

III. The 916 Patent [ 9 ] The 916 Patent is entitled “Pulsed Release Dosage Form of a PPI”. It is the national phase entry of a Patent Co-operation Treaty patent application filed on June 1, 2005, which is based on a United States priority patent application, filed on June 16, 2004. The application for the 916 Patent was published on January 26, 2006 and will expire on June 1, 2025. It names two inventors: Dr. Majid Vakilynejad (a pharmacokineticist) and Dr.

Rajneesh Taneja (a formulator). [ 10 ] Page 1 of the 916 Patent identifies the technical field of the invention of the 916 Patent as relating to PPIs and in particular, dosage forms containing multiple doses of a PPI. [ 11 ] The Background to the 916 Patent describes PPIs as a class of pharmaceutical compounds that inhibit gastric acid secretion by inhibiting the proton pump.

It notes that PPIs rapidly degrade in acidic environments and therefore that dosage forms containing PPIs are generally designed to protect the PPI from the acidic environment of the stomach and to release the PPI in the upper small intestine. [ 12 ] The Background explains that PPIs have a prolonged therapeutic effect that does not directly correlate with serum concentrations of these drugs and their relatively short pharmacokinetic [PK] half-life.

It further explains that despite the prolonged therapeutic effect of PPIs, some patients on PPI therapy experience a nocturnal breakthrough event where the secretory activity of the proton pump returns. The Background states that there is no currently known solution to nocturnal breakthrough effects and that there is a need for a dosage form containing a PPI that can provide a full day of therapeutic effect while being administered on a once-a-day basis. [ 13 ] The

Summary of the Invention [Summary] describes the invention of the 916 Patent as dosage forms comprising a PPI that is released as a first and a second dose in an amount sufficient to raise the plasma concentration of the PPI to at least 100 ng/mL. The

Summary explains that release of the PPI may occur as discrete pulses where the pulses are separated by a pre-selected period of time or alternatively, may be separated by little or no time delay and released continuously. The

Summary states that the invention also provides " “methods of treating gastrointestinal disorders with the dosage forms” " . [ 14 ] In the Detailed Description [Description], the 916 Patent teaches the person skilled in the art [PSA] that the PK properties of the PPI can be used to mitigate the nocturnal breakthrough phenomenon so that a single oral dosage form can be taken once a day.

First, it teaches that alleviation of nocturnal breakthrough is a function of the concentration of the PPI in the patient; and second, it teaches that there is a threshold concentration that must be surpassed in a second dose of the PPI before a therapeutic effect is achieved (916 Patent, Ex1, 2a:8-17): It has unexpectedly and surprisingly been discovered that the breakthrough phenomenon can be mitigated through appropriate use of pharmacokinetic properties of these drugs to establish effective concentrations of the PPI.

In particular, it has been found that it is not sufficient merely to provide an additional dose of PPI sometime after a first daily dose and before nighttime. The appropriate means for alleviating the breakthrough phenomenon is a function of the concentration of the PPI in a patient. Applicants have discovered that there is a threshold concentration of these drugs that must be surpassed in a second dose of the PPI before a therapeutic effect is achieved.

Moreover, the first and the second dose can be administered in a single oral dosage format that can be taken once a day to alleviate nocturnal breakthrough events. [ 15 ] The invention is described as providing a dosage form where each of the first and second dose of PPI is " “in an amount sufficient to achieve a therapeutic effect and thereby alleviate the nocturnal breakthrough phenomenon” " (916 Patent, Ex1, 2a:18-21).

The Description teaches that each dose of PPI should raise the plasma level of PPI to at least 100 ng/mL, preferably above 200 ng/mL, more preferably above 300 ng/mL, even more preferably above 400 ng/mL, and most preferably above 500 ng/mL (916 Patent, Ex1, 3:1-5).

The 916 Patent notes that " “those skilled in the art can readily determine the milligram amounts of any particular PPI that should be included in the first and second dose of the PPI to raise patient plasma levels to the thresholds” " (916 Patent, Ex1, 3:5-7). [ 16 ] The PSA is told that the benefits of the invention are not limited to a particular type of dosage form and that the dosage forms of the invention can exist as either controlled release dosage forms or pulsed release systems. Controlled release dosage forms are described as including matrix systems, osmotic pumps and membrane controlled systems.

Pulsed release systems are described as generally comprising a first drug release and second drug release separated by a predetermined period of time or site of release.

The 916 Patent notes that this may include a combination of an immediate release and extended release formulation and can include particle or granule systems where distinct populations of drug containing particles are used to achieve the pulsed release with different coating polymers targeted to release the drug at different points in time or location (916 Patent, Ex1, 10:23-11:3). [ 17 ] The 916 Patent teaches that when a pulsed release dosage form is employed, the first and second pulses of the drug should each be sufficient to increase the plasma level concentration above the threshold level (916 Patent, Ex1, 12:4-6).

The 916 Patent explains that due to decreasing absorption in the downstream portions of the gastrointestinal [GI] tract, it is preferred to load dosage forms with PPI such that the second dose of PPI is higher than the first dose (916 Patent, Ex1, 12:25-27). The 916 Patent teaches a second dose that is at least 10% more, more preferably at least 50% more, even more preferably at least 100% to 200% more, and most preferably at least 200% to 900% more than the first dose (916 Patent, Ex1, 12:27-31).

The 916 Patent states that a PSA would be able to formulate oral dosage forms containing a PPI that is released in accordance with the threshold concentrations (916 Patent, Ex1, 11:28-30). [ 18 ] The 916 Patent teaches that any PPI can be used in the dosage form as well as their respective enantiomers (916 Patent, Ex1, 2a:22- 27). It refers to lansoprazole or an enantiomer or salt thereof such as R -lansoprazole (dexlansoprazole) as a PPI of the invention (916 Patent, Ex1, 2:24-25).

The 916 Patent states that the dosage forms may be tested empirically in animal and/or human models (916 Patent, Ex1, 13:27-28). [ 19 ] The 916 Patent includes two examples. The first example refers to mathematical modelling based on plasma concentration data from administration of single intravenous [IV] doses of lansoprazole in humans. The example refers to using the IV data to model the pharmacological effect " “using a sigmoid E max model” " , and modelling PK using a two compartment model with a PK compartment linked to a separate effect compartment.

The example refers to the modelling first establishing " “the pharmacokinetic characteristics of

lansoprazole”, then “the relationship between drug plasma concentration and intragastric pH” " , and then " “pharacodynamic [sic] parameter estimates” " (916 Patent, Ex1, 14:24-26).

The results of the modelling are depicted graphically in Figure 1 of the patent, which is described as showing the relationship between plasma concentration at steady-state and gastric pH and as establishing that the threshold concentration of " “approximately 100 ng/mL should be attained for purposes of attaining a minimum change in the desired pharmacological effect from baseline.” " (916 Patent, Ex1, 14:32-15:2). [ 20 ] The second example is a site of absorption study that measures the extent to which lansoprazole was absorbed at different sites in the GI tract (916 Patent, Ex1, 15:5).

The 916 Patent states that Example 2 shows that " “[t]he rate and extent of absorption for lansoprazole from the distal small intestine [is] less than that obtained for the proximal intestine” " and that " “[t]he extent of absorption was reduced when lansoprazole was directly delivered to the colon.” " (916 Patent, Ex1, 17:1-3). IV. Issues [ 21 ] The following issues were identified by the parties as being those in dispute for this action: A . The construction of the Asserted Claims, and specifically, the meaning to be given to the elements: " “a first and a second dose” " and " “threshold concentration” " ; B .

Whether the making, constructing, using or selling of the Apotex Product in accordance with ANDS Control Number 256485 would infringe the Asserted Claims? C . Whether Canadian Application No. 2,499,574 [574 Application] anticipates the subject-matter defined by the Asserted Claims, contrary to paragraph 28.2(1)(

b) of the Patent Act ? D . Whether the subject-matter defined by the Asserted Claims would have been obvious on the claim date of June 16, 2004 to a PSA, contrary to

section 28.3 of the Patent Act ? E . Whether a practical utility relating to the subject-matter of the Asserted Claims was not soundly predicted by the 916 Patent’s Canadian filing date of June 1, 2005? F . Whether the 916 Patent fails to correctly and fully describe the invention and its operation or use as contemplated by the inventors, contrary to subsection of 27(3) of the Patent Act ? G . Whether the Asserted Claims are broader than either the invention made by the named inventors of the 916 Patent or the invention disclosed in the specification of the 916 Patent? H .

