MERCK SHARP & DOHME CORP. v. MERCK CANADA INC., 2022 FC 417

Date: 20220411 Docket: T-419-20 Citation: 2022 FC 417 Toronto, Ontario, April 11, 2022 PRESENT: The Honourable Madam Justice Furlanetto BETWEEN: MERCK SHARP & DOHME CORP. AND MERCK CANADA INC. Plaintiffs and PHARMASCIENCE INC. Defendant PUBLIC JUDGMENT AND REASONS (Identical to the Confidential Judgment and Reasons Issued on March 28, 2022) [ 1 ] This judgment arises from a patent infringement action brought under subsection 6(1) of the Patented Medicines (Notice of Compliance) Regulations , SOR/93-133 [ PMNOC Regulations ]. The patent at issue is Canadian Patent No. 2,529,400 [400 Patent].

The innovative drug relating to the action is JANUVIA®, which is used to treat type 2 diabetes. [ 2 ] Merck Canada Inc. is the " “first person” " in accordance with the PMNOC Regulations .

Merck Sharp & Dohme Corp. is the registered owner of the 400 Patent and is a party to the action pursuant to subsection 6(2) of the PMNOC Regulations . [ 3 ] The Plaintiffs [collectively, Merck] claim that the making, constructing, using or selling by the Defendant Pharmascience Inc. [PMS] of its sitagliptin phosphate tablets in strengths of 25 mg, 50 mg, and 100 mg in accordance with PMS’ Abbreviated New Drug Submission will infringe at least one of claims 4-7, 19, 20, 22, 24 and 26 [Asserted Claims] of the 400 Patent.

PMS asserts in defence that the 400 Patent is invalid for obviousness and/or insufficiency. [ 4 ] The parties agreed to a stipulation that the only issue to be adjudicated at trial was the validity of the 400 Patent. The stipulation provided that should the court find any of the Asserted Claims of the 400 Patent to be valid, the Order sought by the Plaintiffs in the action should issue with the relief requested by the Plaintiffs. [ 5 ] For the reasons that follow, I find the Asserted Claims of the 400 Patent valid and that the relief sought should be ordered accordingly. I.

Background [ 6 ] The 400 Patent is listed on the Patent Register in association with the medicine sitagliptin phosphate monohydrate. Sitagliptin exists as a dihydrogen phosphate salt in crystalline monohydrate form in the tablets sold as JANUVIA®. Sitagliptin is the active ingredient in the drug product. [ 7 ] In type 2 diabetes, cells develop insulin resistance such that the presence of insulin in the blood does not stimulate cells to take up glucose, or the pancreas does not produce enough insulin to overcome the resistance.

Thus, glucose accumulates in the blood. [ 8 ] Sitagliptin inhibits dipeptidyl peptidase-4 [DPP-4, DP-IV or DPP-IV], an enzyme that degrades one of the peptides (Glucagon-Like Peptide-1 [GLP-1]) that stimulates the secretion of insulin. This inhibitory effect modulates the level of insulin and glucose in the blood. Sitagliptin acts only when glucose is elevated in the bloodstream, thereby reducing the risk of hypoglycemia caused by low glucose levels. [ 9 ] In 2006, JANUVIA® became the first DPP-4 inhibitor approved by the United States Food and Drug Administration [FDA] for the treatment of diabetes.

It was approved by Health Canada in 2007. [ 10 ] This action initially alleged infringement of three patents - the 400 Patent, as well as two other patents listed on the Patent Register in association with sitagliptin phosphate monohydrate – Canadian Patent Nos. 2,536,251 [251 Patent] and 2,450,740 [740 Patent]. However, the allegations in respect of the 251 Patent and 740 Patent were discontinued prior to trial. [ 11 ] The 740 Patent is the corresponding Canadian national phase patent of Patent Co-operation Treaty [PCT] patent application WO 03/004498 [WO498].

WO498 discloses a genus of compounds that includes the chemical compound now known as sitagliptin. It specifically exemplifies sitagliptin, amongst other compounds, both as a free base and hydrochloride salt and refers to other salts and crystalline forms as being within its scope. WO498 is referenced in the 400 Patent as discussed further below. [ 12 ] The 400 Patent is directed to the dihydrogenphosphate [DHP] salt of sitagliptin and its crystalline monohydrate form, a process for

making the DHP salt of sitagliptin as a crystalline monohydrate, its formulation as a pharmaceutical composition and its use to treat diseases affected by the inhibition of DPP-4, such as type 2 diabetes. II. Witnesses [ 13 ] Seven experts gave testimony at the trial; three experts were called by PMS and four by Merck. The parties agreed to stipulations as to the expertise of all expert witnesses. A. PMS Experts [ 14 ] Dr. Vassil Elitzin obtained his Ph.D. from Stanford University in 2004, specializing in the synthesis of naturally occurring chemical compounds.

He is currently the Director of Chemistry, Manufacturing and Controls and Chief Chemist at LI-COR Biosciences. He was previously a principal scientist in the Chemical Development group at GlaxoSmithKline. His work focuses on the development of active pharmaceutical ingredients and dosage forms from discovery to commercialization. Dr. Elitzin was admitted as an expert in synthetic organic chemistry and compound characterization, with particular expertise in developing, making, and characterizing different salt and crystalline forms of compounds. [ 15 ] Dr.

Elitzin provided an opinion on whether the Asserted Claims of the 400 Patent would have been obvious to the person skilled in the art [PSA]. He also reviewed some of Merck’s internal documents and provided an opinion on the course of conduct taken by the inventors towards obtaining the DHP salt of sitagliptin and the crystalline monohydrate. [ 16 ] PMS highlights Dr. Elitzin’s experience in industry; however, he was not active in industry at the relevant date for assessing obviousness of the 400 Patent.

His observations as to what was happening at the time are limited to his understanding from the literature and from lectures attended during his Ph.D. studies. While in general I found Dr. Elitzin’s testimony to be helpful to the Court, as highlighted below, he was selective in accepting statements from leading authorities as to the common general knowledge in the art, some of which came from publications he had relied on for his own report. I have therefore approached his evidence in those areas with caution and in some instances have preferred the evidence of Merck’s experts over that of Dr.

Elitzin in those areas. [ 17 ] Dr. Mark Hollingsworth is an Emeritus Research Professor at Kansas State University. He has worked in academia since 1987, first as an Assistant Professor in the Chemistry Department at the University of Alberta, then as an Assistant Professor in the Chemistry Department at Indiana University, and later as an Associate Professor in the Chemistry Department at Kansas State University, where he worked from 1998 to August 2021 when he retired. He has taught and lectured extensively on solid state chemistry and the characterization of crystalline forms. Dr.

Hollingsworth was admitted as an expert in organic chemistry, particularly solid state organic chemistry, including the characterization of the solid state of organic compounds and their properties, with expertise in analytical techniques for characterizing organic solids and the crystallization of organic solids. He was further qualified as an expert in the fields of crystal growth and crystal engineering with expertise in analytical techniques for characterizing organic solids and the crystallization of organic and inorganic compounds, including by x-ray crystallography. [ 18 ] Dr.

Hollingsworth provided opinions on claims 4-7, 19, 20 and 24 of the 400 Patent and on the elements of the test for obviousness relating to those claims, both before and after a review of some of Merck’s internal documents. He also analyzed Merck’s raw data files relating to the x-ray powder diffraction [XRPD] characterization work done during Merck’s polymorph screening and provided an analysis of this work, including with respect to the limitations found in claims 5-7 of the 400 Patent. I found Dr. Hollingsworth to be a knowledgeable and credible witness. [ 19 ] Dr. James E.

Foley is a retired clinical research director with experience in drug development relating to diabetes treatments. He has worked in the field of diabetes since the 1970s and began working on DPP-4 inhibitors in 1995. Dr. Foley was involved in the evaluation of the Novartis candidate drug DPP-728 as a DPP-4 inhibitor in patients, and in the clinical development and profiling of LAF-237 (vildagliptin) as a DPP-4 inhibitor. Dr. Foley was admitted as an expert in pharmacology and drug development, including specifically the history of development of DPP-4 inhibitors as a treatment for diabetes.

He was further admitted as having expertise in drug discovery and development, and in lead compound identification. [ 20 ] Dr. Foley provided background on the development of Novartis’ DPP-728 and vildagliptin compounds as DPP-4 inhibitors. He gave opinions on claims 22 and 26 of the 400 Patent and on the elements of the test for obviousness as it related to those claims. I found Dr. Foley to be a knowledgeable and credible witness. B. Merck Experts [ 21 ] Dr. James Wuest is a Professor of Chemistry at the Université de Montréal where he has worked since 1981.

