Source text

Pfizer Canada Inc. v. Apotex Inc.
Court (s) Database
Federal Court Decisions
Date
2017-08-22
Neutral citation
2017 FC 774
File numbers
T-402-16
Notes
A correction was made on October 18, 2017
Decision Content
Date: 20170922
Docket: T-402-16
Citation: 2017 FC 774
Ottawa, Ontario, September 22, 2017
PRESENT: The Honourable Mr. Justice Brown
BETWEEN:
PFIZER CANADA INC. and WYETH LLC
Applicants
and
APOTEX INC. and
THE MINISTER OF HEALTH
Respondents
PUBLIC JUDGMENT AND REASONS
(Original and Corrected Confidential Judgment and Reasons issued August 22, 2017)
Table of Contents
I. Nature of the Matter 5
II. Procedural Note 5
III. Summary of Conclusions 6
IV. Witnesses 6
V. Facts 8
1. Background 9
2. The Invention Story 11
3. Invention Story in more detail: the evidence of Pfizer’s Dr. Shah 16
4. Experimentation with ODV fumarate 19
5. Attempt to form pro-drug of ODV 21
6. Attempt to form an acceptable salt of ODV 22
7. Polymorph and crystal screening 26
8. Solubility 27
9. The Preparation of ODV Succinate 29
10. Permeability and bioavailability testing 30
11. |||||||||||||||||||||||||||||| 31
12. Rat perfusion test 33
13. Beagle dog testing 36
14. Human testing 39
15. Solid state forms: crystallinity, amorphous solids, polymorphs 42
16. Polymorph screening and subcontracting polymorph screening to SSCI, Inc. 42
17. Dr. Aeri Park at SSCI 45
18. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 51
19. Melting points and differential scanning calorimetry (DSC) 52
20. Further temperature studies and amorphous form 53
21. Hygroscopicity testing (a test relevant to drug stability) 54
22. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 54
23. |||||||||||||| (Crystal Form “C”) 55
24. |||||||||||||||||||||||| (Crystal Form “D”) 56
25. Work on other salt candidates and screens 58
26. Miscellaneous 59
VI. Issues 59
VII. Statutory provisions and burden of proof 60
VIII. Analysis 61
1. Relevant Dates 61
2. Claims Construction 62
A. Construction of Claims 8 and 9 72
B. Construction of Claim 33 80
C. Construction of Claims 43 and 44 81
3. Non-infringement 82
4. Obviousness 85
A. Introductory comments and summary 85
B. Legal principles in the obviousness inquiry and the Sanofi decision 87
C. Federal Court of Appeal jurisprudence including Atazanavir and Beloit 98
D. Analysis of Obviousness 104
1. (a) Identify the notional “person skilled in the art” 104
1. (b) Identify the relevant common general knowledge of the Skilled Person 105
2. Identify the inventive concept of the claim in question or if that cannot readily be done, construe it 121
3. Identify what, if any, differences exist between the matter cited as forming part of the “state of the art” and the inventive concept of the claim or the claim as construed. 126
i. Claims 8 and 9 126
ii. Claim 33 127
iii. Claim 43 and 44 127
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? 129
5. Apply the definition of obvious before Sanofi 129
6. Consider the doctrine of obvious to try 132
7. 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? 135
8. 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? 148
9. Is there a motive provided in the prior art to find the solution the patent addresses? 150
10. What is the course of conduct which was followed which culminated in the making of the invention? 152
11. Conclusion on obvious to try regarding Claims 8 and 9 154
12. Conclusion on obvious to try regarding Claims 33, 43 and 44 155
13. Consideration of the guidance for obvious to try analysis set out in Sanofi 155
14. Conclusion on obviousness 156
5. Inutility 156
A. Are the subject matters of Claims 33, 43 and 44 useful - are they capable of a practical purpose (i.e. an actual result)? 163
B. Conclusion on inutility 165
6. Overpromising in relation to subsection 27(3) of the Patent Act 165
7. Anticipation 173
8. Double patenting 187
IX. Conclusions 194
X. Costs 194
XI. Confidential Reasons 194
***
I. Nature of the Matter
[1] This is an application for an order pursuant to s 6 of the Patented Medicines (Notice of Compliance) Regulations, SOR/1993-133 as amended, SOR/1998-166, SOR/1999-379, SOR/2006-242 [NOC Regulations] prohibiting the Minister of Health from issuing a Notice of Compliance [NOC] in respect of a Notice of Allegation [NOA] sent by Apotex Inc., [Apotex] to Pfizer Canada Inc., previously Wyeth LLC [Pfizer or Wyeth], dated January 21, 2016, in respect of Canadian Patent No. 2,436,668 [668 Patent]. The 668 Patent covers the drug PRISTIQ which is used for the treatment of depression.
[2] At issue are claims 8, 9, 33, 43 and 44. While Apotex advanced other grounds in its NOA and memorandum, some were subsequently abandoned such that now Apotex alleges the 668 Patent is invalid on the grounds of obviousness, inutility, non-infringement, anticipation and double patenting.
II. Procedural Note
[3] As a procedural note, this case was argued after I heard argument in Pfizer Canada Inc and Wyeth LLC v Teva Canada Limited and The Minister of Health, in respect of which I delivered reasons and judgment in 2017 FC 777. These two cases involve different NOAs filed by different second persons, against the same first persons in respect of the same 688 Patent. While the invention story in both is essentially the same, the grounds of alleged invalidity differ. The arguments were similar in some respects and differed in others; therefore there is repetition as between these two sets of reasons. The law is the same in both.
[4] As guidance for those reading both decisions, while obviousness and inutility are at issue in both decisions, Apotex also advanced allegations of non-infringement, anticipation and double patenting which Teva did not advance in its proceeding. Claims construction is contested in this proceeding, but Claims 8 and 9 were agreed upon in the Teva proceeding. Apotex also raised overpromising in this proceeding as a ground of invalidity arising out of subsection 27(3), which Teva did not advance in its proceeding.
III. Summary of Conclusions
[5] In the reasons that follow, I find on a balance of probabilities that Apotex’s allegations of invalidity due to obviousness, inutility, anticipation, and double patenting, together with Apotex’s allegation of non-infringement are not justified. I find no merit in the arguments of invalidity based on “overpromising” contrary to subsection 27(3) of the Patent Act. Therefore, Pfizer will have its Order of prohibition, together with costs on terms the parties agreed on and which are set out in these Reasons.
IV. Witnesses
[6] The parties in their pre-hearing filing provided the following information on the witnesses, to which I have added minimally:
Pfizer’s fact witnesses:
Dr. Syed Shah: Syed Shah is a former employee of Wyeth (and subsequently Pfizer) who has held a number of different titles at both companies. In the late 1990s to early 2000s, he was the Associate Director of the Chemical and Pharmaceutical Development Department at Wyeth and was involved in the development of a suitable form of ODV for clinical research and commercialization. He oversaw the preclinical research conducted on ODV succinate (and other forms of ODV), as well as later clinical research on ODV succinate and Pristiq®. Dr. Shah is a named inventor on the 668 Patent.