Whether the Asserted Claims fail to define distinctly and in explicit terms the subject-matter of the invention for which an exclusive privilege or property is claimed, contrary to subsection 27(4) of the Patent Act ? and I . Whether the Asserted Claims claim patentable subject-matter, as required by

section 2 of the Patent Act ? V. Witnesses [ 22 ] Five experts gave testimony at the trial of this action; two experts gave evidence for Takeda (Dr. Robert J. Timko and Dr. David Armstrong) and three experts for Apotex (Dr. Colin Rowlings, Dr. Neal Davies and Dr. Peter Kahrilas). [ 23 ] As a preliminary matter, I note that Apotex challenged the admissibility of much of Takeda’s expert evidence. While I have determined that the expert evidence should not be rendered inadmissible, I have concerns with certain aspects of Takeda’s expert evidence and attribute those aspects limited weight as set out further below. A

summary of these findings follows. A. Takeda’s Experts [ 24 ] Dr. Robert J. Timko − Dr. Timko obtained his Ph.D. from Rutgers University in 1979, specializing in dissolution, formulation development, and physical pharmacy. He is currently the Founder and President of RhoTau Pharma Services LLC, a pharmaceutical and regulatory sciences consulting firm. Dr. Timko has over 45 years experience working in pharmaceutical formulation and process development for new chemical entities, generics, and consumer (over-the-counter) products, including 30 years with AstraZeneca.

He was admitted as an expert in pharmaceutical formulation, with expertise in respect of the design, development, manufacture and analysis of pharmaceutical dosage forms. [ 25 ] Dr. Timko delivered three expert reports in the proceeding. His first report opined on claims construction and infringement. The second report opined on the validity of the 916 Patent, including the issues of sufficiency and overbreadth and responded to the expert report of Dr. Rowlings on those issues. The second report also commented on documents relating to DEXILANT® and whether DEXILANT® was covered by the claims of the 916 Patent.

The third report replied to certain comments made by Dr. Rowlings and Dr. Davies on infringement. [ 26 ] Dr. Timko was unable to comment on the full scope of Dr. Rowlings’ and Dr. Davies’ critiques of his infringement analysis. During cross-examination, he acknowledged that he did not read the whole of their reports, but only those aspects to which he responded. His evidence therefore did not benefit from a full understanding of the completeness of Dr. Rowlings’ and Dr. Davies’ comments. [ 27 ] In final argument, Apotex challenged the admissibility of Dr.

Timko’s infringement opinion, asserting that he had employed a novel

untested methodology. In his infringement analysis, Dr. Timko identified certain individual plasma concentration curves amongst the bioequivalence test data on the Apotex Product that, in his view, showed that the dexlansoprazole within the Apotex Product was released as two distinct pulses. To determine the amount of dexlansoprazole present in each of the asserted doses (or pulses), Dr. Timko identified a proposed transition point between the two asserted releases and then estimated the " “area under the curve” " [AUC] for each proposed pulse using the trapezoidal mathematical integration method.

The amount of dexlansoprazole in each proposed dose was then determined from the estimated AUC exposure values using the total, starting dose amount. [ 28 ] Apotex asserts that Dr. Timko’s analytical approach is a novel testing methodology that does not meet the reliable foundation test laid down by the U.S. Supreme Court in Daubert v Merrell Dow Pharmaceuticals, Inc, 509 US 579 (1993) [ Daubert ] and cited with approval by the Supreme Court of Canada [SCC] in R v J-LJ , 2000 SCC 51 [ J-LJ ] at paras 33-35 .

In J-LJ , the SCC identified four factors that must be considered when evaluating whether a novel test methodology will be accepted by the Court as admissible evidence: 1) whether the theory or technique can be and has been tested; 2) whether the theory or technique has been subjected to peer review and publication; 3) the known or potential rate of error or the existence of standards; and 4) whether the theory or technique used has been generally accepted. [ 29 ] While I accept many of the concerns raised by Dr. Davies and Dr. Rowlings as to the approach taken by Dr.

Timko in his analysis, and while I find that the cross-examination further undermined Dr. Timko’s approach, in my view these issues are best addressed as a matter of weight, rather than admissibility. [ 30 ] First, I do not accept that Dr. Timko has introduced a new methodology as that term was intended in Daubert . His analysis does not involve the development of a new protocol or experimental procedure, but rather involves an attempt to adapt known analytical techniques ( i.e ., AUC and trapezoidal method) to a new context − that of determining whether the dose amounts claimed are found in the Apotex Product.

Indeed, Apotex’ expert Dr. Davies referred to AUC in his scientific primer as a known PK parameter, reflecting " “the total exposure of the body to the drug” " and discussed the trapezoidal method for determining AUC (Davies, Ex32, para 91). As discussed further below, while the approach taken by Dr. Timko was shown to have flaws, Apotex’ criticisms do not, in my view, engage the Daubert principles. [ 31 ] Second, while Apotex argues that Dr. Timko’s analysis taints the whole of his infringement opinion such that his full report should be rendered inadmissible, I do not accept that it extends this far.

The determination of the dose amounts of dexlansoprazole is but one part of Dr. Timko’s infringement assessment. It is clear that Dr. Timko is an expert in his field and that he has provided some useful information for the Court’s consideration. I do not accept that the whole of his report is subject to concern for admissibility. [ 32 ] Third, I consider Apotex’ argument to arise too late in the day to be dealt with as an admissibility objection. In my view, this type of admissibility argument should have been raised with the Court as soon as Dr.

Timko’s evidence was received so that the Court could have considered the proper approach to be taken and whether a voir dire would benefit its gatekeeper role (Rule 52.5(1), Federal Courts Rules ). As noted in White Burgess Langille Inman v Abbott and Haliburton Co , 2015 SCC 23 [ White Burgess ], one of the key objectives in the Court’s gatekeeping role is to streamline the process and balance relevance, reliability and necessity as against time, prejudice and confusion (at paras 16, 24). By Apotex waiting to raise its concerns, this balancing exercise can no longer serve the same objective. [ 33 ] Dr.

David Armstrong − Dr. Armstrong has practiced gastroenterology in the United Kingdom [UK] and Canada since 1983. He is also a Professor of Medicine at McMaster University. He obtained his medical degree from Cambridge in 1977 and completed post- graduate work at King’s College Hospital Medical School. He is certified by medical boards in Canada and the UK and is a member of many medical associations relating to gastroenterology, including the American Gastroenterological Association [AGA]. He has also served as a peer reviewer for several academic publications. Dr.

Armstrong was admitted as an expert in the use of PPIs in clinical, research and hospital settings and the treatment of gastric acid disorders, including the use of PPIs from the 1990s to present, including the knowledge, trends, and biases held by physicians during this period. Dr. Armstrong was asked to respond to Dr. Kahrilas’ and Dr. Davies’ review of the 916 Patent and their analyses on inventiveness, and to Dr. Davies opinion on anticipation. He was also asked to provide his opinion on the issue of utility and to respond to Dr. Kahrilas and Dr. Davies on this issue. Dr.

Armstrong further commented on the properties and benefits of DEXILANT®. [ 34 ] In final argument, Apotex objected to the admissibility of Dr. Armstrong’s report on the basis that he had failed to fulfill his overriding duty as an expert. As set out in White Burgess at paragraph 32 , an expert has an overriding duty to the Court to provide their evidence impartially, independently and without bias.