He is also the Canada Research Chair in Molecular Materials. He was previously an Assistant Professor of Chemistry at Harvard University and a Research Fellow at Harvard Medical School. Dr. Wuest specializes in molecular design and synthesis of solid state forms, including salt forms, crystalline forms and their polymorphs. He has extensive experience synthesizing compounds and characterizing their resulting structures and properties. Dr.

Wuest was admitted as an expert in molecular design and synthesis, with particular expertise in solid state organic chemistry, including the characterization of the solid state of organic compounds and their properties, with expertise in analytical techniques for characterizing organic solids and the crystallization of organic compounds. [ 22 ] Dr. Wuest provided opinions on claims 4-7, 19, 20, 22 and 24 of the 400 Patent and whether those claims would have been obvious at the relevant date. He also responded to the opinions of Drs. Elitzin and Hollingsworth. [ 23 ] PMS highlights that Dr.

Wuest has never worked on a drug development team. I note that this criticism also applies to PMS’ own expert, Dr. Hollingsworth. While Dr. Wuest’s opinions, like those of Dr. Hollingsworth, must be considered with this limitation in mind,

where opinions relate to scientific principles and information that can be assessed from knowledge of the techniques used and literature available at the time, it does not diminish the weight to be attached to the opinions. [ 24 ] PMS further highlights that Dr. Wuest has testified in a number of cases for innovators, including some for Merck, and was retained in litigation in the U.S. relating to the corresponding patent to the 400 Patent. It suggests that Dr. Wuest has ties to Merck because Dr. Wuest has met Merck’s inventor Dr. Wenslow and had planned to give a lecture at Dr. Wenslow’s company.

I find these criticisms unpersuasive. Dr. Wuest does not receive any financial support for his research from Merck. His involvement in past litigation is not uncommon for an accomplished scientist in the field and he is not currently involved in the U.S. proceeding on the corresponding 400 Patent. As made clear during his cross-examination, Dr. Wuest has not discussed this litigation or sitagliptin with Dr. Wenslow and his lecture at Dr. Wenslow’s company is unrelated to the litigation. There is no basis on the evidence before me to suggest that Dr.

Wuest is not an independent, unbiased witness. [ 25 ] In general, I found Dr. Wuest to be a knowledgeable witness who was of assistance to the Court. However, his view of certain background passages in the 400 Patent relating to inhibitory activity appeared strained and his positon as to whether he could speak to issues involving the potency of compounds and their therapeutic use unclear. I have therefore approached his evidence on those issues with caution. [ 26 ] Dr. Martyn C.

Davies is an Emeritus Professor and pharmaceutical consultant who recently retired from the University of Nottingham where he served in various roles, including as the Head of the Pharmaceutical Sciences and Pharmacy School. He has worked for many years as a consultant and has significant practical experience developing, formulating and characterizing pharmaceutical formulations and advanced drug delivery systems. Dr.

Davies was admitted as an expert in pharmaceutical formulation and drug delivery, including with respect to pre-formulation assessment, formulation design and development, manufacture, characterization, testing and analysis, including for solid oral dosage forms. [ 27 ] Dr. Davies provided an opinion on the issue of obviousness with respect to claims 4-7 and 22 of the 400 Patent from the perspective of the skilled formulator. He also responded to the opinion of Dr. Elitzin on those claims from this perspective. [ 28 ] PMS highlights Dr. Davies history with pharmaceutical litigation on behalf of innovators.

It also suggests that Dr. Davies attempted to bolster the evidence of other Merck witnesses during his testimony. PMS refers to two passages during Dr. Davies cross-examination where Dr. Davies refers to testimony of other Merck witnesses when addressing a question asked. In one instance, the testimony refers to Dr. Wenslow and in the other instance Dr. Wuest. While I agree with PMS’ criticism of the first instance, the second instance appeared to result from Dr. Davies being asked about an area not covered by his expertise.

In any event, I do not consider these two passages to pervade the remaining testimony provided by Dr. Davies. In my view, Dr. Davies was a knowledgeable witness and I consider his testimony to be of assistance to the Court. [ 29 ] Dr. Richard E. Lewanczuk is an endocrinologist and the Senior Medical Director of Health System Integration for Alberta Health Services. He has held various roles in that organization since the 1990s.

He is also a professor of medicine and physiology at the University of Alberta with a research background in diabetes, hypertension, chronic disease management, therapeutic natural products, and drug-disease interactions. Dr. Lewanczuk was admitted as an expert in internal medicine and endocrinology with extensive expertise in managing and treating type 2 diabetes. Dr. Lewanczuk was further qualified as an expert in the conduct of clinical trials for pharmaceutical agents for use in the treatment of type 2 diabetes. [ 30 ] Dr.

Lewanczuk provided background on type 2 diabetes and the history of different therapies used to treat type 2 diabetes, including the role and impact of JANUVIA® and other Merck drug products. Dr. Lewanczuk was also asked to respond to Dr. Foley’s opinions regarding obviousness and claims 22 and 26 of the 400 Patent. [ 31 ] PMS criticizes Dr. Lewanczuk for failing to disclose that he had received honoraria from Merck for sitting on an advisory panel and giving a lecture. This information was readily acknowledged by Dr.

Lewanczuk on cross-examination, where he clarified that honoraria from pharmaceutical companies are common and thus are not included in his CV due to the abundance in which they are provided. Dr. Lewanczuk confirmed that he had never received research support from Merck. I do not consider the omission of the honoraria to affect Dr. Lewanczuk’s credibility or suggest any form of bias. Overall, I viewed Dr. Lewanczuk as a forthright witness who readily acknowledged and helped to clarify these omissions. [ 32 ] PMS also criticized Dr.

Lewanczuk for providing views on salt selection and whether sitagliptin was previously disclosed in the prior art, when this evidence was admittedly outside of his expertise. I agree that there were a few instances where Dr. Lewanczuk strayed outside his expertise, principally when seeking to respond to comments on these same issues made in Dr. Foley’s report. I have not given those aspects of his opinion any weight when reaching my decision. [ 33 ] While I consider Dr. Lewanczuk’s report to have went into unnecessary detail in certain areas, his comments on claims 22 and 26 and his response to Dr.

Foley’s opinion on those claims were of assistance to the court. [ 34 ] Dr. William R. Roush is the Executive Vice President of Chemistry of IFM Therapeutics where he is responsible for leading drug discovery medicinal chemistry research activities. He has over 40 years of experience in organic and medicinal chemistry and is an Emeritus Professor of Chemistry at the Scripps Research Institute.

Between 2005-2017 he was the former Executive Director of Medicinal Chemistry in the Drug Discovery Division of Scripps’ Translational Research Institute where he directed research for optimizing drug candidates for drug discovery projects internal to Scripps. Prior to 2017, he also acted as a consultant to pharmaceutical and biotechnology companies. Dr. Roush was admitted as an expert in organic and medicinal chemistry, and specifically in the areas of synthesis and characterization of organic compounds. Dr.

Roush was further qualified as having expertise in drug discovery and development and in lead compound identification. [ 35 ] Dr. Roush was asked to opine on the 400 Patent and whether the PSA would have chosen to investigate sitagliptin or any of its salts as a potential DPP-4 inhibitor for treating type 2 diabetes as of June 24, 2003, without having the benefit of the 400 Patent. He was also asked to respond to Dr. Foley. In doing so, he provides opinions on claims 4, 22 and 26 of the 400 Patent and whether claims 22 and 26 are obvious. In providing these opinions, Dr.

Roush conducts a prior art search and reviews the steps a medicinal chemist would take to

identify a lead candidate for drug development. [ 36 ] PMS asserts that Dr. Roush has extensive ties to brand pharmaceutical companies. It highlights that at the relevant date Dr. Roush was in academia and not in industry. PMS criticizes Dr. Roush for asserting that he had acquired some expertise on DPP-4 inhibitors after preparing his report and for dedicating a portion of his report to the success of JANUVIA®, while admittedly having no personal knowledge of that success. [ 37 ] I agree these are critiques that can be made of Dr. Roush’s evidence. However, I do not agree that Dr.

Roush presented as a biased witness or that these critiques establish that the substance of Dr. Roush’s evidence is not credible. Further, I do not consider Dr. Roush’s comments on the process involved in lead candidate identification to be affected by the date of his experience. The bigger problem the Court has with Dr. Roush’s evidence is that aspects of it are from the perspective of the medicinal chemist who is evaluating and directing Structure Activity Relationship [SAR] studies on compounds of the prior art to advance the next stages of research.

As will be discussed further below, this is not a focus of the 400 Patent. While I will need to consider whether the PSA would be motivated to move from WO498 to the inventive concept of the 400 Patent, I do not consider a separate medicinal chemist to be a necessary member of the skilled team interpreting the 400 Patent. As such, certain aspects of Dr. Roush’s evidence are not relevant to my analysis. C. Fact Witnesses [ 38 ] There were two fact witnesses introduced by the Plaintiffs. The first, Christine Vincent, is a law clerk with the solicitors for the Plaintiffs.

