Merck Sharp & Dohme Corp. v. Pharmascience Inc

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.

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Merck Canada Inc. is the “first person” in accordance with the PMNOC Regulations.

[2]

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.

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[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

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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.

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[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

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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.

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[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,

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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.

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[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.

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[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.

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[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.

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[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

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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.

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[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

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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.

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(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 the recognized

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 and reliable: Khelawon at paras 42; Coldwater First

Nation v Canada (Attorney General), 2019 FCA 292 [Coldwater] at para 48. A statement is

reliable if there is no real concern about whether the statement is true because of the

circumstances in which it was made, or if the circumstances allow its truth and accuracy to be

sufficiently tested (Khelawon at paras 61-63), such as if it is supported by contemporaneous

documentary evidence (Coldwater at para 49-50). Necessity is a flexible criterion and is not to be

equated with the unavailability of a witness: Khelawon at para 78; Coldwater at para 53. The

nature and practical exigencies of a proceeding can impact the evaluation of necessity

(Coldwater at paras 54-55), such as avoiding an impracticably large number of affidavits or

witnesses, and the resulting promotion of speed and efficiency (Coldwater at para 59; R v

Baldree, 2013 SCC 35 [Baldree] at para 72). One criterion may have an impact on the other

(Khelawon at paras 46 and 77) such that if the reliability of the impugned evidence is sufficiently

established, the necessity requirement can be relaxed (Baldree at para 72).

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[48] This modern approach to hearsay recognizes that evidence may be admissible from

departmental supervisors or individuals who take 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 of mind and reasoning processes. It asserts that

Dr. Wenslow had a limited supervisory role that is insufficient to allow him to testify broadly

about the conduct, activities, and events in Merck’s sitagliptin development process. It contends

that if Merck wanted this evidence 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 his supervisory 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 not hearsay and/or are admissible under the principled

approach to hearsay. I find that Dr. Wenslow’s role within the team was such that he functioned

in a larger supervisory capacity that allows him to speak about many aspects of the team’s

experimental work. Moreover, as to reliability, the impugned statements generally refer to

information from documents that have already been accepted by PMS as being admissible for the

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truth of their contents without further proof, or which raise facts that have otherwise already been

admitted into evidence.

[52] As to necessity, it is difficult to reconcile the inconsistent position taken by PMS to agree

to accept Dr. Wenslow’s testimony as the only testimony of the invention story for the purpose

of discovery, while asserting it is now insufficient for trial. In some instances if PMS’ objections

were to prevail, they would result in PMS reading-in certain facts from discovery as its evidence,

while requiring Merck to introduce those same facts through additional witnesses. The PMNOC

Regulations seek to promote efficiencies and to avoid the impracticality of a large number of

affidavits or witnesses where such testimony is not required. The overly technical position taken

by PMS, splitting and parsing sentences, where the reliability of the impugned statements are

supported by contemporaneous documents or other 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 or opinions drawn from those facts: White Burgess Langille

Inman v Abbott and Haliburton Co, 2015 SCC 23 at para 14. This rule applies unless the witness

is in a better position than the trier of fact to form the conclusions made, the conclusions are ones

that a person of ordinary experience can make, the witness has the experiential capacity to make

the conclusions, or where giving opinions is a convenient mode of stating facts too subtle or

complicated to be narrated as facts: Toronto Real Estate Board v Commissioner of Competition,

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2017 FCA 236 at para 79. The line between fact and opinion is not always clear: Graat v The

Queen, [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 providing impermissible opinion evidence. PMS asserts that

Dr. Wenslow gives unhelpful, and potentially misleading opinion evidence that does not meet

the limited and narrow exceptions for a fact witness. Merck asserts that many of the alleged

objections relate to factual evidence regarding the observations and conclusions drawn by Merck

employees at the time. Merck argues that if any opinion evidence is provided, 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 team and are admissible for this purpose. While some

of the statements are technical in nature, this does not automatically negate the statements,

especially where such statements reflect the understanding of the development team at the time.

In some cases, Dr. Wenslow adds “gloss” to his description of events. However, in most cases

such comments are not of such a character that would mislead the Court or be prejudicial to PMS

and do not warrant the exclusion of the evidence. Such comments can most effectively be dealt

with by considering the weight to be given to the statement. With few exceptions, the objections

made in this category are dismissed.

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(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. To succeed on showing that evidence should be excluded

for relevance, the moving party must show that the evidence is “obviously irrelevant”: 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 of Merck’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

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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^thed (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

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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.

Page: 23

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(8H)-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(8H)-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(8H)-yl]-1-(2,4,5-

trifluorophenyl)butan-2-amine and its crystalline hydrates; in particular, the crystalline

Page: 24

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(8H)-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(8H)-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

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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.

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[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

Page: 27

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

Page: 28

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(8H)-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(8H)-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(8H)-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.

Page: 29

[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.

Page: 30

[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

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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

sitagliptin and 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

or sitagliptin’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 particular

compound and its salts and the crystalline forms thereof have been

selected through a process. So there is a step that’s been taken

from the prior art to the new art in the 400 patent; namely, that

there is now been placed a focus on sitagliptin and its salts.

Q.

It doesn’t say that, though, does it? Does it say

anything here about selecting sitagliptin from the prior art? It

doesn’t say that 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

who has the 400 patent in front of them and knowledge of the prior

art. That knowledge would include the knowledge that sitagliptin

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 this

summary. So there’s clearly a selection of that particular

compound because this describes a new salt of that particular

compound.

Q.

When you say “of that particular compound,” you

meant sitagliptin?

A.

That’s right.

Page: 32

[93] The 400 Patent gives no reason for honing in on sitagliptin over the other compounds

disclosed within WO498. However, it relies on this choice for the further development work

disclosed in the patent. As acknowledged by Dr. Hollingsworth, the PSA knew from the 400

Patent that Merck had selected sitagliptin as its lead compound for further development, and had

successfully made the DHP salt and identified the crystalline monohydrate as being amenable to

sitagliptin formulations (TT V3, P:281 L:4-28). The PSA knew that the solubility, and relative

stability of the DHP salt of sitagliptin crystalline monohydrate had been determined and had

been selected over sitagliptin 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 disclose the 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 selection of a particular salt and crystalline form of a

particular compound from the genus of compounds, salts and crystalline forms encompassed

within WO498, and that the particular salt and crystalline form are said to have advantages over

sitagliptin free base and its hydrochloride salt, which are disclosed in WO498, in my view

favours the 400 Patent being considered a selection patent. Whether the proposed invention of

the 400 Patent is inventive over WO498 and whether the disclosure of the 400 Patent is sufficient

is a matter to be dealt with separately below.

Page: 33

B.

Claims Construction

[96] The principles of claim construction were summarized by the Federal Court of Appeal

[FCA] in Tearlab Corporation v I-Med Pharma 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 three cases

(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.,

1981 CanLII 15 (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 purposive way (at para.

31(c)), with a mind willing to understand (at para. 44). On a

purposive construction, it will be apparent that some elements of

the claimed invention are essential while others are non-essential

(at para. 31(e)). The interpretative task of the court, in claim

construction, is to separate and distinguish between the essential

and the non-essential elements, and to give 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’s common

general knowledge (Free World Trust at paras. 44-45; see

also Frac Shack at para. 60; Whirlpool at para. 53). As noted

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 of the claims.

However, if the inventor has misspoken or

otherwise created an unnecessary or troublesome

limitation 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.]

Page: 34

[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.

Page: 35

[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 IC₅₀values. 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

Page: 36

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).

Page: 37

[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.

Page: 38

[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.

Page: 39

[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(8H)-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^oC.

20.

The process of Claim 19 wherein said organic solvent is a

C₁-C₅linear 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^oC from a mixture of isopropanol and water, such that the water

concentration is above 6.8 weight percent;

(b)

(c)

26.

recovering the resultant solid phase; and

removing the solvent therefrom.

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.

Page: 40

[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(8H)-

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.

Page: 41

[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=2dsinθ (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 C₁-C₅linear 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^oC 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^oC 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

Page: 42

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.

A.

Obviousness

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

Page: 43

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)

(b)

Identify the notional “person skilled in the art”;

Identify the relevant common general knowledge of

that person;

(2)

(3)

Identify the inventive concept of the claim in question or if

that cannot readily be done, construe it;

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?

Page: 44

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.

Page: 45

[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:

Page: 46

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).

Page: 47

[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, Ex 1, para 54(g)).

[138] As acknowledged by the 400 Patent, the PSA also would have known about WO498 and

about the class of compounds disclosed in WO498 as being putative inhibitors of DPP-4, with

the potential to be used in the treatment or prevention of diseases where DPP-4 is involved, such

as type 2 diabetes (Lewanczuk, Ex 55, at paras 115, 117, 121, 122). Dr. Foley testified that this

was the only document published by June 24, 2003 that included the compound now known as

sitagliptin (TT V1, P:61 L:17-23). It did not include any specific activity or efficacy data for any

of its compounds. As of June 2003 no results of any clinical evaluation from Merck had been

published on any of the compounds from WO498 (TT V1, P:56 L:17-27).

(2)

Salt Formation and Selection

[139] The PSA of the 400 Patent would also possess certain CGK relating to salt formation and

selection.

Page: 48

[140] It was undisputed by the experts that by June 24, 2003 standard high throughput

techniques for salt screening were known and used in the industry and allowed for numerous salt

forms to be screened at one time. The experts agreed that salt formation was expected to improve

the possibility of forming stable crystalline solids. However, they did not agree as to how salt

screening would be approached.

[141] Dr. Wuest’s view was that salt screening was an essential but iterative process. Citing

Gould and Stahl 2002 (which were also attached to Dr. Elitzin’s report) and the 1996 chapter on

“Salt Forms of Drugs and Absorption” in the Encyclopedia of Pharmaceutical Technology,

authored by Bighley, Berke and Monkhouse, Dr. Wuest stated that the first course of action for

drug development was to consider the free acid or free base form of the active compound. Only

if the free acid or free base was unacceptable for development would salt formation be necessary.

The first salt to be considered for a basic compound would typically be the hydrochloride salt

and only if that salt proved unacceptable would other mineral salts, such as phosphate, be

considered. Stahl highlighted that phosphate salts had a tendency to form hydrates, which

generally had lower solubility and slower dissolution rates than their corresponding anhydrous

forms.

[142] According to Dr. Elitzin, salt screening was a matter of routine by 2003 and took place at

the outset of every drug development program. He did not agree that consideration of the free

base would influence whether a salt screen was conducted, but referred in his report to initial

physicochemical characterization of the free acid or base API that would be used for comparison

purposes. His view was that hydrochloride salts would not necessarily be the first choice as it

Page: 49

was known that the solubility of hydrochloride salts could be impacted by the common ion effect

in gastric acid medium.

[143] Overall, I favour Dr. Wuest’s comments as they are supported by publications (and

authors) that Dr. Elitzin himself recognized as being authoritative and are also reflective of the

approach taken at Merck. The statistics referenced in Stahl 2002 indicated that by June 2003,

50% of all drugs on the market were in salt form, while the other 50% remained as the free

base/free acid. Of those basic drugs that were salts, more than half were hydrochloride salts.

Phosphate salts were pharmaceutically acceptable inorganic salts that ranked in the top five

preferred salts for basic drugs, although the number commercially made and sold by 2003 were

significantly less than hydrochloride salts.

[144] Both Dr. Wuest and Dr. Elitzin agreed with the statement made in Stahl 2002

(Hollingsworth Report, Ex 68, Schedule 26) that the selection of a salt form that exhibits the

desired pharmacological, toxicological and therapeutic properties was a multidisciplinary task of

varying complexity.

[145] Various analytical techniques were available for salt selection and involved

characterization of structural, physicochemical, and physical properties, as well as analysis of

impurities and stability studies.

Page: 50

(3)

Crystal Form Identification

[146] The parties’ experts generally agreed about the CGK regarding crystal form

identification, which can be summarized in the following paragraphs.

[147] By 2003, it was well-known that most pharmaceutical compounds demonstrated

polymorphism. Crystals incorporating water (i.e. hydrates) were common and it was known that

phosphate salts had a propensity to form hydrates.

[148] As summarized in the paper Byrn 1994 (Hollingsworth Report, Ex 68, Schedule E21 at

1148), which was accepted as being reflective of the CGK:

The mission of those working in the field of solid-state

pharmaceutical chemistry is to provide each drug in a solid form

that has optimum performance in a given application. Pursuit of

this mission requires recognition of several general, interrelated

points: (1) Drugs can exist in a number of solid forms, each having

different properties of pharmaceutical importance, including

stability and bioavailability; the number and properties of these

forms are largely unpredictable and vary considerably from case to

case. (2) The forms of a drug may interconvert under various

conditions. (3) Once a solid form is chosen for a product, methods

for analysis and control of the form must be devised.

[149] It was understood that the most thermodynamically stable form of a drug substance was

typically preferred for pharmaceutical development and it was a routine part of the

pre-formulation process to try to identify the most stable polymorphic form. By 1990, regulatory

guidelines existed for ensuring that companies filing regulatory submissions had investigated

polymorphism and identified what they considered to be the most stable crystalline form of their

API.

Page: 51

[150] By 2003, a variety of routine methods were available and known to the PSA to conduct

polymorph screening and to characterize the crystal forms obtained – i.e., XRPD, NMR, TGA,

DSC. A common strategy for screening included crystallization using a variety of solvents and

solvent mixtures. As stated in Bernstein 2002 (Hollingsworth Report, Ex 68, Schedule E7 at

page 252), another reference accepted as being reflective of the CGK:

Our understanding of the role and choice of solvent has improved

considerably and this information, combined with a knowledge of

zones of stability can aid in determining crystallization conditions

for obtaining metastable forms. In addition, there has also been

considerable progress in understanding and utilizing the interaction

of solvent with the growing crystal. Combining the detailed

structural information available from the single crystal structure

determinations of polymorphs with crystal morphological data (i.e.

crystal habit, and the orientation of molecules projecting from the

particular faces exposed) and with known intermolecular

interactions between solute molecules and solvent functional

groups allows the rational choice of solvent to select a particular

polymorphic form. [citations omitted]

[151] In addition to solvent choice, other factors identified in Byrn 1994 (Hollingsworth

Report, Ex 68, Schedule E21 at 1150), were known to influence crystallization, including

concentration or degree of supersaturation; temperature, including cooling rate and the cooling

profile; additives; seeds; pH; and agitation.

[152] Modelling programs existed for identifying plausible crystals forms; however, there was

no ability to predict which forms could be isolated. As explained in Bernstein 2002

(Hollingsworth Report, Ex 68, Schedule E7 at page 9):

The possibility of polymorphism may exist for any particular

compound, but the conditions required to prepare as yet unknown

polymorphs are by no means obvious....we are almost totally

ignorant about the properties to be expected from any new

polymorphs that might be obtained.

Page: 52

[153] Similarly, Byrn 1994 (Hollingsworth Report, Ex 68, Schedule E21 at page 1148) stated

the challenge faced by those in the field as follows:

... the chief challenge in managing the phenomenon of multiple

solid forms of drugs is our inability to predict how many forms can

be expected in a given case: too often costly delays are

encountered when a less soluble solid form suddenly appears late

in a development program.