The expert’s opinion must reflect an objective assessment of the questions at hand; it must be the product of the expert’s independent judgment, uninfluenced by the party who retained the expert or the outcome of the litigation; and must not unfairly favour one party’s position over another. This overriding duty is reflected in the Expert Code of Conduct, which is discussed in Rule 52.2, and attached as a

Schedule to the Federal Courts Rules . [ 35 ] Apotex points to candid admissions by Dr. Armstrong that he did not read prior art on which his comments relating to obviousness and anticipation were based, instead relying on the summaries provided by Takeda’s counsel. On cross-examination, Dr. Armstrong acknowledged that in view of this reliance he had made inaccurate statements in his report as to the content of prior art, and in particular with respect to the examples of the 574 Application and the disclosure in prior art documents, WO 03061584 A2 [WO 584] and WO 0124777 A1 [WO 777].

He admitted to relying upon information from counsel in an " “unconfirmed” " , " “unsubstantiated” " and " “unverified” " manner and that he was not surprised by certain inaccuracies in his opinion that were brought to his attention during cross-examination. With respect to the 574 Application, Dr. Armstrong admitted that if he had taken greater care to understand this reference that he would have written certain aspects of his opinion differently. He acknowledged that he should have read the entirety of the prior art documents to provide his opinions. [ 36 ] I agree that Dr.

Armstrong’s evidence on the prior art is tainted by the select reading taken, which reflects Takeda’s

interpretation of the references, thereby putting the impartiality and independence of his related opinions in question. The issue before the Court is whether Dr. Armstrong’s evidence should be rendered inadmissible in view of these concerns or whether it should be dealt with as a matter of weight. [ 37 ] In Biogen Canada Inc v Taro Pharmaceuticals Inc , 2020 FC 621 ; aff’d on appeal 2022 FCA 143 , Justice Manson considered the

issue of impartiality in the context of a patent infringement action. In that case, cross-examination revealed that approximately one hundred paragraphs of the expert’s report had been copied verbatim from the Notice of Allegation, which the expert acknowledged he had never reviewed. Justice Manson found that this activity cast significant doubt as to the impartiality and independence of the expert, but dealt with these concerns as a matter of weight rather than rendering the evidence inadmissible: [44] As a preliminary point, the parties’ key witnesses’ evidence was uniformly weakened on cross-examination.

Given the inconsistencies of evidence, advocacy, and unreasonable positions taken by Drs. Oh and Leist for Biogen, and Drs. Ebers and Bailey for the Defendants, unless otherwise specified, the Court gives limited weight to their expert opinion evidence. [...] [70] Dr. Ebers’ report was also far from impartial. Biogen highlighted approximately one hundred paragraphs of his report that were copied nearly verbatim from Taro’s NOA, which Dr.

Ebers acknowledged he had never reviewed. [71] It is certainly permissible for counsel to help an expert prepare his or her report ( Moore v Getahun , 2015 ONCA 55 at paras 55 , 64). Counsel may even point the expert to relevant prior art, as long as the expert reviews and confirms the content of his or her report, as the choice of prior art is entirely in the hands of the party alleging obviousness ( Ciba Specialty Chemicals Water Treatments Limited’s v SNF Inc , 2017 FCA 225 at para 60 ).

It is quite another story for an expert to do little or no independent research and accept, verbatim, large portions of a NOA prepared by legal counsel which the expert has never seen, let alone reviewed.

This crosses the line of propriety and puts into real doubt the impartiality and independence of the expert; key aspects of the expert’s duty to the Court ( White Burgess Langille Inman v Abbott and Haliburton Co , 2015 SCC 23 at paras 26-32 ). [ 38 ] Similarly, in Rovi Guides, Inc v Bell Canada , 2022 FC 1388 [ Rovi ], Justice Lafrenière admitted the expert report in question despite finding that significant portions of the report were unequivocally plagiarized.

Justice Lafrenière held there would be severe prejudice to Rovi in disqualifying its only technical expert, that far outweighed any prejudice to Bell in treating the criticisms of the expert’s report as a matter of weight: [107] However, what happened in this case went well beyond collaboration, consultation, wordsmithing or editing. It was word-for-word copying of a technical expert’s opinions and conclusions on key issues before this Court, all done without any attribution. It is plagiarism pure and simple.

Plagiarism is wrong whether it is intentional or not. [108] A critical distinction must be drawn between counsel assisting an expert in framing their reports in a way that is comprehensible and responsive to the pertinent legal issues in a case and leading, or be seen to have led, an expert to express a particular opinion. The latter crosses the line of propriety and puts into real doubt the impartiality and independence of the expert: White Burgess Langille Inman v Abbott and Haliburton Co , 2015 SCC 23 [ White Burgess ] at paras 26-32 .

It also brings into question what other “assistance” may have been given to the expert in drafting their report.

The expert’s opinion “must be independent in the sense that it is the product of the expert’s independent judgment, uninfluenced by who has retained him or her or the outcome of the litigation” ( White Burgess at para 32 ). [...] [111] In Abbott Laboratories v Canada (Minister of Health) , 2006 FC 76 , aff'd 2009 FCA 94 [ Abbott Laboratories ] at para 19 , Associate Judge Martha Milczynski, then called Prothonotary, set out the proper approach to determine whether or not an expert should be disqualified.

In that case, the plaintiff expressed concern that a proposed expert of one of the defendants had received some confidential information of the plaintiff, thereby placing the expert in a potential conflict of interest. Prothonotary Milczynski stated that there must be an objective review of the facts and circumstances in each case and listed various factors to be analyzed in conducting the review.

For the purpose of the present case, the following factors are relevant: ̶̶ whether the expert knew he or she was relying on plagiarized information; ̶ the nature of the plagiarized information; ̶ the risk of prejudice arising to either the party challenging the expert or to the party seeking to retain the challenged expert; and ̶ the interests of justice and public confidence in the judicial process. [112] After balancing all of the above factors, I conclude that Mr. Wahlers should not be disqualified as a witness. The circumstances in the present case are different than those in Anderson .

In Anderson , the expert report prepared by a family physician was found to be plagiarized and the physician was found to have lied about it. The judge also concluded that the expert was biased, unqualified and not independent. The primary reason the expert was disqualified was because he did not have the appropriate expertise, which is not the case here. [113] While the second factor identified above militates in favour of disqualification, I find there would be a severe prejudice to Rovi to disqualify its only technical expert, one that far outweighs any prejudice to the Defendants. [114] It remains that Mr.

Wahlers lack of candour and his apparent indiscriminate adoption of another expert’s opinions or conclusions, albeit unknowingly, raise serious concerns in my mind as to whether Mr. Wahlers has fulfilled his duty to the Court to provide an independent opinion. The problem is compounded by the fact that, contrary to what is asserted by Rovi, Mr. Wahlers was unable to defend many of his opinions at trial. [...]

[118] Despite my strong reservations as to Mr. Wahlers’ credibility, independence and impartiality, it would not be just to reject his reports or testimony out of hand. There are, after all, some aspects of his evidence that are not controversial and prove useful and reliable. The concerns raised by the Defendants go to weight to be given to Mr. Wahlers’ evidence, rather than to its admissibility. Just to be clear, I have looked upon Mr. Wahlers’ evidence with great skepticism. [ 39 ] Applying the principles set out in Rovi , and considering the potential prejudice to Takeda as Dr.

Armstrong was Takeda’s primary expert on validity and only expert who responded to Apotex’ experts Dr. Davies and Dr. Kahrilas on validity issues, I prefer to deal with his evidence as a matter of weight. While it was revealed that Dr. Armstrong did not complete a full reading of the references, it is clear that he had the requisite expertise to give evidence and that he was willing to concede the shortcomings in the approach he had taken. In my view, these concessions established that Dr. Armstrong was not functioning as an advocate for Takeda.

As was the case in Rovi , even with these difficulties and others highlighted during cross-examination, Dr. Armstrong’s views were still of value to the Court on certain technical issues. Indeed, even Apotex relied on Dr. Armstrong for specific points within its argument, acknowledging in oral submissions that they had cited to Dr. Armstrong various times. B. Apotex’ Experts [ 40 ] Dr. Colin Rowlings − Dr. Rowlings obtained his Ph.D. from the University of Iowa in 1989, specializing in pharmaceutics. He is currently the Senior Vice President of Gossamer Bio Inc.