She provided an affidavit attaching several documents obtained from Health Canada’s website associated with generic submissions involving sitagliptin. The affidavit also attached pleadings from the Merck Sharp & Dohme Corp v JAMP Pharma Corporation T-667-20 proceeding. The significance of these pleadings to the present action was not made known to the Court through the Plaintiffs’ submissions. Ms. Vincent’s affidavit was accepted and it was agreed that she would not be cross-examined. [ 39 ] The second fact witness, Dr. Robert M. Wenslow, is one of the inventors of the 400 Patent. Dr.

Wenslow was the discovery representative for the Plaintiffs and, on agreement of the parties, was the only inventor examined under Rule 237(4) of the Federal Courts Rules , SOR/98-106 [ Federal Courts Rules ]. [ 40 ] Dr. Wenslow joined Merck in 1997 as a Senior Research Chemist in the Process Research & Development Department. At the time of sitagliptin’s development, Dr. Wenslow led a team of scientists in the Physical Measurements group, which was then part of the Analytical Research department, and directly supervised the work of his co-inventors Drs.

Russell Ferlita and Alex Chen, as well as Yaling Wang. [ 41 ] The Physical Measurements Group formed part of the broader multi-disciplinary DPP-4 project team that was involved in sitagliptin’s development. The primary responsibility of the Physical Measurements Group was to perform solid state characterization of candidate drug compounds, including XRPD, solid state nuclear magnetic resonance [NMR] spectroscopy, differential scanning calorimetry [DSC] and thermogravimetric analysis [TGA]. As a lead member of the group, Dr.

Wenslow regularly discussed and collaborated with the broader DPP-4 project team and reviewed research reports and data generated on sitagliptin, including those of the remaining co-inventors Drs. Karl Hansen, Ivan Lee, Stephen Cypes and Vicky Vydra. [ 42 ] As admitted by Dr. Wenslow, he was not directly assigned to the sitagliptin project until March/April 2002, around the time the phosphate salt was chosen for further development (Trial Transcript [TT], Volume [V]4, Page [P]:349 Line [L]:8-13; TT V5, P:190 L:18).

As one of his primary responsibilities upon joining the group, he reviewed the development work up to that point and had discussions with other members of the DPP-4 group to familiarize himself with the work that had been completed prior to his joining the project (TT V4, P:349 L:16 – P:350 L:1). [ 43 ] Dr. Wenslow provided an overview of the invention story, both through oral testimony and through affidavit evidence, including with reference to various documents outlining the history of the invention.

PMS accepted all but one of the documents as being authentic and the vast majority for the truth of their contents by way of joint agreement of the parties. [ 44 ] While it was not disputed that Dr. Wenslow could appear at trial and submit an affidavit introducing those documents covered by the agreement, large portions of the content of his affidavit were hotly contested as being hearsay, improper opinion evidence, covering subject matter beyond the pleadings, and/or being contrary to rules 232 and 248 of the Federal Courts Rules .

In light of the timing of these objections, and on the basis of their nature and number, which in many cases included parsing words and/or sentences from within paragraphs, it was determined that the Court would benefit from hearing Dr. Wenslow’s full oral testimony at trial and that the admissibility of the objected to portions of his affidavit evidence would be dealt with as a preliminary matter as part of this decision. Time was reserved for argument on the motion to take place at the close of the evidence. The parties also agreed that counsel for PMS would provide an update after Dr.

Wenslow testified as to whether any objections would be withdrawn. However, in the end, the motion was not narrowed. Instead, PMS sought to add additional objections arising from Dr. Wenslow’s oral testimony.

PMS was directed to identify the additional objections and the impugned portions of the affidavit to which they related. [ 45 ] As determined by oral ruling during argument on the motion, after-the-fact objections to direct testimony not related to impugned portions of the affidavit were rejected as it was viewed that the failure of PMS to raise the objection during the testimony precluded Merck from properly responding to the objections at the relevant time and potentially curing any deficiency: Teva Canada Ltd v Pfizer Canada Inc , 2017 FC 526 ( Venlaflaxine 2 ) at paras 32- 42.

Answers given on cross-examination were also rejected as being improper objections as such answers were elicited by PMS directly. The remaining objections are set out in the Appendix attached to this decision. The Appendix lists the original objections to the affidavit, along with the objections to the asserted related oral testimony and provides my specific dispositions on each. Below, I provide some general comments on the four primary grounds of objection raised.

(1) Hearsay [ 46 ] Hearsay evidence is evidence that is adduced for its truth without the contemporaneous opportunity to cross-examine the declarant:

R v Khelawon, 2006 SCC 57 [Khelawon] at para 35. Hearsay evidence is presumptively inadmissible unless it falls under one of therecognized exceptions to the hearsay rule: Khelawon at paras 2, 34, and 42; Pfizer Canada Inc v Teva Canada Limited¸ 2016 FCA 161[Venlafaxine] at paras 86-87. [47] Hearsay evidence may also be admitted under the principled approach if the party adducing it can establish it is necessary andreliable: Khelawon at paras 42; Coldwater First Nation v Canada (Attorney General), 2019 FCA 292 [Coldwater] at para 48.

Astatement is reliable if there is no real concern about whether the statement is true because of the circumstances in which it was made, orif the circumstances allow its truth and accuracy to be sufficiently tested (Khelawon at paras 61-63), such as if it is supported bycontemporaneous documentary evidence (Coldwater at para 49-50). Necessity is a flexible criterion and is not to be equated with theunavailability of a witness: Khelawon at para 78; Coldwater at para 53.

The nature and practical exigencies of a proceeding can impactthe evaluation of necessity (Coldwater at paras 54-55), such as avoiding an impracticably large number of affidavits or witnesses, and theresulting promotion of speed and efficiency (Coldwater at para 59; R v Baldree, 2013 SCC 35 [Baldree] at para 72).

One criterion mayhave an impact on the other (Khelawon at paras 46 and 77) such that if the reliability of the impugned evidence is sufficientlyestablished, the necessity requirement can be relaxed (Baldree at para 72). [48] This modern approach to hearsay recognizes that evidence may be admissible from departmental supervisors or individuals whotake on an oversight role and although not performing all of the work, have enough personal knowledge to testify about the conduct,activities and events that have taken place: Coldwater at paras 42-46. [49] PMS argues that much of Dr.

Wenslow’s evidence consists of statements made about work performed by others or their state ofmind and reasoning processes. It asserts that Dr. Wenslow had a limited supervisory role that is insufficient to allow him to testifybroadly about the conduct, activities, and events in Merck’s sitagliptin development process. It contends that if Merck wanted thisevidence admitted, it needed to call other inventors or Merck employees as witnesses. [50] Merck argues that much of the impugned evidence is not hearsay as it arises from Dr. Wenslow’s personal knowledge gained in hissupervisory capacity.

It asserts that the impugned evidence is admissible under the principled approach to hearsay. [51] As set out further in the Appendix, the majority of the objections made based on hearsay cannot succeed, as they are either nothearsay and/or are admissible under the principled approach to hearsay. I find that Dr. Wenslow’s role within the team was such that hefunctioned in a larger supervisory capacity that allows him to speak about many aspects of the team’s experimental work.

Moreover, asto reliability, the impugned statements generally refer to information from documents that have already been accepted by PMS as beingadmissible for the truth of their contents without further proof, or which raise facts that have otherwise already been admitted intoevidence. [52] As to necessity, it is difficult to reconcile the inconsistent position taken by PMS to agree to accept Dr. Wenslow’s testimony as theonly testimony of the invention story for the purpose of discovery, while asserting it is now insufficient for trial.

In some instances ifPMS’ objections were to prevail, they would result in PMS reading-in certain facts from discovery as its evidence, while requiring Merckto introduce those same facts through additional witnesses. The PMNOC Regulations seek to promote efficiencies and to avoid theimpracticality of a large number of affidavits or witnesses where such testimony is not required. The overly technical position taken byPMS, splitting and parsing sentences, where the reliability of the impugned statements are supported by contemporaneous documents orother evidence runs contrary to the fundamental guidelines set out in

section 6.09 of the PMNOC Regulations.

(2) Opinion Evidence [53] The general rule is that a fact witnesses must limit their testimony to the facts of which they are aware and not to inferences oropinions drawn from those facts: White Burgess Langille Inman v Abbott and Haliburton Co, 2015 SCC 23 at para 14.