[154] Further, it was known that different polymorphs could have markedly different

formulation properties, including rate of dissolution. The skilled formulator on the PSA team

was aware that a number of factors can influence the amount and rate at which a medicinal

ingredient gets absorbed into the body, including the inherent properties of the medicinal

ingredient, such as its solubility (Davies Report, Ex 42, para 29). The solubility of a drug

increases with temperature and can vary with pH. Most available drugs are poorly soluble,

which can translate to low bioavailability (the amount of drug absorbed into the bloodstream)

(Davies Report, Ex 42, para 38-39 and Schedule 1).

[155] The PSA knew from accepted references like Aulton 2002 and Stahl 2002 that hydrates

are typically (but not always) less soluble than anhydrous forms and have slower dissolution

rates (Davies Report, Ex 42, Schedule 1; Elitzin Report, Ex 66, Schedule E1). However, it was

not possible to predict the properties of any polymorph, or which would have the most

favourable properties for pharmaceutical development, in advance of discovering, making and

testing it in appropriate assays (Davies, Ex 42, para 56-57).

Page: 53

C.

What is the Starting Point of the Obviousness Analysis – “State of the Art”

[156] The obviousness analysis asks whether the distance between two points in the

development of the art can be bridged by the PSA using only their CGK: Atazanavir at para 65.

The first of the two points is the “state of the prior art” at the relevant date: Atazanavir at

para 65; Sanofi at para 67.

[157] PMS asserts that the state of the prior art is defined by the 400 Patent and should be

limited to the disclosure of sitagliptin and the hydrochloride salt of sitagliptin as a potent

inhibitor of DPP-4 and to its usefulness to treat type 2 diabetes. It relies on Ciba Specialty

Chemicals v SNF, 2017 FCA 225 [Ciba] at paragraph 60 as support for its assertion:

To conclude, a word about "the matter cited as forming part of the

prior art", the phrase used in Pozzoli and Plavix. The matter cited

as forming part of the prior art is simply the prior art relied upon

by the person alleging obviousness. Obviousness is not determined

by reference to the prior art at large. The person alleging

obviousness must point to one or more elements of prior art which

make the impugned invention obvious. The choice of those

elements of prior art is entirely in the hands of the party alleging

obviousness, limited only by section 28.3 of the Act which sets out

the cut-off date for opposable prior art. In fact, the challenger may

rely on a combination of pieces of prior art under the "mosaic"

theory of obviousness: Wenzel Downhole Tools Ltd. v. National-

Oilwell Canada Ltd., 2012 FCA 333 at paragraph 87, [2014] 2

F.C.R. 459.

[158] Merck asserts that the “state of the art” is the prior art at large, not just a single reference

in isolation. It asserts that this includes all of the prior art cited by Dr. Foley relating to P32/98,

DPP-728 and LAF-237 and by Dr. Roush from his prior art and literature search attached to his

report. Even if a medicinal chemist is not accepted as the PSA and Dr. Roush’s report is given

less weight, Merck asserts that the prior art would include at least WO498 in its entirety and the

Page: 54

Deacon, Augustyns and Drucker papers referenced in the 400 Patent, which summarized the

developments relating to P32/98, DPP-728 and LAF-237 and what was known about their DPP-4

inhibitory activity.

[159] Merck refers to Apotex Inc v Janssen Inc, 2021 FCA 45, which states at paragraph 25:

Apotex makes several arguments concerning legal principles

applicable to obviousness analysis. First, Apotex argues that

obviousness is to be assessed by asking whether the distance

between two points (the state of the art and the subject matter of

the claim in question) can be bridged by the POS. Apotex argues

that the second point (the subject matter of the claim) is to be

determined by reference to the language of the claim. This is

consistent with section 28.3 of the Patent Act and with the

jurisprudence. Apotex also argues that the first point (the state of

the art) is to be determined by reference not to the prior art at large,

but rather to the prior art chosen by the party alleging obviousness.

However, I do not understand the authorities cited by Apotex in

support of this argument to limit the scope of prior art that can be

considered for obviousness.

[160] In many cases, the closest prior art is identified by the challenger and frames the analysis.

In other words, if the claims of the patent are not obvious in view of the prior art that is closest to

the claims, they would not be obvious by considering broader prior art, which is less relevant to

the purported invention. However, that does not mean that the broader prior art is not relevant to

other factors, such as motivation, as discussed further below.

[161] In this case, the 400 Patent guides the analysis by identifying WO498 and the Deacon,

Augustyns and Drucker references as being prior art that is relevant. While sitagliptin and the

hydrochloride salt of sitagliptin are disclosed within WO498, the disclosure of these compounds

Page: 55

must be read and understood in context – that is, within WO498 – as this is how they would be

known to the PSA (as noted by the 400 Patent).

[162] Indeed, even Dr. Hollingsworth points to WO498 as being the starting point for the

analysis in his report, where he states:

190. In my view, the difference between the state of the art and

Claim 4 (and its dependent claims) is the choice of the

monohydrate crystal form of sitagliptin phosphate from the

crystalline forms (including hydrates) that the PSA would have

understood to be part of the WO 498 and would have presumed

arose from a standard polymorph screen.

...

192. The 400 Patent identifies the WO 498 as the starting point.

It acknowledges that sitagliptin and sitagliptin hydrochloride were

known and disclosed (which they plainly were).

[163] Applying this to the obviousness analysis, the question to be answered is whether

bridging the gap between WO498 (which discloses sitagliptin and its hydrochloride salt, amongst

other compounds) and the inventive concept of the claims of the 400 Patent would have been

obvious to the PSA having regarding to the CGK and prior art. This includes consideration of

the Deacon, Augustyns and Drucker references and the prior art relating to DPP-4 inhibitors as

discussed under the motivation section below.

D.

Inventive Concept of the Claims in Question

[164] There is some debate in the jurisprudence as to whether the obviousness analysis requires

identification of an inventive concept or whether the essential elements as construed by the

claims is the more appropriate end-point: Atazanavir at paras 65-70, 74-78; Ciba at paras 64-68,

72-77.

Page: 56

[165] As noted in Atazanavir, the intention of the obviousness test set out in Sanofi was not to

change the law of obviousness; the term “inventive concept” is not materially different from the

previously used term “solution taught by the patent”: Atazanavir at paras 65-68, 75.

[166] PMS argues that recourse should not be made to the inventive concept. Rather, the

second point in the obviousness analysis should be the essential elements of the claims. It argues

that the focus of the obviousness analysis should be on claim 4 and the claimed DHP salt of

sitagliptin crystalline monohydrate, as the other claims do not add any features that can be

inventive. It similarly asserts that if the inventive concept is to be considered, it would be

focussed on the identification of sitagliptin as a phosphate salt that is in crystalline monohydrate

form.

[167] Merck argues that the inventive concept must be determined as it is a mandatory part of

the Sanofi test. It contends that PMS’ argument ignores the latest word on the inventive concept

from the FCA in Shire. Its experts assert that the inventive concept of claim 4 is the identification

of sitagliptin phosphate monohydrate as a compound with: potent DPP-4 inhibitory properties;

pharmaceutic advantages over sitagliptin free base and the hydrochloride salt; and particular

advantages for preparing medicines of the pharmacologically active ingredient because of its

enhanced chemical and physical stability (as compared to sitagliptin free base and the

hydrochloride salt), and its high solubility. It asserts that claims 5-7 have the same inventive

concept, but that the inventive concept of claims 19, 20 and 24 would be the process claimed to

prepare the monohydrate. Similarly, it asserts that the inventive concept of claim 22 is that the

monohydrate is useful to prepare medicaments to treat type 2 diabetes on account of its disclosed

Page: 57

properties, and that the inventive concept of claim 26 is the use of the monohydrate for treating

type 2 diabetes with a therapeutically effective amount.

[168] As noted in Shire at paragraphs 75 and 76, while identification of the inventive concept

follows from, and is informed by, claims construction, claims construction and determination of

the inventive concept serve two different purposes. Claims construction occurs before any

assessment of the validity of the claims; its purpose being to interpret and determine the scope of

the claim by looking at its subject matter. Identification of the inventive concept occurs within

the assessment of the validity of the claims. Its purpose is to determine the proposed inventive

aspect of the claim, to facilitate the obviousness analysis.

[169] This is particularly important if recourse to the specification is required, such as in the

case where a bare chemical formula is claimed or in the case of a selection patent: Sanofi at

77-78; Shire at para 76. In such case, not all the chemical’s properties will inform its inventive

concept, rather only those that provide the solution taught by the patent: Shire at para 76;

Atazanavir at paras 74-75.

[170] As was acknowledged by PMS in oral argument, if the patent is a selection patent, the

Court may have regard to the inventive concept and may look to the disclosure to nourish what it

is about the species that is claimed that is selective over the genus. However, PMS asserts that

the 400 Patent is not a selection patent and there is no advantage explicitly disclosed with respect

to the crystalline monohydrate claimed in the 400 Patent.

Page: 58

[171] It argues in such a case where the inventive concept cannot be easily grasped, the

comments of the FCA in Ciba at paragraphs 74-77 should apply and the inventive concept

should be avoided:

[74] The reminder in Unilever that it is inventive concept of the

claim which is in issue, “not some generalised concept to be

derived from the specification as a whole,” is very apt: Unilever at

page 569. Part of the difficulty in the search for the inventive

concept is the use made, or to be made of the disclosure portion of

the specification of the patent. In Connor Medsystems Inc v

Angiotech Pharmaceuticals Inc [2008] UKHL 49, [2008] R.P.C.

28 (Connor), Lord Hoffman wrote at paragraph 19 that “[t]he

patentee is entitled to have the question of obviousness determined

by reference to his claim and to some vague paraphrase based upon

the extent of his disclosure in the description.”

[75] This emphasis on the claims is consistent with section 28.3

of the Act which stipulates that it is “the subject-matter defined by

a claim” which must not be obvious.

[76] Lord Jacob was alive to the possibility that difficulties in

the identification of the inventive concept could lead to

“unnecessary satellite debate”. His counsel was that “if a

disagreement about the inventive concept of a claim starts getting

too involved, the sensible way to proceed is to forget it and simply

to work on the features of the claim”: Pozzoli at paragraph 19.

Lord Hoffman wrote, once again in Connor at paragraph 20, that

the inventive concept “is a distraction almost as soon as there is an

argument as to what it is.”

[77] There may be cases in which the inventive concept can be

grasped without difficulty but it appears to me that because

“inventive concept” remains undefined, the search for it has

brought considerable confusion into the law of obviousness. That

uncertainty can be reduced by simply avoiding the inventive

concept altogether and pursuing the alternate course of construing

the claim. Until such time as the Supreme Court is able to develop

a workable definition of the inventive concept, that appears to me

to be a more useful use of the parties’ and the Federal Court’s time

than arguing about a distraction or engaging in an unnecessary

satellite debate.

Page: 59

[172] The primary differences between the experts’ views on the inventive concept is whether

it should include the purported advantages of the DHP salt of sitagliptin crystalline monohydrate

and whether the inventive concept should be considered on a claim-by-claim basis. As set out

above, in my view, the 400 Patent can be viewed as a selection patent. All experts, including

PMS’ experts, recognized that the DHP salt of sitagliptin crystalline monohydrate purports to

have enhanced chemical and physical properties.

[173] As stated by Dr. Elitzin (Elitzin Report, Ex 66, paras 67-68):

...the problem of the 400 Patent may be stated as a search for

enhanced chemical and physical stability over the earlier sitagliptin

disclosures in WO 03/004498 (free base and hydrochloride salt).

... The summary of the invention section states plainly what the

authors of the patent believe the solution to these problems is,

namely sitagliptin phosphate monohydrate.

[174] In my view, the inventive concept of claim 4 is the identification of the compound

sitagliptin dihydrogenphosphate monohydrate with its enhanced chemical and physical

properties over sitagliptin free base and the hydrochloride salt.

[175] This overall inventive concept of the 400 Patent underlies the inventive concept of the

remaining dependent claims, where claim 24 is directed to a process for reliably making the

compound of claim 4 and claims 19 and 20 claim processes that can make the non-stereospecific

compound. Claim 22 is directed to the enhanced ability to formulate the crystalline monohydrate

into a medicament, and claim 26 recognizes the therapeutic efficacy of the crystalline

monohydrate to treat type 2 diabetes.

Page: 60

[176] I do not agree with PMS that it can be concluded upfront that the Court does not need to

take a claim specific approach in its analysis. The approach will depend on the Court’s findings

with respect to claim 4. If I find that the compound of claim 4 is not obvious, then I agree that a

process for making that compound and the use of the compound in a medicament or as a

treatment would not be obvious. However, this same logic does not necessarily apply if I find

that the compound is obvious. In that circumstance, the additional elements of claims 5-7, 19, 20,

22, 24 and 26 would need to be considered to determine if they impart their own inventiveness:

Section 58, Patent Act, Shire at para 27.

E.

Differences between the State of the Art and the Inventive Concept of the Claims

[177] Following from the analysis above, the differences between the state of the art and the

inventive concept can be summarized as:

For Claim 4:

 identifying sitagliptin from amongst the other compounds disclosed within

WO498 and the landscape of promising DPP-4 inhibitors, as a lead

compound for further development;

 the choice to proceed with further salt screening and with polymorph

screening;

 the formation and selection of the DHP salt of sitagliptin;

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 the isolation of the crystalline monohydrate form of the DHP salt and the

recognition of its enhanced chemical and physical properties for

formulation over sitagliptin free base and the hydrochloride salt.

For Claims 5-7:

 the x-ray crystallographic characterization of the DHP salt of sitagliptin

crystalline monohydrate

For Claim 19, 20 and 24:

 the identification of a reliable process for making the DHP salt of the

crystalline monohydrate

For Claims 22 and 26:

 the recognition of the ability to use the DHP salt of the crystalline

monohydrate in a pharmaceutical composition (claim 22) and in a

therapeutically effective amount to treat type 2 diabetes (claim 26)

F.

Do the Differences Constitute Obvious Steps / Was it Obvious to Try

[178] For an invention to be “obvious to try”, the evidence must show, on a balance of

probabilities, that it was more or less self-evident for the skilled person to try to obtain the

invention. Mere possibility that something might turn up is not enough: Sanofi at para 66.

Page: 62

[179] The parties drew the Court’s attention to three cases, which they asserted were factually

relevant to the obvious to try analysis: Pfizer Limited v Ratiopharm Inc, 2010 FCA 204

[Amlodipine]; Atazanavir; and Teva Canada Limited v Pfizer Canada Inc, 2019 FCA 15 [ODV].

In two of the cases, Amlodipine and Atazanavir, the claims at issue dealt with a new salt and did

not include claims to a crystalline form. Each of these cases turned on the issue of motivation,

with the claims held obvious and the inventive concepts obvious to try.