Dr. Aeri Park: A former Principal at SSCI Inc., the research laboratory hired by Wyeth to conduct polymorph studies on ODV succinate. She managed the team of scientists who conducted the ODV succinate work, which included identifying, analyzing, and generating various solid state forms of ODV succinate. Dr. Park is a named inventor on the 668 Patent.
Pfizer’s expert witnesses:
Dr. Syed Shah: Syed Shah is a former employee of Wyeth (and subsequently Pfizer) who has held a number of different titles at both companies. In the late 1990s to early 2000s, he was the Associate Director of the Chemical and Pharmaceutical Development Department at Wyeth and was involved in the development of a suitable form of ODV for clinical research and commercialization. He oversaw the preclinical research conducted on ODV succinate (and other forms of ODV), as well as later clinical research on ODV succinate and Pristiq®. Dr. Shah is a named inventor on the 668 Patent.
Dr. James Polli: James Polli is a Professor of Industrial Pharmacy and Pharmaceutics at the University of Maryland School of Pharmacy. His main research interests are (1) maximizing oral bioavailability through formulation and chemical approaches, and (2) developing public quality standards for oral dosage forms. He has experience in the fields of pharmaceutics, pharmacokinetics and bioavailability.
Dr. Pierre Blier, MD: Pierre Blier is a full professor in the Departments of Psychiatry and Cellular and Molecular Medicine at the University of Ottawa in Ontario, Canada. He also serves as the Director of the Mood Disorders Research Program at the University of Ottawa Institute of Mental Health Research at the Royal Ottawa Hospital. He has experience in the fields of neuropharmacology and psychiatry.
Dr. Jerry Atwood: Jerry Atwood is Chairman of the Department of Chemistry and Curators’ Professor at the University of Missouri-Colombia. He has research and academic experience in the fields of supramolecular chemistry, solid-state chemistry, crystal growth, crystal engineering, materials testing, X-ray crystallography, organic chemistry, pharmaceutical chemistry, inorganic chemistry and polymer chemistry.
Dr. Allen Myerson: Allan Myerson is a Professor of the Practice of Chemical Engineering at the Massachusetts Institute of Technology (“MIT”). He has research and academic experience in industrial crystallization and the crystallization of pharmaceutical solids.
Apotex’s expert witnesses:
Dr. Alan Parr, Ph.D.: Dr. Alan Parr is an independent consultant on matters related to the biopharmaceutics of pharmaceuticals. He has approximately 30 years of experience working in the pharmaceutical industry, including with Glaxo and its successor companies Glaxo Wellcome and GlaxoSmithKline. Dr. Parr has experience in the in vivo evaluation of dosage forms, biopharmaceutics, pharmacokinetics, drug absorption and bioavailability/bioequivalence testing.
Richard J. Bastin: Richard J. Bastin is the Director of RJB Pharma Consulting Ltd., a consultancy business that offers advice, support and training on drug developability, process development, product development and Chemistry Manufacturing Controls strategy to pharmaceutical and biotechnology companies.
Jonathan Steed, Ph. D.: Jonathan Steed is a Professor of Chemistry at Durham University in the United Kingdom. His research focusses on crystallography, crystallization, solid state chemistry, coordination chemistry and intermolecular interactions in solids.
V. Facts
1. Background
[7] The 668 Patent concerns a drug called o-desmethyl-venlafaxine, henceforth referred to as ODV. ODV is a serotonin and norepinephrine reuptake inhibitor [SNRI] used for the treatment of depression. ODV works by simultaneously inhibiting the reuptake of both serotonin and norepinephrine, which are two neurotransmitters believed to be implicated in depression and anxiety. The specific active pharmaceutical ingredient (API) at issue in this proceeding is Form I ODV succinate, which is a particular crystal form of a particular salt of ODV namely ODV succinate. Pfizer argues and as will be seen, I have accepted that Form I ODV succinate is a novel composition of matter, and is the subject of Claims 8 and 9, on which Claims 33, 43 and 44 depend.
[8] ODV is an active metabolite of ODV’s parent drug, venlafaxine. ODV is called a metabolite because ODV is produced by the body when venlafaxine is administered, that is, venlafaxine is chemically modified in the body to form ODV; it is ODV that is responsible for delivering some or all of the pharmacological effect.
[9] It is common ground that ODV itself and its use to treat depression have been known for some time. Venlafaxine - which metabolizes into ODV - was previously patented and approved to treat depression. Wyeth had ODV in hand since at least 1990. Wyeth and Pfizer have marketed ODV, as the known metabolite of venlafaxine, under the names EFFEXOR and EFFEXOR XR. EFFEXOR is the immediate release version of venlafaxine (which converts in the body to ODV); EFFEXOR XR is the extended or sustained release version of venlafaxine (which also converts in the body to ODV but at a slower rate). ODV is the API in both EFFEXOR and EFFEXOR XR.
[10] Both EFFEXOR and EFFEXOR XR contain venlafaxine hydrochloride which is a salt; venlafaxine hydrochloride is henceforth simply referred to as venlafaxine.
[11] ODV and “pharmaceutically acceptable salt forms thereof” were known and are claimed in both claim 22 in US Patent No. 4,535,186 (US 186), issued in 1985, and in claim 21 of Canadian Patent No. 1,248,540 (CA 540), issued to a Pfizer predecessor company in 1989.
[12] “Pharmaceutically acceptable salts” as the term is used in US 186 and CA 540 are formed by reacting an acid together with and a base. ODV is a base; therefore, to make a salt an appropriate acid is required for such reaction. Both US 186 and CA 540 claim ODV succinate as one of 11 “illustrative” pharmaceutically acceptable salts, and therefore include a reference to reacting ODV with succinic acid.
[13] However, there is no suggestion in either US 186 and CA 540, or elsewhere in the prior art, that the salt ODV succinate had ever been made before. Likewise there is no suggestion that any crystalline form of the salt ODV succinate had ever been known or made before. Further, there is no evidence or argument that the crystal Form I ODV succinate, which Wyeth alleges is the inventive concept of Claims 8 and 9, had ever been known or made before it was made by Wyeth.
[14] In addition to disclosure in the Canadian (CA 540) and American (US 186) patents just referred to, it is agreed that another form of ODV, namely its free base, i.e., the drug ODV itself as opposed to a salt or crystalline form of the drug, was disclosed in International Patent Publication No. WO OO/59851 (WO 851) published in October 12, 2000. WO 851 listed 26 “pharmaceutically acceptable salts”, again including succinic acid. Once again however there is no suggestion that ODV succinate had ever been made, or that the crystalline ODV succinate had ever been made, or that Form I ODV succinate had ever been made before it was created in Wyeth’s laboratories.