This rule appliesunless the witness is in a better position than the trier of fact to form the conclusions made, the conclusions are ones that a person ofordinary experience can make, the witness has the experiential capacity to make the conclusions, or where giving opinions is aconvenient mode of stating facts too subtle or complicated to be narrated as facts: Toronto Real Estate Board v Commissioner ofCompetition, 2017 FCA 236 at para 79. The line between fact and opinion is not always clear: Graat v The Queen, (SCC), [1982] 2 SCR 819 at 835. [54] PMS objects to all or part of 26 paragraphs of Dr.

Wenslow’s affidavit and related oral testimony on the basis that he is providingimpermissible opinion evidence. PMS asserts that Dr. Wenslow gives unhelpful, and potentially misleading opinion evidence that doesnot meet the limited and narrow exceptions for a fact witness. Merck asserts that many of the alleged objections relate to factual evidenceregarding the observations and conclusions drawn by Merck employees at the time. Merck argues that if any opinion evidence isprovided, it is admissible because Dr.

Wenslow is well positioned to provide that evidence and has the experiential capacity to do so. [55] The majority of the statements alleged to be opinion set out the reasoning behind the choices made by the DPP-4 development teamand are admissible for this purpose. While some of the statements are technical in nature, this does not automatically negate thestatements, especially where such statements reflect the understanding of the development team at the time. In some cases, Dr. Wenslowadds "“gloss”" to his description of events.

However, in most cases such comments are not of such a character that would mislead theCourt or be prejudicial to PMS and do not warrant the exclusion of the evidence. Such comments can most effectively be dealt with byconsidering the weight to be given to the statement. With few exceptions, the objections made in this category are dismissed.

(3) Beyond the Pleadings [56] Relevance is a threshold requirement for the admission of evidence. Evidence is relevant if it tends to establish a fact in issue. Tosucceed on showing that evidence should be excluded for relevance, the moving party must show that the evidence is "“obviouslyirrelevant”": Coldwater at para 14. PMS has failed to do so in this case. [57] The impugned evidence is relevant to the obvious to try analysis and the inventor’s course of conduct. While all of the details ofMerck’s invention story were not specifically pleaded in Merck’s Reply, the evidence is clearly responsive to the issues in the proceeding

and to PMS’ evidence. The objections in this category accordingly have been dismissed.

(4) Rule 232 and 248 Objections [ 58 ] Rules 232 and 248 aim to avoid a party being prejudiced by the late disclosure of documents and to prohibit " “trial by ambush” " : Airbus Helicopters, S.A.S. v Bell Helicopter Textron Canada Limitée , 2017 FC 170 at para 81 ; Apotex Inc v Sanofi Aventis , 2010 FC 481 at para 6 .

Rule 248 only applies where a party fails to produce documents, or refuses to answer a proper question and later seeks to introduce such evidence at trial: Human Care Canada Inc v Evolution Technologies Inc , 2018 FC 1302 [ Human Care ] at paras 60-61 ; Pollard Banknote Limited v BABN Technologies Corp , 2016 FC 883 at para 215 .

The Court retains the discretion to admit evidence that is given in violation of rule 248. [ 59 ] In general, where a party seeks to introduce evidence that is perceived as being inconsistent with testimony given on discovery, the correct approach is to present the inconsistency to the witness through cross-examination: §16.178, Sidney N Lederman, Alan W Bryant and Michelle K Fuerst, ed, Sopinka, Lederman and Bryant: The Law of Evidence in Canada , 5 th ed (Toronto, LexisNexis Canada, 2018); JD Irving Limited v Siemens Canada Limited , 2016 FC 69 at para 43 . [ 60 ] PMS raises 14 objections under rules 232 and 248.

One of these objections is to an email that was not disclosed prior to Dr. Wenslow’s discovery or in response to undertakings. The email chain confirms the date certain experiments were conducted. This information is not controversial in light of the admission into evidence of other details relating to those experiments in documents that have been accepted as being admissible for the truth of their contents. As a result, I see no prejudice to admitting the document. [ 61 ] The remainder of the rule 248 objections fall into three groups.

The first group relate to subject matter that was not refused during discovery, but rather relate to statements that PMS perceives as being inconsistent. These are not appropriate for a rule 248 objection. The second group are based on refusals to very specific points that have only a tenuous connection to the evidence being objected to. The third group relate to objections that lack foundation or were not sufficiently particularized in PMS’ submissions. [ 62 ] In addition to the formal objections raised to Dr. Wenslow’s evidence, PMS also seeks an adverse credibility finding against Dr. Wenslow.

It asserts that this finding is separate and distinct from the issue of admissibility, yet sits " “hand in glove” " with these admissibility objections. It argues that Dr. Wenslow has not acknowledged that his evidence is grounded in hearsay and that his affidavit is based on information and belief.

Pursuant to Rule 81(2) of the Federal Courts Rules , PMS asserts that an adverse inference must be drawn as Merck has not provided evidence from persons having personal knowledge of material facts. [ 63 ] While evidence was not provided by those who conducted the experiments, as set out earlier in my decision, in most instances I consider Dr. Wenslow to have sufficient knowledge through his interaction within the DPP-IV development team to be able to provide the evidence given.

Such evidence outlines the invention story supported by the contemporaneous documents, accepted as being admissible for the truth of their contents. I find such evidence to be credible and any elaborations given shall be addressed through weight. III. Issues [ 64 ] The following issues were identified in the parties’ Joint Statement of Issues as being those in dispute for this action: A . Obviousness: As of the claim date (June 24, 2003), would the subject matter defined by the Asserted Claims have been obvious and/or obvious to try to a PSA? B .

Insufficiency: Does the 400 Patent satisfy the requirements of subsections 27(3) (

a) and (

b) of the Patent Act , R.S.C., 1985, c. P-4 (the Patent Act) ? [ 65 ] In addition to these issues raised by the parties, and before determining the validity of the 400 Patent, the Court must construe the Asserted Claims of the 400 Patent. In order to do so, the Court must put the 400 Patent in context by determining whether it is a selection patent and by defining the PSA of the 400 Patent. IV. The 400 Patent [ 66 ] The 400 Patent is entitled “Phosphoric Acid Salt of a Dipeptidyl Peptidase-IV Inhibitor”.

It is the national phase entry of a PCT application filed on June 18, 2004 based on a US priority patent application, filed June 24, 2003. The 400 Patent will expire on June 18, 2024. [ 67 ] The Field of the Invention, at page 1 of the 400 Patent, states that the invention of the 400 Patent relates to the DHP salt of the compound 4-oxo-4-[3-(trifuoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3- a ]pyrazin-7(8 H )-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine, now known as sitagliptin, which is a potent inhibitor of DPP-4.

It explains that the DHP salt and its crystalline hydrates are useful for the treatment and prevention of diseases and conditions for which an inhibitor of DPP-4 is indicated, in particular type 2 diabetes, obesity and high blood pressure. It also states that the invention further concerns pharmaceutical compositions comprising the salt and crystalline hydrates and processes for preparing them. [ 68 ] The Background to the 400 Patent refers to several articles relating to DPP-4 inhibition for the treatment of type 2 diabetes.

It also refers to Merck & Co’s prior patent application WO498 as disclosing a class of compounds that are potent inhibitors of DPP-4 and to the disclosure of 4-oxo-4-[3-(trifuoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3- a ]pyrazin-7(8 H )-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine within this class.

[ 69 ] The

summary of the invention characterizes the invention as the DHP salt of 4-oxo-4-[3-(trifuoromethyl)-5,6- dihydro[1,2,4]triazolo[4,3- a ]pyrazin-7(8 H )-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine and its crystalline hydrates; in particular, the crystalline monohydrate. It explains that the DHP salt and crystalline hydrates have advantages in the preparation of pharmaceutical compositions, such as " “ease of processing handling, and dosing” " .

They also exhibit “ " improved physical and chemical stability, such as stability to stress, high temperatures and humidity, as well as improved physicochemical properties, such as solubility and rate of solution” " , which make them particularly suitable for pharmaceutical dosage forms. The

section states that the invention further concerns " “pharmaceutical compositions containing the novel salt and hydrates as well as methods for using them as DP-IV inhibitors, in particular for the prevention or treatment of Type 2 diabetes, obesity, and high blood pressure.” " [ 70 ] The Detailed Description includes as structural formulas (I), (II) and (III) respectively, depictions of the monobasic DHP salt of 4- oxo-4-[3-(trifuoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3- a ]pyrazin-7(8 H )-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine in its racemic, R - enantiomer and S -enantiomer forms. [ 71 ] The 400 Patent teaches that the monobasic DHP salt of 4-oxo-4-[3-(trifuoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3- a ]pyrazin-7(8 H )- yl]-1-(2,4,5-trifluorophenyl)butan-2-amine is a 1:1 salt with one molar equivalent of mono-protonated compound to one molar equivalent of DHP anion.

It also teaches that the salts of the compounds of each of formulas (I), (II) and (III) can be crystalline monohydrates.