[180] In Amlodipine, the patent at issue was a selection patent that claimed the besylate salt of

amlodipine. The inventors started with the specific task of looking at amlodipine maleate to see

if it could be made into a final formulation for regulatory approval. The evidence established that

it was (and would be) quickly determined that there were problems with stability and stickiness

and that routine salt testing would then be used. The Court agreed with the trial judge’s factual

finding that the skilled person “would be motivated to test sulphonic acid salts in general and

would have every reason to test the besylate salt as this had already been shown to offer

advantages over other salts in terms of stability” (at para 28).

[181] In Atazanavir, the claims of the second of two patents were to the bisulfate salt of

atazanavir, and to a pharmaceutical dosage form comprising the bisulfate salt. In that case, the

FCA identified the inventive concept of the second patent as “atazanavir bisulfate, a salt of

atazanavir which is pharmaceutically acceptable because it has equal or better bioavailability

than the atazanavir free base.” It found there was no difference between the earlier patent, which

claimed atazanavir and its pharmaceutically acceptable salts and atazanavir bisulfate, a salt that

was pharmaceutically acceptable because of its bioavailability. The Court found that the skilled

Page: 63

person would have expected that a salt screen would likely identify at least one salt with

improved pharmaceutical properties, specifically bioavailability, compared to the free base, with

only routine work to characterize the salt’s properties.

[182] In the third case, ODV, claims to a particular crystalline form of a particular salt of ODV

(succinate salt) were held to be unobvious. In that case, the CGK included ODV as the active

metabolite of venlafaxine, and ODV as a free base and fumarate salt. The prior art also disclosed

ODV succinate as a potential salt, although there was some reason to believe that it might not

work. The Court concluded that none of the prior case law, including Amlodipine and

Atazanavir, supported a view that all salt screens and all polymorph screens were obvious to try

or routine. Rather, each case had to turn on its own facts. On the evidence it found that the

amount of experimentation required and the unpredictability of the outcome was high and

rendered the solution taught not obvious to try. There was no finite number of predictable

outcomes or number of potential experiments. The facts did not support a view that the PSA

could predict that Form I ODV succinate existed, what properties it would have, or how it could

be prepared, if at all.

[183] While these cases serve as useful illustrations of the application of the obvious to try

analysis to cases involving new salt and polymorphic forms, I adopt the same approach as the

Court in ODV that each proceeding must turn on its own facts, evidence and arguments. There is

no overriding principle that all salt screens are obvious to try and matters of routine, or that

polymorph identification will always be unobvious. None of these cases can be used to force a

conclusion that is not supported by the facts and evidence, an analysis of which is set out below.

Page: 64

Was it More or Less Self-evident that What was Being Tried Ought to Work

(1)

[184] There is no requirement to show that it is more or less self-evident that what is being tried

ought to work; however, this factor remains as one of the factors to be considered in the obvious

to try analysis: Hospira Healthcare Corporation v The Kennedy Trust for Rheumatology

Research, 2020 FCA 30 [Infliximab] at para 90.

[185] As set out above, the PSA, as part of their CGK, would have been aware of accepted,

automated methods for salt and polymorph screening that were expected to yield results. They

would have known that salt form determines the physicochemical properties of the product,

including its stability, solubility and dissolution rate, and would influence how the drug is

absorbed, distributed, eliminated and excreted by the body (TT V1, P:74, L:10-22). While it

would have been expected that salt forms could improve chemical and/or physical properties and

the overall therapeutic and pharmaceutical effects of an API, it was also understood that the

wrong salt form might affect the compound negatively (TT V2, P:124 L:18-P:125 L:22; TT V3,

P:280 L:6-17). Each salt imparts unique properties to the parent compound (TT V2, P:167

L:21-27).

[186] It is undisputed that phosphoric acid is one of the preferred acids referenced in WO498

for possible salt formation with the basic compounds of the application. As agreed by the

experts, phosphoric acid would have been one of the preferred acids that a PSA would include in

a salt screening experiment with sitagliptin free base because of their differences in pK_a(i.e. the

level of acidity of the acid).

Page: 65

[187] However, the experts disagreed as to whether it was possible to predict that the DHP salt

would form. Dr. Elitzin stated that a PSA could predict with a high level of certainty whether a

salt would form between an acid and a basic compound by looking at the pK_a. Dr. Wuest agreed

that the PSA might expect a phosphate salt of sitagliptin to form, but stated that the possibility of

isolating the salt as a solid, or a crystalline solid of particular stoichiometry, remained

unpredictable. All experts agreed that it would not have been possible to predict whether a given

salt would possess advantageous properties for formulation into a dosage form.

[188] There are, and were by 2003, very few phosphate salts marketed as commercial products.

Between 1997 and 2001 only 1.7% of anions used in APIs of salts formed of basic entities were

phosphate as compared to 46.6% for chloride (Elitzin Report, Ex 66, Schedule E-10,

pages 6666-6667; Wuest Report, Ex 29, p. 36).

[189] From the CGK as stated in Stahl 2002, the PSA would be aware that phosphate salts had

a high propensity to form hydrates. However, hydrates were also known to have low solubility,

which was undesirable for formulation (TT V6, P:486 L:4-10). As explained by Dr. Davies this

made the “high solubility” of the DHP salt of sitagliptin crystalline monohydrate so surprising

and unpredictable.

[190] Whether a crystalline monohydrate could be isolated and reliably made, and found to

provide advantageous chemical and physical properties, added unpredictability that was not

disputed by any of the experts. As acknowledged by Dr. Elitzin, when running polymorphic

screening experiments, there were a number of factors that could influence whether a crystalline

Page: 66

salt was found. Reading WO498, the PSA would have no way of knowing whether any of the

compounds would form a hydrate. As of June 2003, WO498 proposed only a possibility that the

DHP salt and crystalline monohydrate would form (TT V2, P:201 L:4-P:202 L:26). As accepted

by Dr. Foley, it would not have been self-evident from WO498 that the crystalline monohydrate

could be used as an active pharmaceutical ingredient (TT V1, P:77 L:11-23).

[191] PMS argues that there is no blanket proposition that in every case where a skilled person

cannot predict the properties of a compound in advance of making it that this means that it will

not be obvious to try to obtain the compound: Atazanavir at paras 19-20. I agree, each case will

turn on its own facts.

[192] However, in this case, where a specific problem was not identified in WO498 or in the

prior art, it is difficult to see how a course of action would have been obvious to try without there

being known and expected advantages from taking further steps. Just because there were known

methods does not mean that a person would necessarily apply them unless they were more or less

self-evident to try: Sanofi at para 85; Allergan Inc v Sandoz Canada Inc, 2020 FC 1189 at

para 193.

[193] As set out further below, it is my view that there was no motivation arising from WO498

or the prior art to take further steps with sitagliptin specifically, including by conducting a salt

and polymorph screen. The PSA would not have been looking for or expecting the advantages

obtained.

Page: 67

(2)

Motivation

[194] Motivation examines whether the PSA had good reason to pursue the solution taught by

the proposed invention: AstraZeneca Canada Inc v Teva Canada Limited, 2013 FC 246 at

para 49. Merck argues that there was no motivation from WO498 and from the broader prior art

to select sitagliptin as a lead compound and even if chosen, there was no motivation for the PSA

to conduct a salt screen or to obtain the monohydrate. I address each of these assertions below.

(a)

Would WO498 motivate the PSA to proceed forward with sitagliptin

[195] As set out above, the 400 Patent is a selection patent whose prior genus application

(WO498) discloses a large class of compounds with some recognized utility, in this case, for

treating type 2 diabetes. WO498 identifies 33 specific compounds in its examples that come

within its scope, one of which is the compound now known as sitagliptin (example 7). As

acknowledged by all of the experts, WO498 does not point directly or indirectly to sitagliptin as

being a preferred compound of the compounds disclosed. Nor does it provide any data or

scientific justification for selecting any of the compounds it discloses over any of the others as a

lead compound.

[196] PMS highlights that only seven detailed examples exist within WO498 and of those

seven examples only two (examples 6 and 7) resulted in the formation of a solid compound (the

others are described as being either foamy solids or an oil). PMS argues that this would narrow

the compounds of interest for the PSA to those of examples 6 and 7. However, there is no

evidence to support this argument.

Page: 68

[197] Neither Dr. Elitzin nor Dr. Hollingsworth highlighted this language in examples 6 and 7.

Instead Dr. Elitzin stated that there was no reason given in WO498 for exploring sitagliptin over

any of the other compounds of WO498 (TT V2, P:115 L:6-9). Similarly, Dr. Hollingsworth

agreed that none of the seven examples were singled out over any of the others (TT V3, P:275

L:17-P:276 L:9).

[198] When taken to the specific language of the examples, Dr. Wuest indicated that the PSA

would not draw any meaningful distinction between the seven detailed examples and the rest of

the examples given in WO498, and would not place any emphasis on the descriptor of the solid

used within the examples. As stated by Dr. Wuest: “There are different ways of qualifying the

word “solid” that a skilled person would recognize as being used in experimental procedures. ...

The only thing that’s clear is that in this 498 application the material is described as a solid and

the qualifier doesn’t necessarily add any significant information” (TT V6, P:476 L:22-P:478

L:20).

[199] Dr. Wuest’s evidence was that there was no information in WO498 that would lead the

PSA to select sitagliptin or sitagliptin hydrochloride as the starting point to develop a DPP-4

inhibitor over the other exemplified compounds in WO498 (TT V6, P:472 L:14-20).

[200] Similarly, Dr. Davies’ evidence was that WO498 does not provide any data or other

information in the examples to distinguish any compound as a stand-out from a formulation

perspective (Davies Report, Ex 42, para 76).

Page: 69

[201] It was suggested by Dr. Roush that the skilled team would need to make all 33 example

compounds in order to properly determine if any of the compounds were appropriate to be a lead

compound for further development (Roush Report, Ex 50, para 95). Dr. Foley similarly

acknowledged that the PSA would not know which, if any, of the compounds WO498 addresses

could be selected as a lead compound from reading WO498 (TT V1, P:67 L:1-6).

[202] There is also no differentiation between the activity of any of the compounds of WO498.

Rather, WO498 only includes the general statement that the compounds of the examples of

WO498, of which sitagliptin is one, has activity in inhibiting DPP-4 “generally with an IC50 of

less than about 1 µM.” All experts agreed that the PSA would not know the activity of

sitagliptin, or of any other specific compound disclosed within WO498, from this statement and

would not know which compounds were more active than others (TT V1, P:63 L:15-22;

Lewanczuk, Ex 55, at paras 131, 141; Roush Report, Ex 50, para 94). There were no reported in

vivo studies involving the compounds of WO498 and no specific IC₅₀data on sitagliptin or on

any other compounds disclosed in the application (TT V1, P:62 L:1-4).

[203] The evidence indicates that the PSA would not have any specific motivation arising from

WO498 to focus on the particular crystalline form of a salt of sitagliptin over the other

compounds disclosed within WO498.

(b)

Did the prior art teach away from proceeding with sitagliptin

[204] Merck further argues that the PSA would not have motivation from the broader prior art

to focus on sitagliptin. To the contrary, it asserts that the prior art on P32/98, DPP-728 and

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LAF237 “taught away” from using sitagliptin as a lead compound for further development. The

evidence in support of this contention is set out in the expert report of Dr. Roush who conducted

a literature search on what would have been known about DPP-4 inhibitors and sitagliptin as of

June 2003.

[205] Dr. Roush’s evidence was that, to the extent not already known, the PSA would have

quickly come across publications reporting on P32/98 and DPP-728, including that these

compounds had already undergone testing in human trials, with promising results (Roush Report,

Ex 50, para 36). He asserted that these compounds would have likely formed the starting point

for the PSA’s work.

[206] As explained by Dr. Roush, P32/98, DPP-728 and LAF237 (depicted below with

sitagliptin) had distinct chemical structures from sitagliptin that would have been strongly

favoured. In particular, DPP-728 and LAF237 included a cyanopyrrolidine functional group

(5-membered ring with a nitrogen bound to the carbon chain) and P32/98 a thiazolidine group

(5-membered ring with one sulfur and one nitrogen atom) that were known to bind well to DPP-

4, while maintaining the overall stability of the compound. Both of these functional groups were

believed to contribute to the inhibitory activity of the compound (Roush Report, Ex 50,

para 114-127).

Page: 71

P32/98

Sitagliptin

[207] This evidence from Dr. Roush is not challenged by PMS. Rather, PMS argues that it is

not relevant to the analysis on obviousness. PMS asserts that the choice of sitagliptin as the

starting point does not form part of the inventive concept. It contends that the inventive concept

is narrower, focussing only on the phosphate salt of sitagliptin in crystalline monohydrate form.

[208] As set out above, the 400 Patent teaches that prior art relating to P32/98, DPP-728 and

LAF-237 is relevant background to the 400 Patent. It also teaches that the disclosure of

sitagliptin and its hydrochloride salt arises from the prior genus application WO498, which

includes other compounds.

[209] Prior art that teaches away from a purported invention is a relevant consideration for

obviousness: Bayer AG v Apotex Inc, 2003 FC 1199 at paras 78-79. The question is whether the

conventional wisdom in the industry at the relevant time or the prior art discouraged the PSA

from exploring a particular solution: Bauer Hockey Ltd v Sport Maska Inc (CCM Hockey), 2020

FC 624 at para 149.

[210] In June 2003, the only publication on sitagliptin was WO498. There was no indication as

to its activity, efficacy, toxicity or tolerability. Further, the general level of potency reported in

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WO498 indicated a level of potency that was 45 to 167 times less than the IC₅₀values of

0.022 µM, 0.007 µM and 0.006 µM published for DPP-728 (Roush Report, Ex 50, para 94).

[211] As acknowledged by Dr. Foley, a PSA considering a potential DPP-4 inhibitor compound

would want to see what happened in animal models (TT V1, P:59 L:12-24). At June 2003, the

PSA didn’t know whether sitagliptin would actually work to treat type 2 diabetes in patients as

there was no data to allow for that determination (TT V1, P:56 L:17-27; P:67 L:18-P:68 L:1;

P:69 L:3-8).

[212] There is no evidence that the PSA would be drawn to sitagliptin as a starting point for

further development. On the basis of the prior art, it cannot be concluded that there was

motivation for anyone other than Merck to move forward with sitagliptin as a lead compound.

(c)

Was there motivation to try to make the phosphate salt and isolate the

monohydrate

[213] As stated above, I accept as CGK that if the PSA were looking to develop a compound

they would first look to the compound in free base form.

[214] WO498 does not identify any problem with sitagliptin as a free base or hydrochloride

salt. While the PSA would know that the general activity level cited in the 400 Patent – i.e., an

IC₅₀of less than 1 µM – is not an activity level of high potency, all experts agreed that this

general statement does not reflect the potency of any particular compound of the patent. Rather,

it suggests that some compounds may be more active than others. WO498 provides no express

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statement that improved activity should be targeted by further salt screening, nor does it suggest

that any chemical or physical properties could be improved with another salt form.