[15] The prior art also disclosed that venlafaxine as EFFEXOR or EFFEXOR XR and their metabolite ODV were useful to treat depression.
[16] As is also well known, depression is a serious medical condition that can be and is often debilitating. It is not disputed that all of these drugs including Form I ODV succinate help patients suffering from depression to regain and live more full and functional lives.
2. The Invention Story
[17] The essence of the inventive story is not generally in dispute, although aspects of it are; the parties disagree on its characterization, and how the inventive story relates to the obviousness and obvious to try and other principles in patent law. The inventive story is also relevant to the dispute over the alleged lack of utility and in other respects as well. In my view the inventive story warrants being set out in some detail; I will summarize it first.
[18] The inventive story as I have found it is set out below. It is drawn generally from the affidavits of Dr. Shah and Dr. Park; Dr. Shah who was at Wyeth at the time and was in charge of commercializing ODV generally and then commercializing ODV succinate. Dr. Park was in charge of the polymorph screening of ODV succinate at a specialized company that performed polymorph screening for Wyeth, namely, SSCI, Inc. [SSCI].
[19] I accept the evidence of Dr. Park and Dr. Shah because they were there at the time of the invention, and have first-hand knowledge of the matters they describe. I appreciate they are both named inventors on the 668 Patent, but am not in any way persuaded that this affected their evidence whether deposed to in their affidavits, or in cross-examination.
[20] Wyeth, now Pfizer, had venlafaxine as one of its drugs. As such, it knew that ODV was the active metabolite of venlafaxine. Pfizer at first through a predecessor company and then in its own name marketed venlafaxine as EFFEXOR and EFFEXOR XR. EFFEXOR delivered venlafaxine immediately, but for many patients that meant it had to be administered several times a day. EFFEXOR XR, a sustained release version of EFFEXOR, could be delivered once-a day; it delivered a larger dose at the outset but once inside the body its release was spread over a prolonged period of time. EFFEXOR XR is an extended or sustained release formulation which was better for many if not most patients, including those suffering depression, because taking a once-a-day pill was more convenient and led to greater compliance than taking multiple pills throughout the day. In addition, the sustained release form would reduce side effects by reducing the amount of the drug released into the body at any one time versus EFFEXOR, the immediate release form of venlafaxine.
[21] Wyeth’s problem with venlafaxine was that while its active metabolite was ODV, there was no solid-state form of ODV itself that could be safely stored, formulated into a drug, and effectively delivered to patients. Wyeth only had venlafaxine which relied on the body to be metabolized or converted into ODV, which then acted as the anti-depressant in the brain.
[22] The new ODV drug that Wyeth sought to discover required several key characteristics: stability, solubility, permeability and bioavailability. Permeability is the ability of a drug to permeate through the lining of the GI tract. Bioavailability is the ability of a drug to get into the bloodstream, which in the oral dose sought, involves permeating the gastrointestinal [GI] tract.
[23] The searched-for new ODV drug had to be a stable, that is, a drug that could be stored safely throughout the manufacturing and distribution processes. The searched for ODV had to remain stable throughout these processes and also in the hands hospitals and patients over different ambient temperatures and humidity levels one would find in the places where it might be manufactured, stored, distributed, and or used.
[24] The ODV drug form Wyeth was searching for had to be able to dissolve in the gastrointestinal [GI] tract i.e., it had to be a drug that was soluble. It also had to be a drug that would cross over from the GI tract into the bloodstream where it could do its work in the body’s systems and in particular, in the brain, i.e., it had to be a drug that was permeable and bioavailable.
[25] In addition to having stability, solubility, permeability and bioavailability, the searched for new ODV drug needed to have these qualities without unacceptable adverse side effects such as nausea and vomiting which were known issues with ODV.
[26] In summary, over some two years - with increased activity towards the end of this period - experimentation and drug development was conducted, initially by Wyeth, and then by Wyeth together with a specialized contract laboratory, SSCI. Employees of both Wyeth and SSCI are named inventors on the 668 Patent.
[27] Wyeth and SSCI eventually identified a solid crystalline form of ODV that was stable, soluble, permeable and bioavailable. This crystalline form is known now as Form I ODV succinate, and Pfizer alleges this as the inventive concept in Claims 8 and 9 of the 668 Patent. It is common ground that this crystalline form is a new composition of matter that was never before made or disclosed until it was created by Wyeth. I should note that Apotex raises invalidity based on anticipation therefore newness is in issue, and will be dealt with later in these Reasons.
[28] I referred to the experiments that Wyeth and SSCI conducted in which Wyeth created the crystalline Form I ODV succinate, and in which |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| In this connection, the experts agree it would have been impossible for the Skilled Person to know or predict whether ODV succinate salt would form as a solid, whether that solid could be formed as a crystalline compound, or what the properties of any hypothetical crystalline solid, let alone Form I ODV succinate would be in terms of stability, solubility, permeability, bioavailability and adverse effects; none of this would be known without doing empirical research. As will be discussed further, in my view the extent of research envisioned by the Skilled Person and actually required in this connection was not routine, but in the nature of a research program.
[29] I wish to note that an issue in this proceeding is whether the experimentation involved was routine experimentation, and if so, what legal consequences flow from such a finding. This is because the work done by Wyeth included performing salt screening, and because the work done by SSCI entailed a different type of screening, known as polymorph or crystal screening. Pfizer and Apotex agree that in general terms both salt screens and polymorph screens were generally known to a person skilled in the art at the time (the Skilled Person).
[30] Wyeth not only created the ODV succinate salt, but went further and discovered and created a crystalline form of that salt which has become known as the crystalline Form I ODV succinate. Wyeth however did not know that the crystal it created |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Wyeth with its subcontractor SSCI went further. SSCI found another three crystalline and one amorphous forms of ODV succinate in addition to crystalline Form I ODV succinate created by Wyeth and relied upon by Pfizer in Claims 8 and 9 of the 668 Patent.
[31] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| This discovery allowed Wyeth to develop sustained release oral formulations that could deliver therapeutic concentrations of ODV over a prolonged period of time, reduce the overall incidence of certain side effects associated with higher peak blood concentrations of the drug, and give patients a once daily pill instead of having to take multiple pills throughout the day.
3. Invention Story in more detail: the evidence of Pfizer’s Dr. Shah
[32] Pfizer’s Dr. Shah, a pharmaceutical engineer, was the lead investigator involved in Wyeth’s development of ODV for clinical research and commercialization between 1999 and 2004. Dr. Shah’s evidence was that at the outset of the course of Wyeth’s experimentation, Wyeth’s Discovery Group considered that ODV might be a successful drug candidate for several reasons. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| For example, it was thought that by administering the metabolite ODV directly one could have a faster and more potent effect.