The crystalline monohydrate of the R -enantiomeric form (structural formula (II)) of sitagliptin DHP salt is the form of the medicine used in JANUVIA®. [ 72 ] The 400 Patent teaches that the DHP salt of structural formulas (I) – (III) in its crystalline monohydrate form can act as an active pharmaceutical ingredient and exhibits pharmaceutic advantages and enhanced chemical and physical stability over the free base and hydrochloride salt previously disclosed in WO498, in the preparation of a pharmaceutical drug product containing the pharmacologically active ingredient. [ 73 ] Page 6 of the 400 Patent teaches how pharmaceutical compositions of the invention may be administered to patients.

The 400 Patent notes that the dosage regimen is to be selected considering the " “type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; and the renal and hepatic function of the patient” " (page 6, lines 3-5). It notes that the " “skilled physician, veterinarian, or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition” " (page 6, lines 5-7).

The 400 Patent goes on to provide general guidance as to the various dosage ranges for tablet and intravenous [IV] administration, noting that intranasal and transdermal administration is also possible (page 6, lines 8-22). [ 74 ] It describes dosage forms of the compositions and provides examples, at pages 18 and 19, of the DHP salt of sitagliptin monohydrate formulated as a tablet by direct compression and roller compaction and as an IV formulation. The 400 Patent notes that the DHP salt of sitagliptin monohydrate of structural formula (

I) has high solubility in water (72 mg/mL) making it especially amendable to the preparation of formulations. [ 75 ] The 400 Patent teaches that the DHP salt exhibits potent DPP-4 inhibitory properties, useful for the prevention and treatment of type 2 diabetes, obesity and high blood pressure. [ 76 ] The 400 Patent outlines general methods for crystallizing the monohydrate of the DHP salt of structural formula (

I) and provides more detailed instructions for preparing the crystalline monohydrate of structural formula (II). It also includes structural characterization spectra (XRPD, NMR, TGA and DSC) for the crystalline monohydrate of structural formula (II). A.

Is the 400 Patent a Selection Patent? [ 77 ] A selection patent is a patent devoted to the selection of a particular compound, or compounds, from a larger grouping of compounds previously disclosed in general terms and claimed in a pre-existing genus patent: Apotex Inc v Shire LLC , 2021 FCA 52 [ Shire ] at para 31 . [ 78 ] As set out in Apotex v Sanofi , 2008 SCC 61 [ Sanofi ] at paragraph 10 , three conditions must be satisfied for there to be a selection patent: 1. There must be a substantial advantage to be secured or disadvantage to be avoided by the use of the selected members. 2.

The whole of the selected members (subject to “a few exceptions here and there”) possess the advantage in question. 3. The selection must be in respect of a quality of a special character peculiar to the selected group. If further research revealed a small number of unselected compounds possessing the same advantage, that would not invalidate the selection patent.

However, if research showed that a larger number of unselected compounds possessed the same advantage, the quality of the compound claimed in the selection patent would not be of a special character. [ 79 ] Where the patent is a selection patent, the asserted advantage or nature of the characteristic possessed by the selected group must be stated in the specification in clear terms: Eli Lilly Canada Inc v Novopharm Limited , 2010 FCA 197 [ Eli Lilly ] at para 78 ; Sanofi at para 114 .

Such disclosure serves to define the characteristic features of the inventive compounds that purport to distinguish them over other compounds in the genus. [ 80 ] The classification of a patent as a selection patent serves to assist the Court in understanding " “the nature of the beast” " it is dealing with ( Shire at para 33 ; Eli Lilly at para 28 ) for the purpose of the Court’s analysis of validity. The classification contextualizes the patent and makes it easier to compare the facts of the particular case before the court with other previous fact scenarios: Shire at para 33 ; Eli Lilly at paras 27-28 .

However, the validity analysis and the requirements for a valid patent stay the same, whether the patent is a selection patent or not: Shire at para 34 ; Eli Lilly at paras 33-34 . The finding that the characteristics of a selection patent have or have not been met does not constitute an independent basis upon which to attack the validity of the patent: Shire at para 32 ; Eli Lilly at paras 27-

28, 33, 48 . [ 81 ] PMS raises a preliminary objection to the characterization of the 400 Patent as a selection patent. It asserts that Merck is prohibited from raising this characterization because it was not expressly in Merck’s pleadings. I do not find this argument persuasive. [ 82 ] PMS raised the issue of selection patents in its Statement of Defence, where it pleaded that if the Plaintiffs assert that the 400 Patent is a selection patent, such framework does not " “save the 400 Patent.” " Merck traversed this allegation in its Reply.

It is clear that PMS has not been " “caught by surprise” " by any assertion that the 400 Patent is a selection patent. In any event, there has been no claim that the 400 Patent is " “saved” " by recourse to the law of selection patents. As acknowledged by Merck, the same rules of validity still apply. Both parties assert that the obviousness analysis does not turn on whether the 400 Patent is characterized as a selection patent.

Nonetheless, the Court must determine the " “nature of the beast” " in order to provide context for its validity analysis. [ 83 ] In this case, the 400 Patent refers to the compound 4-oxo-4-[3-(trifuoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3- a ]pyrazin-7(8 H )-yl]- 1-(2,4,5-trifluorophenyl)butan-2-amine, now know as sitagliptin, as being disclosed within the genus of compounds in WO498, and as to its pharmaceutically acceptable salts being generically encompassed within the scope of WO498, without specific disclosure of the DHP salt of sitagliptin (structural formula I).

As stated in the Background to the Invention, at page 1: WO 03/004498 (published 16 January 2003), assigned to Merck & Co, describes a class of beta-amino tetrahydrotriazolo[4,3- a ]pyrazines, which are potent inhibitors of DP-IV and therefore useful for the treatment of Type 2 diabetes. Specifically disclosed in WO 03/004498 is 4-oxo-4-[3-(trifuoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3- a ]pyrazin- 7(8 H )-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine. Pharmaceutically acceptable salts of this compound are generically encompassed within the scope of WO 03/004498.

However, there is no specific disclosure in the above reference of the newly discovered monobasic dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3- a ]pyrazin-7(8 H )-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine of structural formula I below. [ 84 ] WO498 exemplifies the compound now known as sitagliptin as one of 33 examples specifically disclosed within the application.

It discloses a process for making sitagliptin and its hydrochloride salt and claims the compound, together with the 33 compounds exemplified and their pharmaceutically acceptable salts, in a separate claim of the application. [ 85 ] WO498 refers to phosphoric acid as being one of the eight particularly preferred pharmaceutically acceptable non-toxic acids that may be used to prepare a salt with the basic compounds of WO498, which would include sitagliptin (page 10, lines 14-25). [ 86 ] Similarly, WO498 refers to the salts prepared from the genus of compounds as being in the solid form and states that they " “may exist in more than one crystal structure” " and " “may be in the form of hydrates” " (page 9, lines 32-34). [ 87 ] It is clear that the DHP salt of sitagliptin and the monohydrate are generically encompassed within WO498, but not specifically exemplified or claimed.

Indeed, the 400 Patent refers to the DHP salt and crystalline monohydrate as being " “newly discovered” and novel " . [ 88 ] The 400 Patent asserts that the crystalline DHP salt of sitagliptin has pharmaceutical advantages over the sitagliptin free base and hydrochloride salt in WO498; in particular, enhanced chemical and physical stability, which provide advantageous properties in preparing solid pharmaceutical dosage forms.

At stated at page 4, lines 26-34 of the 400 Patent: The crystalline dihydrogenphosphate salt of the present invention exhibits pharmaceutic advantages over the free base and the previously disclosed hydrochloride salt (WO 03/004498) in the preparation of a pharmaceutical drug product containing the pharmacologically active ingredient. In particular, the enhanced chemical and physical stability of the crystalline dihydrogenphosphate salt monohydrate constitute advantageous properties in the preparation of solid pharmaceutical dosage forms containing the pharmacologically active ingredient.

The dihydrogenphosphate salt of the present invention, which exhibits potent DP-IV inhibitory properties, is particularly useful for the prevention or treatment of Type 2 diabetes, obesity, and high blood pressure. [ 89 ] As explained by Dr. Wuest, enhanced chemical stability would be understood by the PSA to mean that there is reduced chemical degradation/decomposition when sitagliptin is prepared and formulated into a medicine using the crystalline monohydrate DHP salt; thus, ensuring that its therapeutic effect is beneficially maintained.

Enhanced physical stability means that the crystalline monohydrate DHP salt does not readily convert to other physical forms that might have unknown or undesirable properties. The physical stability is also shown in the TGA and DSC analyses at Figures 4 and 5, which demonstrate the high thermal stability of the crystalline monohydrate (Wuest Report, Ex 29, paras 22, 51-53). [ 90 ] The 400 Patent, at page 7, lines 10-11, also states that the crystalline monohydrate has " “high solubility in water” " , with a solubility of about 72 mg/mL. I accept Dr.