[215] PMS argues that the PSA would know from the chemical structure of the free base that it

is susceptible to degradation and that salt formation would improve its formulation properties. It

relies on the following passage from Dr. Wuest’s cross-examination (TT V6, P:521 L:1-16) as

well as on Merck’s internal findings:

A.

I think that the skilled person reading the 400 patent

would be capable because of training in organic chemistry to look

at the sitagliptin structure and recognize that that particular

molecule has chemical vulnerability. It contains parts that are

susceptible to different types of chemistry reactions. We’ve talked

about acid-base reactions, but there are other reactions that are

possible; one being hydrolysis of the amide link, another would be

deamination, another would be of sensitivity to the fluorinated

aromatic ring to different types of substitutions and so on and so

forth. So the potential for degradation would be something that a

skilled person would recognize.

Q.

And I take it you would have the same opinion in

respect of sitagliptin hydrochloride?

A.

Yes, that’s a possibility too.

[216] However, the comments of Dr. Wuest do not apply restrictively to the free base form.

Rather, they apply to both the free base and to the hydrochloride salt. Dr. Wuest was not

questioned on whether any susceptibility to degradation would be different with another salt and

if so, why. There is no basis from this testimony to conclude that the PSA would be led to the

conclusion PMS proposes.

Page: 74

[217] The evidence filed through the Vincent Affidavit was that as of 2021 at least one other

generic had developed a hydrochloride salt of sitagliptin for commercial purposes (Vincent

Affidavit, Ex 7).

[218] PMS’s further reliance on Merck’s internal findings does not assist as it imparts a level of

hindsight. While it is true that the inventors understood from their own analyses and work on the

compound L-221869 that degradation of the free base and hydrochloride salt was an issue, there

is no basis to suggest on the information that was available to the PSA that the PSA would be

able to arrive at this same conclusion without conducting some analytical work as Merck had to

do. Without the information that was privy to Merck, the PSA would not be motivated to

conduct a broader salt screen at the outset. The PSA might eventually get to the same point as

Merck did in their analyses; however, there is insufficient evidence to suggest how readily this

would happen or if it would happen at all.

[219] I agree with PMS that if there was motivation to pursue sitagliptin and to pursue a

further salt form such as the phosphate salt, there would similarly be motivation to isolate the

most stable polymorphic form as required by regulatory guidelines. However, the PSA would

need to be motivated to take all of those other steps before it would engage in this exercise. In

my view, the PSA would not be motivated to get there from WO498, the CGK and the prior art.

(3)

Extent Nature and Amount of Effort Required to Achieve the Purported Invention

[220] The PSA need not be able to conduct the same experiments that the inventors did to reach

the claimed invention (Infliximab at para 94), nonetheless the actual course of conduct of the

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inventors sheds light on the amount of effort that is required to reach the claimed invention and

whether it was obvious to try: Janssen v Teva Canada Ltd, 2020 FC 593 at para 205. This is

particularly so where the knowledge of such inventors is no lower than what would be expected

of the skilled person: Sanofi at para 70. As stated at paragraph 71 of Sanofi:

...if the inventor and his or her team reached the invention quickly,

easily, directly and relatively inexpensively, in light of the prior art

and common general knowledge, that may be evidence supporting

a finding of obviousness, unless the level at which they worked

and their knowledge base was above what should be attributed to

the skilled person. Their course of conduct would suggest that a

skilled person, using his/her common general knowledge and the

prior art, would have acted similarly and come up with the same

result. On the other hand, if time, money and effort was expended

in research looking for the result of the invention ultimately

provided before the inventor turned or was instructed to turn to

search for the invention, including what turned out to be fruitless

“wild goose chases”, that evidence may support a finding of non-

obviousness. It would suggest that the skilled person, using his/her

common general knowledge and the prior art, would have done no

better. Indeed, where those involved including the inventor and his

or her team were highly skilled in the particular technology

involved, the evidence may suggest that the skilled person would

have done a lot worse and would not likely have managed to find

the invention. It would not have been obvious to him/her to try the

course that led to the invention.

[221] In this case, the inventors’ course of conduct was introduced through Merck’s documents

and Dr. Wenslow’s testimony. As set out above, portions of Dr. Wenslow’s affidavit and oral

testimony were objected to by PMS for admissibility. My disposition on those objections is set

out in the attached Appendix. The summary that follows overviews the invention story as

derived predominantly from the documents that have been admitted for the truth of their

contents, as supplemented by the admissible aspects of Dr. Wenslow’s testimony, and from the

discovery read-ins.

Page: 76

(a)

The Inventors’ Course of Conduct

[222] Merck began its work on DPP-4 inhibitors in the middle of 1999. At that time, Novartis

already had a compound in clinical development and Merck decided to “jump start” their

program by in-licensing the Probiodrug compound P32/98 (PMS Read-ins, Ex 65, A9). Merck

also synthesized LAF-237 and measured its DPP-4 activity to determine its enzyme selectivity

(PMS Read-ins, Ex 65, B4).

[223] Merck first made sitagliptin free base on June 20, 2001. The priority application for

WO498 was filed two weeks later, on July 6, 2001. It is unclear how many compounds from

WO498 Merck studied and tested before deciding to proceed forward with sitagliptin. Studies on

at least one of the compounds L-221869 (example 6 of WO498) preceded sitagliptin and was

reported in the documents filed by Merck. An internal memorandum dated April 9, 2002

indicated that sitagliptin had “an improved in vitro profile over the Probiodrug compound P32/98

(L-000826), previously in development, and its backup, L-221869” (Wenslow Affidavit, Ex 17,

Exhibit J, section 2).

[224] In December 2001, Merck scientist Leigh Shultz reported that the crystalline free base

L-221869 showed significant degradation in bulk as compared to the amorphous fumarate salt.

As such, the free base was eliminated as a development candidate in favor of a crystalline salt

form. The hydrochloride salt of L-221869 was also eliminated due to its hygroscopicity, and its

propensity to hydrate reversibly. Early stability data on tartrate and besylate salt forms appeared

promising.

Page: 77

[225] In and around the same time, in December 2001, Leigh Shultz, separately concluded that

the free base form of sitagliptin was not suitable for development due to degradation in bulk after

conducting physical and chemical stability studies, including on hygroscopicity. Based on the

solubility data for the structurally similar compound L-221869, crystalline salts of sitagliptin

were expected to have improved solubility over the free base, without affecting bioavailability. It

was recommended that identifying an acceptable crystalline salt form be made a priority.

[226] On December 12, 2001, Merck conducted an acid salt screen on the sitagliptin free base

using a 96-well plate assay incorporating 11 standard acid stock solutions. The assay was

conducted by a junior scientist Vicky Vydra that had joined Merck only months before. I agree

with PMS that the experiment conducted was a “rote task” using a standard procedure that could

be applied readily.

[227] Four potential crystalline salts were detected from the experiment, following XRPD

analysis: phosphate, sulfate, tartrate, and besylate. In January 2002, an internal memorandum

reported that the besylate and tartrate salts would likely be pursued first, while noting that the

tartrate salt was also being developed in the ongoing work on L-221869. Crystalline sitagliptin

hydrochloride salt was also separately made, but was given less priority based on the experience

with L-221869.

[228] By March 2002, three potential salts had been identified as promising – the besylate,

tartrate and phosphate salts. Merck decided to proceed with the phosphate salt because of the

flake-like morphology of the salt, which was believed to impart preferred formulation properties.

Page: 78

The decision was reported in a memorandum dated April 9, 2002, which reported on the physical

characterization of the salt, its stability data, and its biopharmaceutical and mechanical

properties. The memorandum indicated that at that time, it existed as “a single anhydrous

polymorph”.

[229] In March 2002, the DHP salt of sitagliptin was formulated into tablets and used for

clinical studies.

[230] In February 2002, the DPP-4 project team also began a polymorph study of the DHP salt.

This was a multi-disciplinary team effort that involved the active participation of numerous

scientists from several working groups. Merck understood that they were behind Novartis and

others in the development timeline and took an “all hands on deck” approach. Dr. Wenslow

estimated that the DPP-IV team conducted “over 1,000 polymorph experiments on the 1:1 DHP

salt by exposing it to a vast array of different solvents, and reaction conditions”. He described

this work in his affidavit as “challenging” because the polymorphs “exhibited very similar

energies”. As a result, the analytical tools had difficulty distinguishing between the polymorphs.

[231] The initial polymorph screening work was conducted by scientist Chris Lindemann and

included multiple crystallizations in a variety of solvents, including water. The results reported in

May 2002, indicated a single anhydrous crystal phase as well as a potentially amorphous

material that recrystallized to what was believed to be a hydrate and was later, in 2003,

determined to be another anhydrous form.

Page: 79

[232] During 2002, two high throughput polymorph screens were conducted searching for

possible polymorphs, each involving a variety of solvents, including water, in 96-well screens,

followed by evaluation of the results by the Physical Measurements Group. This screening was

described by Dr. Wenslow as being “atypical” and reflective of the significant investment Merck

had made in the project.

[233] In addition to these high throughput screens, Dr. Wenslow referred to extensive

additional testing to investigate the impact of different solvents conducted along with

characterization of the crystal structure, using a variety of techniques, including XRPD, NMR,

and Raman spectroscopy. On any given day, Dr. Wenslow described 10-15 members of the DPP-

IV project team conducting or analysing polymorph experiments.

[234] By the end of 2002, a significant volume of solid state characterization data had amassed,

suggesting a complex system of “four unique forms”, including a solvated form with ethanol and

a form thought to be a hydrate (Type A). The DPP-IV team was able to isolate Type A in

January 2003, and determined it to be another anhydrous polymorph.

[235] By January 2003, Merck had identified at least three primary anhydrous polymorphs,

some of which interconverted under manufacturing conditions in the presence of solvent.

Mixtures of different crystal forms were appearing in batches for use in the clinic and had to be

controlled for clinical studies.

Page: 80

[236] Merck conducted a solvent screen to find a non-solvating solvent that could control the

interconversion of its Form I anhydrous form. As explained by Dr. Wenslow “[t]o try and find

different conditions to prepare a single crystalline form of pure anhydrous 1:1 DHP salt, our

team surprisingly and unexpectedly discovered a completely novel crystalline monohydrate form

in March 2003”. On March 26, 2003, an experiment conducted by Stephen Cypes in isoamyl

alcohol [IAA]/water (95/5%) yielded for the first time the crystalline monohydrate, which was

confirmed by XRPD. Shortly after, another scientist, Dina Zhang, also prepared the monohydrate

in a different lab using the same type of slurry experiment (Elitzin Report, Ex 66, paras 202,

215(a); Ex 4, F-17).

[237] Dr. Wenslow described the preparation of the monohydrate as a “serendipitous discovery

that resulted in drastic and profound changes for Merck and the DPP-IV team.” Through further

research, Merck was able to develop conditions that could prepare the anhydrous forms as well

as the crystalline monohydrate by controlling the reaction conditions and the water activity. At

the same time, Merck, characterized the monohydrate’s physical properties and behaviour in

formulations. Merck concluded overall that the monohydrate displayed improved physical and

chemical stability over the anhydrous forms, primarily as it did not exhibit form conversion upon

compaction. The monohydrate also exhibited some improved sticking characteristics over the

anhydrous forms.

[238] The long-term decision to proceed forward with the monohydrate over the mixture of

anhydrous forms took place the week of May 12, 2003. While this did not mean that work

Page: 81

stopped on the mixture of anhydrous forms, the monohydrate became the priority and the

anhydrous mixture took on a secondary role.

[239] As explained by Dr. Wenslow:

7.

Quite fortuitously, the monohydrate’s physical stability,

chemical stability, and its improved pharmaceutical processability

(notably, reduced stickiness) led the DPP-IV project team to select

the monohydrate over the anhydrous forms for further

development. We were very fortunate to discover that the

crystalline monohydrate was bioequivalent with the previous

anhydrous form used for Phase I and Phase II clinical trials

because of its unexpectedly high solubility. This was a “game

changer” for Merck. The monohydrate was not only superior to the

anhydrous forms, but it was also a suitable replacement for

Merck’s upcoming Phase IIB trials.

[240] Dr. Elitzin asserts that Merck should have arrived at the monohydrate sooner, but did not

take steps to characterize the hydrate form they saw initially in 2002, choosing instead to chase

the anhydrous form and trying to exclude water. However, I do not view the experimentation in

this way. Until Type A was isolated and confirmed to be an anhydrous form, Merck was of the

view that it had a hydrate as one of its forms. Its initial screening included water as part of the

solvent system.

[241] I interpret the work conducted by Merck as establishing that the journey to the

monohydrate was not straight-forward or predictable.

[242] A further issue is how to put in context the timing taken to obtain the DHP salt and

crystalline monohydrate form, in the face of an overall accelerated timeline for obtaining a final

product that could be used in Phase II clinical trials.

Page: 82

[243] The evidence establishes that Merck had to leap-frog Novartis who was well ahead of

Merck in the race to market a DPP-4 inhibitor. This required Merck to compress the amount of

time typically taken to move to the clinic from 21 months to 6 months by conducting

preformulation biopharmaceutical studies simultaneously with Phase I formulation development,

overlapping Phase I formulation development with Phase I formulation development, and

shortening the timing of steps. As described by Dr. Foley, this required both resource investment

and taking on risks that steps might be missed and experiments might need to be repeated if

unexpected results were received.

[244] In this case, Merck benefited from its experience with L-221869 and was able to

accelerate the steps involved in its salt screening process, which involved the application of

otherwise routine processes. Similarly, once the monohydrate was reliably formed and was

determined to have a bioavailability profile similar to the anhydrous form, Merck was able to

accelerate clinical testing by relying on its Phase I studies conducted with the anhydrous

compound.

[245] From my review of the work completed, I do not consider the accelerated timeline to

suggest that the monohydrate was arrived at readily or easily. Rather, the evidence indicates that

the multi-disciplinary team took over a year to find the monohydrate and only found it by

chance. While the route to the DHP salt was straightforward, a significant amount of work and

effort was involved in arriving at the crystalline monohydrate without predictable results. The

path of the inventors does not support an obviousness finding.

Page: 83

(4)

Secondary Factors

[246] While not part of the obvious to try analysis, secondary factors have also been recognized

as being relevant to the obviousness analysis.

[247] As set out earlier, JANUVIA® was the first DPP-4 inhibitor to come to market.

Dr. Lewanczuk described JANUVIA® as a practice changing drug that satisfied an unmet need

by being able to lower blood glucose when it was high but do nothing when it was normal,

thereby avoiding hypoglycemia and other side effects typical of type 2 diabetes (TT V8, P: 734

L:15-P:735 L:6).

[248] While I do not consider this evidence as dispositive, in my view it further supports the

inventiveness of identifying the DHP salt of sitagliptin in crystalline monohydrate form, with its

advantageous properties, as becoming the medicine in JANUVIA®.

G.

Conclusion on Obviousness of the Asserted Claims

[249] On the basis of the analysis above, it is my view that there was insufficient motivation to

try to obtain the compound of claim 4 and that the work and effort required to obtain the

crystalline monohydrate was extensive and not predicable. The compound, and a process for

making it, would not have been self-evident to explore or arrive at, nor would its suitability for

making medicaments or its capability of being used as a therapeutic. For all these reasons, I find

that the Asserted Claims are not obvious.