He has over 34 years experience working in the pharmaceutical industry primarily on small-molecule, new chemical entity development, encompassing a variety of dosage forms. He has contributed to multiple product approvals and has significant experience in the field of oral modified release dosage forms, including pulse release dosage forms and the use of enteric coatings. Dr.

Rowlings was admitted as an expert in the field of pharmaceutical sciences, pre-formulation, formulation development and analytical testing, with specific expertise in oral modified release dosage forms (extended release formulations, pulsatile release formulations, gastro-retentive formulations, and mini-tablet and pellet formulations), characterization of excipients, and the design,

interpretation and application of site of absorption studies. His expertise includes analysis and

interpretation of PK and pharmacodynamic [PD] data from studies conducted for the purpose of developing oral formulations. [ 41 ] Dr. Rowlings provided two reports: a first report opining on claims construction, anticipation, obviousness, overbreadth, sufficiency and ambiguity; and a second report opining on the issue of infringement and responding to Dr. Timko’s evidence on this issue. [ 42 ] Overall, I found Dr. Rowlings to be a forthright and fair witness who was knowledgeable about pharmaceutical formulation and whose testimony assisted the Court.

He conceded points that were against the interests of Apotex where it was evident that he should do so. For the most part, I rely heavily on Dr. Rowlings’ evidence with one reservation relating to his obviousness analysis, where he admittedly reviewed prior art references in an effort to " “find” " certain elements in the claims. In my view, this suggests a degree of hindsight in the approach taken to the references such that the Court must consider his evidence on this issue with some caution. [ 43 ] Dr. Neal Davies − Dr.

Davies is a pharmacologist and registered pharmacist with over 25 years experience in drug development, pharmacokinetics, drug delivery and pre-clinical and clinical pharmaceutical sciences. He obtained his Ph.D. from the University of Alberta in 1996, specializing in pharmacokinetics. He is currently a Professor in the Faculty of Pharmacy and Pharmaceutical Sciences at the University of Alberta and is also a Fellow in the Canadian Academy of Health Sciences. Dr. Davies has significant experience in the analysis of plasma profiles and the use of PK models.

His work focuses on drug development, pharmacokinetics and drug delivery, as well as on basic and clinical pharmaceutical sciences. Dr.

Davies was admitted as an expert in the fields of pharmacology, pharmacokinetics (including drug absorption, distribution, metabolism and excretion), pharmacodynamics and pharmaceutical sciences, with specific expertise in PK/PD modelling, designing and interpreting PK/PD studies, analytical techniques to measure drug concentration, drug development, drug delivery and formulations, determining appropriate dosages in animals and humans, chirality of drugs, gastrointestinal disorders and PPIs. Like Dr. Rowlings, Dr. Davies provided two reports.

His first report opined on claims construction, anticipation, obviousness, utility, overbreadth, insufficiency and ambiguity. His second report opined on the issue of infringement and responded to Dr. Timko’s evidence on this issue. [ 44 ] Dr. Davies is undoubtedly a very knowledgeable witness. He gave helpful information on pharmacology, pharmacokinetics, pharmacodynamics, including PK/PD modelling and how the PSA would read and understand Example 1 of the 916 Patent.

He was the only true pharmacokinetics expert in the proceeding and the only expert who understood all facets of the effect compartment modelling that was used by the inventors. While I found Dr. Davies to be very knowledgeable, at times I found him to be unnecessarily difficult when answering straight-forward questions and to be fixated on problems which made him unable to respond meaningfully to questions directed at understanding the significance of some of his comments.

I had difficulty with his testimony regarding the calculation of the dose amounts from the 574 Application where I found he read the examples without trying to understand them in a practical way. In that instance where the evidence was in conflict with Dr. Rowlings, I preferred the evidence of Dr. Rowlings. I have highlighted these matters further in my analysis below. [ 45 ] Dr. Peter Kahrilas − Dr. Kahrilas is a gastroenterologist with 40 years of clinical experience treating patients with acid-related disorders, such as GERD.

He also conducts research and is a Professor of Medicine at Northwestern University where he has worked since 1999. His research concerns esophageal physiology and pathophysiology with a focus on motility disorders and GERD. Dr. Kahrilas is certified by several medical boards in the United States [US] and is a fellow of a number of medical organizations, including the AGA. Dr. Kahrilas was admitted as an expert in the field of gastroenterology with specific expertise in the diagnosis and treatment of patients with esophageal disorders, such as GERD and esophageal motility disorders. Dr.

Kahrilas provided a single expert report, offering opinions on claims construction, obviousness and utility. [ 46 ] Dr. Kahrilas was a knowledgeable witness who provided clear and straight-forward answers, giving his responses simply and directly even if answers were not in Apotex’ favour. I found Dr. Kahrilas’ evidence to be helpful and where it conflicted with that of Takeda’s experts, I preferred the evidence of Dr. Kahrilas unless otherwise stated below. Similar to Dr. Rowlings, the only reservation I had with Dr.

Kahrilas’ evidence related to his approach to the third part of the obviousness analysis and his review of prior art references in an effort to " “find” " elements in the claims. I discuss this concern in greater detail below.

C. Fact Witnesses [ 47 ] Three fact witnesses gave evidence at trial. The first fact witness, Dr. Majid Vakilynejad, is one of the inventors of the 916 Patent. His evidence provided background on the proposed invention and Examples 1 and 2 of the 916 Patent. The remaining two fact witnesses, Jason Goodfield and Rose Guthrie, are current and former employees of Takeda who spoke to the introduction and impact of DEXILANT® on the Canadian market. Apotex objected to the admissibility of certain aspects of the Goodfield and Guthrie evidence on the basis that it was hearsay, opinion evidence, or contrary to Rule 248 of the Federal Courts Rules . I address these objections and provide a brief

summary of the fact evidence below. [ 48 ] In addition to Takeda’s fact witnesses, Apotex introduced one fact witness affidavit from Julie Szirtes, the Director of Clinical Research and Development at Apotex. Ms. Szirtes provided an affidavit attaching several documents relating to |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||| submitted as part of Apotex’s ANDS that compared the 60 mg Apo- dexlansoprazole capsules to the 60 mg DEXILANT® capsules.

(1) Dr. Vakilynejad [ 49 ] Dr. Vakilynejad joined Takeda Abbott Pharmaceuticals (TAP) in September 2000 and began investigating the PPI, lansoprazole, in late 2001. His role was as a member of the Drug Metabolism and Pharmacokinetics group. Dr. Taneja, the other co-inventor, worked in a separate department and was part of the formulation group. At the time, several PPIs including lansoprazole were already on the market; however, none were able to provide patients with a full day of therapeutic relief. To address nocturnal breakthrough events, Dr. Vakilynejad was asked by Dr.

Taneja to conduct mathematical modelling to determine the impact of PPIs on gastric acid pH over 24 hours. [ 50 ] As a starting point, Dr. Vakilynejad testified that he modified a model developed at the University of Buffalo by Thomas A. Puchalski to create an exposure response analysis using the data from a Phase I oral dose study (M93-006) that looked at the effect of multiple dose regimens of lansoprazole on intragastric pH.

However, this analysis failed to yield a direct relationship between intragastric pH and the concentration of lansoprazole because of various factors, including absorption and elimination rates of the drug, thus creating a counter-clockwise loop (hysteresis loop) of the data when plotted.

A one compartment open model for PK, looking at lansoprazole plasma concentration versus time data, was designed to account for the absorption and elimination rates of the drug after oral ingestion. [ 51 ] Empirical modelling was also conducted to establish systemic threshold concentrations of lansoprazole required to increase intragastric pH in the absence of food and circadian rhythm. For this, the model was first fit to data from a different clinical study (M95- 306), involving IV administration of lansoprazole that included 24-hour gastric pH monitoring.

As this was an IV study, absorption in the GI tract and the impact of food were not interfering factors. Again, the results initially yielded a counter-clockwise loop where no direct relationship between intragastric pH and the concentration of lansoprazole could be determined. To try to collapse the loop and unmask the relationship, Dr.