Davies’ explanation that this reference refers to the solubility classification under the Biopharmaceutics Classification System [BCS] and would be understood to be indicating the solubility in light of intended dose. Under the BCS, a " “highly soluble” " drug is one where the highest dose is soluble in 250 mL of dissolution medium.

The high solubility of the monohydrate indicates that the monohydrate is especially suitable for formulation without the need for dissolution enhancing techniques (Davies Report, Ex 42, paras 44-46, 48). [ 91 ] The only comparison made in the 400 Patent is between the DHP salt of sitagliptin crystalline monohydrate and the sitagliptin free base and hydrochloride salt. [ 92 ] The 400 Patent is not devoted, as described in Shire , to the selection of sitagliptin over the other compounds of WO498. Nonetheless, the PSA would understand that a selection of sitagliptin has taken place. Dr.

Wuest explained this further on cross- examination as follows (TT V6, P:497 L:12-P:498 L:21):

Q. Okay. Let’s go to the

section of the patent that’s entitled “Summary of the Invention,” which is on the next page. Under the heading “The

Summary of the Invention”, it states: “The present invention is concerned with a novel dihydrogen phosphate salt of the DP-IV inhibitor sitagliptinand crystal hydrates thereof, in particular a crystalline monohydrate.” You’ll agree with me, Dr. Wuest, there’s nothing here telling the reader that the invention is about discovering sitagliptin orsitagliptin’s ability to inhibit DP-IV. A. It would be clear from reading this particular

section by someone of with [sic] skill in this art that this particularcompound and its salts and the crystalline forms thereof have been selected through a process. So there is a step that’s beentaken from the prior art to the new art in the 400 patent; namely, that there is now been placed a focus on sitagliptin and itssalts. Q. It doesn’t say that, though, does it? Does it say anything here about selecting sitagliptin from the prior art? It doesn’t saythat here. It talks about a novel salt form and a novel hydrate form. A. I’m not sure I understand how you can maintain that.

I’m looking at this from the perspective of the skilled person whohas the 400 patent in front of them and knowledge of the prior art. That knowledge would include the knowledge thatsitagliptin and its hydrochloride salt [are] in the 498 application. And so the issue that -- is how you would get from that to where of this

summary -- this situation that is described in thissummary. So there’s clearly a selection of that particular compound because this describes a new salt of that particularcompound. Q. When you say “of that particular compound,” you meant sitagliptin? A. That’s right. [93] The 400 Patent gives no reason for honing in on sitagliptin over the other compounds disclosed within WO498. However, it relieson this choice for the further development work disclosed in the patent. As acknowledged by Dr.

Hollingsworth, the PSA knew from the400 Patent that Merck had selected sitagliptin as its lead compound for further development, and had successfully made the DHP saltand identified the crystalline monohydrate as being amenable to sitagliptin formulations (TT V3, P:281 L:4-28).

The PSA knew that thesolubility, and relative stability of the DHP salt of sitagliptin crystalline monohydrate had been determined and had been selected oversitagliptin free base and the hydrochloride salt (TT V3, P:281 L:10-15; P:282 L:3-8). [94] This is no different than Sanofi where the genus patent exemplified the racemate of the compound, but did not specifically disclosethe dextro-rotatory isomer of the racemate, or the advantages of using the bisulfate salt in combination with the dextro-rotatory isomer,which were the subject matter of the later selection patent. [95] There is no explanation as to why sitagliptin was chosen for further development.

However, the fact that there has been a selectionof a particular salt and crystalline form of a particular compound from the genus of compounds, salts and crystalline forms encompassedwithin WO498, and that the particular salt and crystalline form are said to have advantages over sitagliptin free base and itshydrochloride salt, which are disclosed in WO498, in my view favours the 400 Patent being considered a selection patent. Whether theproposed invention of the 400 Patent is inventive over WO498 and whether the disclosure of the 400 Patent is sufficient is a matter to bedealt with separately below. B.

Claims Construction [96] The principles of claim construction were summarized by the Federal Court of Appeal [FCA] in Tearlab Corporation v I-MedPharma Inc., 2019 FCA 179 at paragraphs 30 to 34: [30] The general principles of claim construction are now well established and were set out by the Supreme Court in threecases (Whirlpool at paras. 49-55; Free World Trust v. Électro Santé Inc., 2000 SCC 66, [2000] 2 S.C.R. 1024 at paras. 31-67[Free World Trust]; Consolboard Inc. v. MacMillan Bloedel (Sask.) Ltd., (SCC), [1981] 1 S.C.R. 504 at p.520 [Consolboard]).

These principles can be summarized as follows. [31] The Patent Act promotes adherence to the language of the claims, which in turn promotes fairness and predictability(Free World Trust at paras. 31(a), (

b) and 41). The words of the claims must, however, be read in an informed and purposiveway (at para. 31(c)), with a mind willing to understand (at para. 44). On a purposive construction, it will be apparent thatsome elements of the claimed invention are essential while others are non-essential (at para. 31(e)).

The interpretative taskof the court, in claim construction, is to separate and distinguish between the essential and the non-essential elements, and togive the legal protection to which the holder of a valid patent is entitled only to the essential elements (at para. 15). [32] To identify these elements, the claim language must be read through the eyes of a POSITA, in light of the latter’scommon general knowledge (Free World Trust at paras. 44-45; see also Frac Shack at para. 60; Whirlpool at para. 53).

Asnoted in Free World Trust: [51] …The words chosen by the inventor will be read in the sense the inventor is presumed to have intended,and in a way that is sympathetic to accomplishment of the inventor’s purpose expressed or implicit in the text ofthe claims. However, if the inventor has misspoken or otherwise created an unnecessary or troublesomelimitation in the claims, it is a self-inflicted wound. The public is entitled to rely on the words used provided the

words used are interpreted fairly and knowledgeably. [Emphasis in the original.] [33] Claim construction requires that the disclosure and the claims be looked at as a whole “to ascertain the nature of the invention and methods of its performance, … being neither benevolent nor harsh, but rather seeking a construction which is reasonable and fair to both patentee and public” ( Consolboard at p. 520; see also Teva Canada Ltd. v. Pfizer Canada Inc ., 2012 SCC 60 , [2012] 3 S.C.R. 625 at para. 50 ). Consideration can thus be given to the patent specifications to understand what was meant by the words in the claims.

One must be wary, however, not to use these so as “to enlarge or contract the scope of the claim as written and … understood” ( Whirlpool at para. 52; see also Free World Trust at para. 32 ). The Supreme Court recently emphasized that the focus of the validity analysis will be on the claims; specifications will be relevant where there is ambiguity in the claims ( AstraZeneca Canada Inc. v.

Apotex Inc ., 2017 SCC 36 , [2017] 1 S.C.R. 943 at para. 31 ; see also Ciba at paras. 74-75). [34] Finally, it is important to stress that claim construction must be the same for the purpose of validity and for the purpose of infringement ( Whirlpool at para. 49(b)). [ 97 ] The 400 Patent is to be construed from the viewpoint of the PSA to which it pertains as of its publication date, January 13, 2005.

(1) PSA of the 400 Patent [ 98 ] The PSA is the hypothetical person to whom the patent is addressed. This may be a single individual or a team of individuals representing different disciplines, depending on the nature of the invention.

The PSA is deemed to be unimaginative and uninventive, but at the same time is understood to have an ordinary level of competence and knowledge incidental to the field to which the patent relates and to be reasonably diligent in keeping up with advances: Merck & Co v Pharmascience Inc , 2010 FC 510 [ Merck ] at para 35-36 , 39; Teva Canada Limited v Janssen Inc , 2018 FC 754 , at paras 65-66 , aff’d 2019 FCA 273 . [ 99 ] While the experts agreed that the PSA is a team of individuals, PMS’ experts assert that the team is limited to those that would be involved in the steps of pharmaceutical development that bridge the gap between the active pharmaceutical ingredient [API] and finished dosage form; that is, an analytical chemist, process chemist and formulator.

Merck’s experts do not disagree that the team comprising the PSA would include a chemist, or chemists, with knowledge of analytical techniques and processing, but also assert that the PSA would include a medicinal chemist and a medical doctor as the invention involves the selection of sitagliptin and its use as a DPP-4 inhibitor. [ 100 ] As set out above, I agree that the 400 Patent requires that a selection of sitagliptin has taken place. However, that does not mean that it must follow that the patent is directed to a medicinal chemist.