Page: 84

[250] I note that while I have not considered each of the dependent claims separately, as I have

found that claim 4 of the 400 Patent is not obvious and each of claims 5-7, 19, 20, 22, 24 and 26

depend on the compound of claim 4, or include it within its scope, it is also, as set out in the

preceding paragraph, my view that these dependent claims are not obvious too.

VI.

Insufficiency

[251] Pursuant to subsections 27(3)(a) and (b) of the Patent Act, the specification of an

invention must:

Specification

Mémoire descriptif

(3) The specification of an

(3) Le mémoire descriptif doit

invention must

:

(a) correctly and fully

describe the invention and

its operation or use as

contemplated by the

inventor;

a) décrire d’une façon

exacte et complète

l’invention et son

application ou

exploitation, telles que les

a conçues son inventeur;

(b) set out clearly the

various steps in a process,

or the method of

b) exposer clairement les

diverses phases d’un

procédé, ou le mode de

construction, de

confection, de

composition ou

constructing, making,

compounding or using a

machine, manufacture or

composition of matter, in

such full, clear, concise

and exact terms as to

enable any person skilled

in the art or science to

which it pertains, or with

which it is most closely

connected, to make,

construct, compound or

use it;

d’utilisation d’une

machine, d’un objet

manufacturé ou d’un

composé de matières, dans

des termes complets,

clairs, concis et exacts qui

permettent à toute

personne versée dans l’art

ou la science dont relève

l’invention, ou dans l’art

ou la science qui s’en

rapproche le plus, de

confectionner, construire,

Page: 85

composer ou utiliser

l’invention;

[252] The skilled person must be able to produce the invention using only the instructions

contained within the disclosure and the skilled person’s common general knowledge: Teva v

Pfizer, 2012 SCC 60 [Teva] at para 50, 70-71; Teva Canada Ltd v Leo Pharma Inc, 2017 FCA

50 [Leo Pharma] at para 43-44. A disclosure is insufficient if it necessitates the working out of a

problem: Idenix Pharmaceuticals Inc v Gilead Pharmasset LLC, 2017 FCA 161 [Idenix] at

para 19. The disclosure must teach the skilled person how to put all embodiments of the

invention into practice, without the need for exercising inventive ingenuity or undue

experimentation, although some non-inventive trial and error experimentation may be required:

Seedlings Life Science Ventures LLC v Pfizer Canada ULC, 2021 FCA 154 at para 68; Leo

Pharma at para 59.

[253] The party challenging the sufficiency of the patent (here, PMS) bears the burden of proof:

Whirlpool Corp v Camco Inc, 2000 SCC 67 at para 75. Sufficiency is a question of fact (Leo

Pharma at para 44), to be determined as of the date the application was filed; in this case,

June 18, 2004: Teva at para 90. PMS must establish by way of evidence, on a balance of

probabilities, that the patent is insufficient as of that date: Merck Sharp & Dohme Corp v Wyeth

LLC, 2021 FC 317 at para 135.

[254] As a preliminary matter, I note that in oral argument PMS asserted that the filing date of

the 400 Patent was in 2003. However, June 24, 2003 refers to the claim date of the 400 Patent,

Page: 86

not its filing date. The filing date as identified on the face of the 400 Patent is its PCT filing date

of June 18, 2004.

[255] As confirmed in oral submissions, PMS’ only argument on the issue of insufficiency is

whether the process details disclosed in the 400 Patent for making the crystalline monohydrate

are sufficient. Despite evidence led on the d-spacings relating to claims 5-7, it does not advance

any further arguments on a claim specific basis.

[256] The 400 Patent provides both general and specific methods for preparing the crystalline

monohydrate. The general methods are set out at pages 7 and 8 of the patent and provide seven

methods for crystallizing the monohydrate of the non-stereospecific DHP salt of structural

formula I. The general methods refer to several different processing conditions, including using

ethanol/water at 25^oC, with crystallization at a water concentration of 31 wt% (method A);

isoamyl alcohol [IAA]/water at 25^oC, 40^oC and 60^oC, with crystallization at a water

concentration of 2.9 wt%, 3.6 wt% and 4.5 wt% (methods B, C and D, respectively); and

isopropyl alcohol [IPA]/water at 25^oC, 40^oC and 75^oC, with crystallization at a water

concentration of 7.0 wt%, 8.1 wt% and 20 wt% (methods E, F and G, respectively). Each of the

methods requires the further steps of “recovering the resultant solid phase” and “removing the

solvent therefrom”.

[257] A more detailed method for making the crystalline monohydrate of the DHP salt of

sitagliptin (the R-enantiomer depicted as structural formula II) is set out at page 15 of the 400

Patent. This process describes preparation of the crystalline monohydrate using an IPA/water

Page: 87

solvent system and involves first preparing the DHP salt from the free base of sitagliptin and

phosphoric acid.

[258] As admitted by Dr. Hollingsworth, if the PSA had the 400 Patent and wanted to make the

crystalline monohydrate of the DHP salt of sitagliptin, a logical method to follow would be the

detailed method at page 15 of the 400 Patent (TT V3, P:305 L:26-P:306 L:8; P:308 L:15-23).

Dr. Elitzin acknowledged that the PSA would have no difficulty in understanding or following

the instructions given at page 15 (TT V2, P:219 L:17-23; TT V2, Conf, P:20 L:15-20).

[259] In its written argument, PMS advanced an argument that the PSA would not be able to

produce the crystalline monohydrate because the 400 Patent does not teach the nucleation step

that was necessary for Stephen Cypes to make the monohydrate in March of 2003, and the PSA

would not have the seed crystals of monohydrate necessary to coax the crystallization of the

monohydrate out of solution.

[260] In oral argument, PMS indicated that it was not relying on its seeding theory. Rather, it

asserted that this had only been raised in rebuttal to Merck’s evidence and the expectation of

arguments that Merck might raise. Instead, PMS indicated that its sufficiency argument was

based on Merck’s failure to make the monohydrate in 2002 using what it asserts were similar

methods; its further failure to make the monohydrate for a period of time after the Cypes

experiment in March 2003; and the purported insufficient details in the 400 Patent. PMS argues

that the disclosure does not direct the PSA to the critical conditions required for the initial

nucleation step and as such, the PSA would not be able to make the monohydrate. PMS argues

Page: 88

there is nothing in the 400 Patent that would alert the PSA to the pitfalls Merck faced or how to

escape them.

[261] Merck asserts that PMS’ argument is speculative. It asserts that the experiments Merck

conducted in 2002 and in April 2003 were not the same as the methods set out in the 400 Patent.

Further, Merck contends that these experiments are of no moment as Merck was able to reliably

make the crystalline monohydrate after April 2003 following the conditions set out in the patent.

Merck asserts that there is no evidence to suggest that the crystalline monohydrate would not be

made by the methods set out in the 400 Patent, if followed by the PSA at the filing date.

[262] Dr. Elitzin considered the experiments conducted in 2002 to be similar in nature to the

experiments that yielded the monohydrate in 2003. He opined that the reason that the

experiments in 2002 did not yield the monohydrate could be because of contamination within the

experiment or because some parameter of the experiment did not allow for formation of the

monohydrate (Elitzin Report, Ex 66, para 202). Dr. Elitzin acknowledged that there were some

differences between the 2002 experiments and those that led to the monohydrate in 2003 and that

could explain why the same results were not achieved (Elitzin Report, Ex 66, para 204). He

could not identify from looking at the inconsistencies what was missing from the 2002

experiments to explain why the monohydrate was not formed (TT V2, P:211 L24-P:212 L:20).

[263] Dr. Wenslow explained that the critical step that took place on March 26, 2003 was the

initial nucleation event for the monohydrate (Wenslow Affidavit, Ex 17, para 91; TT V4, Conf,

P:126 L:5-20). He explained that Merck still does not fully understand why the solvent system

Page: 89

and conditions used by Stephen Cypes triggered the nucleation for the first time (Wenslow

Affidavit, Ex 17, para 63).

[264] PMS argues that the PSA needs to be told how they can avoid the problems that befell

Merck. There is no dispute that certain details of the Cypes experiment are not disclosed in the

400 Patent. However, PMS has not shown that any of the additional details from the Cypes

experiment that are not in the 400 Patent are necessary to make the crystalline monohydrate.

[265] As noted by Dr. Wenslow (Wenslow Affidavit, Ex 17, paras 74, 76):

74

... following the appearance of the crystalline monohydrate,

processes we had previously employed that never made the

monohydrate, now reliabl[y] did. Specifically, after its first

creation (nucleation), slurrying the 1:1 DHP salt in water would

reliably result in the formation of the crystalline monohydrate. This

was unexpected because, prior to the initial creation of the

crystalline monohydrate (i.e., the first nucleation event), such

slurr[y]ing experiments only yielded anhydrous 1:1 DHP salt

forms.

...

76.

...It seems the crystalline monohydrate was extremely

difficult to nucleate. But once this happened for the very first time,

there [was] no problem making this crystal grow using the process

of claim 24. We determined this scientifically by measuring the

solubility of each form at various conditions, and then prepared

“Van’t Hoff’plots, which show the inflection point as to when the

monohydrate crystallizes out. For example, in the case of isopropyl

alcohol and 25^oC (i.e. the conditions of claim 24 of the 400

Patent), we determined through our experimentation that as long as

the water concentration was higher than 6.8%, the crystalline

monohydrate could be prepared. ...

Page: 90

[266] There is a live debate between the parties as to whether there are any experiments

conducted by Merck subsequent to March 26, 2003 that followed the process of the 400 Patent

and did not make the crystalline monohydrate.

[267] Drs. Elitzin and Hollingsworth pointed to two experiments conducted in April 2003 by

Dr. Hansen, after the crystalline monohydrate was formed by Stephen Cypes, that used

IAA/water but did not make the monohydrate. In each of these experiments, the solvent was

removed from the compounds by drying the compounds in an oven. In one of the experiments,

the temperature at drying was 70^oC and the other was at 45^oC under nitrogen flow. On

cross-examination, Drs. Elitzin and Hollingsworth were taken to page 18 of the 400 Patent,

which states that the crystalline monohydrate converts to a dehydrated monohydrate if heated

above 40^oC under very dry nitrogen flow. It was acknowledged by Dr. Hollingsworth that in

view of this teaching, the PSA would not heat a sample above 40^oC under dry nitrogen flow if

they wanted to make the crystalline monohydrate (TT V3, P:311 L:16-P:312 L:3).

[268] Merck argues that the April 2003 experiments accordingly cannot be considered to follow

the protocol of the patent. They assert that the differences in drying method and temperature

explain why the monohydrate did not form.

[269] At trial, Dr. Wenslow sought to introduce evidence that the Hansen experiments from

April 2003 did not produce the monohydrate because they were not complete. However, I have

held these comments cannot be accepted on the basis of hearsay as there are no contemporaneous

documents to support these facts.

Page: 91

[270] PMS asserts that an adverse inference should be drawn because neither Mr. Hansen nor

Mr. Cypes, both of whom are inventors on the 400 Patent, appeared at the trial to provide

testimony about the 2003 experiments. As noted above, some explanation for this may be

because of the agreement between the parties entered into in advance of discovery that

Dr. Wenslow would be the sole inventor examined for discovery and the sole inventor to appear

at trial. There was no evidence indicating that PMS was dissatisfied with Dr. Wenslow’s

testimony on the inventorship issues on discovery. There would be no basis for Merck to

anticipate that an objection would be raised for the trial. While I agree that Dr. Hansen’s

testimony would have assisted with understanding these 2003 experiments, nothing turns on the

details of these experiments.

[271] Indeed, irrespective of whether the experiments conducted in April 2003 produced the

monohydrate, PMS has not identified any evidence to suggest that after April 2003, and as of the

filing date of the 400 Patent, which was over one year thereafter, the crystalline monohydrate

could not be made following the methods set out in the patent. Dr. Elitzin acknowledged in

cross-examination that he had found no examples of any of the general methods at pages 7 and 8

of the 400 Patent (methods A-G) being followed after April 2003 that did not produce the

monohydrate (TT V2, Conf, P:29 L:8-P:30 L:8). Similarly, Dr. Elitzin acknowledged in

cross-examination that there were no examples of Merck having performed the detailed method

set out at page 15 of the patent after April 2003 and producing a product other than the

monohydrate (TT V2, Conf, P:30 L:9-17).

Page: 92

[272] Even if seeding were to be considered as a possible explanation for Merck’s reliable

production of the crystalline monohydrate after April 2003, it is undisputed that in three of four

experiments that were run by Merck after April 2003, following the method set out in the 400

Patent, no seed crystals were used and crystalline monohydrate was still made (Wenslow

Affidavit, Ex 17, para 92; Elitzin Report, Ex 4, F44, pp. MRK21629, 32, 36, MRK21646, 49, 52

and MRK21708, 10, 14; TT V4, Conf, P:121 L:21-P:122 L:18).

[273] Crystalline monohydrate was also made by Dina Zhang outside the laboratory where

Stephen Cypes conducted his experiment, making it further unlikely that this could be explained

by unintentional seeding through contamination of the equipment in the laboratory with the

monohydrate (Dunitz, Ex 9, p. 194). While Dina Zhang’s notebook was not produced in the

action, the success of her experiment was reported in several documents, accepted by PMS for

the truth of their contents and was accepted by Dr. Elitzin in his analysis (TT V2, Conf, P:15

L:1-5).

[274] As noted by Merck, it is not necessary for an inventor to provide a theory of why the

invention works to support the sufficiency of the patent: Valeant Canada LP/Valeant Canada

SEC v Generic Partners Canada Inc, 2019 FC 253 at para 115; Eurocopter at para 150.

[275] As highlighted by Merck, there is no evidence that the methods of the 400 Patent would

not produce the crystalline monohydrate if followed by a skilled person. Indeed, Dr. Elitzin

admits that he does not know what the outcome would be if the PSA were to try to make the

crystalline monohydrate without seed crystals (TT V2, P:220 L:10-17).

Page: 93

[276] Merck argues that PMS’ experts should have done their own experiments to show that the

disclosure was not sufficient but chose, to their detriment, not to introduce any such testing. Both

Dr. Elitzin and Dr. Hollingsworth confirmed that they could have followed the methods had they

chosen to do so (TT V2, P:222 L:2-10; TT V3, Conf, P:70 L:27-P:71 L:2). PMS relies on the

comments made by the FCA in Idenix to suggest that current tests cannot be used to inform the

issue. In Idenix, the issue of sufficiency turned on whether the skilled person would be able to

synthesize the claimed compound when one of the steps in the synthesis (fluorination) was not

taught by the patent. The plaintiff sought to rely on evidence that showed, after the filing date,

that all three possible synthetic pathways that worked could have been chosen by the skilled

person. However, the FCA found these results benefited from hindsight. They were not relevant

to the issue of sufficiency as they did not reflect the knowledge of the skilled person at the

relevant date. I do not read this case, however, as suggesting the opposite to be true. If the PSA

could not make the crystalline monohydrate in 2022 following the instructions of the patent,

there would be no basis to suggest that the PSA could have made the crystalline monohydrate

with those same instructions, and without the benefit of hindsight, at the filing date in 2004.