Vakilynejad applied a hypothetical effect compartment with a two compartment open model. [ 52 ] This work was followed by modelling of the oral dosing data from M93-006 to create simulations that looked at the impact of dual- pulse dosing regimens on gastric pH both for the whole day and for the nocturnal period. [ 53 ] Dr. Vakilynejad concluded from the modelling work that intragastric pH could be increased if a dosage form provided a plasma concentration of at least 80-100 ng/mL of drug. Dr.

Vakilynejad’s modelling of the IV data is set out in the patent as being the basis for Example 1 and Figure 1 of the 916 Patent. [ 54 ] In addition to the modelling work, the inventors also designed another study that measured the absorption of lansoprazole at different portions of the GI tract using gamma scintigraphy to trace the absorption of a special remote-triggered capsule containing lansoprazole and a radioactive marker.

The results confirmed a slightly lower but comparable absorption of lansoprazole from the distal small intestine as compared to the proximal small intestine and reduced absorption in the colon. Results of the study were reported in Example 2 of the 916 Patent and were the basis for the inventors’ determination that in a pulsatile release formulation, the second dose of PPI needed to be at least 10 percent higher than the first dose of PPI due to decreased absorption. [ 55 ] I found Dr.

Vakilynejad to be a credible witness; however, his evidence at times was brief and glossed over details relating to the modelling work conducted. This presented certain challenges as highlighted by Dr. Davies and discussed further below.

(2) Jason Goodfield and Rose Guthrie [ 56 ] Jason Goodfield is an employee of Takeda who holds the title of “Data & Insights Lead”. His affidavit attaches as Exhibit 1 a report prepared using IQVIA data (formerly referred to as IMS data) that sets out information on the number of prescriptions of DEXILANT®, and of all PPI products in Canada, from March 2011 to December 2021 [Report]. Takeda asserts that the Report and Mr. Goodfield’s evidence is relevant to the issue of commercial success. While not a current employee of IQVIA, Mr.

Goodfield did work at IMS Brogan (the predecessor company to IQVIA) from 2013 to 2017 and had familiarity with how data of the type attached to his affidavit was generated, although he could not speak to the generation of the specific data attached in the Report. [ 57 ] Apotex raised two objections to the Goodfield Affidavit. First, it objected to the Report and to the paragraphs that describe how it was prepared and what it says, on the basis of hearsay (paragraphs 4, 5, 6, 9, 10 (second sentence) and 11).

Second, and related to the first objection, it argued that two of the sentences from the impugned paragraphs disclosed opinion evidence. [ 58 ] The second fact witness, Rose Guthrie, is a former employee of Takeda who was involved with the launch and marketing of DEXILANT® in Canada. Her evidence was also introduced to support Takeda’s claim of commercial success. [ 59 ] Ms. Guthrie introduced evidence relating to DEXILANT®’s launch, physician and consumer reception, and regulatory approval.

As part of her affidavit, she attached a series of third party recall studies on DEXILANT® (Exhibits H through K to her affidavit), with

results prepared between October 2012 and May 2014 [Recall Studies]. Apotex objected to this evidence and to its related paragraphs, aswell as to an attachment of IQVIA prescription data on the basis of hearsay and that it was opinion evidence.

Three other sentences werealso objected to on the basis of Rule 248 of the Federal Courts Rules and refusals given during discovery. [60] It is trite law that hearsay evidence is presumptively inadmissible unless it falls under one of the recognized exceptions to thehearsay rule or meets the criteria of necessity and reliability: R v Khelawon, 2006 SCC 57 at paras 2, 34, and 42; Pfizer Canada Inc vTeva Canada Limited¸ 2016 FCA 161 at paras 86-87.

While business records are one such exception, a party seeking to assert that adocument is a business record has the onus to establish that it meets the requirements set out in subsection 30(1) of the Canada EvidenceAct, RSC 1985, c C-5, which provides as follows: "30

(1) Where oral evidence in respect of amatter would be admissible in a legalproceeding, a record made in the usual andordinary course of business that containsinformation in respect of that matter isadmissible in evidence under this

section inthe legal proceeding on production of therecord. " "30

(1) Lorsqu’une preuve orale concernantune chose serait admissible dans uneprocédure judiciaire, une pièce établie dansle cours ordinaire des affaires et qui contientdes renseignements sur cette chose est, envertu du présent article, admissible enpreuve dans la procédure judiciaire surproduction de la pièce. " [61] Takeda argues that the Report and the Recall Studies are business records.

While it acknowledges that the Report was prepared forthe purposes of the litigation, it argues that the underlying data exists independently as a business record and was downloaded from arepository within Takeda that is maintained in the usual and ordinary course of business. It asserts that Mr. Goodfield has extensiveexperience with IQVIA/IMS data and was qualified to answer Apotex’ questions.

It further asserts that the Court has recognized IMSdata as an independent source of reliable evidence. [62] Both parties directed the Court to the decision in Hospira Healthcare Corporation v Kennedy Trust for Rheumatology Research,2018 FC 259 [Hospira FC], in which the Court commented on the admissibility of IMS data. In that case, the Court did not find the IMSdata to fall within the business record exception; however, it nonetheless found the data necessary and reliable and to be corroborated byother evidence that was before the Court.

As stated in the decision: [305] The IMS data does not fall within the business record exception to hearsay for the reasons described in Eli LillyCanada Inc v Teva Canada Limited, 2017 FC 88 at para 18, 279 ACWS (3d) 763: In my view, the Deloitte report does not meet the test for the business records exception. That exception requiresthat the author of the record have a duty to create it, and did so contemporaneously and based on personalknowledge (Ares v Venner, (SCC), [1970] SCR 608 at p 626; see also Canada Evidence Act,RSC 1985, c C-5, s 30).

Since the author of the Deloitte report is unknown and the details surrounding thereport’s preparation were not in evidence, the report cannot meet these criteria. [306] However, the IMS data is information that is commonly put into evidence in patent cases in the Federal Court. I findthat this evidence is necessary and reliable. [307] With respect to necessity, I observe that Kennedy did not call any witnesses with direct knowledge of combinationtreatment (such as patients or prescribing rheumatologists).

Kennedy’s witness Bensen was forced to conclude, in cross-examination, that he had no real knowledge of how many patients at his clinics were receiving combination therapy withMTX and Inflectra. [308] Nonetheless, I find that this IMS data evidence is necessary. A patient or a medical professional would not be able togive the overview provided by the IMS data with respect to the approximate percentage of patients on combinationtreatment.

Bensen attempted, but was ultimately unable, to provide this type of evidence (i.e., are the majority of patientsreceiving Inflectra also receiving combination treatment?). [309] Further, this evidence is reliable because, as discussed in Bradshaw, it is corroborated by the other evidence in thiscase. Hospira states that about 100 patients have received Inflectra in Canada.

The IMS data is therefore consistent with theparty's own admission – it shows that 93 patients have received Inflectra in Canada. [310] Moreover, the entirety of the evidence put forward in this case tends to confirm the reliability of the IMS data. Asnoted during the trial, IMS data is a common source of evidence in these types of trials and its reliability is generallyaccepted by the Federal Court. ... [330] Hospira argued that a number of conclusions Kennedy wishes to draw from the IMS data are speculative.

This may betrue if the IMS data were considered in isolation; however, the other evidence in this case (including the product monographand the product label) supports the

interpretation that this data shows that at least some patients are receiving adjunctivetherapy with Inflectra and MTX. [63] While the admissibility of the IMS data in Hospira FC was challenged on appeal (reported at 2020 FCA 30 [Hospira FCA]), theFederal Court of Appeal [FCA] found it unnecessary to address the hearsay argument based on the additional evidence that alreadysupported the Judge’s conclusion on the use of Inflectra (at paragraphs 27-28).

Thus, the admissibility finding made in Hospira FC wasnot substantively reviewed. [64] In my view, neither the Report nor the Recall Surveys fall within the business record exception. The Report was prepared for thepurpose of litigation and not out of a duty to create it. While it relies on IQVIA data, such data was commissioned for purchase. It is not

data that was generated for Takeda in the ordinary course of business. Similarly, the Recall Surveys are not records that were created byTakeda itself in the usual and ordinary course of business. Rather, Takeda hired third party companies to generate this data. The FCArecently found brand awareness surveys inadmissible as business records in Clorox Company of Canada, Ltd v Chloretec SEC, 2020 FCA76 at paragraphs 26-27. In that case, the affiant’s business knowledge of the existence and contents of the surveys did not alleviateconcerns about their relevance and methodology.