[33] In addition, it was known that individuals varied in their ability to metabolize venlafaxine into ODV in the liver, which would affect the effectiveness of venlafaxine. By getting rid of the metabolic step (in which venlafaxine is converted by the body into ODV) it was thought this variability could be addressed. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
[34] Wyeth was also interested in two further matters: 1) improving patient compliance, that is, improving the chances of patients actually taking their medication as prescribed, and 2) the need to develop a new drug with reduced side effects. One way to do this would be to develop a drug that could be dosed once per day, which meant developing a sustained release formulation of ODV.
[35] Wyeth’s invention story had several components in addition to this background knowledge.
[36] Initially, Wyeth worked with ODV fumarate, a known salt form of ODV, but without success.
[37] Wyeth also attempted to make a pro-drug of ODV, again without success.
[38] In addition, and previously, Wyeth had also worked with a number of other salt forms of ODV, but without success.
[39] Wyeth then set out to determine if it could identify a more appropriate salt form, a route in respect of which there was internal and science-based skepticism, a point Apotex challenged and which I will address shortly. Eventually Wyeth found the ODV succinate salt form, which it then with further research and experimentation, developed into a crystalline form then known as Form “A”, which subsequently became known as Form I ODV succinate. Having identified positive properties of this new crystal Form I ODV succinate in terms of solubility and stability, it engaged SSCI to test the crystalline Form I ODV succinate and identify and test for other crystalline forms; SSCI did so and identified three other crystalline forms of ODV succinate plus one amorphous form of ODV succinate.
[40] Wyeth conducted studies in vivo (in the body) in mice, and in cells in vitro (outside the body), together with in vivo tests on rats, beagle dogs and ultimately with human volunteers.
[41] Wyeth determined that the crystalline Form I ODV succinate had the requisite stability, together with solubility in addition to both suitable permeability and bioavailability. Wyeth then performed additional studies to develop sustained release formulations of Form I ODV succinate.
[42] The following outlines these steps in more detail.
4. Experimentation with ODV fumarate
[43] Pre-clinical work on ODV by Wyeth’s Discovery Group had been conducted on the fumarate salt form of ODV, known as ODV fumarate. ODV fumarate is formed by reacting ODV, which is a base, with fumaric acid to make a salt known as ODV fumarate. ODV fumarate is a salt form of ODV. ODV fumarate was a known salt form of ODV, which is one of the reasons it was looked at by Wyeth. ODV fumarate was known in the art at the time because it was disclosed as Example 26 of US 186 as a crystalline salt.
[44] However, ODV fumarate had problems with bioavailability. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
[45] This evidence indicates and I accept that oral bioavailability of ODV fumarate was relatively poor compared to ODV fumarate |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||| The problem with the ODV fumarate’s bioavailability was considered by Wyeth as “likely due to low solubility and/or permeability” of ODV fumarate. |||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||
[46] As indicated previously, |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||, as Dr. Shah deposed in his affidavit, salts that are reasonably soluble like ODV fumarate are usually completely dissociated by the time they get to the GI tract. In other words, if the drug ODV became dissociated when it ceased to be in salt form ODV fumarate, in the GI tract, where it lacked suitable bioavailability, the same dissociation but poor bioavailability could obtain with the drug ODV when reacted to form other salts. In other words, if the dissociated drug ODV did not do well in terms of permeability when orally dosed as ODV fumarate, it was unclear why another salt form of ODV might behave any better:
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||
Affidavit of Dr. Shah, para 22.
[47] Apotex argues that |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| To the extent Dr. Shah refers to the views of others at Wyeth, Apotex is correct. However, Dr. Shah also deposed to and certainly had personal knowledge of the fact that |||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||, namely that since salts that are reasonably soluble (like ODV fumarate) are usually completely dissociated by the time they get to the GI tract, it was unclear how much impact a new salt would have on improving permeability. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
5. Attempt to form pro-drug of ODV
[48] Wyeth also attempted to develop a pro-drug of ODV in 1999-2000. A pro-drug is a compound which is chemically altered in the body to become its bio-active chemical form. Pro-drugs are also described as being created by chemically modifying the active compound to produce a pharmacologically inactive molecule that will be metabolized into an active form in the body following absorption by the body. Depending on the modifications that are made, a pro-drug may have improved solubility, dissolution or absorption over the active molecule.
[49] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
[50] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| In this evidence, Dr. Shah was relying on what had been reported to him as I agree with Apotex that he had no involvement in Wyeths’ ODV pro-drug development program, which it appears led to at least one successful patent application of which Dr. Shah was unaware.
[51] However, I accept Dr. Shah’s main evidence on this point, namely that Wyeth conducted pro-drug development work apart from Dr. Shah’s salt and crystalline drug development work in connection with ODV. While Apotex calls the Wyeth’s attempt to find a pro-drug a “diversion”, the fact is that both parties agree that Wyeth undertook pro-drug exploration and development work. I accept Dr. Shah’s evidence that it took place: this is not disputed by Apotex’s expert Dr. Steed who disparaged pro-drug development regarding ODV. Accepting Apotex’s argument that Wyeth succeeded in making and even patenting a pro-drug does not establish that pro-drug development was irrational or unreasonable; in my view, it proves the opposite and justifies pro-drug development work that Apotex says would not have been done by a Skilled Person.
6. Attempt to form an acceptable salt of ODV
[52] The third option pursued by Wyeth (after the fumarate salt and pro-drug) to improve ODV’s absorption/permeability was to attempt to identify a new salt form of ODV. It was known that ODV existed as the salt form ODV fumarate as discussed above, but ODV fumarate was not pursued as such. It was also known that ODV existed as a free base, but ODV as a free base is insoluble in water which I accept leads to absorption issues; therefore the ODV free base was not pursued.
[53] I also accept that it was known, as stated by Dr. Shah, that salt formation provides a means of altering the physicochemical properties of a drug - like solubility and stability - without modifying its chemical structure. It is also accepted that salts are formed by interacting an acid and a base together to form a salt.
[54] ODV is a base. Therefore, in order to attempt to make a salt with ODV, it was necessary to interact the base, ODV, with an acceptable acid.
[55] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| As a result, most of the pre-clinical work on ODV conducted by the Discovery Group was conducted on ODV fumarate, but as noted already, ODV fumarate displayed poor oral bioavailability.