[277] Without some evidence that any early difficulties at Merck would behold the PSA, there

is no basis to conclude that the PSA would not have been able to make the crystalline

monohydrate at the filing date following the methods set out in in the 400 Patent. There is

similarly no basis to conclude that the public would not be able to make the same successful use

of the teachings of the patent when it expires in 2024. PMS’ burden has not been met.

[278] I accordingly cannot conclude that the 400 Patent is invalid for insufficiency.

Page: 94

VII. Conclusion

[279] For the reasons set out above, the Asserted Claims of the 400 Patent are not invalid for

either obviousness or insufficiency and judgment in favour of Merck shall accordingly issue.

VIII. Costs

[280] Despite the Court’s request, the parties did not provide any substantive submissions as to

directions for costs. However, they did agree that a lump sum award of costs would be

appropriate for the successful party, provided that the party was able to support the quantum

claimed.

[281] The Court will accordingly provide a schedule for cost submissions based on a lump sum

award as part of its Judgment.

Page: 95

APPENDIX

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

1.

17. After sitagliptin was found to have

biological activity, the DPP-IV project

team initially studied the free base of

sitagliptin for potential development. The

team’s work is recorded in a memorandum

from December 2001 entitled “Preliminary

Pharmaceutical Assessment of L-224715”

authored by Dr. Shultz. As the

memorandum indicates, the DPP-IV project

team conducted numerous analyses to

assess the free base’s suitability for further

development as a drug candidate, including

its physical and chemical stability, as well

as hygroscopicity. This research

unfortunately revealed an unexpected

degradation problem with the free base that

was previously unknown. In light of this

finding, the DPP-IV project team

determined sitagliptin free base was

unsuitable for further development and

made finding a suitable salt form for

sitagliptin a priority.

Hearsay,

Opinion,

Rules 232

and 248,

Beyond the

Pleadings

Objections to para 17 dismissed as

the statements arise from the

1. TT V4, Conf, P:84 L:17-20

2. TT V4, Conf, P:84 L:26-P:85

L:1

memorandum which has been

accepted for the truth of its contents.

It is also supported by the April 9,

2002 memorandum (Wenslow

Affidavit, Ex 17, Exhibit J).

3. TT V4, Conf, P:85 L:2-6

4. TT V4, Conf, P:85 L:23-P:86

L:14

The statements are relevant to the

invention story.

8. TT V4, Conf, P:88 L:19-24

Rule 232/248 objection lacks

sufficient connection.

Oral objection 1 dismissed – This

testimony does not relate to the

objection at paragraph 17. The date

of sitagliptin’s first synthesis is the

subject of two PMS read-ins (Ex 65,

Items C9 and A4), was

acknowledged by PMS in response

to Merck’s Request to Admit (Ex

62) and was already accepted

without objection as part of

paragraph 16 to Dr. Wenslow’s

Affidavit.

Remaining oral objections are after

the fact and should have been raised

during testimony. Further, this

testimony relates to information

supported by the document.

Page: 96

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

2.

18. At the time, the DPP-IV project

team already had significant knowledge

and experience working with previous

DPP-IV inhibitor compounds. This

included a compound having the internal

code “L-221869”, which was a structural

analog of sitagliptin having a near

identical chemical structure to

Hearsay,

Opinion,

Rule 232 and

248,

Beyond the

Pleadings

Objections dismissed.

1. TT V4, Conf, P:84 L:17-20;

see Item 1.

Statements reflect documentary

evidence accepted as being

4. TT V4, Conf, P:85 L:23-P:86

L:14; see Item 1.

admissible for their truth. Rule

232/248 objection lacks foundation.

The statements are relevant to the

invention story, which was put in

issue by PMS’ pleading.

6. TT V4, Conf, P:86 L:27-P:87

L:11

sitagliptin, differing only in a single

fluorine (F) atom:

The reference to “we” in the oral

testimony is understood to mean the

DPP-IV project team.

3.

19. In considering potential salts of

sitagliptin to try, we knew that weakly

basic compounds, like sitagliptin, were

commonly formulated as the

hydrochloride salt. We also knew that

the hydrochloride salt of sitagliptin

could be made according to the process

used by the team back in June 2001.

Therefore, we believed the “natural” salt

candidate to evaluate was the

hydrochloride salt. However, the DPP-IV

team had previously made salts of L-

221869 in an effort to find a form that

would be suitable (L- 221869 free base

had issues), having no idea what salts

might form as a solid or which (if any)

would have properties making

Hearsay,

Opinion,

Rule 232 and to at the hearing.

248, Beyond

Oral objection 12 sustained; this

evidence was successfully objected

1. TT V4, Conf, P:84 L:17-20;

see Item 1.

4. TT V4, Conf, P:85 L:23-P:86

L:14; see Item 1.

Oral objections 7, 9 and part of 13

the Pleadings

(91:2 – 92:2) sustained as they relate

to specific details of the salt

formation work before Dr. Wenslow

was on the project that do not clearly

arise from the documentary

evidence.

5. TT V4, Conf, P:86 L:19-24

6. TT V4, Conf, P:86 L:27-P:87

L:11; see Item 2.

7. TT V4, Conf, P:87 L:27-P:88

L:11

Oral objection 11 dismissed as it is

uncontroversial and explains a

comment made during testimony.

8. TT V4, Conf, P:88 L:19-24;

see Item 1.

The remaining objections are

dismissed. The reliability of these

statements arise from the

9. TT V4, Conf, P:89 L:1-8

them suitable as a development

candidate for further study. As a

11. TT V4, Conf, P:89 L:14-20

Page: 97

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

documentary evidence accepted as

being admissible for its truth.

memorandum issued by Dr. Shultz in

December 2001 on L- 226189 states, it

was determined that the hydrochloride

salt of this closely related compound was

“eliminated as a development candidate

due to its hygroscopicity and propensity

[to] hydrate reversibly”.⁴As it turned

out, investigation of L-

226189 led the team to conclude that

the tartrate and besylate salts of L-

226189 showed good solubility, and

slight to no hygroscopicity.⁵In fact,

they were superior to the phosphate

salt of L-226189.

12. TT V4, Conf, P:89 L:23-24

13. TT V4, Conf, P:90 L:20 -

P:92 L:2

The statements otherwise reflect

Dr. Wenslow’s experience in drug

development generally, or are

uncontroversial statements.

Although these statements contain

some of the “gloss” PMS impugns,

this does not mislead the Court and

otherwise directly relates to the

content of the documents.

The statements about the 869

compound relate to Merck’s course

of conduct, which was put in issue

by PMS’ pleading.

The rule 232/248 objection is not

borne out by the cross-examination

referenced for the remaining items.

Page: 98

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

4.

20. When it came to deciding what we

should with sitagliptin, we relied on our

past experience with DPP-IV inhibitor

compounds, and in particular, L-221869.

By December 2001, our colleagues had

already made the sitagliptin hydrochloride

salt described above. Even though it had

not yet been evaluated, our experience

with the hydrochloride salt of L-221869

led us to worry that the hydrochloride

salt of sitagliptin might potentially suffer

from the same issues since the compound

structures were near identical. Similarly,

we thought tartrate and besylate salts

might be possible for sitagliptin as well.

This would, of course, need to be

Hearsay,

The objection to sentences 3 to 6 of

1 . TT V4, Conf, P:84 L:17-20;

see Item 1.

Rule 232 and paragraph 20 are upheld.

248, Beyond

The remaining statements from

the Pleadings

2. TT V4, Conf, P:84 L:26-P:85

L:1; see Item 1.

paragraph 20 reflect the cited report

from Leigh Shultz, admitted for its

truth.

3. TT V4, Conf, P:85 L: 2-6; see

Item 1.

4. TT V4, Conf, P:85 L:23-P:86

L:14; see Item 1.

5. TT V4, Conf, P:86 L:19-24;

see Item 3.

6. TT V4, Conf, P: 86 L:27-P:87

L:11; see Item 2.

evaluated. But since we were under

significant time pressures, we decided not

to focus on the sitagliptin hydrochloride

salt. Instead, based on our experience

with DPP-IV inhibitors, we decided to

conduct a broad salt selection project

looking for any solid sitagliptin salts that

might have suitable properties. Given the

team’s work on L-221869, it was

8. TT V4, Conf, P:88 L:19-24;

see Item 1.

hypothesized that we should be able to

make salts with improved solubility over

sitagliptin free base. This decision is

reflected in the memorandum summarizing

the analyses conducted on sitagliptin free

base.⁶

Page: 99

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

5.

21. Drawing on this in-house knowledge,

the DPP-IV project team attempted a

broad salt screen on sitagliptin instead of

solely focusing on the hydrochloride

sitagliptin salt that had initially been

made, despite it being the otherwise

natural candidate. The team conducted

salt experiments in December 2001,

attempting to form various salts of

Hearsay,

Opinion

Objections dismissed.

5. TT V4, Conf, P:86 L:19-24;

see Item 3

Statements reflect the documentary

evidence admitted for its truth.

7. TT V4, Conf, P:87 L:27-P:88

L:11; see Item 3.

9. TT V4, Conf, P:89 L:1-8; see

Item 3.

11. TT V4, Conf, P:89 L:14-20;

see Item 3

sitagliptin.⁷The various acids and solvents

that were used are depicted below:⁸

12. TT V4, Conf, P:89 L:23-24;

see Item 3.

13. TT V4, Conf, P:90 L:20-P:

92 L: 2; see Item 3

6.

23. We did not know if any of these solids

obtained were crystalline, however, until

they were analyzed by XRPD. As

reflected from the below snapshot, we

were only able to obtain crystalline salts

with less than half (four of the eleven

acids attempted): phosphate salt, sulfate

salt, tartrate salt, and besylate salt:¹⁰

Hearsay,

Opinion

Objection dismissed. Statements

supported by documentary evidence

accepted as being admissible for

their truth.

Facts relating to these statements

also admitted through PMS read-ins

(e.g., Ex 65; Item C22).

Dr. Wenslow was also asked about

details of the Vydra salt screen

during cross-examination.

7.

24. Interestingly, we did not obtain a

crystalline hydrochloride salt in these salt

experiments using hydrochloric acid, even

though Merck had previously made a

hydrochloride salt back in June 2001 using

Opinion

Objection allowed

10. TT V4, Conf, P:89 L:9-12

Page: 100

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

different reaction conditions. This result

reflects the unpredictability our team

faced with salt formation, and the

importance of finding the right reaction

conditions that could potentially drive

salt formation.

8.

25. We did not yet know if any of these

crystalline salts were suitable for further

development either. In January 2002, the

DPP-IV development team set out to

investigate which, if any, of the crystalline

salts were suitable for further development.

As recorded in a memorandum from

Dr. Hansen on January 7, 2002, the besylate

and tartrate salts would be pursued first.¹¹

While we did not know if either would be

suitable, we hoped based on our

Hearsay,

Beyond the

Pleadings

Objections dismissed.

4. TT V4, Conf, P:85 L:23-P:86

L:14; see Item 1.

These statements reflect the

documentary evidence accepted as

being admissible for its truth. The

evidence goes to the invention story

and is responsive to the issue of

obviousness.

6. TT V4, Conf, P:86 L:27-P:87

L:11; see Item 2.

experience with L-226189 [sic] that these

two salts would also have promising

properties. In an e- mail dated January 11,

2002, Dr. Schultz instructed Dr. Hansen to

try the tartrate salt of sitagliptin first, as

that was looking to be the best salt for

the near identical compound, L-221869.¹²

29. Thereafter, we studied these salts

with the hope that one would be our lead

development candidate. Based on the

results of our experimentation, the

9.

Hearsay

Objection dismissed. Statement

supported by documents admitted

for their truth.

phosphate salt was ultimately selected as

the most promising and was recommended

for Phase I clinical development and safety

assessment studies.¹⁴

Page: 101

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

10.

33. This experimentation revealed that

the 1:1 DHP salt possessed distinct

advantages over the other sitagliptin

salts. We did not know of these

Hearsay,

Objections dismissed except for last

sentence of paragraph 33.

1. TT V4, Conf, P:84 L:17-20;

see Item 1.

Opinion,

Beyond the

Pleadings

2. TT V4, Conf, P:84 L:26- P:85

L:1; see Item 1.

advantages until we had synthesized the

sitagliptin salts and conducted

3. TT V4, Conf, P:85 L:2-6; see

Item 1.

experimentation on them. For example,

the team found the 1:1 DHP salt to be

significantly more chemically stable than

the sitagliptin free base, besylate salt and

tartrate salt, which were all prone to

undesirable degradation, as illustrated in

the below graph:¹⁷

8. TT V4, Conf, P:88 L:19-24;

see Item 1.

11.

34. In the above graph, “Salt A” (aqua) is

the tartrate salt, and “Salt B” is the besylate

(green) salt of sitagliptin. Following 4-week

stability studies, the 1:1 DHP salt (royal

blue) demonstrated significantly lower

levels of hydrolysis and deamination,

meaning lower amounts of degradation

products. This indicated to the team that

the 1:1 DHP salt had superior chemical

stability.

Hearsay,

Objections dismissed.

3. TT V4, Conf, P:85 L:2-6; see

Item 1.

Opinion,

Beyond the

Pleadings

Dr. Wenslow has the experiential

background to explain the meaning

of these scientific terms, which do

not appear controversial.

The last sentence flows from the

remainder of the paragraph to which

there is no objection.

12.

35. My team also conducted DSC and TGA

analysis of the salts, which revealed the

1:1 DHP salt had superior physical

stability in terms of its stability to stress,

high temperature and humidity. The

team also looked carefully at the

morphology, or the shape and

appearance, of the crystalline salts. To do

this, we relied on specialists at

Opinion,

Beyond the

Pleadings

Objections dismissed except for oral

testimony excerpt 92:16-22.

14. TT V4, Conf, P:92 L:16 -

P:93 L: 9

The statements reflect the team’s

understanding at the time and are

supported by documents accepted as

being admissible for their truth.

PMS’ qualification raised in

argument about Ex L is not accepted

in view of the parties’ document

agreement and PMS’ own reliance

Page: 102

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

on Ex L in their written argument

[same note applies to items 13, 19,

26, 27, 32, 33, 35, 37 and 38 below].

Merck who were trained in conducting

and analyzing electron microscope

images. Based on this work, we

discovered the DHP to possess better

morphology than the tartrate and

besylate salts.¹⁸

The statements are responsive to the

obviousness issue.

13.

36. As reflected in the above images, the

tartrate and besylate salts all exhibited

“needle-like” morphology. Our analysis of

the hydrochloride salt prepared in January

2002 also revealed that it suffered from

similar “needle-like” morphology.¹⁹

Through our research, needle-like

morphology was found undesirable for

solid dosage formulations due to flow

issues and a propensity for sticking. By

being “sticky”, we observed certain salts

would stick to our manufacturing

equipment during tableting. We

Hearsay,

Objections dismissed.