The determination of the PSA involves consideration as to who would have an interest in the teachings of the patent. [ 101 ] The 400 Patent does not disclose the type of studies or data that would be characteristically of interest to the medicinal chemist, such as SAR studies or IC 50 values. The 400 Patent does not describe the process involved in selecting sitagliptin over the other compounds of WO498, including over the free base and hydrochloride salt exemplified within WO498.

Rather, it is directed to the identification of the DHP salt of sitagliptin and its crystalline monohydrate with its purported advantageous properties. While I would agree that someone on the skilled team would need to have a general understanding as to how to get from WO498 to the teachings of the 400 Patent, in my view this does not require that the team of individuals that comprise the PSA include a separate medicinal chemist. Rather, it would be sufficient for one of the members of the team to have some general background knowledge of medicinal chemistry and/or lead compound identification.

Indeed, I note that even PMS considered it important to have an expert who could speak to lead compound identification as part of its case – i.e., Dr. Foley. [ 102 ] In my view, the team of individuals that comprises the PSA would also include a clinician or someone with knowledge of the treatment of type 2 diabetes. Both the Field of the Invention and the

Summary of the Invention refer to the use of the DHP salt of sitagliptin crystalline monohydrate for the treatment and prevention of type 2 diabetes and other diseases and conditions for which an inhibitor of DPP-4 is indicated. It also refers to the use of the DHP salt of sitagliptin crystalline monohydrate in pharmaceutical compositions to treat patients with these conditions as being part of the invention.

Indeed, Claims 22 and 26 are directed to such uses. [ 103 ] Page 6, lines 5-7 of the 400 Patent states that an " “ordinarily skilled physician, veterinarian, or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition” " . Drs. Elitzin and Foley state that this passage makes clear that a different skilled person was intended to deal with the dosing regimen for the drug than the skilled person to whom the patent is directed.

However, I prefer the evidence of Merck’s experts on this passage. [ 104 ] As set out in Merck , a patent may be directed to different persons, each having a different interest ( Merck at para 39 ). [ 105 ] I accept the evidence of Dr. Lewanczuk that page 6 is indicating that this part of the patent’s teachings - i.e., dosing regimen and therapeutic use - is directed to the skilled clinician as opposed to other members of the team that comprise the PSA (Lewanczuk Report, Ex 55, paras 104-109). [ 106 ] Notably, despite his arguments that a skilled clinician would not be included as a member of the PSA, Dr.

Foley testified to the importance of the clinician in evaluating aspects of the patent. As acknowledged by Dr. Foley, it is the clinician who would be keeping up with the literature and patent filings pertaining to DPP-4 inhibitors, and it is the clinician who would have appreciated whether there was any therapeutic advantage being described in the 400 Patent relating to the monohydrate or DHP salt of sitagliptin over what had been described in WO498 (TT V1, P:53 L:20-P:54 L:8). [ 107 ] Indeed, each of Drs.

Foley and Lewanczuk provided useful insight as to the skilled clinician’s understanding of those portions of the 400 Patent dealing with the use of the monohydrate. Dr. Foley was asked to speak to claims 22 and 26 of the 400 Patent and to the prior art landscape involving clinical studies using DPP-4 inhibitors. PMS relies heavily on Dr. Foley’s testimony relating to his understanding and

interpretation of these claims.

[ 108 ] When asked about this in oral argument, PMS asserted that Dr. Foley’s evidence was only intended to provide background on the invention story.

However, this response runs contrary to the mandate set out in the Foley Report and to his opinions, which speak directly to the obviousness analysis. [ 109 ] In my view, the PSA would include someone with clinical knowledge of the treatment of patients with type 2 diabetes, who could be a medical doctor and/or someone who has acquired this knowledge through experience on a clinical team. [ 110 ] Accordingly, I find that the PSA would include a chemist with experience in compound characterization and processing, and some general background knowledge of medicinal chemistry and/or lead compound identification.

This could be one individual with this skill- set or separate analytical and process chemists. The team would also include a formulator, and a clinician or individual with clinical knowledge of the treatment of patients with type 2 diabetes. [ 111 ] While the experts were not entirely at idem as to the experience of the members of the team comprising the PSA, they appeared to consistently agree that the members of the team could have a Bachelor’s, Master’s or Ph.D., depending on the years of supplemental experience.

The number of years needed would be greater for someone with a Master’s degree and greater still for someone with a Bachelor’s degree. All experts agreed that at least one year of experience would be required for a member of the team, even if holding a Ph.D.

(2) Construction of the Asserted Claims of the 400 Patent [ 112 ] The 400 Patent includes 27 claims, nine of which are in issue for this action: claims 4-7, 19, 20, 22, 24 and 26. The parties are in general agreement as to the construction to be given to these claims. [ 113 ] Claims 4-7, 19, 20, 22, 24 and 26 of the 400 Patent read as follows: 4. The salt of Claim 2 characterized in being a crystalline monohydrate. 5. The salt of Claim 4 characterized by characteristic absorption bands obtained from the X-ray powder diffraction pattern at spectral d-spacings of 7.42, 5.48, 3.96 angstroms. 6.

The salt of Claim 5 further characterized by characteristic absorption bands obtained from the X-ray powder diffraction pattern at spectral d-spacings of 6.30, 4.75, and 4.48 angstroms. 7. The salt of Claim 6 further characterized by characteristic absorption bands obtained from the X-ray powder diffraction pattern at spectral d-spacings of 5.85, 5.21 and 3.52 angstroms. 19.

A process for preparing the salt of Claim 1 comprising the step of contacting one equivalent of 4-oxo-4-[3- (trifluoromethyl)-5,6-didydro[1,2,4]triazolo[4,3- a ]pyrazin-7(8 H )-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine in an organic solvent or aqueous organic solvent with about a one equivalent of phosphoric acid at a temperature in the range of about 25- 100 o C. 20. The process of Claim 19 wherein said organic solvent is a C 1 -C 5 linear or branched alkanol. 22. Use of the salt of Claim 4 as active ingredient in the manufacture of a medicament for use in the treatment of type 2 diabetes. 24.

The process for preparing the crystalline monohydrate of Claim 4 comprising the steps of: (

a) crystallizing said dihydrogenphosphate salt of Claim 1 at 25 o C from a mixture of isopropanol and water, such that the water concentration is above 6.8 weight percent; (

b) recovering the resultant solid phase; and (

c) removing the solvent therefrom. 26. A use of a therapeutically effective amount of the salt according to Claim 4 for the treatment of type 2 diabetes in a patient in need of such treatment. [ 114 ] Claim 4 is a dependent claim, which stems from Claim 2 of the 400 Patent, which itself depends from Claim 1. [ 115 ] Claim 1 is directed to the DHP salt of sitagliptin and its hydrate, without any specific stereochemistry: 1. A dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-didydro[1,2,4]triazolo[4,3- a ]pyrazin-7(8 H )-yl]-1-(2,4,5- trifluorophenyl)butan-2-amine of structural formula 1:

or a pharmaceutically acceptable hydrate thereof. [ 116 ] Claim 2 is directed to the R -enantiomer of the DHP salt of sitagliptin and its hydrate: 2. The salt of Claim 1 of structural formula II having the ( R )-configuration at the chiral center marked with an * [ 117 ] It is understood from these dependencies that Claim 4 (and all claims that depend from claim 4) claim the R -enantiomer of the DHP salt of sitagliptin in its crystalline monohydrate form. [ 118 ] Claims 5-7 include characterization data arising from the XRPD spectra for the crystalline monohydrate form.

The PSA would know that the d -spacings arise from the formulaic conversion of the 2θ values of the crystalline form as obtained through calculation using Bragg’s law: nλ=2 d sinθ (Hollingsworth Report, Ex 68, para 143). [ 119 ] Claims 19 and 20 set out general methods for preparing the non-stereospecific DHP salt of sitagliptin monohydrate. Through the process description, it is understood that about one molar equivalent of phosphoric acid should be reacted with about one molar equivalent of free base.

Claim 20 specifies that the organic solvent is a C 1 -C 5 linear or branched alkanol. [ 120 ] Claim 24 provides a process for making the R -enantiomer of the DHP salt of sitagliptin in its crystalline monohydrate form. The PSA would understand that this process does not specify its starting materials (TT V3, Conf, P:58 L:15-P:59: L:6), but only requires that crystallization occur from the DHP salt at a temperature of 25 o C using a mixture of isopropanol and water, such that the water concentration is above 6.8 weight percent. The process also requires that the crystals be recovered and the solvent removed.

The process does not specify the process for solvent removal (TT V3, P:309 L:8-17). [ 121 ] The PSA would understand from the teachings of the 400 Patent that the crystalline monohydrate is vulnerable to conversion to its dehydrated (anhydrous) form if heated to above 40 o C under very dry nitrogen flow and that it will convert back from the anhydrous form to the monohydrate under ambient conditions (page 18, lines 5-8 of the 400 Patent) (TT V2, P:223 L:17-21; TT V2, Conf, P:41 L:2-7; TT V3, P:311 L:16-24; TT V6, P:523 L:4-13).