[56] ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||, Dr. Shah proceeded to investigate other salt forms of ODV. This work began by his consulting Dr. Hadfield of Wyeth’s Salt Selection Committee for assistance with preparing and screening new salts. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

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Pfizer Canada Inc. v. Apotex Inc. Court (s) Database Federal Court Decisions Date 2017-08-22 Neutral citation 2017 FC 774 File numbers T-402-16 Notes A correction was made on October 18, 2017 Decision Content Date: 20170922 Docket: T-402-16 Citation: 2017 FC 774 Ottawa, Ontario, September 22, 2017 PRESENT: The Honourable Mr. Justice Brown BETWEEN: PFIZER CANADA INC. and WYETH LLC Applicants and APOTEX INC. and THE MINISTER OF HEALTH Respondents PUBLIC JUDGMENT AND REASONS (Original and Corrected Confidential Judgment and Reasons issued August 22, 2017) Table of Contents I. Nature of the Matter 5 II. Procedural Note 5 III. Summary of Conclusions 6 IV. Witnesses 6 V. Facts 8 1. Background 9 2. The Invention Story 11 3. Invention Story in more detail: the evidence of Pfizer’s Dr. Shah 16 4. Experimentation with ODV fumarate 19 5. Attempt to form pro-drug of ODV 21 6. Attempt to form an acceptable salt of ODV 22 7. Polymorph and crystal screening 26 8. Solubility 27 9. The Preparation of ODV Succinate 29 10. Permeability and bioavailability testing 30 11. |||||||||||||||||||||||||||||| 31 12. Rat perfusion test 33 13. Beagle dog testing 36 14. Human testing 39 15. Solid state forms: crystallinity, amorphous solids, polymorphs 42 16. Polymorph screening and subcontracting polymorph screening to SSCI, Inc. 42 17. Dr. Aeri Park at SSCI 45 18. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 51 19. Melting points and differential scanning calorimetry (DSC) 52 20. Further temperature studies and amorphous form 53 21. Hygroscopicity testing (a test relevant to drug stability) 54 22. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 54 23. |||||||||||||| (Crystal Form “C”) 55 24. |||||||||||||||||||||||| (Crystal Form “D”) 56 25. Work on other salt candidates and screens 58 26. Miscellaneous 59 VI. Issues 59 VII. Statutory provisions and burden of proof 60 VIII. Analysis 61 1. Relevant Dates 61 2. Claims Construction 62 A. Construction of Claims 8 and 9 72 B. Construction of Claim 33 80 C. Construction of Claims 43 and 44 81 3. Non-infringement 82 4. Obviousness 85 A. Introductory comments and summary 85 B. Legal principles in the obviousness inquiry and the Sanofi decision 87 C. Federal Court of Appeal jurisprudence including Atazanavir and Beloit 98 D. Analysis of Obviousness 104 1. (a) Identify the notional “person skilled in the art” 104 1. (b) Identify the relevant common general knowledge of the Skilled Person 105 2. Identify the inventive concept of the claim in question or if that cannot readily be done, construe it 121 3. Identify what, if any, differences exist between the matter cited as forming part of the “state of the art” and the inventive concept of the claim or the claim as construed. 126 i. Claims 8 and 9 126 ii. Claim 33 127 iii. Claim 43 and 44 127 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? 129 5. Apply the definition of obvious before Sanofi 129 6. Consider the doctrine of obvious to try 132 7. 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? 135 8. 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? 148 9. Is there a motive provided in the prior art to find the solution the patent addresses? 150 10. What is the course of conduct which was followed which culminated in the making of the invention? 152 11. Conclusion on obvious to try regarding Claims 8 and 9 154 12. Conclusion on obvious to try regarding Claims 33, 43 and 44 155 13. Consideration of the guidance for obvious to try analysis set out in Sanofi 155 14. Conclusion on obviousness 156 5. Inutility 156 A. Are the subject matters of Claims 33, 43 and 44 useful - are they capable of a practical purpose (i.e. an actual result)? 163 B. Conclusion on inutility 165 6. Overpromising in relation to subsection 27(3) of the Patent Act 165 7. Anticipation 173 8. Double patenting 187 IX. Conclusions 194 X. Costs 194 XI. Confidential Reasons 194 *** I. Nature of the Matter [1] This is an application for an order pursuant to s 6 of the Patented Medicines (Notice of Compliance) Regulations, SOR/1993-133 as amended, SOR/1998-166, SOR/1999-379, SOR/2006-242 [NOC Regulations] prohibiting the Minister of Health from issuing a Notice of Compliance [NOC] in respect of a Notice of Allegation [NOA] sent by Apotex Inc., [Apotex] to Pfizer Canada Inc., previously Wyeth LLC [Pfizer or Wyeth], dated January 21, 2016, in respect of Canadian Patent No. 2,436,668 [668 Patent]. The 668 Patent covers the drug PRISTIQ which is used for the treatment of depression. [2] At issue are claims 8, 9, 33, 43 and 44. While Apotex advanced other grounds in its NOA and memorandum, some were subsequently abandoned such that now Apotex alleges the 668 Patent is invalid on the grounds of obviousness, inutility, non-infringement, anticipation and double patenting. II. Procedural Note [3] As a procedural note, this case was argued after I heard argument in Pfizer Canada Inc and Wyeth LLC v Teva Canada Limited and The Minister of Health, in respect of which I delivered reasons and judgment in 2017 FC 777. These two cases involve different NOAs filed by different second persons, against the same first persons in respect of the same 688 Patent. While the invention story in both is essentially the same, the grounds of alleged invalidity differ. The arguments were similar in some respects and differed in others; therefore there is repetition as between these two sets of reasons. The law is the same in both. [4] As guidance for those reading both decisions, while obviousness and inutility are at issue in both decisions, Apotex also advanced allegations of non-infringement, anticipation and double patenting which Teva did not advance in its proceeding. Claims construction is contested in this proceeding, but Claims 8 and 9 were agreed upon in the Teva proceeding. Apotex also raised overpromising in this proceeding as a ground of invalidity arising out of subsection 27(3), which Teva did not advance in its proceeding. III. Summary of Conclusions [5] In the reasons that follow, I find on a balance of probabilities that Apotex’s allegations of invalidity due to obviousness, inutility, anticipation, and double patenting, together with Apotex’s allegation of non-infringement are not justified. I find no merit in the arguments of invalidity based on “overpromising” contrary to subsection 27(3) of the Patent Act. Therefore, Pfizer will have its Order of prohibition, together with costs on terms the parties agreed on and which are set out in these Reasons. IV. Witnesses [6] The parties in their pre-hearing filing provided the following information on the witnesses, to which I have added minimally: Pfizer’s fact witnesses: Dr. Syed Shah: Syed Shah is a former employee of Wyeth (and subsequently Pfizer) who has held a number of different titles at both companies. In the late 1990s to early 2000s, he was the Associate Director of the Chemical and Pharmaceutical Development Department at Wyeth and was involved in the development of a suitable form of ODV for clinical research and commercialization. He oversaw the preclinical research conducted on ODV succinate (and other forms of ODV), as well as later clinical research on ODV succinate and Pristiq®. Dr. Shah is a named inventor on the 668 Patent. Dr. Aeri Park: A former Principal at SSCI Inc., the research laboratory hired by Wyeth to conduct polymorph studies on ODV succinate. She managed the team of scientists who conducted the ODV succinate work, which included identifying, analyzing, and generating various solid state forms of ODV succinate. Dr. Park is a named inventor on the 668 Patent. Pfizer’s