I consider the Recall Surveys to be of the same vein. Contrary to Takeda’s assertion,Ms. Guthrie is not in a position to speak to these surveys as she did not conduct them. [65] There is also, in my view, insufficient evidence to otherwise establish necessity and reliability. While Takeda argued that the IQVIAdata was necessary because there was no one witness who could speak about the market, it did not put forward any evidence as to theavailability of the authors of the Report or the Recall Surveys to provide evidence.

Further, although the jurisprudence suggests somegeneral acceptance of IMS/IQVIA data due to its common usage in patent cases and its nature (Hospira FC at para 306; see alsoAstraZeneca Canada Inc v Canada (Minister of Health), 2004 FC 1277 at para 11), unlike in Hospira FC, there was no independentevidence to corroborate the alleged market share growth of DEXILANT® or otherwise support the reliability of the IQVIA data. WhileMr.

Goodfield, as a former employee of IMS, was able to address certain issues relating to the computation of the data, his evidence alsohighlighted several unknowns, particularly as it related to the nature of the prescriptions that comprised the data and the details of themarket. There was similarly no evidence to otherwise corroborate the Recall Surveys. [66] Even if the data was deemed to meet the requirements of necessity and threshold reliability, I find the evidence to be of limitedprobative value to establish commercial success.

First, as mentioned, there are unknowns associated with the data which undermine itsusefulness. Second, the numbers proposed by IQVIA suggest at most only modest market share growth and is devoid of information asto the money spent on advertising and promotion. Third, and moreover, to establish commercial success, it must be clear that success isthe result of the invention itself and not because of some other advancement associated with the product: Tearlab Corporation v I-MEDPharma Inc, 2019 FCA 179 [Tearlab] at para 69.

In this case, further evidence suggests that any commercial success may be attributedat least in part to there being no food effect associated with the drug such that it could be taken at any time of day, with or without food(TT 8A, 1111:2-1112:14). This effect is highlighted along with the dual release dosage form in Takeda’s marketing materials and inpublications, and is separately claimed in Canadian Patent No. 2,702,356 (Guthrie, Ex40, Exhibits Q and R; TT 8A, 1113:1-6, 1114:8-21; TT 1A, 60:26-63:6, 70:28-72:6; 356 Patent, Ex5).

Thus, it not clear to what extent any perceived increase in market share forDEXILANT® could be attributed to the proposed invention of the 916 Patent. [67] On the basis of these findings, it is my view that the impugned evidence should be excluded. As such, and as agreed by the parties, Ineed not go on to consider the opinion evidence objections. [68] The remaining objection to the Guthrie affidavit relates to statements in her affidavit where she describes the purported benefits ofDEXILANT® that were set out in Takeda’s marketing and sales documents (Exhibits L to R to the Guthrie affidavit).

Rule 248 of theFederal Courts Rules provides that where a party examined for discovery has refused to answer a proper question, the party may notintroduce the information sought by the question at trial without leave of the Court. Apotex points to paragraphs from Takeda’s Replywhere Takeda alleges commercial success and refers to the success being attributable to "“the properties and advantages of the subject-matter of the Asserted Claims”" and to DEXILANT® providing patients with "“a significantly beneficial treatment option”".

Questionsrelating to the meaning of these statements were refused on discovery on the basis that they sought opinion evidence. In my view, theimpugned sentences from the Guthrie affidavit go directly to the refused information (the alleged benefit of the Apotex Product) andinvoke Rule 248. Such statements cannot be introduced into evidence in view of the objections taken. I therefore agree that the firstsentence of paragraph 22 and the third and fourth sentences of paragraph 23 should be excluded from the Guthrie affidavit. VI.

Claims Construction [69] The first task for the Court in a patent infringement action is to construe the claims in issue. Claims construction is not a results-oriented exercise. Rather, the claims are to receive one and the same

interpretation for all purposes: Whirlpool Corp v Camco Inc, 2000SCC 67 [Whirlpool] at para 49(b). [70] The focus of claims construction is on the language of the claims: Free World Trust v Électro Santé Inc, 2000 SCC 66 [Free WorldTrust] at para 39.

The specification describes the invention so that a PSA can understand what the invention is and, when the patentexpires, put it into practice, but it is the claims that carve out the boundaries of the proprietary right granted by the patent: Free WorldTrust at para 33; Merck & Co, Inc v Pharmascience Inc, 2010 FC 510 at para 44. [71] Purposive construction involves the Court trying to understand the inventor’s objective intention and the particular words or phrasesin the claims that describe what the inventor considered to be the essential elements of the invention: Whirlpool at para 45; Free WorldTrust at para 31(e); Biogen Canada Inc v Pharmascience Inc, 2022 FCA 143 [Biogen] para 74.

The interpretative task of the Court istwo-fold: to separate and distinguish between the essential and non-essential elements so that legal protection is given only to theessential elements of the invention claimed (Free World Trust at paras 15 and 31(e); Tearlab at para 31); and, to ascertain what is meantand encompassed by the essential elements so that the invention as claimed is properly characterized: Biogen at para 74. [72] To ascertain the inventor’s objective intention, however, purposive construction involves looking at the words of the claims incontext, which includes the claims individually and as a whole, and considering their purpose, as well as, the patent’s description: Biogenat paras 71-72; Whirlpool at para 49(e).

Although the entire patent must be considered, the disclosure should not be used "“to enlarge orcontract the scope of the claims as written and … understood”": Whirlpool at para 52; Free World Trust at para 32. Adherence to theclaim language allows the claims to be read in a way in which the inventor is presumed to have intended, thereby promoting fairness andpredictability: Biogen at para 72; Free World Trust at paras 31(a), (

b) and 41. [73] The objective of the analysis is to interpret and respect the inventor’s objective intention as manifested in the words of the claimsused, being neither benevolent nor harsh, but rather seeking a construction that is reasonable and fair to both the patentee and the public:Biogen at para 73; Consolboard Inc v MacMillan Bloedel (Sask) Ltd, (SCC), [1981] 1 SCR 504 at p 520; Teva CanadaLtd v Pfizer Canada Inc, 2012 SCC 60 [Teva] at para 50; Tearlab at para 33. The words of the claims are to be read in an informed way,

with a mind willing to understand, and in a way that is sympathetic to accomplishment of the inventor’s purpose, expressed or implicit inthe text of the claims: Free World Trust at paras 31(

c) and 44. However, as highlighted in Free World Trust at paragraph 51, "“...if theinventor has misspoken or otherwise created an unnecessary or troublesome limitation in the claims, it is a self-inflicted wound.

Thepublic is entitled to rely on the words used provided the words used are interpreted fairly and knowledgeably.”" [Emphasis in theoriginal.] [74] Although the claim language must be read through the eyes of a PSA, as equipped with their common general knowledge [CGK](Free World Trust at paras 44-45; Tearlab at para 32), a Court is entitled to differ from the construction put forward by either party inarriving at its construction as it is the task of the Court alone to construe the claims as a matter of law: Biogen at para 73; Whirlpool atpara 61.

The role of experts are to put the judge in the best position to do so in an informed and knowledgeable way: Biogen at para 73;Whirlpool at para 57. [75] I will now go on to consider the PSA and the nature of their CGK before engaging in the claims construction exercise. A. PSA of the 916 Patent [76] The PSA is a hypothetical person to whom the patent is addressed. This may be a single individual or a team of individualsrepresenting different disciplines, depending on the nature of the invention: Pfizer Canada Inc v Pharmascience Inc, 2013 FC 120 atpara 28.

The PSA is deemed to be unimaginative and uninventive, but at the same time is understood to have an ordinary level ofcompetence and knowledge incidental to the field to which the patent relates and to be reasonably diligent in keeping up with advances:AstraZeneca Canada Inc v Apotex Inc, 2014 FC 638 at para 51, aff’d 2015 FCA 158, rev’d on other grounds 2017 SCC 36.