The skilled person would understand that ambient conditions would be room temperature. [ 122 ] Claims 22 and 26 are directed to the therapeutic use of the DHP salt of sitagliptin crystalline monohydrate. Claim 22 claims the use of the DHP salt of sitagliptin crystalline monohydrate as the active ingredient in the manufacture of a medicament to treat type 2 diabetes. Claim 26 claims the use of a therapeutically effective amount of the DHP salt of sitagliptin crystalline monohydrate for treating a patient with type 2 diabetes. No specific dose is claimed. As explained by Dr.

Lewanczuk, the PSA would understand a " “therapeutically effective amount” " to mean an amount of the claimed compound that effectively contributes to improving the patient’s glycemic control by lowering blood glucose levels (Lewanczuk, Ex 55, para 111). V. Obviousness A. Legal Principles [ 123 ]

Section 28.3 of the Patent Act provides that the subject matter of a claim in an application for a patent in Canada must be subject matter that would not have been obvious on the claim date (here, June 24, 2003) to the PSA, having regard to information that was made available to the public: (

a) more than one year before the filing day by the applicant, or by a person who obtained knowledge directly or indirectly from the applicant; and, (

b) before the claim date, by a person not mentioned in (a). [ 124 ] Obviousness is a difficult test to satisfy because it necessitates showing that the PSA would have come directly and without difficulty to the invention, without the benefit of hindsight: Bridgeview Manufacturing Inc v 931409 Alberta Ltd (cob Central Alberta Hay Centre) , 2010 FCA 188 at para 50 . [ 125 ] The Supreme Court of Canada in Sanofi set out a four-step approach to the obviousness analysis at paragraph 67 of its decision, as follows : (1) (

a) Identify the notional “person skilled in the art”; (

b) Identify the relevant common general knowledge of that person;

(2) Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;

(3) Identify what, if any, differences exist between the matter cited as forming part of the “state of the art” and the inventive concept of the claim or the claim as construed;

(4) Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?

[ 126 ] In areas of endeavour where advances are often won by experimentation, an " “obvious to try” " analysis may be appropriate to take into consideration at the fourth step of the obviousness inquiry. The critical question is whether it " “was more or less self-evident to try to obtain the invention” " having regard to the following factors, while noting that " “[m]ere possibility that something might turn up is not enough” " ( Sanofi at paras 66, 68-69 ): 1. Is it more or less self-evident that what is being tried ought to work?

Are there a finite number of identified predictable solutions known to persons skilled in the art? 2. What is the extent, nature and amount of effort required to achieve the invention? Are routine trials carried out or is the experimentation prolonged and arduous, such that the trials would not be considered routine? 3.

Is there a motive provided in the prior art to find the solution the patent addresses? [ 127 ] The Court must be cautious, however, when approaching the obvious to try analysis as it remains as only one factor amongst many that may assist in the obviousness inquiry: Bristol Myers Squibb Canada Co v Teva Canada Limited , 2017 FCA 76 [ Atazanavir ] at para 38 ; Sanofi at para 64 . It is not intended to displace other tests.

As the Supreme Court in Sanofi made clear, the Court favours " “an expansive and flexible approach that would include ‘any secondary considerations that [will] prove instructive’” " : Sanofi at para 63 ; Atazanavir at para 61 . B. Common General Knowledge [CGK] and Prior Art [ 128 ] The reference for the test for obviousness is the PSA. After identifying the credentials and characteristics of the PSA (as done earlier in these reasons), the next step is to identify the CGK of the PSA.

CGK means knowledge generally known by the PSA at the relevant time ( Sanofi at para 37 ), in this case June 24, 2003. [ 129 ] CGK is to be distinguished from the prior art, which is a broad category encompassing all previously disclosed information in the field. CGK includes knowledge of patents, but does not include knowledge of all patents; nor does it include knowledge of all journal articles or other technical information.

It is the subset of patents, journal articles and technical information of which the PSA has become generally aware and which has been accepted: Eurocopter v Bell Helicopter Textron Canada Ltée , 2013 FCA 219 [ Eurocopter ] at paras 64-65 ; Mylan Pharmaceuticals ULC v Eli Lilly Canada Inc ., 2016 FCA 119 at para 24 . [ 130 ] The parties differ on their positions as to what constitutes the CGK of the PSA and whether this would include general information pertaining to DPP-4 inhibitors and the treatment of type 2 diabetes in addition to CGK relating to salt formation and crystal form identification.

As I have already determined that the PSA would include someone with clinical knowledge, it is my view that CGK relating to DPP-4 inhibition and treatment of type 2 diabetes would be known to this PSA (TT V1, P:55 L:11-27). Indeed, the 400 Patent references this information as part of the relevant background to the invention.

(1) DPP-4 Inhibition and Treatment of Type 2 Diabetes [ 131 ] By 1997, type 2 diabetes was recognized as a serious disease condition that required medical attention to avoid long-term health risks. GLP-1 and its role in stimulating secretion of insulin had been identified. It was known that DPP-4 acted to degrade GLP-1 and that inhibiting DPP-4 could have effects on modulating insulin and glucose levels in the blood. [ 132 ] The 400 Patent acknowledges certain information known to the PSA as of June 24, 2003 regarding the inhibition of DPP-4 as an approach to treat type 2 diabetes.

As stated at page 1 of the 400 Patent: Inhibition of dipeptidyl peptidase-IV (DP-IV), an enzyme that inactivates both glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1), represents a novel approach to the treatment and prevention of Type 2 diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM). The therapeutic potential of DP-IV inhibitors for the treatment of Type 2 diabetes has been reviewed: C.F. Deacon and J.J.

Holst, “Didpeptidyl peptidase IV inhibition as an approach to the treatment and prevention of Type 2 diabetes: a historical perspective,” Biochem, Biophys. Res. Commun ., 294: 1-4 (2000); K. Augustyns, et al., “Didpeptidyl peptidase IV inhibitors as new therapeutic agents for the treatment of Type 2 diabetes,” Expert, Opin. Ther. Patents , 13: 499-510 (2003); and D.J. Drucker, “Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of Type 2 diabetes,” Expert Opin. Investig.

Drugs , 12: 87-100 (2003). [ 133 ] By admission of the patentee, through inclusion of these references in the background to the 400 Patent, the Deacon, Augustyns and Drucker papers form part of the relevant prior art: Shire Biochem Inc v Canada (Minister of Health) 2008 FC 538 at para 25 ; Eli Lilly Canada Inc v Novopharm Ltd , 2007 FC 596 at para 142 ; Pfizer Canada Inc v Novopharm Ltd , 2005 FC 1299 at para 78 .

These papers summarize the developments known in the field regarding compounds that had already shown DPP-4 inhibitory activity, including Probiodrug’s compound P32/98 and the Novartis compounds, DPP-728 and LAF-237. [ 134 ] As noted by Drs. Foley and Lewanczuk, P32/98 (depicted at paragraph 206 below) had already been tested for potency in animal studies (Foley Report, Ex 1,

Schedule E19) and was reported to enhance the insulin response and improve glucose tolerance in diabetic humans administered with a 60 mg single dose (Lewanczuk, Ex 55, para 102 and Appendix K). [ 135 ] It was also known that DPP-728 (depicted at paragraph 206 below) had shown activity in animal studies and some clinical efficacy in a 4-week Phase II study in humans (Foley Report, Ex 1, paras 30 and 54 and

Schedule E19; TT V1, P:55 L:11-27). The results of a study reported by Ahrén in 2002, showed the safety and tolerability of DPP-728, with only minimal adverse events. The study reported lower glucose levels in human patients without hypoglycemia when administered in 100 mg and 150 mg doses and identified inhibition by DPP-728 as a feasible treatment for type 2 diabetes (Foley Report, Ex 1, para 54(

f) and

Schedule E11; Lewanczuk, Ex 55, para 102). [ 136 ] Kinetic studies showed that DPP-728 did not function as a simple competitive inhibitor, but as a substrate for the DPP-4 catalytic site. A derivative of DPP-728 (LAF-237, depicted at paragraph 206 below), eventually known as vildagliptin, was developed by

Novartis to improve on the compound’s kinetics and dissociation rate (Foley Report, Ex 1,

Schedule E19). [ 137 ] In 2003, Villhauer reported on the in vivo efficacy of vildagliptin in rat models (Foley Report, Ex 1,

Schedule E17). Other in vivo work in monkeys also indicated that vildagliptin had a longer half-life in inhibiting DPP-4 than DPP-728, and might be suitable for a once-a-day treatment (Foley Report, E

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