14. TT V4, Conf, P:92 L:16 -

P:93 L:9; see item 12.

Opinion,

Beyond the

Pleadings

These statements are supported by

Ex L accepted as being admissible

for its truth. The statements reflect

the team’s understanding during the

sitagliptin project.

33. TT V4, Conf, P:124 L:21-23

understood this to be a problematic

formulation issue because if the material

sticks to the equipment, there is the

potential for unequal amounts of the

active ingredient being formulated into

dosage forms.

Page: 103

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

14.

38. At the time the 1:1 DHP salt was

promoted to clinical development, the

DPP-IV project team understood that it

existed as a single anhydrous crystalline

form. We commenced our polymorph

experiments on the 1:1 DHP salt in early

2002 (see e.g., Dr. Hansen e-mail of

February 7, 2002, indicating “Chris

[Lindemann] will try to find other

polymorphs and further characterize this

salt”).²⁰On February 15, 2002,

Dr. Lindemann informed the team that he

had conducted multiple crystallizations in

variety of solvents, including water, and

only found a single crystal phase (the

anhydrous form), as well as potentially

amorphous material:²¹

Hearsay,

Rules 232

and 248

Objection to Exhibit N dismissed as

the information in the document is

not controversial or prejudicial in

light of the admission into evidence

of the remainder of the paragraph

and the details of the experiment.

The additional facts in the objection

are within Dr. Wenslow’s direct

knowledge and are also supported by

contemporaneous documents

accepted as being admissible for

their truth.

15.

41. We came to this eventual

Hearsay,

Opinion,

Rules 232

and 248

Objections dismissed.

7. TT V4, Conf, P:87 L:27 -

P:88 L:11; see Item 3.

understanding by extensively and

systematically investigating the impact of

different solvents on the formation of the

1:1 DHP salt, thus evaluating it for

polymorphism. Each time we exposed the

solid 1:1 DHP salt to solvent, it would

dissolve, and its crystal structure would

be destroyed. Every time we

recrystallized it, the 1:1 DHP salt had the

opportunity to exist as a new solid form.

We considered each such test to be a

polymorph experiment or polymorph

screen, as some might describe it.

Following the variability we observed in

April 2002, on any given day, at least

These statements reflect Dr.

Wenslow’s knowledge and

understanding during the sitagliptin

project. The statements explain the

sentence to which there is no

objection and is consistent with it.

9. TT V4, Conf, P:89 L:1-8; see

Item 3.

11. TT V4, Conf, P:89 L: 14-20;

see Item 3.

Oral objection 15 sustained on the

basis of hearsay.

12. TT V4, Conf, P:89 L:23-24;

see Item 3.

Rule 232/248 objection is not

sufficiently particularized.

13. TT V4, Conf, P:90 L:20 -

P:92 L:2; see Item 3.

15. TT V4, Conf, P:94 L:6 – 21

Page: 104

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

10-15 members of the DPP-IV project

team were conducting or analyzing

polymorph experiments to gain insight

into the complex sitagliptin polymorph

system. This additional experimentation,

over and above the systematic polymorph

screens we conducted, allowed the team’s

scientists to use their own creativity in

searching for additional polymorphs. This

creative and unconstrained search for

polymorphs is not the sort of

experimentation we

had done before and was also only made

possible because of the immense

resources Merck devoted to this project.

Our directive at the time and throughout

the program was to leave no stone

overturned. I will return to this work

below.

16.

42. During the 2002 time, I

Hearsay,

Opinion,

Rules 232

and 248,

Beyond the

Pleadings

Objections dismissed.

These statements reflect

Dr. Wenslow’s knowledge of what

occurred during the sitagliptin

project.

16. TT V4, Conf, P:96 L:21 -

P:97 L:5

conservatively estimate that the DPP-IV

project team performed over a 1,000

polymorph experiments on the 1:1 DHP

salt as a part of this systematic

polymorphism evaluation. My group was

responsible for then analyzing the crystal

structure of the resulting experiments by not

only XRPD but also F-ssNMR, and

Carbon ssNMR (“C- ssNMR”). The DPP-

IV project team also employed Raman

Spectroscopy to assist our analysis.

During the 2002 time, and in addition to

the polymorph experiments, I

18. TT V4, Conf, P:97 L:13 – 18

21. TT V4, Conf, P:102 L:2 – 3

The first sentence of paragraph 42

refers to the estimate found in

paragraph 3 of the affidavit to which

there is no objection.

Page: 105

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

conservatively estimate that we

performed over 1,000 XRPD, F-ssNMR,

C-ssNMR, and Raman spectroscopy

analyses on the 1:1 DHP salt. This

amount of experimentation reflects our

desire to gain a deep and exceptional

understand the polymorph system, and

the significant resources invested in the

experimentation necessary to achieve this

objective.

17.

43. As part of our experimentation, we

conducted not one but two high throughput

polymorph screens – one in May 2002,²⁵

and another in November 2002²⁶–

searching for possible polymorphs. This

systematic screening involved crystallizing

the 1:1 DHP salt with a variety of different

solvents in 96-well plates, and then

evaluating any resulting solids for their

crystal form. The use of 96-well plates

allowed numerous samples to be tested

simultaneously. This high throughput

screening was expensive and not common

to Merck at the time and represents

another example of the atypical level of

investigation and significant investment

Merck made into the 1:1 DHP salt project.

Opinion,

Rules 232

and 248

Objections to the affidavit

dismissed.

7. TT V4, Conf, P:87 L:27 -

P:88 L:11; see Item 3.

The first and second underlined

portions arise from the documentary

evidence accepted as being

admissible for its truth and repeat

facts contained in other paragraphs

of the affidavit to which there is no

objection.

9. TT V4, Conf, P:89 L:1-8; see

Item 3.

11. TT V4, Conf, P:89 L:14-20;

see Item 3.

12. TT V4, Conf, P:89 L:23-24;

see Item 3.

The third statement reflects

Dr. Wenslow’s understanding at the

time.

13. TT V4, Conf, P:90 L:20 -

P:92 L:2; see Item 3.

The oral testimony does not relate to

the objections to the affidavit.

20. TT V4, Conf, P:100 L:10 -

P:101 L:10

Rule 232/248 objection not

sufficiently explained and lacks

sufficient connection to the objected

to portions of the affidavit.

Page: 106

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

18.

56. The complex phase relationships

between the anhydrous forms and the

shear-sensitive conversion of Form I to

Form III posed a problem for the DPP-

IV project team. Because these

Hearsay,

Opinion

Objections dismissed.

24. TT V4, Conf, P:105 L:21 –

26

These statements reflect Dr.

Wenslow’s knowledge and

understanding at the time.

Dr. Wenslow was cross-examined

on the interconversion of the

anhydrous forms and the comparison

of the anhydrous forms to the

monohydrate (TT V4, P: 381 L:27-

P:382 L:11).

anhydrous forms readily interconverted

under normal manufacturing and

processing conditions, a high degree of

control of both the manufacture of the

1:1 DHP salt, and its pharmaceutical

processing during formulation, would

have been required to control the identity

and proportion of the polymorphic forms

in the final drug product.

19.

57. To avoid having to implement these

controls, the DPP-IV project team

hypothesized that it might be possible to

obtain pure Form I directly—without

having to go through the metastable de-

solvated Form II—by recrystallizing the

1:1 DHP salt in a non-solvating solvent

and then maintained by adequate storage

controls.

Hearsay

Objection dismissed.

24. TT V4, Conf, P:105 L:21 –

26; see Item 18.

The statement reflects Dr.

Wenslow’s knowledge and

understanding and are supported by

Ex L, which has been accepted as

being admissible for its truth.

20.

59. On February 7, 2003, Dr. Cypes

discovered that a non-solvated crystal of

the 1:1 DHP salt could be crystallized in

a rather obscure solvent that we did not

often use, isoamyl alcohol (“IAA”). Based

on XRPD analysis, it was determined

that this form was anhydrous Form I.

Hearsay,

Rules 232

and 248

Objection sustained.

Page: 107

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

21.

60. This was promising. However, it was

also discovered that the needle-like

morphology of the Form I crystals made

in this manner was poor for

processability. As a result, efforts were

made to try to improve the morphology of

the Form I crystals. During the February to

March 2003 time, the team performed

experiments using a mixture of IAA/water

at different temperatures to see it the crystal

structure would have better morphology.⁴⁰

The resulting particles had a more

favorable rod morphology.

Hearsay,

Opinion

Objections dismissed.

14. TT V4, Conf, P:92 L:16 -

P:93 L:9; see Item 12.

These statements reflect Dr.

Wenslow’s factual understanding of

the results of the work conducted by

the team and arises from

documentary evidence accepted as

being admissible for its truth. PMS

also cross-examined Dr. Wenslow

on the differences in morphology

between the monohydrate and the

anhydrous forms (TT V4, P:379 L:9-

27).

27. TT V4, Conf, P:111 L:23 –

28

Facts relating to the morphology and

stickiness of the monohydrate and

differences between the forms are

the subject of PMS read-ins (Ex 65;

Items C27, C28, C39, E9, and E18).

22.

63. To give some sense of how lucky we

ended up, I can say that in my 25-year

career as a scientist, including my time at

Merck on the DPP-IV project team, this

is the only time I am personally aware of

isoamyl alcohol being used in

crystallization experiments. To this day,

we do not fully understand why this

solvent system, and the conditions used,

triggered the nucleation of the crystalline

monohydrate for the very first time.

Opinion

Objection dismissed.

The first sentence reflects

Dr. Wenslow’s personal experience.

The second sentence reflects

Dr. Wenslow’s factual

understanding and was relied on by

PMS in their closing argument (TT

V10, P:869 L:16-22).

Page: 108

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

23.

64. The creation of the crystalline

Hearsay

Objection to first part of paragraph

64 and oral objection 25 sustained as

it speaks to the state of mind of

others.

25. TT V4, Conf, P:109 L:19 –

20

monohydrate was a highly surprising

development to the DPP-IV project team

as a whole—and to me and the Physical

Measurements group.

Objection to last sentence of

Over a year of development on the 1:1 DHP

salt had taken place, including extensive

experiments with the 1:1 DHP salt in both

water and aqueous solvent mixtures, as well

as significant systematic efforts to identify

any polymorphs, including hydrates and

solvates. Despite this, the DPP-IV project

team had not observed an actual hydrated

form of the 1:1 DHP salt until the surprising

and unexpected creation of the crystalline

monohydrate using the odd mixture of IAA

and water, very late in the development

cycle. It was a serendipitous discovery

that resulted in drastic and profound

changes for Merck and the DPP-IV team.

The discovery of the crystalline

paragraph 64 dismissed. This

statement reflects Dr. Wenslow’s

factual recollection of events and the

team’s understanding at the time.

PMS also relies on parts of the last

statement in their closing argument

(TT V10, P:869 L:16-22).

monohydrate was initially met with

panic.

Page: 109

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

24.

65. The sudden appearance of a hydrate

so late in the development cycle was

concerning, to say the least. I and other

members of the team knew of cautionary

tales discussed in the literature of

polymorphs suddenly appearing in

similar situations with very negative

consequences. For example, I was keenly

aware of and immediately thought of the

well-known story of Abbott’s experience

with ritonavir, where the sudden

Opinion

Objections dismissed.

The statements reflect

Dr. Wenslow’s factual recollection

of events and the team’s

19. TT V4, Conf, P:99 L:28 -

P:100 L:6

28. TT V4, Conf, P:113 L:5 – 7

understanding at the time.

29. TT V4, Conf, P:113 L:24 –

25

Oral objection 19 sustained.

Oral objection 29 unrelated to initial

objection.

emergence of a new polymorph during

commercial manufacture turned out to

be disastrous. It ended up being the most

stable form but was problematic because

it did not have the properties of the form

that had been clinically approved and

marketed. As a result, Abbott had to

withdraw from the market. I panicked

because the monohydrate was also very

stable, and I expected it would be less

soluble than the anhydrous form and we

might have to start over in the clinic. As a

result, we worked intensely and quickly to

study this new crystalline monohydrate.

70. We were fortunate. The monohydrate

ended up being very amenable to

25.

Beyond the

Pleadings

Objection dismissed.

Statements are relevant to the

invention story and the issue of

obviousness.

formulation. Ultimately, and

serendipitously, the monohydrate’s

physical stability, chemical stability, high

solubility, and improved pharmaceutical

processability (notably, reduced

Further, these statements arise from

documentary evidence accepted as

being admissible for its truth and

stickiness) led the DPP-IV project team

Page: 110

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

repeat facts stated elsewhere in the

affidavit to which there is no

objection. Dr. Wenslow was cross-

examined on the properties of the

anhydrous forms compared to the

monohydrate and the reasons it was

selected (TT V4, P:379 L:28-P: 382

L:11).

to select the monohydrate over the

anhydrous forms for further

development. These data are summarized

in an April 9, 2003 memorandum⁴³co-

authored by me and other scientists from

Physical Measurements, PR&D, and

CERD, as well as an internal presentation,

“Parallel Development of Multiple Crystal

forms for M-0431,” I delivered with Cindy

Starbuck on or around June 2003.⁴⁴The

work reported in the April 2003

Facts relating to the properties of the

monohydrate are also the subject of

various PMS read-ins (see Ex 65;

Items C28, E9-12, E18, and E19).

memorandum and my June 2003

presentation accurately capture the work the

DPP-IV project team conducted to

characterize the crystalline monohydrate.

Below, I describe the superior properties

of the crystalline monohydrate, with

reference to the slides from the 2003

presentation.

26.

71. Merck’s worked showed that the

crystalline monohydrate a) does not

exhibit form conversion, an issue that

Merck saw with the anhydrous forms⁴⁵;

(b) had favorable rod-like morphology;⁴⁶

(c) is non-hygroscopic⁴⁷; (d) has no

potential for dehydration;⁴⁸and (e)

showed reduced tablet sticking⁴⁹as

compared to anhydrous forms.⁵⁰

Beyond the

Pleadings,

Rules 232

and 248

Objections dismissed.

14. TT V4, Conf, P:92 L:16 -

P:93 L:9; see Item 12.

Statements arise from a document

separately relied on by PMS and

accepted as being admissible for its

truth.

Dr. Wenslow was cross-examined

on the properties of the anhydrous

forms compared to the monohydrate

and the reasons it was selected (TT

V4, P:379 L:28-P: 382 L:11).

Page: 111

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

The properties of the monohydrate

are also the subject of various PMS

read-ins (see Ex 65; Items C28, E9-

12, E18, and E19).

27.

28.

72. The monohydrate was shown to be

stable against dehydration under

ordinary conditions through dynamic

vapor sorption experiments conducted at

25°C and 40°C.

Beyond the

Pleadings

Objection dismissed.

The statement arises from a

document accepted as being

admissible for its truth and is

relevant to the teachings of the 400

Patent.

73. The monohydrate’s stability was also

demonstrated by DSC and TGA, which

are reported in the 400 Patent.