It is theperson, or team of individuals, that would work the patent in a real sense: Alcon Canada Inc v Cobalt Pharmaceuticals Company, 2014FC 462 at para 37. [77] By the time of final argument both parties agreed that the PSA comprised a team of individuals having knowledge in: drug productformulation, with experience making different types of dosage forms using different formulation technologies; pharmacokinetics, withexperience in mathematical modelling; and PPI treatment as either a medical doctor or gastroenterologist. [78] Each party provided evidence from a pharmaceutical formulator (Dr.

Timko (Takeda) and Dr. Rowlings (Apotex)) and agastroenterologist (Dr. Armstrong (Takeda) and Dr. Kahrilas (Apotex)). However, as noted earlier, it was only Apotex who providedexpert evidence from a pharmacokineticist or PK specialist (Dr. Davies). [79] Takeda submitted that expert evidence from a PK specialist was not necessary as Dr. Vakilynejad, the inventor, was a PK specialistand had provided all of the necessary evidence from this perspective. While Dr.

Vakilynejad was equipped to provide factual backgroundas to the development of the invention, it is the skilled person who must interpret the patent, including its examples. The inventor bynature is not independent and cannot step into the shoes of the PSA to provide a neutral

interpretation of the patent’s teachings: MerckFrosst Canada Inc v Canada (Minister of National Health and Welfare), (FC), [1998] FCJ No 1882, 160 FTR 161(FC) at para 22. As discussed further below, the absence of expert evidence from Takeda in this area leaves a void in aspects of theiranalysis. B. CGK of the PSA [80] To properly equip myself for the claims construction exercise, I must consider the CGK of the PSA. CGK is the knowledgegenerally known at the relevant date by the PSA to whom the patent relates.

However, it does not include all information in the publicdomain: Apotex Inc v Sanofi-Synthelabo Canada Inc, 2008 SCC 61 [Sanofi] at para 37; Bell Helicopter Textron Canada Limitée vEurocopter, société par actions simplifiée, 2013 FCA 219 [Bell Helicopter] at paras 64-65. [81] CGK is relevant to both the purposive construction of the claims, as well as to my analysis on obviousness, which will come later. Ithas been described as the information that a PSA would become aware of and accept as a "“good basis for further action”": MylanPharmaceuticals ULC v Eli Lilly Canada Inc, 2016 FCA 119 [Mylan] at para 24.

As no expert suggested a substantial change in CGKbetween the relevant date for obviousness (June 16, 2004) and that for construction (the publication date of January 26, 2006), I willaddress the CGK as of this earlier date. [82] In general, there was little dispute as to what comprised the CGK, which can be summarized as follows. [83] The PSA knew about PPIs and their mechanism of action as set out in the background

section above, and was aware of theirusefulness to treat GI disorders, such as esophageal disease, GERD, peptic and gastric ulcers and reflux disease. It was known that non-human mammals suffered from the same types of GI disorders as humans and that PPIs could be effective in both humans and animalsfor treating GI disorders. By 2004, known PPIs included omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole, all ofwhich were on the market as single release dosage forms that released drug after it passed through the stomach into the proximalintestine.

While dexlansoprazole was known to be a PPI and the R-enantiomer of lansoprazole, it was not yet on the market as part of anapproved medicine. [84] The gastroenterologist who was part of the skilled team was also aware of different dosing strategies that had been used to addressnocturnal breakthrough events, including multi-day dosing.

Such multi-day dosing could involve administering the same dose that hadbeen administered a second time, or splitting the dose by administering the same total dosage amount over the course of the day, butgiving half in the morning and half in the evening. [85] As PPIs were known to be unstable in acid, the PSA knew that dosage forms containing PPIs had to be protected from the acidicenvironment of the stomach through the use of an enteric coating that dissolved at pH values higher than those in the stomach.

The PSAwas aware of a number of approaches for formulating delayed release dosage forms, including those that released PPIs. It was knownthat pulsatile release formulations delivered two doses from one dosage form and could be made for PPIs; however, none were yet on the

market. [ 86 ] The PSA knew how to design a PK model to evaluate PK properties – i.e ., absorption, distribution, metabolism and elimination; and how to measure PK parameters, such as bioavailability, AUC, C max (the maximum concentration of drug in the bloodstream after it has been administered) and T max (the time taken for a drug to reach its C max ).

By 2004, the PSA knew that while each PPI had a different C max value after being administered, the drug’s therapeutic effect lasted longer than their pharmacokinetic half-life. [ 87 ] The PSA knew about the study of pharmacodynamics and how drugs affect physiological processes in the body such as gastric acid function. The PSA knew about PK/PD mathematical modelling and how it was used to understand the relationship between drug concentration in the body and pharmacological effect, as well as to predict optimal dosing.

One compartment and two compartment models had been used along with effect compartment modelling for the purpose of collapsing a hysteresis loop. [ 88 ] The PSA also knew that the small intestine was the principal site of absorption for drugs and that it included three regions (duodenum, jejunum and ileum) that gradually increased in pH from around 4 to 8. The stomach was known to have a much more acidic pH which could be dramatically altered by the presence of food.

It was recognized that the transit time of a drug through the small intestine was 3-4 hours in both fasted and fed states, while the transit time through the stomach could vary between 0.5 and 12 hours and could be slowed by food and affected by the size of the dosage form; although, the absorption of PPIs in the small intestine had not yet been studied. [ 89 ] As of June 2004, the PSA’s CGK, thus, included knowledge of: PPIs and how they function in the body to treat GI disorders; Pulsed release dosage forms and how to make them; PK and PD properties and how to measure such properties using effect compartment modelling; and Transit times and the pH environment in the small intestine.

C. Construction of the Asserted Claims of the 916 Patent [ 90 ] Armed with the CGK of the PSA, I will now go on to construe the claims. The Asserted Claims of the 916 Patent include claims 1, 5-8, 10-11 and 16, which read as follows: 1.

A dosage form comprising a PPI wherein the PPI is released from the dosage form as a first and a second dose, wherein the first and second dose are released from the dosage form as discrete pulses of the PPI, wherein each pulse of the PPI is sufficient to raise plasma concentrations above a threshold concentration of at least 100 ng/mL, wherein the second dose contains at least 10% more of the PPI than the first dose, and wherein the first and the second dose independently comprise between 5 mg and 300 mg of the PPI. 5.

The dosage form of any one of claims 1 to 4 wherein each pulse of the PPI is sufficient to maintain plasma concentrations above the threshold concentration of at least 100 ng/mL for at least 30 minutes. 6. The dosage form of any one of claims 1 to 5 wherein the second dose contains at least 50% more than the first dose. 7. The dosage form of any one of claims 1 to 5 wherein the second dose contains at least 100% to 200% more than the first dose. 8. The dosage form of any one of claims 1 to 5 wherein the second dose contains at least 200% to 900% more than the first dose. 10.

The dosage form of claim 1 wherein each of the first and second dose comprise a sufficient amount of the PPI to raise plasma levels of the PPI to a threshold concentration of at least 200 ng/mL. 11. The dosage form of claim 1 wherein each of the first and second dose comprise a sufficient amount of the PPI to raise plasma levels of the PPI to a threshold concentration of at least 450 ng/mL. 16.

The dosage form of claim 15 wherein the PPI is the R -enantiomer of lansoprazole. [ 91 ] Claim 1 is the only independent claim and claim 16 is the claim that is specifically directed to dexlansoprazole. [ 92 ] The parties assert, and I agree, that all elements of the Asserted Claims are essential, with claim 1 reciting the following required elements: 1 .

A dosage form that includes a PPI 2 . the PPI is released as a first and a second dose 3 . the first and second dose are released as discrete pulses 4 . each pulse of the PPI is sufficient to raise plasma concentrations above a threshold concentration of at least 100 ng/mL 5 . the second dose contains at least 10% more of the PPI than the first dose; and

6 . the first and the second dose independently comprise between 5 mg and 300 mg of the PPI [ 93 ] There is general agreement as to the PSA’s understanding of these essential elements, including that the first and second doses being released from the dosage form as two discrete pulses means that the doses appear as two distinguishable peaks on a plasma concentration-time profile. [ 94 ] However, there is disagreement relating to the

interpretation to be given to two terms originating in claim 1:

a) the meaning of " “a first and a second dose” " ; and

b) what is meant by " “a threshold concentration” " and whether, as used in the claims, it is restricted to humans. [ 95 ] The parties assert and I agree that claims 5-8, 10-11 and 16, as they depend from claim 1, add the recited additional limitations, which are all essential elements of those claims.