expert witnesses: Dr. Syed Shah: Syed Shah is a former employee of Wyeth (and subsequently Pfizer) who has held a number of different titles at both companies. In the late 1990s to early 2000s, he was the Associate Director of the Chemical and Pharmaceutical Development Department at Wyeth and was involved in the development of a suitable form of ODV for clinical research and commercialization. He oversaw the preclinical research conducted on ODV succinate (and other forms of ODV), as well as later clinical research on ODV succinate and Pristiq®. Dr. Shah is a named inventor on the 668 Patent. Dr. James Polli: James Polli is a Professor of Industrial Pharmacy and Pharmaceutics at the University of Maryland School of Pharmacy. His main research interests are (1) maximizing oral bioavailability through formulation and chemical approaches, and (2) developing public quality standards for oral dosage forms. He has experience in the fields of pharmaceutics, pharmacokinetics and bioavailability. Dr. Pierre Blier, MD: Pierre Blier is a full professor in the Departments of Psychiatry and Cellular and Molecular Medicine at the University of Ottawa in Ontario, Canada. He also serves as the Director of the Mood Disorders Research Program at the University of Ottawa Institute of Mental Health Research at the Royal Ottawa Hospital. He has experience in the fields of neuropharmacology and psychiatry. Dr. Jerry Atwood: Jerry Atwood is Chairman of the Department of Chemistry and Curators’ Professor at the University of Missouri-Colombia. He has research and academic experience in the fields of supramolecular chemistry, solid-state chemistry, crystal growth, crystal engineering, materials testing, X-ray crystallography, organic chemistry, pharmaceutical chemistry, inorganic chemistry and polymer chemistry. Dr. Allen Myerson: Allan Myerson is a Professor of the Practice of Chemical Engineering at the Massachusetts Institute of Technology (“MIT”). He has research and academic experience in industrial crystallization and the crystallization of pharmaceutical solids. Apotex’s expert witnesses: Dr. Alan Parr, Ph.D.: Dr. Alan Parr is an independent consultant on matters related to the biopharmaceutics of pharmaceuticals. He has approximately 30 years of experience working in the pharmaceutical industry, including with Glaxo and its successor companies Glaxo Wellcome and GlaxoSmithKline. Dr. Parr has experience in the in vivo evaluation of dosage forms, biopharmaceutics, pharmacokinetics, drug absorption and bioavailability/bioequivalence testing. Richard J. Bastin: Richard J. Bastin is the Director of RJB Pharma Consulting Ltd., a consultancy business that offers advice, support and training on drug developability, process development, product development and Chemistry Manufacturing Controls strategy to pharmaceutical and biotechnology companies. Jonathan Steed, Ph. D.: Jonathan Steed is a Professor of Chemistry at Durham University in the United Kingdom. His research focusses on crystallography, crystallization, solid state chemistry, coordination chemistry and intermolecular interactions in solids. V. Facts 1. Background [7] The 668 Patent concerns a drug called o-desmethyl-venlafaxine, henceforth referred to as ODV. ODV is a serotonin and norepinephrine reuptake inhibitor [SNRI] used for the treatment of depression. ODV works by simultaneously inhibiting the reuptake of both serotonin and norepinephrine, which are two neurotransmitters believed to be implicated in depression and anxiety. The specific active pharmaceutical ingredient (API) at issue in this proceeding is Form I ODV succinate, which is a particular crystal form of a particular salt of ODV namely ODV succinate. Pfizer argues and as will be seen, I have accepted that Form I ODV succinate is a novel composition of matter, and is the subject of Claims 8 and 9, on which Claims 33, 43 and 44 depend. [8] ODV is an active metabolite of ODV’s parent drug, venlafaxine. ODV is called a metabolite because ODV is produced by the body when venlafaxine is administered, that is, venlafaxine is chemically modified in the body to form ODV; it is ODV that is responsible for delivering some or all of the pharmacological effect. [9] It is common ground that ODV itself and its use to treat depression have been known for some time. Venlafaxine - which metabolizes into ODV - was previously patented and approved to treat depression. Wyeth had ODV in hand since at least 1990. Wyeth and Pfizer have marketed ODV, as the known metabolite of venlafaxine, under the names EFFEXOR and EFFEXOR XR. EFFEXOR is the immediate release version of venlafaxine (which converts in the body to ODV); EFFEXOR XR is the extended or sustained release version of venlafaxine (which also converts in the body to ODV but at a slower rate). ODV is the API in both EFFEXOR and EFFEXOR XR. [10] Both EFFEXOR and EFFEXOR XR contain venlafaxine hydrochloride which is a salt; venlafaxine hydrochloride is henceforth simply referred to as venlafaxine. [11] ODV and “pharmaceutically acceptable salt forms thereof” were known and are claimed in both claim 22 in US Patent No. 4,535,186 (US 186), issued in 1985, and in claim 21 of Canadian Patent No. 1,248,540 (CA 540), issued to a Pfizer predecessor company in 1989. [12] “Pharmaceutically acceptable salts” as the term is used in US 186 and CA 540 are formed by reacting an acid together with and a base. ODV is a base; therefore, to make a salt an appropriate acid is required for such reaction. Both US 186 and CA 540 claim ODV succinate as one of 11 “illustrative” pharmaceutically acceptable salts, and therefore include a reference to reacting ODV with succinic acid. [13] However, there is no suggestion in either US 186 and CA 540, or elsewhere in the prior art, that the salt ODV succinate had ever been made before. Likewise there is no suggestion that any crystalline form of the salt ODV succinate had ever been known or made before. Further, there is no evidence or argument that the crystal Form I ODV succinate, which Wyeth alleges is the inventive concept of Claims 8 and 9, had ever been known or made before it was made by Wyeth. [14] In addition to disclosure in the Canadian (CA 540) and American (US 186) patents just referred to, it is agreed that another form of ODV, namely its free base, i.e., the drug ODV itself as opposed to a salt or crystalline form of the drug, was disclosed in International Patent Publication No. WO OO/59851 (WO 851) published in October 12, 2000. WO 851 listed 26 “pharmaceutically acceptable salts”, again including succinic acid. Once again however there is no suggestion that ODV succinate had ever been made, or that the crystalline ODV succinate had ever been made, or that Form I ODV succinate had ever been made before it was created in Wyeth’s laboratories. [15] The prior art also disclosed that venlafaxine as EFFEXOR or EFFEXOR XR and their metabolite ODV were useful to treat depression. [16] As is also well known, depression is a serious medical condition that can be and is often debilitating. It is not disputed that all of these drugs including Form I ODV succinate help patients suffering from depression to regain and live more full and functional lives. 