Beyond the

Pleadings

Objection dismissed.

The statement is factual, non-

contentious information that is

relevant background to the patent

Page: 112

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

29.

75. These data indicated that, unlike the

anhydrous forms, it was possible to

maintain a single polymorphic form of the

1:1 DHP salt in its crystalline monohydrate

form at ambient conditions. This was an

extremely positive result that overcome a

critical challenge in the development of

sitagliptin – adequate control of crystal

polymorphism and the overall properties of

the drug substances – and one that was not

predictable even after the creation of the

monohydrate. The surprising stability of

this crystalline monohydrate at ambient

conditions is also reported in the 400

Patent.

Opinion,

Beyond the

Pleadings

Objection to the first passage

dismissed. The statement is factual

and reflects the belief of the team at

the time.

Objections to the remaining

passages sustained as being opinion.

30.

76. Following the creation of the

Hearsay,

Objection dismissed.

Opinion,

Beyond the

Pleadings

crystalline monohydrate in 2003, we also

determined that if water concentration

was above a certain threshold (around

6.8%), the process conditions reported in

the 400 Patent and claimed by claim 24

would reliably make the crystalline

monohydrate, and not the anhydrous 1:1

DHP salt. It seems the crystalline

monohydrate was extremely difficult to

nucleate. But once this happened for the

very first time, there is no problem making

this crystal grow using the process of claim

24. We determined this scientifically by

measuring the solubility of each form at

various conditions, and then prepared

“Van’t Hoff” plots, which show the

This statement is factual and arises

from documentary evidence that is

accepted as being admissible for its

truth. The statement is consistent

with the remainder of the paragraph

to which there is no objection.

The statement reflects Dr.

Wenslow’s knowledge and

understanding of the project at the

time.

inflection point as to when the monohydrate

Page: 113

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

crystallizes out. For example, in the case of

isopropyl alcohol and 25°C (i.e. the

conditions of claim 24 of the 400 Patent),

we determined through our experimentation

that as long as the water concentration was

higher than 6.8%, the crystalline

monohydrate could be prepared. This work

is summarized in an email from Dr. Ferlita

to me dated May 6, 2003:⁵⁵

31.

77. Additionally, unlike the anhydrous

forms, the monohydrate did not convert

to another crystal form under shear or

pressure. As shown below, compression

of an anhydrous lot (“L- 224715-

006F024” or “Lot 24”) at 200 MPa

resulted in a material with different

XPRD pattern, while compression of the

new crystalline monohydrate did not.⁵⁶

This property was another unexpected

benefit of the monohydrate over the

previous anhydrous forms.

Hearsay,

Objections dismissed except for last

sentence (opinion).

Opinion,

Beyond the

Pleadings

Statements reflect documentary

evidence accepted as being

admissible for its truth and are

responsive to PMS’ evidence.

The statements are responsive to the

issue of obviousness.

These properties of the monohydrate

are also the subject of PMS read-ins

(see Item E12).

32.

78. The monohydrate was also

Hearsay,

Beyond the

Pleadings

Objections dismissed, except for

parenthesis.

5. TT V4, Conf, P:86 L:19-24;

see Item 3.

unexpectedly found to have improved

chemical stability as compared to the

anhydrous forms (already determined to

be superior to other salt forms, including

the hydrochloride salt) by having lower

degradation, as shown below:⁵⁷

Statements arise from a document

accepted as being admissible for its

truth, and repeat statements already

made in the affidavit to which there

is no objection. The statements are

responsive to the issue of

obviousness.

Page: 114

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

33.

79. In probe stability studies conducted

at 40°C and 75% relative humidity,

formulations using the monohydrate

were found to generate fewer impurities

than comparable formulations using

anhydrous forms.⁵⁸Additionally, in

formaldehyde stress tests, the bulk

monohydrate was shown to resist

discoloration as compared to the bulk

anhydrous forms.⁵⁹

Hearsay,

Beyond the

Pleadings

Objection sustained.

34.

80. Both the bulk monohydrate active

ingredient and formulations of the

monohydrate were also unexpectedly

found to have reduced sticking compared

to the bulk anhydrous active ingredient

and comparable formulations, as can be

seen in the image below. Using a Carver

press with a punch surface embossed

with “MSD,” a sample of the

monohydrate (“L-224715-66839- 113”)

was determined to produce less sticking

compared a sample of anhydrous forms

(“Lot24”), with only about 150 µg of

monohydrate remaining on the punch

surface, as compared to over 300 µg of

the anhydrous forms.⁶⁰

Hearsay,

Opinion,

Beyond the

Pleadings,

Rules 232

and 248

Objection dismissed.

These statements arise from

documentary evidence that Dr.

Wenslow co-authored and that has

been accepted as being admissible

for the truth of its contents.

Rule 232/248 objection not

particularized by PMS. The

statement is responsive to the issue

of obviousness

The reduced stickiness is also the

subject of a PMS read-in (Ex 65,

Item E18).

35.

81. Comparable formulations of the

monohydrate and anhydrous forms were

additionally subjected to a 5-minute

compression run using a Korsch tablet

press applying approximately 9 kN of

force. As shown below, a smaller amount

of the monohydrate formulation was left

Hearsay,

Opinion,

Beyond the

Pleadings,

Rules 232

and 248

Objections dismissed.

The statement arises from a

document accepted as being

admissible for its truth. The

statement reflects Dr. Wenslow’s

understanding of the team’s work at

Page: 115

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

on the surface of the tablet punch.⁶¹This

result was a further surprising and

unexpected property of the monohydrate

that led to it selection over the anhydrous

forms for further development.

the time and also repeats conclusions

found elsewhere in the affidavit to

which there is no objection.

Rule 232/248 objection not

particularized by PMS.

The statement is responsive to the

issue of obviousness

36.

82. Another fortunate and unexpected

benefit of the crystalline monohydrate

was its high solubility. This was of crucial

importance because up until the creation

of the crystalline monohydrate, the clinical

studies were being conducted with the

anhydrous forms of the 1:1 DHP salt, and

we had received positive clinical data. If

the crystalline monohydrate turned out

be the most predominant polymorph but

had lower bioavailability (due to lower

solubility) and thus, lower therapeutic

efficacy than the anhydrous form, our

team would have faced nothing short of a

disaster.

Hearsay,

Opinion,

Beyond the

Pleadings,

Rules 232

and 248

Objection to the affidavit dismissed.

These statements reflect Dr.

Wenslow’s knowledge and

understanding of the team’s work at

the time.

26. TT V4, Conf, P:111 L:2- 5

Rule 232/248 objection not

particularized by PMS. These

statements are responsive to the

issue of obviousness.

Oral objection sustained on the basis

of hearsay

37.

83. As a result, the DPP-IV project team

conducted bioequivalence studies in

mice, rats, and dogs. As indicated in the

below slide, this “disaster check” confirmed

that the crystalline monohydrate was

bioequivalent to the anhydrous form,

meaning that we could expect the

monohydrate to confer the same therapeutic

effectiveness as the anhydrous forms, and

could rely on the data already generated in

Hearsay,

Opinion,

Beyond the

Pleadings,

Rules 232

and 248

Objection dismissed. The statement

is factual and is supported by

documentary evidence that has been

admitted for its truth. The statement

relates to the invention story and is

not beyond the pleadings.

Rule 232/248 objection not

particularized by PMS.

Page: 116

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

the clinic using the anhydrous forms

without having to start over again.⁶²

38.

84. Given the crystalline monohydrate’s

improved physical stability, chemical

stability, pharmaceutical processing, and

high solubility that rendered it

bioequivalent to the anhydrous form, the

DPP-IV project team decided to switch

from the anhydrous form to the

crystalline monohydrate in clinical

studies, as summarized by the below

slide.⁶³

Hearsay,

Beyond the

Pleadings

Objections dismissed.

Statement arises from documentary

evidence that has been accepted as

being admissible for its truth and

reflects Dr. Wenslow’s knowledge,

and understanding of the work and

team’s objectives at the time. The

paragraph is repetitive of content

that appears elsewhere in the

affidavit to which there is no

objection.

The statement is responsive to the

issue of obviousness.

The properties of the monohydrate

are also the subject of various PMS

read-ins (see Ex 65, Items C28, E9-

12, E18, and E19).

39.

85. During this period, my group also

conducted XRPD, TGA, and DSC analysis

on a new hydrated crystalline hydrochloride

salt the DPP-IV project team prepared. Our

TGA analysis showed that the

hydrochloride salt (which was a hydrate,

and superior to the original hydrochloride

salt that our team made back around June

2001) began to lose water at room

Hearsay,

Objections dismissed.

5. TT V4, Conf, P:86 L:19-24 –

see Item 3.

Opinion,

Beyond the

Pleadings

Statements reflect Dr. Wenslow’s

knowledge and understanding of the

work at the time and arise from

documentary evidence accepted as

being admissible for its truth.

30. TT V4, Conf, P:114 L:20-

P:115 L: 5

The statements are responsive to the

issue of obviousness.

temperature. This property is

Page: 117

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

disadvantageous for solid dosage

formulations since the loss

of water can lead to a phase change

involving loss of crystallinity or

formation of less-desirable amorphous

forms. As such, we learned the crystalline

monohydrate has superior physical

stability versus the hydrochloride salts.

We also learned that sitagliptin’s

chemical stability varied as a function of

pH.⁶⁴Through this experimentation, we

determined that the crystalline

monohydrate has superior chemical

stability to the sitagliptin hydrochloride

salts.

Page: 118

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

40.

87. Merck’s criteria for selecting the

monohydrate: At paragraph 209,

Dr. Elitzin states “it appears the key

criterion used by Merck in selecting the

monohydrate was the fact that it was less

susceptible to polymorphic form

interconversion” and that it did not have

“any other significant advantages over

other forms”. This is not correct. As I

explain above, the crystalline

Opinion

Objection sustained.

monohydrate exhibited several

surprising and unexpected advantages,

including improved physical and

chemical stability, its high solubility and

bioequivalence to the anhydrous form,

stability at ambient conditions, and

improved chemical and pharmaceutical

processability.

Page: 119

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

41.

94. Dr. Elitzin references two experiments

in April 2003 conducted by Karl Hansen

that led to the formation of Form I.⁷³

Dr. Hansen’s notebook indicates the solvent

ratio he used was “95:5 IAA/H2O”,

Hearsay,

Opinion

Objections sustained on both

grounds.

35. TT V4, Conf, P:128 L:25-

P:129 L: 9

meaning he used approximately 5% by

weight water, but he obtained Form I and

not the monohydrate.⁷⁴As I discuss above,

Dr. Cypes initially prepared pure

monohydrate by using 95:5 IAA/H2O at

60°C, with the XRPD pattern of the

resulting monohydrate matching Figure 1 of

the 400 Patent. The reason Karl Hansen

got Form I when he used these

conditions, instead of the monohydrate,

is that his reaction was incomplete.

97. Merck’s approach to polymorph

screening: At paragraph 179, Dr. Elitzin

states “Merck did not begin

systematically investigating sitagliptin

phosphate polymorphism until late 2002

or early 2003”. This is also incorrect. In

the 2002 time, the DPP-IV project team

systematically conducted over a 1,000

polymorph experiments on the 1:1 DHP

salt. These efforts included two formal

high throughput polymorph screens in

May 2002 and November 2002. Both

used Merck’s most advanced 96-well

plate screening technology, and neither

resulted in the crystalline monohydrate.⁷⁷

42.

Rules 232

and 248

Objection dismissed. The statements

are repetitive of other passages in

the affidavit to which there is no

objection and reflect facts set out in

the documents admitted for the truth

of their contents.

Page: 120

Item Objections to Wenslow Affidavit (bolded

and underlined)

Objection

Ruling

Objections to Oral Testimony

Asserted to be Related

43.

102. Both Drs. Foley and Elitzin observe

that the “original” and “fasttrack”

sitagliptin timelines both begin with salt

selection, but do not include the

“physiochemical characterization’ step

from the EDT paradigm.⁷⁹This is not

correct. The “salt selection” step in these

sitagliptin timelines is just shorthand and

conveys the same work as the

Rules 232

and 248

Objection sustained

The last sentence is also

inadmissible as being opinion

evidence.

“physiochemical characterization”. As I

discuss above, this work was in fact

conducted, and it was comprehensive.

For this reason, if anything, Merck

mitigated its risk (not increased it) by its

immense investment of money, scientific

expertise, and technology into the

project.

Page: 121

JUDGMENT IN T-419-20

THIS COURT’S JUDGMENT is that

1.

The Defendant’s allegation that claims 4-7, 19, 20, 22, 24 and 26 of

Canadian Patent No. 2,529,400 are invalid for obviousness and/or

insufficiency is dismissed and such claims are accordingly found to be

valid.

2.

In view of the finding in paragraph 1 and pursuant to the agreement of the

parties, the Court declares that the making, constructing, using or selling

by Pharmascience Inc. of sitagliptin phosphate tablets in strengths of 25

mg, 50 mg and 100 mg in accordance with the Abbreviated New Drug

Submission bearing Submission No. 233922 will directly or indirectly

infringe at least one of claims 4-7, 19, 20, 22, 24 or 26 of Canadian Patent

No. 2,529,400.

3.

Costs of the action, including the motion determined herein, are reserved.

Should the parties be unable to come to an agreement on costs, the costs

shall be awarded in an amount to be determined after further submissions

from the parties according to the following schedule:

(a)

the Plaintiffs submissions, which shall not exceed 10 pages, shall

be served and filed within 30 days from the date of this Judgment;

Page: 122

the Defendant’s submissions, which shall not exceed 10 pages,

(b)

(c)

shall be served and filed within 30 days after receiving the

Plaintiffs’ submissions; and

any reply submissions from the Plaintiffs, which shall not exceed 5

pages, shall be served and filed within 15 days of step (b).

"Angela Furlanetto"

Judge

FEDERAL COURT

SOLICITORS OF RECORD

T-419-20

DOCKET:

MERCK v PHARMASCIENCE INC.

STYLE OF CAUSE:

HELD BY VIDEOCONFERENCE

PLACE OF HEARING:

DATE OF HEARING:

JANUARY 10-14, 2022, JANUARY 17-20, 2022,

FEBRUARY 2, 2022

FURLANETTO J.

MARCH 28, 2022

JUDGMENT AND REASONS:

CONFIDENTIAL JUDGMENT

AND REASONS ISSUED:

APRIL 11, 2022

PUBLIC JUDGMENT AND

REASONS ISSUED:

APPEARANCES:

David Tait

FOR THE PLAINTIFFS

FOR THE DEFENDANT

Sanjaya Mendis

Michael Burgess

Laura MacDonald

Kavita Ramamoorthy

Neil Fineberg

Ben Wallwork

Kerry Andrusiak

Kristin Marks

SOLICITORS OF RECORD:

McCarthy Tetrault

Barristers and Solicitors

Toronto, Ontario

FOR THE PLAINTIFFS

FOR THE DEFENDANT

Fineberg Ramamoorthy LLP

Barristers and Solicitors

Toronto, Ontario