To the extent there are claim terms used in claims 5-8, 10-11 and 16 that are the same as terms used in claim 1, they have the same meaning: Nova Chemicals Corporation v Dow Chemical Company, 2016 FCA 216 [ Nova Chemicals ] at para 82 . [ 96 ] The following discussion will address the claim elements in dispute. (a) “a first and a second dose” [ 97 ] Apotex asserts that " “a first and a second dose” " relate to distinct amounts of PPI that are loaded into the dosage form prior to administration and that are available to be released from the dosage form upon administration.

Takeda asserts that " “a first and a second dose” " refers to the amounts of PPI released from the dosage form after administration devoid of its loading. In my view, both the expert evidence and the 916 Patent favour Apotex’ position. [ 98 ] As highlighted by Dr. Rowlings, " “[t]hat each “dose” corresponds to a distinct dose amount within the dosage form itself ... is ... consistent with how the skilled formulator would understand the 916 Patent.

For example, the first sentence of the 916 Patent states that its invention relates to “proton pump inhibitors and in particular, relates to dosage forms containing multiple doses of a proton pump inhibitor” " (page 1, lines 4-5; emphasis added). " ” " (Rowlings, Ex25, para 133). [ 99 ] As explained by Dr. Davies, in order to have release of a first and second dose of PPI from the dosage form, the first and second dose must be contained in the dosage form (TT 6A, 707:17-18). I agree, this is a matter of logic.

Consistent with this view, the 916 Patent speaks to each dose of PPI being present in the dosage form in an amount sufficient to raise the plasma levels of the PPI to at least 100 ng/mL (916 Patent, Ex1, 2:3-4; 2a:18-19). The description refers to loading the dosage form with drug for each pulse or dose (916 Patent, Ex1, 12:19-27): ... As further guidance, however, in cases where a pulsed release dosage form is employed, drug loading for each pulse is independently and typically between 5 mg and 300 mg, more typically between 20 mg and 200 mg.

In cases where an extended release dosage form is employed, typical drug loading for the combined first and second PPI dose in such a formulation will be in the range of 50 mg to 1000 mg, and more typically 75 mg to 500 mg.

It has also been discovered, that due to the decreasing absorption in the downstream portions of the gastrointestinal tract, it is preferred to load the dosage forms with the PPI such that the second dose is higher than the first dose of the PPI. [ 100 ] Interpreting the first and second dose to refer to amounts of drug that are loaded into the dosage form also accords with the reference in the claim to the second dose containing at least 10% more of the PPI than the first dose and the first and second dose independently comprising a quantifiable amount of PPI between 5 and 300 mg.

These latter elements require quantification of the dose amounts before release and correspond with the teaching of the patent that the increased second dose is reflected in the total drug loading (916 Patent, Ex1, 13:1-2). [ 101 ] While not consistent with his first report, Dr. Timko expressed the same

interpretation as Apotex’ experts in his second report, stating that the dosage form of the patent " “contains two dose amounts and that the second dose is greater than the first” " (Timko, Ex11, para 92). Although Dr. Timko attempted to resile from this statement on cross-examination, he employed an approach consistent with the statement when he later calculated the dose amount in the two pulses released from DEXILANT® using the amount of drug loaded into the dosage form for the two different bead types. [ 102 ] When taken to the patent, Dr.

Armstrong similarly conceded that the description of the first and second dose was " “consistent with the dosages being contained in the dosage form” " (TT 8A, 971:15-18) and that the reference in the claim to the second dose containing at least 10% more of the PPI than the first dose made clear that " “dose” " was referring to an amount of medicament contained in the dosage form before administration (TT 8A, 968:9-971:18). [ 103 ] As conceded by Apotex, such

interpretation of " “a first and a second dose” " does not import any specific formulation design. While the first and second dose may be contained within the dosage form as two distinct populations of delayed release beads or granules as in DEXILANT®, there is no requirement for the first and second dose to be present in the dosage form as two discrete populations.

Indeed, the 916 Patent is clear that the invention is not limited to a particular type of dosage form and that multiple formulation configurations are suitable for pulsed release dosage formulations (916 Patent, Ex1, 3:9-14, 10:24). [ 104 ] I agree with Apotex, the amount of drug released from the dosage form cannot be divorced from the amount of drug (or dose) loaded into the dosage form; otherwise, there would be no certainty as to the dose amount. It would be site specific, and subject to variation from food effects and as between individuals.

If the first dose and the second dose were intended to be something different from the amount of drug loaded into the dosage form, it could only be determined after the patient consumed the dosage form and then had their blood drawn and analyzed. In my view, the direct targeting of a dosage form that can provide a specific threshold plasma concentration and a second dose that contains at least 10% more PPI than the first dose runs contrary to this alternative

interpretation.

(b) “threshold concentration” [ 105 ] The second term in dispute is " “threshold concentration” " . Apotex gives a plain meaning to this phrase, asserting that it refers to the plasma concentration level that must be surpassed when the dosage form is administered. It argues that " “threshold” " describes a limit or target, and has the same meaning as it would in common usage. [ 106 ] Takeda asserts that " “threshold concentration” " is the concentration of PPI required to have an effect on a human’s gastric pH. As argued by Takeda, the use of the term " “threshold” " is purposive and must be read in context.

As used in claim 1, it must mean something more than a concentration above at least 100 ng/mL; otherwise, it would have no additional meaning over plasma concentration in the cited phrase. Takeda asserts that when read within the context of the 916 Patent as a whole and its teachings, including Example 1, it is clear that the plasma concentration level of 100 ng/mL is the concentration above which a pharmacological effect is achieved ( i.e ., an effect on gastric pH).

Thus, the PSA would attribute " “threshold concentration” " to take on this meaning. [ 107 ] While I agree that the word " “threshold” " indicates a target concentration for achieving pharmacological effect, I do not agree that any specific effect can be attributed to this phrase. As noted earlier, a word used in the claims can only have one and the same meaning: Nova Chemicals at para 82 . Thus, the same meaning for " “threshold concentration” " must apply not only to claim 1 of the 916 Patent, but also to claims 5, 10 and 11.

Claim 10 refers to " “the first and second dose compris[ing] a sufficient amount of the PPI to raise plasma levels of the PPI to a threshold concentration of at least 200 ng/mL” " while claim 11 provides that " “the first and second dose comprise a sufficient amount of the PPI to raise plasma levels of the PPI to a threshold concentration of at least 450 ng/mL.” " [ 108 ] On cross-examination, it was shown that Dr. Armstrong adapted and adjusted his

interpretation of " “threshold concentration” " as between the claims to match his

interpretation of Example 1 and Figure 1 of the 916 Patent. For claim 1, he viewed the " “threshold concentration” " of 100 ng/mL to " “align with the baseline concentration that must be met to achieve an effect on the patient’s gastric pH” " . For claim 10, he viewed the " “threshold concentration” " of 200 ng/mL to correlate with the point on the curve of Figure 1 where there was a high slope, " “meaning small changes in plasma PPI concentration have a large resulting effect on gastric pH” " .

For claim 11, he noted that 450 ng/mL in Example 1 was identified as the point where the effect on gastric pH had plateaued. He interpreted achieving a concentration of 450 ng/mL as ensuring that " “a maximal effect on gastric pH has been achieved” " (Armstrong, Ex46, para 37). Ultimately, Dr. Armstrong acknowledged that his

interpretation of " “threshold concentration” " was subjective and based on his

interpretation of Example 1 and Figure 1 of the 916 Patent (TT 8A, 988:16-998:19). It did not provide for one and the same meaning in accordance with the principles of claim construction. [ 109 ] I

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