2. The Invention Story [17] The essence of the inventive story is not generally in dispute, although aspects of it are; the parties disagree on its characterization, and how the inventive story relates to the obviousness and obvious to try and other principles in patent law. The inventive story is also relevant to the dispute over the alleged lack of utility and in other respects as well. In my view the inventive story warrants being set out in some detail; I will summarize it first. [18] The inventive story as I have found it is set out below. It is drawn generally from the affidavits of Dr. Shah and Dr. Park; Dr. Shah who was at Wyeth at the time and was in charge of commercializing ODV generally and then commercializing ODV succinate. Dr. Park was in charge of the polymorph screening of ODV succinate at a specialized company that performed polymorph screening for Wyeth, namely, SSCI, Inc. [SSCI]. [19] I accept the evidence of Dr. Park and Dr. Shah because they were there at the time of the invention, and have first-hand knowledge of the matters they describe. I appreciate they are both named inventors on the 668 Patent, but am not in any way persuaded that this affected their evidence whether deposed to in their affidavits, or in cross-examination. [20] Wyeth, now Pfizer, had venlafaxine as one of its drugs. As such, it knew that ODV was the active metabolite of venlafaxine. Pfizer at first through a predecessor company and then in its own name marketed venlafaxine as EFFEXOR and EFFEXOR XR. EFFEXOR delivered venlafaxine immediately, but for many patients that meant it had to be administered several times a day. EFFEXOR XR, a sustained release version of EFFEXOR, could be delivered once-a day; it delivered a larger dose at the outset but once inside the body its release was spread over a prolonged period of time. EFFEXOR XR is an extended or sustained release formulation which was better for many if not most patients, including those suffering depression, because taking a once-a-day pill was more convenient and led to greater compliance than taking multiple pills throughout the day. In addition, the sustained release form would reduce side effects by reducing the amount of the drug released into the body at any one time versus EFFEXOR, the immediate release form of venlafaxine. [21] Wyeth’s problem with venlafaxine was that while its active metabolite was ODV, there was no solid-state form of ODV itself that could be safely stored, formulated into a drug, and effectively delivered to patients. Wyeth only had venlafaxine which relied on the body to be metabolized or converted into ODV, which then acted as the anti-depressant in the brain. [22] The new ODV drug that Wyeth sought to discover required several key characteristics: stability, solubility, permeability and bioavailability. Permeability is the ability of a drug to permeate through the lining of the GI tract. Bioavailability is the ability of a drug to get into the bloodstream, which in the oral dose sought, involves permeating the gastrointestinal [GI] tract. [23] The searched-for new ODV drug had to be a stable, that is, a drug that could be stored safely throughout the manufacturing and distribution processes. The searched for ODV had to remain stable throughout these processes and also in the hands hospitals and patients over different ambient temperatures and humidity levels one would find in the places where it might be manufactured, stored, distributed, and or used. [24] The ODV drug form Wyeth was searching for had to be able to dissolve in the gastrointestinal [GI] tract i.e., it had to be a drug that was soluble. It also had to be a drug that would cross over from the GI tract into the bloodstream where it could do its work in the body’s systems and in particular, in the brain, i.e., it had to be a drug that was permeable and bioavailable. [25] In addition to having stability, solubility, permeability and bioavailability, the searched for new ODV drug needed to have these qualities without unacceptable adverse side effects such as nausea and vomiting which were known issues with ODV. [26] In summary, over some two years - with increased activity towards the end of this period - experimentation and drug development was conducted, initially by Wyeth, and then by Wyeth together with a specialized contract laboratory, SSCI. Employees of both Wyeth and SSCI are named inventors on the 668 Patent. [27] Wyeth and SSCI eventually identified a solid crystalline form of ODV that was stable, soluble, permeable and bioavailable. This crystalline form is known now as Form I ODV succinate, and Pfizer alleges this as the inventive concept in Claims 8 and 9 of the 668 Patent. It is common ground that this crystalline form is a new composition of matter that was never before made or disclosed until it was created by Wyeth. I should note that Apotex raises invalidity based on anticipation therefore newness is in issue, and will be dealt with later in these Reasons. [28] I referred to the experiments that Wyeth and SSCI conducted in which Wyeth created the crystalline Form I ODV succinate, and in which |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| In this connection, the experts agree it would have been impossible for the Skilled Person to know or predict whether ODV succinate salt would form as a solid, whether that solid could be formed as a crystalline compound, or what the properties of any hypothetical crystalline solid, let alone Form I ODV succinate would be in terms of stability, solubility, permeability, bioavailability and adverse effects; none of this would be known without doing empirical research. As will be discussed further, in my view the extent of research envisioned by the Skilled Person and actually required in this connection was not routine, but in the nature of a research program. [29] I wish to note that an issue in this proceeding is whether the experimentation involved was routine experimentation, and if so, what legal consequences flow from such a finding. This is because the work done by Wyeth included performing salt screening, and because the work done by SSCI entailed a different type of screening, known as polymorph or crystal screening. Pfizer and Apotex agree that in general terms both salt screens and polymorph screens were generally known to a person skilled in the art at the time (the Skilled Person). [30] Wyeth not only created the ODV succinate salt, but went further and discovered and created a crystalline form of that salt which has become known as the crystalline Form I ODV succinate. Wyeth however did not know that the crystal it created |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Wyeth with its subcontractor SSCI went further. SSCI found another three crystalline and one amorphous forms of ODV succinate in addition to crystalline Form I ODV succinate created by Wyeth and relied upon by Pfizer in Claims 8 and 9 of the 668 Patent. [31] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| This discovery allowed Wyeth to develop sustained release oral formulations that could deliver therapeutic concentrations of ODV over a prolonged period of time, reduce the overall incidence of certain side effects associated with higher peak blood concentrations of the drug, and give patients a once daily pill instead of having to take multiple pills throughout the day. 3. Invention Story in more detail: the evidence of Pfizer’s Dr. Shah [32] Pfizer’s Dr. Shah, a pharmaceutical engineer, was the lead investigator involved in Wyeth’s development of ODV for clinical research and commercialization between 1999 and 2004. Dr. Shah’s evidence was that at the outset of the course of Wyeth’s experimentation, Wyeth’s Discovery Group considered that ODV might be a successful drug candidate for several reasons. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| For example, it was thought that by administering the metabolite ODV directly one could have a faster and more potent effect. [33] In addition, it was known that individuals varied in their ability to metabolize venlafaxine into ODV in the liver, which would affect the effectiveness of venlafaxine. By getting rid of the metabolic step (in which venlafaxine is converted by the body into ODV) it was thought this variability could be addressed. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| [34] Wyeth was also interested in two further matters: 1) improving patient compliance, that is, improving the chances of patients actually taking their medication as prescribed, and 2) the need to develop a new drug with reduced side effects. One way to do this would be to develop a drug that could be dosed once per day, which meant developing a sustained release formulation of ODV. [35] Wyeth’s invention story had several components in addition to this background knowledge. [36] Initially, Wyeth worked with ODV fumarate, a known salt form of ODV, but without success. [37] Wyeth also attempted to make a pro-drug of ODV, again without success. [38] In addition, and previously, Wyeth had also worked with a number of other salt forms of ODV, but without success. [39] Wyeth then set out to determine if it could identify a more appropriate salt form, a route in respect of which there was internal and science-based skepticism, a point Apotex challenged and which I will address shortly. Eventually Wyeth found the ODV succinate salt form, which it then with further research and experimentation, developed into a crystalline form then known as Form “A”, which subsequently became known as Form I ODV succinate. Having identified positive properties of this new crystal Form I ODV succinate in terms of solubility and stability, it engaged SSCI to test the crystalline Form I ODV succinate and identify and test for other crystalline forms; SSCI did so and identified three other crystalline forms of ODV succinate plus one amorphous form of ODV succinate. [40] Wyeth conducted studies in vivo (in the body) in mice, and in cells in vitro (outside the body), together with in vivo tests on rats, beagle dogs and ultimately with human volunteers. [41] Wyeth determined that the crystalline Form I ODV succinate had the requisite stability, together with solubility in addition to both suitable permeability and bioavailability. Wyeth then performed additional studies to develop sustained release formulations of Form I ODV succinate. [42] The following outlines these steps in more detail. 4. Experimentation with ODV fumarate [43] Pre-clinical work on ODV by Wyeth’s Discovery Group had been conducted on the fumarate salt form of ODV, known as ODV fumarate. ODV fumarate is formed by reacting ODV, which is a base, with fumaric acid to make a salt known as ODV fumarate. ODV fumarate is a salt form of ODV. ODV fumarate was a known salt form of ODV, which is one of the reasons it was looked at by Wyeth. ODV fumarate was known in the art at the time because it was disclosed as Example 26 of US 186 as a crystalline salt. [44] However, ODV fumarate had problems with bioavailability. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| [45] This evidence indicates and I accept that oral bioavailability of ODV fumarate was relatively poor compared to ODV fumarate |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||| The problem with the ODV fumarate’s bioavailability was considered by Wyeth as “likely due to low solubility and/or permeability” of ODV fumarate. |||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||| [46] As indicated previously, |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||, as Dr. Shah deposed in his affidavit, salts that are reasonably soluble like ODV fumarate are usually completely dissociated by the time they get to the GI tract. In other words, if the drug ODV became dissociated when it ceased to be in salt form ODV fumarate, in the GI tract, where it lacked suitable bioavailability, the same dissociation but poor bioavailability could obtain with the drug ODV when reacted to form other salts. In other words, if the dissociated drug ODV did not do well in terms of permeability when orally dosed as ODV fumarate, it was unclear why another salt form of ODV might behave any better: |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||| Affidavit of Dr. Shah, para 22. [47] Apotex argues that |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| To the extent Dr. Shah refers to the views of others at Wyeth, Apotex is correct. However, Dr. Shah also deposed to and certainly had personal knowledge of the fact that |||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||, namely that since salts that are reasonably soluble (like ODV fumarate) are usually completely dissociated by the time they get to the GI tract, it was unclear how much impact a new salt would have on improving permeability. |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 5. Attempt to form pro-drug of ODV [48] Wyeth also attempted to develop a pro-drug of ODV in 1999-2000. A pro-drug is a compound which is chemically altered in the body to become its bio-active chemical form. Pro-drugs are also described as being created by chemically modifying the active compound to produce a pharmacologically inactive molecule that will be metabolized into an active form in the body following absorption by the body. Depending on the modifications that are made, a pro-drug may have improved solubility, dissolution or absorption over the active molecule. [49] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| [50] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| In this evidence, Dr. Shah was relying on what had been reported to him as I agree with Apotex that he had no involvement in Wyeths’ ODV pro-drug development program, which it appears led to at least one successful patent application of which Dr. Shah was unaware. [51] However, I accept Dr. Shah’s main evidence on this point, namely that Wyeth conducted pro-drug development work apart from Dr. Shah’s salt and crystalline drug development work in connection with ODV. While Apotex calls the Wyeth’s attempt to find a pro-drug a “diversion”, the fact is that both parties agree that Wyeth undertook pro-drug exploration and development work. I accept Dr. Shah’s evidence that it took place: this is not disputed by Apotex’s expert Dr. Steed who disparaged pro-drug development regarding ODV. Accepting Apotex’s argument that Wyeth succeeded in making and even patenting a pro-drug does not establish that pro-drug development was irrational or unreasonable; in my view, it proves the opposite and justifies pro-drug development work that Apotex says would not have been done by a Skilled Person. 6. Attempt to form an acceptable salt of ODV [52] The third option pursued by Wyeth (after the fumarate salt and pro-drug) to improve ODV’s absorption/permeability was to attempt to identify a new salt form of ODV. It was known that ODV existed as the salt form ODV fumarate as discussed above, but ODV fumarate was not pursued as such. It was also known that ODV existed as a free base, but ODV as a free base is insoluble in water which I accept leads to absorption issues; therefore the ODV free base was not pursued. [53] I also accept that it was known, as stated by Dr. Shah, that salt formation provides a means of altering the physicochemical properties of a drug - like solubility and stability - without modifying its chemical structure. It is also accepted that salts are formed by interacting an acid and a base together to form a salt. [54] ODV is a base. Therefore, in order to attempt to make a salt with ODV, it was necessary to interact the base, ODV, with an acceptable acid. [55] |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| As a result, most of the pre-clinical work on ODV conducted by the Discovery Group was conducted on ODV fumarate, but as noted already, ODV fumarate displayed poor oral bioavailability. [56] ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||, Dr. Shah proceeded to investigate other salt forms of ODV. This work began by his consulting Dr. Hadfield of Wyeth’s Salt Selection Committee for assistance with preparing and screening new salts. ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Pfizer Canada Inc. v. Apotex Inc.

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Hadley v Baxendale

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Pfizer Canada Inc. v. Apotex Inc.

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Full judgment (source text)

Hadley v Baxendale

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Hadley v Baxendale

Sattva Capital Corp v Creston Moly Corp

Exam & revision prep